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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2012; · 8.30 Impact Factor
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U Creutzig,
M Zimmermann,
J-P Bourquin,
M N Dworzak,
B Kremens,
T Lehrnbecher,
C von Neuhoff,
A Sander,
A von Stackelberg,
I Schmid,
J Starý,
D Steinbach, J Vormoor,
D Reinhardt
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ABSTRACT: Infants <1 year of age have a high prevalence of prognostically unfavorable leukemias and a presumed susceptibility to treatment-related toxicities. A total of 125 infants with acute myeloid leukemia (AML) were treated in studies AML-BFM-98 (n = 59) and -2004 (n = 66). Treatment regimens of both studies were comparable, consisting of intensive induction followed by four courses (mainly high-dose cytarabine and anthracyclines). Allogeneic-hematopoietic stem-cell-transplantation (allo-HSCT) in 1st remission was optional for high-risk (HR) patients. Most infants (120/125=96%) were HR patients according to morphological, cytogenetic/molecular genetic and response criteria. Five-year overall survival was 66 ± 4%, and improved from 61 ± 6% in study-98 to 75 ± 6% in study-2004 (P(logrank) 0.14) and event-free survival rates were 44 ± 6% and 51 ± 6% (P(logrank) 0.66), respectively. Results in HR infants were similar to those of older HR children (1-<2- or 2-<10-year olds, P(logrank) 0.90 for survival). Survival rates of HSCT in 1st remission, initial partial response and after relapse were high (13/14, 2/8 and 20/30 patients, respectively). The latter contributes to excellent 5-year survival after relapse (50±8%). Despite more severe infections and pulmonary toxicities in infants, treatment-related death rate was identical to that of older children (3%). Our data indicate that intensive frontline and relapse AML treatment is feasible in infants, toxicities are manageable, and outcome is favorable.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2011; 26(4):654-61. · 8.30 Impact Factor
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ABSTRACT: MLL/AF4 and AML/MTG8 represent two leukemic fusion genes, which are most frequently found in infant acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), respectively. We examined the influence of MLL/AF4 and AML1/MTG8 fusion genes on the expression of TERT coding for the telomerase protein subunit, and subsequently telomerase activity in t(4;11)-positive ALL and t(8;21)-positive cell lines, respectively. MLL/AF4 suppression diminished telomerase activity and expression of TERT. Blocking pro-apoptotic caspase activation in conjunction with MLL/AF4 knockdown enhanced the inhibition of TERT gene expression, which suggests that MLL/AF4 depletion does not reduce TERT expression levels by inducing apoptosis. Knockdown of HOXA7, a direct transcriptional target of MLL/AF4 fusion gene, caused a reduction of telomerase and TERT to an extent similar to that observed with MLL/AF4 suppression. Chromatin immunoprecipitation of SEM cells, using ectopically expressed FLAG-tagged Hoxa7, indicates HOXA7 binding site in the TERT promoter region. Furthermore, suppression of the AML1/MTG8 fusion gene was associated with severely reduced clonogenicity, induction of replicative senescence, impaired TERT expression and accelerated telomere shortening. We thus present findings that show a mechanistic link between leukemic fusion proteins, essential for development and maintenance of leukemia, and telomerase, a key element of both normal and malignant self-renewal.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2010; 24(10):1751-9. · 8.30 Impact Factor
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ABSTRACT: The last 15 years has seen an explosion of interest in the cancer stem cell (CSC). Although it was initially believed that only a rare population of stem cells are able to undergo self-renewing divisions and differentiate to form all populations within a malignancy, a recent work has shown that these cells may not be as rare as thought first, at least in some malignancies. Improved experimental models are beginning to uncover a less rigid structure to CSC biology, in which the concepts of functional plasticity and clonal evolution must be incorporated into the traditional models. Slowly the genetic programmes and biological processes underlying stem cell biology are being elucidated, opening the door to the development of drugs targeting the CSC. The aim of ongoing research to understand CSCs is to develop novel stem cell-directed treatments, which will reduce therapy resistance, relapse and the toxicity associated with current, non-selective agents.
British Journal of Cancer 08/2010; 103(4):439-45. · 5.04 Impact Factor
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S Landmeier,
B Altvater,
S Pscherer,
J Meltzer,
N Sebire,
M Pule,
J Vera,
M Hotfilder,
H Juergens, J Vormoor,
C Rossig
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 03/2010; 24(5):1080-4. · 8.30 Impact Factor
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B Meissner,
A Borkhardt,
D Dilloo,
D Fuchs,
W Friedrich,
R Handgretinger,
C Peters,
A Schrauder,
F R Schuster, J Vormoor,
B Maecker,
K W Sykora,
F Zintl,
K Welte,
M Sauer
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ABSTRACT: We report a retrospective analysis of 11 children with Down syndrome (DS) treated by SCT in eight German/Austrian SCT centres. Indications for transplantation were acute lymphoblastic leukaemia (N=8) and acute myeloid leukaemia (N=3). A reduced intensity conditioning (RIC) containing 2 Gy TBI was given to two patients, another five received a myeloablative regimen with 12 Gy TBI. Treosulphan or busulphan was used in the remaining four children. Four of eleven (36%) patients are alive. All of them were treated with a myeloablative regimen. One of the four surviving children relapsed 9 months after SCT and is currently receiving palliative outpatient treatment. The main cause of death was relapse (5/11). Two children died of regimen-related toxicity (RRT), one from severe exfoliative dermatitis and multiorgan failure after a treosulphan-containing regimen, the other from GvHD-related infections after RIC. Acute GvHD of the skin was observed in 10 of 10 evaluable patients, and chronic GvHD in 4 of 8. Our data show that DS patients can tolerate commonly used, fully myeloablative preparative regimens. The major cause of death is relapse rather than RRT resulting in an event-free survival of 18% and over all survival of 36%.
Bone Marrow Transplantation 12/2007; 40(10):945-9. · 3.75 Impact Factor
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Annals of the Rheumatic Diseases 01/2007; 65(12):1665-6. · 8.73 Impact Factor
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Bone Marrow Transplantation 12/2006; 38(9):639-40. · 3.75 Impact Factor
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ABSTRACT: Times Cited: 2
Meeting Abstract
English
320
Cited References Count: 0
111GS
1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA
WASHINGTON
Part 1
Blood 11/2006; 108(11):99A. · 9.90 Impact Factor
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ABSTRACT: Expression of tumour antigen-specific chimaeric receptors in T lymphocytes can redirect their effector functions towards tumour cells. Integration of the signalling domains of the co-stimulatory molecule CD28 into chRec enhances antigen-specific proliferation of polyclonal human T cell populations. While CD28 plays an essential role in the priming of naive CD4(+) T cells, its contribution to effector memory T cell responses is controversial. We compared the function of the chRec with and without the CD28 co-stimulatory domain, expressing it in peripheral blood T cells or Epstein-Barr virus (EBV)-specific T cell lines. The chimaeric T cell receptors contain an extracellular single-chain antibody domain, to give specificity against the tumour ganglioside antigen G(D2). The transduced cytotoxic T lymphocytes (CTL) maintained their specificity for autologous EBV targets and their capacity to proliferate after stimulation with EBV-infected B cells. Intracellular cytokine staining demonstrated efficient and comparable antigen-specific interferon (IFN)-gamma secretion by CTL following engagement of both the native and the chimaeric receptor, independent of chimaeric CD28 signalling. Furthermore, tumour targets were lysed in an antigen-specific manner by both chRec. However, while antigen engagement by CD28 zeta chRec efficiently induced expansion of polyclonal peripheral blood lymphocytes in an antigen-dependent manner, CD28 signalling did not induce proliferation of EBV-CTL in response to antigen-expressing tumour cells. Thus, the co-stimulatory requirement for the efficient activation response of antigen-specific memory cells cannot be mimicked simply by combining CD28 and zeta signalling. The full potential of this highly cytolytic T cell population for adoptive immunotherapy of cancer requires further exploration of their co-stimulatory requirements.
Clinical & Experimental Immunology 07/2006; 144(3):447-57. · 3.36 Impact Factor
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J Neudenberger,
M Hotfilder,
A Rosemann,
C Langebrake,
D Reinhardt,
R Pieters,
A Schrauder,
M Schrappe,
S Röttgers,
J Harbott, J Vormoor
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ABSTRACT: It has increasingly been acknowledged that only a few leukaemic cells possess the capability to renew themselves and that only these self-renewing leukaemic stem cells are able to initiate relapses. Therefore, these leukaemic stem cells should be the target cells for therapy and for minimal residual disease (MRD) detection. Because of its presence on blasts of 11q23-rearranged high-risk leukaemic patients, neuron-glial antigen 2 (NG2) is thought to be a valuable marker for detecting leukaemic stem cells. Six acute myeloid leukaemia (AML)/abn(11q23) and three acute lymphoblastic leukaemia (ALL)/t(4;11) samples were analysed by four-colour flow cytometry for NG2 expression on primitive cell populations. Candidate leukaemic cell populations were defined by the antigen profiles CD34+CD38- in AML and CD34+CD19-CD117+ in ALL. Surprisingly, in all patients these candidate stem cell populations were shown to lack expression of NG2. Instead, a correlation between the expression of the myeloid differentiation marker CD33 and increasing levels of NG2 on maturing cells could be demonstrated. Similarly, in ALL patients CD34+CD19+ cells showed a higher expression of NG2 mRNA compared with CD34+CD19-. Thus, NG2 appears to be upregulated with differentiation and not to be expressed on primitive disease-maintaining cells. This hampers the clinical use of NG2 as a therapeutic target and as a sensitive marker for MRD detection.
British Journal of Haematology 06/2006; 133(3):337-44. · 4.94 Impact Factor
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ABSTRACT: While in vitro studies had shown that fibroblast growth factor 2 (FGF2) can induce cell death in Ewing tumours, it remained unclear how Ewing tumour cells survive in vivo within a FGF2-rich microenvironment. Serum- and integrin-mediated survival signals were, therefore, studied in adherent monolayer and anchorage-independent colony cell cultures. In a panel of Ewing tumour cell lines, either adhesion to collagen or exposure to serum alone only had a minor protective effect against FGF2. However, both combined led to complete resistance to 5 ng ml(-1) FGF2 in three of four FGF2-sensitive cell lines (RD-ES, RM-82 and WE-68), and to an increased survival as compared to other culture conditions in TC-71 cells. Inhibition studies with LY294002 demonstrated that the serum signal is mediated via the phosphoinositide 3-OH kinase/AKT pathway. Thus, Ewing tumour cells escape FGF2-induced cell death by modulating FGF2 signalling. The tumour microenvironment provides the necessary survival signals by integrin-mediated adhesion and soluble serum factor(s). These survival signals warrant further investigation as a potential resistance mechanism to other apoptosis-inducing agents in vivo.
British Journal of Cancer 03/2005; 92(4):705-10. · 5.04 Impact Factor
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ABSTRACT: The objective of this study was to investigate heterogeneity of radiation induced apoptosis on a single cell level. Two Ewing tumor cell lines were characterized in vitro before and 24 and 72 h after radiation with 5 Gy by multiparametric flow cytometry. Annexin V, 7-AAD and fluorescence conjugated antibodies that were directed against HLA-ABC, CD11a and CD62L were used. Based on these markers radiation induced apoptosis was quantified, multiple apoptotic subpopulations were identified and a characteristic individual apoptotic profile was characterized. The characterization of HLA-ABC, CD11a and CD62L was informative to detect subpopulations of apoptotic cells. The observed heterogeneity and the identification of multiple apoptotic subpopulations reflect the complexity and diversity of biology of radiation induced cell death. This might be an indication for co-existing apoptotic pathways or it might represent sequential steps of the apoptotic cascade.
APOPTOSIS 02/2005; 10(1):177-84. · 4.79 Impact Factor
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ABSTRACT: Times Cited: 0
Meeting Abstract
English
4394
Cited References Count: 0
871JO
1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA
WASHINGTON
Part 2
Blood 11/2004; 104(11):182B. · 9.90 Impact Factor
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P Bader,
H Kreyenberg,
W Hoelle,
G Dueckers,
B Kremens,
D Dilloo,
K-W Sykora,
C Niemeyer,
D Reinhardt, J Vormoor,
B Gruhn,
P Lang,
J Greil,
R Handgretinger,
D Niethammer,
T Klingebiel,
J F Beck
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ABSTRACT: Children with leukemias and increasing mixed chimerism (increasing MC) after allogeneic stem cell transplantation have the highest risk to relapse. Early immunological intervention was found to be effective in these cases. To substantiate this on a defined group of pediatric acute myelogenous leukemia (AML) patients, we performed serial analysis of post transplant chimerism and pre-emptive immunotherapy in patients with increasing MC. In total, 81 children were monitored, 62 patients revealed complete chimerism (CC), low-level MC or decreasing MC. Increasing MC was detected in 19 cases. Despite early immunological intervention relapse was still significantly more frequent in patients with increasing MC (9/19) than in patients with CC, low-level or decreasing MC (8/62, P<0.005). The probability of 3-year event-free survival (EFS) was 52% for all patients (n=81), 59% for patients with CC, low-level MC, 60% for patients with decreasing MC (n=62), and 28% for patients with increasing MC (n=19, P<0.005). Patients with increasing MC who received early immunological intervention showed a significantly enhanced probability for event-free survival (pEFS 36%, n=15) compared to patients with increasing MC without intervention (pEFS 0%, n=4, P<0.05). These results prove that pediatric AML patients with increasing MC are at highest risk for relapse and that early immunological intervention can prevent relapse in these patients.
Bone Marrow Transplantation 04/2004; 33(8):815-21. · 3.75 Impact Factor
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S Könemann,
T Bölling,
J Malath,
A Kolkmeyer,
K Janke,
D Riesenbeck,
S Hesselmann,
R Diallo, J Vormoor,
N Willich,
A Schuck
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ABSTRACT: Cytokines and their corresponding cell surface receptors are involved in intercellular signalling pathways and in the radioresistance of normal and malignant cells. The aim was the characterization of the expression of intracellular cytokines, their receptors and apoptosis-associated markers under the influence of radiation.
Two Ewing tumours were characterized in vitro before and 4, 24 and 72 h after radiation with 5 and 10 Gy, and in vivo 4, 6 and 15 days after radiation with 5 and 30 Gy by five parameter flow cytometry. Direct fluorescence-conjugated antibodies directed against intracellular cytokines (interferon-gamma, tumour necrosis factor [TNF]-alpha, interleukin 1) and their receptors (CD119, CD120a, CD121a) were used. Annexin V and 7-amino-actinomycin D were used to identify radiation-induced apoptosis.
Inter- and intra-individual heterogeneities were identified by the expression of cytokine receptors and the intracellular cytokine profile before radiation. Time- and dose-dependent up-regulation of the cytokines TNF-alpha and interleukin 1 were found in vitro. In vivo, an up-regulation of CD120a and CD121a was detectable on tumour cell subpopulations. For interferon-gamma and CD119, no changes were seen.
The observed radiation-induced changes of cytokine and receptor profile are an indication for complex intercellular interactions in view of radioresistance-associated mechanisms between cell populations within one individual tumour. The observed heterogeneous response on radiation might have therapeutic implications for an individualized therapy based on combined radiation and cytokine modulation, defined by flow cytometric characterization of markers potentially informative for radioresistance.
International Journal of Radiation Biology 12/2003; 79(11):897-909. · 2.28 Impact Factor
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ABSTRACT: Osteosarcoma, one of the most frequent secondary malignancies after the treatment of young patients with cancer, has only very rarely been observed in association with hematopoietic stem cell transplantation (HSCT). We report four patients who were identified by searching the database of the Cooperative Osteosarcoma Study Group (COSS) for patients whose osteosarcoma arose following HSCT. Transplant indications had been acute lymphoblastic leukemia (3). and sickle cell disease (1). and the stem cell source was bone marrow in all cases (three allogeneic, one syngeneic). All four had received chemotherapy with alkylators as part of their conditioning regimen and/or first line therapy. The conditioning regimen included total body irradiation in three patients. The osteosarcomas arose at the age (adolescence) and sites (around the knee) typical for the disease. All four patients received chemotherapy as part of multimodal osteosarcoma treatment, and all four are currently alive, three in continuous remission at 5 7/12, 2 11/12, and 0 6/12 years and one with relapsed osteosarcoma at 4 1/12 years. One of the osteosarcoma-free survivors suffered a third malignancy, myelodysplastic syndrome. Osteosarcoma should be included among the secondary malignancies that can arise following HSCT. Multi-modal therapy according to guidelines for de novo osteosarcoma can lead to long-term survival in selected patients.
Bone Marrow Transplantation 04/2003; 31(5):353-9. · 3.75 Impact Factor
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S Könemann,
T Bölling,
A Schuck,
J Malath,
A Kolkmeyer,
K Horn,
D Riesenbeck,
S Hesselmann,
R Diallo, J Vormoor,
N A Willich
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ABSTRACT: Adhesion molecules, cytokines and their corresponding cell-surface receptors are involved in intercellular signalling pathways, radioresistance and metastasis-mediating mechanisms of malignant cells. The aim was the characterization of changes in the marker profile of Ewing tumour cell subpopulations under the influence of radiation.
Three Ewing tumours were characterized in vitro and in vivo in a xenograft model before and after radiation by five-parameter flow cytometry. Antibodies directed against cell surface and intracellular antigens, apoptosis-associated markers and the DNA dye 7-aminoactinomycin D were used.
Tumour cell subpopulations were identified by expression of adhesion molecules and cytokine receptors, intracellular cytokines, apoptotic markers and DNA content. Heterogeneous changes of flow cytometric profile were identified on tumour cell subpopulations after radiation.
The changed profile of tumour cells under radiation might be associated with biological changes of tumour subpopulations in view of radioresistance and metastatic potential and might be useful to identify intercellular regulation mechanisms and to define parameters being predictive for a response to therapy.
International Journal of Radiation Biology 04/2003; 79(3):181-92. · 2.28 Impact Factor
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ABSTRACT: Human Epstein-Barr virus-specific T cells were genetically modified to express chimeric receptors specific for human CD19, which is expressed on the cell surface of most B cell malignancies. The receptor-modified EBV-specific T cells can be expanded and maintained long term in the presence of EBV-infected B cells. They recognize autologous EBV-infected targets through their conventional T cell receptor, and allogeneic EBV-infected targets and tumor targets through their chimeric receptor. They efficiently lyse both EBV and CD19-positive tumor targets in the absence of background cytotoxicity against CD19-negative targets. Donor-derived EBV-specific T cells expressing chimeric anti-tumor receptors may represent a source of effector cells that could be safely administered to leukemia patients to eradicate minimal residual disease after allogeneic bone marrow transplantation.
Annals of Hematology 02/2002; 81 Suppl 2:S42-3. · 2.62 Impact Factor
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ABSTRACT: We report the clinical course of a 6.5-year-old boy with refractory auto-immune haemolytic anaemia. Due to failure of conventional immunosuppressive therapy, an autologous peripheral blood stem cell transplantation was performed. The conditioning regimen consisted of cyclophosphamide and anti-thymocyte globulin. The patient was reinfused with 2.6 x 10(6) CD34 positive selected, B- and T-cell-depleted peripheral blood stem cells per kg body weight. He showed a partial response with a reduced demand for red blood cell transfusions. However, due to persistence of the haemolytic process he was started on rituximab therapy on day +40 post-transplant. Following two doses of rituximab, the patient improved rapidly and developed a sustained complete response. After 10 months, haemolysis recurred and responded again to rituximab therapy without the necessity for red blood cell transfusions. 15 months after initial antibody treatment, however, the patient developed a second relapse which was now refractory to rituximab therapy although CD20+ B-lymphocytes were cleared from the peripheral blood. CONCLUSION: Our case report suggests that rituximab and autologous peripheral blood stem cell transplantation are important though not curative elements in the treatment of patients with severe auto-immune haemolytic anaemia who are refractory to conventional immunosuppressive therapy.
European Journal of Pediatrics 09/2001; 160(8):492-6. · 1.88 Impact Factor
