Sorafenib prevents human retinal pigment epithelium cells from light-induced overexpression of VEGF, PDGF and PlGF

Background Cumulative light exposure is significantly associated with progression of age-related macular degeneration (AMD). Inhibition of vascular endothelial growth factor is the main target of current antiangiogenic treatment strategies in AMD. However, other growth factors, such as platelet-derived growth factor (PDGF) and placenta growth factor (PlGF), have a substantial impact on development of AMD. Previous reports indicate that sorafenib, an oral multikinase inhibitor, might have beneficial effects on exudative AMD. This study investigates the effects of sorafenib on light-induced overexpression of growth factors in human retinal pigment epithelial (RPE) cells. Methods Primary human RPE cells were exposed to white light and incubated with sorafenib. Viability, expression, and secretion of VEGF-A, PDGF-BB, and PlGF and their mRNA were determined by reverse transcription-polymerase chain reactions, immunohistochemistry and enzyme-linked immunosorbent assays. Results Light exposure decreased cell viability and increased expression and secretion of VEGF-A, PDGF-BB and PlGF. These light-induced effects were significantly reduced when cells were treated with sorafenib at a dose of 1 mu g/ml. Conclusion The results show that sorafenib has promising properties as a potential antiangiogenic treatment for AMD

Validation of the prognostic relevance of plasma C-reactive protein levels in soft-tissue sarcoma patients

Background: The concept of the involvement of systemic inflammation in cancer progression and metastases has gained attraction within the past decade. C-reactive protein (CRP), a non-specific blood-based marker of the systemic inflammatory response, has been associated with decreased survival in several cancer types. The aim of the present study was to validate the prognostic value of pre-operative plasma CRP levels on clinical outcome in a large cohort of soft-tissue sarcoma (STS) patients. Methods: Three hundred and four STS patients, operated between 1998 and 2010, were retrospectively evaluated. CRP levels and the impact on cancer-specific survival (CSS), disease-free survival (DFS) and overall survival (OS) were assessed using Kaplan–Meier curves and univariate as well as multivariate Cox proportional models. Additionally, we developed a nomogram by supplementing the plasma CRP level to the well-established Kattan nomogram and evaluated the improvement of predictive accuracy of this novel nomogram by applying calibration and Harrell’s concordance index (c-index). Results: An elevated plasma CRP level was significantly associated with established prognostic factors, including age, tumour grade, size and depth (P<0.05). In multivariate analysis, increased CRP levels were significantly associated with a poor outcome for CSS (HR=2.05; 95% CI=1.13–3.74; P=0.019) and DFS (HR=1.88; 95% CI=1.07–3.34; P=0.029). The estimated c-index was 0.74 using the original Kattan nomogram and 0.77 when the plasma CRP level was added. Conclusion: An elevated pre-operative CRP level represents an independent prognostic factor that predicts poor prognosis and improves the predictive ability of the Kattan nomogram in STS patients. Our data suggest to further prospectively validate its potential utility for individual risk stratification and clinical management of STS patients

Clonality Assessment in a Case of Multifocal Adamantinoma and a Review of the Literature

Adamantinoma is a low-grade, malignant biphasic bone tumour predominantly located in the tibia. In up to 50% of all cases this is combined with one or more lesions in the ipsilateral fibula. Whether these lesions represent regional metastases or arise de novo is not yet exactly known. In order to address this question, we extracted DNA from the respective fresh frozen tumour tissues in a case of a young woman with a multifocal adamantinoma of both the tibia and ipsilateral fibula. Afterwards the X inactivation pattern was studied by means of methylation-sensitive polymerase chain reaction and primers that target the polymorphic CGG trinucleotide repeat of FMR1 gene and the polymorphic CAG repeat, on exon 1 of the human androgen receptor gene (AR). The analysis of the AR was homozygous and not informative. Studying the FMR1 gene, we detected a 100% skewing of the X inactivation pattern of both locations and found that the same allele was methylated. Even if the fibula lesion arose de novo there would have been a 50 : 50 chance that the same allele was methylated. As this methylation pattern was found we cannot provide a valid explanation for the origin of the fibula lesion. Analysis of X inactivation patterns in future cases of polyfocal adamantinoma might provide further evidence for one of the two theories

General population normative data for the EORTC QLQ-C30 health-related quality of life questionnaire based on 15,386 persons across 13 European countries, Canada and the Unites States

OBJECTIVE: The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 health-related quality of life questionnaire is one of the most widely used cancer-specific health-related quality of life questionnaires worldwide. General population norm data can facilitate the interpretation of QLQ-C30 data obtained from cancer patients. This study aimed at systematically collecting norm data from the general population to develop European QLQ-C30 norm scores and to generate comparable norm data for individual countries in Europe and North America. METHODS: We collected QLQ-C30 data from the general population across 11 European Union (EU) countries, Russia, Turkey, Canada and United States (n \u3e /= 1000/country). Representative samples were stratified by sex and age groups (18-39, 40-49, 50-59, 60-69 and \u3e /= 70 years). After applying weights based on the United Nations population distribution statistics, we calculated QLQ-C30 domain scores to generate a \u27European QLQ-C30 Norm\u27 based on the EU countries. Further, we calculated QLQ-C30 norm scores for all 15 individual countries. RESULTS: A total of 15,386 respondents completed the online survey. For the EU sample, most QLQ-C30 domains showed differences by sex/age, with men scoring somewhat better health than women, while age effects varied across domains. Substantially larger differences were seen in inter-country comparisons, with Austrian and Dutch respondents reporting consistently better health compared with British and Polish respondents. CONCLUSIONS: This study is the first to systematically collect EORTC QLQ-C30 general population norm data across Europe and North America applying a consistent data collection method across 15 countries. These new norm data facilitate valid intra-country as well as inter-country comparisons and QLQ-C30 score interpretation

Establishing the European Norm for the health-related quality of life domains of the computer-adaptive test EORTC CAT Core

OBJECTIVE: The computer-adaptive test (CAT) of the European Organisation for Research and Treatment of Cancer (EORTC), the EORTC CAT Core, assesses the same 15 domains as the EORTC QLQ-C30 health-related quality of life questionnaire but with increased precision, efficiency, measurement range and flexibility. CAT parameters for estimating scores have been established based on clinical data from cancer patients. This study aimed at establishing the European Norm for each CAT domain based on general population data. METHODS: We collected representative general population data across 11 European Union (EU) countries, Russia, Turkey, Canada and the United States (n \u3e /= 1000/country; stratified by sex and age). We selected item subsets from each CAT domain for data collection (totalling 86 items). Differential item functioning (DIF) analyses were conducted to investigate cross-cultural measurement invariance. For each domain, means and standard deviations from the EU countries (weighted by country population, sex and age) were used to establish a T-metric with a European general population mean = 50 (standard deviation = 10). RESULTS: A total of 15,386 respondents completed the online survey (n = 11,343 from EU countries). EORTC CAT Core norm scores for all 15 countries were calculated. DIF had negligible impact on scoring. Domain-specific T-scores differed significantly across countries with small to medium effect sizes. CONCLUSION: This study establishes the official European Norm for the EORTC CAT Core. The European CAT Norm can be used globally and allows for meaningful interpretation of scores. Furthermore, CAT scores can be compared with sex- and age-adjusted norm scores at a national level within each of the 15 countries

Item response theory assumptions were adequately met by the Oxford hip and knee scores

Objectives: To develop item response theory (IRT) models for the Oxford hip and knee scores which convert patient responses into continuous scores with quantifiable precision and provide these as web applications for efficient score conversion. Study Design and Setting: Data from the National Health Service patient-reported outcome measures program were used to test the assumptions of IRT (unidimensionality, monotonicity, local independence, and measurement invariance) before fitting models to preoperative response patterns obtained from patients undergoing primary elective hip or knee arthroplasty. The hip and knee datasets contained 321,147 and 355,249 patients, respectively. Results: Scree plots, Kaiser criterion analyses, and confirmatory factor analyses confirmed unidimensionality and Mokken analysis confirmed monotonicity of both scales. In each scale, all item pairs shared a residual correlation of ≤ 0.20. At the test level, both scales showed measurement invariance by age and gender. Both scales provide precise measurement in preoperative settings but demonstrate poorer precision and ceiling effects in postoperative settings. Conclusion: We provide IRT parameters and web applications that can convert Oxford Hip Score or Oxford Knee Score response sets into continuous measurements and quantify individual measurement error. These can be used in sensitivity analyses or to administer truncated and individualized computerized adaptive tests