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1.  Early versus deferred androgen suppression therapy for patients with lymph node-positive prostate cancer after local therapy with curative intent: a systematic review 
BMC Cancer  2013;13:131.
There is currently no consensus regarding the optimal timing for androgen suppression therapy in patients with prostate cancer that have undergone local therapy with curative intent but are proven to have node-positive disease without signs of distant metastases at the time of local therapy. The objective of this systematic review was to determine the benefits and harms of early (at the time of local therapy) versus deferred (at the time of clinical disease progression) androgen suppression therapy for patients with node-positive prostate cancer after local therapy.
The protocol was registered prospectively (CRD42011001221; We searched the MEDLINE, EMBASE, and CENTRAL databases, as well as reference lists, the abstracts of three major conferences, and three trial registers, to identify randomized controlled trials (search update 04/08/2012). Two authors independently screened the identified articles, assessed trial quality, and extracted data.
Four studies including 398 patients were identified for inclusion. Early androgen suppression therapy lead to a significant decrease in overall mortality (HR 0.62, 95% CI 0.46-0.84), cancer-specific mortality (HR 0.34, 95% CI 0.18-0.64), and clinical progression at 3 or 9 years (RR 0.29, 95% CI 0.16-0.52 at 3 years and RR 0.49, 95% CI 0.36-0.67 at 9 years). One study showed an increase of adverse effects with early androgen suppression therapy. All trials had substantial methodological limitations.
The data available suggest an improvement in survival and delayed disease progression but increased adverse events for patients with node-positive prostate cancer after local therapy treated with early androgen suppression therapy versus deferred androgen suppression therapy. However, quality of data is low. Randomized controlled trials with blinding of outcome assessment, planned to determine the timing of androgen suppression therapy in node-positive prostate cancer using modern diagnostic imaging modalities, biochemical testing, and standardized follow-up schedules should be conducted to confirm these findings.
PMCID: PMC3621662  PMID: 23510155
Prostatic neoplasms; Lymphatic metastasis; Lymph node excision; Androgen suppression therapy; Systematic review; Meta-analysis
2.  Plasmacytoid variant of bladder cancer defines patients with poor prognosis if treated with cystectomy and adjuvant cisplatin-based chemotherapy 
BMC Cancer  2013;13:71.
Since the definition of different histologic subtypes of urothelial carcinomas by the World Health Organization (WHO) 2004 classification, description of molecular features and clinical behavior of these variants has gained more attention.
We reviewed 205 tumor samples of patients with locally advanced bladder cancer mainly treated within the randomized AUO-AB05/95 trial with radical cystectomy and adjuvant cisplatin-based chemotherapy for histologic subtypes. 178 UC, 18 plasmacytoid (PUC) and 9 micropapillary (MPC) carcinomas of the bladder were identified. Kaplan Meier analysis and backward multivariate Cox’s proportional hazards regression analysis were performed to compare overall survival between the three histologic subtypes.
Patients suffering from PUC have the worst clinical outcome regarding overall survival compared to conventional UC and MPC of the bladder that in turn seem have to best clinical outcome (27.4 months, 62.6 months, and 64.2 months, respectively; p=0.013 by Kaplan Meier analysis). Backward multivariate Cox´s proportional hazards regression analysis (adjusted to relevant clinicopathological parameters) showed a hazard ratio of 3.2 (p=0.045) for PUC in contrast to patients suffering from MPC.
Histopathological diagnosis of rare variants of urothelial carcinoma can identify patients with poor prognosis.
PMCID: PMC3572418  PMID: 23394492
Chemotherapy; Cystectomy; Micropapillary; Plasmacytoid; Prognosis; Urinary bladder neoplasm
3.  Tamoxifen for the management of breast events induced by non-steroidal antiandrogens in patients with prostate cancer: a systematic review 
BMC Medicine  2012;10:96.
Tamoxifen has emerged as a potential management option for gynecomastia and breast pain due to non-steroidal antiandrogens, and it is considered an alternative to surgery or radiotherapy. The objective of this systematic review was to assess the benefits and harms of tamoxifen, in comparison to other treatment options, for either the prophylaxis or treatment of breast events induced by non-steroidal antiandrogens in prostate cancer patients.
We searched CENTRAL, MEDLINE, EMBASE, reference lists, the abstracts of three major conferences and three trial registers to identify ongoing randomized controlled trials (RCTs). Two authors independently screened the articles identified, assessed the trial quality and extracted data. The protocol was prospectively registered (CRD42011001320;
Four studies were identified. Tamoxifen significantly reduced the risk of suffering from gynecomastia (risk ratio 9RR0 0.10, 95% CI 0.05 to 0.22) or breast pain (RR 0.06, 95% CI 0.02 to 0.17) at six months compared to untreated controls. Tamoxifen also showed a significant benefit for the prevention of gynecomastia (RR 0.22, 95% CI 0.08 to 0.58) and breast pain (RR 0.25, 95% CI 0.10 to 0.64) when compared to anastrozole after a median of 12 months. One study showed a significant benefit of tamoxifen for the prevention of gynecomastia (RR 0.24, 95% CI 0.09 to 0.65) and breast pain (RR 0.20, 95% CI 0.06 to 0.65) when compared with radiotherapy at six months. Radiotherapy increased the risk of suffering from nipple erythema and skin irritation, but there were no significant differences for any other adverse events (all P > 0.05).
The currently available evidence suggests good efficacy of tamoxifen for the prevention and treatment of breast events induced by non-steroidal antiandrogens. The impact of tamoxifen therapy on long-term adverse events, disease progression and survival remains unclear. Further large, well-designed RCTs, including long-term follow-ups, are warranted. Also, the optimal dose needs to be clarified.
PMCID: PMC3464149  PMID: 22925442
Prostatic neoplasms; Androgen suppression therapy; Gynecomastia; Tamoxifen; Systematic review; Meta-analysis
4.  Distinct Mesenchymal Alterations in N-Cadherin and E-Cadherin Positive Primary Renal Epithelial Cells 
PLoS ONE  2012;7(8):e43584.
Renal tubular epithelial cells of proximal and distal origin differ markedly in their physiological functions. Therefore, we hypothesized that they also differ in their capacity to undergo epithelial to mesenchymal alterations.
We used cultures of freshly isolated primary human tubular cells. To distinguish cells of different tubular origin we took advantage of the fact that human proximal epithelial cells uniquely express N-cadherin instead of E-cadherin as major cell-cell adhesion molecule. To provoke mesenchymal alteration we treated these cocultures with TGF-β for up to 6 days. Within this time period, the morphology of distal tubular cells was barely altered. In contrast to tubular cell lines, E-cadherin was not down-regulated by TGF-β, even though TGF-β signal transduction was initiated as demonstrated by nuclear localization of Smad2/3. Analysis of transcription factors and miRNAs possibly involved in E-cadherin regulation revealed high levels of miRNAs of the miR200-family, which may contribute to the stability of E-cadherin expression in human distal tubular epithelial cells. By contrast, proximal tubular epithelial cells altered their phenotype when treated with TGF-β. They became elongated and formed three-dimensional structures. Rho-kinases were identified as modulators of TGF-β-induced morphological alterations. Non-specific inhibition of Rho-kinases resulted in stabilization of the epithelial phenotype, while partial effects were observed upon downregulation of Rho-kinase isoforms ROCK1 and ROCK2. The distinct reactivity of proximal and distal cells was retained when the cells were cultured as polarized cells.
Interference with Rho-kinase signaling provides a target to counteract TGF-β-mediated mesenchymal alterations of epithelial cells, particularly in proximal tubular epithelial cells. Furthermore, primary distal tubular cells differed from cell lines by their high phenotypic stability which included constant expression of E-cadherin. Our cell culture system of primary epithelial cells is thus suitable to understand and modulate cellular remodeling processes of distinct tubular cells relevant for human renal disease.
PMCID: PMC3422254  PMID: 22912891
5.  Do urology journals enforce trial registration? A cross-sectional study of published trials 
BMJ Open  2011;1(2):e000430.
(1) To assess endorsement of trial registration in author instructions of urology-related journals and (2) to assess whether randomised controlled trials (RCTs) in the field of urology were effectively registered.
Cross-sectional study of author instructions and published trials.
Journals publishing in the field of urology.
First, the authors analysed author instructions of 55 urology-related journals indexed in ‘Journal Citation Reports 2009’ (12/2010). The authors divided these journals in two groups: those requiring and those not mentioning trial registration as a precondition for publication. Second, the authors chose the five journals with the highest impact factor (IF) from each group.
MEDLINE search to identify RCTs published in these 10 journals in 2009 (01/2011); search of the clinical trials meta-search interface of WHO (International Clinical Trials Registry Platform) for RCTs that lacked information about registration (01–03/2011). Two authors independently assessed the information.
Outcome measures
Proportion of journals providing advice about trial registration and proportion of trials registered.
Of 55 journals analysed, 26 (47.3%) provided some editorial advice about trial registration. Journals with higher IFs were more likely to mention trial registration explicitly (p=0.015). Of 106 RCTs published in 2009, 63 were registered (59.4%) with a tendency to an increase after 2005 (83.3%, p=0.035). 71.4% (30/42) of the RCTs that were published in journals mentioning and requiring registration, and 51.6% (33/64) of the RCTs that were published in journals that did not mention trial registration explicitly were registered. This difference was statistically significant (p=0.04).
The existence of a statement about trial registration in author instructions resulted in a higher proportion of registered RCTs in those journals. Journals with higher IFs were more likely to mention trial registration.
Article summary
Article focus
Trial registration can increase scientific transparency, but its implementation in specialty fields such as urology is unclear.
To assess the endorsement of trial registration in the author instructions of urology-related journals.
To assess whether randomised controlled trials in the field were effectively registered.
Key messages
A statement of trial registration in author instructions resulted in a higher proportion of registered randomised controlled trials.
Journals with high impact factors were more likely to mention trial registration.
We suggest, though, that ensuring trial registration is not the responsibility only of the editors. Medical scientists should realise that trial registration is necessary to contribute to transparency in research.
Strength and limitations of this study
Two authors independently assessed information regarding editorial advice about trial registration and identified the randomised controlled trials.
Potential bias occurred if registered randomised controlled trials were reported without giving a registration number and we could not identify them in the meta-search interface of WHO (International Clinical Trials Registry Platform).
Results might not be representative of the uro-nephrological field as a whole and reported figures may overestimate compliance with trial registration.
PMCID: PMC3236819  PMID: 22146890
6.  Perisylvian white matter connectivity in the human right hemisphere 
BMC Neuroscience  2009;10:15.
By using diffusion tensor magnetic resonance imaging (DTI) and subsequent tractography, a perisylvian language network in the human left hemisphere recently has been identified connecting Brocas's and Wernicke's areas directly (arcuate fasciculus) and indirectly by a pathway through the inferior parietal cortex.
Applying DTI tractography in the present study, we found a similar three-way pathway in the right hemisphere of 12 healthy individuals: a direct connection between the superior temporal and lateral frontal cortex running in parallel with an indirect connection. The latter composed of a posterior segment connecting the superior temporal with the inferior parietal cortex and an anterior segment running from the inferior parietal to the lateral frontal cortex.
The present DTI findings suggest that the perisylvian inferior parietal, superior temporal, and lateral frontal corticies are tightly connected not only in the human left but also in the human right hemisphere.
PMCID: PMC2653039  PMID: 19257886

Results 1-6 (6)