Faculty Bibliography

OBJECTIVE: The purpose of this study was to evaluate the utility of multiparametric MRI in localization of the index lesion of prostate cancer. MATERIALS AND METHODS: Fifty-one patients who underwent 3-T MRI of the prostate with a pelvic phased-array coil that included T2-weighted, diffusion-weighted, and dynamic contrast-enhanced sequences before prostatectomy were included. Six radiologists assessed all images to identify the lesion most suspicious of being the index lesion, which was localized to one of 18 regions. A uropathologist using the same 18-region scheme reviewed the prostatectomy slides to localize the index lesion. MRI performance was assessed by requiring either an exact match or an approximate match (discrepancy of up to one region) between the MRI and pathologic findings in terms of assigned region. RESULTS: The pathologist identified an index lesion in 49 of 51 patients. In exact-match analysis, the average sensitivity was 60.2% (range, 51.0-63.3%), and the average positive predictive value (PPV) was 65.3% (range, 61.2-69.4%). In approximate-match analysis, the average sensitivity was 75.9% (range, 65.3-69.6%), and the average PPV was 82.6% (range, 79.2-91.4%). The sensitivity was higher for index lesions with a Gleason score greater than 6 in exact-match (74.8% vs 15.3%, p < 0.001) and approximate-match (88.7% vs 36.1%, p = < 0.001) analyses and for index lesions measuring at least 1 cm in approximate-match analysis (80.3% vs 58.3%, p = 0.016). In exact-match analysis, 30.0%, 44.9%, and 79.1% of abnormalities found with one, two, and three MRI parameters represented the index lesion (p < 0.001). CONCLUSION: The sensitivity and PPV of multiparametric MRI for index lesion localization were moderate, although they improved in the setting of more aggressive pathologic features and a greater number of abnormal MRI parameters, respectively.

PURPOSE: The GR gene produces GRalpha and GRbeta isoforms by alternative splicing of a C-terminal exon. GRalpha binds glucocorticoids, modulates transcription in a glucocorticoid dependent manner and has a growth inhibitory role in prostate cells. Due to this role glucocorticoids are often used to treat androgen independent prostate cancer. In contrast, GRbeta has intrinsic transcriptional activity and binds mifepristone (RU486) but not glucocorticoids to control gene expression. To our knowledge the role of GRbeta in prostate cell proliferation is unknown. MATERIALS AND METHODS: We determined GRbeta levels in various prostate cancer cell lines by reverse transcriptase-polymerase chain reaction and Western blot. The effect of GRbeta on the kinetics of prostate cancer cell growth was determined by cell counting and flow cytometry upon mifepristone and dexamethasone treatment. Cell proliferation was also examined after siRNA mediated knockdown and over expression of GRbeta. RESULTS: GRbeta mRNA and protein were up-regulated in LNCaP cells that over expressed the androgen receptor co-factor ARA70beta. Treatment of LNCaP-ARA70beta with mifepristone or siRNA targeting GRbeta inhibited proliferation compared to that of parental LNCaP cells. The immortal but nontumorigenic RC165 prostate cell line and the tumorigenic DU145 prostate cell line with endogenous GRbeta also showed partial growth reduction upon GRbeta depletion but to a lesser extent than LNCaP-ARA70beta cells. The growth stimulatory effect of ARA70beta on LNCaP cells was partly GRbeta dependent, as was the proliferation of RC165 cells and to a lesser extent of DU145 cells. CONCLUSIONS: Results suggest that patients with a primary tumor that expresses GRbeta and ARA70beta may benefit from mifepristone.