Bruno Nahar

Re-examining Prostate-specific Antigen (PSA) Density: Defining the Optimal PSA Range and Patients for Using PSA Density to Predict Prostate Cancer Using Extended Template Biopsy

OBJECTIVE To compare the predictive accuracy of prostate-specific antigen (PSA) density vs PSA across different PSA ranges and by prior biopsy status in a prospective cohort undergoing prostate biopsy. MATERIALS AND METHODS Men from a prospective trial underwent an extended template biopsy to evaluate for prostate cancer at 26 sites throughout the United States. The area under the receiver operating curve assessed the predictive accuracy of PSA density vs PSA across 3 PSA ranges (<4 ng/mL, 4-10 ng/mL, >10 ng/mL). We also investigated the effect of varying the PSA density cutoffs on the detection of cancer and assessed the performance of PSA density vs PSA in men with or without a prior negative biopsy. RESULTS Among 1290 patients, 585 (45%) and 284 (22%) men had prostate cancer and significant prostate cancer, respectively. PSA density performed better than PSA in detecting any prostate cancer within a PSA of 4-10 ng/mL (area under the receiver operating characteristic curve [AUC]: 0.70 vs 0.53, P < .0001) and within a PSA >10 mg/mL (AUC: 0.84 vs 0.65, P < .0001). PSA density was significantly more predictive than PSA in detecting any prostate cancer in men without (AUC: 0.73 vs 0.67, P < .0001) and with (AUC: 0.69 vs 0.55, P < .0001) a previous biopsy; however, the incremental difference in AUC was higher among men with a previous negative biopsy. Similar inferences were seen for significant cancer across all analyses. CONCLUSION As PSA increases, PSA density becomes a better marker for predicting prostate cancer compared with PSA alone. Additionally, PSA density performed better than PSA in men with a prior negative biopsy.

Reclassification Rates of Patients Eligible for Active Surveillance After the Addition of Magnetic Resonance Imaging-Ultrasound Fusion Biopsy: An Analysis of 7 Widely Used Eligibility Criteria

OBJECTIVES To evaluate the impact of adding magnetic resonance imaging-ultrasound (MRI-US) fusion biopsy cores to standard 12-core biopsy in selecting men for active surveillance (AS). MATERIALS AND METHODS Among men undergoing a fusion biopsy for evaluation of prostate cancer, we selected men who were eligible for at least 1 of 7 different AS criteria based on the standard biopsy alone. We assessed each patients eligibility for each AS criterion with and without the inclusion of fusion biopsy cores. The primary end point was the proportion of men who were initially eligible for AS but became ineligible after addition of the fusion biopsy cores. RESULTS A total of 100 men were eligible for at least 1 AS criterion. After addition of fusion biopsy cores, the proportion of men who became ineligible for AS varied from 10.3% to 40.7%. Criteria that incorporated an absolute maximum number of cores positive had the highest rates of ineligibility. Using a percentage of cores positive helped to reduce the number of patients who would have been excluded. Combining the targeted biopsy cores into one, or taking the single core with the highest grade or volume did not appear to reduce the proportion of men who became ineligible. CONCLUSIONS The addition of fusion biopsy to standard 12-core biopsy significantly increased the number of men who became ineligible for AS. Using the percent of cores positive, instead of an absolute number, allowed fewer exclusions. AS criteria may need to be updated to prevent the unnecessary exclusion of men due to an oversampling of low-risk disease.

The 4Kscore Predicts the Grade and Stage of Prostate Cancer in the Radical Prostatectomy Specimen: Results from a Multi-institutional Prospective Trial

BACKGROUND The 4Kscore accurately predicts aggressive prostate cancer (PCa) on prostate biopsy. OBJECTIVE We assessed how well the 4Kscore predicts pathology at radical prostatectomy (RP). DESIGN, SETTING, AND PARTICIPANTS Among 1312 men who prospectively underwent a 4Kscore and biopsy of the prostate at 26 sites throughout the United States from October 2013 to April 2014, we selected men who were diagnosed with cancer and underwent RP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary outcome was the presence of high-grade PCa or extracapsular extension. We assessed the association between the 4Kscore and the grade and extent of PCa at RP using the Wilcoxon rank sum test. We used logistic regression to investigate the added value of the 4Kscore in predicting a high-grade or non-organ-confined tumor when added to available postbiopsy clinical predictive tools. RESULTS AND LIMITATIONS A total of 144 men were diagnosed with PCa and underwent RP. Higher 4Kscores were associated with higher grade at RP. For men with Gleason scores ≥6, 7, and 8 cancers in the surgical specimen, the median 4Kscores were 7% (interquartile range [IQR]: 4-2), 25% (IQR: 12-38), and 47% (IQR: 24-66) (p<0.0001), respectively. The median 4Kscore among men with non-organ-confined cancer was significantly higher then men with organ-confined cancers (36% [IQR: 19-58] vs 19% [IQR: 9-35]; p=0.002). The 4Kscore did not significantly add to available clinical prediction tools for determining the likelihood of a high grade or non-organ-confined cancer; however, we were limited by a small sample size for this analysis. CONCLUSIONS In a subset of men who underwent RP, the 4Kscore was significantly associated with pathologic grade and extracapsular extension in the surgical specimen, with higher scores associated with higher grade and more aggressive histology. The 4Kscore test may be helpful in selecting men who are likely to have adverse pathologic features at RP that may preclude them from being safely observed. PATIENT SUMMARY Among men with prostate cancer who underwent removal of the prostate, the 4Kscore was associated with the final grade and extent of cancer.

Trends in Utilization of Robotic and Open Partial Nephrectomy for Management of cT1 Renal Masses

BACKGROUND Partial nephrectomy is widely used for surgical management of small renal masses. Use of robotic (RPN) versus open partial nephrectomy (OPN) among various populations is not well characterized. OBJECTIVE To analyze trends in utilization of RPN and disparities that may be associated with this procedure for management of cT1 renal masses in the USA. DESIGN, SETTING, AND PARTICIPANTS Patients who underwent RPN or OPN for clinical stage T1N0M0 renal masses in the USA from 2010 to 2013 were identified in the National Cancer Data Base. A total of 23 154 patients fulfilled the inclusion criteria. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Univariable and multivariable logistic regression analyses were performed to evaluate differences in receiving RPN or OPN across various patient groups. RESULTS AND LIMITATIONS Utilization of RPN increased from 41% in 2010 to 63% in 2013. Black patients (adjusted odds ratio [aOR] 0.91, 95% confidence interval [CI] 0.84-0.98) and Hispanic patients (aOR 0.85, 95% CI 0.77-0.95) were less likely to undergo RPN. RPN was less likely to be performed in rural counties (aOR 0.80, 95% CI 0.66-0.98) and in patients with no insurance (aOR 0.52, 95% CI 0.44-0.61) or patients covered by Medicaid (aOR 0.81, 95% CI 0.73-0.90). There was no significant difference in RPN utilization between academic and non-academic facilities. Patients with higher clinical stage (aOR 0.58, 95% CI 0.55-0.62) and comorbidities (aOR 0.79, 95% CI 0.71-0.88) were also less likely to undergo RPN. CONCLUSIONS Utilization of RPN has continued to increase over time; however, there are significant disparities in its utilization according to race and socioeconomic status. Black and Hispanic patients and patients in rural communities and with limited insurance were more likely to be treated with OPN instead of RPN. PATIENT SUMMARY The use of robotic surgery in partial nephrectomy for management of small renal masses has increased over time. We found a significant disparity across different racial and socioeconomic groups in use of robotic partial nephrectomy compared to open surgery. Patients living in rural areas, with limited insurance, and multiple medical comorbidities were more likely to undergo open than robotic partial nephrectomy.

Subcutaneous Leydig Stem Cell Autograft: A Promising Strategy to Increase Serum Testosterone

Exogenous testosterone therapy can be used to treat testosterone deficiency; however, it has several adverse effects including infertility due to negative feedback on the hypothalamic–pituitary–gonadal (HPG) axis. Leydig stem cell (LSC) transplantation could provide a new strategy for treating testosterone deficiency, but clinical translatability of injecting stem cells inside the testis is not feasible. Here, we explore the feasibility of subcutaneously autografting LSCs in combination with Sertoli and myoid cells to increase testosterone. We also studied whether the grafted LSCs can be regulated by the HPG axis and the molecular mechanism behind this regulation. LSCs were isolated from the testes of 12‐week‐old C57BL/6 mice, and subcutaneously autografted in combination with Sertoli cells and myoid cells. We found that LSCs alone were incapable of self‐renewal and differentiation. However, in combination with Sertoli cells and myoid cells, LSCs underwent self‐renewal as well as differentiation into mature Leydig cells. As a result, the recipient mice that received the LSC autograft showed testosterone production with preserved luteinizing hormone. We found that testosterone production from the autograft was regulated by hedgehog (HH) signaling. Gain of function and loss of function study confirmed that Desert HH (DHH) agonist increased and DHH antagonist decreased testosterone production from autograft. This study is the first to demonstrate that LSCs, when autografted subcutaneously in combination with Sertoli cells and myoid cells, can increase testosterone production. Therefore, LSC autograft may provide a new treatment for testosterone deficiency while simultaneously preserving the HPG axis. Stem Cells Translational Medicine 2019;8:58–65

Optimizing patient's selection for prostate biopsy: A single institution experience with multi-parametric MRI and the 4Kscore test for the detection of aggressive prostate cancer

Objectives To evaluate the performance of mpMRI and the 4Kscore test together for the detection of significant prostate cancer. Material and methods We selected a consecutive series of men who were referred for evaluation of prostate cancer at an academic institution and underwent mpMRI and the 4Kscore test. The primary outcome was the presence of Gleason 7 or higher cancer on biopsy of the prostate. We used logistic regression and Decision Curve Analysis to report the discrimination and clinical utility of using mpMRI and the 4Kscore test for prostate cancer detection. We modeled the probability of harboring a Gleason 7 or higher prostate cancer based on the 4Kscore test and mpMRI findings. Finally, we examined various combinations and sequences of mpMRI and the 4Kscore test and assessed the impact on biopsies avoided and cancers missed. Results Among 300 men who underwent a 4Kscore test and mpMRI, 149 (49%) underwent a biopsy. Among those, 73 (49%) had cancer, and 49 (33%) had Gleason 7 cancer. The area under the curve (AUC) for using the 4Kscore test and mpMRI together 0.82 (0.75–0.89) was superior to using the 4Kscore 0.70 (0.62–0.79) or mpMRI 0.74 (0.66–0.81) individually (p = 0.001). Similarly, decision analysis revealed the highest net benefit was achieved using both tests. Conclusions The 4Kscore test and mpMRI results provide independent, but complementary, information that enhances the prediction of higher-grade prostate cancer and improves patient’s selection for a prostate biopsy. Prospective trials are required to confirm these findings.

High-Intensity Focused Ultrasound (HIFU) Options for High-Risk Prostate Cancer

Radical treatment of the entire prostate gland is still the standard of care for high-risk PCa. However, focal HIFU ablation is a safe procedure and has shown promising short-term oncological outcomes, with acceptable complication rate and excellent functional outcomes. Prospective studies with long-term follow-up are needed to determine the true role of focal HIFU for PCa. Until then, focal HIFU should be offered only in the setting of clinical trials, particularly for high-risk PCa.

A comparison of overall survival and perioperative outcomes between partial and radical nephrectomy for cT1b and cT2 renal cell carcinoma-Analysis of a national cancer registry

OBJECTIVES Partial nephrectomy (PN) is the standard management of cT1a renal cell carcinoma (RCC), and there is a basis for expanding its indications to larger tumors (cT1b and cT2). We analyzed a large population-based cancer registry to compare the overall survival (OS) and perioperative outcomes in patients with cT1b and cT2 RCC undergoing PN with those undergoing radical nephrectomy (RN). MATERIALS AND METHODS Patients with cT1bN0M0 and cT2N0M0 RCC were identified from the National Cancer Database (2004-2013). Patients were classified by the surgery performed and 1:1 propensity matched based on the likelihood of receiving PN. They were then compared for OS, 30-day readmission rates and 30- and 90-day mortality. RESULTS A total of 6,072 patients underwent PN. PN was associated with better OS in cT1b tumors on multivariate analyses (OR = 0.8; 95% CI: 0.72-0.89; P<0.001). For cT2 tumors, PN was associated with better OS, however this was not statistically significant (OR = 0.8; 95% CI: 0.62-1.04; P = 0.092). Unplanned readmission at 30 days was significantly more common in patients undergoing PN (4.2%) vs. RN (2.9%) but there was no difference in 30- and 90-day mortality between the 2 groups. CONCLUSIONS PN was associated with a significantly better OS than RN for cT1b but not cT2 RCC. PN had a higher 30-day readmission rate than RN in these tumors and appropriate patient selection is crucial. These results require further validation, ideally via randomized trials.

Imaging for the selection and monitoring of men on active surveillance for prostate cancer

Traditional prostate imaging is fairly limited, and only a few imaging modalities have been used for this purpose. Until today, grey scale ultrasound was the most widely used method for the characterization of the prostatic gland, however its limitations for prostate cancer (PCa) detection are well known and hence ultrasound is primarily used to localize the prostate and facilitate template prostate biopsies. In the past decade, multiparametric magnetic resonance imaging (mpMRI) of the prostate has emerged as a promising tool for the detection of PCa. Evidence has shown the value of mpMRI in the active surveillance (AS) population, given its ability to detect more aggressive disease, with data building up and supporting its use for the selection of patients suitable for surveillance. Additionally, mpMRI targeted biopsies have shown an improved detection rate of aggressive PCa when compared to regular transrectal ultrasound (TRUS) guided biopsies. Current data supports the use of mpMRI in patients considered for AS for reclassification purposes; with a negative mpMRI indicating a decreased risk of reclassification. However, a percentage of patients with negative imaging or low suspicion lesions can experience reclassification, highlighting the importance of repeat confirmatory biopsy regardless of mpMRI findings. At present, no robust data is available to recommend the substitution of regular biopsies with mpMRI in the follow-up of patients on AS and efforts are being made to determine the role of integrating genomic markers with imaging with the objective of minimizing the need of biopsies during the follow up period.

MP38-04 IS AN UPGRADED PIRADS 4 EQUIVALENT TO A TRUE PIRADS 4? A VALIDATION OF PIRADS VERSION 2 IN A PROSPECTIVE COHORT OF MEN UNDERGOING MRI-US FUSION BIOPSY OF THE PROSTATE

the outcome of 12-core transrectal ultrasound (TRUS) guided prostate biopsy. Herein, we aim to decipher the predictive value of mp-MRI in detection and exclusion of prostate cancer using TRUS prostate biopsy. METHODS: UK multicentre study. Data from 592 patients scheduled to undergo mp-MRI and/or 12-core TRUS-guided prostate biopsy from January till September 2016 was reviewed retrospectively from a prospective database. Mp-MRIs were reported using the Prostate Imaging Reporting and Data System (PI-RADS). Only patients who had pre biopsy mp-MRIs followed by prostate biopsy were included in the study. 108 patient were excluded as they did not have mp-MRI or biopsy due to contraindications. RESULTS: Prebiopsy mp-MRIs followed by a 12-core TRUSguided prostate biopsy were completed in 484 patients. The sensitivity and specificity of mp-MRI for prostate cancer detected on prostate biopsy were 92.6% and 74.4%, respectively. The negative predictive and positive predictive values of mp-MRI for prostate cancer detected on biopsy were 89.7% and 80.8%, respectively. 129 patients had a PIRADS score of 5 on mp-MRI, with prostate cancer detected in 92%(n1⁄4119) of patients on biopsy. The incidence of Gleason scores 6,7,8 and 9 in patients with PI-RADS 5 were 15.9%(n1⁄419), 51.2%(n1⁄461), 6.7%(n1⁄48) and 26%(n1⁄431), respectively. 117 patients had a PI-RADS score of 4 on mp-MRI, with prostate cancer detected in 53.8%(n1⁄463) of patients on biopsy. The incidence of Gleason scores 6,7,8 and 9 in patients with PI-RADS 4 were 60%(n1⁄436), 33.3% (n1⁄421), 4.7% (n1⁄43) and 1.5% (n1⁄41), respectively. 153 patients had a PI-RADS score of 3 on mp-MRI, with prostate cancer detected in 29% (n1⁄445) of patients on biopsy. The incidence of Gleason scores 6,7 and 9 cancers in patients with PI-RADS score of 3 were 68% (n1⁄431), 26.6% (n1⁄412) and 4.4% (n1⁄42), respectively. Overall there was a statistically significant association between patients with PIRADS scores 3 and cancer positive biopsies (p1⁄40.001). CONCLUSIONS: Mp-MRI has a high predictive value for both diagnosing and excluding prostate cancer. Patients with PI-RADS scores 3 had a significant association with detection of prostate cancer on biopsy. These findings could aid in guiding follow-up protocols in men suspected of prostate cancer.