The incidence of renal cell carcinoma (RCC) is increasing worldwide, and its prevalence is particularly high in some parts of Central Europe. Here we undertake whole-genome and transcriptome sequencing of clear cell RCC (ccRCC), the most common form of the disease, in patients from four different European countries with contrasting disease incidence to explore the underlying genomic architecture of RCC. Our findings support previous reports on frequent aberrations in the epigenetic machinery and PI3K/mTOR signalling, and uncover novel pathways and genes affected by recurrent mutations and abnormal transcriptome patterns including focal adhesion, components of extracellular matrix (ECM) and genes encoding FAT cadherins. Furthermore, a large majority of patients from Romania have an unexpected high frequency of A:T4T:A transversions, consistent with exposure to aristolochic acid (AA). These results show that the processes underlying ccRCC tumorigenesis may vary in different populations and suggest that AA may be an important ccRCC carcinogen in Romania, a finding with major public health implications.

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ObjectivesTo evaluate our clinical experience with percutaneous image-guided radiofrequency ablation (RFA) of 200 renal tumours in a large tertiary referral university institution.Patients and MethodsImage-guided RFA (ultrasonography or computed tomography [CT]) of 200 renal tumours in 165 patients from June 2004 to 2012 was prospectively evaluated. Institutional Review Board approval was granted.The treatment response and technical success were defined by absence of contrast enhancement within the tumour on contrast enhanced CT or magnetic resonance imaging. Both major and minor complications, glomerular filtration rate (GFR) before and after RFA, the management and outcomes of the complications, as well as oncological outcome were prospectively documented. Multivariate analysis was used to determine variables associated with major complications and also the percentage GFR change after RFA. The overall (OS), 5-year cancer-specific (CSS), local recurrence-free (LRFS) and metastasis-free survival (MFS) rates are presented using the Kaplan–Meier curves. Results In all, 200 tumours were RF ablated with a mean (range) tumour size of 2.9 (1–5.6) cm and the mean (range) patient age was 67.7 (21–88.6) years with a mean follow-up period of 46.1 months. The primary technical and overall technical success rate was 95.5% and 98.5%, respectively. Two independent predictors of successful RFA in a single sitting were tumour size (<3 cm) and exophytic location in multivariate logistic regression analysis. Major complications included ureteric injury (six patients), calyceal-cutaneous fistula (one), acute tubular necrosis (one) and abscess (two). Two independent predictors of ureteric injury were central location and lower pole position. Within this cohort of patients, only four patients developed significant renal function deterioration i.e. >25% decreased in GFR. In all, 161 (98%) patients of the 165 patients have preservation of renal function. Any change in renal function after RFA was not influenced by tumour factors or solitary kidney status. In our clinical series, this yielded a 5-year OS, CSS, LRFS and MFS rates of 75.8%, 97.9%, 93.5% and 87.7% respectively. ConclusionsImage-guided RFA is a safe, nephron sparing and effective treatment for small renal cell carcinoma (RCC) tumours with a low rate of recurrence and has good 5-year CSS and MFS rates.

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Objective To determine if advanced glycation endproducts (AGEs) are responsible for the lower neuronal and endothelial-derived nitric oxide (NO)-mediated relaxation of corpus cavernosum in tissue in diabetic rats than in control rats. Materials and methods Diabetes was induced in maleWistar rats by an intraperitoneal injection with streptozotocin (60 mg/kg). One group of diabetic rats was given free access to water and standard diet. A second group was given standard diet and aminoguanidine with their water (50 mg/100 mL) from the initiation of diabetes. Two groups of rats that were not diabetic acted as age-matched controls. After 8 weeks animals were killed by cervical dislocation, corpus cavernosal tissue strips harvested and mounted in an organ bath to measure isometric tension. After 90 min of equilibration at optimal resting tension and contraction with 1 mmol/L noradrenaline, the response to either acetylcholine or electrical ®eld stimulation (EFS) after adding guanethidine (5 mmol/L) and atropine (1 mmol/L) was determined for each group. Results There was no difference between the baseline characteristics of all the experimental groups. After 8 weeks the mean body mass and glycosylated haemoglobin (HbA 1c ) were signi®cantly greater in the diabetic than in control animals. Aminoguanidine had no effect on the recorded body mass or HbA 1c . The in vitro relaxation response to the application of acetylcholine or EFS of tissue strips from age-matched control animals fed a standard diet and those supplemented with aminoguanidine were the same. The administration of aminoguanidine to diabetic animals for 8 weeks reversed the expected impaired relaxation response to acetylcholine; the response to EFS was similar. Conclusion AGEs are more prevalent in erectile tissue from diabetic than in control animals. Aminoguanidine reversed the impairment in neuronal and endothelial NO-mediated penile smooth muscle relaxation seen in diabetes. As aminoguanidine prevents AGE formation, erectile dysfunction in diabetes is probably caused partly by the generation of AGEs.

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Background:Validated objective biomarkers are needed for patients with renal cell carcinoma (RCC) to guide patient management and define high-risk populations for follow-up or for therapeutic purposes.Methods:Patients undergoing nephrectomy for RCC (n=286 all stages, 84% with conventional clear cell type) were included with a median duration follow-up of 5 years. The prognostic significance of pre-operative haematological and biochemical variables, including C-reactive protein (CRP) values were examined and whether they added additional information to a recently published pre-operative scoring system was determined.Results:C-reactive protein was the most significant predictor of overall survival (OS; χ2=50.9, P<0.001). Five-year OS for patients with CRP⩽15 mg l−1 vs >15 mg l−1 was 72% (95% CI 65–78%) and 33% (95% CI 23–44%), respectively. Similar results were seen for cancer-specific survival (CSS) and disease-free survival. On multivariate analysis, CRP remained highly significant for CSS (χ2=17.3, P<0.0001) and OS (χ2=9.8, P<0.002), in addition to other pre-operative variables including log of neutrophil/lymphocyte ratio, red blood cell count and white cell count. C-reactive protein was significant in addition to the pre-operative nomogram score (χ2=12.5, P=0.0004 for OS, χ2=16.2, P=0.0001 for CSS and χ2=8.6, P=0.003 for DFS) and was still significant when other pre-operative variables were included.Conclusion:C-reactive protein and other haematological and biochemical variables have independent prognostic significance in RCC and may enhance pre-operative scoring systems.

The functional state of the penis, flaccid or erect is governed by smooth muscle tone. Sympathetic contractile factors maintain flaccidity whilst parasympathetic factors induce smooth muscle relaxation and erection. It is generally accepted that nitric oxide (NO) is the principal agent responsible for relaxation of penile smooth muscle. NO is derived from two principal sources: directly from non-adrenergic non-cholinergic parasympathetic nerves and indirectly from the endothelium lining cavernosal sinusoids and blood vessels in response to cholinergic stimulation. The generation of NO from L-arginine is catalysed by nitric oxide synthase (NOS). There has been controversy over the relative prevalence of endothelial or neuronal NOS within the penis of different animal species. This review examines the role of NO in the penis in detail. Established and new treatments for erectile dysfunction whose effects are mediated via manipulation of the NO pathway are also described.