Analysis of topographical distribution of prostate cancer and related pathological findings in prostatectomy specimens using cMDX document architecture.

INTRODUCTION: Understanding the topographical distribution of prostate cancer (PCa) foci is necessary to optimize the biopsy strategy. This study was done to develop a technical approach that facilitates the analysis of the topographical distribution of PCa foci and related pathological findings (i.e., Gleason score and foci dimensions) in prostatectomy specimens. MATERIAL & METHODS: The topographical distribution of PCa foci and related pathologic evaluations were documented using the cMDX documentation system. The project was performed in three steps. First, we analyzed the document architecture of cMDX, including textual and graphical information. Second, we developed a data model supporting the topographic analysis of PCa foci and related pathologic parameters. Finally, we retrospectively evaluated the analysis model in 168 consecutive prostatectomy specimens of men diagnosed with PCa who underwent total prostate removal. The distribution of PCa foci were analyzed and visualized in a heat map. The color depth of the heat map was reduced to 6 colors representing the PCa foci frequencies, using an image posterization effect. We randomly defined 9 regions in which the frequency of PCa foci and related pathologic findings were estimated. RESULTS: Evaluation of the spatial distribution of tumor foci according to Gleason score was enabled by using a filter function for the score, as defined by the user. PCa foci with Gleason score (Gls) 6 were identified in 67.3% of the patients, of which 55 (48.2%) also had PCa foci with Gls between 7 and 10. Of 1173 PCa foci, 557 had Gls 6, whereas 616 PCa foci had Gls>6. PCa foci with Gls 6 were mostly concentrated in the posterior part of the peripheral zone of the prostate, whereas PCa foci with Gls>6 extended toward the basal and anterior parts of the prostate. The mean size of PCa foci with Gls 6 was significantly lower than that of PCa with Gls>6 (P<0.0001). CONCLUSION: The cMDX-based technical approach facilitates analysis of the topographical distribution of PCa foci and related pathologic findings in prostatectomy specimens.

Does postoperative radiation therapy impact survival in non-metastatic sarcomatoid renal cell carcinoma? A SEER-based study.

INTRODUCTION: The effect of adjuvant radiation therapy on survival in sarcomatoid renal cell carcinoma (sRCC) with no evidence of distant metastasis remains unclear. METHODS: Subjects diagnosed with non-metastatic sRCC were identified using the Surveillance Epidemiology and End Results (SEER) (2004-2012) database and divided into groups based on their surgical treatment (ST): no surgery or radiation therapy (NSR); partial nephrectomy (PNE); radical nephrectomy with ureterectomy and bladder cuff resection (RNE + UE + BLAD); and radical nephrectomy (RNE). Certain radical nephrectomy cases also received adjuvant external-beam radiation therapy (RNE + RAD). The Kaplan-Meier method was used to estimate overall survival (OS). A multivariable competing risks regression analysis was used to calculate disease-specific survival (DSS) probability and to determine factors associated with cause-specific mortality (CSM). RESULTS: A total of 408 patients were included in this study. The 5-year OS and predicted DSS were significantly higher in the patients who underwent STs (i.e., PNE, RNE + UE + BLAD, RNE, and RNE + RAD) (20.1-54.0 and 20.1-59.9 %, respectively) than in the NSR group (9.0 and 11.6 %, respectively) (P < 0.001). ST was independently associated with a decreased CSM (P < 0.0001). No significant differences in OS or the 1-, 3-, or 5-year DSS probabilities between the RNE and RNE + RAD groups were observed. RNE + RAD was not significantly associated with a decrease in 1-year CSM [subhazard ratio (SHR) 0.95; 95 % CI 0.23-3.96; P = 0.947]. CONCLUSIONS: Adjuvant external-beam radiation therapy did not increase OS in non-metastatic sRCC patients.

Retroperitoneal schwannomas of renal and pararenal origin: presentation of two case reports.

Retroperitoneal schwannomas are a rare entity. They originate from the Schwann cells of the nerve sheaths and may be of renal or pararenal origin. We report on two patients with retroperitoneal schwannomas, who received surgery under the suspicion of renal cell carcinoma.

Effects of pumpkin seed in men with lower urinary tract symptoms due to benign prostatic hyperplasia in the one-year, randomized, placebo-controlled GRANU study.

INTRODUCTION: The German Research Activities on Natural Urologicals (GRANU) study was a randomized, partially blinded, placebo-controlled, parallel-group trial that investigated the efficacy of pumpkin seed in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH/LUTS). SUBJECTS AND METHODS: A total of 1,431 men (50-80 years) with BPH/LUTS were randomly assigned to either pumpkin seed (5 g b.i.d.), capsules with pumpkin seed extract (500 mg b.i.d.) or matching placebo. The primary response criterion was a decrease in International Prostate Symptom Score (IPSS) of ≥5 points from baseline after 12 months. Secondary outcome measures included IPSS-related quality of life, IPSS single items and diary-recorded nocturia. RESULTS: After 12 months, the response rate (intention-to-treat/last-observation-carried-forward approach) did not differ between pumpkin seed extract and placebo. In the case of pumpkin seed (responders: 58.5%), the difference compared with placebo (responders: 47.3%) was descriptively significant. The study products were well tolerated. Overall, in men with BPH, 12 months of treatment with pumpkin seed led to a clinically relevant reduction in IPSS compared with placebo. CONCLUSION: In order to fully justify a recommendation for the use of pumpkin seed to treat moderate LUTS, these findings need to be substantiated in a confirmatory study or systematic review.

Complementary medicine down-regulates side-effects of hormone therapy in prostate cancer patients.

AIM: The present clinical investigation was performed to evaluate the benefits of complementary medicine in prostate cancer patients undergoing hormone therapy (HT). PATIENTS AND METHODS: Patients (N=93) were treated according to international guidelines. All patients suffered from side-effects induced by the HT. To reduce the side-effects, the patients were complementarily treated with a combination of sodium selenite, proteolytic plant enzymes and Lens culinaris (Lc) lectin. On case report formulas (CRFs), self assessment of defined side-effects of HT (arthralgia, mucosal dryness, bone pain and hot flushes) were documented before (T-0) and on days 25 (T-1) and 50 (T-2) after complementary treatment. Validation was carried-out by scoring from 1 (no side-effects/optimal tolerability) to 6 (extreme side-effects/extremely bad tolerability), however, only patients suffering from severe side-effects (symptom scores >3) were enrolled in this investigation. RESULTS: The severity of side-effects of HT was reduced by complementary treatment with sodium selenite, proteolytic plant enzymes and Lc-lectin. The mean scores of side-effects declined for arthralgia from 4.72 (T-0) to 3.66 (T-1) to 2.76 (T-2), for mucosal dryness from 4.45 (T-0) to 3.65 (T-1) to 2.90 (T-2), for bone pain from 4.74 (T-0) to 3.44 (T-1) to 2.82 (T-2), for hot flushes from 4.97 (T-0) to 3.70 (T-1) to 3.15 (T-2). The reduced severity of the side-effects was statistically significant (p<0.001) for T-1 and T-2, compared to T-0. CONCLUSION: This investigation demonstrates benefits of indication-based complementary treatment with the combination of sodium selenite, proteolytic plant enzymes and Lc-lectin in prostate cancer patients, e.g. reduction of side-effects of HT.

Catheterless long-term ambulatory urodynamic measurement using a novel three-device system.

AIMS: Long-term urodynamics are required because bladder-emptying disorders are often not clearly revealed by conventional urodynamics. Patients with severe clinical overactive bladder symptoms, for instance, often show normal results. This may be due to the short evaluation time and psychological factors that complicate conventional urodynamics. This study aimed to develop an ambulatory three-component urodynamic measurement system that is easy to operate, registers urodynamic parameters for several days, and has no negative impact on the patient. METHODS: We developed an intravesical capsule combined with a hand-held device to register voiding desire and micturition, and an alarm pad device that detects urine loss. Recently, the intravesical capsule and its proven function were detailed in the literature. Here, we present detailed in vitro results using a female bladder model. The flexible capsule was C-shaped to minimize the risk of expulsion from the bladder during micturition. Results of biocompatibility evaluation of the intravesical capsule, which is called Wille Capsule (WiCa) are described. RESULTS: The WiCa with an oval nose and a maximum outer diameter of 5.5 mm was easily inserted through a 25-French cystoscope. Removing the WiCa by grasping the nose using the female model with bladder was easily conducted. Expulsion of the WiCa during voiding was avoided through a novel C-shaped device design. Based on in vitro cytotoxicity studies, the capsule is a promising and safe device. CONCLUSION: Our novel system is an innovative minimally-invasive tool for accurate long-term urodynamic measurement, and does not require inserting a transurethral catheter.

Is there an urban-rural-gradient in patients with urinary incontinence?

INTRODUCTION: The objective of this study was to determine whether the responses to the same questionnaire differ between women living in a large city and women living in a rural area. METHODS: We evaluated the medical records of 88 patients living in the large city of Cologne and of 86 patients living in Brühl and its surrounding rural regions. The responses on the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) of 88 patients who suffer from urinary incontinence and live in a large city were compared to the responses 86 patients who live the rural region of Brühl. In addition, ages, frequency of micturition, use of pads, prior and desired treatment were compared. Limitations of this study include its retrospective study design and the absence of sociodemographic data. Furthermore, the use of a pad test could objectify the extent of incontinence. RESULTS: On average, patients from Cologne used of 6.2 pads and patients from Brühl used 3 pads. Patients from the large city scored 14 out of 21 points on the ICIQ-SF, and women from Brühl scored 11 out of 21 points. This difference was significant. Patients from Cologne had received medicinal treatment or physical therapy significantly more often. CONCLUSION: The results suggest that urinary incontinence is perceived as a greater impairment by patients residing in (large) cities compared to patients residing in rural areas. An urban-rural gradient in patients with urinary incontinence can be described.

Linkage of data from diverse data sources (LDS): a data combination model provides clinical data of corresponding specimens in biobanking information system.

To provide sufficient clinical data for corresponding specimens from diverse databases established before the implementation of biobanks for research purposes with respect to data privacy regulations. For this purpose, we developed a data model called "linkage of data from diverse data sources (LDS)". The data model was developed to merge clinical data from an existing local database with biospecimen repository data in our serum bank for uro-oncology. This concept combines two data models based on XML: the first stores information required to connect multiple data sources and retrieve clinical data, and the second provides a data architecture to acquire clinical and repository data. All data were anonymized and encrypted using the Advanced Encryption Standard. X.509 certificates were applied to secure data access. Furthermore, we tested the feasibility of implementing these models in the information management system for biobanking. The data concept can provide clinical and repository data of biospecimens. Only authorized receivers can access these data. Sensitive and personal data are not accessible by the data receivers. The data receiver cannot backtrack to the individual donor using the data model. The acquired data can be converted into a text file format supported by familiar statistical software. Supplementary tools were implemented to generate and view XML documents based on these data models. This data model provides an effective approach to distribute clinical and repository data from different data sources to enable data analysis compliant with data privacy regulations.

Urodynamic effect of 80 watt photoselective laser vaporization of the prostate.

OBJECTIVE: The aim of the analysis was to measure the pressure-flow urodynamic changes following GreenLight(™) laser vaporization of the prostate based on pressure-flow studies. MATERIAL AND METHODS: Sixty-two patients suffering from voiding dysfunction due to lower urinary tract symptoms underwent potassium titanyl phosphate (KTP) laser vaporization. A pressure-flow study was performed at baseline and at 3 months postoperatively. Symptoms and quality of life (QoL) were assessed using the International Prostate Symptom Score (IPSS) and questions regarding sexuality were assessed using the International Index of Erectile Function (IIEF). RESULTS: IPSS and QoL scores changed from 24 and 5 at baseline to 6 and 2 at 3 months, respectively. The initial median prostate volume was 35 ml (range 16-60 ml), the median maximum uroflow (Q max) was 9.2 ml/s (4-14.9 ml/s) and the median postvoiding residual urine was 80 ml (20-400 ml) (95% confidence interval 89.14, 135.44). The median IPSS and QoL score were significantly improved (p < 0.001). There was a significant decrease in median detrusor pressure at Q max from 83.1 to 40.45 cmH2O, and the median obstruction grade according to Schäfer's classification was also decreased significantly, from 4 to 1 postoperatively. CONCLUSION: This study showed that significant deobstruction can be demonstrated using a pressure-flow study at 3 months postoperatively.

MicroRNA 15a, inversely correlated to PKCα, is a potential marker to differentiate between benign and malignant renal tumors in biopsy and urine samples.

NF-κB signal transduction is a potential therapeutic target in many malignant tumors. We have recently shown, in malignant renal proximal tumor cells, that a transcription complex, consisting of NF-κB p65 and mitogen-activated protein kinase p38α, joined by protein kinase C (PKC) α, transmigrates into the nucleus. There, PKCα suppresses the nuclear release of primary microRNA (pri-miRNA) 15a. Induced by endothelin (ET)-1, a decrease in PKCα levels leads to increased miRNA 15a (miR-15A) expression. An identical system can be identified in renal carcinomas, in which, after nuclear transmigration, PKCα binds directly to pri-miRNA 15a in the nucleus. However, the pattern of PKC isoforms differs between malignant renal cell carcinoma (RCC) and benign oncocytoma. PKCα, a component of the transcription complex in tumors, is up-regulated in benign oncocytoma but down-regulated in RCC. Conversely, miRNA 15a is up-regulated in RCC and down-regulated in oncocytoma. A similar behavior is observed in chromophobe carcinoma, whereas differences are less pronounced in papillary RCC (type I): NF-κB target gene expression (ie, ET-1, ET-A and ET-B receptors, vascular cell adhesion molecule-1, IL-6, and fractalkine) is particularly high in malignant RCCs. Up-regulated miRNA 15a can be measured in urine from patients with RCC but is nearly undetectable in oncocytoma, other tumors, and urinary tract inflammation. Thus, the up-regulation of miRNA 15a may be an important marker to help identify malignant clear-cell RCCs in both biopsy and urine samples.

Differential effects of ibandronate, docetaxel and farnesol treatment alone and in combination on the growth of prostate cancer cell lines.

Ibandronate, one of the most potent bisphosphonates, has been shown to inhibit growth of various cancer cell lines. In contrast, little is known about the effects of ibandronate on prostate cancer cells. Therefore the aim of our study was to characterize the effects of ibandronate alone and in combination with docetaxel on the growth of prostate cancer cell lines and to identify the underlying signalling pathways. Material and methods. The prostate cancer cell lines LNCaP and PC-3 were treated with increasing concentrations of ibandronate and docetaxel alone and in combination. Viable cell number was measured after five days using a hemocytometer and the MTT-method. The effects of ibandronate were tentatively antagonized by addition of farnesyl-pyrophosphate (FPP) or farnesol (FOH). Results. Ibandronate inhibits growth of both prostate cancer cell lines in a dose dependent manner. In combination with docetaxel, synergistic effects are found as evidenced by a combination index (CI) of <1. Addition of FOH and FPP completely antagonized the growth inhibitory effects of ibandronate on both cell lines. Surprisingly, in combination with ibandronate and docetaxel, FOH further increased growth inhibition instead of antagonizing the growth inhibitory effects of ibandronate. Furthermore, FOH alone appeared to be a potent inhibitor of tumor cell growth. Discussion. Ibandronate effectively inhibits growth of prostate cancer cell lines via inhibition of the farnesyl-IPP-synthase and exhibits synergistic effects with docetaxel. In addition, FOH is a potent inhibitor of prostate cancer cell lines and may display an interesting treatment option for patients with CRPC.

Improving the efficacy of targeted trials by multiple-marker analysis in castration-resistant prostate cancer.

OBJECTIVES: In order to improve the efficacy of targeted therapy trials, the expression profiles of several molecular markers that are potential candidates for targeted therapy were analyzed in patients with progressive castration-resistant prostate cancer. METHODS AND MATERIALS: Paraffin-embedded samples of tumor tissue from 51 patients obtained from biopsies of metastases or remaining prostates were analyzed immunohistochemically for the expression of EGFR, PDGFRß, Her-2/neu, c-Kit, and VEGF. Staining was analyzed according to the percentage of positively stained tumor cells and the intensity of staining. RESULTS: According to the different cut-off values of 10%, 30%, 50%, or 70% for the percentage of positively stained cells, different rates of expression were found. Expression rates ranged from 30.6% to 61.2% for EGFR, from 34.7% to 57.1% for PDGFRß, from 9.6% to 28.8% for Her-2/neu, from 12.5% to 22.4% for c-Kit, and from 51.1% to 74.5% for VEGF. Defining positive expression as ≥ 30% positively stained tumor cells, with an intensity of staining of ≥ 2+, resulted in positive expression of EGFR in 38.8%, PDGFRß in 24.5%, Her-2/neu in 13.5%, c-Kit in 6.4%, and VEGF in 44.7% of the patients. CONCLUSIONS: Our results demonstrate simultaneous expression of several markers in castration-resistant prostate cancer tissue. Translation of the results into modern, multi-arm clinical trial designs will improve the efficacy of recruiting and obtaining results, compared with multiple double-arm trials.

Distribution of EphB4 and EphrinB2 in normal and malignant urogenital tissue.

OBJECTIVE: Ephrin (Eph) receptors are receptor tyrosine kinases; both EphrinB2, as a ligand, and EphB4, as a receptor, are involved in angiogenesis. EphrinB2 is expressed on arteries and EphB4, a specific receptor for EphrinB2, is expressed on veins. It is unknown whether involvement of arteries and veins in tumor angiogenesis is distinctive. Here we investigated their distribution in normal and malignant tissue of the urogenital tract. MATERIALS AND METHODS: Five-micrometer-thick paraffin sections from nontumoral and tumoral tissues of kidney (n = 12), bladder (n = 33), and prostate (n = 20) were immunoreacted with antisera against EphB4 and EphrinB2 using the avidin-biotin-peroxidase complex technique. Comparisons of EphB4 and EphrinB2 stained arterial and venous vessels in the nontumoral and tumoral sections were evaluated in a semiquantitative analysis as frequency of the vessels in a predetermined tumor area counted under light microscopy. RESULTS: Expression of EphrinB2 in arterial and EphB4 in venous endothelium was significantly greater in tumoral sections compared with nontumoral sections. No statistically significant correlation in comparing the labeling patterns for EphrinB2 with the labeling patterns for EphB4 was observed in nontumoral as well as tumoral sections. CONCLUSIONS: The high expression of EphrinB2 in arterial and EphB4 in venous endothelium of urogenital tract tumors might contribute to their involvement in the progression of tumor angiogenesis. The relation between arteries and veins in the normal and tumor tissues is unchanged.

Neonatal testicular infarction--possibly due to compression of the umbilical cord?

Neonatal testicular infarction is a rare occurrence. We report on a newborn infant with bilateral testicular infarction. At birth, the uncut umbilical cord ran taut between the thighs making a complete loop around the genitals, compressing the testes. At the age of 6 hours, because of increasing agitation and the beginnings of scrotal discoloration, the infant was operated on, showing a bilateral testicular infarction potentially induced by strangulation of the twisted umbilical cord. Here, we discuss the clinical findings of neonatal testicular infarction and give advice as to the management of this serious complication with regard to the available published data.

Longevity of spermatozoa in the post-ejaculatory urine of fertile men.

Many scientists of varying clinical backgrounds have described the phenomenon of spermaturia in animals, adolescents as well as fertile and infertile men. Nevertheless, research for an expert opinion on a law case in the field of forensic medicine revealed a lack of valid information about the longevity of spermatozoa in post-ejaculatory urine (PEU) of fertile men. Our goal was to measure the appearance of vivid sperm in PEU while considering the factor of time in order to predict a realistic interval, in which positive sperm findings might occur. Therefore ten healthy, young men donated their sperm for fertility analysis and a urine sample prior to and after ejaculation. The time intervals between ejaculation and the first micturition were preset ranging between 30 min and maximal 11h. Each ejaculate underwent a semen analysis. The pre- and post-ejaculatory urine samples were screened for the presence of viable and motile spermatozoa. Semen parameters were determined and related to the sperm findings in the precipitate of the urine samples. The amount, the viability and motility status of the detected spermatozoa were recorded after each preset time interval. The results showed that none of the 10 participants had sperm in their urine samples prior to ejaculation. The average sperm concentration was 50.1+/-25.8 million/ml. After a time span of 30 min 59.5% of the first fractions of PEU samples were sperm positive, after 2 and 4h still 70%, and after 5h sperm were no longer detected. The last motile spermatozoa could be found after 4.5h. It seems that remaining sperm in the urethra are washed out with the first micturition in the majority of fertile men, however, the conclusion as to whether sperm findings >5h after ejaculation are improbable needs to be confirmed by further investigations.

Efficacy and safety of a combination of Sabal and Urtica extract in lower urinary tract symptoms--long-term follow-up of a placebo-controlled, double-blind, multicenter trial.

In an open-label extension of a randomized, double-blind clinical trial, the long-term efficacy and tolerability of a fixed combination of 160 mg Sabal fruit extract WS 1473 and 120 mg Urtica root extract WS 1031 per capsule (PRO 160/120) were investigated in elderly men with moderate or severe lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH). Two hundred and fifty-seven patients were randomly treated with 2 x 1 capsule/day PRO 160/120 or placebo for 24 weeks, followed by a 24-week control period and a 48-week follow-up period in which all patients received PRO 160/120. Efficacy measures included the assessment of LUTS [International Prostate Symptom Score ((I-PSS) self-rating questionnaire] and uroflow and sonographic parameters. Two hundred and nineteen subjects participated in the follow-up. Between baseline and end of observation (week 96) the I-PSS total score was reduced by 53% (P < 0.001), peak and average urinary flow increased by 19% (P < 0.001), and residual urine volume decreased by 44% (P = 0.03). The incidence of adverse events during follow-up was one in 1,181 treatment days; in only one event a causal relationship with intake of PRO 160/120 could not be excluded. Treatment with PRO 160/120 thus provides a clinically relevant benefit over a period of 96 weeks.

Improved spontaneous erectile function in men with mild-to-moderate arteriogenic erectile dysfunction treated with a nightly dose of sildenafil for one year: a randomized trial.

AIM: To test the hypothesis that sildenafil (50 mg nightly for one year) can improve spontaneous erectile function (EF) in men with mild-to-moderate arteriogenic erectile dysfunction (ED) responsive to erectogenic treatment. METHODS: In a prospective open-label trial, 112 men with ED were randomized to sildenafil 50 mg nightly or sildenafil 50 or 100 mg as needed for 12 months, followed by one-month and 6-month non-medicated periods. Non-randomized, non-medicated men with ED were also assessed. The EF domain of the International Index of Erectile Function (IIEF EF) and the peak systolic velocity (PSV) of penile cavernous arteries were used to measure the efficacy. RESULTS: After sildenafil treatment and a subsequent non-medicated month, IIEF EF was normal in 29 of 48 (60.4%, 95% confidence interval [CI]: 45.3-74.2%) of the nightly group vs. 4 of 49 (8.2%, 95% CI: 2.3-19.6%) of the as-needed group. PSV improved by 11.2 cm/s (95% CI: 4.7-21.4; P=0.012) in the nightly group but only by 3.4 cm/s (-5.1-14.7; P=0.435) in the as-needed group. IIEF EF normalized in 1 of 18 (5.6%, 95% CI: 0.1-27.3%) non-medicated men and the PSV declined slightly. Six months after treatment, the IIEF EF remained normal and PSV was stabilized in most (28/29, 97%) nightly group men who had initially normalized. CONCLUSION: Sildenafil nightly for one year resulted in ED regression that persisted well beyond the end of treatment, so that spontaneous EF was characterized as normal on the IIEF in most men. The results from this open-label, randomized trial warrant verification under double-blind, placebo-controlled conditions.