FGFR3 is frequently activated by mutation in urothelial carcinoma (UC) and represents a potential target for therapy. In multiple myeloma, both over-expression and mutation of FGFR3 contribute to tumour development. To define the population of UC patients who may benefit from FGFRtargeted therapy, we assessed both mutation and receptor over-expression in primary UCs from a population of new patients. Manual or laser capture microdissection was used to isolate pure tumour cell populations. Where present, non-invasive and invasive components in the same section were microdissected. A screen of the region of highest tumour stage in each sample yielded a mutation frequency of 42%. Mutations comprised 61 single and 5 double mutations, all in hotspot codons previously identified in UC. There was a significant association of mutation with low tumour grade and stage. Subsequently, non-invasive areas from the 43 tumours with both non-invasive and invasive components were analysed separately. Eighteen of these had mutation in at least one region, including 9 with mutation in all regions examined, 8 with mutation in only the non-invasive component and one with different mutations in different regions. Of the 8 with mutation in only the non-invasive component, 6 were predicted to represent a single tumour and 2 showed morphological dissimilarity of fragments within the block, indicating possible presence of distinct tumour clones. Immunohistochemistry showed over-expression of FGFR3 protein in many tumours compared to normal bladder and ureteric controls. Increased expression was associated with mutation (85% of mutant tumours showed high-level expression). Overall, 42% of tumours with no detectable mutation showed over-expression including many muscle invasive tumours. This may represent a non-mutant subset of tumours in which FGFR3 signalling contributes to the transformed phenotype and which may benefit from FGFR-targeted therapies.

OBJECTIVE To assess whether the longer half‐life of tadalafil is associated with longer lasting or more severe side‐effects than the other phosphodiesterase type 5 inhibitors (PDE‐5Is), as clinical trials have shown that the efficacy and safety of the three available are similar, but tadalafil has a half‐life four times longer than the other two drugs. PATIENTS AND METHODS Treatment‐naive men beginning PDE5‐I therapy were recruited from a specialist clinic. Data on the type and duration of drug‐associated side‐effects were collected prospectively. Levels of bother were assessed with a visual analogue scale (VAS). Differences in type, duration and bother of side‐effect were compared between drugs. RESULTS In all, 409 men provided data; there were no differences between drugs in the proportion of men responding, or the overall prevalence of side‐effects. The mean duration of side‐effects with tadalafil was 14.9 h, compared to 3.9 and 7.7 h for sildenafil and vardenafil. Of men taking tadalafil, 30% had side‐effects lasting >12 h. There were no differences in mean VAS scores between the drugs. Individual side‐effects caused similar levels of bother, except for facial flushing, which was less bothersome. CONCLUSIONS Men taking tadalafil are at risk of prolonged side‐effects, although levels of bother associated with these side‐effects are not significantly greater than those seen with short‐acting PDE5‐Is.

The study demonstrates for the first time impaired peak cardiac performance and cardiac functional reserve in asymptomatic CKD patients. The evidence of myocardial dysfunction in the absence of comorbid cardiac disease and diabetes warrants further evaluation of current pathophysiological concepts of cardiovascular disease in CKD.

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OBJECTIVETo determine the prevalence of newly diagnosed hypercholesterolaemia and hypertriglyceridaemia in patients presenting to an andrology clinic with erectile dysfunction (ED), and to assess the relationship between serum lipid levels and the severity of ED. PATIENTS AND METHODSIn all, 199 consecutive men attending an ED clinic were assessed for risk factors for ED; patients completed the International Index of Erectile Function (IIEF)-15 questionnaire and provided venous blood samples for assaying fasting total cholesterol and total triglyceride levels. The proportion of newly diagnosed hyperlipidaemia in patients presenting with ED was calculated and related to patient age, total IIEF score and severity of ED. RESULTSUsing a threshold of 5.0 mmol/L, there was newly diagnosed hypercholesterolaemia in 40% of the men, while there was undiagnosed hypertriglyceridaemia ( > 2 mmol/L) in 29% of the population. There was no clear correlation between patient age and the fasting lipid levels, and no association between total IIEF-15 score or severity of ED and serum cholesterol and triglyceride levels. CONCLUSIONThis study shows the high prevalence of undiagnosed hypercholesterolaemia and hypertriglyceridaemia in men presenting with ED. The opportunity to screen for and treat these risk factors has long-term benefits in preventing cardiovascular disease in this group of patients.

Background Impaired exercise capacity is a significant symptom of CKD and is associated with poor survival. Furthermore, there is a growing interest in applying exercise as a diagnostic tool or as therapy in CKD. However, an in-depth understanding of exercise physiology in CKD is still lacking. Methods To evaluate the role of cardiac (central) and noncardiac (peripheral) determinants of exercise capacity in CKD, we conducted a cross-sectional study of 70 male CKD patients (stages 2-5) without diabetes or cardiac disease, 35 healthy controls, and 25 patients with heart failure. An integrated cardiopulmonary exercise test using a CO2 rebreathing technique was used to measure peak O2 consumption (VO2peak) and peak cardiac output simultaneously, and to calculate peak peripheral O2 extraction [C(a-v)O2], the peripheral determinant (the ability of exercising skeletal muscles to extract oxygen). We performed multiple regression analysis and used Bayesian information criteria (BIC) changes to quantitatively assess the individual contribution of central and peripheral factors. Results Compared with healthy controls, in patients with CKD, the VO2peak was impaired proportionate to its severity. Peak cardiac output was the predominant determinant of VO2peak in healthy controls and patients with heart failure, whereas C(a-v)O2 played a more significant role in determining VO2peak in CKD (β=0.68, P<0.001) compared with cardiac output (β=0.63, P<0.001). In addition, the magnitude of BIC reduction was greater for C(a v)O2 compared with cardiac output (BIC, 298.72 versus 287.68) in CKD. Conclusions In CKD, both peak cardiac output and peak C(a-v)O2 are independent predictors of VO2peak, and the more significant role played by peak C(a-v)O2 highlights the importance of noncardiac factors in determining exercise capacity in CKD.

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