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960 Publications visible to you, out of a total of 960
A biomathematical model of human thrombopoiesis under chemotherapy.
HaematoOpt - Individualized model-based managing of the next-cycle thrombopenia of CHOEP/CHOP treated patients based on platelets dynamics during the previous cycles

Abstract (Expand)

Intensification of cytotoxic chemotherapy enhances the outcome of several malignancies but is limited by haematotoxicity. While neutropenia and anaemia can be treated with supportive growth factor … applications, thrombocytopenia remains a dose-limiting side effect due to the lack of clinically approved pharmaceutical growth factors. Hence, it is necessary to assess the degree of thrombocytopenia of newly designed intensified regimens in the planning phase of a clinical trial. We present a simple ordinary differential equations model of thrombopoiesis under chemotherapy which maps the dynamics of stem cells, CFU-Mk, megakaryocytes and platelets in spleen and circulation. Major regulatory cytokine of thrombopoiesis is thrombopoietin (TPO) whose production and consumption is explicitly modelled. TPO acts by increasing the number of mitoses of CFU-Mk and increasing the mass and maturation of megakaryocytes. Chemotherapy is modelled by a drug-dose and cell-stage specific acute cell loss. Most of the cell kinetic parameters of the model were taken from literature. Parameters regarding TPO regulation and chemotherapy toxicity were estimated by fitting the predictions of the model to time series data of platelets received from large clinical data sets of patients under seven different chemotherapies. We obtained a good agreement between model and data for all scenarios. Parameter estimates were biologically plausible throughout. For validation, the model also explains data of TPO and platelet dynamics after thrombopheresis taken from literature. We used the model to make clinically relevant predictions. Regarding thrombocytopenia we estimated that the CHOP regimen for the treatment of high-grade non-Hodgkin's lymphoma can be time-intensified to a cycle duration of 12 days while the time-intensified CHOEP regimen would result in severe cumulative toxicity. We conclude that our proposed model proved validity for both, different chemotherapeutic regimens and thrombopheresis as well. It is useful to assess the thrombocytopenic risk in the planning phase of a clinical trial.

Authors: M. Scholz, A. Gross, M. Loeffler

Date Published: 21st May 2010

Publication Type: Not specified

Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era.
GLA - German Lymphoma Alliance

Abstract (Expand)

PURPOSE: The International Prognostic Index (IPI) is widely used for risk stratification of patients with aggressive B-cell lymphoma. The introduction of rituximab has markedly improved outcome, and … R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, prednisone) has become the standard treatment for CD20(+) diffuse large B-cell lymphoma. To investigate whether the IPI has maintained its power for risk stratification when rituximab is combined with CHOP, we analyzed the prognostic relevance of IPI in three prospective clinical trials. PATIENTS AND METHODS: In total, 1,062 patients treated with rituximab were included (MabThera International Trial [MInT], 380 patients; dose-escalated regimen of cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (MegaCHOEP) trial, 72 patients; CHOP + rituximab for patients older than age 60 years [RICOVER-60] trial, 610 patients). A multivariate proportional hazards modeling was performed for single IPI factors under rituximab on event-free, progression-free, and overall survival. RESULTS: IPI score was significant for all three end points. Rituximab significantly improved treatment outcome within each IPI group resulting in a quenching of the Kaplan-Meier estimators. However, IPI was a significant prognostic factor in all three end points and the ordering of the IPI groups remained valid. The relative risk estimates of single IPI factors and their order in patients treated with R-CHOP were similar to those found with CHOP. CONCLUSION: The effects of rituximab were superimposed on the effects of CHOP with no interactions between chemotherapy and antibody therapy. These results demonstrate that the IPI is still valid in the R-CHOP era.

Authors: M. Ziepert, D. Hasenclever, E. Kuhnt, B. Glass, N. Schmitz, M. Pfreundschuh, M. Loeffler

Date Published: 10th May 2010

Publication Type: Not specified

Human Diseases: B-cell lymphoma

Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Germline mutations in a number of genes involved in the recombinational repair of DNA double-strand breaks are associated with predisposition to breast and ovarian cancer. RAD51C is essential for … homologous recombination repair, and a biallelic missense mutation can cause a Fanconi anemia-like phenotype. In index cases from 1,100 German families with gynecological malignancies, we identified six monoallelic pathogenic mutations in RAD51C that confer an increased risk for breast and ovarian cancer. These include two frameshift-causing insertions, two splice-site mutations and two nonfunctional missense mutations. The mutations were found exclusively within 480 pedigrees with the occurrence of both breast and ovarian tumors (BC/OC; 1.3%) and not in 620 pedigrees with breast cancer only or in 2,912 healthy German controls. These results provide the first unambiguous evidence of highly penetrant mutations associated with human cancer in a RAD51 paralog and support the ’common disease, rare allele’ hypothesis.

Authors: Alfons Meindl, Heide Hellebrand, Constanze Wiek, Verena Erven, Barbara Wappenschmidt, Dieter Niederacher, Marcel Freund, Peter Lichtner, Linda Hartmann, Heiner Schaal, Juliane Ramser, Ellen Honisch, Christian Kubisch, Hans E. Wichmann, Karin Kast, Helmut Deissler, Christoph Engel, Bertram Müller-Myhsok, Kornelia Neveling, Marion Kiechle, Christopher G. Mathew, Detlev Schindler, Rita K. Schmutzler, Helmut Hanenberg

Date Published: 1st May 2010

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

A BRCA1 promoter variant (rs11655505) and breast cancer risk
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND A study of Chinese women recently suggested that the minor allele of rs11655505 in the BRCA1 promoter (c.-2265C–\textgreaterT) increases promoter activity and has a protective effect on …n breast cancer risk. METHODS We genotyped rs11655505 in 2912 female breast cancer cases and 2783 unaffected female controls from four Caucasian breast cancer studies. RESULTS No evidence for an association between rs11655505 and breast cancer risk was found. CONCLUSIONS Our study failed to confirm a role of rs11655505 in breast cancer risk. Larger studies are necessary to determine if there is a weak association between this SNP and breast cancer risk.

Authors: Paolo Verderio, Sara Pizzamiglio, Melissa C. Southey, Amanda B. Spurdle, John L. Hopper, Xiaoqing Chen, Jonathan Beesley, Rita K. Schmutzler, Christoph Engel, Barbara Burwinkel, Peter Bugert, Filomena Ficarazzi, Siranoush Manoukian, Monica Barile, Barbara Wappenschmidt, Georgia Chenevix-Trench, Paolo Radice, Paolo Peterlongo

Date Published: 22nd Apr 2010

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Bortezomib sensitizes primary human esthesioneuroblastoma cells to TRAIL-induced apoptosis
Genetical Statistics and Systems Biology

Abstract (Expand)

TNF-related apoptosis-inducing ligand (TRAIL), a promising novel anti-cancer cytokine of the TNF superfamily, and Bortezomib, the first-in-class clinically used proteasome inhibitor, alone or in … combination have been shown to efficiently kill numerous tumor cell lines. However, data concerning primary human tumor cells are very rare. Using primary esthesioneuroblastoma cells we analyzed the anti-tumor potential and the mechanism employed by Bortezomib in combination with TRAIL for the treatment of this rare but aggressive tumor. Expression of components of the TRAIL pathway was analyzed in tumor specimens and isolated primary tumor cells at the protein level. Cells were treated with TRAIL, Bortezomib, and a combination thereof, and apoptosis induction was quantified. Clonogenicity assays were performed to elucidate the long-term effect of this treatment. Despite expressing all components of the TRAIL pathway, freshly isolated primary esthesioneuroblastoma cells were completely resistant to TRAIL-induced apoptosis. They could, however, be very efficiently sensitized by subtoxic doses of Bortezomib. The influence of Bortezomib on the TRAIL pathway was analyzed and showed upregulation of TRAIL death receptor expression, enhancement of the TRAIL death-inducing signaling complex (DISC), and downregulation of anti-apoptotic proteins of the TRAIL pathway. Of clinical relevance, TRAIL-resistant primary tumor cells could be repeatedly sensitized by Bortezomib, providing the basis for repeated clinical application schedules. This is the first report on the highly synergistic induction of apoptosis in primary esthesioneuroblastoma cells by Bortezomib and TRAIL. This combination, therefore, represents a promising novel therapeutic option for esthesioneuroblastoma.

Authors: Ronald Koschny, Heidrun Holland, Jaromir Sykora, Hande Erdal, Wolfgang Krupp, Manfred Bauer, Ulrike Bockmuehl, Peter Ahnert, Jürgen Meixensberger, Wolfgang Stremmel, Henning Walczak, Tom M. Ganten

Date Published: 1st Apr 2010

Publication Type: Journal article

A functional polymorphism in the NAD(P)H oxidase subunit CYBA is related to gene expression, enzyme activity, and outcome in non-Hodgkin lymphoma.
GLA - German Lymphoma Alliance

Abstract (Expand)

NAD(P)H oxidase is a major endogenous source of reactive oxygen species (ROS). ROS may not only be involved in carcinogenesis but also in efficacy of chemotherapeutic agents like doxorubicin. By a … comprehensive genotyping approach covering 48 genetic polymorphisms (single-nucleotide polymorphisms) in five subunits of phagocytic NAD(P)H oxidase, we asked whether they affect gene expression, enzymatic activity, and outcome of CHO(E)P chemotherapy. A highly consistent effect was observed for the CYBA 640A>G variant. In peripheral blood granulocytes of 125 healthy volunteers, the G allele of 640A>G was associated with lower NAD(P)H oxidase activity (P = 0.006). Moreover, the G allele was associated with lower mRNA and protein expression (both P = 0.02). Of clinical importance, the outcome of patients suffering from non-Hodgkin lymphoma and treated with CHO(E)P regimen was dependent on the CYBA 640A>G polymorphism. In an exploratory study (n = 401), carriers of 640GG had an event-free survival (EFS) risk ratio of 1.95 [95% confidence interval (95% CI), 1.31-2.90; P = 0.001] compared with 640AA. In a confirmatory set (n = 477), the risk ratios were 1.53 (1.04-2.25, P = 0.03). The complete set of 878 patients showed a relative risk of 1.72 (1.30-2.26) and 1.59 (1.14-2.21) for EFS and overall survival, respectively. Further molecular-biological experiments showed lower expression and reduced stability of transcripts with the G allele in lymphoblastoid cell lines. Transfection of allele-specific plasmids into HEK293 cells elicited lower activity for the G allele in a luciferase reporter gene construct. Thus, CYBA 640A>G was shown to be a functional polymorphism with possible consequences for patients receiving CHO(E)P chemotherapy and might have further implications for other ROS-mediated modalities.

Authors: M. Hoffmann, M. A. Schirmer, M. V. Tzvetkov, M. Kreuz, M. Ziepert, L. Wojnowski, D. Kube, M. Pfreundschuh, L. Trumper, M. Loeffler, J. Brockmoller

Date Published: 15th Mar 2010

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma

Practice of volume therapy in patients with severe sepsis: results from a nationwide sepsis prevalence study
SepNet - German Competence Network Sepsis

Abstract

Not specified

Authors: Christiane S. Hartog, Frank M. Brunkhorst, Frank Bloos, Holger Bogatsch, Christoph Engel, Kerstin Sengebusch, Konrad Reinhart, Maximilian Ragaller

Date Published: 1st Mar 2010

Publication Type: Journal article

Human Diseases: disease by infectious agent

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