Timothy C. Brand

A Biopsy-based 17-gene Genomic Prostate Score Predicts Recurrence After Radical Prostatectomy and Adverse Surgical Pathology in a Racially Diverse Population of Men with Clinically Low- and Intermediate-risk Prostate Cancer

BACKGROUND Biomarkers that are validated in independent cohorts are needed to improve risk assessment for prostate cancer (PCa). OBJECTIVE A racially diverse cohort of men (20% African American [AA]) was used to evaluate the association of the clinically validated 17-gene Genomic Prostate Score (GPS) with recurrence after radical prostatectomy and adverse pathology (AP) at surgery. DESIGN, SETTING, AND PARTICIPANTS Biopsies from 431 men treated for National Comprehensive Cancer Network (NCCN) very low-, low-, or intermediate-risk PCa between 1990 and 2011 at two US military medical centers were tested to validate the association between GPS and biochemical recurrence (BCR) and to confirm the association with AP. Metastatic recurrence (MR) was also evaluated. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Cox proportional hazards models were used for BCR and MR, and logistic regression was used for AP. Central pathology review was performed by one uropathologist. AP was defined as primary Gleason pattern 4 or any pattern 5 and/or pT3 disease. RESULTS AND LIMITATIONS GPS results (scale: 0-100) were obtained in 402 cases (93%); 62 men (15%) experienced BCR, 5 developed metastases, and 163 had AP. Median follow-up was 5.2 yr. GPS predicted time to BCR in univariable analysis (hazard ratio per 20 GPS units [HR/20 units]: 2.9; p<0.001) and after adjusting for NCCN risk group (HR/20 units: 2.7; p<0.001). GPS also predicted time to metastases (HR/20 units: 3.8; p=0.032), although the event rate was low (n=5). GPS was strongly associated with AP (odds ratio per 20 GPS units: 3.3; p<0.001), adjusted for NCCN risk group. In AA and Caucasian men, the median GPS was 30.3 for both, the distributions of GPS results were similar, and GPS was similarly predictive of outcome. CONCLUSIONS The association of GPS with near- and long-term clinical end points establishes the assay as a strong independent measure of PCa aggressiveness. Tumor aggressiveness, as measured by GPS, and outcomes were similar in AA and Caucasian men in this equal-access health care system. PATIENT SUMMARY Predicting outcomes in men with newly diagnosed prostate cancer is challenging. This study demonstrates that a new molecular test, the Genomic Prostate Score, which can be performed on a patients original prostate needle biopsy, can predict the aggressiveness of the cancer and help men make decisions regarding the need for immediate treatment of their cancer.

Content and Construct Validation of a Robotic Surgery Curriculum Using an Electromagnetic Instrument Tracker

PURPOSE Rapid adoption of robot-assisted surgery has outpaced our ability to train novice roboticists. Objective metrics are required to adequately assess robotic surgical skills and yet surrogates for proficiency, such as economy of motion and tool path metrics, are not readily accessible directly from the da Vinci® robot system. The trakSTAR™ Tool Tip Tracker is a widely available, cost-effective electromagnetic position sensing mechanism by which objective proficiency metrics can be quantified. We validated a robotic surgery curriculum using the trakSTAR device to objectively capture robotic task proficiency metrics. MATERIALS AND METHODS Through an institutional review board approved study 10 subjects were recruited from 2 surgical experience groups (novice and experienced). All subjects completed 3 technical skills modules, including block transfer, intracorporeal suturing/knot tying (fundamentals of laparoscopic surgery) and ring tower transfer, using the da Vinci robot with the trakSTAR device affixed to the robotic instruments. Recorded objective metrics included task time and path length, which were used to calculate economy of motion. Student t test statistics were performed using STATA®. RESULTS The novice and experienced groups consisted of 5 subjects each. The experienced group outperformed the novice group in all 3 tasks. Experienced surgeons described the simulator platform as useful for training and agreed with incorporating it into a residency curriculum. CONCLUSIONS Robotic surgery curricula can be validated by an off-the-shelf instrument tracking system. This platform allows surgical educators to objectively assess trainees and may provide credentialing offices with a means of objectively assessing any surgical staff member seeking robotic surgery privileges at an institution.

Crowd-sourced assessment of technical skills: an adjunct to urology resident surgical simulation training.

Abstract Background: Crowdsourcing is the practice of obtaining services from a large group of people, typically an online community. Validated methods of evaluating surgical video are time-intensive, expensive, and involve participation of multiple expert surgeons. We sought to obtain valid performance scores of urologic trainees and faculty on a dry-laboratory robotic surgery task module by using crowdsourcing through a web-based grading tool called Crowd Sourced Assessment of Technical Skill (CSATS). Methods: IRB approval was granted to test the technical skills grading accuracy of Amazon.com Mechanical Turk™ crowd-workers compared to three expert faculty surgeon graders. The two groups assessed dry-laboratory robotic surgical suturing performances of three urology residents (PGY-2, -4, -5) and two faculty using three performance domains from the validated Global Evaluative Assessment of Robotic Skills assessment tool. Results: After an average of 2 hours 50 minutes, each of the five videos received 50...

Prospective quality‐of‐life outcomes for low‐risk prostate cancer: Active surveillance versus radical prostatectomy

For patients with low‐risk prostate cancer (PCa), active surveillance (AS) may produce oncologic outcomes comparable to those achieved with radical prostatectomy (RP). Health‐related quality‐of‐life (HRQoL) outcomes are important to consider, yet few studies have examined HRQoL among patients with PCa who were managed with AS. In this study, the authors compared longitudinal HRQoL in a prospective, racially diverse, and contemporary cohort of patients who underwent RP or AS for low‐risk PCa.

Crowd-sourced assessment of technical skills: an opportunity for improvement in the assessment of laparoscopic surgical skills.

BACKGROUND Objective, unbiased assessment of surgical skills remains a challenge in surgical education. We sought to evaluate the feasibility and reliability of Crowd-Sourced Assessment of Technical Skills. METHODS Seven volunteer general surgery interns were given time for training and then testing, on laparoscopic peg transfer, precision cutting, and intracorporeal knot-tying. Six faculty experts (FEs) and 203 Amazon.com Mechanical Turk crowd workers (CWs) evaluated 21 deidentified video clips using the Global Objective Assessment of Laparoscopic Skills validated rating instrument. RESULTS Within 19 hours and 15 minutes we received 662 eligible ratings from 203 CWs and 126 ratings from 6 FEs over 10 days. FE video ratings were of borderline internal consistency (Krippendorffs alpha = .55). FE ratings were highly correlated with CW ratings (Pearsons correlation coefficient = .78, P < .001). CONCLUSION We propose the use of Crowd-Sourced Assessment of Technical Skills as a reliable, basic tool to standardize the evaluation of technical skills in general surgery.

Elevated alkaline phosphatase velocity strongly predicts overall survival and the risk of bone metastases in castrate-resistant prostate cancer.

OBJECTIVES In patients with a rising prostate-specific antigen (PSA) level during treatment with androgen deprivation therapy, identification of men who progress to bone metastasis and death remains problematic. Accurate risk stratification models are needed to better predict risk for bone metastasis and death among patients with castration-resistant prostate cancer (CRPC). This study evaluates whether alkaline phosphatase (AP) kinetics predicts bone metastasis and death in patients with CRPC. METHODS AND MATERIALS A retrospective cohort study of 9,547 patients who underwent treatment for prostate cancer was conducted using the Center for Prostate Disease Research Multi-center National Database. From the entire cohort, 347 were found to have CRPC and, of those, 165 had 2 or more AP measurements during follow-up. To determine the AP velocity (APV), the slope of the linear regression line of all AP values was plotted over time. Rapid APV was defined as the uppermost quartile of APV values, which was found to be ≥6.3 IU/l/y. CRPC was defined as 2 consecutive rising PSA values after achieving a PSA nadir<4 ng/ml and documented testosterone values less than 50 ng/dl. The primary study outcomes included bone metastasis-free survival (BMFS) and overall survival (OS). RESULTS Rapid APV and PSA doubling time (PSADT) less than 10 months were strong predictors of both BMFS and OS in a multivariable analysis. Faster PSADT was a stronger predictor for BMFS (odds ratio [OR] = 12.1, P<0.0001 vs. OR = 2.7, P = 0.011), whereas rapid APV was a stronger predictor of poorer OS (OR = 5.11, P = 0.0001 vs. OR = 3.98, P = 0.0034). In those with both a rapid APV and a faster PSADT, the odds of developing bone metastasis and death exceeded 50%. CONCLUSION APV is an independent predictor of OS and BMFS in patients with CRPC. APV, in conjunction with PSA-based clinical parameters, may be used to better identify patients with CRPC who are at the highest risk of metastasis and death. These findings need validation in prospective studies.

Effects of Valproic Acid and Dexamethasone Administration on Early Bio-Markers and Gene Expression Profile in Acute Kidney Ischemia-Reperfusion Injury in the Rat

Renal ischemia-reperfusion (IR) causes acute kidney injury (AKI) with high mortality and morbidity. The objective of this investigation was to ameliorate kidney IR injury and identify novel biomarkers for kidney injury and repair. Under general anesthesia, left renal ischemia was induced in Wister rats by occluding renal artery for 45 minutes, followed by reperfusion and right nephrectomy. Thirty minutes prior to ischemia, rats (n = 8/group) received Valproic Acid (150 mg/kg; VPA), Dexamethasone (3 mg/kg; Dex) or Vehicle (saline) intraperitoneally. Animals were sacrificed at 3, 24 or 120 h post-IR. Plasma creatinine (mg/dL) at 24 h was reduced (P<0.05) in VPA (2.7±1.8) and Dex (2.3±1.2) compared to Vehicle (3.8±0.5) group. At 3 h, urine albumin (mg/mL) was higher in Vehicle (1.47±0.10), VPA (0.84±0.62) and Dex (1.04±0.73) compared to naïve (uninjured/untreated control) (0.14±0.26) group. At 24 h post-IR urine lipocalin-2 (μg/mL) was higher (P<0.05) in VPA, Dex and Vehicle groups (9.61–11.36) compared to naïve group (0.67±0.29); also, kidney injury molecule-1 (KIM-1; ng/mL) was higher (P<0.05) in VPA, Dex and Vehicle groups (13.7–18.7) compared to naïve group (1.7±1.9). Histopathology demonstrated reduced (P<0.05) ischemic injury in the renal cortex in VPA (Grade 1.6±1.5) compared to Vehicle (Grade 2.9±1.1). Inflammatory cytokines IL1β and IL6 were downregulated and anti-apoptotic molecule BCL2 was upregulated in VPA group. Furthermore, kidney DNA microarray demonstrated reduced injury, stress, and apoptosis related gene expression in the VPA administered rats. VPA appears to ameliorate kidney IR injury via reduced inflammatory cytokine, apoptosis/stress related gene expression, and improved regeneration. KIM-1, lipocalin-2 and albumin appear to be promising early urine biomarkers for the diagnosis of AKI.

Racial/Ethnic Patterns in Prostate Cancer Outcomes in an Active Surveillance Cohort

Introduction. Concern regarding overtreatment of prostate cancer (CaP) is leading to increased attention on active surveillance (AS). This study examined CaP survivors on AS and compared secondary treatment patterns and overall survival by race/ethnicity. Methods. The study population consisted of CaP patients self-classified as black or white followed on AS in the Center for Prostate Disease Research (CPDR) multicenter national database between 1989 and 2008. Secondary treatment included radical prostatectomy (RP), external beam radiation therapy or brachytherapy (EBRT-Br), and hormone therapy (HT). Secondary treatment patterns and overall survival were compared by race/ethnicity. Results. Among 886 eligible patients, 21% were black. Despite racial differences in risk characteristics and secondary treatment patterns, overall survival was comparable across race. RP following AS was associated with the longest overall survival. Conclusion. Racial disparity in overall survival was not observed in this military health care beneficiary cohort with an equal access to health care.

Patient-specific Meta-analysis of 2 Clinical Validation Studies to Predict Pathologic Outcomes in Prostate Cancer Using the 17-Gene Genomic Prostate Score

OBJECTIVE To perform patient-specific meta-analysis (MA) of two independent clinical validation studies of a 17-gene biopsy-based genomic assay as a predictor of favorable pathology at radical prostatectomy. MATERIALS AND METHODS Patient-specific MA was performed on data from 2 studies (732 patients) using the Genomic Prostate Score (GPS; scale 0-100) together with Cancer of the Prostate Risk Assessment (CAPRA) score or National Comprehensive Cancer Network (NCCN) risk group as predictors of the likelihood of favorable pathology (LFP). Risk profile curves associating GPS with LFP by CAPRA score and NCCN risk group were generated. Decision curves and receiver operating characteristic curves were calculated using patient-specific MA risk estimates. RESULTS Patient-specific MA-generated risk profiles ensure more precise estimates of LFP with narrower confidence intervals than either study alone. GPS added significant predictive value to each clinical classifier. A model utilizing GPS and CAPRA provided the most risk discrimination. In decision-curve analysis, greater net benefit was shown when combining GPS with each clinical classifier compared with the classifier alone. The area under the receiver operating characteristic curve improved from 0.68 to 0.73 by adding GPS to CAPRA, and 0.64 to 0.70 by adding GPS to NCCN risk group. The proportion of patients with LFP >80% increased from 11% using NCCN risk group alone to 23% using GPS with NCCN. Using GPS with CAPRA identified the highest proportion-31%-of patients with LFP >80%. CONCLUSION Patient-specific MA provides more precise risk estimates that reflect the complete body of evidence. GPS adds predictive value to 3 widely used clinical classifiers, and identifies a larger proportion of low-risk patients than identified by clinical risk group alone.

The Effect of Race/Ethnicity on the Accuracy of the 2001 Partin Tables for Predicting Pathologic Stage of Localized Prostate Cancer

OBJECTIVES To test the accuracy of the 2001 Partin Tables in African American men who underwent radical prostatectomy at multiple centers throughout the United States. METHODS We compiled a large multiethnic cohort of men (n = 3748) treated with radical prostatectomy at multiple sites, including all of the sites of the Department of Veterans Affairs-based Shared Equal Access Regional Cancer Hospital (SEARCH) database (n = 1524), Wayne State University (n = 1305), the University of Texas Health Science Center (n = 522), and the Henry Ford Hospital (n = 397). We evaluated the accuracy of the 2001 Partin Tables using area under the receiver operator characteristic curve (AUC) separately among African American and white men. RESULTS African American men (n = 1188, 32%), despite being more likely to have clinical Stage T1c disease (56% versus 47%, chi-square P <0.001), had higher preoperative PSA values (9.1 versus 7.7 ng/mL, rank-sum P <0.001) and were more likely to have higher-grade disease on diagnostic biopsy (chi-square P = 0.005). Despite these differences in baseline clinical characteristics, the 2001 Partin Tables performed equally well in both racial groups. Specifically, there were no differences in the AUC for African American and white men for predicting organ-confined disease (AUC 0.73 versus 0.72; P = 0.56), extraprostatic extension (AUC 0.62 versus 0.62; P = 0.99), or seminal vesicle invasion (AUC 0.77 versus 0.79; P = 0.53). CONCLUSIONS These data lend further support to the idea that although baseline differences between the races existed that may underlie an overall more aggressive disease among African American men, for the individual patient, race is not valuable for prognostication.