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Objectives: Primary objectives: To determine whether local anesthetic transperineal (LATP) prostate biopsy improves the detection of clinically significant prostate cancer (csPCa), defined as International Society of Urological Pathology (ISUP) Grade Group ≥2 disease (i.e. any Gleason pattern 4 disease), compared to transrectal ultrasound-guided (TRUS) prostate biopsy, in biopsy-naïve men undergoing biopsy based on suspicion of csPCa. Secondary objectives: To compare i) infection rates, ii) health-related quality of life (HRQoL), iii) patient-reported procedure tolerability, iv) patient-reported biopsy-related complications (including bleeding, bruising, pain, loss of erectile function), v) number of subsequent prostate biopsy procedures required, vi) cost-effectiveness, vii) other histological parameters, and viii) burden and rate of detection of clinically insignificant PCa (ciPCa) (ISUP Grade Group 1 disease) in men undergoing these two types of prostate biopsy. Patients and Methods: The TRANSLATE trial is a UK-wide, multi-centre, randomised clinical trial that meets the criteria for level-one evidence in diagnostic test evaluation. TRANSLATE is investigating whether LATP biopsy leads to a higher rate of detection of csPCa compared to TRUS prostate biopsy. Both biopsies are being performed with an average of 12 systematic cores in 6 sectors (depending on prostate size), plus 3-5 target cores per multi-parametric/bi-parametric magnetic resonance imaging (mp/bp-MRI) lesion. LATP biopsy is performed using an ultrasound probe-mounted needle guidance device (either the “Precision-Point” or BK UA1232 system). TRUS biopsy is performed according to each hospital's standard practice. The study is 90% powered to detect a 10% difference (LATP biopsy hypothesised at 55% detection rate for csPCa, versus 45% for TRUS biopsy). 1,042 biopsy-naïve men referred with suspected PCa need to be recruited. Conclusions: This trial will provide robust prospective data to determine the diagnostic ability of LATP biopsy versus TRUS biopsy in the primary diagnostic setting.

Introduction: Promoter methylation has been established as a mechanism for silencing of tumour suppressor genes (TSGs) in TCC. Detection of aberrant methylation has been proposed as a novel diagnostic test, but the desired sensitivity and specificity has not been proven. The gene specific nature of methylation necessitates investigators to identify a panel of TSG's, that when analysed for aberrant methylation in tumour DNA, demonstrate a high sensitivity, specificity and diagnostic accuracy for clinical use. Here, we analyse a panel of 16 genes in the DNA of 96 TCCs and 30 samples of normal urothelium. Methods: DNA was obtained from 96 TCCs and 30 normal bladders. The DNA was bisulphite modified and quantitative methylation specific PCR (QMSP) was performed for 16 gene promoters. Results: Methylation was detected for all 16 genes in the 96 TCCs. This ranged from 3% to 75%. The genes with the highest frequency of methylation were RASSF1a (54%), E-cadherin (41%), BCL2 (45%), TNFRS25 (75%), EDNRB (66%), IGFBP3 (43%) and WIF1 (56%). High levels of methylation were detected in the normal controls for RASSF1a (50%) and E-cadherin (20%), with 11 other genes having low levels of methylation. Using a panel of 5 heavily methylated genes, a sensitivity of 57%, specificity of 89% and a diagnostic accuracy of 80% resulted. Conclusion: The frequency of methylation varied widely for different genes, confirming the gene specific nature of aberrant methylation in TCC. Using our panel of gene loci, the sensitivity and specificity of methylation DNA analysis was not adequate. However, our study does demonstrate the feasibility of TCC DNA methylation analysis and with the identification of further cancer specific gene loci, it may prove a useful early detection strategy.

Many molecular events in cancer occur at the epigenetic rather than genetic level. The best studied of these is DNA cytosine methylation. This occur most frequently in DNA promoter regions and results in loss of gene expression. Tumour suppressor gene silencing by aberrant hypermethylation has been demonstrated in several carcinogenic pathways. Here we present the latest results of our studies regarding promoter methylation in urothelial cancer (UC). Firstly, using 280 UC of the upper and lower urinary tracts we show that promoter methylation (at 11 tumour suppressor genes) occurs frequently (86%) and in an anatomically distinct pattern. Higher methylation levels are seen in the upper (94%) than lower urinary (76%) tracts (P

In order to identify novel candidates associated with prostate cancer metastasis, we compared the proteomic profile of the poorly metastatic human prostate cancer cell line LNCaP, with its highly metastatic variant LNCaP-LN3, by two-dimensional gel electrophoresis. A major protein spot (pI of 5.9 and molecular weight of 37 KDa) was seen in LNCaP cells, but not in LNCaP-LN3 cells and was identified as Lactate dehydrogenase-B (LDHB), by tandem mass spectrometry. Furthermore, enzyme kinetic assays and Zymography showed a higher LDH enzyme activity in LNCaP cells compared with LNCaP-LN3. Bisulfite modified DNA sequencing showed promoter hypermethylation in LNCaP-LN3 cells but not in LNCaP, Du145, PC3, CWR22 or BPH45 cells. Treatment of LNCaP-LN3 cells with 5’-azacytidine caused re-expression of LDHB transcripts. In tissues, LDHB promoter hypermethylation occurred at a higher frequency in prostate cancer 14/31 (45%), compared to adjacent non-malignant or benign tissue, 2/19 (11%), (P