[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.

[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.

The influence of skull base chordoma on lower urinary tract symptoms.

OBJECTIVE: To provide the first insights into the potential role of skull base chordoma, which causes brainstem compression in and around Barrington's nucleus and its effect on the micturition center. Chordoma is a rare malignant bone tumor that originates from the remnants of the embryonic notochord, which normally forms and dissolves during early fetal development. Although it is a slowly growing tumor, it displays local invasive growth. METHODS: Urodynamic testing of 22 symptomatic patients was performed. All women and men with skull base chordoma treated in 2 hospitals in Germany between 1986 and 2007 were studied. Follow-up periods ranged from 6 months to 10 years. Lower urinary tract symptoms were documented in patients with acute brainstem compression because of local chordoma growth. RESULTS: Of 74 patients treated, 22 (7 women, 15 men) with a median age of 37 years were evaluated with voiding diaries and computer urodynamic investigation. Urodynamic testing of 22 symptomatic patients revealed detrusor overactivity in 55%, low compliance bladder in 14%, detrusor-sphincter dyssynergia in 45%, and uninhibited sphincter relaxation in 27%. Despite the description of incomplete emptying and urgency, 4 patients had normal urodynamic findings (18%). Brain magnetic resonance images of the lesions of the symptomatic patients were obtained to determine the side of lesions. CONCLUSION: The dorsolateral pons, including pontine reticular nucleus and the reticular formation and the locus coeruleus, seems to be mainly responsible for lower urinary tract symptoms in our patients with skull base chordoma and brainstem compression.

Expression of vascular endothelial growth factor receptor 2 (VEGFR-2), inducible nitric oxide synthase (iNOS), and Ki-M1P in skull base chordoma: a series of 145 tumors.

Chordomas are locally invasive tumors that have a tendency to relapse despite optimal treatment. Specific biological markers might be used to describe their behavior. There is currently no agreement regarding the best way to manage intracranial chordomas. We studied the expression of vascular endothelial growth factor receptor 2 (VEGFR-2), inducible nitric oxide synthase (iNOS), and Ki-M1P in 145 paraffin-embedded tumors. The purpose of our study was to determine: (a) the role of potent angiogenic factors VEGFR-2 and iNOS and their relationship to each other in skull base chordoma and (b) the role of monocytes/macrophages as a potential iNOS source in the angiogenic process. A series of 74 chordoma patients for a total of 145 lesions (including 71 recurrent lesions) and 10 specimens from embryonic notochord were investigated for the expression of iNOS, VEGFR-2, Ki-M1P, and CD-34 using immunohistochemistry. In the majority of the chordomas, correlations were found between iNOS and the immunoreactivity of Ki-M1P (r = 0.5303, P < 0.0001). Furthermore, the expressions of Ki-M1P was correlated with VEGFR-2 (r = 0.4181, P < 0.0001). Our results indicate that chordomas may respond to receptor tyrosine kinase inhibitors such as VEGFR-2 or modulators of other downstream signaling molecules. The future of VEGFR-2 and iNOS inhibitors as therapeutic agents in the treatment of chordoma will be clearer over the next years as results of the current clinical trials become available and as the factors regulating angiogenesis and the interactions between these factors are elucidated. However, appropriate functional experiments remain to be conducted to prove such a hypothesis.

[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.

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.

Effect of parathyroid hormone on hypogonadism induced bone loss of proximal femur of orchiectomized rat.

PURPOSE: Management of hypogonadism-induced osteoporosis in elderly men is still a challenge. We investigated the short-term effects of parathyroid hormone (PTH) treatments on strength, micro-architecture, and mineral density of trochanteric region of orchiectomized rat femur. METHODS: Eight-month-old male Sprague-Dawley rats (n = 44) were divided into two groups: (1) orchiectomized (ORX) and (2) sham group. Twelve weeks after orchiectomy, half of the orchiectomized animals were treated with daily subcutaneously injected PTH (0.040 mg/kg/BW) (ORX-PTH) for 5 weeks. The other half remained untreated (ORX). The sham-operated group was divided and treated in the same way (sham, sham-PTH). After 5 weeks, both femurs were excised for biomechanical and histomorphometric analysis, trabecular measurements, mineral content assessment, and immunofluorescence analysis. RESULTS: The femoral trochanteric strength after PTH treatment was enhanced in the breaking test (ORX-F(max) = 158.7 N vs. ORX + PTH-F(max) = 202 N). Stiffness of treated ORX animals reached nearly the levels observed in untreated sham rats. PTH therapy improved the trabecular connectivity, width, and area (ORX-Tb.Ar = 47.79% vs. ORX + PTH-Tb.Ar = 68.47%, P < 0.05) in the proximal femur. The treated rats showed significantly improved mineral content in ashed femurs (ORX-mineral content = 43.73% vs. ORX + PTH-mineral content = 49.49%) when compared to the untreated animals. A comparison of widths of fluorescence bands in cortical bone of the subtrochanteric cross-sections showed a significant increase in oppositions after the PTH therapy. CONCLUSIONS: Our finding supports the hypothesis that PTH therapy seems to be a rational therapy in patients with hypogonadism induced bone loss and improves the bone strength of trochanteric region of rat femur.

Effect of testosterone, raloxifene and estrogen replacement on the microstructure and biomechanics of metaphyseal osteoporotic bones in orchiectomized male rats.

INTRODUCTION: Currently, osteoporosis research is rarely undertaken in males but an increase in male life expectancy in the company of hypogonadism suggests the necessity for potential therapeutic options. MATERIALS AND METHODS: In this study, the changes in bone structure under standardized testosterone- (T), raloxifene- (R) and estrogen (E)-supplemented diets were analyzed in osteoporotic castrated male rats. RESULTS: Unexpected biomechanical results could be only explained by the histomorphometry, but not by BMD measurements obtained from the qCT. All tested substances showed a significant improvement in the trabecular network (trabecular bone area for C: 2.55 mm(2), T: 4.25 mm(2), R: 4.22 mm(2) and E: 4.28 mm(2)), and suggests that the bone structure was preserved. For the metaphyseal cortical bone, a significant loss was detected in T (CBP: 18.7%) compared to R (CBP: 30.0%), E (CBP: 26.8%) and even to the osteoporotic control (CBP: 28.6%). This explains the observed early mechanical final failure after T supplementation. However, due to the preserved trabecular bone in T, the occurrence of the first microfractures (yL: 49 +/- 21.4 N) was significantly later than in the osteoporotic control (yL: 39.5 +/- 15.5 N). Raloxifene performed well in hindering the bone loss associated with osteoporosis. However, its effect (yL: 83.3 +/- 16.5 N) did not approach the protective effect of E (yL: 99.2 +/- 21.1 N). CONCLUSION: Testosterone only preserved the deterioration of the trabecular bone but not of the cortical bone. Raloxifene prevented the bone loss associated with osteoporosis at all bony structures. This effect did not approach the protective effect of estrogen on trabecular bone, but it is more suitable for male individuals because it has no feminizing effects on the subject.

[Methylation of the RASSF1A tumor suppressor gene promoter. Risk factor for carcinogenesis of urological tumors]. / Die Methylierung des RASSF1A-Tumorsuppressorgenpromotors. Risikofaktor für die Karzinogenese urologischer Tumoren.

Molecular targets of known risk factors for the development of urological tumors, such as age, smoking, and adiposity, have not yet been elucidated. Hypermethylation of CpG islands in promoters can lead to silencing of gene expression and has frequently been detected in tumors. Age-dependent accumulation of methylation of gene promoters has been observed in various normal tissues and is discussed as a common risk factor for carcinogenesis.Here we describe the RASSF1A tumor suppressor gene as exhibiting an age-dependent promoter methylation in normal kidney tissue, which is additionally affected by the risk factors of anthracosis and adiposity. Furthermore, we found significantly increased methylation of the RASSF1A promoter when comparing peripheral versus central zone prostatic tissue samples.Preliminary expression analysis indicates that RASSF1A could be involved in early tumorigenesis. Our results support the hypothesis that age and other lifestyle-dependent factors may influence promoter methylation of specific genes, possibly serving as future individual tumor risk markers.

[Expression of corticotropin releasing factor receptor 2 (CRFR2) in the human prostate. A new potential target for medical therapy of benign prostatic hyperplasia]. / Expression des "Corticotropin releasing faktor rezeptors 2" (CRFR2) in der humanen Prostata. Ein möglicher Ansatzpunkt bei der Therapie der benignen Prostatahyperplasie.

BACKGROUND: Expression of urocortin (Ucn), a 40-amino-acid neuropeptide, was demonstrated in the prostatic tissue of patients with benign prostatic hyperplasia (BPH). Ucn showed a significant role in the regulation of local inflammation, proliferation, and relaxation of smooth muscle tone in different organs through activation of corticotropin releasing factor receptor 2 (CRFR2). However, CRFR2 expression in human benign prostatic tissue remains unknown. Our study therefore aimed to investigate CRFR2 expression in prostatic tissue. METHODS: CRFR2 expression was evaluated in tissue samples of human prostate (n=8) by means of reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. RESULTS: mRNA of CRFR2 was abundantly present in RT-PCR of prostate lysates. Immunohistochemistry revealed CRFR2 expression in the cytoplasm of basal and luminal epithelial cells as well as in cystic glands. Smooth muscle components of the stroma and vascular endothelial cells also showed extensive staining for CRFR2. CONCLUSIONS: Our study showed for the first time that human prostatic tissue expresses CRFR2. Pharmacological CRFR2 modulation might be a potential medical treatment for clinical BPH.

[Anomaly of the vena cava inferior with paracaval venous aneurysm and renal collateralisation]. / Achsenanomalien der Vena cava inferior mit paracavalem venösen Aneurysma und renalem Kollateralkreislauf.

Aneurysms of the great venous vessels represent anatomical rarities. Most malformations of the venous system published so far concern mainly the inferior vena cava and arise in different formations. Reports of malformations of the renal veins are limited to a few case reports and may lead to diagnostic and therapeutic difficulties. We report on an case of a asymptomatic, aneurysmatic venous malformation of the vena cava inferior With consideration of the entire findings we preferred a conservative treatment of the patient.

FlexGuard: a new laser insertion sheath: functional aspects in ureterorenoscopy (URS).

The evolution of flexible ureteroscopes led to a widespread use for the management of upper urinary tract abnormalities. The cost of purchase, maintenance and the durability of these instruments has become a major issue. This work describes a new device to avoid damages due to incorrect use of the Holmium laser during insertion of the laser fibre. A laser fibre with an optical core of 271 and 430 muicrom outside diameter was slid inside the FlexGuard laser fibre insertion sheath (LISA laser products, Germany). The outside diameter of the sheath measures 2.7 F (0.9 mm) and 2.1 F (0.7 mm) luminal diameter. The distal fibre tip was brought up to a position app. 2 mm inside the distal end of the sheath. The loaded sheath was pushed through the working channel of various ureteroscopes which were in maximum deflection. With the insertion sheath protruding about 2 mm from the distal tip of the URS the fibre was effortless forwarded out of the sheath to approach the stone. Once the laser fibre was in position, the sheath was removed, to increase the volume of irrigation fluid during laser lithotripsy. The radius of curvature (ROC) of the URS in maximum deflection and the integrity of the working channel was investigated. Using the insertion sheath the laser fibre reached the working position without any recognition of scratching or resistance. The integrity of the ureterorenoscopes was checked thoroughly be manually operated manometry. No damage of the inner surface of the working channel occurred. The ROC of the instrument did not change significantly during this procedure. After removal of the sheath the ROC remained stable. With the extended use of ureteroscopy, durability and repair costs are of concern. Damage resulting from incorrect use of laser fibres is a major issue in this respect. FlexGuard proved to avoid this damage in all flexible ureteroscopes investigated without limiting their mobility.

Oncological and functional results of open, robot-assisted and laparoscopic radical prostatectomy: does surgical approach and surgical experience matter?

The treatment of prostate cancer has undergone a fundamental change in the last decade. New surgical and nonsurgical minimal invasive methods have evolved. As the methodology of the different treatments is commonly known to urologists, this article focuses on oncological and functional outcome of open retropubic (ORP), trans- or extraperitoneal endoscopical (LRP), and robot-assisted radical prostatectomy (RALP), based on personal experience and review of the literature. A MEDLINE search was performed to review the literature on LRP and RALP between 1982 and 2007 with special emphasis on oncological and functional results, technical considerations, comparison of LRP and RALP to ORP, laparoscopic training, historical aspects, and cost-efficiency of the techniques. Based on diligent training and proctoring programs, a continuous dissemination of laparoscopic techniques takes place. There is a trend towards the extraperitoneal access in most of the minimal invasive programs at least in the European community. Mid-term outcomes of LRP and short-term outcomes of RALP achieved equivalence to open surgery with regards to complications, oncologic and functional results. Distinct advantages of LRP include less postoperative pain, lower transfusion rates, shorter convalescence, and better cosmetics. In contrast to RALP, LRP reaches cost-equivalence with open surgery in selected centers. LRP and RALP reproduce the short-term results of open surgery while providing the advantages of a minimal access. Video-assisted teaching improves the transfer of anatomical knowledge and technical knowhow, but the discussion about the longer learning curve for laparoscopy handling remains. The future will show if European centers adopt the use of robots comparable to the United States.

Pharmacology and biology of corticotropin-releasing factor (CRF) receptors.

The biology of corticotropin-releasing factor (CRF) finds increasing interest in the scientific community because of the neuromodulatory actions of CRF on brain functions such as learning, anxiety, feeding, and locomotion. Additional actions on immunumodulation and apoptosis have recently been discovered. All actions of CRF are mediated by G protein-coupled receptors, which trigger different, sometimes opposite actions in different regions of the central nervous system. The CRF system exhibits considerable plasticity by the involvement of numerous different ligands, splice variants, and transductional couplings. The generation of multiple splice variants is facilitated by the intron exon structure of the CRF receptor genes.

A single amino acid serves as an affinity switch between the receptor and the binding protein of corticotropin-releasing factor: implications for the design of agonists and antagonists.

In view of the observation that corticotropin-releasing factor (CRF) affects several brain functions through at least two subtypes of G protein-dependent receptors and a binding protein (CRFBP), we have developed synthetic strategies to provide enhanced binding specificity. Human/rat CRF (h/rCRF) and the CRF-like peptide sauvagine (Svg), differing in their affinities to CRFBP by two orders of magnitude, were used to identify the residues determining binding to CRFBP. By amino acid exchanges, it was found that Ala(22) of h/rCRF was responsible for this peptide's high affinity to CRFBP, whereas Glu(21) located in the equivalent position of Svg prevented high affinity binding to CRFBP. Accordingly, [Glu(22)]h/rCRF was not bound with high affinity to CRFBP in contrast to [Ala(21)]Svg, which exhibited such high affinity. Furthermore, the affinity of both peptides to either CRF receptor (CRFR) subtype was not reduced by these replacements, and their subtype preference was not changed. Thus, exchange of Ala and Glu and vice versa in positions 22 and 21 of h/rCRF and Svg, respectively, serves as a switch discriminating between CRFBP and CRFR. On the basis of this switch function, development of new specific CRF agonists and antagonists is expected to be facilitated. One application was the modification of the CRF antagonist astressin (Ast), whose employment in animal experiments is limited by its low solubility in cerebrospinal fluid. Introduction of Glu residues into Ast generated with [Glu(11,16)]Ast an acidic astressin, which efficiently antagonized in vivo the CRFR1-dependent reduction of locomotion induced by ovine CRF without detectable binding to CRFBP.