Publications

958 Publications visible to you, out of a total of 958

Abstract (Expand)

BACKGROUND Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes BRCA1 and BRCA2 is essential for appropriate genetic counselling of individuals carryingg these variants. We previously showed that variant BRCA1 c.5096G\textgreaterA p.Arg1699Gln in the BRCA1 transcriptional transactivation domain demonstrated equivocal results from a series of functional assays, and proposed that this variant may confer low to moderate risk of cancer. METHODS Measures of genetic risk (report of family history, segregation) were assessed for 68 BRCA1 c.5096G\textgreaterA p.Arg1699Gln (R1699Q) families recruited through family cancer clinics, comparing results with 34 families carrying the previously classified pathogenic BRCA1 c.5095C\textgreaterT p.Arg1699Trp (R1699W) mutation at the same residue, and to 243 breast cancer families with no BRCA1 pathogenic mutation (BRCA-X). RESULTS Comparison of BRCA1 carrier prediction scores of probands using the BOADICEA risk prediction tool revealed that BRCA1 c.5096G\textgreaterA p.Arg1699Gln variant carriers had family histories that were less ’BRCA1-like’ than BRCA1 c.5095C\textgreaterT p.Arg1699Trp mutation carriers (p\textless0.00001), but more ’BRCA1-like’ than BRCA-X families (p=0.0004). Further, modified segregation analysis of the subset of 30 families with additional genotyping showed that BRCA1 c.5096G \textgreaterA p.Arg1699Gln had reduced penetrance compared with the average truncating BRCA1 mutation penetrance (p=0.0002), with estimated cumulative risks to age 70 of breast or ovarian cancer of 24%. CONCLUSIONS Our results provide substantial evidence that the BRCA1 c.5096G\textgreaterA p.Arg1699Gln (R1699Q) variant, demonstrating ambiguous functional deficiency across multiple assays, is associated with intermediate risk of breast and ovarian cancer, highlighting challenges for risk modelling and clinical management of patients of this and other potential moderate-risk variants.

Authors: Amanda B. Spurdle, Phillip J. Whiley, Bryony Thompson, Bingjian Feng, Sue Healey, Melissa A. Brown, Christopher Pettigrew, Christi J. van Asperen, Margreet G. E. M. Ausems, Anna A. Kattentidt-Mouravieva, Ans M. W. van den Ouweland, Annika Lindblom, Maritta H. Pigg, Rita K. Schmutzler, Christoph Engel, Alfons Meindl, Sandrine Caputo, Olga M. Sinilnikova, Rosette Lidereau, Fergus J. Couch, Lucia Guidugli, Thomas Overeem van Hansen, Mads Thomassen, Diana M. Eccles, Kathy Tucker, Javier Benitez, Susan M. Domchek, Amanda E. Toland, Elizabeth J. van Rensburg, Barbara Wappenschmidt, Åke Borg, Maaike P. G. Vreeswijk, David E. Goldgar

Date Published: 12th Aug 2012

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Abstract (Expand)

Double heterozygosity for disease-causing BRCA1 and BRCA2 mutations is a very rare condition in most populations. Here we describe genetic and clinical data of eight female double heterozygotes (DH) for BRCA1 and BRCA2 mutations found in a cohort of 8162 German breast/ovarian cancer families and compare it with the data of their single heterozygous relatives and of the index patients of the German Consortium for Hereditary Breast and Ovarian Cancer. Furthermore, we analyze the phenotypic features of these patients with respect to age at onset of first cancer, first breast/ovarian cancer and the number of disease manifestations and compare them to that of published Caucasian female DHs and their single heterozygous female relatives. German DHs were not significantly younger at diagnosis of first breast cancer than the single heterozygous index patients of the German Consortium. However, if the data of our study were pooled with that of the literature, DHs were substantially younger at onset of first cancer (mean age 40.4 years, 95 % CI = 36.6-44.1) than their single heterozygous female relatives (mean age 51.9 years, 95 % CI = 46.8-57.0). The two groups also differed concerning the onset of first breast cancer (mean age 40.6 years, 95 % CI = 36.6-44.5 vs. 52.6, 95 % CI = 47.5-57.6). In addition, DHs had a more severe disease than their female relatives carrying a single BRCA mutation (1.4 vs. 0.6 manifestations per person). In contrast to Ashkenazi Jewish females, Caucasian DH females might develop breast cancer at an earlier age and have a more severe disease than single heterozygous BRCA mutation carriers. Therefore, DHs may benefit from more intensive surveillance programs/follow-up care and prophylactic surgery.

Authors: Simone Heidemann, Christine Fischer, Christoph Engel, Barbara Fischer, Lana Harder, Brigitte Schlegelberger, Dieter Niederacher, Timm O. Goecke, Sandra C. Doelken, Nicola Dikow, Walter Jonat, Susanne Morlot, Rita C. Schmutzler, Norbert K. Arnold

Date Published: 1st Aug 2012

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Abstract (Expand)

In this article, a new surgical model for evaluating telemanipulators used in middle ear surgery is presented. The purpose of this work was to develop an evaluation and training system which imitates a typical surgical task of middle ear surgery and which can easily be repeated in order to get significant result. The abstract task can be performed manually or by means of a microsurgical telemanipulator and guaranties stable experimental conditions between different subjects at any time. As a task the stapedotomy was chosen, due to the high demands in positioning and in applying forces to the delicate structures in the middle ear. The manual and telemanipulated performance of 15 ENT surgeons and 17 medical students was compared using this evaluation and training system. In this article, a new surgical model for evaluating telemanipulators used in middle ear surgery is presented. The purpose of this work was to develop an evaluation and training system which imitates a typical surgical task of middle ear surgery and which can easily be repeated in order to get significant result. The abstract task can be performed manually or by means of a microsurgical telemanipulator and guaranties stable experimental conditions between different subjects at any time. As a task the stapedotomy was chosen, due to the high demands in positioning and in applying forces to the delicate structures in the middle ear. The manual and telemanipulated performance of 15 ENT surgeons and 17 medical students was compared using this evaluation and training system.

Authors: Thomas Maier, Gero Strauss, Markus Scholz, Thomas Berger, Anne Kielhorn, Konrad Entsfellner, Christian Willim, Wolfgang Buscher, Andreas Dietz, Tim C. Lueth

Date Published: 1st Aug 2012

Publication Type: Journal article

Abstract (Expand)

PURPOSE: Peripheral T-cell non-Hodgkin lymphomas (T-NHL) represent a small but heterogeneous and clinically aggressive subset of NHLs with a poor outcome. Cytokines or their receptors might be associated with the clinical outcome of these lymphomas. Therefore, we tested whether gene variations and serum levels of soluble TNF receptor (TNFR)I (sTNFRI), sTNFRII, interleukin (IL)-10, or sIL-4R are predictive for treatment response in T-NHLs. EXPERIMENTAL DESIGN: Peripheral blood DNA from 117 patients with T-NHL treated in prospective clinical trials was subjected to genotyping analysis. Whenever possible, pretreatment sera were obtained, and circulating levels of sTNFRI, sTNFRII, IL-10, and sIL-4R were determined with a specific capture enzyme-linked immunoassay. RESULTS: Patients characterized by TNFRI-609GG (rs4149570) showed a trend toward better event free survival [EFS; univariate: P = 0.041; multivariate: HR, 1.76; confidence interval (CI), 0.99-3.14 with P = 0.056]. A protective role of IL-10-1087A, -824T, and -597A reported in another study was not confirmed in our cohort. Patients with circulating levels of soluble TNFRII >/=2.16 ng/mL had a 2.07-fold increased relative risk for shorter overall survival (OS; univariate: P = 0.0034; multivariate: HR, 2.07; CI, 0.92-4.70 with P = 0.081) and a 2.49-fold higher risk for shorter EFS (univariate: P = 0.00068; multivariate: HR, 2.49; CI, 1.22-5.08 with P = 0.012). Elevations of circulating levels of sTNFRI, IL-10, and sIL-4R are frequent, but the clinical response in these patients is not significantly different. CONCLUSIONS: Our findings suggest a critical role for TNF-TNFR signaling for the clinical outcome of patients with peripheral T-NHLs.

Authors: C. Heemann, M. Kreuz, I. Stoller, N. Schoof, F. von Bonin, M. Ziepert, M. Loffler, W. Jung, M. Pfreundschuh, L. Trumper, D. Kube

Date Published: 1st Jul 2012

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma

Abstract (Expand)

BACKGROUND: Analysis of clinical studies often necessitates multiple graphical representations of the results. Many professional software packages are available for this purpose. Most packages are either only commercially available or hard to use especially if one aims to generate or customize a huge number of similar graphical outputs. We developed a new, freely available software tool called KMWin (Kaplan-Meier for Windows) facilitating Kaplan-Meier survival time analysis. KMWin is based on the statistical software environment R and provides an easy to use graphical interface. Survival time data can be supplied as SPSS (sav), SAS export (xpt) or text file (dat), which is also a common export format of other applications such as Excel. Figures can directly be exported in any graphical file format supported by R. RESULTS: On the basis of a working example, we demonstrate how to use KMWin and present its main functions. We show how to control the interface, customize the graphical output, and analyse survival time data. A number of comparisons are performed between KMWin and SPSS regarding graphical output, statistical output, data management and development. Although the general functionality of SPSS is larger, KMWin comprises a number of features useful for survival time analysis in clinical trials and other applications. These are for example number of cases and number of cases under risk within the figure or provision of a queue system for repetitive analyses of updated data sets. Moreover, major adjustments of graphical settings can be performed easily on a single window. CONCLUSIONS: We conclude that our tool is well suited and convenient for repetitive analyses of survival time data. It can be used by non-statisticians and provides often used functions as well as functions which are not supplied by standard software packages. The software is routinely applied in several clinical study groups.

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

Date Published: 23rd Jun 2012

Publication Type: Not specified

Abstract (Expand)

CONTEXT: Early appropriate antimicrobial therapy leads to lower mortality rates associated with severe sepsis. The role of empirical combination therapy comprising at least 2 antibiotics of different mechanisms remains controversial. OBJECTIVE: To compare the effect of moxifloxacin and meropenem with the effect of meropenem alone on sepsis-related organ dysfunction. DESIGN, SETTING, AND PATIENTS: A randomized, open-label, parallel-group trial of 600 patients who fulfilled criteria for severe sepsis or septic shock (n = 298 for monotherapy and n = 302 for combination therapy). The trial was performed at 44 intensive care units in Germany from October 16, 2007, to March 23, 2010. The number of evaluable patients was 273 in the monotherapy group and 278 in the combination therapy group. INTERVENTIONS: Intravenous meropenem (1 g every 8 hours) and moxifloxacin (400 mg every 24 hours) or meropenem alone. The intervention was recommended for 7 days and up to a maximum of 14 days after randomization or until discharge from the intensive care unit or death, whichever occurred first. MAIN OUTCOME MEASURE: Degree of organ failure (mean of daily total Sequential Organ Failure Assessment [SOFA] scores over 14 days; score range: 0-24 points with higher scores indicating worse organ failure); secondary outcome: 28-day and 90-day all-cause mortality. Survivors were followed up for 90 days. RESULTS: Among 551 evaluable patients, there was no statistically significant difference in mean SOFA score between the meropenem and moxifloxacin group (8.3 points; 95% CI, 7.8-8.8 points) and the meropenem alone group (7.9 points; 95% CI, 7.5-8.4 points) (P = .36). The rates for 28-day and 90-day mortality also were not statistically significantly different. By day 28, there were 66 deaths (23.9%; 95% CI, 19.0%-29.4%) in the combination therapy group compared with 59 deaths (21.9%; 95% CI, 17.1%-27.4%) in the monotherapy group (P = .58). By day 90, there were 96 deaths (35.3%; 95% CI, 29.6%-41.3%) in the combination therapy group compared with 84 deaths (32.1%; 95% CI, 26.5%-38.1%) in the monotherapy group (P = .43). CONCLUSION: Among adult patients with severe sepsis, treatment with combined meropenem and moxifloxacin compared with meropenem alone did not result in less organ failure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00534287.

Authors: F. M. Brunkhorst, M. Oppert, G. Marx, F. Bloos, K. Ludewig, C. Putensen, A. Nierhaus, U. Jaschinski, A. Meier-Hellmann, A. Weyland, M. Grundling, O. Moerer, R. Riessen, A. Seibel, M. Ragaller, M. W. Buchler, S. John, F. Bach, C. Spies, L. Reill, H. Fritz, M. Kiehntopf, E. Kuhnt, H. Bogatsch, C. Engel, M. Loeffler, M. H. Kollef, K. Reinhart, T. Welte

Date Published: 13th Jun 2012

Publication Type: Not specified

Human Diseases: bacterial infectious disease

Abstract (Expand)

In patients with chronic hepatitis C virus (HCV) infection, several variants of the interleukin-28B (IL28B) gene have been shown to correlate significantly with a sustained virologic response (SVR). Recent evidence shows that determination of one single IL28B polymorphism, rs12979860, is sufficient for predicting treatment outcome. We examined whether the combined determination of the IL28B single-nucleotide polymorphisms (SNPs), rs12979860, rs8099917, rs12980275, and rs8103142, might improve the prediction of SVR in patients with HCV. In the study cohort, 54% of 942 patients with chronic HCV type 1 infection had SVR. The IL28B SNPs, rs12979860CC and rs8099917TT, correlated significantly with SVR (68% and 62%). The SNPs, rs12980275 and rs8103142, were in strong linkage disequilibrium with rs12979860 and were not included in further analysis. In homozygous carriers of the rs12979860 responder allele C, additional genotyping of the rs8099917 SNP had no effect on response prediction, whereas in carriers of the rs12979860 nonresponder allele, the rs8099917 SNP improved the response prediction. In heterozygous carriers of the rs12979860 nonresponder T allele, SVR rates were 55% in the presence of the rs8099917TT genotype and 40% in patients carrying the rs8099917 TG or GG genotype. Analysis of an independent confirmation cohort of 377 HCV type 1-infected patients verified the significant difference in SVR rates between the combined genotypes, rs12979860CT/rs8099917TT and rs12979860CT/rs8099917TG (38% versus 21%; P = 0.018). Conclusion: Treatment outcome prediction could not be improved in homozygous carriers of the IL28B rs12979860 C responder allele by the additional determination of the rs8099917 SNP. There is evidence that a significant proportion of heterozygous carriers of the rs12979860 T nonresponder allele can profit with respect to SVR prediction by further determination of the rs8099917 SNP. (HEPATOLOGY 2012;55:1700-1710).

Authors: Janett Fischer, Stephan Böhm, Markus Scholz, Tobias Müller, Heiko Witt, Jacob George, Christoph Sarrazin, Simone Susser, Eckart Schott, Vijayaprakash Suppiah, David R. Booth, Graeme J. Stewart, Florian van Bömmel, Annika Brodzinski, Balazs Fülöp, Pascal Migaud, Thomas Berg

Date Published: 1st Jun 2012

Publication Type: Journal article

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