STIMULATION OF THE CYCLIC AMP/GMP SIGNALLING ENHANCES THE RELAXATION OF ISOLATED HUMAN DETRUSOR SMOOTH MUSCLE ACHIEVED BY PHOSPHODIESTERASE INHIBITORS.

Phosphodiesterase (PDE) enzymes are considered being key proteins in controlling the function of smooth musculature in the human urinary tract. The use of PDE inhibitors (PDE-Is) to treat erectile dysfunction and lower urinary tract symptomatology (LUTS) secondary to benign prostatic hyperplasia (BPH) is well established. It has been shown that PDE-Is can reverse the tension induced by means of muscarinergic agents of detrusor smooth muscle and enhance the production of cyclic nucleotides. In clinical settings, the PDE1 inhibitor vinpocetine had beneficial effects in patients presenting with voiding dysfunctions. This prompted us to evaluate further the mechanism of action of PDE-Is on bladder smooth musculature. Using the tissue bath technique, relaxant responses of human detrusor smooth muscle, challenged by acetylcholine (1 µM), to vinpocetine (PDE1-I), rolipram (PDE4-I), MY 5445 and sildenafil (PDE5-Is) (0.1 µM, 1 µM, and 10 µM) were investigated with and without pre-exposure of the tissue to threshold concentrations of the NO donor drug sodium nitroprusside (SNP) or adenylyl cyclase activator forskolin (0.02 µM). The non-specific PDE-I papaverine was used as a reference compound. The cumulative addition of forskolin or SNP exerted a pronounced reversion of the tension induced by means of ACh, starting at a concentration of 1 µM (forskolin, -25,6%) and 0.1 µM (SNP, -20%), respectively. There were marginal responses of the detrusor smooth musculature to the PDE-Is, the relaxation measured ranged from -12% (vinpocetine/sildenafil) to -19% (rolipram, MY 5445). Exposure of the tissue to a threshold concentration of SNP increased the reversion of tension induced by vinpocetine (-40%), rolipram (-50%) and MY 5445 (-45%). An enhancement in the potency of the drugs was also registered. A threshold concentration of SNP did not significantly affect the maximum reversion of tension brought about by sildenafil but added positively to the in vitro potency of the PDE5-I. PDE inhibitors may tend to be more effective in systems characterized by an enhanced production of cyclic AMP/GMP (such as urogenital tissues in vivo). Our findings may explain how PDE inhibitors can affect symptoms of the overactive bladder.

Endopeptidase inhibition attenuates the contraction induced by big endothelin-1 of isolated human penile erectile tissue.

Peptides, such as C-type natriuretic peptide (CNP), vasoactive intestinal polypeptide (VIP) and endothelin 1 (ET-1), are involved in the control of penile erectile tissue (corpus cavernosum = CC). Inhibiting the degradation of CNP and VIP or conversion of Big ET-1 into ET-1 by endopeptidase enzymes should result in an enhancement of CC smooth muscle relaxation. Using the tissue bath technique, responses of isolated CC, challenged by noradrenaline (NA, 1 µm), to increasing concentrations of the endopeptidase inhibitor KC 12615 (1 nm - 10 µm), CNP and VIP (0.1 nm - 1 µm), were investigated. Effects of CNP, VIP and Big ET-1 (0.1 nm - 100 nm) on the tissue tension were also evaluated following pre-exposure to 10 µm of KC 12615. Big ET-1 induced contraction of the CC amounting to a force generation of 1,200 mg. The contraction was attenuated in the presence of KC 12615 by 35% and 50%, respectively. The tension induced by NA was reversed by VIP and CNP to 38.7% ± 15.8% and 61% ± 13%, respectively, of the initial force. The findings might be of significance with regard to future pharmacological treatment options for male ED, where an endothelial dysfunction exists.

Expression and distribution of key proteins of the endocannabinoid system in the human seminal vesicles.

The endocannabinoid system (ECS), comprising the cannabinoid receptors (CBR), their ligands, and enzymes controlling the turnover of endocannabinoids, has been suggested to be involved in male reproductive function. As information is scarce on the expression of the ECS in human male reproductive tissues, this study aimed to investigate by means of molecular biology (RT-PCR) and immunohistochemistry/immunofluorescence the expression and distribution of CB1 and CB2, GPR55 (an orphan G protein-coupled receptor that recognises cannabinoid ligands) and FAAH (isoforms 1 and 2) in the human seminal vesicles (SV). The specimens expressed PCR products corresponding to CB1 (66 bp), CB2 (141 bp), GPR55 (112 bp), FAAH1 (260 bp) and FAAH2 (387 bp). Immumohistochemistry revealed dense expression of CB1, CB2 and GPR55 located to the pseudo-stratified columnar epithelium and varicose nerves (also characterised by the expression of vasoactive intestinal polypeptide and calcitonin gene-related peptide). Cytosolic staining for FAAH1 and FAAH2 was seen in cuboidal cells of all layers of the epithelium. No immunoreactivity was detected in the smooth musculature or nerve fibres. CB1, CB2, GPR55, FAAH1 and FAAH2 are highly expressed in the human SV. Considering their localisation, the ECS may be involved in epithelial homeostasis, secretory function or autonomic mechano-afferent signalling.

Expression and distribution of the transient receptor potential cationic channel A1 (TRPA1) in the human clitoris-comparison to male penile erectile tissue.

The transient receptor potential cationic channel ankyrin 1 (TRPA1) is a channel protein assumed to act in various human tissues as mechano- and pain sensor and play a role in neurotransmission. The expression of TRPA has already been investigated in the human prostate and urethra, however, only very few studies have addressed the expression and distribution in the male and female genital tract. The present study aimed to investigate by means of immunohistochemistry (double-labeling technique, laser fluorescence microscopy) in the human clitoris and penile erectile tissue the localization of TRPA1 in relation to nNOS, the vasoactive intestinal polypeptide (VIP) and vesicular acetylcholine transporter (VAChT). In the clitoral tissue, TRPA1 was observed in basal epithelial cells and slender nNOS-positive nerve fibers transversing the subepithelial space. To a certain degree, in the clitoral epithelial cells, TRPA1 was found co-localized with vimentin. In human corpus cavernosum, immunoreactivity for TRPA1 was seen in nerves transversing the cavernous sinusoidal space and running alongside small arteries, these nerves also displayed expression of the vesicular acetylcholine transporter protein (VAChT). Varicose nerves containing nNOS or VIP were not immunoreactive for TRPA1. It seems likely that TRPA1 is involved in nitric oxide-mediated afferent sensory transmission in the clitoris while, in penile erectile tissue, a role for TRPA1 in cholinergic signaling might be assumed.

Protein kinase enzymes in the human vagina-relation to key mediators of the cyclic AMP and cyclic GMP pathways.

Aside from phosphodiesterase (PDE) isoenzymes, protein kinases (cAK=cyclic AMP-binding protein kinase, cGK=cyclic GMP-binding protein kinase) have also been identified as important receptors for cyclic nucleotides. A significance of protein kinases in the control of the function of the male and female reproductive tract has been suggested; however, up until today, only a few approaches have addressed these enzymes in female genital tissues. The present study aimed to investigate by means of biochemical and immunohistochemical methods the expression of cAK and cGK. The distribution of cAK(I) and cGK(I) in relation to the vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP) and PDE type 4 (PDE4) was also evaluated. Cytosolic supernatants prepared from specimens of vaginal wall smooth muscle or epithelium were subjected to anion exchange chromatography and the activities of cAK and cGK(I) measured. To evaluate the distribution of cAK(I) and cGK(I) in relation to VIP, CGRP and PDE4, immunohistochemistry was conducted in sections of the human vaginal wall (full-wall specimens). Activities representing cGK(I) and cAK(I) were resolved from the chromatography column. Staining specific for cAK(Iα) was identified in both vascular and non-vascular vaginal smooth musculature, immunoreactivity for cGK(Iß) was observed in the smooth muscle and endothelium of small arteries interspersing the sections. cAK(Iα)-positive vessels were found innervated by slender varicose nerve fibers presenting the expression of VIP and CGRP. These arteries also expressed PDE4. Localization of cAK and cGK in close relation to key mediators of the cyclic AMP (PDE4, VIP) and cyclic GMP (CGRP) pathways indicate that both signaling systems may synergistically work together in human vaginal tissue.

[Massive bleeding of the urogenital tract]. / Massive Urogenitalblutung.

Massive bleeding of the urogenital tract is, in the same way as acute bleeding from all other organs, a medical emergency and necessitates precise diagnostics and treatment. In this article the topic is addressed in four main categories: first the inflammatory causes are discussed, followed by surgical, traumatic and neoplastic causes of massive bleeding. Subsequently, the rare but clinically relevant causes of acute and massive bleeding are described.

Effects of endopeptidase inhibition on the relaxation response of isolated human penile erectile tissue to vasoactive peptides.

Peptides, such as CNP, CGRP and VIP, are involved in the function of male penile erectile tissue. Tissue levels of said peptides are controlled by the endopeptidase enzymes. Theoretically, the inhibition of the degradation of CNP, CGRP and/or VIP should result in an enhancement in penile smooth muscle relaxation. The effects were investigated of CNP or VIP (0.1 nm-1 µm), without and following pre-exposure of the tissue to a threshold concentration of the endopeptidase inhibitor KC 12615 (10 µm, for 20 min), on the reversion of tension induced by means of electrical field stimulation. Drug effects on the production of cyclic AMP/GMP were also evaluated. Neither KC 12615, CNP and VIP nor the combination of CNP plus KC 12615 or VIP plus KC 12615 increased the response of the tissue to EFS. While no effects were observed of a pre-exposure of the tissue to KC 12615 on the production of cyclic AMP in the presence of VIP, an enhancement was registered in the accumulation of cyclic AMP in the presence of CNP plus KC 12615. Further studies are indicated to investigate whether endopeptidase inhibitors might tend to be more effective in tissues affected by a decreased local production of vasoactive peptides.

[Partial Nephrectomy in cT1 Renal Tumours: Conventional Laparoscopic Partial Nephrectomy Compared with LESS Partial Nephrectomy in SITUS Technique]. / Nierenteilresektion bei cT1 Nierentumoren: Vergleich der konventionellen laparoskopischen Nierenteilresektion mit der LESS Nierenteilresektion in SITUS-Technik.

BACKGROUND: Partial nephrectomy is the treatment of choice for clinical stage 1 renal tumours. Open partial nephrectomy is the standard operative technique. The use of minimally-invasive strategies such as laparoscopic, robot-assisted partial nephrectomy or laparoendoscopic single site (LESS) partial nephrectomy has increased in recent years. PATIENTS/MATERIAL AND METHODS: In this retrospective study, patients undergoing laparoscopic partial nephrectomy between December 2008 and November 2013 were evaluated. All patients presented with renal lesions suspicious for malignancy. Operations were performed as conventional laparoscopic transperitoneal partial nephrectomies (cLPN) or LESS partial nephrectomies (LESS-PN) in SITUS technique (single incision transumbilical surgery). The aim of the study was to compare perioperative outcome parameters such as duration of surgery, time of ischaemia, complications, need for transfusion, conversion rates, changes in renal function and duration of hospital stay in both groups. RESULTS: A total of 85 laparoscopic partial nephrectomies were performed in this study (72 cLPN and 13 LESS-PN). The average tumour size was 2.68±1.47 cm (cLPN) vs. 2.46±1.11 cm (LESS-PN). The mean duration of surgery was 175.17±50.026 min (cLPN) and 185.77±35.991 min (LESS-PN). 45 (62.5%) operations (cLPN) vs. 10 (76.9%) (LESS-PN) were performed in zero-ischaemia technique. There were no significant differences in perioperative outcome parameters between both groups. Postoperative complication rates (Clavien-Dindo≥3) were 11.1% (cLPN) vs. 7.7% (LESS-PN). CONCLUSIONS: LESS partial nephrectomy in SITUS technique is an attractive alternative to conventional laparoscopic and open partial nephrectomy.

[Implications of TCGA Network Data on 2nd Generation Immunotherapy Concepts Based on PD-L1 and PD-1 Target Structures]. / Implikationen der TCGA Netzwerkdaten für Zweit-Generations-Immuntherapiekonzepte auf Basis der PD-L1 und PD-1 Zielstrukturen.

The era of cytokines, given to patients with metastatic renal cell carcinoma (mRCC) as part of an unspecific immunomodulatory treatment concept, seems to have ended with the introduction of targeted therapies. However, preliminary data from studies on treatment with checkpoint inhibitors (e. g. anti-PD-1 and anti-PD-L1) may point the way to second-generation immunotherapy. The rationale of such immunomodulatory treatment is to stop or interrupt the tumour from "escaping" the body's immune defence. Thompson et al. report that increased protein expression of PD-L1 (CD274/ B7-H1) in tumour cells and tumour-infiltrating immune cells (TILs; lymphocytes and histiocytes) is associated with unfavourable clinical pathological parameters as well as poor survival. In small pilot groups of mRCC patients it was found that increased PD-L1 protein expression in tumours and TILs may be correlated with the objective response to anti-PD-1 treatment. Sometimes, however, a very wide variety of response rates was observed, which raises the question if this can be explained by individual expression levels of PD-L1 (CD 274) or PD-1 (PDCD1).Recently published data from the Cancer Genome Atlas (TCGA) Kidney Renal Clear Cell Carcinoma (KIRC) Network now provide a genome-wide data base that allows us to review or validate the molecular results obtained in clear cell renal cell carcinomas (ccRCC) to date.In this study, we analysed the TCGA KIRC mRNA expression data for PD-L1 and PD-1 for a possible association with clinical pathological parameters and the survival of 417 ccRCC patients.The mRNA expression of PD-L1 in primary nephrectomy specimens revealed no significant association with unfavourable clinical parameters. Interestingly, though, a positive correlation with patient survival was found (HR=0,59, p=0,006).These results, which partly contradict the concept applied to date, point out the necessity to ascertain the characteristics of PD-L1 and PD-1 expression at mRNA and protein level in an appropriately sized patient population and evaluate the clinical significance.

[Neoadjuvant or Adjuvant Chemotherapy for Bladder Cancer?]. / Neo- oder adjuvante Chemotherapie beim Harnblasenkarzinom?

Advanced urothelial carcinoma of the bladder is associated with a high metastatic potential. Life expectancy for metastatic patients is poor and rarely exceeds more than one year without further therapy. Neoadjuvant chemotherapy can decrease the tumour burden while reducing the risk of death. Adjuvant chemotherapy has been discussed controversially. Patients with lymph node-positive metastases seem to benefit the most from adjuvant chemotherapy. In selected patients, metastasectomy can prolong survival. In metastastic patients, the combination of gemcitabine and cisplatin has become the new standard regimen due to a lower toxicity in comparison to the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). For second-line treatment, vinflunine is the only approved therapeutic agent.

[Castration resistant prostate cancer 2015]. / Kastrationsresistentes Prostatakarzinom 2015.

Prostate cancer is still the most common urological cancer of the elderly man. In some patients, a metastatic prostate cancer arises which may remain a stable disease for years with palliative antiandrogen therapy. On average, after 3-4 years, affected men develop a PSA rise and disease progression with the formation of a so-called castration-resistant disease. 5 years ago cytotoxic chemotherapy with docetaxel was the only life-prolonging treatment option in this situation. In the last 5 years, the results of randomised phase III studies have led to the approval of 5 new agents for the treatment of metastatic castration resistant prostate cancer (mCRPC). The results and approval status of the substances, Abiraterone, Enzalutamide, Cabazitaxel, Sipuleucel-T and radium-223 are described below. In addition, some aspects of sequential therapy and possible future molecular approaches are discussed.

Expression and distribution of the transient receptor potential cationic channel ankyrin 1 (TRPA1) in the human vagina.

The transient receptor potential cationic channel type A1 (TRPA1), belonging to a superfamily of cationic membrane channels, has been suggested to act as mechano- and pain sensor and, thus, to play a role in neurotransmission in the human body, including the urogenital tract. While the expression of TRPA1 has been investigated in a variety of tissues, up until today, no study has addressed the expression and distribution in the female genital tract. The present study aimed to investigate the expression and distribution of TRPA1 protein in human vaginal tissue. Reverse transcriptase PCR (RT-PCR) was applied in order to identify messenger ribonuleic acid specifically encoding for TRPA/A1. The distribution of TRPA1 in relation to the neuronal nitric oxide synthase (nNOS) and the signaling peptide calcitonin gene-related peptide (CGRP) was examined by means of immunohistochemical methods (double-antibody technique, laser fluorescence microscopy). RT-PCR analysis revealed the expression of mRNA encoding sequences specific for TRPA in the vaginal wall and epithelium. Immunostaining related to TRPA1 was observed in the basal epithelium and in slender varicose nerve fibers transversing the subepithelial and stromal space of the vaginal sections. In addition, these fibers presented immunoreactivity specific for nNOS or CGRP. The smooth musculature of the vaginal wall and small vessels interspersing the tissue did not present signals related to TRPA1. The findings indicate that TRPA1 might be involved in afferent neurotransmission in the vagina and work synergistically together with the nitric oxide/cyclic guanosine monophosphate pathway.

[Induratio penis plastica and the capability of vaginal penetration in the context of forensic evaluation]. / Induratio Penis Plastica und Vaginale Penetrationsfähigkeit im Kontext der Forensischen Begutachtung.

The so-called Induratio penis plastica (IPP), also known as Peyronie Disease or Morbus Peyronie, is the most common cause for deviation of the male penis. In most cases, the deviation is directed to the dorsal side. In face of a lawsuit related to a sexual offence, the opponent might argue that, due to an existing IPP, he is generally unable to insert his penis into a female's vagina. The aim of the present study was to examine the clinical files of thirty (30) consecutive patients who presented with IPP. Particular attention was given to the individual degree of penile deviation and the ability of the subjects to conduct vaginal intercourse. Subjects who had a dorsal penile deviation of 800 to 900, or a lateral deviation of 600, were unable to commence vaginal coitus. In contrast, three (3) subjects who presented with a ventral deviation of 30° to 40° had no difficulties in performing vaginal penetration. The medicolegal aspects of these findings are being discussed.

[Visual diagnosis while performing transurethral resection of bladder tumors: power or myth?]. / Blickdiagnose bei der transurethralen Resektion von Harnblasentumoren : Macht oder Mythos?

INTRODUCTION: The gold standard for diagnosis and immediate therapy of bladder cancer is a transurethral resection (TURB) followed by histopathologic evaluation. The aim of this study was to assess the reliability of visual diagnosis by the operating urologist concerning dignity (malignant/benign) and staging compared to histopathologic evaluation. This is especially crucial since early mitomycin C instillation is based on the urologist's first impression. STUDY DESIGN AND METHODS: This prospective study included 311 cases of TURB from five German institutions. Surgeons were asked to estimate dignity of the neoplasm, tumor stage, and grade according to a standardized questionnaire. RESULTS: The subjective estimation/visual diagnosis of the operating urologist achieved a sensitivity with respect to identifying malignant tumors as such of 97%, while specificity was only 41%. Accordingly, the positive (PPV) and negative predictive values (NPV) were 76% and 88%, respectively. In general, muscle invasive cancer was predicted more often than confirmed by pathology (PPV 52%). However, whenever muscle invasive cancer was excluded by the urologist, this was confirmed by the pathologist in most the cases (NPV 95%). The educational degree did not influence the reliability and predictive value of visual diagnosis. CONCLUSION: This study shows that urologists cannot reliably distinguish benign from malignant lesions of bladder mucosa-regardless of their educational degree. A reliable diagnosis of a pathologist is definitely needed to plan final therapeutic steps.

[Influence of ureter stenting before ureterorenoscopic treatment of ureteral calculi]. / Einfluss der Ureterschienung vor ureterorenoskopischer Behandlung von Harnleitersteinen.

BACKGROUND: Due to a worldwide rise of incidence, urolithiasis presents an increasing strain on the health system. Ureterorenoscopy (URS) is a standard treatment to extract stones in case of ureteral calculi. To increase the success rate of URS and to minimize complications, preoperative ureteral stenting (prestenting) has previously been described as suitable. However, published data are still conflicting. This article describes our single-center experience on the influence of prestenting on the outcome of ureterorenoscopic stone therapy. METHODS: A total of 442 patients who had undergone ureterorenoscopic stone extraction at the Wolfsburg Clinic between 2010 and 2011 were retrospectively evaluated regarding peri- and postoperative results. The Fisher's exact, the χ(2), and the Mann-Whitney U test were used to compare the group of patients with and without prestenting. RESULTS: Even though patients with prestenting suffered from stones with larger diameter that were more frequently located in the proximal ureter, the rates for postoperative stenting, perioperative complications, and retreatment were much lower then in the group of patients without prestenting (p<0.001). Furthermore, patients who had received prestenting had a significantly shorter hospital stay (median, 3 vs. 2 days, p<0.001) and higher rates of stone clearance (83.0 vs. 69.7%, p=0.001). CONCLUSION: According to our retrospective monocentric analysis, prestenting may significantly reduce the risk of complications as well as intra-/post-URS restenting and can increase the rate of complete stone clearance.

[C-reactive protein prior to radical cystectomy: preoperative determination of CRP]. / C-reaktives Protein vor radikaler Zystektomie : Präoperative Bestimmung von CRP.

BACKGROUND: Numerous studies have shown a positive correlation between elevated C-reactive protein (CRP) and systemic spread of malignancies. The goal of the current study was to assess the predictive significance of preoperative CRP in patients undergoing radical cystectomy (RC). MATERIAL AND METHODS: Preoperative CRP values were measured in 194 patients undergoing RC because of urothelial carcinoma between 1996 and 2005. Elevated CRP level was defined as ≥ 5 mg/l. RESULTS: Preoperative increased CRP values were detected in 89 (45.9%) patients and these patients were more likely to have advanced tumor stages (pT3-4), positive resection margins and positive lymph nodes. Advanced urinary diversions were more common in patients with normal CRP values. In multivariate analysis, CRP was identified as an independent prognostic indicator for poor cancer-specific survival. CONCLUSION: The results confirm previous reports that showed a prognostic significance of preoperative CRP elevation.

[Utility of the serum CRP value for assessing the prognosis and therapeutic response of urological malignancies]. / Stellenwert des Serum-CRP-Wertes zur Einschätzung von Prognose und therapeutischem Ansprechen urologischer Malignome.

C-reactive protein (CRP) is an unspecific marker of systemic inflammation. It is known to be elevated in autoimmune disease, traumata and malignancies. Increased CRP levels have specifically been shown to be associated with disease progression and prognosis in various studies on renal cell carcinoma and transitional cell carcinoma. Although CRP, unlike PSA, is neither organ-specific nor tumour-specific, studies were able to show that increased CRP values are an independent prognostic marker for tumour-specific survival of patients with prostate cancer. In metastatic and castration-resistant prostate cancer elevated CRP levels have been approved as a useful marker to estimate the extent of disease and mortality. CRP measurements in serum are standardised worldwide and widely used in daily clinical routine. However, until CRP can be firmly established as a prognostic marker in daily routine, we need validation of its prognostic and predictive value with large and preferably prospective multicentre studies.

[Influence of obesity on urological malignancies]. / Der Einfluss von Adipositas auf urologische Tumorerkrankungen.

BACKGROUND: Overweight presents a growing problem in our society; therefore, there is an increasing interest to understand the influence of obesity on urological forms of cancer. AIM: In prostate cancer the development of a more aggressive phenotype seems to correlate with obesity. In renal cell cancer (RCC) obesity is both, a risk factor for occurrence -and is also associated with an improved tumour-specific survival in patients with organ-confined disease following kidney surgery as well as overall survival of patients with advanced disease receiving VEGF(R)-targeted treatment. In contrast, even though an association between body mass index (BMI) and bladder cancer has been described the role of obesity in bladder cancer remains largely unclear as published data are contradictory. RESULTS: An update on currently available data focusing on the relationship between obesity and genitourinary malignancies is given in this review; however, basic research which is necessary to define the biological and metabolic effects associated with obesity and which might affect the development and progression of urological cancers, is indicated.

Hsa-mir-124-3 CpG island methylation is associated with advanced tumours and disease recurrence of patients with clear cell renal cell carcinoma.

BACKGROUND: Whether methylation of the microRNA (mir)-124-3 CpG island is of relevance for the clinical course of a solid cancer and whether it shows association with clinicopathology or survival of patients with renal cell cancer (RCC) is not known as yet. METHODS: In a cross-sectional study, relative methylation of mir-124-3 was measured in 111 RCC samples and 77 paired normal appearing tissues using quantitative methyl-specific PCR. Results were statistically compared with tumour histology, clinicopathological parameters and disease recurrence. RESULTS: We found tumour-specific hypermethylation of mir-124-3 in samples of RCCs with clear cell histology (ccRCC) compared with paired normal appearing tissues (P<0.0001). Methylation was significantly increased in tumours with state of advanced disease (P<0.0001). Higher relative methylation was associated with worse recurrence-free survival in both univariate (hazard ratio=9.37; P=0.0005) as well as bivariate Cox regression analyses considering age, sex, diameter of tumours and state of advanced disease, metastasis and lymph node metastases as covariates (hazard ratios=5.9-18.2; P-values of 0.0003-0.008). CONCLUSION: We identified mir-124-3 CpG islands (CGI) methylation as a relevant epigenetic mark for ccRCC thus underlining the need for functional studies of potentially affected signalling pathways in kidney tumour models. Methylation of mir-124-3 is suggested as an independent prognosticator for ccRCC.

[Pathophysiology and therapy of castration-resistant prostate cancer]. / Pathophysiologie und Androgendeprivationstherapie des kastrationsresistenten Prostatakarzinoms.

Advanced prostate cancer that progresses under androgen deprivation therapy has long been thought to be refractory to further hormonal treatment. The identification of the mechanism of cancer cells has revolutionized this understanding. Today it is known that castration-resistant prostate cancer (CRPC) still receives signals through the androgen receptor transduction pathways and furthermore is sensitive to hormone therapy. New substances, such as abiraterone, enzalutamide (MDV3100) and TAK 700 target these mechanisms of resistance of cancer cells, stop testosterone production and show not only better tolerance but also effective antitumor activity. Due to the heterogeneity of tumors with cells in varying states of differentiation, the treatment of CRPC with androgen deprivation therapy remains a cornerstone of disease management. To what extent the experimental findings and the recommendations in the guidelines are put into practice was the subject of a survey among urologists analyzing their treatment strategies with CRPC patients.