632 results on '"Luft, Thomas"'
Search Results
202. IL-1β Enhances CD40 Ligand-Mediated Cytokine Secretion by Human Dendritic Cells (DC): A Mechanism for T Cell-Independent DC Activation
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Luft, Thomas, primary, Jefford, Michael, additional, Luetjens, Petra, additional, Hochrein, Hubertus, additional, Masterman, Kelly-Anne, additional, Maliszewski, Charlie, additional, Shortman, Ken, additional, Cebon, Jonathan, additional, and Maraskovsky, Eugene, additional
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- 2002
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203. Exogenous Peptides Presented by Transporter Associated with Antigen Processing (TAP)-Deficient and TAP-Competent Cells: Intracellular Loading and Kinetics of Presentation
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Luft, Thomas, primary, Rizkalla, Mark, additional, Tai, Tsin Yee, additional, Chen, Qiyuan, additional, MacFarlan, Roderick I., additional, Davis, Ian D., additional, Maraskovsky, Eugene, additional, and Cebon, Jonathan, additional
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- 2001
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204. In vitro testing of drug combinations employing nilotinib and alkylating agents with regard to pretransplant conditioning treatment of advanced-phase chronic myeloid leukemia.
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Radujkovic, Aleksandar, Luft, Thomas, Dreger, Peter, Ho, Anthony, Jens Zeller, W., Fruehauf, Stefan, and Topaly, Julian
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TREATMENT of chronic myeloid leukemia , *NILOTINIB , *ALKYLATING agents , *STEM cell transplantation , *DRUG synergism - Abstract
Purpose: The prognosis of patients with advanced-phase chronic myeloid leukemia (CML) remains dismal despite the availability of targeted therapies and allogeneic stem cell transplantation (allo-SCT). Increasing the antileukemic efficacy of the pretransplant conditioning regimen may be a strategy to increase remission rates and duration. We therefore investigated the antiproliferative effects of nilotinib in combination with drugs that are usually used for conditioning: the alkylating agents mafosfamide, treosulfan, and busulfan. Methods: Drug combinations were tested in vitro in different imatinib-sensitive and imatinib-resistant BCR-ABL-positive cell lines. A tetrazolium-based MTT assay was used for the assessment and quantification of growth inhibition after exposure to alkylating agents alone or to combinations with nilotinib. Drug interaction was analyzed using the median-effect method of Chou and Talalay, and combination index (CI) values were calculated according to the classic isobologram equation. Results: Treatment of imatinib-sensitive, BCR-ABL-positive K562 and LAMA84 cells with nilotinib in combination with mafosfamide, treosulfan, or busulfan resulted in synergistic (CI < 1), additive (CI ~ 1), and predominantly antagonistic (CI > 1) effects, respectively. In imatinib-resistant K562-R and LAMA84-R cells, all applied drug combinations were synergistic (CI < 1) at higher growth inhibition levels. Conclusions: Our in vitro data warrant further investigation and may provide the basis for nilotinib-supplemented conditioning regimens for allo-SCT in advanced-phase CML. [ABSTRACT FROM AUTHOR]
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- 2014
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205. Azacitidine and low-dose cytarabine in palliative patients with acute myeloid leukemia and high bone marrow blast counts - a retrospective single-center experience.
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Radujkovic, Aleksandar, Dietrich, Sascha, Bochtler, Tilmann, Krämer, Alwin, Schöning, Tilman, Ho, Anthony D., Dreger, Peter, and Luft, Thomas
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ACUTE myeloid leukemia ,AZACITIDINE ,CYTARABINE ,BONE marrow ,FEBRILE neutropenia ,MULTIVARIATE analysis ,PATIENTS ,THERAPEUTICS - Abstract
We retrospectively analyzed and compared the efficacy and toxicity of azacitidine ( AZA) and low-dose cytarabine ( LD- Ara- C) in 65 palliative patients with acute myeloid leukemia ( AML) showing high bone marrow blast counts (≥30%) before start of treatment. Twenty-seven and 38 patients received AZA and LD- Ara- C, respectively. The median patient age was 71 yr. Patient and disease characteristics did not differ between the treatment groups, except for BM blast counts, and peripheral leukocyte and blast counts which were significantly higher in the LD- Ara- C group. AZA and LD- Ara- C were first-line treatment in 12 (44%) and 17 patients (45%), respectively. Response and hematologic improvement rates were low and similar in both treatment groups. In both treatment groups, most common non-hematologic toxicities included febrile neutropenia, pneumonia, and bleedings without significant differences regarding frequencies. Estimated 1-yr survival rates were 15% (95% CI 8-22) and 13% (95% CI 7-19) in the AZA and LD- Ara- C groups, respectively, without statistically significant difference. In multivariate analysis ( n = 65), previous treatment ( HR 2.27, 95% CI 1.00-5.22, P = 0.05) and adverse cytogenetics ( HR 2.50, 95% CI 1.20-5.22, P = 0.02) were independent predictors of poor survival. In our center and within the limitations of a retrospective study, both treatment regimens showed similar but limited efficacy in palliative patients with AML and high BM blast counts. [ABSTRACT FROM AUTHOR]
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- 2014
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206. Imatinib-supplemented myeloablative total-body irradiation/cyclophosphamide conditioning prior to allogeneic stem cell transplantation as consolidation treatment in patients with blast crisis of chronic myeloid leukemia.
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Radujkovic, Aleksandar, Dreger, Peter, Hegenbart, Ute, Buss, Eike C., Luft, Thomas, Ho, Anthony D., Fruehauf, Stefan, and Topaly, Julian
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IMATINIB ,CHRONIC myeloid leukemia ,STEM cell transplantation ,PATIENTS - Abstract
A letter to the editor is presented which discusses the prospective studies on the effect of pretransplant imatinib in patients with blast crisis of chronic myeloid leukemia (BC-CML) after myeloablative allogeneic stem cell transplantation (allo-SCT).
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- 2014
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207. Type I IFNs Enhance the Terminal Differentiation of Dendritic Cells
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Luft, Thomas, primary, Pang, Ken C., additional, Thomas, Elisabeth, additional, Hertzog, Paul, additional, Hart, Derek N. J., additional, Trapani, Joseph, additional, and Cebon, Jonathan, additional
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- 1998
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208. Pre-Transplant Serum Leptin Levels and Relapse of Acute Myeloid Leukemia after Allogeneic Transplantation.
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Schwarzbich, Mark-Alexander, Dai, Hao, Kordelas, Lambros, Beelen, Dietrich W., Radujkovic, Aleksandar, Müller-Tidow, Carsten, Dreger, Peter, and Luft, Thomas
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ACUTE myeloid leukemia ,LEPTIN ,PEPTIDE hormones ,STEM cell transplantation ,ACUTE leukemia - Abstract
Weight loss and metabolic activity influence outcome after allogeneic stem cell transplantation (alloSCT). This study evaluates pre-conditioning Leptin, a peptide hormone involved in metabolism and immune homeostasis, as a prognostic factor for survival, relapse and non-relapse mortality (NRM) following alloSCT. Leptin serum levels prior to conditioning were determined in a cohort of patients transplanted for various hematologic malignancies (n = 524) and correlated retrospectively with clinical outcome. Findings related to patients with acute leukemia (AL) from this sample were validated in an independent cohort. Low pre-conditioning serum Leptin was an independent prognostic marker for increased risk of relapse (but not of NRM and overall mortality) following alloSCT for AL of intermediate and advanced stage (beyond first complete remission). Multivariate analysis revealed a hazard ratio (HR) for relapse of 0.75 per log2 increase (0.59–0.96, p = 0.020). This effect was similar in an independent validation cohort. Pre-conditioning serum Leptin was validated as a prognostic marker for early relapse by fitting the multivariate Cox model to the validation data. Pre-conditioning serum Leptin levels may serve as an independent prognostic marker for relapse following alloSCT in intermediate and advanced stage AL patients. Prospective studies are required to prove whether serum Leptin could be used for guiding nutritional intervention in patients with AL undergoing alloSCT. [ABSTRACT FROM AUTHOR]
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- 2022
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209. Humoral Responses and Chronic GVHD Exacerbation after COVID-19 Vaccination Post Allogeneic Stem Cell Transplantation.
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Pabst, Caroline, Benning, Louise, Liebers, Nora, Janssen, Maike, Caille, Leandra, Speer, Claudius, He, Lixiazi, Schubert, Maria-Luisa, Simons, Laura, Hegenbart, Ute, Schönland, Stefan, Radujkovic, Aleksandar, Schmitt, Michael, Schnitzler, Paul, Müller-Tidow, Carsten, Dietrich, Sascha, Dreger, Peter, and Luft, Thomas
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STEM cell transplantation ,COVID-19 vaccines ,ANTIBODY titer ,DISEASE exacerbation - Abstract
The COVID-19 pandemic threatens patients with a compromised immune and endothelial system, including patients who underwent allogeneic stem cell transplantation (alloSCT). Thus, there is an unmet need for optimizing vaccination management in this high-risk cohort. Here, we monitored antibodies against SARS-CoV-2 spike protein (anti-S1) in 167 vaccinated alloSCT patients. Humoral immune responses were detectable in 81% of patients after two vaccinations with either mRNA-, vector-based, or heterologous regimens. Age, B-cell counts, time interval from vaccination, and the type of vaccine determined antibody titres in patients without systemic immunosuppression (sIS). Similar to a healthy control cohort, mRNA vaccine-based regimens induced higher titres than vector-based vaccines. Patients on two or more immunosuppressants rarely developed immunity. In contrast, 62% and 45% of patients without or on only one immunosuppressant, respectively, showed a strong humoral vaccination response (titre > 100). Exacerbation of cGVHD upon vaccination was observed in 6% of all patients and in 22% of patients receiving immunosuppression for cGVHD. cGVHD exacerbation and low antibody titres were both associated with higher angiopoietin-2 (ANG2) serum levels. In conclusion, mRNA-based vaccines elicit strong humoral responses in alloSCT patients in the absence of double sIS. Biomarkers such as ANG2 might help with weighing cGVHD risk versus beneficial responses. [ABSTRACT FROM AUTHOR]
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- 2022
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210. Pretransplant Metabolic Distress Predicts Relapse of Acute Myeloid Leukemia After Allogeneic Stem Cell Transplantation
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Dietrich, Sascha, Radujkovic, Aleksandar, Stölzel, Friedrich, Falk, Christine S., Benner, Axel, Schaich, Markus, Bornhäuser, Martin, Ehninger, Gerhard, Krämer, Alwin, Hegenbart, Ute, Ho, Anthony D., Dreger, Peter, and Luft, Thomas
- Abstract
The impact of nutritional status on outcome of allogeneic stem cell transplantation (alloSCT) is controversial. This study investigates the influence of pretransplant weight loss and serologic indicators of nutritional homeostasis on relapse and death of acute myeloid leukemia (AML) after alloSCT.
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- 2015
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211. Was macht ein Wissensingenieur?
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Luft, Thomas and Wartzack, Sandro
- Abstract
Copyright of Wissens Management is the property of Nicole Lehnert - wissensmanagement and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2015
212. Verschiedene Rollen im Wissensmanagement - eine bibliografische Studie.
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Luft, Thomas and Wartzack, Sandro
- Abstract
Copyright of Wissens Management is the property of Nicole Lehnert - wissensmanagement and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2014
213. Myelodysplastische Syndrome (MDS).
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Luft, Thomas and Dreger, Peter
- Abstract
Copyright of Onkopipeline is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2009
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214. Real-Time Watercolor for Animation.
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Luft, Thomas and Deussen, Oliver
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We present algorithms that allow for real-time rendering of 3D-scenes with a watercolor painting appearance. Our approach provides an appropriate simplification of the visual complexity, imitates characteristic natural effects of watercolor, and provides two essential painting techniques: the wet-on-wet and the wet-on-dry painting. We concentrate on efficient algorithms based on image space processing rather than on an exact simulation. This allows for the real-time rendering of 3D-scenes. During an animation a high frame-to-frame coherence can be achieved due to a stable segmentation scheme. Finally, we seamlessly integrate a smooth illumination into the watercolor renderings using information from the 3D-scene. [ABSTRACT FROM AUTHOR]
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- 2006
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215. Overexpression, purification and characterization of SimL, an amide synthetase involved in simocyclinone biosynthesis.
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Luft, Thomas, Shu-Ming Li, Scheible, Holger, Kammerer, Bernd, and Heide, Lutz
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AMIDES , *LIGASES , *BIOSYNTHESIS , *BIOCHEMICAL engineering , *BIOCHEMISTRY , *ORGANIC synthesis - Abstract
Simocyclinone D8 is a potent inhibitor of bacterial gyrase, produced by Streptomyces antibioticus Tü 6040. It contains an aminocoumarin moiety, similar to that of novobiocin, which is linked by an amide bond to a structurally complex acyl moiety, consisting of an aromatic angucycline polyketide nucleus, the deoxysugar olivose and a tetraene dicarboxylic acid. We have now investigated the enzyme SimL, responsible for the formation of the amide bond of simocyclinone. The gene was cloned, expressed in S. lividans T7, and the protein was purified to near homogeneity, and characterized. The 60 kDa protein catalyzed both the ATP-dependent activation of the acyl component as well as its transfer to the amino group of the aminocoumarin ring, with no requirement for a 4′-phosphopantetheinyl cofactor. Besides its natural substrate, simocyclinone C4, SimL also accepted a range of cinnamic and benzoic acid derivatives and several other, structurally very diverse acids. These findings make SimL a possible tool for the creation of new aminocoumarin antibiotics. [ABSTRACT FROM AUTHOR]
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- 2005
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216. Novobiocin biosynthesis: inactivation of the putative regulatory gene novE and heterologous expression of genes involved in aminocoumarin ring formation.
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Eustáquio, Alessandra S., Luft, Thomas, Zhao-Xin Wang, Gust, Bertolt, Chater, Keith F., Shu-Ming Li, and Heide, Lutz
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BIOSYNTHESIS , *BIOCHEMICAL engineering , *BIOCHEMISTRY , *GENES , *HYDROXYLATION , *CHEMICAL reactions - Abstract
The left ends of the biosynthetic gene clusters of novobiocin (nov), clorobiocin (clo) and coumermycin A1 (cou) from Streptomyces spheroides (syn. S. caeruleus) NCIMB 11891, S. roseochromogenes var. oscitans DS 12.976 and S. rishiriensis DSM 40489 were cloned and sequenced. Sequence comparison suggested that novE, cloE and couE, respectively, represent the borders of these three clusters. Inactivation of novE proved that novE does not have an essential catalytic role in novobiocin biosynthesis, but is likely to have a regulatory function. The gene products of novF and cloF show sequence similarity to prephenate dehydrogenase and may produce 4-hydroxyphenylpyruvate (4HPP) as a precursor of the substituted benzoate moiety of novobiocin and clorobiocin. Coumermycin A1 does not contain this benzoate moiety, and correspondingly the coumermycin cluster was found not to contain a functional novF homologue. The coumermycin biosynthetic gene cluster apparently evolved from an ancestral cluster similar to those of novobiocin and clorobiocin, and parts of the ancestral novF homologue have been deleted in this process. No homologue to novC was identified in the gene clusters of clorobiocin and coumermycin, questioning the postulated involvement of novC in aminocoumarin biosynthesis. Heterologous expression of novDEFGHIJK in Streptomyces lividans resulted in the formation of 2,4-dihydroxy-α-oxy-phenylacetic acid, suggesting that at least one of the proteins encoded by these genes may participate in a hydroxylation reaction. [ABSTRACT FROM AUTHOR]
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- 2003
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217. Knowledge Based Engineering: Konstruktionsrelevantes Wissen erfassen & nutzbar machen.
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Luft, Thomas, Roth, Daniel, and Wartzack, Sandro
- Abstract
Copyright of Wissens Management is the property of Nicole Lehnert - wissensmanagement and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2016
218. Application and Validation of the Matrix-based Product Description in a Case Study by Using the Software Loomeo
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Luft, Thomas, Ewringmann, Niklas, and Wartzack, Sandro
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The main task of product developers is to meet the ever increasing demands on quality, cost and functionality of technical products by setting the appropriate characteristics in order to realize the product properties desired by the customer. The overall objective of the authors is to develop a suitable procedure model for property-based product development, which guides the developers purposefully through the development process. An essential part of this procedure model is the matrix-based product description, which is in the focus of this paper. The matrix-based product description is basically a so-called multi domain matrix. By using this matrix-based product description, dependencies between requirements, behaviors of the product and the product's properties and characteristics can be mapped and analyzed systematically during the product development process. Thereby, for example, the effects of characteristic changes on product properties become visible and traceable and also differential requirements are set into relationship with properties and characteristics of the product.
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- 2014
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219. Welches Wissensmanagement-System passt zum Unternehmen?
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Luft, Thomas, Frey, Dennis, and Wartzack, Sandro
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- 2014
220. Easix As Prediction Score before CAR-T Cells Vs Allogeneic Hematopoietic Cell Transplantation (alloHCT) for Relapsed/Refractory (r/r) Large B Cell Lymphoma (LBCL)
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Korell, Felix, Luft, Thomas, Schmitt, Michael, Dietrich, Sascha, Schmitt, Anita, Mueller-Tidow, Carsten, and Dreger, Peter
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- 2020
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221. Chapter 14 - Dendritic cells as recipients of cytokine signals
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Cebon, Jonathan, Davis, Ian, Luft, Thomas, and Maraskovsky, Eugene
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- 2001
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222. Kynurenine Pathway Activation and Deviation in Fibrosing Chronic Graft-Versus-Host Disease
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Laura, Orsatti, Stiehl, Thomas, Dischinger, Katharina, Speziale, Roberto, Di Pasquale, Pamela, Monteagudo, Edith, Mueller-Tidow, Carsten, Radujkovic, Aleksandar, Dreger, Peter, and Luft, Thomas
- Abstract
Background: Fibrosing chronic graft-versus-host disease (cGVHD) is a debilitating complication after allogeneic stem cell transplantation (allo-SCT), and its pathophysiology is poorly understood. Kynurenine and its metabolites were shown to associate with both, interferon-gamma (IFNg) activation and fibrosis. This study investigates the interplay between members of the IFNγ pathway and Kynurenin-derived metabolites in cGVHD.
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- 2021
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223. Venetoclax-Azacitidine As Salvage Therapy and Bridge to Allogeneic Cell Transplantation in Relapsed/Refractory AML Compared to Historical Data of the SAL Registry Study
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Unglaub, Julia M., Schlenk, Richard F., Hanoun, Maher, Reinhardt, H. Christian, Middeke, Jan Moritz, Schäfer-Eckart, Kerstin, Steffen, Björn, Krause, Stefan W., Schliemann, Christoph, Kaufmann, Martin, Haenel, Mathias, Jost, Edgar, Crysandt, Martina, Fransecky, Lars, Kraus, Sabrina, Einsele, Hermann, Niemann, Dirk, Neubauer, Andreas, Seggewiss-Bernhardt, Ruth, Scholl, Sebastian, Klein, Stefan, Schmid, Christoph, Schaich, Markus, Platzbecker, Uwe, Baldus, Claudia D., Bornhäuser, Martin, Serve, Hubert, Rollig, Christoph, Kramer, Michael, Katelari, Elena, Janssen, Maike, Pabst, Caroline, Luft, Thomas, Dreger, Peter, Müller-Tidow, Carsten, and Sauer, Tim
- Abstract
Background
- Published
- 2021
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224. Th22 and Tfh Cell Elevation Is Associated with Clinical Response of Photopheresis Therapy in Patients with Steroid-Refractory/ Resistant Graft-Versus-Host Disease (GvHD)
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Ding, Yuntian, Wang, Lei, Ni, Ming, Gong, Wenjie, Wang, Sanmei, Neuber, Brigitte, Schubert, Maria-Luisa, Sauer, Tim, Hückelhoven-Krauss, Angela, Luft, Thomas, Hegenbart, Ute, Schönland, Stefan, Eckstein, Volker, Wang, Jishi, Krüger, William Hermann, Müller-Tidow, Carsten, Dreger, Peter, Schmitt, Michael, and Schmitt, Anita
- Abstract
In patients with steroid-refractory/resistant graft-versus-host disease (GvHD), extracorporeal photopheresis (ECP) has been identified as a promising therapeutic strategy due to its safety profile and convincing clinical response rates.
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- 2021
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225. Easix before Conditioning Therapy Predicts Sepsis after Allogeneic Stem Cell Transplantation
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Korell, Felix, Schreck, Nicholas, Benner, Axel, Liebregts, Tobias, Schönland, Stefan, Hegenbart, Ute, Radujkovic, Aleksandar, Schmitt, Michael, Dreger, Peter, and Luft, Thomas
- Abstract
Purpose: Endothelial complications are principal causes of non-relapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). Sepsis is a dysfunctional endothelial response to harmful microorganisms with increased risk of microvascular damage and organ failure. We hypothesized that the endothelial activation and stress index (EASIX) predicts risk of sepsis after alloSCT.
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- 2021
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226. Easix Predicts Severe Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neuro-Toxicity Syndrome (ICANS) in Patients Receiving CD19-Directed Chimeric Antigen Receptor T (CAR-T) Cell Therapy
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Korell, Felix, Penack, Olaf, Schmitt, Michael, Müller-Tidow, Carsten, Bullinger, Lars, Dreger, Peter, and Luft, Thomas
- Abstract
Background: Endothelial dysfunction underlies the two main complications of chimeric antigen receptor T (CAR-T) cell therapy, i.e. cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The purpose of this retrospective analysis was to evaluate and validate the Endothelial Activation and Stress Index (EASIX)) as predictor for CRS and ICANS in patients receiving CD19-directed CAR-T cells.
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- 2021
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227. Kynurenine pathway activation and deviation to anthranilic and kynurenic acid in fibrosing chronic graft-versus-host disease
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Orsatti, Laura, Stiehl, Thomas, Dischinger, Katharina, Speziale, Roberto, Di Pasquale, Pamela, Monteagudo, Edith, Müller-Tidow, Carsten, Radujkovic, Aleksandar, Dreger, Peter, and Luft, Thomas
- Abstract
Fibrosing chronic graft-versus-host disease (cGVHD) is a debilitating complication of allogeneic stem cell transplantation (alloSCT). A driver of fibrosis is the kynurenine (Kyn) pathway, and Kyn metabolism patterns and cytokines may influence cGVHD severity and manifestation (fibrosing versus gastrointestinal [GI] cGVHD). Using a liquid chromatography-tandem mass spectrometry approach on sera obtained from 425 patients with allografts, we identified high CXCL9, high indoleamine-2,3-dioxygenase (IDO) activity, and an activated Kyn pathway as common characteristics in all cGVHD subtypes. Specific Kyn metabolism patterns could be identified for non-severe cGVHD, severe GI cGVHD, and fibrosing cGVHD, respectively. Specifically, fibrosing cGVHD was associated with a distinct pathway shift toward anthranilic and kynurenic acid, correlating with reduced activity of the vitamin-B2-dependent kynurenine monooxygenase, low vitamin B6, and increased interleukin-18. The Kyn metabolite signature is a candidate biomarker for severe fibrosing cGVHD and provides a rationale for translational trials on prophylactic vitamin B2/B6 supplementation for cGVHD prevention.
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- 2021
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228. GSK-3 mediates differentiation and activation of proinflammatory dendritic cells
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Rodionova, Elena, Conzelmann, Michael, Maraskovsky, Eugene, Hess, Michael, Kirsch, Michael, Giese, Thomas, Ho, Anthony D., Zöller, Margot, Dreger, Peter, and Luft, Thomas
- Abstract
The key components of the intracellular molecular network required for the expression of a specific function of dendritic cells (DCs) are as yet undefined. Using an in vitro model of human monocyte-derived DC differentiation, this study investigates the role of glycogen synthase kinase 3 (GSK-3), a multifunctional enzyme critical for cellular differentiation, apoptosis, self-renewal, and motility, in this context. We demonstrate that GSK-3 (1) inhibits macrophage development during differentiation of DCs, (2) is constitutively active in immature DCs and suppresses spontaneous maturation, and (3) acquires a proinflammatory functional status mediating high levels of IL-12, IL-6, and TNF-α secretion, and partially inhibits IL-10 in the context of DC activation. In particular, GSK-3 enhances IL-12p35 mRNA expression and thus the production of the proinflammatory cytokine IL-12p70 by integrating the activities of other kinases priming GSK-3 targets and the inhibitory effects of Akt-1. GSK-3 may therefore act as a key integrator of activating and inhibitory pathways involved in proinflammatory DC differentiation and activation.
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- 2007
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229. Adaptive functional differentiation of dendritic cells: integrating the network of extra- and intracellular signals
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Luft, Thomas, Rodionova, Elena, Maraskovsky, Eugene, Kirsch, Michael, Hess, Michael, Buchholtz, Christian, Goerner, Martin, Schnurr, Max, Skoda, Radek, and Ho, Anthony D.
- Abstract
Phenotypic maturation, cytokine secretion, and migration are distinct functional characteristics of dendritic cells (DCs). These functions are independently regulated by a number of extracellular variables, such as type, strength, and persistence of an array of soluble and membrane-bound mediators. Since the exact composition of these variables in response to infection may differ between individuals, the intracellular signaling pathways activated by these extracellular networks may more closely correlate with DC function and predict the course of adaptive immunity. We found that activation of p38 kinase (p38K), extracellular signal–related kinase 1/2 (ERK1/2), and phosphatidylcholine-specific phospholipase C (PC-PLC) enhanced cytokine secretion, whereas p38K, cyclic adenosine monophosphate (cAMP), and PC-PLC enhanced migration. In contrast, phosphatidylinositol 3-kinase (PI3K)/Akt-1 and cAMP inhibited cytokine secretion while ERK1/2 inhibited migration. Migration and cytokine secretion further differed in their sensitivity to inhibition over time. However, although DCs could be manipulated to express migration, cytokine secretion, or both, the level of activation or persistence of intracellular pathway signaling was not predictive. Our results suggest a modular organization of function. We hypothesize that the expression of specific DC functions integrates a large variety of activating and inhibitory variables, and is represented by the formation of a functional unit of molecular networks—the signal response module (SRM). The combined activities of these modules define the functional outcome of DC activation.
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- 2006
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230. Functionally distinct dendritic cell (DC) populations induced by physiologic stimuli: prostaglandin E2regulates the migratory capacity of specific DC subsets
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Luft, Thomas, Jefford, Michael, Luetjens, Petra, Toy, Tracey, Hochrein, Hubertus, Masterman, Kelly-Anne, Maliszewski, Charlie, Shortman, Ken, Cebon, Jonathan, and Maraskovsky, Eugene
- Abstract
Migration of antigen (Ag)-loaded dendritic cells (DCs) from sites of infection into draining lymphoid tissues is fundamental to the priming of T-cell immune responses. We evaluated monocyte-derived DCs (MoDCs) and peripheral blood DCs (PBDCs) to respond to proinflammatory mediators, CD40L, and intact bacteria. All classes of stimuli induced DC phenotypic maturation. However, for MoDCs, only prostaglandin E2(PGE2)–containing stimuli induced migratory-type DCs. Thus, immature MoDCs that encountered proinflammatory cytokines or CD40L or intact bacteria in the presence of PGE2acquired migratory capacity but secreted low levels of cytokines. Conversely, MoDCs that encountered pathogens or CD40L alone become nonmigratory cytokine-secreting cells (proinflammatory type). Interestingly, both migratory- and proinflammatory-type DCs expressed equivalent levels of chemokine receptors, suggesting that the role of PGE2was to switch on migratory function. We demonstrate that PGE2induces migration via the E-prostanoid 2/E-prostanoid 4 (EP2/EP4) receptors and the cAMP pathway. Finally, migratory-type MoDCs stimulated T-cell proliferation and predominantly IL-2 secretion, whereas proinflammatory-type MoDCs induced IFN-γ production. In contrast, CD1b/c+PBDC rapidly acquired migratory capacity irrespective of the class of stimulus encountered and secreted low levels of cytokines. This suggests that not all mature stages of DCs are destined to migrate to lymphoid organs and that the sequence in which stimuli are encountered significantly affects which functions are expressed. Thus, certain immature DC subsets recruited from the resting precursor pool may have multiple functional fates that play distinct roles during the induction and effector phases of the immune response. These findings have important implications for the clinical utility of DCs in immunotherapy.
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- 2002
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231. IFN-alpha enhances CD40 ligand-mediated activation of immature monocyte-derived dendritic cells.
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Luft, Thomas, Luetjens, Petra, Hochrein, Hubertus, Toy, Tracey, Masterman, Kelly-Anne, Rizkalla, Mark, Maliszewski, Charlie, Shortman, Ken, Cebon, Jonathan, and Maraskovsky, Eugene
- Abstract
Type I IFN are immune modulatory cytokines that are secreted during early stages of infection. Type I IFN bridge the innate and the adaptive immune system in humans and mice. We compared the capacity of type I and II IFN to induce the functional maturation of monocyte-derived dendritic cells (MoDC). Extending our earlier observation that type I IFN promote DC maturation, we report that these cytokines also enhance DC differentiation by augmenting CD40 ligand (CD40L)-induced cytokine secretion by MoDC. Type I IFN alone were poor inducers of MoDC maturation as compared with other stimuli. They up-regulated the expression of HLA-DR, CD80, CD86, partially CCR7 but not CD83, partially reduced antigen-uptake function, increased the levels of IL-12p35 mRNA, and prolonged surface expression of peptide-MHC class I complexes for presentation to cytotoxic T lymphocytes, but did not induce migration towards CCL21 chemokine. However, type I IFN were potent co-factors for CD40L-mediated function. Here, they enhanced CD40L-mediated IL-6, IL-10 and IL-12p70 secretion. Furthermore, when combined with IL-1beta and/or IL-4, IFN-alpha2a type I IFN increased CD40L-mediated IL-12p70 production by 2- to 3-fold, and biased the IL-12 p40/p70 ratio towards the IFN-gamma inducing p70 heterodimer, this correlating with higher levels of IFN-gamma secretion by allogeneic T cell subsets and NK cells. Our results suggest that the rapid expression of CD40L, IFN and IL-1beta at sites of infection and inflammation can act in concert on immature DC, thereby linking innate and adaptive immune responses. In this way, type I IFN play a dual role as DC maturation factors and enhancers of CD40L-mediated DC activation.
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- 2002
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232. Clorobiocin Biosynthesis in Streptomyces Identification of the Halogenase and Generation of Structural Analogs
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Eustáquio, Alessandra S, Gust, Bertolt, Luft, Thomas, Li, Shu-Ming, Chater, Keith F, and Heide, Lutz
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polycyclic compounds - Abstract
Clorobiocin (clo) and novobiocin (nov) are potent inhibitors of bacterial DNA gyrase. The two substances differ in the substitution pattern at C-8′ of the aminocoumarin ring, carrying a chlorine atom or a methyl group, respectively. By gene inactivation, clo-hal was identified as the gene of the halogenase responsible for the introduction of the chlorine atom of clorobiocin. Inactivation of cloZ did not affect clorobiocin formation, showing that this ORF is not essential for clorobiocin biosynthesis. Expression of the methyltransferase gene novO in the clo-hal− mutant led to the very efficient formation of a hybrid antibiotic containing a methyl group instead of a chlorine atom at C-8′. Comparison of the antibacterial activity of clorobiocin analogs with -Cl, -H, or -CH3 at C-8′ showed that chlorine leads to 8-fold higher activity than hydrogen and to 2-fold higher activity than a methyl group.
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233. Clinical Response to the CD95-Ligand Inhibitor Asunercept Is Defined by a Pro-Inflammatory Serum Cytokine Profile.
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Radujkovic, Aleksandar, Boch, Tobias, Nolte, Florian, Nowak, Daniel, Kunz, Claudia, Gieffers, Alexandra, Müller-Tidow, Carsten, Dreger, Peter, Hofmann, Wolf-Karsten, and Luft, Thomas
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BLOOD serum analysis ,ANEMIA ,APOPTOSIS ,BIOMARKERS ,CALCIUM-binding proteins ,CONFIDENCE intervals ,CYTOKINES ,ERYTHROPOIESIS ,INFLAMMATION ,INTERLEUKINS ,MYELODYSPLASTIC syndromes ,MYELOFIBROSIS ,RECOMBINANT proteins ,RISK assessment ,STATISTICS ,SURVIVAL ,DATA analysis ,RETROSPECTIVE studies ,DESCRIPTIVE statistics ,CHEMICAL inhibitors ,DISEASE risk factors - Abstract
Simple Summary: Asunercept showed promising clinical efficacy in anemic, transfusion-dependent patients with low and intermediate risk myelodysplastic syndrome. In this retrospective post hoc analysis, serum levels of biomarkers were measured in study patients focusing on cytokines associated with erythropoiesis, inflammation, apoptosis, bone marrow fibrosis, and inflammasome activity. Baseline serum biomarkers were correlated with treatment response in order to propose a hypothetical responder serum profile. Response to asunercept was associated with improved overall survival. Higher baseline values of interleukin-18 (IL-18), S100 calcium-binding protein A9 (S100A9) and soluble p53 were predictive of non-response to asunercept. Non-responding patients showed a distinct, pro-inflammatory serum cytokine profile which was persistent throughout the first half of the treatment phase and appeared unaffected by asunercept. Our post hoc analysis suggests that serum cytokine profiling based on IL-18, S100A9 and soluble p53 may represent an approach to identify and select low-risk myelodysplastic syndrome patients most likely to benefit from asunercept treatment. Asunercept (APG101) is a well-tolerated CD95-ligand inhibitor that showed promising efficacy in a prospective, single-arm phase I study in anemic, transfusion-dependent patients with low and intermediate risk myelodysplastic syndrome (MDS). In this retrospective post hoc analysis, serum levels of biomarkers were measured in study patients focusing on cytokines associated with erythropoiesis, inflammation, apoptosis, bone marrow fibrosis, and inflammasome activity. Baseline serum biomarkers were correlated with treatment response, in order to propose a hypothetical responder serum profile. After an updated median follow-up of 54 months (range 7–65), response to asunercept was associated with improved overall survival (at 3-years: 67% [95%CI 36–97] versus 13% [95%CI 0–36] in responders versus non-responders, respectively). Higher baseline values of interleukin-18 (IL-18), S100 calcium-binding protein A9 (S100A9) and soluble p53 were predictive of non-response to asunercept (area under the receiver operating characteristic curve 0.79–0.82). Furthermore, non-responding patients showed a distinct, pro-inflammatory serum cytokine profile which was persistent throughout the first half of the treatment phase and appeared unaffected by asunercept. Although prospective validation is required, our post hoc analysis suggests that serum cytokine profiling based on IL-18, S100A9 and soluble p53 may represent an approach to identify and select low-risk MDS patients most likely to benefit from asunercept treatment. [ABSTRACT FROM AUTHOR]
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- 2020
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234. Interleukin-18 and Hematopoietic Recovery after Allogeneic Stem Cell Transplantation.
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Radujkovic, Aleksandar, Kordelas, Lambros, Bogdanov, Rashit, Müller-Tidow, Carsten, Beelen, Dietrich W., Dreger, Peter, and Luft, Thomas
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HEMATOPOIETIC stem cell transplantation ,INTERLEUKINS ,POSTOPERATIVE care - Abstract
Simple Summary: We have previously shown that high pre-conditioning levels of Interleukin-18 were associated with worse survival after allogeneic stem cell transplantation due to increased non-relapse mortality. While no correlations with acute graft-versus-host disease were observed, interleukin-18-related excess mortality was mainly driven by fatal infectious complications. In multiple studies, delayed hematopoietic recovery and poor graft function following allogeneic stem cell transplantation has been demonstrated as a powerful predictor of non-relapse mortality. The present study links high interleukin-18 to delayed platelet recovery in allografted patients. Given the functions of interleukin-18 in regulating the quiescence of hematopoietic stem/progenitor cells, our findings may be explained by Interferon gamma-independent inhibitory effects of interleukin-18 on stem cell proliferation and hematopoietic reconstitution in allografted patients. Importantly, considering recent successful interleukin-18-neutralizing approaches in autoimmune disorders, our results provide a rationale to explore modulation of interleukin-18 for improving hematopoietic recovery and outcomes in allogeneic stem cell transplantation recipients. Interleukin-18 (IL-18) is an immunoregulatory cytokine and a context-dependent regulator of hematopoietic stem/progenitor cell (HSPC) quiescence in murine models. In a previous study, high pre-conditioning levels of IL-18 were associated with increased non-relapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). To investigate the clinical impact of IL-18 status on hematopoietic function, the associations of pre-conditioning and day 0–3 cytokine levels with platelet and neutrophil recovery were analyzed in a training cohort of 714 allografted patients. In adjusted logistic regression analyses, both increasing pre-conditioning and day 0–3 IL-18 levels had a significantly higher adjusted odds ratio (aOR) of delayed platelet and neutrophil recovery on day +28 post-transplant (aOR per two-fold increase: 1.6–2.0). The adverse impact of high pre-conditioning IL-18 on day +28 platelet recovery was verified in an independent cohort of 673 allografted patients (aOR per two-fold increase: 1.8 and 1.7 for total and free IL-18, respectively). In both cohorts, a platelet count ≤20/nL on day +28 was associated with a significantly increased hazard of NRM (hazard ratio 2.13 and 2.94, respectively). Our findings support the hypothesis that elevated peritransplant IL-18 levels affect post-transplant HSPC function and may provide a rationale to explore modulation of IL-18 for improving alloSCT outcomes. [ABSTRACT FROM AUTHOR]
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- 2020
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235. Direct Comparison by Limiting Dilution Analysis of Long-Term Culture-Initiating Cells in Human Bone Marrow, Umbilical Cord Blood, and Blood Stem Cells
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Pettengell, Ruth, Luft, Thomas, Henschler, Reinhard, Hows, Jill M., Dexter, T. Michael, Ryder, David, and Testa, Nydia G.
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Limiting-dilution analysis of long-term culture-initiating cells (LTCIC) is a quantitative method of estimating hematopoietic stem cell activity in clinical samples. We compared the numbers of LTCIC in bone marrow (BM), umbilical cord blood, and blood progenitor cells (obtained from patients with solid tumors at leukapheresis after mobilization with induction chemotherapy and filgrastim administration), using a two-stage long-term culture system and a limiting-dilution technique, scoring cobblestone areas of greater than 15 hematopoietic cells weekly for up to 8 weeks. Samples were obtained from 30 normal BMs, 20 human umbilical cords, and 32 leukapheresis products. Direct comparison of LTCIC in the three sources showed that the median proportions of cells generating hematopoietic foci from unfractionated mononuclear cells at 5 and 8 weeks, respectively, were 1:13,314 and 1:33,949 for BM, 1:12,506 and 1:34,546 for umbilical cord blood, and 1:10,302 and 1:12,891 for leukapheresis product. The estimated proportions of LTCIC from unfractionated mononuclear cells and CD34+cells were similar in experiments with leukapheresis product. Leukapheresis product was superior to umbilical cord blood and cord blood to BM at 5 and 8 weeks of culture (P= .01). In two-stage long-term cultures, more colonies per flask and CD34+cells were found in assays of leukapheresis product than in BM or umbilical cord blood cultures (P= .0005). Results obtained by this simplified limiting-dilution analysis correlated well with standard long-term cultures and can be used as a measure of the stem cell population. These data suggest that the incidence of putative stem cells in leukapheresis product and umbilical cord blood are at least comparable with that of BM.
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- 1994
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236. The Impact of Allogeneic Hematopoietic Cell Transplantation (alloHCT) on the Outcome of Poor-Risk Non-Hodgkin Lymphoma (NHL): A Retrospective Intent-to-Transplant (ITT) Analysis
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Selberg, Lorenz, Stadtherr, Peter, Dietrich, Sascha, Luft, Thomas, Bondong, Andrea, Hegenbart, Ute, Meissner, Julia, Liebers, Nora, Schmitt, Michael, Mueller-Tidow, Carsten, and Dreger, Peter
- Abstract
Luft: Neovii: Research Funding; JAZZ: Research Funding. Schmitt:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Therakos Mallinckrodt: Other: Financial Support. Dreger:Neovii, Riemser: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy.
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- 2019
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237. High Pre-Transplant Free Interleukin-18 Is Associated with Poor Hematopoietic Recovery after Allogeneic Stem Cell Transplantation
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Kordelas, Lambros, Radujkovic, Aleksandar, Dai, Hao, Bogdanov, Rashit, Beelen, Dietrich W., Müller-Tidow, Carsten, Dreger, Peter, and Luft, Thomas
- Abstract
Bogdanov: Jazz Pharmaceuticals, MSD.: Other: Travel subsidies. Beelen:Medac GmbH Wedel Germany: Consultancy, Honoraria. Dreger:AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; Neovii, Riemser: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia. Luft:Neovii: Research Funding; JAZZ: Research Funding.
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- 2019
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238. Early Hyperbilirubinemia Is an Independent Predictor of Outcome after Allogeneic Stem Cell Transplantation and Correlates with Markers of Endothelial Cell Dysfunction
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Luft, Thomas, Dai, Hao, Radujkovic, Aleksandar, Schult, David, Majer-Lauterbach, Joshua, Blau, Olga, Bullinger, Lars, Jiang, Sihe, Müller-Tidow, Carsten, Dreger, Peter, and Penack, Olaf
- Abstract
Luft: Neovii: Research Funding; JAZZ: Research Funding. Bullinger:Bayer: Other: Financing of scientific research; Amgen: Honoraria; Astellas: Honoraria; Sanofi: Honoraria; Seattle Genetics: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Daiichi Sankyo: Honoraria; Gilead: Honoraria; Hexal: Honoraria; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria; Menarini: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Abbvie: Honoraria. Dreger:Neovii, Riemser: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau.
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- 2019
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239. Easix for Prediction of Survival in Myelodysplastic Syndromes
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Merz, Almuth Maria Anni, Germing, Ulrich, Kobbe, Guido, Kaivers, Jennifer, Jauch, Anna, Radujkovic, Aleksandar, Hummel, Manuela, Benner, Axel, Merz, Maximilian, Dreger, Peter, and Luft, Thomas
- Abstract
Germing: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria. Kobbe:Neovii: Honoraria, Other: Travel support; Pfizer: Honoraria, Other: Travel support; Medac: Honoraria, Other: Travel support; Abbvie: Honoraria, Other: Travel support; Biotest: Honoraria, Other: Travel support; Jazz: Honoraria, Other: Travel support; Celgene: Honoraria, Other: Travel support, Research Funding; Roche: Honoraria, Other: Travel support; Amgen: Honoraria, Other: Travel support, Research Funding; MSD: Honoraria, Other: Travel support; Novartis: Honoraria, Other: Travel support; Takeda: Honoraria, Other: Travel support. Kaivers:Jazz Pharmaceuticals: Other: Travel Support. Merz:Janssen: Other: Travel grants; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Abbvie: Other: Travel grants; Celgene: Other: Travel grants; Takeda Vertrieb GmbH: Other: Travel grants, Research Funding. Dreger:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Neovii, Riemser: Research Funding; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy.
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- 2019
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240. Letermovir Prophylaxis Is Effective for Cytomegalovirus Reactivation after Allogeneic Hematopoietic Cell Transplantation: Single Center Real-World Data
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Derigs, Patrick, Schubert, Maria-Luisa, Schnitzler, Paul, Müller-Tidow, Carsten, Luft, Thomas, Dreger, Peter, and Schmitt, Michael
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Derigs: MSD: Honoraria. Müller-Tidow:MSD: Membership on an entity's Board of Directors or advisory committees. Luft:Neovii: Research Funding; JAZZ: Research Funding. Dreger:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; Neovii, Riemser: Research Funding; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau. Schmitt:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Therakos Mallinckrodt: Other: Financial Support.
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- 2019
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241. Cell-specific proteome analyses of human bone marrow reveal molecular features of age-dependent functional decline.
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Hennrich, Marco L., Romanov, Natalie, Horn, Patrick, Jaeger, Samira, Eckstein, Volker, Steeples, Violetta, Ye, Fei, Ding, Ximing, Poisa-Beiro, Laura, Lai, Mang Ching, Lang, Benjamin, Boultwood, Jacqueline, Luft, Thomas, Zaugg, Judith B., Pellagatti, Andrea, Bork, Peer, Aloy, Patrick, Gavin, Anne-Claude, and Ho, Anthony D.
- Abstract
Diminishing potential to replace damaged tissues is a hallmark for ageing of somatic stem cells, but the mechanisms remain elusive. Here, we present proteome-wide atlases of age-associated alterations in human haematopoietic stem and progenitor cells (HPCs) and five other cell populations that constitute the bone marrow niche. For each, the abundance of a large fraction of the ~12,000 proteins identified is assessed in 59 human subjects from different ages. As the HPCs become older, pathways in central carbon metabolism exhibit features reminiscent of the Warburg effect, where glycolytic intermediates are rerouted towards anabolism. Simultaneously, altered abundance of early regulators of HPC differentiation reveals a reduced functionality and a bias towards myeloid differentiation. Ageing causes alterations in the bone marrow niche too, and diminishes the functionality of the pathways involved in HPC homing. The data represent a valuable resource for further analyses, and for validation of knowledge gained from animal models. Ageing causes an inability to replace damaged tissue. Here, the authors perform proteomics analyses of human haematopoietic stem cells and other cells in the bone marrow niche at different ages and show changes in central carbon metabolism, reduced bone marrow niche function, and enhanced myeloid differentiation. [ABSTRACT FROM AUTHOR]
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- 2018
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242. Prehabilitative high-intensity interval training and resistance exercise in patients prior allogeneic stem cell transplantation.
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Kuehl, Rea, Feyer, Jule, Limbach, Matthias, Pahl, Antonia, Stoelzel, Friederike, Beck, Heidrun, Wegner, Annika, Rosenberger, Friederike, Dreger, Peter, Luft, Thomas, and Wiskemann, Joachim
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STEM cell transplantation , *RESISTANCE training , *INTERVAL training , *HIGH-intensity interval training , *EXERCISE therapy , *PHYSICAL mobility , *PATIENT reported outcome measures - Abstract
Physical capacity prior allogeneic stem cell transplantation (allo-HCT) has been shown as a relevant prognostic factor for survival after transplant. Therefore, we evaluated feasibility and preliminary efficacy of a high-intensity interval training (HIIT) and moderate to high-intensity resistance exercise (RE) to increase physical capacity in patient's prior allo-HCT. In this multicentre single arm pilot study, a supervised exercise program was performed twice weekly for 4–12 weeks prior allo-HCT, depending on the individual time remaining. Outcomes were feasibility (recruitment, adherence, safety), physical capacity (cardiorespiratory fitness [VO2peak], muscle strength) and patient reported outcomes (physical functioning, fatigue). Thirty patients were intended, 16 could be included, and 14 completed post intervention assessment (75% male, 55 ± 11 years). The study was stopped early due to a low recruitment rate. Nine patients (64%) reached the initial minimum planned number of eight exercise sessions. Individual adherence was high with 92% for HIIT and 85% for RE. 87% of all performed exercise sessions were completed without complaints and VO2peak increased significantly from 20.4 to 23.4 ml/kg/min. The low recruitment rate suggests that initiation of the intervention concept immediately before allo-HCT is feasible only in a small number of patients. In particular, the timeframe directly prior allo-HCT seems too short for exercise interventions, although the exercise program was designed to improve outcomes in a very short time frame. HIIT and RE were feasible, effective and well accepted by the included patients. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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243. Favorable Long-Term Outcomes after Allogeneic Transplantation for Elderly Patients with Myelodysplastic Syndromes: A Report from the Chronic Malignancies Working Party of EBMT
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Schetelig, Johannes, de Wreede, Liesbeth C, Van Gelder, Michel, Koster, Linda, Beelen, Dietrich W, Mufti, Ghulam, Niederwieser, Dietger, Socie, Gerard, Platzbecker, Uwe, Finke, Jürgen, Maertens, Johan, Vitek, Antonin, Sengeloev, Henrik, Stuhler, Gernot Hermann, Volin, Liisa, Ljungman, Per, Kanz, Lothar, Ganser, Arnold, Luft, Thomas, Kobbe, Guido, Arnold, Renate, Alessandrino, Emilio Paolo, Russell, Nigel H., Robin, Marie, and Nicolaus, Kroger
- Abstract
Introduction:Communicating about the risk of mortality after allogeneic hematopoietic stem cell transplantation (HCT) is a challenging task for physicians. This is especially true for elderly patients with aggressive hematologic malignancies. Mortality after HCT may be split in three major parts, death after relapse, therapy-related mortality (including late complications of previous treatments of the hematologic malignancies) and background or general population mortality from causes unrelated to the treatment or disease. In the framework of the competing endpoints, relapse and non-relapse mortality, background mortality mainly determines the magnitude of non-relapse mortality. To estimate the size of the background mortality, the risk of an age-, sex-, country- and calendar year matched population can be used as approximation. This can be done with methods from relative survival analysis. By nature, background mortality increases among elderly patients. In order to study the size of background and excess mortality we analyzed mortality in a population of adult transplant recipients with myelodysplastic syndromes (MDS) because this indication is characterized by a high median age already at diagnosis and large numbers of transplanted patients.
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- 2017
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244. High Progression-Free Survival after Reduced Intensity Total Body Irradiation-Based Conditioning in Patients Allografted for Chronic Myelomonocytic Leukemia (CMML)
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Radujkovic, Aleksandar, Hegenbart, Ute, Müller-Tidow, Carsten, Dreger, Peter, and Luft, Thomas
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Background:In CMML, allogeneic stem cell transplantation (alloSCT) remains the only potentially curative treatment modality. However, despite the advent of reduced intensity conditioning (RIC) and advances in supportive care, transplant results in CMML are still hampered by relatively high risks of non-relapse mortality (NRM) and relapse, and novel transplant strategies aimed at reducing NRM while preserving the anti-leukemic activity are needed. Prompted by the results obtained in patients with acute myeloid leukemia considered ineligible for conventional conditioning that demonstrated low 2-year NRM rates and satisfactory disease control, we adopted fractionated intermediate-dose total body irradiation (TBI) in combination with fludarabine as routine conditioning for CMML from 2012 onwards. This retrospective analysis investigated the outcomes of patients with CMML undergoing alloSCT focusing on the impact of the conditioning treatment.
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- 2017
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245. Biomarkers for Clinical Response of Extracorporeal Photopheresis
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Ni, Ming, Wang, Lei, Hückelhoven, Angela, Sellner, Leopold, Hoffmann, Jean-Marc, Luft, Thomas, Hegenbart, Ute, Schönland, Stefan, Kleist, Christian, Sill, Martin, Chen, Bao-an, Wuchter, Patrick, Eckstein, Volker, Krüger, William Hermann, Hilgendorf, Inken, Nagler, Arnon, Müller-Tidow, Carsten, Ho, Anthony D., Dreger, Peter, Schmitt, Michael, and Schmitt, Anita
- Abstract
Introduction:Post-transplant morbidity and mortality are majorly determined by GvL effect counter-balanced by GvHD. Treatment with systemic steroids represents the first-line therapy for GvHD, but is associated with increased incidence of infection and relapse. ECP can reduce the extent of GvHD while preserving anti-virus/-tumor activity. However, ECP, a time-consuming and relatively expensive therapy, requires specialized equipment and staff expertise as well as the mechanism of action remains unclear. Therefore, this study was performed to address these unsolved questions.
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- 2017
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246. Mortality after Allogeneic Stem Cell Transplantation Associates with Gene Polymorphisms in CD40L and Thrombomodulin in the Absence of Statins
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Luft, Thomas, Rachakonda, Sivaramakrishna P., Dai, Hao, Penack, Olaf, Blau, Olga, Blau, Igor Wolfgang, Radujkovic, Aleksandar, Müller-Tidow, Carsten, Dreger, Peter, and Kumar, Rajive
- Abstract
Purpose:
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- 2017
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247. Validation of pre-conditioning EASIX for prediction of sepsis after allogeneic stem cell transplantation.
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Korell, Felix, DeFilipp, Zachariah, Schreck, Nicholas, Luft, Thomas, Mau, Marcela V., Benner, Axel, Dreger, Peter, Chen, Yi-Bin, and Müller-Tidow, Carsten
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STEM cell transplantation , *SEPSIS , *HEMATOPOIETIC stem cell transplantation - Abstract
Patient numbers for EASIX calculation are listed in following order (no neutropenic fever or sepsis / neutropenic fever without sepsis/neutropenic fever with sepsis) for the different timepoints: prior conditioning n = 125/200/27, day-3 n = 85/159/23, day 0 n = 84/159/23, day 3 n = 86/157/23, day 5 n = 87/153/22, day 7 n = 89/157/22, day 14 n = 108/161/20, day 21 n = 119/185/21, day 28 n = 120/194/17. As numbers of patients with sepsis were still small, these results warrant confirmation in larger multicenter trials with more sepsis patients. Sepsis patients were subgrouped by no neutropenic fever or sepsis, and neutropenic fever without and with sepsis. [Extracted from the article]
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- 2023
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248. Statin‐based endothelial prophylaxis and outcome after allogeneic stem cell transplantation.
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Pabst, Caroline, Schreck, Nicholas, Benner, Axel, Hegenbart, Ute, Schönland, Stefan, Radujkovic, Aleksandar, Schmitt, Michael, Müller‐Tidow, Carsten, Orsatti, Laura, Dreger, Peter, and Luft, Thomas
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STEM cell transplantation , *HEMATOPOIETIC stem cell transplantation , *ENDOTHELIUM diseases , *INDOLEAMINE 2,3-dioxygenase , *ADVERSE health care events , *ENZYME metabolism - Abstract
Background: Allogeneic haematopoietic stem cell transplantation (alloSCT) often remains the only curative therapy for hematologic malignancies. Although the management of transplant‐associated adverse events considerably improved over the last decades, nonrelapse mortality (NRM) remains a challenge, and endothelial dysfunction was identified as a major contributor to NRM. Methods: Statin‐based endothelial prophylaxis (SEP) has been implemented in the standard of care in our transplant centre to reduce NRM caused by endothelial injury. Here, we retrospectively analysed the impact of SEP on clinical outcome in a cohort of 347 alloSCT patients. Results: SEP (n = 209) was associated with significantly reduced NRM (hazard ratio 0.61, 95% CI 0.38–0.96) and better overall survival (OS) after acute graft‐versus‐host disease (HR 0.59, 95% CI 0.37–0.93). Subgroup analyses showed that the NRM benefit was mainly found in patients with an intermediate endothelial activation and stress index (EASIX), while relapse risk was not affected. On day 100 post‐alloSCT, patients receiving SEP had significantly higher levels of the rate‐limiting enzyme of tryptophan metabolism, indoleamine 2,3‐dioxygenase (IDO), higher kynurenine to tryptophan ratios as a proxy of IDO activity and tended to have lower levels of the endothelial injury marker ST2 (p =.055). No significant differences in interferon‐gamma or IL18 levels were observed. These biomarker signatures suggest that the beneficial effects of SEP might be mediated by both endothelial protection and immunomodulation. Conclusions: Together, these data suggest that SEP improves NRM and OS post‐alloSCT in particular in patients with intermediate endothelial risk and provide first mechanistic clues about its potential mode of action. [ABSTRACT FROM AUTHOR]
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- 2023
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249. Efficacy Of Azacitidine VersusLow-Dose Cytarabine In Patients With Acute Myeloid Leukemia - A Retrospective Single Center Experience
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Radujkovic, Aleksandar, Dietrich, Sascha, Krämer, Alwin, Bochtler, Tilmann, Ho, Anthony D., Dreger, Peter, and Luft, Thomas
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Azacitidine (AZA) treatment has been shown to be superior to conventional care regimens including low dose cytarabine (LD-Ara-C) in acute myeloid leukemia (AML) patients with low bone marrow (BM) blast counts (20-30%). In contrast, data on efficacy of AZA in patients with blast counts exceeding 30% are scarce. Here we present a retrospective, single center analysis, comparing the efficacy and toxicity of AZA versusLD-Ara-C in AML patients with high BM blast counts (≥30%) prior to treatment.
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- 2013
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250. Impact of Resistance Exercise and Nutritional Endorsement on physical performance in patients with GvHD (IRENE-G study) - design and rational of a randomized controlled trial.
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Bujan Rivera, Janina, Kühl, Rea, Zech, Ulrike, Hendricks, Anne, Luft, Thomas, Dreger, Peter, Friedmann-Bette, Birgit, Betz, Theresa-Maria, and Wiskemann, Joachim
- Abstract
Background: Graft-versus-host disease (GvHD) remains a major complication and limitation to successful allogeneic hematopoietic stem cell transplantation. Treatment of GvHD is challenging due to its heterogeneous nature of presentation, with steroids remaining the established first-line treatment. Long-term doses of systemic corticosteroids have many well-known side-effects including muscle atrophy. Despite the fact that reports in non-cancer clinical populations treated with glucocorticoids demonstrated that resistance training can reverse atrophy and weakness, no RCT has evaluated the potential of resistance training on preventing the disease- and treatment-induced loss of skeletal muscle mass and function in GvHD patients yet. In this context, ensuring adequate nutrition is important as protein deprivation may accelerate the wasting process. As GvHD patients are commonly found to be malnourished, nutritional medical care should be considered when investigating the effect of exercise in GvHD patients. Therefore, the aim of the present "Impact of Resistance Exercise and Nutritional Endorsement on physical performance in patients with GvHD" - Study (IRENE-G) is to evaluate the effects of resistance exercise in combination with nutritional endorsement on physical, nutritional and patient-reported outcomes in GvHD patients.Methods: IRENE-G is a 24-week prospective interventional RCT. One hundred twelve participants will be randomly allocated (1:1) to one of two arms: resistance exercise and nutritional optimization (experimental) vs. nutritional optimization only (control). Participants in the experimental group will engage in a supervised, progressive moderate-to-high intensity resistance training that is consistent with exercise guidelines for cancer patients, while additionally receiving nutritional support/therapy. Subjects of the control group solely receive nutritional support/therapy based on individual needs. Participants will be assessed at baseline, at 8, 16, 24 weeks for physical performance and various physiological, nutritional and patient-reported outcomes. Follow-up will be 6 months after intervention completion.Discussion: To our knowledge, this will be the first RCT to assess and compare the effects of a resistance intervention supplemented by nutritional support/therapy against nutritional support only on various health-related outcomes in GvHD patients. The study will contribute to our understanding of the value of exercise and nutritional endorsement in counteracting the negative consequences of GvHD and its treatment.Trial Registration: ClinicalTrials.gov : NCT05111834 . Registered 8 November 2021 - Retrospectively registered. [ABSTRACT FROM AUTHOR]- Published
- 2022
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