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468 Publications visible to you, out of a total of 468
Screening in women at elevated risk for breast cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract

Not specified

Authors: Rita Katharina Schmutzler, Christoph Engel, Ingrid Schreer

Date Published: 20th Oct 2010

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed … with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P(trend) = 2.3 \times 10^-^9 to P(trend) = 3.9 \times 10^-^7), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P(trend) = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P(trend) = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (P(trend) = 1 \times 10^-^7) to P(trend) = 8 \times 10^-^5; rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P(trend) = 1.1 \times 10^-^7

Authors: Antonis C. Antoniou, Xianshu Wang, Zachary S. Fredericksen, Lesley McGuffog, Robert Tarrell, Olga M. Sinilnikova, Sue Healey, Jonathan Morrison, Christiana Kartsonaki, Timothy Lesnick, Maya Ghoussaini, Daniel Barrowdale, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Diana Eccles, D. Gareth Evans, Ros Eeles, Louise Izatt, Carol Chu, Fiona Douglas, Joan Paterson, Dominique Stoppa-Lyonnet, Claude Houdayer, Sylvie Mazoyer, Sophie Giraud, Christine Lasset, Audrey Remenieras, Olivier Caron, Agnès Hardouin, Pascaline Berthet, Frans B. L. Hogervorst, Matti A. Rookus, Agnes Jager, Ans van den Ouweland, Nicoline Hoogerbrugge, Rob B. van der Luijt, Hanne Meijers-Heijboer, Encarna B. Gómez García, Peter Devilee, Maaike P. G. Vreeswijk, Jan Lubinski, Anna Jakubowska, Jacek Gronwald, Tomasz Huzarski, Tomasz Byrski, Bohdan Górski, Cezary Cybulski, Amanda B. Spurdle, Helene Holland, David E. Goldgar, Esther M. John, John L. Hopper, Melissa Southey, Saundra S. Buys, Mary B. Daly, Mary-Beth Terry, Rita K. Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Sabine Preisler-Adams, Norbert Arnold, Dieter Niederacher, Christian Sutter, Susan M. Domchek, Katherine L. Nathanson, Timothy Rebbeck, Joanne L. Blum, Marion Piedmonte, Gustavo C. Rodriguez, Katie Wakeley, John F. Boggess, Jack Basil, Stephanie V. Blank, Eitan Friedman, Bella Kaufman, Yael Laitman, Roni Milgrom, Irene L. Andrulis, Gord Glendon, Hilmi Ozcelik, Tomas Kirchhoff, Joseph Vijai, Mia M. Gaudet, David Altshuler, Candace Guiducci, Niklas Loman, Katja Harbst, Johanna Rantala, Hans Ehrencrona, Anne-Marie Gerdes, Mads Thomassen, Lone Sunde, Paolo Peterlongo, Siranoush Manoukian, Bernardo Bonanni, Alessandra Viel, Paolo Radice, Trinidad Caldes, Miguel de La Hoya, Christian F. Singer, Anneliese Fink-Retter, Mark H. Greene, Phuong L. Mai, Jennifer T. Loud, Lucia Guidugli, Noralane M. Lindor, Thomas v. O. Hansen, Finn C. Nielsen, Ignacio Blanco, Conxi Lazaro, Judy Garber, Susan J. Ramus, Simon A. Gayther, Catherine Phelan, Stephen Narod, Csilla I. Szabo, Javier Benitez, Ana Osorio, Heli Nevanlinna, Tuomas Heikkinen, Maria A. Caligo, Mary S. Beattie, Ute Hamann, Andrew K. Godwin, Marco Montagna, Cinzia Casella, Susan L. Neuhausen, Beth Y. Karlan, Nadine Tung, Amanda E. Toland, Jeffrey Weitzel, Olofunmilayo Olopade, Jacques Simard, Penny Soucy, Wendy S. Rubinstein, Adalgeir Arason, Gad Rennert, Nicholas G. Martin, Grant W. Montgomery, Jenny Chang-Claude, Dieter Flesch-Janys, Hiltrud Brauch, Gianluca Severi, Laura Baglietto, Angela Cox, Simon S. Cross, Penelope Miron, Sue M. Gerty, William Tapper, Drakoulis Yannoukakos, George Fountzilas, Peter A. Fasching, Matthias W. Beckmann, Isabel Dos Santos Silva, Julian Peto, Diether Lambrechts, Robert Paridaens, Thomas Rüdiger, Asta Försti, Robert Winqvist, Katri Pylkäs, Robert B. Diasio, Adam M. Lee, Jeanette Eckel-Passow, Celine Vachon, Fiona Blows, Kristy Driver, Alison Dunning, Paul P. D. Pharoah, Kenneth Offit, V. Shane Pankratz, Hakon Hakonarson, Georgia Chenevix-Trench, Douglas F. Easton, Fergus J. Couch

Date Published: 1st Oct 2010

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Variability of structures in German intensive care units–a representative, nationwide analysis
SepNet - German Competence Network Sepsis

Abstract (Expand)

BACKGROUND Structures in intensive care medicine comprise human as well as material resources, organization, and management and may be related to processes thereby affecting patients’ outcomes. Utilizing …g a unique data base we evaluated structures of German intensive care units (ICUs). METHODS The study was carried out by the German Competence Network Sepsis (SepNet). Data were prospectively collected on a cross-sectional basis in a representative random sample of German hospitals utilizing a questionnaire. Structures were related to ICU outcome of patients with severe sepsis or septic shock. The sample was subdivided in 5 strata according to hospital size. RESULTS A total of 454 ICUs cared for 3877 patients including 415 patients (11%) with severe sepsis or septic shock. The mean number of beds per ICU was 10.4, the ratio of ICU to hospital beds 1:27, both with significant differences depending on hospital size. 81% of the ICUs provided around the clock physician presence (range: 66-98% across hospital strata, p \textless 0.001). Shift-wise, one nurse was responsible for a mean number of 2.7 patients (morning 1:2.3, afternoon 1:2.6, night 1:3.3 patients) with significant variation according to hospital size (smaller hospitals 1:2.9, university hospitals 1:2.1, p \textless 0.001). More than half of all German ICUs are lead by anesthesiologists. Neither physician nor nurse staffing was associated with mortality in the subset of patients with sepsis. CONCLUSIONS In a representative, nationwide sample of German ICUs key elements of structures varied considerably with respect to hospital size. This has to be considered when proposing standards, reimbursement strategies, or quality assessment.

Authors: Jürgen Graf, Andrea Reinhold, Frank M. Brunkhorst, Max Ragaller, Konrad Reinhart, Markus Loeffler, Christoph Engel

Date Published: 1st Oct 2010

Publication Type: Journal article

Human Diseases: disease by infectious agent

Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally … identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additional risk modifiers for BRCA1 and BRCA2 may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (P \textless 1 x 10(-3)) in two breast cancer GWAS studies were genotyped in 3451 BRCA1 and 2006 BRCA2 mutation carriers from nine centers. Associations with breast cancer risk were assessed using Cox models weighted for penetrance. Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk (P(trend) \textless 0.01). The minor alleles of rs6138178 in SNRPB and rs6602595 in CAMK1D displayed the strongest associations in BRCA1 carriers (HR = 0.78, 95% CI: 0.69-0.90, P(trend) = 3.6 x 10(-4) and HR = 1.25, 95% CI: 1.10-1.41, P(trend) = 4.2 x 10(-4)), whereas rs9393597 in LOC134997 and rs12652447 in FBXL7 showed the strongest associations in BRCA2 carriers (HR = 1.55, 95% CI: 1.25-1.92, P(trend) = 6 x 10(-5) and HR = 1.37, 95% CI: 1.16-1.62, P(trend) = 1.7 x 10(-4)). The magnitude and direction of the associations were consistent with the original GWAS. In subsequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. Promising candidate SNPs from GWAS were identified as modifiers of breast cancer risk in BRCA1 and BRCA2 carriers. Upon further validation, these SNPs together with other genetic and environmental factors may improve breast cancer risk assessment in these populations.

Authors: Xianshu Wang, V. Shane Pankratz, Zachary Fredericksen, Robert Tarrell, Mary Karaus, Lesley McGuffog, Paul D. P. Pharaoh, Bruce A. J. Ponder, Alison M. Dunning, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Olga M. Sinilnikova, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Claude Houdayer, Frans B. L. Hogervorst, Maartje J. Hooning, Marjolijn J. Ligtenberg, Amanda Spurdle, Georgia Chenevix-Trench, Rita K. Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Susan M. Domchek, Katherine L. Nathanson, Timothy R. Rebbeck, Christian F. Singer, Daphne Gschwantler-Kaulich, Catherina Dressler, Anneliese Fink, Csilla I. Szabo, Michal Zikan, Lenka Foretova, Kathleen Claes, Gilles Thomas, Robert N. Hoover, David J. Hunter, Stephen J. Chanock, Douglas F. Easton, Antonis C. Antoniou, Fergus J. Couch

Date Published: 15th Jul 2010

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Image-processing chain for a three-dimensional reconstruction of basal cell carcinomas.
ProstataCA

Abstract (Expand)

Basal cell carcinoma (BCC) is the most common malignant skin cancer. For a deeper insight into the specific growth patterns of the tumorous tissue in BCC, we have focused on the development of a novel … automated image-processing chain for 3D reconstruction of BCC using histopathological serial sections. For fully automatic delineation of the tumor within the tissue, we apply a fuzzy c-means segmentation method. We used a novel multi-grid form of the non-linear registration introduced by Braumann and Kuska in 2005 effectively suppressing registration runs into local minima (possibly caused by diffuse nature of the tumor). Our method was successfully applied in a proof-of-principle study for automated reconstruction.

Authors: P. Scheibe, U. D. Braumann, J. P. Kuska, M. Loffler, J. C. Simon, U. Paasch, T. Wetzig

Date Published: 1st Jul 2010

Publication Type: Not specified

Human Diseases: basal cell carcinoma

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

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