Faculty Bibliography

OBJECTIVE. The objective of this study was to compare the performance of different methodologies for interpretation of dynamic contrast-enhanced MRI (DCE-MRI) in localization of peripheral zone prostate cancer. MATERIALS AND METHODS. Forty-three men (mean age, 59 +/- 8 years) with biopsy-proven prostate cancer who underwent prostate MRI including DCE-MRI before prostatectomy were included. Two observers independently reviewed DCE-MRI data using three methodologies: qualitative, in which kinetic curves of signal intensity versus time were generated for foci showing rapid enhancement on subtracted contrast-enhanced images; semiquantitative, in which a biexponential heuristic model was used to generate color-coded maps depicting maximum slope and washout of contrast enhancement; and quantitative, in which a Tofts model was used to generate color-coded influx rate transfer constant (K(trans)) and efflux rate transfer constant (Kep) maps. Findings were stratified by whether suspicious foci showed evidence of washout with each method and compared with histopathologic results in each sextant. RESULTS. There was similar accuracy for the semiquantitative and quantitative models for both observers irrespective of requiring evidence of washout. For the more experienced observer, requiring washout resulted in lower sensitivity and higher specificity for the qualitative and semiquantitative models. Also for the more experienced observer, use of either a semiquantitative or quantitative model provided greater sensitivity compared with a qualitative model when requiring washout. There was no association between tumor detection and Gleason score for any DCE-MRI methodology for either reader. CONCLUSION. For the experienced reader, sensitivity for peripheral zone tumor was increased by use of either a semiquantitative or quantitative model compared with a qualitative model and decreased by requiring washout. We failed to identify a difference in performance between semiquantitative and quantitative models.

Integration of cellular signaling pathways with androgen receptor (AR) signaling can be achieved through phosphorylation of AR by cellular kinases. However, the kinases responsible for phosphorylating the AR at numerous sites and the functional consequences of AR phosphorylation are only partially understood. Bioinformatic analysis revealed AR serine 213 (S213) as a putative substrate for PIM1, a kinase overexpressed in prostate cancer. Therefore, phosphorylation of AR serine 213 by PIM1 was examined using a phosphorylation site-specific antibody. Wild-type PIM1, but not catalytically inactive PIM1, specifically phosphorylated AR but not an AR serine-to-alanine mutant (S213A). In vitro kinase assays confirmed that PIM1 can phosphorylate AR S213 in a ligand-independent manner and cell type-specific phosphorylation was observed in prostate cancer cell lines. Upon PIM1 overexpression, AR phosphorylation was observed in the absence of hormone and was further increased in the presence of hormone in LNCaP, LNCaP-abl and VCaP cells. Moreover, phosphorylation of AR was reduced in the presence of PIM kinase inhibitors. An examination of AR-mediated transcription showed that reporter gene activity was reduced in the presence of PIM1 and wild-type AR, but not S213A mutant AR. Androgen-mediated transcription of endogenous PSA, Nkx3.1 and IGFBP5 was also decreased in the presence of PIM1, whereas IL6, cyclin A1 and caveolin 2 were increased. Immunohistochemical analysis of prostate cancer tissue microarrays showed significant P-AR S213 expression that was associated with hormone refractory prostate cancers, likely identifying cells with catalytically active PIM1. In addition, prostate cancers expressing a high level of P-AR S213 were twice as likely to be from biochemically recurrent cancers. Thus, AR phosphorylation by PIM1 at S213 impacts gene transcription and is highly prevalent in aggressive prostate cancer.Oncogene advance online publication, 17 September 2012; doi:10.1038/onc.2012.412.

PURPOSE: To assess the utility of diffusion-weighted imaging (DWI) findings as an indirect marker of side-specific risk of extracapsular extension (ECE) of prostate cancer. MATERIALS AND METHODS: Fifty-one patients underwent 3T magnetic resonance imaging (MRI) before prostatectomy. Radiologists 1 and 2 (4 and 1 years experience) assessed each side for ECE using T2-weighted imaging (T2WI) and evaluated apparent diffusion coefficient (ADC) maps for the presence of apparent tumor in each lobe and to measure peripheral zone ADC. A uropathologist measured the extent of any ECE. RESULTS: In all, 28/102 lobes had ECE, of which 12 measured 1 mm and 2 mm. Side-specific accuracies for detection of ECE for readers 1 and 2 were respectively: T2WI 68.6% and 74.5%; presence of apparent tumor on ADC map 66.7% and 60.8%; ADC value 75.5% and 69.6%. For ECE >2 mm, both readers achieved 100% sensitivity based on apparent tumor on ADC map or ADC values and 80% sensitivity using T2WI. For detection of ECE