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959 Publications visible to you, out of a total of 959
Validation of the Manchester scoring system for predicting BRCA1/2 mutations in 9,390 families suspected of having hereditary breast and ovarian cancer.
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

The Manchester scoring system (MSS) allows the calculation of the probability for the presence of mutations in BRCA1 or BRCA2 genes in families suspected of having hereditary breast and ovarian cancer. … In 9,390 families, we determined the predictive performance of the MSS without (MSS-2004) and with (MSS-2009) consideration of pathology parameters. Moreover, we validated a recalibrated version of the MSS-2009 (MSS-recal). Families were included in the registry of the German Consortium for Hereditary Breast and Ovarian Cancer, using defined clinical criteria. Receiver operating characteristics (ROC) analysis was used to determine the predictive performance. The recalibrated model was developed using logistic regression analysis and tested using an independent random validation sample. The area under the ROC curves regarding a mutation in any of the two BRCA genes was 0.77 (95%CI 0.75-0.79) for MSS-2004, 0.80 (95%CI 0.78-0.82) for MSS-2009, and 0.82 (95%CI 0.80-0.83) for MSS-recal. Sensitivity at the 10% mutation probability cutoff was similar for all three models (MSS-2004 92.2%, MSS-2009 92.2%, and MSS-recal 90.3%), but specificity of MSS-recal (46.0%) was considerably higher than that of MSS-2004 (25.4%) and MSS-2009 (32.3%). In the MSS-recal model, almost all predictors of the original MSS were significantly predictive. However, the score values of some predictors, for example, high grade triple negative breast cancers, differed considerably from the originally proposed score values. The original MSS performed well in our sample of high risk families. The use of pathological parameters increased the predictive performance significantly. Recalibration improved the specificity considerably without losing much sensitivity.

Authors: K. Kast, R. K. Schmutzler, K. Rhiem, M. Kiechle, C. Fischer, D. Niederacher, N. Arnold, T. Grimm, D. Speiser, B. Schlegelberger, D. Varga, J. Horvath, M. Beer, S. Briest, A. Meindl, C. Engel

Date Published: 15th Nov 2014

Publication Type: Not specified

Human Diseases: breast cancer, ovarian cancer

Three gangliogliomas: results of GTG-banding, SKY, genome-wide high resolution SNP-array, gene expression and review of the literature.
Genetical Statistics and Systems Biology

Abstract (Expand)

According to the World Health Organization gangliogliomas are classified as well-differentiated and slowly growing neuroepithelial tumors, composed of neoplastic mature ganglion and glial cells. It is … the most frequent tumor entity observed in patients with long-term epilepsy. Comprehensive cytogenetic and molecular cytogenetic data including high-resolution genomic profiling (single nucleotide polymorphism (SNP)-array) of gangliogliomas are scarce but necessary for a better oncological understanding of this tumor entity. For a detailed characterization at the single cell and cell population levels, we analyzed genomic alterations of three gangliogliomas using trypsin-Giemsa banding (GTG-banding) and by spectral karyotyping (SKY) in combination with SNP-array and gene expression array experiments. By GTG and SKY, we could confirm frequently detected chromosomal aberrations (losses within chromosomes 10, 13 and 22; gains within chromosomes 5, 7, 8 and 12), and identify so far unknown genetic aberrations like the unbalanced non-reciprocal translocation t(1;18)(q21;q21). Interestingly, we report on the second so far detected ganglioglioma with ring chromosome 1. Analyses of SNP-array data from two of the tumors and respective germline DNA (peripheral blood) identified few small gains and losses and a number of copy-neutral regions with loss of heterozygosity (LOH) in germline and in tumor tissue. In comparison to germline DNA, tumor tissues did not show substantial regions with significant loss or gain or with newly developed LOH. Gene expression analyses of tumor-specific genes revealed similarities in the profile of the analyzed samples regarding different relevant pathways. Taken together, we describe overlapping but also distinct and novel genetic aberrations of three gangliogliomas.

Authors: L. X. Xu, H. Holland, H. Kirsten, P. Ahnert, W. Krupp, M. Bauer, R. Schober, W. Mueller, D. Fritzsch, J. Meixensberger, R. Koschny

Date Published: 8th Nov 2014

Publication Type: Journal article

Association of the apolipoprotein E genotype with memory performance and executive functioning in cognitively intact elderly.
LIFE Adult

Abstract (Expand)

OBJECTIVE: To test for a possible effect of the apolipoprotein E epsilon 4 (APOE epsilon4) allele on memory performance and executive functioning (EF) in cognitively intact elderly. METHOD: The authors … studied 202 randomly selected and cognitively intact older adults (65+ years) of the Leipzig Research Center for Civilization Diseases Health Care Study. Intact global cognitive functioning was defined using a Mini-Mental Status Examination (MMSE) score >/= 28. Performance in memory was assessed with the CERAD Word List and Constructional Praxis Recall, performance in EF with the Trail Making Test Part B (TMT-B). Multivariable linear regressions were used to evaluate the association between cognitive performance and APOE status, controlled for covariates. RESULTS: Among the cognitively intact older adults, 21.3% (n = 43) were carriers of the APOE epsilon4 allele. Carriers did not differ significantly from noncarriers in terms of age, gender, intelligence level, or performance in memory but showed a significantly lower TMT-B performance as a measure of EF (TMT-B M time/SD = 105.6/36.2 vs. 91.9/32.7 s; Mann-Whitney U = 4,313.000; p = .009). The association between lower TMT-B performance and APOE epsilon4 genotype remained significant in multivariable linear regression analysis. Similar findings were found for the subsample of those 78 elderly, who reached a perfect MMSE-score of 30. CONCLUSIONS: A lower EF performance in cognitively intact older APOE epsilon4 allele carriers might be related to an early Alzheimer's dementia (AD) prodrome. In this case, a stronger focus on first subtle changes in EF may help to improve early AD detection in those being at genetic risk.

Authors: T. Luck, F. S. Then, M. Luppa, M. L. Schroeter, K. Arelin, R. Burkhardt, J. Thiery, M. Loffler, A. Villringer, S. G. Riedel-Heller

Date Published: 4th Nov 2014

Publication Type: Not specified

Spatial Analysis of Anthropometric and Lifestyle Data for Children and Adolescents
LIFE Child

Abstract (Expand)

LIFE Child is an epidemiological cohort study at the Leipzig Research Center for Civilization Dis-eases (University of Leipzig). A main goal of LIFE Child is to study the influence of environment and … lifestyle factors to the development of children and adolescent in and near Leipzig. In particu-lar, we search for predominant aspects in the development of children with obesity. Typically, data is analyzed by different statistical methods and approaches to find (perhaps multi-variate) pre-dominant markers. Additionally, we map selected data to geographical maps to study their spatial distribution over urban districts of Leipzig, on the one hand. This allows to compara-tively analyze anthropometric measurements, such as age- and gender-corrected height, weight, and body mass index, together with further participant-related data including social indicators, e.g., in-come, education, socio economic indexes and lifestyle data, to distinguish city districts with a high correlation to those with low or no correlation. On the other hand, we associate anthropometric measurements with publicly available data, such as official statistics including district-specific un-employment rates and inhabitant densities by taking the participant's place of living into account. We developed a spatial analysis pipeline of anthropometric and lifestyle data according to Leipzig city districts. While cohort and publicly available data is managed by a database system, the analysis pipeline is implemented by dedicated R scripts. The sample is with more than 2,500 children large enough for first analyses. … Our first results show that unemployment of parents could be a factor for obesity of children especially in districts with low social index.

Authors: M. Vogel, A. Kiel, M. Rühle, Toralf Kirsten, M. Geserick, R. Gausche, G. Grande, D. Molis, U. Igel, S. Alvanides, W. Kiess

Date Published: 1st Nov 2014

Publication Type: Not specified

Data Quality Control and Data Analysis of Body-Scanner Measurement Values in Children and Adolescents
LIFE Child

Abstract (Expand)

Introduction LIFE child as a part of the 'Leipzig Research Centre for Civilization Diseases' is a longitudinal cohort study aiming, inter alia, at monitoring normal development in children and … adolescents from fetal life to adulthood. As an important part of the study, anthropometric dimensions are measured via classic methods, e.g. stadiometer or tape measure (ca. 15 items), but also via 3D body scanner technology (ca. 150 items). Because of missing standards data quality control and analysis of the latter one is a particular challenge. Methods We address the problem of absent reference values by using the data itself as a reference sample. Applying the LMS-method using the VGAM/GAMLSS packages [XXX] on a reference sample which is large enough results in age and gender corrected standard deviation scores (SDS) respectively percentile curves. A combination of variable clustering and clustering of values using these SDS is applied to the detect groups of dependend variables and peculiar cases respectively. Results In LIFE child the current reference sample consists of around 4000 scans of 1700 children. The age dependend l, m, and s values for each item are generated by dedicated R-routines and stored in a relational database system. The transformation algorithm by Cole is implemented as database function and dynamically applied on all associated raw data. Conspiciuous values can be detected using the SDS itself or the SDS in comparison with the belonging variable cluster and/or taking into account the follow-up data of the respective participant. These values can be reported and visualized using automated routines.

Authors: M. Vogel, A.L. Fischer, C. Bucher, W. Kiess, Toralf Kirsten

Date Published: 1st Nov 2014

Publication Type: Not specified

Molecular characterization of long-term survivors of glioblastoma using genome- and transcriptome-wide profiling.
GGN - German Glioma Network

Abstract (Expand)

The prognosis of glioblastoma, the most malignant type of glioma, is still poor, with only a minority of patients showing long-term survival of more than three years after diagnosis. To elucidate the … molecular aberrations in glioblastomas of long-term survivors, we performed genome- and/or transcriptome-wide molecular profiling of glioblastoma samples from 94 patients, including 28 long-term survivors with >36 months overall survival (OS), 20 short-term survivors with <12 months OS and 46 patients with intermediate OS. Integrative bioinformatic analyses were used to characterize molecular aberrations in the distinct survival groups considering established molecular markers such as isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations, and O(6) -methylguanine DNA methyltransferase (MGMT) promoter methylation. Patients with long-term survival were younger and more often had IDH1/2-mutant and MGMT-methylated tumors. Gene expression profiling revealed over-representation of a distinct (proneural-like) expression signature in long-term survivors that was linked to IDH1/2 mutation. However, IDH1/2-wildtype glioblastomas from long-term survivors did not show distinct gene expression profiles and included proneural, classical and mesenchymal glioblastoma subtypes. Genomic imbalances also differed between IDH1/2-mutant and IDH1/2-wildtype tumors, but not between survival groups of IDH1/2-wildtype patients. Thus, our data support an important role for MGMT promoter methylation and IDH1/2 mutation in glioblastoma long-term survival and corroborate the association of IDH1/2 mutation with distinct genomic and transcriptional profiles. Importantly, however, IDH1/2-wildtype glioblastomas in our cohort of long-term survivors lacked distinctive DNA copy number changes and gene expression signatures, indicating that other factors might have been responsible for long survival in this particular subgroup of patients.

Authors: G. Reifenberger, R. G. Weber, V. Riehmer, K. Kaulich, E. Willscher, H. Wirth, J. Gietzelt, B. Hentschel, M. Westphal, M. Simon, G. Schackert, J. Schramm, J. Matschke, M. C. Sabel, D. Gramatzki, J. Felsberg, C. Hartmann, J. P. Steinbach, U. Schlegel, W. Wick, B. Radlwimmer, T. Pietsch, J. C. Tonn, A. von Deimling, H. Binder, M. Weller, M. Loeffler

Date Published: 15th Oct 2014

Publication Type: Not specified

Human Diseases: brain glioma

Vitamin D deficiency impairs rituximab-mediated cellular cytotoxicity and outcome of patients with diffuse large B-cell lymphoma treated with but not without rituximab.
GLA - German Lymphoma Alliance

Abstract (Expand)

PURPOSE: To investigate the impact and mechanisms of vitamin D deficiency (VDD) on the outcome of elderly patients with diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: Three hundred … fifty-nine pretreatment 25-hydroxyvitamin D3 (25[OH]D3) serum levels from the RICOVER-60 study (Six Versus Eight Cycles of Biweekly CHOP-14 With or Without Rituximab in Elderly Patients With Aggressive CD20+ B-Cell Lymphomas) and 63 from the RICOVER-noRTh study (an amendment to the RICOVER-60 study in which patients received six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone administered at an interval of 2 weeks plus two cycles of rituximab [R-CHOP-14], but without radiotherapy) were determined by chemoluminescent immunoassay. Rituximab-mediated cellular cytotoxicity (RMCC) was assessed by lactate dehydrogenase release assay of CD20+ Daudi cells. RESULTS: RICOVER-60 patients with VDD (</= 8 ng/mL) and vitamin D levels more than 8 ng/mL treated with rituximab had 3-year event-free survival (EFS) of 59% and 79% and 3-year overall survival (OS) of 70% and 82%, respectively. These differences were significant in a multivariable analysis adjusting for International Prognostic Index risk factors with a hazard ratio (HR) of 2.1 (P = .008) for EFS and 1.9 (P = .040) for OS. EFS was not significantly different in patients with vitamin D levels </= 8 or more than 8 ng/mL (HR, 1.2; P = .388) treated without rituximab. This was confirmed in an independent validation set of 63 RICOVER-noRTh patients. RMCC increased significantly (P < .001) in seven of seven individuals with VDD after substitution and normalization of their vitamin D levels. CONCLUSION: VDD is a risk factor for elderly patients with DLBCL treated with R-CHOP. That VDD impairs RMCC and substitution improves RMCC strongly suggests that vitamin D substitution enhances rituximab efficacy, which must be confirmed in appropriately designed prospective trials addressing VDD and substitution not only in DLBCL, but also in malignancies treated with other antibodies, of which the major mechanism of action is antibody-dependent cellular cytotoxicity (eg, trastuzumab in breast cancer and cetuximab in colorectal cancer).

Authors: J. T. Bittenbring, F. Neumann, B. Altmann, M. Achenbach, J. Reichrath, M. Ziepert, J. Geisel, E. Regitz, G. Held, M. Pfreundschuh

Date Published: 10th Oct 2014

Publication Type: Not specified

Human Diseases: diffuse large B-cell lymphoma

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