Bauerschlag D.O.,RWTH Aachen |
Schem C.,University of Kiel |
Weigel M.T.,University of Kiel |
Von Kaisenberg C.,Leibniz University of Hanover |
And 4 more authors.
Journal of Cancer Research and Clinical Oncology
Introduction: In advanced ovarian cancers (OCs), p53 mutations are frequently observed. The objective of this study was to explore the value of the p53 mutational status, using four different techniques, in advanced OC patients as a predictive marker for responsiveness to platinum-based chemotherapy. Methods: One hundred and four, mostly serous papillary OC specimens were analyzed, of which all received a platinum containing chemotherapy after optimal cyto-reductive surgery. To verify the p53 mutational status, immunohistochemical staining with monoclonal antibodies, functional yeast assay (FASAY), single-strand conformation polymorphism analysis (SSCP) and genomic sequencing was performed in parallel. Results: Out of ten OC patients [2 low malignant potential (LMP)/8 G1] only two had a mutant p53, whereas eight showed a wild-type p53. 40 out of 63 (G2/3) patients with G2/3 OC showed mutant p53 and 23 patients showed a wild-type pattern. p53 status was significantly different between these two groups (LMP/G1 vs. G2/3) (P = 0.015). A progressive disease after chemotherapy completion was noted in 35.6% of the patients (26 out of 73); in 69.2%, a mutated p53 and in 30.8%, a wild-type p53 was found. Nine (12.3%) patients showed a complete response at the end of the first-line chemotherapy. Out of these nine patients five had a mutated and four a wild-type p53. A partial response was observed in nine (12.3%) patients of whom four had a mutated p53. With respect to response to first-line chemotherapy (six cycles of platinum containing regimen), the p53 status was not predictive; no statistical significance regarding the p53 mutational status was observed when the two extreme groups PD versus PR/CR were compared (P > 0.05). Conclusion: In this study, the p53 mutational status was not predictive for responsiveness to platinum-based chemotherapy; but p53 was significantly more frequently mutated in poorly differentiated OCs. © 2009 Springer-Verlag. Source
Scagliotti G.V.,University of Turin |
Pastorino U.,Italian National Cancer Institute |
Vansteenkiste J.F.,University Hospital Gasthuisberg |
Spaggiari L.,Italian National Cancer Institute |
And 7 more authors.
Journal of Clinical Oncology
Purpose: This study aimed to determine whether three preoperative cycles of gemcitabine plus cisplatin followed by radical surgery provides a reduction in the risk of progression compared with surgery alone in patients with stages IB to IIIA non-small-cell lung cancer (NSCLC). Patients and Methods: Patients with chemotherapy-naive NSCLC (stages IB, II, or IIIA) were randomly assigned to receive either three cycles of gemcitabine 1,250 mg/m2 days 1 and 8 every 3 weeks plus cisplatin 75 mg/m2 day 1 every 3 weeks followed by surgery, or surgery alone. Randomization was stratified by center and disease stage (IB/IIA v IIB/IIIA). The primary end point was progression-free survival (PFS). Results: The study was prematurely closed after the random assignment of 270 patients: 129 to chemotherapy plus surgery and 141 to surgery alone. Median age was 61.8 years and 83.3% were male. Slightly more patients in the surgery alone arm had disease stage IB/IIA (55.3% v 48.8%). The chemotherapy response rate was 35.4%. The hazard ratios for PFS and overall survival were 0.70 (95% CI, 0.50 to 0.97; P = .003) and 0.63 (95% CI, 0.43 to 0.92; P = .02), respectively, both in favor of chemotherapy plus surgery. A statistically significant impact of preoperative chemotherapy on outcomes was observed in the stage IIB/IIIA subgroup (3-year PFS rate: 36.1% v 55.4%; P = .002). The most common grade 3 or 4 chemotherapy-related adverse events were neutropenia and thrombocytopenia. No treatment-by-histology interaction effect was apparent. Conclusion: Although the study was terminated early, preoperative gemcitabine plus cisplatin followed by radical surgery improved survival in patients with clinical stage IIB/IIIA NSCLC. © 2011 by American Society of Clinical Oncology. Source
Chapple C.R.,Sheffield Hallam University |
Roehrborn C.G.,Southwestern Medical Center at Dallas |
McVary K.,University of Illinois at Springfield |
Ilo D.,Lilly UK |
And 2 more authors.
Background The international prostate symptom score (IPSS) evaluates lower urinary tract symptoms (LUTS) in men with suspected benign prostatic hyperplasia (BPH); the total score does not differentiate between storage and voiding and is unevenly weighted (four questions [57%] on voiding, three questions [43%] on storage). Objective To evaluate the relative contributions of storage and voiding IPSS subscores to total IPSS at baseline and in response to treatment with tadalafil. Design, setting, and participants Integrated analysis of data from four placebo-controlled, 12-wk studies of tadalafil (5 mg once daily) in 1499 men with LUTS/BPH. Outcome measurements and statistical analysis Relationships between total IPSS and the storage and voiding subscores were assessed using graphical exploration and linear regression modelling. Linear modelling was performed for the baseline and endpoint and for changes in subscores. The optimal storage subscore to total IPSS (S:T) ratio for IPSS improvement was identified using nonparametric regression and gradient-descent optimisation. Results and limitations The contribution of storage and voiding subscores at baseline and endpoint was 38.8% and 61.2%, and 39.2% and 60.7%, respectively. This intuitive 40:60 storage-to-voiding ratio was similar at baseline and endpoint by treatment group and for changes in subscores, but spanned the entire range for individuals. Changes in total IPSS were greatest for a storage subscore percentage contribution to total IPSS of 42.7%. There was no statistical association between S:T ratio (≥40% vs <40%) at baseline and response to tadalafil. The main limitation was the use of unvalidated storage and voiding IPSS subscores. Conclusions A constant S:T ratio of 4:10 was observed at baseline and endpoint. The greatest effect on total IPSS was noted for an S:T percentage contribution of 42.7%. Tadalafil efficacy was unaffected by the level of storage dysfunction at baseline. Patient summary This analysis shows that for men with BPH, improvements during treatment with tadalafil apply to both storage and voiding symptoms at a constant ratio. The extent of storage dysfunction before treatment did not affect the response to treatment. © 2014 European Association of Urology. Source
Gallwitz B.,University of Tubingen |
Guzman J.,Celaya Center for Specialist Medicine |
Dotta F.,Endocrine and Metabolic science |
Guerci B.,Nancy University Hospital Center |
And 7 more authors.
Background Glycaemic control deteriorates progressively over time in patients with type 2 diabetes. Options for treatment escalation remain controversial after failure of first-line treatment with metformin. We compared add-on exenatide with glimepiride for durability of glycaemic control in patients with type 2 diabetes inadequately controlled by metformin alone. Methods We did an open-label, randomised controlled trial at 128 centres in 14 countries between Sept 5, 2006, and March 29, 2011. Patients aged 18-85 years with type 2 diabetes inadequately treated by metformin were randomly assigned via a computer-generated randomisation sequence to receive exenatide twice daily or glimepiride once daily as add-on to metformin. Randomisation was stratified by predetermined categories of glycated haemoglobin (HbA 1C) concentration. The primary outcome was time to inadequate glycaemic control and need for alternative treatment, defined as an HbA 1c concentration of more than 9% after the first 3 months of treatment, or more than 7% at two consecutive visits after the first 6 months. Analysis was by intention to treat. This trial is registered with EudraCT, number 2005-005448-21, and ClinicalTrials.gov, number NCT00359762. Findings We randomly assigned 515 patients to the exenatide group and 514 to the glimepiride group, of whom 490 versus 487 were the intention-to-treat population. 203 (41%) patients had treatment failure in the exenatide group compared with 262 (54%) in the glimepiride group (risk difference 12·4 [95% CI 6·2-18·6], hazard ratio 0·748 [0·623-0·899]; p=0·002). 218 (44%) of 490 patients in the exenatide group, and 150 (31%) of 487 in the glimepiride group achieved an HbA 1c concentration of less than 7% (p<0·0001), and 140 (29%) versus 87 (18%) achieved concentrations of 6·5% and less (p=0·0001). We noted a significantly greater decrease in bodyweight in patients given exenatide than in those given glimepiride (p<0·0001). Five patients in each treatment group died from causes unrelated to treatment. Significantly fewer patients in the exenatide group than in the glimepiride group reported documented symptomatic (p<0·0001), nocturnal (p=0·007), and non-nocturnal (p<0·0001) hypoglycaemia. Discontinuation because of adverse events (mainly gastrointestinal) was significantly higher (p=0·0005) in the exenatide group than in the glimepiride group in the first 6 months of treatment, but not thereafter. Interpretation These findings provide evidence for the benefits of exenatide versus glimepiride for control of glycaemic deterioration in patients with type-2 diabetes inadequately controlled by metformin alone. Source
Liebl A.,Center for Diabetes and Metabolism |
Jones S.,James Cook University |
Benroubi M.,Polyclinic General Hospital |
Castell C.,Generalitat de Catalonia |
And 6 more authors.
Current Medical Research and Opinion
Objectives: To examine insulin regimens and factors that affect glycaemic control at 6 months after initiation of insulin therapy in patients with type 2 diabetes mellitus. Research design and methods: Information on patients requiring insulin initiation as part of usual care was collected in a prospective, observational, open-label study in five European countries. Univariate and multiple regression analyses were used to investigate factors associated with HbA1c achieved at 6 months. Results: Mean HbA1c for all patients at baseline was 9.6 ± 1.8%. Long/intermediate-acting insulin only was most commonly initiated in France and Spain, while long/intermediate or pre-mixed formulations were initiated in Greece and UK. This was consistent with guidelines used in those countries and there was little change in insulin regimen at 6 months in these countries. In Germany, short-acting insulin only was favoured at baseline and there was a shift towards basal/bolus regimens at 6 months, which reflected the local guidelines for insulin initiation in Germany. Mean HbA1c reduction was greatest in Germany (-2.3%), which was the only country to achieve a mean of <7% at 6 months. In all countries, HbA1c achieved at 6 months was associated with baseline HbA1c. Differences between countries were seen for influence of factors such as BMI, duration of diabetes, insulin regimen, insulin dose and number of oral anti-diabetes drugs on HbA1c achieved. Explained variability for the factors ranged from 5.6% to 22.9%. Conclusions: Differences in insulin regimen were observed between countries, and appeared to reflect the guidelines and treatment regimens used. © 2011 Informa UK Ltd. Source