Assessing blood platelets as RNA biomarker source for prostate cancer.

CONTEXT: Blood platelets may offer as RNA biomarker source for cancer as recently described for an oncogenic transcript in glioma patients and for PCA3 in prostate cancer (PCa) patients. OBJECTIVE: Here, we elaborated on this aspect for PCa. MATERIALS AND METHODS: PCA3 and other PCa-associated RNA markers were measured in platelets of PCa patients (cases) and healthy subjects (controls) in comparison to PCa cell lines by relative quantitative RT-PCR. RESULTS: The RNA markers displayed heterogeneous expression patterns in cell lines and platelets, however, without significant differences between cases and controls. DISCUSSION AND CONCLUSION: The data do not support platelets as a profitable RNA source for early detection of PCa. Nonetheless, certain PCa-derived RNA markers in platelets may merit further investigation as potential prognostic biomarkers for PCa.

Lymphoceles Post-Radical Retropubic Prostatectomy: A Retrospective Evaluation of Epidemiology, Risk Factors and Outcome.

INTRODUCTION: We aimed at evaluating the incidence of lymphoceles, a common complication after radical retropubic prostatectomy (RRP), at a high volume centre, define risk factors and assess the clinical outcome. MATERIALS AND METHODS: 454 patients receiving RRP and pelvic lymph node dissection were assessed for postoperative lymphoceles using the ultrasound method. Findings were correlated to clinical parameters from a database (age, BMI, initial PSA, number of lymph nodes removed, prostate weight, duration of surgery, hospital stay, duration of catheterisation) and possible unconventional risk factors using meteorological data. RESULTS: Overall, 15.4% developed a lymphocele, 2.6% had a symptomatic lymphocele requiring treatment. The mean size of the lymphoceles requiring treatment was significantly higher (400 vs. 115 ml). Patients with lymphocele stayed longer in hospital. No correlation could be found between the clinical parameters and the risk for lymphoceles. Functional results in terms of urinary continence were similar. The assessment of meteorological risk factors showed a correlation of lymphoceles with air humidity. CONCLUSION: Lymphoceles are common after RRP, but few cases require intervention. There is no reliable clinical predictor for the risk of lymphocele development. Data sets have been published suggesting several risk factors but may be subject to statistical error like in the case of the meteorological predictors in this study.

Changes in prostaglandin E2 in patients with idiopathic overactive bladder syndrome after botulinum toxin type A treatment: is there a clinical benefit?

BACKGROUND: The causality of overactive bladder syndrome (OAB) is still not fully understood. Several studies indicate a significant increase of prostaglandin E2 (PGE2) in patients with OAB. However, in order to clarify whether these compounds can help to objectify the clinical diagnosis, further studies are needed. This prospective study aims to analyze PGE2 blood levels (sPGE2) in patients with OAB before and after botulinum toxin type A (BoNT-A) therapy. METHODS: Blood samples were obtained from 56 patients (52y, 18-87) with idiopathic OAB. sPGE2 levels were measured before and 4 weeks after BoNT-A treatment by enzyme linked immunosorbent assay (ELISA). 31 healthy persons with normal bladder function served as control group (59 y, 21-72). sPGE2 was set in relation to clinical data and the severity of OAB (wet/dry). The statistical data analysis was performed by using the non-parametric Mann-Whitney U test and paired t-test. RESULTS: Significant higher sPGE2 levels were detected in patients with OAB compared to members of the control group (2750 pg/ml vs. 1674 pg/ml, p < 0.005). Furthermore sPGE2 levels were increased in patients with OAB wet compared to OAB dry (p <0.01). In 30 patients sPGE2 levels decreased significantly after BoNT-A treatment compared to baseline (2995 pg/ml vs. 1486 pg/ml, p <0.005). Patients reported an average drug effect of 9 month (0-19); incontinence pads were needed significantly less frequent (p < 0.05). 3 patients reported no postoperative effect. sPGE2 increased in two patients compared to initial levels, a single patient showed a remotely decreased sPGE2. Six patients were treated repeatedly with BoNT-A after showing an sPGE2 re-rise. CONCLUSIONS: sPGE2-level is increased in patients with OAB. We could prove a significant decrease of sPGE2 after BoNT-A treatment. In this small cohort we could demonstrate a correlation between OAB and sPGE2, especially in the non-responder group. The use of sPGE2 as a biomarker in diagnostics and follow-up after therapy seems promising. To what extent sPGE2 can be useful as such needs to be examined prospectively in a larger population.

TOT approach in stress urinary incontinence (SUI) - outcome in obese female.

BACKGROUND: Only limited data are available on the outcome of tension-free obturator tape (TOT) procedures in overweight and obese women. We would like to verify the objective and subjective outcomes of TOT in women with a higher body mass index (BMI). METHODS: We evaluated the records of 116 patients who had undergone TOT, stratifying by BMI into normal weight (n = 31), overweight (n = 56), and obese (n = 29) groups. We compared pre- and postoperative evaluations, including subjective and objective outcome of TOT, complications, and quality of life assessed by validated questionnaires (ICIQ-SF and KHQ). RESULTS: The median follow-up was 21 months. There were no significant differences between different groups in terms of objective cure rate and subjective success, quality of life scores and postoperative complications. CONCLUSIONS: Our data demonstrate that TOT procedure is safe and effective. BMI did not influence the outcome of TOT procedures at a median of 21 months after surgery and represents no contraindication for continence surgery. The success of the outcome of TOT procedure in females and the occurrence of complications are not negatively affected by obesity.

[The 1-cm lower calyx calculus: SWT, URS or Mini-PCNL? Guidelines vs. reality.] / Der 1 cm UKG-Stein: ESWL, URS oder Mini-PCNL? Leitlinien versus Realität.

Urinary stones of the upper urinary tract can be considered a widespread public health concern due to their high incidence and prevalence and their health policy-related and financial implications. A significant proportion of newly diagnosed kidney stones are lower-pole stones, i.e., stones affecting the lower calyx group of the renal pelvicalyceal system. These are often diagnosed by chance, i.e., as incidental findings during ultrasound or CT scans performed for other reasons, or as "secondary stones" detected during the diagnostic work-up of symptomatic urinary stones in other locations. Residual disintegrates after extracorporeal shock-wave lithotripsy (ESWL) or endoscopic stone therapy constitute a further, quantitatively significant group. These incidentally discovered lower-pole stones are often characterised by their small size and lack of symptoms. It stands to reason that some of these small, asymptomatic lower-pole stones do not always remain small and asymptomatic, and that treatment tends to become more complex with increasing size. There has been an astonishing lack of published studies with a high level of evidence over the last 20 years to provide a conclusive and reproducible answer to the question posed in this review. Small, asymptomatic stones can be monitored. Symptomatic and rapidly growing stones should be treated. There is a lack of valid risk factors allowing an identification of subgroups that should be treated prophylactically at the asymptomatic stage. In active therapy, a 10-to-20-year-old principle still holds true today: a high stone-free rate in one therapy session is offset by an increased complication rate, with increasing miniaturisation in endourology (retrograde and percutaneous) and increasingly effective laser disintegration shifting this basic principle more and more in favour of flexible URS and (mini, micro) PCNL. The range of indications for ESWL is undoubtedly becoming smaller, and this also applies to lower-pole stones. The results of an ongoing prospective randomised study comparing the different treatment modalities, albeit with recruitment difficulties, are still pending.

Isolated upper pole access in percutaneous nephrolithotomy: a large-scale analysis from the CROES percutaneous nephrolithotomy global study.

PURPOSE: We analyzed the indications for and outcomes of percutaneous nephrolithotomy using upper pole access. MATERIALS AND METHODS: Between 2007 and 2009 prospective data were collected by the Clinical Research Office of the Endourological Society (CROES) from consecutive patients at 96 centers globally. Data on 4,494 patients were included in this analysis. Patients were divided into upper and lower pole access groups based on the location of percutaneous renal access. Preoperative characteristics and outcomes were compared between the 2 groups by univariate and multivariate tests. RESULTS: The upper pole access group had more staghorn stones (21.7% vs 15.5%, p <0.001) and a greater stone burden (mean ± SD 476 ± 390.5 vs 442 ± 344.9 mm(2), p = 0.091). Mean operative time was 92.4 ± 46.1 and 75.1 ± 41.3 minutes in the upper and lower pole groups, respectively (p <0.001). The stone-free rate was lower in the upper pole access group (77.1% vs 81.6%, p = 0.030). The overall complication rate was higher in the upper pole group with a higher incidence of hydrothorax (5.8% vs 1.5%) but a lower incidence of pelvic perforation (1.8% vs 3.2%). Mean hospital stay was longer in the upper pole group (p = 0.048). Success and complication rates were similar in upper pole access subgroups, defined as definitive (staghorn and isolated upper calyceal stones) and elective (pelvic, middle calyceal and lower pole stones) indications. CONCLUSIONS: Isolated upper pole access is indicated in a select group of patients with complex stones. Upper calyceal and staghorn stones are more commonly managed by upper pole access, which is associated with a higher complication rate and longer hospital stay as well as a lower stone-free rate due to procedure complexity.

Epithelial mesenchymal transition status is associated with anti-cancer responses towards receptor tyrosine-kinase inhibition by dovitinib in human bladder cancer cells.

BACKGROUND: Dovitinib (TKI-258) is a receptor tyrosine kinase (RTK) inhibitor targeting fibroblast growth factor receptor (FGFR) and further related RTKs. TKI-258 is under investigation as anticancer drug for the treatment of various cancers including bladder cancer with aberrant RTK signaling. Here, we analyzed the responses of ten human bladder cancer cell lines towards TKI-258 treatment in relation to the epithelial mesenchymal transition (EMT) status of the cells. METHODS: Expression of epithelial marker E-cadherin as well as mesenchymal markers N-cadherin and vimentin was determined by quantitative RT-PCR and Western-blot in RNA and protein extracts from the cultured cell lines. The cell responses were analyzed upon addition of TKI-258 by viability/proliferation (XTT assay) and colony formation assay for measurement of cell contact independent growth. RESULTS: The investigated bladder cancer cell lines turned out to display quite different EMT patterns as indicated by the abundance of E-cadherin or N-cadherin and vimentin. Protein and mRNA levels of the respective components strongly correlated. Based on E-cadherin and N-cadherin mRNA levels that were expressed approximately mutual exclusively, an EMT-score was calculated for each cell line. A high EMT-score indicated mesenchymal-like cells and a low EMT-score epithelial-like cells. Then, we determined the IC50 values for TKI-258 by dose response curves (0-12 µM TKI-258) in XTT assays for each cell line. Also, we measured the clonogenic survival fraction after adding TKI-258 (1 µM) by colony formation assay. We observed significant correlations between EMT-score and IC50 values (r = 0.637, p = 0.0474) and between EMT-score and clonogenic survival fraction (r = 0.635, p = 0.0483) as analyzed by linear regression analyses. CONCLUSIONS: In sum, we demonstrated that the EMT status based on E-cadherin and N-cadherin mRNA levels may be useful to predict responses towards TKI-258 treatment in bladder cancer.

Frequency of microsatellite instability (MSI) in upper tract urothelial carcinoma: comparison of the Bethesda panel and the Idylla MSI assay in a consecutively collected, multi-institutional cohort.

AIMS: Upper tract urothelial carcinoma (UTUC) is a rare malignancy with a poor prognosis which occurs sporadically or in few cases results from a genetic disorder called Lynch syndrome. Recently, examination of microsatellite instability (MSI) has gained importance as a biomarker: MSI tumours are associated with a better response to immunomodulative therapies. Limited data are known about the prevalence of MSI in UTUC. New detection methods using the fully automated Idylla MSI Assay facilitate analysis of increased patient numbers. METHODS: We investigated the frequency of MSI in a multi-institutional cohort of 243 consecutively collected UTUC samples using standard methodology (Bethesda panel), along with immunohistochemistry of mismatch repair (MMR) proteins. The same tumour cohort was retested using the Idylla MSI Assay by Biocartis. RESULTS: Using standard methodology, 230/243 tumours were detected as microsatellite stable (MSS), 4/243 tumours as MSI and 9/243 samples as invalid. In comparison, the Idylla MSI Assay identified four additional tumours as MSS, equalling 234/243 tumours; 4/243 were classified as MSI and only 5/243 cases as invalid. At the immunohistochemical level, MSI results were supported in all available cases with a loss in MMR proteins. The overall concordance between the standard and the Idylla MSI Assay was 98.35%. Time to result differed between 3 hours for Idylla MSI Assay and 2 days with the standard methodology. CONCLUSION: Our data indicate a low incidence rate of MSI tumours in patients with UTUC. Furthermore, our findings highlight that Idylla MSI Assay can be applied as an alternative method of MSI analysis for UTUC.

Advantage of robotic needle placement on a prostate model in HDR brachytherapy.

PURPOSE: To compare the accuracy of the robot-assisted needle positioning with that of the conventional template-guided method with the help of a prostate model in high dose rate (HDR) brachytherapy. MATERIALS AND METHODS: A prostate model of fresh porcine abdomen and special polyvinylchloride (PVC) sheets was developed. To verify the model, deviations from 311 needle placements of real prostate implants were analyzed. Second, the accuracy of the template-guided positioning versus robot-assisted positioning was measured with 20 needle insertions in the model. For robot-assisted positioning, different velocities (2.7, 5.4, 9.8 mm/s) of needle insertion were investigated. RESULTS: The average needle positioning accuracies of manual template guidance on the model closely resembled those of real patients (approximately 3 mm). The average needle positioning accuracy for the robot-assisted method on the prostate model was 1.8 ± 0.6 mm, at a velocity of 2.7 mm/s and, in comparison to the template-guided method (2.7 ± 0.7 mm), was statistically more precise (p < 0.001). At higher robotic velocities, the measured needle positioning accuracy showed no significant difference from that of the manual insertion procedure. CONCLUSION: By employing a prostate model, we showed for the first time that robot-assisted needle placement for HDR brachy-therapy is significantly more precise than the conventional method at a velocity of 2.7 mm/s. The robot-assisted needle positioning technique improves the degree of freedom by providing additional oblique insertion channels and could be potentially exploited not only for LDR but also for HDR brachytherapy.

Antibodies after botulinum toxin A injection into musculus detrusor vesicae: incidence and clinical relevance.

OBJECTIVES: Botulinum toxin A (BTX-A) injection into the detrusor muscle has changed therapy options for patients with overactive bladder (OAB). However, in some patients, therapy fails or the effects of BTX-A decrease. The aim of this prospective study was to evaluate the incidence of BTX-A antibodies (BTX-A Abs) after injection of BTX-A and its clinical relevance. METHODS: 31 patients (27 women, 4 men) were treated with BTX-A for OAB between January 2009 and August 2010. Eleven patients were treated once, 16 patients were treated twice and 4 patients were treated three times. Blood was collected before and 3 months after the BTX-A injection and BTX-A Abs were determined. RESULTS: In 5 patients (16%) BTX-A Abs were detectable after the BTX-A injection. The BTX-A Ab titer was clearly positive in 1 patient (3.2%). This patient showed complete failure of BTX-A therapy. In 4 patients (13%) BTX-A Abs were slightly positive after the first BTX-A injection. The second BTX-A injection showed no positive effects in only 1 patient with borderline BTX-A Ab titers; the second BTX-A injection was successful in 2 patients. CONCLUSIONS: The incidence of BTX-A Abs should be verified in nonresponders. More data are necessary to check the clinical relevance and risk of BTX-A Ab formation, especially in long-term follow-up, to optimize patient selection for this minimally invasive treatment option in OAB.

[CpG-ODN instillation boosts ICAM-1 expression in an orthotopic murine UCC model: immunohistochemical evaluation of the local response to immunostimulatory DNA]. / ICAM-1-Induktion durch CpG-ODN im murinen, orthotopen UCC-Modell ­ Immunhistochemische Analyse der lokalen Immunantwort auf immunstimulatorische DNA-Sequenzen.

BACKGROUND: Immunostimulatory CpG oligodeoxynucleotides (CpG-ODN) have been verified as an effective antineoplastic agent for intravesical application in a murine orthotopic C57-BL6 /MB-49 urothelial cell carcinoma (UCC). To date, many details in the mode of action have remained unclear. Preceding studies pointed towards a Th1-weighted response. The aim of this work was to identify the local lymphocyte subsets in murine tumour-bearing bladders and to examine effects on the expression of Intercellular Adhesion Molecule 1 (ICAM-1) after treatment with CpG-ODN. MATERIAL AND METHODS: Different instillation schedules were applied in an established orthotopic C57-BL6 /MB49 UCC model. After 13 days, fresh frozen sections of the harvested bladders were immunohistochemically examined for the infiltration density of lymphocytes expressing CD 3, CD4, CD8 and CD19. In a second series of the same animal model, healthy and tumour-bearing bladders were exposed to CpG-ODN or PBS and later stained for the expression of ICAM-1. RESULTS: CpG-ODN instillation led to augmented T-cell infiltration (represented by CD3). Further T-cell subdifferentiation between T-helper cells (CD4) and cytotoxic T cells (CD 8a) did not show a perceptible variety between groups. The B-cell population (CD19) was found to decrease over the course of treatment. In the second series, treatment provoked a strong expression of ICAM-1 by infiltrating leukocytes, endothelial cells and particularly by the cancer cells themselves. DISCUSSION: The previously observed augmented lymphocyte density was classified as T-cell infiltration. The decline of the B-cell concentration over the course of treatment suggests a Th2 suppression in favour of a Th-1 polarisation. These findings support the assumption that a cell-mediated immune response is the mode of action underlying the antineoplastic CpG-ODN capacities. The marked upregulation of ICAM-1 expression, especially on tumour cells, suggests a crucial role of this membrane protein for the initiation and maintenance of anticancer immune response. CONCLUSION: CpG-ODN might be a prospective alternative to established instillation therapies. With a view to the current BCG shortage and the well-known toxicities, an amplification of the topic therapy armamentarium could be achievable. The now described capability of ICAM-1 induction on carcinoma cells and, by association, the reversal of escape strategies to cancer immunity may also make the agent interesting as an adjuvant for modern checkpoint inhibition.

[Lasers in urology : Relevant principles]. / Laser in der Urologie : Relevante Grundlagen.

A fundamental understanding of the physical properties is necessary for the application of lasers in medicine in order to be able to understand and appreciate the biological effect. The most important parameters are emission mode, wavelength of the laser and power output measured in watts. Pulsed lasers can be used for the treatment of stones and soft tissues, whereby in urology this essentially applies to the prostate gland and to a lesser extent also for the ureter, urethra, bladder and kidneys.

Efficacy and safety of the Accordion stone-trapping device: in vitro results from an artificial ureterolithotripsy model.

One of the challenges of intracorporeal ureterolithotripsy is undesired stone migration. Stone-trapping devices have been designed to prevent this quite common phenomenon. These devices have to be effective in terms of ureteral obstruction and safe in terms of resistance to the action of commonly used lithotriptors. This work was conducted to evaluate the efficacy and safety of the recently approved Accordion stone-trapping device in vitro. In a rigid, submerged ureteral model with two different diameters (8 and 10 mm), artificial stones were positioned in direct contact with the engaged Accordion device. A defined number of pneumatic pulses of the LithoClast master at different performance levels was applied and the migration distance of the stone was measured after each single pulse. As a control, the same series was repeated without the stone-trapping device. Secondly, the Accordion device was exposed to a previously defined number of pneumatic or Ho:YAG-laser pulses, in direct contact with the lithotripsy probe, up to a total activation time of 2 min. At different time points, the device was controlled for damage and functionality. The mean stone migration distance without the Accordion device was between 39.2 and 52.8 mm and between 37.8 and 75.4 mm in the 8 and 10 mm tubes, respectively. In comparison, the stone or fragment travelling distance with the device was in the 0-2 mm range. This difference was highly significant. Both pneumatic and laser lithotriptor did not affect the functionality of the Accordion device. The Ho:YAG laser causes small perforations of the film without affecting the devices' stability. The Accordion device appears to be highly efficient and safe in vitro. Clinical trials will have to assess its value in endourological practice. Randomised comparative trials comparing different stone-trapping devices are needed.

In vitro and in vivo effects of CpG-Oligodeoxynucleotides (CpG-ODN) on murine transitional cell carcinoma and on the native murine urinary bladder wall.

BACKGROUND: Intravesical BCG instillation is established and efficient in the prophylaxis of recurrent transitional cell carcinoma. A Th-1 biased immune response is postulated. Recent work has proven the efficacy of synthetic CpG-Oligodeoxynucleotides (ODN) as inducers and adjuvants for a strong Th1-response and there is evidence for a direct and/or adjuvant anti-neoplastic effect. The purpose of this study was to examine the local effects of CpG-ODN on the murine bladder wall after intravesical instillation and the effects on cytokine expression in an orthotopic murine bladder cancer model. MATERIALS AND METHODS: Histopathology, immunohistochemistry and fluorescence microscopy were performed after different instillation schedules of stimulatory, non-stimulatory biotinylized and FITC-labelled CpG-ODN into the murine bladder. MB-49 murine bladder cancer cells were tested for TLR-9 expression to exclude a potential direct responsiveness to CpG-ODN. Furthermore induction of apoptosis was tested by annexin V staining and FACS analysis of CpG-ODN stimulated tumor cells. In an orthotopic C57/Bl6 murine bladder cancer model, the expressions of IL-12, IFNgamma, IL-10 and TGF-beta were evaluated after repeated CpG-ODN treatment. RESULTS: Single and repeated instillation of CpG-ODN induced subepithelial and urothelial lymphocytic infiltrations with consecutive apoptoses. PBS and non-stimulative ODN induced no visible reaction. Bladder submucosa stained positive for biotin. Controls showed no endogenic biotin staining. FITC-labelled ODN adhered to the bladder mucosa and penetration of the mucosal barrier was not detected. MB-49 TCC cells did not express TLR-9 and CpG-ODN did not induce apoptosis in these cells. Repeated intravesical instillations of CpG-ODN in orthotopic murine tumor bearing urinary bladders resulted in significant up-regulation of both Th-1 and Th-2 cytokines. CONCLUSION: CpG-ODNs have promising anti-neoplastic potential. They exert a pronounced immunological response both in the native murine urinary bladder and in murine TCC. The mechanisms of action appear to be mediated immunologically, There was no direct effect of CpG-ODN on the tumor cells in this model.

Comparison of a 20-min pad test with the 1-hour pad test of the international continence society to evaluate post-prostatectomy incontinence.

OBJECTIVES: Urinary incontinence is a hygienic and socially distressing problem for affected people and causes high healthcare costs. Objective standardized noninvasive quantification of urinary incontinence is highly important and, in addition, enables control of therapeutic efficacy. The aim of this prospective study was to evaluate the feasibility, accuracy and reproducibility of a standardized 20-min pad test to measure urinary incontinence after radical prostatectomy in comparison to the 1-hour pad-weighing test recommended by the International Continence Society (ICS). METHODS: We applied a standardized questionnaire, the ICS 1-hour pad test and a simplified 20-min pad test to evaluate subjective and objective post-prostatectomy urinary incontinence in 56 men. RESULTS: The technical feasibility of the 20-min pad test was excellent; the results correlated significantly with both the self-assessment via questionnaire (r = 0.63; p < 0.001) and the 1-hour pad test (ICS; r = 0.66; p < 0.001). Moreover, it was highly reliable (r = 0.74; p < 0.0005) with excellent patient acceptance. CONCLUSIONS: The 20-min pad test qualified as a reliable, cost-effective and noninvasive tool which can easily be applied in urologic or physiotherapeutic practice to assess post-prostatectomy urinary incontinence and to evaluate the success of therapeutic approaches.

Urinary collecting system invasion in renal cell carcinoma: incidence and long-term prognosis.

OBJECTIVES: Current data on the prognostic impact of urinary collecting system (UCS) invasion by renal cell carcinoma (RCC) are highly conflicting. The aim of the present study was to assess incidence and long-term prognosis of RCC patients with and without UCS involvement. METHODS: We evaluated 780 patients who had undergone renal surgery between 1990 and 2005. The mean follow-up was 5.44 years. RESULTS: Sixty-seven patients (8.6%) demonstrated UCS invasion. These patients had a significant increase in the likelihood of cancer-related death (hazard ratio [HR] 1.9, 95% confidence interval: 1.4-2.7; P = 0.001). Their median 5-year tumor-specific survival rate was 61%, as opposed to 79% for patients without UCS invasion (P = 0.001). UCS invasion was significantly associated with tumor stage, grade, clinical symptoms, lymph node and visceral metastasis at diagnosis, but not with age, gender, histologic subtype or body mass index. However, by means of multivariate analysis, UCS invasion was disqualified as an individual prognostic marker for RCC. CONCLUSION: We do not advocate the inclusion of UCS invasion into upcoming Tumor-Nodes-Metastasis staging systems. In contrast, future research should focus on the prognostic role of novel molecular tumor markers and/or specific immunological characteristics of RCC patients.

Biochemical markers for monitoring response to therapy: evidence for higher bone specificity by a novel marker compared with routine markers.

The aim of the present study was to compare a novel marker for high bone turnover with two routine markers for screening in prostate cancer patients. The markers were evaluated in two studies: (a) a cross-sectional study of 170 prostate cancer patients with local disease stratified by +/-lymph node metastases (N 0, N1) compared with controls and (b) a longitudinal study of 40 hormone refractory prostate cancer patients stratified by skeletal involvement and followed during docetaxel (+/-BM) and zoledronate (+BM) treatment. Presence or absence of bone metastases (BM) was assessed by imaging techniques (magnetic resonance imaging or X-ray) and technetium-99m scintigraphy. The serum or urinary levels of alpha C-telopeptide of collagen type I (alphaalphaCTX), prostate-specific antigen (PSA), and total alkaline phosphatase (tALP) were assessed. PSA was elevated in both N 0 and N1 patients compared with controls, whereas alphaalphaCTX was elevated only in N1 patients. tALP exhibited no difference in any of the groups. In the treatment study, PSA decreased with treatment in both the -BM and +BM groups compared with baseline values, showing similar effect of docetaxel or docetaxel/zoledronate treatment on this marker. On the contrary, alphaalphaCTX and tALP did not decrease with docetaxel treatment in the -BM group compared with baseline, whereas it decreased significantly with docetaxel/zoledronate treatment in the +BM group, already after 1 month of treatment for alphaalphaCTX. Results suggest that alphaalphaCTX is superior to PSA and tALP for identifying patients having a high risk of metastatic disease and for monitoring skeletal progression in +BM prostate cancer patients during treatment.

Metastatic non-clear cell renal cell carcinoma: current therapeutic options.

Non-clear cell (ncc) renal cell carcinoma (RCC) accounts for approximately 25% of all patients with metastatic RCC. It is refractory to standard immuno(chemo)therapy and, to date, no specific trials have been reported to evaluate the efficacy of novel targeted drugs in the different subtypes of metastatic nccRCC. We review all available data from subgroup analyses of the global sorafenib and sunitinib expanded access programmes, current phase-III trials, and smaller multi- and single-centre studies focusing on the activity of targeted agents in these specific and rare RCC subtypes. Both sorafenib and sunitinib have significant activity in metastatic nccRCC, but the efficacy of each agent seems to vary between different nccRCC forms. Preliminary clinical data for temsirolimus appear to be promising but more extensive and long-term data are awaited. With the advent of novel therapeutic options, specific controlled multicentre trials are urgently needed to define their exact value and efficacy for treating the historically resistant nccRCC forms. The medium-term aim should be to tailor the most advantageous therapy for each patient with respect to his/her individual RCC subtype and physical condition.

CD34+ fibrocytes in chronic cystitis and noninvasive and invasive urothelial carcinomas of the urinary bladder.

CD34+ fibrocytes are constitutive elements of the connective tissue where they play a role in matrix synthesis and tumor-associated stromal remodeling. Secreted protein, acidic, and rich in cysteine (SPARC) is a pivotal mediator of stromal remodeling precipitated by invasive carcinomas. The present study was undertaken to investigate CD34+ fibrocytes in the stroma of the tumor-free urinary bladder, chronic cystitis, and urothelial carcinomas together with stromal expression of alpha-smooth muscle actin (alpha-SMA), CD117, and SPARC. In tumor-free urinary bladder and chronic cystitis, CD34+ fibrocytes were found in the deep lamina propria and tunica muscularis, whereas the superficial lamina propria disclosed a CD34-negative and alpha-SMA-positive fibrocyte-like cell. Invasive urothelial carcinomas revealed a complete loss of CD34+ fibrocytes and concomitant appearance of alpha-SMA-reactive myofibroblasts which showed strong expression of SPARC. CD117 expression of tumor-free and tumor-associated stroma revealed no differences. We in this study for the first time describe CD34+ fibrocytes in the urinary bladder and an up-to-now unknown population of alpha-SMA-positive fibrocytes exclusively occurring in the superficial lamina propria. Stromal remodeling associated with invasive carcinomas in the urinary bladder is characterized by a loss of CD34+ fibrocytes paralleled by a gain of alpha-SMA-positive myofibroblasts and increased expression of SPARC.

Immunohistochemiocal subtyping using CK20 and CK5 can identify urothelial carcinomas of the upper urinary tract with a poor prognosis.

PURPOSE: Genome-wide analyses revealed basal and luminal subtypes of urothelial carcinomas of the bladder. It is unknown if this subtyping can also be applied to upper tract urothelial carcinomas. MATERIALS AND METHODS: Tumor samples from 222 patients with upper tract urothelial carcinomas who were treated with radical nephroureterectomy were analyzed for the expression of seven basal/luminal immunohistochemical markers (CK5, EGFR, CD44, CK20, p63, GATA3, FOXA1). RESULTS: Hierarchical clustering revealed a basal-like subtype (enrichment of CK5, EGFR and CD44) in 23.9% and a luminal-like subtype (enrichment of CK20, GATA3, p63 and FOXA1) in 13.1% of the patients. In 60.8%, little to no markers were expressed, whereas markers of both subtypes were expressed in 2.2%. By using CK5 and CK20 as surrogate markers for the basal and luminal subtypes, we defined four subtypes of upper tract urothelial carcinomas: (i) exclusively CK20 positive and CK5 negative (CK20+/CK5-), (ii) exclusively CK5 positive and CK20 negative (CK20-/ CK5+), (iii) both markers positive (CK20+/CK5+) and (iv) both markers negative (CK20-/CK5-). A receiver-operator analysis provided the optimal cut-off values for this discrimination. An immunoreactive score >1 for CK5 and >6 for CK20 were defined as positive. In multivariate Cox's regression analysis, the CK20+/CK5- subtype was an independent negative prognostic marker with a 3.83-fold increased risk of cancer-specific death (p = 0.02) compared to the other three subtypes. CONCLUSIONS: Immunohistochemical subgrouping of upper tract urothelial carcinomas by analyzing CK5 and CK20 expression can be performed in a routine setting and can identify tumors with a significantly worse cancer-specific survival prognosis.