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The risk of contralateral breast cancer in patients from BRCA1/2 negative high risk families as compared to patients from BRCA1 or BRCA2 positive families: a retrospective cohort study
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

INTRODUCTION While it has been reported that the risk of contralateral breast cancer in patients from BRCA1 or BRCA2 positive families is elevated, little is known about contralateral breast cancer …r risk in patients from high risk families that tested negative for BRCA1/2 mutations. METHODS A retrospective, multicenter cohort study was performed from 1996 to 2011 and comprised 6,235 women with unilateral breast cancer from 6,230 high risk families that had tested positive for BRCA1 (n = 1,154) or BRCA2 (n = 575) mutations or tested negative (n = 4,501). Cumulative contralateral breast cancer risks were calculated using the Kaplan-Meier product-limit method and were compared between groups using the log-rank test. Cox regression analysis was applied to assess the impact of the age at first breast cancer and the familial history stratified by mutation status. RESULTS The cumulative risk of contralateral breast cancer 25 years after first breast cancer was 44.1% (95%CI, 37.6% to 50.6%) for patients from BRCA1 positive families, 33.5% (95%CI, 22.4% to 44.7%) for patients from BRCA2 positive families and 17.2% (95%CI, 14.5% to 19.9%) for patients from families that tested negative for BRCA1/2 mutations. Younger age at first breast cancer was associated with a higher risk of contralateral breast cancer. For women who had their first breast cancer before the age of 40 years, the cumulative risk of contralateral breast cancer after 25 years was 55.1% for BRCA1, 38.4% for BRCA2, and 28.4% for patients from BRCA1/2 negative families. If the first breast cancer was diagnosed at the age of 50 or later, 25-year cumulative risks were 21.6% for BRCA1, 15.5% for BRCA2, and 12.9% for BRCA1/2 negative families. CONCLUSIONS Contralateral breast cancer risk in patients from high risk families that tested negative for BRCA1/2 mutations is similar to the risk in patients with sporadic breast cancer. Thus, the mutation status should guide decision making for contralateral mastectomy.

Authors: Kerstin Rhiem, Christoph Engel, Monika Graeser, Silke Zachariae, Karin Kast, Marion Kiechle, Nina Ditsch, Wolfgang Janni, Christoph Mundhenke, Michael Golatta, Dominic Varga, Sabine Preisler-Adams, Tilman Heinrich, Ulrich Bick, Dorothea Gadzicki, Susanne Briest, Alfons Meindl, Rita K. Schmutzler

Date Published: 1st Dec 2012

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Pharmacokinetic and -dynamic modelling of G-CSF derivatives in humans
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnThe human granulocyte colony-stimulating factor (G-CSF) is routinely applied to support recovery of granulopoiesis during the course of cytotoxic chemotherapies. However, … optimal use of the drug is largely unknown. We showed in the past that a biomathematical compartment model of human granulopoiesis can be used to make clinically relevant predictions regarding new, yet untested chemotherapy regimen. In the present paper, we aim to extend this model by a detailed pharmacokinetic and -dynamic modelling of two commonly used G-CSF derivatives Filgrastim and Pegfilgrastim.\backslashr\backslashnRESULTS\backslashr\backslashnModel equations are based on our physiological understanding of the drugs which are delayed absorption of G-CSF when applied to the subcutaneous tissue, dose-dependent bioavailability, unspecific first order elimination, specific elimination in dependence on granulocyte counts and reversible protein binding. Pharmacokinetic differences between Filgrastim and Pegfilgrastim were modelled as different parameter sets. Our former cell-kinetic model of granulopoiesis was essentially preserved, except for a few additional assumptions and simplifications. We assumed a delayed action of G-CSF on the bone marrow, a delayed action of chemotherapy and differences between Filgrastim and Pegfilgrastim with respect to stimulation potency of the bone marrow. Additionally, we incorporated a model of combined action of Pegfilgrastim and Filgrastim or endogenous G-CSF which interact via concurrent receptor binding. Unknown pharmacokinetic or cell-kinetic parameters were determined by fitting the predictions of the model to available datasets of G-CSF applications, chemotherapy applications or combinations of it. Data were either extracted from the literature or were received from cooperating clinical study groups. Model predictions fitted well to both, datasets used for parameter estimation and validation scenarios as well. A unique set of parameters was identified which is valid for all scenarios considered. Differences in pharmacokinetic parameter estimates between Filgrastim and Pegfilgrastim were biologically plausible throughout.\backslashr\backslashnCONCLUSION\backslashr\backslashnWe conclude that we established a comprehensive biomathematical model to explain the dynamics of granulopoiesis under chemotherapy and applications of two different G-CSF derivatives. We aim to apply the model to a large variety of chemotherapy regimen in the future in order to optimize corresponding G-CSF schedules or to individualize G-CSF treatment according to the granulotoxic risk of a patient.

Authors: Markus Scholz, Sibylle Schirm, Marcus Wetzler, Christoph Engel, Markus Loeffler

Date Published: 1st Dec 2012

Publication Type: Journal article

Impact of age on the efficacy of bone marrow mononuclear cell transplantation in experimental stroke
Genetical Statistics and Systems Biology

Abstract (Expand)

Bone marrow-derived mononuclear cells (BM MNC) have been effectively used to treat experimental stroke. Most of the preclinical trials have been performed in young and healthy laboratory animals, even … though age and hypertension are major risk factors for stroke. To determine the influence of age on the properties of BM MNCs after cerebral ischemia, we compared the efficacy of aged and young BM MNC in an in vitro model of cerebral hypoxia and in an adapted in vivo model of stroke. Human BM MNCs were obtained from healthy young or aged donors and either co-cultured with rat hippocampal slices exposed to oxygen glucose deprivation (OGD), or transplanted intravenously 24 h after permanent middle cerebral artery occlusion in aged (18 months) spontaneously hypertensive rats (SHR). Efficacy was examined by quantification of hippocampal cell death, or respectively, by neurofunctional tests and MR investigations. Co-cultivation with young, but not with aged BM MNCs significantly reduced the hippocampal cell death after OGD. Transplantation of both young and old BM MNCs did not reduce functional deficits or ischemic lesion volume after stroke in aged SHR. These results suggest a significant impact of age on the therapeutic efficacy of BM MNCs after cerebral ischemia.

Authors: Daniel-Christoph Wagner, Mitja Bojko, Myriam Peters, Marlene Lorenz, Cornelia Voigt, Alexander Kaminski, Dirk Hasenclever, Markus Scholz, Alexander Kranz, Gesa Weise, Johannes Boltze

Date Published: 1st Dec 2012

Publication Type: Journal article

Manifest: Kundeninduzierte Orchestrierung komplexer Dienstleistungen - Gestaltung eines Paradigmenwechsels
Management of health information systems

Abstract

Not specified

Authors: Alfred Winter, Rainer Alt, Jan Ehmke, Reinhold Haux, Wolfram Ludwig, Dirk Mattfeld, Andreas Oberweis, Barbara Paech

Date Published: 1st Dec 2012

Publication Type: Journal article

Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002-1).
GLA - German Lymphoma Alliance

Abstract (Expand)

BACKGROUND: High-dose therapy (HDT) followed by transplantation of autologous haemopoietic stem cells is frequently done as part of first-line therapy in young patients with high-risk aggressive B-cell … lymphoma. We investigated whether HDT with cytotoxic agents identical to those used for conventional therapy followed by autologous stem-cell transplantation (ASCT) improved survival outcome compared with conventional chemotherapy when rituximab was added to both modalities. METHODS: We did an open-label, randomised trial comparing conventional chemotherapy (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone) and rituximab (R-CHOEP-14) with dose-escalated sequential HDT and rituximab (R-MegaCHOEP) followed by repetitive ASCT in high-risk (age-adjusted International Prognostic Index [IPI] 2 or 3) patients aged 18-60 years with aggressive B-cell lymphoma. Eligible patients received radiotherapy for bulky, extranodal disease, or both. Randomisation (1:1) used the Pocock minimisation algorithm; patients were stratified by age-adjusted IPI factors, bulky disease, and centre. The primary endpoint was event-free survival. All analyses were done on the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00129090. FINDINGS: 136 patients were randomly assigned to R-CHOEP-14 and 139 to R-MegaCHOEP. 130 patients in the R-CHOEP-14 group and 132 in the R-MegaCHOEP group were included in the intention-to-treat population. After a median of 42 months (IQR 29-59), 3-year event-free survival was 69.5% (95% CI 61.3-77.7) in the R-CHOEP-14 group and 61.4% (52.8-70.0) in the R-MegaCHOEP group (p=0.14; hazard ratio 1.3, 95% CI 0.9-2.0). All 128 evaluable patients treated with R-MegaCHOEP had grade 4 leucopenia, as did 48 (58.5%) of 82 patients with documented blood counts in the R-CHOEP-14 group. All 128 evaluable patients in the R-MegaCHOEP group had grade 3-4 thrombocytopenia, as did 26 (33.8%) of 77 patients in the R-CHOEP-14 group with documented blood counts. The most important non-haematological grade 3 or 4 adverse event was infection, which occurred in 96 (75.0%) of 128 patients treated with R-MegaCHOEP and in 40 (31.3%) of 128 patients treated with R-CHOEP-14. INTERPRETATION: In young patients with high-risk aggressive B-cell lymphoma, R-MegaCHOEP was not superior to conventional R-CHOEP therapy and was associated with significantly more toxic effects. R-CHOEP-14 with or without radiotherapy remains a treatment option for these patients, with encouraging efficacy. FUNDING: Deutsche Krebshilfe.

Authors: N. Schmitz, M. Nickelsen, M. Ziepert, M. Haenel, P. Borchmann, C. Schmidt, A. Viardot, M. Bentz, N. Peter, G. Ehninger, G. Doelken, C. Ruebe, L. Truemper, A. Rosenwald, M. Pfreundschuh, M. Loeffler, B. Glass

Date Published: 22nd Nov 2012

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma

BRCA1/2 testing: uptake, phenocopies, and strategies to improve detection rates in initially negative families
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

In families with clustering of breast and ovarian cancer, molecular testing of the major susceptibility genes BRCA1/2 helps to identify patients with disease mutations and healthy persons at high risk … who can participate in targeted intervention programs. We investigated 5559 families from the German Consortium for Hereditary Breast and Ovarian Cancer included between 1997 and 2008 and treated under clinical routine conditions. In each family an index patient/person had been screened for deleterious mutations in BRCA1/2. Healthy relatives agreed to predictive testing in 888 of 1520 BRCA1/2 mutation-positive families (58%). Of 2646 eligible unaffected first-degree relatives 1143 decided to be tested (43%). In 325 families with BRCA1/2-positive index patients one related BC/OC patient was tested and 39 (12.0%; 95% confidence interval: 8.7-16.0%) discrepant cases found. A second related individual was screened in 163 of 3388 (4.9%) families with BRCA1/2-negative index patient and in eight families a BRCA1/2 mutation was found. In BRCA1/2 mutation-positive families, BC/OC patients lacking the familial mutation have to be expected at a rather high rate. In families with BRCA1/2-negative index patient we recommend a second screening if another patient with a high probability of carrying a BRCA1/2 mutation is available.

Authors: C. Fischer, C. Engel, C. Sutter, S. Zachariae, R. Schmutzler, A. Meindl, S. Heidemann, T. Grimm, T. O. Goecke, I. Debatin, D. Horn, P. Wieacker, D. Gadzicki, K. Becker, D. Schäfer, F. Stock, T. Voigtländer

Date Published: 1st Nov 2012

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Automated photoplethysmography-based determination of ankle-brachial index: a validation study against Doppler sonography
Genetical Statistics and Systems Biology

Abstract (Expand)

INTRODUCTION\backslashr\backslashnDetermination of ankle-brachial-index (ABI) by manual Doppler is well established to screen for lower extremity arterial disease (LEAD) and to predict cardiovascular … risk. A new generation of digital-controlled devices promises automated ABI determination. The aim of this study was to determine comparability of automated photoplethysmography (PPG)-derived ABI calculation with the Doppler-ABI algorithm commonly used in cohort studies.\backslashr\backslashnMETHODS\backslashr\backslashnAutomated PPG-based ABI measurements [Vascular Explorer (VE) and Vicorder (VI)] were recorded from 112 limbs of healthy subjects and 22 limbs of patients with confirmed LEAD. Validity was evaluated on the basis of receiver-operating characteristic (ROC) analysis of clinical status and concordance with Doppler-ABI. Differences between cuff inflation [inf]- and deflation [def]-based method were studied in VE.\backslashr\backslashnRESULTS\backslashr\backslashnPPG-based ABI values were higher compared to Doppler-ABI (VI +0.06, VEinf +0.15, VEdef +0.09, p \textless 0.001, respectively). The difference was pronounced in pathological (\textless0.9), borderline (0.9-0.99) and low normal (1.0-1.09) ABI, but less in ABI \geq1.1. However, ROC analysis revealed excellent diagnostic value for LEAD (sensitivity/specificity) and comparable area under the curve at method-adapted ABI thresholds for all methods: Doppler (95/90 %, 0.95), VI (75/96 %, 0.91), VEinf (85/89 %, 0.93) and VEdef (80/98 %, 0.94).\backslashr\backslashnCONCLUSIONS\backslashr\backslashnDigital-controlled PPG-based ABI determination is a useful diagnostic application for LEAD. However, the systematic higher ABI in PPG-based measurement compared to Doppler and remarkable differences between the deflationary and inflationary method are critical for the interpretation of borderline and low normal ABI values where precise reading is essential to detect mild LEAD and subclinical disease and to predict cardiovascular risk. INTRODUCTION Determination of ankle-brachial-index (ABI) by manual Doppler is well established to screen for lower extremity arterial disease (LEAD) and to predict cardiovascular risk. A new generation of digital-controlled devices promises automated ABI determination. The aim of this study was to determine comparability of automated photoplethysmography (PPG)-derived ABI calculation with the Doppler-ABI algorithm commonly used in cohort studies. METHODS Automated PPG-based ABI measurements [Vascular Explorer (VE) and Vicorder (VI)] were recorded from 112 limbs of healthy subjects and 22 limbs of patients with confirmed LEAD. Validity was evaluated on the basis of receiver-operating characteristic (ROC) analysis of clinical status and concordance with Doppler-ABI. Differences between cuff inflation [inf]- and deflation [def]-based method were studied in VE. RESULTS PPG-based ABI values were higher compared to Doppler-ABI (VI +0.06, VEinf +0.15, VEdef +0.09, p \textless 0.001, respectively). The difference was pronounced in pathological (\textless0.9), borderline (0.9-0.99) and low normal (1.0-1.09) ABI, but less in ABI \geq1.1. However, ROC analysis revealed excellent diagnostic value for LEAD (sensitivity/specificity) and comparable area under the curve at method-adapted ABI thresholds for all methods: Doppler (95/90 %, 0.95), VI (75/96 %, 0.91), VEinf (85/89 %, 0.93) and VEdef (80/98 %, 0.94). CONCLUSIONS Digital-controlled PPG-based ABI determination is a useful diagnostic application for LEAD. However, the systematic higher ABI in PPG-based measurement compared to Doppler and remarkable differences between the deflationary and inflationary method are critical for the interpretation of borderline and low normal ABI values where precise reading is essential to detect mild LEAD and subclinical disease and to predict cardiovascular risk.

Authors: Frank Beutner, Andrej Teren, Stephan Gielen, Gerhard Schuler, Kerstin Wirkner, Daniel Tiller, Markus Loeffler, Markus Scholz

Date Published: 1st Nov 2012

Publication Type: Journal article

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