Faculty Bibliography

Increases in fatty acid metabolism have been demonstrated to promote the growth and survival of a variety of cancers, including prostate cancer (PCa). Here, we examine the expression and function of the fatty acid activating enzyme, long-chain fatty acyl-CoA synthetase 4 (ACSL4), in PCa. Ectopic expression of ACSL4 in ACSL4-negative PCa cells increases proliferation, migration and invasion, while ablation of ACSL4 in PCa cells expressing endogenous ACSL4 reduces cell proliferation, migration and invasion. The cell proliferative effects were observed both in vitro, as well as in vivo. Immunohistochemical analysis of human PCa tissue samples indicated ACSL4 expression is increased in malignant cells compared with adjacent benign epithelial cells, and particularly increased in castration-resistant PCa (CRPC) when compared with hormone naive PCa. In cell lines co-expressing both ACSL4 and AR, proliferation was independent of exogenous androgens, suggesting that ACSL4 expression may lead to CRPC. In support for this hypothesis, ectopic ACSL4 expression induced resistance to treatment with Casodex, via decrease in apoptosis. Our studies further indicate that ACSL4 upregulates distinct pathway proteins including p-AKT, LSD1 and beta-catenin. These results suggest ACSL4 could serve as a biomarker and potential therapeutic target for CRPC.

Accurate recognition of Gleason pattern 5 (GP5) prostate adenocarcinoma on needle biopsy is critical as it is associated with disease progression and adverse clinical outcome. Despite important implications of this diagnosis, interobserver variation in the diagnosis of GP5 has not been adequately studied. Digital images of 66 prostate adenocarcinoma cases that potentially contained a GP5 component were distributed to 16 urologic pathologists who were asked to classify whether GP5 was present. Each image was initially classified into 1 of 4 morphologic subpatterns by 2 coauthors (R.B.S. and M.Z.): solid nests (15), comedocarcinoma (8), single cells and/or cords (35), and variant morphology (8). Additional features captured included: size (large: >20 cells, medium: 10 to 20 cells, and small: <10 cells) and distribution of nuclei (uniform vs. nonuniform) for nests pattern; intraluminal coagulative tumor necrosis, karyorrhectic debris, and amorphous material for comedocarcinoma pattern; and quantity (10) and distribution (clustered vs. intermixed with adjacent well-formed glands) for single cells/cords pattern. Interobserver reproducibility of a diagnosis of GP5 was assessed and the morphologic subpatterns and features were correlated with the consensus diagnosis (defined as 75% agreement). Interobserver reproducibility for overall diagnostic agreement was fair (kappa=0.376). Among subpatterns, comedocarcinoma had highest reproducibility (kappa=0.499), followed by variant morphology (kappa=0.443), single cells/cords (kappa=0.369), and nests (kappa=0.347). All cases with the following features achieved consensus for GP5: large nests regardless of nuclear distribution; coagulative necrosis with or without karyorrhectic debris; single cells/cords >10 or 6 to 10 in a cluster; and signet ring-like cells in single cells or within nests pattern. A majority of cases with the following features achieved consensus against GP5: medium-size nests; exclusive intraluminal amorphous material; single cells/cords 1 level. The diagnostic reproducibility of GP5 within certain morphologies was only fair among urologic pathologists. However, the diagnosis of GP5 was more reproducible when certain restrictive morphologic and quantitative criteria were applied. These findings suggest that additional studies are needed to find highly reproducible features of GP5 associated with documented aggressive clinical outcome.

OBJECTIVE: To report outcomes of MRI-ultrasound fusion (MRF-TB) and 12-core systematic biopsy (SB) over a 26-month period in men with prior negative prostate biopsy. METHODS: Between 6/12 and 8/14, 210 men presenting to our institution for prostate biopsy with >/=1 prior negative biopsy underwent multiparametric MRI followed by MRF-TB and SB and were entered into a prospective database. Clinical characteristics, MRI suspicion scores (mSS), and biopsy results were queried from the database and the detection rates of Gleason >/=7 prostate cancer (PCa) and overall PCa were compared between biopsy techniques using McNemar's test. RESULTS: Fifty-three (31%) of 172 men meeting inclusion criteria (mean age 65+/-8 years; mean PSA 8.9+/-8.9) were found to have PCa. MRF-TB and SB had overall cancer detection rates (CDR) of 23.8% and 18.0% (p=0.12), respectively, and CDR for Gleason score (GS)>/=7 disease of 16.3% and 9.3% (p=0.01), respectively. Of 31 men with GS>/=7 disease, MRF-TB detected 28 (90.3%) while SB detected 16 (51.6%) (p<0.001). Using UCSF-CAPRA criteria, only one man was re-stratified from low-risk to higher risk based on SB results compared to MRF-TB alone. Among men with mSS<4, 80% of detected cancers were low-risk by UCSF-CAPRA criteria. CONCLUSIONS: In men with previous negative biopsies and persistent suspicion for PCa, SB contributes little to the detection of GS>/=7 disease by MRF-TB, and avoidance of SB bears consideration. Based on the low likelihood of detecting GS>/=7 cancer and overall low-risk features of PCa in men with mSS<4, limiting biopsy to men with mSS>/=4 warrants further investigation.