FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer.

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 FGFR-targeted 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 the highest tumour stage in each sample yielded a mutation frequency of 42%. Mutations comprised 61 single and five 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; 18 of these had mutation in at least one region, including nine with mutation in all regions examined, eight with mutation in only the non-invasive component and one with different mutations in different regions. Of the eight with mutation in only the non-invasive component, six were predicted to represent a single tumour and two showed morphological dissimilarity of fragments within the block, indicating the 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.

The impact of the Dornier Compact Delta lithotriptor on the management of primary ureteric calculi.

OBJECTIVE: To assess the effectiveness of the Dornier Compact Delta lithotriptor on the management of in situ primary ureteric stones. PATIENTS AND METHODS: 137 patients with primary ureteric stones were treated at a tertiary urological center using the latest Dornier Compact Delta lithotriptor between January 1999 and January 2002. Effectiveness of lithotripsy, retreatment rate, reasons for failure and complications were assessed. RESULTS: 102 males and 35 females with primary ureteric stones underwent ESWL treatment at our center. 74 patients had upper, 37 middle and 26 lower ureteric locations respectively. Mean stone size was 10 mm (range 8-25 mm). Mean numbers of sessions required were 1.8 (range 1-3). The retreatment rate was 33% in upper ureteric, 29% in mid ureteric and 26% in lower ureteric locations respectively. Complete clearance rate at 3 months was 86% for upper ureteric, 79% for mid ureteric and 79% for lower ureteric. 29 patients had auxiliary treatment in the form of double J ureteric stenting or percutaneous nephrostomies. 26 patients failed treatment and underwent ureteroscopic or ante grade percutaneous removal. Stone size was the only significant factor correlating with failure. The mean size of stones in the successful group was 12 mm as compared to 17 mm in failure group. The likelihood of success following a failed second session (no disintegration or disintegration with fragments more than 6 mm) of treatment was 13.4%. Complications including, steinstrasse, colic, UTI and petechial haemorrhage were seen in 35 patients. One patient developed pyonephrosis and subsequently required nephrectomy. CONCLUSION: An electromagnetic shock wave lithotriptor using the EMSE-150 shock wave emitter is an effective in situ treatment of primary ureteric stones. Patients with large stone size are likely to have a higher retreatment rate, more auxiliary procedures and complications. Having a failed second treatment session, the likelihood of a successful outcome after third session of ESWL is poor.