Faculty Bibliography

Importance: Potential survival benefits from treating aggressive (Gleason score, >/=7) early-stage prostate cancer are undermined by harms from unnecessary prostate biopsy and overdiagnosis of indolent disease. Objective: To evaluate the a priori primary hypothesis that combined measurement of PCA3 and TMPRSS2:ERG (T2:ERG) RNA in the urine after digital rectal examination would improve specificity over measurement of prostate-specific antigen alone for detecting cancer with Gleason score of 7 or higher. As a secondary objective, to evaluate the potential effect of such urine RNA testing on health care costs. Design, Setting, and Participants: Prospective, multicenter diagnostic evaluation and validation in academic and community-based ambulatory urology clinics. Participants were a referred sample of men presenting for first-time prostate biopsy without preexisting prostate cancer: 516 eligible participants from among 748 prospective cohort participants in the developmental cohort and 561 eligible participants from 928 in the validation cohort. Interventions/Exposures: Urinary PCA3 and T2:ERG RNA measurement before prostate biopsy. Main Outcomes and Measures: Presence of prostate cancer having Gleason score of 7 or higher on prostate biopsy. Pathology testing was blinded to urine assay results. In the developmental cohort, a multiplex decision algorithm was constructed using urine RNA assays to optimize specificity while maintaining 95% sensitivity for predicting aggressive prostate cancer at initial biopsy. Findings were validated in a separate multicenter cohort via prespecified analysis, blinded per prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) criteria. Cost effects of the urinary testing strategy were evaluated by modeling observed biopsy results and previously reported treatment outcomes. Results: Among the 516 men in the developmental cohort (mean age, 62 years; range, 33-85 years) combining testing of urinary T2:ERG and PCA3 at thresholds that preserved 95% sensitivity for detecting aggressive prostate cancer improved specificity from 18% to 39%. Among the 561 men in the validation cohort (mean age, 62 years; range, 27-86 years), analysis confirmed improvement in specificity (from 17% to 33%; lower bound of 1-sided 95% CI, 0.73%; prespecified 1-sided P = .04), while high sensitivity (93%) was preserved for aggressive prostate cancer detection. Forty-two percent of unnecessary prostate biopsies would have been averted by using the urine assay results to select men for biopsy. Cost analysis suggested that this urinary testing algorithm to restrict prostate biopsy has greater potential cost-benefit in younger men. Conclusions and Relevance: Combined urinary testing for T2:ERG and PCA3 can avert unnecessary biopsy while retaining robust sensitivity for detecting aggressive prostate cancer with consequent potential health care cost savings.

OBJECTIVE: Prior studies in prostate diffusion-weighted magnetic resonance imaging (MRI) have largely explored the impact of b-value and diffusion directions on estimated diffusion coefficient D. Here we suggest varying diffusion time, t, to study time-dependent D(t) in prostate cancer, thereby adding an extra dimension in the development of prostate cancer biomarkers. METHODS: Thirty-eight patients with peripheral zone prostate cancer underwent 3-T MRI using an external-array coil and a diffusion-weighted image sequence acquired for b = 0, as well as along 12 noncollinear gradient directions for b = 500 s/mm using stimulated echo acquisition mode (STEAM) diffusion tensor imaging (DTI). For this sequence, 6 diffusion times ranging from 20.8 to 350 milliseconds were acquired. Tumors were classified as low-grade (Gleason score [GS] 3 + 3; n = 11), intermediate-grade (GS 3 + 4; n = 16), and high-grade (GS >/=4 + 3; n = 11). Benign peripheral zone and transition zone were also studied. RESULTS: Apparent diffusion coefficient (ADC) D(t) decreased with increasing t in all zones of the prostate, though the rate of decay in D(t) was different between sampled zones. Analysis of variance and area under the curve analyses suggested better differentiation of tumor grades at shorter t. Fractional anisotropy (FA) increased with t for all regions of interest. On average, highest FA was observed within GS 3 + 3 tumors. CONCLUSIONS: There is a measurable time dependence of ADC in prostate cancer, which is dependent on the underlying tissue and Gleason score. Therefore, there may be an optimal selection of t for prediction of tumor grade using ADC. Controlling t should allow ADC to achieve greater reproducibility between different sites and vendors. Intentionally varying t enables targeted exploration of D(t), a previously overlooked biophysical phenomenon in the prostate. Its further microstructural understanding and modeling may lead to novel diffusion-derived biomarkers.

Purpose To compare standard diffusion-weighted (DW) imaging and diffusion kurtosis (DK) imaging for prostate cancer (PC) detection and characterization in a large patient cohort, with attention to the potential added value of DK imaging. Materials and Methods This retrospective institutional review board-approved study received a waiver of informed consent. Two hundred eighty-five patients with PC underwent 3.0-T phased-array coil prostate magnetic resonance (MR) imaging, including a DK imaging sequence (b values 0, 500, 1000, 1500, and 2000 sec/mm2) before prostatectomy. Maps of apparent diffusion coefficient (ADC) and diffusional kurtosis (K) were derived by using maximal b values of 1000 and 2000 sec/mm2, respectively. Mean ADC and K were obtained from volumes of interest (VOIs) placed on each patient's dominant tumor and benign prostate tissue. Metrics were compared between benign and malignant tissue, between Gleason score (GS) /= 3 + 4 tumors, and between GS /= 4 + 3 tumors by using paired t tests, analysis of variance, receiver operating characteristic (ROC) analysis, and exact tests. Results ADC and K showed significant differences for benign versus tumor tissues, GS /= 3 + 4 tumors, and GS /= 4 + 3 tumors (P < .001 for all). ADC and K were highly correlated (r = -0.82; P < .001). Area under the ROC curve was significantly higher (P = .002) for ADC (0.921) than for K (0.902) for benign versus malignant tissue but was similar for GS /= 3 + 4 tumors (0.715-0.744) and GS /= 4 + 3 tumors (0.694-0.720) (P > .15). ADC and K were concordant for these various outcomes in 80.0%-88.6% of patients; among patients with discordant results, ADC showed better performance than K for GS /= 4 + 3 tumors (P = .016) and was similar to K for other outcomes (P > .136). Conclusion ADC and K were highly correlated, had similar diagnostic performance, and were concordant for the various outcomes in the large majority of cases. These observations did not show a clear added value of DK imaging compared with standard DW imaging for clinical PC evaluation. (c) RSNA, 2017 Online supplemental material is available for this article.

Advancements in magnetic resonance imaging (MRI) and MRI-ultrasound (US)-fusion targeted biopsy have resulted in a paradigm shift in the diagnosis of prostate cancer by overcoming the limitations of systematic biopsy. Prebiopsy MRI and MRI-US-fusion biopsy results in an increased detection of clinically significant disease, reduction in the detection of indolent disease, and allows for tumor localization during targeted biopsy. With these advantages, we have adopted a prebiopsy MRI and MRI-US-fusion biopsy diagnostic care pathway for all men at risk for prostate cancer and have performed more than 1900 biopsies to date. Herein we present our institutional development of MRI-US-fusion biopsy and highlight our results in those men who have had a previous negative biopsy, no prior biopsy, and those with a prior cancer diagnosis who may be candidate for active surveillance. Risk stratification with biomarkers and nomograms may allow for further counseling on the need for biopsy and the risk of harboring clinically significant disease.

PURPOSE: To assess the impact of patient race and age on the performance of apparent diffusion coefficient (ADC) values for assessment of prostate cancer aggressiveness. MATERIALS AND METHODS: 457 prostate cancer patients who underwent 3T phased-array coil prostate MRI including diffusion-weighted imaging (DWI; maximal b-value 1000 s/mm2) before prostatectomy were included. Mean ADC of a single dominant lesion was measured in each patient, using histopathologic findings from the prostatectomy specimen as reference. In subsets defined by race and age, ADC values were compared between Gleason score (GS) /= 4 + 3 tumors. RESULTS: 81% of patients were Caucasian, 12% African-American, 7% Asian-American. 13% were <55 years, 42% 55-64 years, 41% 65-74 years, and 4% >/=75 years. 63% were GS /= 4 + 3. ADC was significantly lower in GS >/= 4 + 3 tumors than in GS /= 4 + 3 as well as optimal ADC threshold was Caucasian: 0.73//=75 years, 0.79//=75 years than <55 years or 55-64 years (100.0% vs. 53.6%-73.3%; P < 0.001). CONCLUSION: Patients' race and age may impact the diagnostic performance and optimal threshold when applying ADC values for evaluation of prostate cancer aggressiveness.

Active surveillance (AS) has emerged as a beneficial strategy for management of low risk prostate cancer (PCa) and prevention of overtreatment of indolent disease. However, selection of patients for AS using traditional 12-core transrectal prostate biopsy is prone to sampling error and presents a challenge for accurate risk stratification. In fact, around a third of men are upgraded on repeat biopsy which disqualifies them as appropriate AS candidates. This uncertainty affects adoption of AS among patients and physicians, leading to current AS protocols involving repetitive prostate biopsies and unclear triggers for progression to definitive treatment. Prostate magnetic resonance imaging (MRI) has the potential to overcome some of these limitations through localization of significant tumors in the prostate. In conjunction with MRI-targeted prostate biopsy, improved sampling and detection of clinically significant PCa can help streamline the process of selecting suitable men for AS and early exclusion of men who require definitive treatment. MRI can also help minimize the invasive nature of monitoring for disease progression while on AS. Men with stable MRI findings have high negative predictive value for Gleason upgrade on subsequently biopsy, suggesting that men may potentially be monitored by serial MRI examinations with biopsy reserved for significant changes on imaging. Targeted biopsy on AS also allows for specific sampling of concerning lesions, although further data is necessary to evaluate the relative contribution of systematic and targeted biopsy in detecting the 25-30% of men who progress on AS. Further research is also warranted to better understand the nature of clinically significant cancers that are missed on MRI and why certain men have progression of disease that is not visible on prostate MRI. Consensus is also needed over what constitutes progression on MRI, when prostate biopsy can be safely avoided, and how to best utilize this additional information in current AS protocols. Despite these challenges, prostate MRI, either alone or in conjunction with MRI-targeted prostate biopsy, has the potential to significantly improve our current AS paradigm and rates of AS adoption among patients moving forward.