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.

[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.

[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.

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.

Akt signalling parameters are different in oncocytomas compared to renal cell carcinoma.

PURPOSE: Renal oncocytomas are assigned as benign tumours, and their detailed molecular mechanism is poorly characterised. Activation of the PKB/Akt pathway is assumed to contribute to the pathogenesis and progression of malignant disease. For oncocytomas, hardly any data are available for Akt signalling parameters. Aim of the present work was to determine the alterations of Akt parameters PTEN, phosphorylated Akt (p-Akt) and p27(Kip1) in oncocytoma to better understand the dedifferentiation of renal tumours. METHODS: By tissue microarray analysis 15 oncocytoma, 18 clear cell renal cell carcinoma (ccRCC) and the corresponding benign tissue were investigated. Significant expression differences between PTEN, p-Akt and p27(Kip1) were determined by immunohistochemistry using One-way ANOVA with all pairs Tukey-Kramer as post hoc analyses. To investigate Akt parameter interactions in the oncocytoma, linear regression analyses were performed. RESULTS: Expression of all proteins was significantly different between the groups and in all groups the lowest for oncocytoma: PTEN: 32.9 ± 13.0 versus 75.5 ± 8.0 versus 123.7 ± 8.8; p < 0.001 for oncocytoma, benign parenchyma and ccRCC and 2.7 ± 1.2 versus 40.8 ± 9.5 versus 143.6 ± 12.2; p < 0.001 for p27(Kip1). p-Akt expression was significantly different between oncocytoma and ccRCC (67.3 ± 15.7 vs. 144.0 ± 26.6; p < 0.05). CONCLUSION: All three investigated parameters were the lowest in oncocytoma when compared to ccRCC. Expression of PTEN and p27(Kip1) seems to be exceedingly associated with malignant conditions of ccRCC. These findings might contribute to the understanding of tumorous signalling of the PKB/Akt axis in renal tumours.

Is there a significance of histamine in the control of the human male sexual response?

Although histamine has been suggested to be involved in the control of male sexual function, including the induction of penile erection, its role in the human corpus cavernosum penis is still poorly understood. The aim of our study was to evaluate the course of histamine plasma levels through different stages of sexual arousal in the systemic and cavernous blood of healthy male subjects. Thirty four (34) healthy men were exposed to erotic stimuli to elicit penile erection. Blood was aspirated from the corpus cavernosum and a cubital vein during the penile conditions flaccidity, tumescence, rigidity and detumescence. Blood was also collected in the post-ejaculatory period. Plasma levels of histamine (ng ml(-1)) were determined by means of a radioimmunoassay. Histamine slightly decreased in the cavernous blood when the penis became tumescent. During rigidity, histamine decreased further but remained unaltered in the phase of detumescence and after ejaculation. In the systemic circulation, no alterations were observed with the initiation or termination of penile erection, whereas a significant drop was registered following ejaculation. Results are not in favour of the hypothesis of an excitatory role of histamine in the control of penile erection. Nevertheless, the amine might mediate biological events during the post-ejaculatory period.

Systemic and cavernous plasma levels of neuropeptide Y during sexual arousal in healthy males.

Neuropeptide Y (NPY) has been shown to induce contraction of isolated human penile erectile tissue and potentiate the response to noradrenaline. The purpose of our study was to measure in the cavernous and systemic blood of healthy male volunteers the course of NPY through different stages of sexual arousal. Whole blood was drawn simultaneously from the corpus cavernosum and the cubital vein of 16 healthy male volunteers during penile flaccidity, tumescence, rigidity and detumescence. Tumescence and erection were induced by applying audiovisual and tactile stimulation. Plasma levels of NPY (given in pmol l(-1)) were determined by means of an enzyme-linked immunoassay. NPY significantly decreased in the cavernous blood on sexual arousal, when the flaccid penis became tumescent and, finally, rigid (F: 88.8 ± 35.8, T: 62.4 ± 22.7, R: 62.3 ± 19.7), and only slightly rose in the phase of detumescence (64.8 ± 23). In the systemic circulation, no pronounced alterations in the concentration of NPY were registered (F: 64.4 ± 27, T: 65.8 ± 19, R: 59.6 ± 25, D: 67.6 ± 29.3). Our findings are in favour of the hypothesis that NPY could contribute to the maintenance of the resting state of cavernous smooth muscle.

[Synchronous oligometastatic renal cell carcinoma-what is the role of surgery?] / Primär oligometastasiertes Nierenzellkarzinom ­ Welchen Stellenwert hat heutzutage die Chirurgie?

BACKGROUND: Long-term remission can be achieved by surgery in patients with metastatic renal cell carcinoma (mRCC), without chronic toxicity due to systemic treatment. Data on metastasectomy are mostly based on observations of metachronous metastasis. However, it is unclear whether patients with synchronous oligometastasis may also benefit from surgery alone as an alternative to highly effective systemic treatment combined with resection of the primary tumor. MATERIALS AND METHODS: The authors performed an unstructured literature search in PubMed including systematic reviews and meta-analyses. Results are discussed in regard of the current data and clinical practice. RESULTS AND DISCUSSION: Although there is no uniform definition for oligometastasis in mRCC, cytoreductive nephrectomy in selected patients seems to be mandatory before metastasectomy is performed in primary oligometastatic RCC. In particular, in those patients with oligometastasis of the lung, bone, central nervous system, liver, adrenal gland, and thyroid, metastasectomy appears to be an important therapeutic option. Ultimately, among the therapeutic options, surgery is also an important therapeutic approach in primary oligometastatic mRCC. A balanced consideration between surgery, other local therapies, and modern systemic treatment demands interdisciplinary decision-making that takes into account the patients' preference.

C-kit-positive multipolar cells in human penile erectile tissue: expression of connexin 43 and relation to trabecular smooth muscle cells.

The aim of this study was to evaluate the hypothesis that interstitial cells might play a role in controlling and synchronizing via gap junctions the electrical activity of smooth muscle cells. The expression and distribution of interstitial cells in human penile erectile tissue was evaluated to determine whether or not cavernous interstitial cells express the gap junction protein connexin 43. Specimens of human corpus cavernosum were excised from full preparations of human penises. Cryostat sections (10 microm to 15 microm) of formaldehyde-fixated tissue segments were incubated using a double-labelling technique with antibodies directed against smooth muscle alpha-actin, c-kit, and connexin 43. Then, sections were exposed to secondary antibodies. Visualization was commenced by means of laser fluorescence microscopy. Double-staining techniques revealed immunosignals specific for c-kit (transmembrane receptor protein) and connexin 43 (gap junction protein) in multipolar cells located adjacent to smooth muscle cells. The number of c-kit-positive cells was significantly lower within the smooth musculature than within bundles of connective tissue surrounding smooth muscle cells of corpus cavernosum or cavernous arteries. Our findings demonstrate the distribution of c-kit- and connexin 43-positive interstitial cells in the connective tissue and smooth musculature of the corpus cavernosum. Additional studies are needed in order to evaluate further the ultrastructure of human penile erectile tissue and enable the identification of gap junctions mediating direct cell-to-cell communication.

[In vitro effects of a novel class of nitric oxide donating compounds on isolated human urinary bladder]. / In vitro-Effekte einer neuen Klasse Stickstoffmonoxid (NO) freisetzender Substanzen auf die glatte Muskulatur des humanen Detrusors.

Nitric oxide (NO) has been identified an important neurotransmitter involved in the control of the human urinary tract. It has been suggested that NO is one of the factors keeping the bladder relaxed during the filling phase. This function might be mediated by the NO-induced elevation of intracellular cyclic GMP. Prostaglandins (PG) are known to exert contractile effects on the bladder smooth musculature, especially in pathological conditions. The aim of the present study was to examine the effects of a new class of NO donor drugs, combining both anti-phlogistic and NO-donating activity (NCX 2111 and HCT 1026), on the contraction induced by PG or electrical field stimulation (EFS) of isolated human detrusor. Effects were compared to those of sodium nitroprusside (SNP), forskolin, tolterodine, and oxybutynin. Using the organ bath technique, drug effects on the contraction induced by PG ((F2 alpha)) or EFS of isolated human detrusor smooth muscle were investigated. Detrusor strips were also exposed to increasing concentrations of the compounds (0.1 microM - 10 microM) and the accumulation of cyclic GMP and cyclic AMP was determined by means of radioimmunoassays. The tension induced by PG was dose-dependently reversed by the drugs. The rank order of efficacy was: forskolin > SNP > NCX 2111 > HCT 1026. R(max) values ranged from 57% (forskolin) to 24% (HCT 1026). Compounds also dose-dependently reduced the amplitudes of contraction induced by EFS (tolterodine > oxybutynin > NNP = forskolin > HCT 1026 > 2111). The effects of forskolin, HCT 1026, NCX 2111 and SNP were paralleled by an increase in cyclic AMP or cyclic GMP. Our results provide evidence that the NO-cGMP pathway is not of utmost significance in the control of human detrusor smooth muscle. In vitro, the combination of NO-donating with anti-phlogistic activity does not seem to be of functional advantage with regard to the facilitation of detrusor relaxation.

[Value of targeted therapies for renal cell cancer]. / Der Stellenwert der Targeted-Therapie beim Nierenzellkarzinom.

Therapeutic approaches based solely on cytokine are meanwhile no longer recommended without restrictions as the primary therapy for metastatic renal cancer due to the reduced clinical response and the promising available data regarding molecular therapy. Several randomized controlled studies have been performed since the introduction of the so-called targeted therapies for metastatic renal cancer. Substantial data relevant for drug approval are available for the multikinase inhibitors sorafenib (Nexavar) and sunitinib (Sutent), the mTOR inhibitor temsirolimus (Torisel), and the monoclonal antibody bevacizumab (Avastin) in combination with interferon-alpha. Sunitinib, temsirolimus, and bevacizumab are approved for first-line treatment, whereas sorafenib was approved for second-line treatment in Germany.Clinical trials are currently investigating the questions of optimal timing, value of neoadjuvant or adjuvant treatment, form, and sequence of the molecular targeted therapy. Experimental investigations for a better understanding of signaling pathways will preferably allow preselecting patients for an individualized therapy in metastatic renal cell cancer (RCC). The aim of the present paper is to address and to critically discuss the clinical data that are currently available regarding"targeted" therapeutics during the treatment of metastatic RCC.

[Minimally invasive percutaneous nephrolitholapaxy (MIP)]. / Minimal-invasive perkutane Nephrolitholapaxie (MIP).

Minimally invasive percutaneous nephrolithopaxy (MIP) was developed to combine the excellent stone-free rates of the conventional percutaneous nephrolithopaxy (PCNL) technique with the low morbidity of the miniaturized PCNL (Mini-Perc) and, at the same time, achieve a high level of patient comfort. The procedure is characterized not only by the diameter of the miniaturized 18-Fr Amplatz sheath that was adopted from the Mini-Perc but also by the following features: ultrasound-guided puncture of the kidney; single-step dilatation of the access tract; ballistic lithotripsy; a low-pressure irrigation system together with stone retraction by irrigation with a specially designed nephroscope sheath, for the so-called vacuum cleaner effect; and a sealed and tubeless access tract with primary closure of the channel independent of hemorrhage and without a second-look procedure.The results of the first 57 patients demonstrate primary stone-free rates of 92.9% with operating times averaging 62 (25-123) min. Severe complications, such as sepsis or bleeding requiring blood transfusion, did not occur. The high and predictable stone-free rate and a low morbidity comparable to that of ureteroscopy and extracorporeal shock-wave lithotripsy make MIP an attractive option for patients and urologists. The "vacuum cleaner effect" with quick removal of stone fragments reduces operating time and prevents new stone formation by avoiding residual fragments. The direct and primary closure of the access tract increases patient comfort and is justified by the reintervention rate of less than 8% in the presented cohort.The lack of a need for second-look nephroscopies, the vacuum cleaner effect, improved patient comfort without nephrostomy tubes, as well as surgery times comparable to that of traditional PCNL demonstrate a consequent evolution of the Mini-Perc. MIP therefore represents a promising and future-oriented module in modern stone therapy.

[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.

[Somatostatin analogs for the treatment of advanced, hormone-refractory prostate cancer: a possibility for secondary hormonal ablation?]. / Somatostatin-Analoga in der Therapie des fortgeschrittenen hormonrefraktären Prostatakarzinoms: Eine Möglichkeit der sekundären Hormonablation?

Almost all patients with hormone-refractory prostate cancer under primary androgen deprivation therapy will develop progression, frequently initially marked by an asymptomatic increase of prostate-specific antigen (PSA). Recent data showed that taxane-based chemotherapy offers significant survival benefit to patients with advanced prostate cancer; however, the toxic side effects frequently exert a significant negative impact on the quality of life. At the androgen-independent stage of the cancer, before becoming hormone refractory, progression might still be delayed by secondary manipulation of either androgen or confounding receptors and their signaling pathways. Secondary hormonal manipulations traditionally included antiandrogen withdrawal, second-line antiandrogens, direct adrenal androgen inhibitors, estrogens, and progestins.We discuss the mode of action and application of somatostatin analogs as an emerging secondary hormonal treatment concept in patients with advanced prostate cancer on the basis of the current literature.

[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.

Heterogeneous p27(Kip1) expression within primary renal cell cancers, their invasive margins and peritumoral renal parenchyma correlation with pathological and prognostic features.

INTRODUCTION: The expression of the negative cell cycle regulator p27(Kip1) is frequently found to be deregulated in various human cancer types. Whether expression of p27(Kip1) can be used as prognostically relevant biological variables for renal cell cancer patients still remains to be clarified. Therefore, in the present investigation the expression within different tissue areas obtained from renal cell carcinomas was determined. PATIENTS AND METHODS: For analysis of p27(Kip1) in 420 tumor nephrectomy specimens obtained from 420 consecutively included patients, tissue microarrays were used comprising of 1,260 tissue samples each obtained from the tumor itself, the invasive front as well as non-malignant surrounding parenchyma. A sufficient follow-up after surgical therapy was available in 251 cases. RESULTS: In univariate survival analysis, decreased expression of p27(Kip1) within tissue cores obtained from the invasion front was significantly correlated with the patients' disease-specific long-term survival (p = 0.02, log-rank test). In contrast, expression of p27(Kip1) protein within the primary tumors was not identified to reveal any prognostically important information. In Cox regression analysis, histological stage and grade (p < 0.01), the presence of regional lymph node (p < 0.01) or distant metastases at the time of surgery (p < 0.01) as well as decreased expression of p27(Kip1) (p = 0.04) within the invasion front tissue samples independently predicted the disease-specific long-term survival following surgery. CONCLUSION: Our analysis demonstrated that p27(Kip1) is heterogeneously expressed in renal cell carcinomas. Moreover, the result of the present study supports the prognostic value of p27(Kip1) protein expression for patients diagnosed with renal cell carcinoma.

[Efficacy of multikinase inhibitors in the treatment of advanced renal cell cancer. A snapshot]. / Wirksamkeit von Multikinaseinhibitoren in der Therapie des fortgeschrittenen Nierenzellkarzinoms. Eine Momentaufnahme.

Due to the chemoresistance of renal cell cancer, cytokine-based therapeutic approaches were considered the standard treatment for patients with metastatic disease. At present, data that are available from a few phase II/III studies, dealing both with the first- and second-line treatment of patients suffering from systemic progression of RCC, indicate the significantly higher clinical efficacy of multikinase inhibitors when compared with cytokine-based therapeutic regimens. In this context, sorafenib (Nexavar, BAY 43-9006) and sunitinib (Sutent, SU 011248) are the most frequently applied and most intensively investigated substances. In Germany, with regard to a phase III study reported at the ASCO congress in 2006, sunitinib received approval for the first-line therapy of metastatic RCC. The application of multikinase inhibitors follows the principle of targeting such mediators that are considered to be substantially involved in the pathogenesis and particularly progression of renal cell cancer within relatively well-defined molecular pathways. The aim of the present paper is to address and to critically discuss the clinical data that are currently available regarding the therapeutic efficacy of kinase inhibitors during the treatment of metastatic RCC.