This study examined androgen receptor (AR) gene amplification and protein expression in 102 matched paired hormone sensitive and resistant tumours from 51 patients. AR gene amplification and X chromosome copy number were assessed by fluorescent in situ hybridisation, and protein expression was assessed by immunohistochemistry. All tumours were stained for PSA protein expression. Significantly more tumours exhibited AR amplification following the development of hormone resistance (20%, 10 out of 49) compared to matched hormone-sensitive tumours from the same patient (2%, one out of 48) (P ¼ 0.0085). The level of AR expression was significantly higher in hormone-resistant tumours compared to matched hormone-sensitive tumours from the same patient (130, interquartile range, 55 -167 vs 94.5 interquartile range, 55 -120, P ¼ 0.019). AR expression levels in hormone-resistant tumours with and without AR amplification were not significantly different. However, an increase in AR expression was seen with the development of AR amplification in paired tumours. The rate of AR gene amplification and/or an increase in AR protein expression during androgen resistant is too low to wholly explain the development of androgen resistance. Alternative mechanisms for modulating the function of the AR, or other signalling pathways, must be considered as key factors in the development of hormoneresistant prostate.

The majority of patients can be treated with minimal investigations and simple reassurance. In older patients or those with persistent hemospermia or associated symptoms modern diagnostic techniques are of proven benefit.

Molecular mechanisms underlying the development of androgen-insensitive prostate cancer (AIPC) are poorly understood. However, there is growing evidence that different molecular profiles may result in the development of AIPC. Cell line studies demonstrate that c-Jun and c-Fos, via formation of the transcription factor activated protein 1 (AP-1), activate androgen-regulated genes independent of androgens and that c-Jun alone acts as an androgen receptor co-factor. The aim of this study was to investigate whether increased levels of c-Jun and phosphorylated c-Jun are associated with the development of AIPC using clinical material. Material from a cohort of 51 patients with paired tumours, obtained before and after the development of AIPC, and with full clinical biochemical follow-up, was retrieved from the archives. Tumour c-Jun, activated c-Jun, c-Fos, and pan protein kinase C (PKC) protein expression were analysed by immunohistochemistry and protein expression was scored by two independent observers using a weighted histoscore. No evidence was found to suggest that c-Jun acting as an androgen receptor co-factor influences the development of AIPC. However, it was observed that patients with high expression levels of phosphorylated c-Jun had a significantly shorter survival from relapse compared with patients with low phosphorylated c-Jun protein expression (p = 0.023), suggesting that increased AP-1 levels may promote AIPC tumour growth. Whilst PKC did not appear to activate c-Jun in vivo, increased PKC expression in AIPC tumours was also associated with decreased patient survival from time of relapse (p = 0.014). In conclusion, the data support the hypothesis that activation of c-Jun plays a role in the development of AIPC via AP-1 formation in some patients. However, PKC appears to promote the development of AIPC independently of c-Jun activation via an as yet unexplained mechanism.

Aims: Keratinizing squamous metaplasia is infrequently found in bladder biopsies and its clinical significance remains unclear, with studies linking it to the development of invasive squamous cell carcinoma. Once diagnosed, there is a dilemma how to treat and follow-up this group. Methods: We reviewed the literature on the topic with particular emphasis on natural history, management and subsequent follow-up. Results: Keratinizing squamous metaplasia of the bladder is rare. Pathognomonic findings on biopsy are required to confirm the diagnosis. Both synchronous diagnosis of urothelial tumour and subsequent tumour development on follow-up has been identified. Risk of malignant transformation increases in the presence of dysplasia as well as with extensive keratinization. Lesions should be treated with local transurethral resection. Considering the lack of evidence cystectomy cannot be justified for those with extensive lesions. Conclusion: Currently there is not enough data to identify keratinizing squamous metaplasia of the bladder as a pre-malignant condition; this term being reserved for those with obvious histological dysplasia. However at present all patients should undergo regular follow-up.