[Show abstract][Hide abstract] ABSTRACT: Since recent studies revealed the feasibility to detect blood-based microRNAs (miRNAs, miRs) in breast cancer (BC) patients a new field has been opened for circulating miRNAs as potential biomarkers in BC. In this pilot study, we evaluated to our knowledge for the first time whether distinct pattern of urinary miRNAs might be also applicable as innovative biomarkers for BC detection.
Urinary miRNA expression levels of nine BC-related miRNAs (miR-21, miR-34a, miR-125b, miR-155, miR-195, miR-200b, miR-200c, miR-375, miR-451) from 24 untreated, primary BC patients and 24 healthy controls were quantified by realtime-PCR. The receiver operating characteristic analyses (ROC) and logistic regression were calculated to assess discriminatory accuracy.
Significant differences were found in the expression of four BC-associated miRNAs quantified as median miRNA expression levels. Urinary miR-155 levels were significantly higher in BC patients compared to healthy controls (1.49vs.0.25; p < 0.001). In contrast, compared to healthy controls, BC patients exhibited significantly lower urinary expression levels of miR-21 (2.27vs.5.07; p < 0.001), miR-125b (0.71vs.1.62; p < 0.001), and miR-451 (0.02vs.0.59 p = 0.004), respectively. The ROC including all miRNAs as well as the group of the four significant deregulated miRNAs separated BC patients from healthy controls with a very high (area under the receiver operating characteristic curve [AUC] = 0.932) and high accuracy (AUC = 0.887), respectively.
We were able to demonstrate for the first time the feasibility to detect distinct BC-dependent urinary miRNA profiles. The expression levels of four urinary miRNAs were specifically altered in our cohort of BC patients compared to healthy controls. This distinct pattern offers the possibility for a specific discrimination between healthy women and primary BC patients. This sustains the potential role of urinary miRNAs as non-invasive innovative urine-based biomarkers for BC detection.
BMC Cancer 12/2015; 15(1). DOI:10.1186/s12885-015-1190-4 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A variety of psychological interventions to treat depressive disorders have been developed and are used in primary care. In a systematic review, we compared the effectiveness of psychological treatments grouped by theoretical background, intensity of contact with the health care professional, and delivery mode for depressed patients in this setting.
Randomized trials comparing a psychological treatment with usual care, placebo, another psychological treatment, pharmacotherapy, or a combination treatment in adult depressed primary care patients were identified by database searches up to December 2013. We performed both conventional pairwise meta-analysis and network meta-analysis combining direct and indirect evidence. Outcome measures were response to treatment (primary outcome), remission of symptoms, post-treatment depression scores and study discontinuation.
A total of 37 studies with 7,024 patients met the inclusion criteria. Among the psychological treatments investigated in at least 150 patients face-to-face cognitive behavioral therapy (CBT; OR 1.80; 95 % credible interval 1.35-2.39), face-to-face counselling and psychoeducation (1.65; 1.27-2.13), remote therapist lead CBT (1.87; 1.38-2.53), guided self-help CBT (1.68; 1.22-2.30) and no/minimal contact CBT (1.53; 1.07-2.17) were superior to usual care or placebo, but not face-to-face problem-solving therapy and face-to-face interpersonal therapy. There were no statistical differences between psychological treatments apart from face-to-face interpersonal psychotherapy being inferior to remote therapist-lead CBT (0.60; 0.37-0.95). Remote therapist-led (0.86; 0.21-3.67), guided self-help (0.93; 0.62-1.41) and no/minimal contact CBT (0.85; 0.54-1.36) had similar effects as face-to-face CBT.
The limited available evidence precludes a sufficiently reliable assessment of the comparative effectiveness of psychological treatments in depressed primary care patients. Findings suggest that psychological interventions with a cognitive behavioral approach are promising, and primarily indirect evidence indicates that it applies also when they are delivered with a reduced number of therapist contacts or remotely.
01KG1012 at http://www.gesundheitsforschung-bmbf.de/de/2852.php.
BMC Family Practice 12/2015; 16(1):103. DOI:10.1186/s12875-015-0314-x · 1.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
We aimed to evaluate the underlying assumptions of a network meta-analysis investigating which depression treatment works best in primary care and to highlight challenges and pitfalls of interpretation under consideration of these assumptions.
Study design and setting:
We reviewed 100 randomized trials investigating pharmacological and psychological treatments for primary care patients with depression. Network meta-analysis was carried out within a frequentist framework using response to treatment as outcome measure. Transitivity was assessed by epidemiological judgment based on theoretical and empirical investigation of the distribution of trial characteristics across comparisons. Homogeneity and consistency were investigated by decomposing the Q statistic.
There were important clinical and statistically significant differences between 'pure' drug trials comparing pharmacological substances with each other or placebo (63 trials) and trials including a psychological treatment arm (37 trials). Overall network meta-analysis produced results well comparable with separate meta-analyses of drug trials and psychological trials. While the homogeneity and consistency assumptions were mostly met, we considered the transitivity assumption unjustifiable.
An exchange of experience between reviewers and, if possible, some guidance on how reviewers addressing important clinical questions can proceed in situations where important assumptions for valid network meta-analysis are not met would be desirable.
Journal of clinical epidemiology 11/2015; DOI:10.1016/j.jclinepi.2015.10.010 · 3.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
To investigate whether treatment as required 'pro re nata' (PRN) versus regular monthly treatment regimens lead to differences in outcomes in neovascular age-related macular degeneration (nAMD). Regular monthly administration of vascular endothelial growth factor (VEGF) inhibitors is an established gold standard treatment, but this approach is costly. Replacement of monthly by PRN treatment can only be justified if there is no difference in patient relevant outcomes.
Systematic review and meta-analysis. The intervention was PRN treatment and the comparator was monthly treatment with VEGF-inhibitors. Four bibliographic databases were searched for randomised controlled trials comparing both treatment regimens directly (head-to-head studies). The last literature search was conducted in December 2014. Risk of bias assessment was performed after the Cochrane Handbook for Systematic Reviews of Interventions.
We included 3 head-to-head studies (6 reports) involving more than 2000 patients. After 2 years, the weighted mean difference in best corrected visual acuity (BCVA) was 1.9 (95% CI 0.5 to 3.3) ETDRS letters in favour of monthly treatment. Systemic adverse events were higher in PRN treated patients, but these differences were not statistically significant. After 2 years, the total number of intravitreal injections required by the patients in the PRN arms were 8.4 (95% CI 7.9 to 8.9) fewer than those having monthly treatment. The studies were considered to have a moderate risk of bias.
PRN treatment resulted in minor but statistically significant decrease in mean BCVA which may not be clinically meaningful. There is a small increase in risk of systemic adverse events for PRN treated patients. Overall, the results indicate that an individualized treatment approach with anti-VEGF using visual acuity and OCT-guided re-treatment criteria may be appropriate for most patients with nAMD.
PLoS ONE 09/2015; 10(9):e0137866. DOI:10.1371/journal.pone.0137866 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Network meta-analysis is used to compare three or more treatments for the same condition. Within a Bayesian framework, for each treatment the probability of being best, or, more general, the probability that it has a certain rank can be derived from the posterior distributions of all treatments. The treatments can then be ranked by the surface under the cumulative ranking curve (SUCRA). For comparing treatments in a network meta-analysis, we propose a frequentist analogue to SUCRA which we call P-score that works without resampling.
P-scores are based solely on the point estimates and standard errors of the frequentist network meta-analysis estimates under normality assumption and can easily be calculated as means of one-sided p-values. They measure the mean extent of certainty that a treatment is better than the competing treatments.
Using case studies of network meta-analysis in diabetes and depression, we demonstrate that the numerical values of SUCRA and P-Score are nearly identical.
Ranking treatments in frequentist network meta-analysis works without resampling. Like the SUCRA values, P-scores induce a ranking of all treatments that mostly follows that of the point estimates, but takes precision into account. However, neither SUCRA nor P-score offer a major advantage compared to looking at credible or confidence intervals.
BMC Medical Research Methodology 08/2015; 15(1):58. DOI:10.1186/s12874-015-0060-8 · 2.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Children with congenital heart disease often undergo heart surgery at a young age. They are at risk for postoperative low cardiac output syndrome (LCOS) or death. Milrinone may be used to provide inotropic and vasodilatory support during the immediate postoperative period.
This review examines the effectiveness of prophylactic postoperative use of milrinone to prevent LCOS or death in children having undergone surgery for congenital heart disease.
Electronic and manual literature searches were performed to identify randomised controlled trials. We searched CENTRAL, MEDLINE, EMBASE and Web of Science in February 2014 and conducted a top-up search in September 2014 as well as clinical trial registries and reference lists of published studies. We did not apply any language restrictions.
Only randomised controlled trials were selected for analysis. We considered studies with newborn infants, infants, toddlers, and children up to 12 years of age.
Two review authors independently extracted data according to a pre-defined protocol. We obtained additional information from all study authors.
Three of the five included studies compared milrinone versus levosimendan, one study compared milrinone with placebo, and one compared milrinone verus dobutamine, with 101, 242, and 50 participants, respectively. Three trials were at low risk of bias while two were at higher risk of bias. The number and definitions of outcomes were non-uniform as well. In one study comparing two doses of milrinone and placebo, there was some evidence in an overall comparison of milrinone versus placebo that milrinone lowered risk for LCOS (risk ratio (RR) 0.52, 95% confidence interval (CI) 0.28 to 0.96; 227 participants). The results from two small studies do not provide enough information to determine whether milrinone increases the risk of LCOS when compared to levosimendan (RR 1.22, 95% CI 0.32 to 4.65; 59 participants). Mortality rates in the studies were low, and there was insufficient evidence to draw conclusions on the effect of milrinone compared to placebo or levosimendan or dobutamine regarding mortality, the duration of intensive care stay, hospital stay, mechanical ventilation, or maximum inotrope score (where available). Numbers of patients requiring mechanical cardiac support were also low and did not allow a comparison between studies, and none of the participants of any study received a heart transplantation up to the end of the respective follow-up period. Time to death within three months was not reported in any of the included studies. A number of adverse events was examined, but differences between the treatment groups could not be proven for hypotension, intraventricular haemorrhage, hypokalaemia, bronchospasm, elevated serum levels of liver enzymes, or a reduced left ventricular ejection fraction < 50% or reduced left ventricular fraction of shortening < 28%. Our analysis did not prove an increased risk of arrhythmias in patients treated prophylactically with milrinone compared with placebo (RR 3.59, 95% CI 0.83 to 15.42; 238 participants), a decreased risk of pleural effusions (RR 1.78, 95% CI 0.92 to 3.42; 231 participants), or a difference in risk of thrombocytopenia on milrinone compared with placebo (RR 0.86, 95% CI 0.39 to 1.88; 238 participants). Comparisons of milrinone with levosimendan or with dobutamine, respectively, did not clarify the risk of arrhythmia and were not possible for pleural effusions or thrombocytopenia.
There is insufficient evidence of the effectiveness of prophylactic milrinone in preventing death or low cardiac output syndrome in children undergoing surgery for congenital heart disease, compared to placebo. So far, no differences have been shown between milrinone and other inodilators, such as levosimendan or dobutamine, in the immediate postoperative period, in reducing the risk of LCOS or death. The existing data on the prophylactic use of milrinone has to be viewed cautiously due to the small number of small trials and their risk of bias.
[Show abstract][Hide abstract] ABSTRACT: Interobserver variability in the definition of target volumes (TVs) is a well-known confounding factor in (multicentre) clinical studies employing radiotherapy. Therefore, detailed contouring guidelines are provided in the prospective randomised multicentre PET-Plan (NCT00697333) clinical trial protocol. This trial compares strictly FDG-PET-based TV delineation with conventional TV delineation in patients with locally advanced non-small cell lung cancer (NSCLC). Despite detailed contouring guidelines, their interpretation by different radiation oncologists can vary considerably, leading to undesirable discrepancies in TV delineation. Considering this, as part of the PET-Plan study quality assurance (QA), a contouring dummy run (DR) consisting of two phases was performed to analyse the interobserver variability before and after teaching.
In the first phase of the DR (DR1), radiation oncologists from 14 study centres were asked to delineate TVs as defined by the study protocol (gross TV, GTV; and two clinical TVs, CTV-A and CTV-B) in a test patient. A teaching session was held at a study group meeting, including a discussion of the results focussing on discordances in comparison to the per-protocol solution. Subsequently, the second phase of the DR (DR2) was performed in order to evaluate the impact of teaching.
Teaching after DR1 resulted in a reduction of absolute TVs in DR2, as well as in better concordance of TVs. The Overall Kappa(κ) indices increased from 0.63 to 0.71 (GTV), 0.60 to 0.65 (CTV-A) and from 0.59 to 0.63 (CTV-B), demonstrating improvements in overall interobserver agreement.
Contouring DRs and study group meetings as part of QA in multicentre clinical trials help to identify misinterpretations of per-protocol TV delineation. Teaching the correct interpretation of protocol contouring guidelines leads to a reduction in interobserver variability and to more consistent contouring, which should consequently improve the validity of the overall study results.
Strahlentherapie und Onkologie 02/2015; 191(6). DOI:10.1007/s00066-015-0812-8 · 2.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Statisticians investigate new methods in simulations to evaluate their properties for future real data applications. Results are often presented in a number of figures, e.g., Trellis plots. We had conducted a simulation study on six statistical methods for estimating the treatment effect in binary outcome meta-analyses, where selection bias (e.g., publication bias) was suspected because of apparent funnel plot asymmetry. We varied five simulation parameters: true treatment effect, extent of selection, event proportion in control group, heterogeneity parameter, and number of studies in meta-analysis. In combination, this yielded a total number of 768 scenarios. To present all results using Trellis plots, 12 figures were needed.
Choosing bias as criterion of interest, we present a ‘nested loop plot’, a diagram type that aims to have all simulation results in one plot. The idea was to bring all scenarios into a lexicographical order and arrange them consecutively on the horizontal axis of a plot, whereas the treatment effect estimate is presented on the vertical axis.
The plot illustrates how parameters simultaneously influenced the estimate. It can be combined with a Trellis plot in a so-called hybrid plot. Nested loop plots may also be applied to other criteria such as the variance of estimation.
The nested loop plot, similar to a time series graph, summarizes all information about the results of a simulation study with respect to a chosen criterion in one picture and provides a suitable alternative or an addition to Trellis plots.
BMC Medical Research Methodology 12/2014; 14(1):129. DOI:10.1186/1471-2288-14-129 · 2.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Non-steroidal antiandrogens and castration are the main therapy options for advanced stages of prostate cancer. However, debate regarding the value of these treatment options continues.
[Show abstract][Hide abstract] ABSTRACT: This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the efficacy of early palliative care in adults diagnosed with advanced cancer compared with standard cancer care alone.
[Show abstract][Hide abstract] ABSTRACT: PurposeOCT became an essential tool to manage antiVEGF therapy in patients with AMD. We set out a systematic review to evaluate diagnostic test accuracy of OCT in the diagnosis and management of AMD.
MethodsMedline, Embase and the Cochrane Library were searched for clinical studies without restrictions on date. We selected studies that assessed the diagnostic accuracy (sensitivity [SE] and specificity [SP]) of any OCT model for detecting or monitoring of neovascular AMD. Methodological study quality was evaluated after the “Quality of Diagnostic Accuracy Studies” (QUADAS) checklist.
ResultsOf 4572 citations retrieved, 9 studies met the inclusion criteria (632 patients, 657 eyes, 880 measurements). CNV was the target condition and fluoresceine angiography (FA) the goldstandard in all studies. Prevalence of CNV varied between 14.9% to 83.0% (median 56.9%). Two studies included patients with suspected CNV (205 patients, 218 eyes, 218 measurements): thereby, the SE of OCT for detecting CNV lesions was 69.0% and 96.4%, respectively and SP 66% in both studies (both studies used time-domain OCT). Seven studies evaluated diagnostic accuracy for retreatment decisions (427 patients, 439 eyes, 662 measurements): pooled SE was 86.3% (95% CI 74.4-93.1%) and SP was 50.7% (95% CI 39.9-61.4%). From these 7 studies, 2 studies applied spectral-domain OCT. A subgroup analysis showed no significant difference in both SE and SP between spectral- and time-domain OCT, which can be most likely explained by the low number of included trials. Overall methodological study quality was adequate for most QUADAS items (e.g., most studies were masked, the cut-off for a positive OCT finding was intraretinal and/or subretinal fluid). However, some of the current study data show an “unit of analysis issue” as both eyes or multiple measurments in one eye of one patient were treated in the data analysis as they were independent.
ConclusionsFA remains the most reliable method to detect suspected (or new) CNV. Due to the fact that most published studies are evaluating time-domain OCT, diagnostic accuracy of spectral-domain OCT in comparison to FA still needs to be established. Disagreements between OCT measurements and FA (especially the apparent high false positive rate) may be explained that intraretinal fluid decrease is traceable with OCT but not with FA - at least in monitoring the activity of occult CNV after antiVEGF therapy.
The Association for Research in Vision and Ophthalmology (ARVO), Orlando, Florida; 04/2014