Jennifer Linehan

Investigative UrologyExpressed Prostatic Secretion Biomarkers Improve Stratification of NCCN Active Surveillance Candidates: Performance of Secretion Capacity and TMPRSS2:ERG Models

PURPOSE Active surveillance is a viable patient option for prostate cancer provided that a clinical determination of low risk and presumably organ confined disease can be made. To standardize risk stratification schemes the NCCN (National Comprehensive Cancer Network®) provides guidelines for the active surveillance option. We determined the effectiveness of expressed prostatic secretion biomarkers for detecting occult risk factors in NCCN active surveillance candidates. MATERIALS AND METHODS Expressed prostatic secretion specimens were obtained before robot-assisted radical prostatectomy. Secretion capacity biomarkers, including total RNA and expressed prostatic secretion specimen volume, were measured by standard techniques. RNA expression biomarkers, including TXNRD1 mRNA, prostate specific antigen mRNA, TMPRSS2:ERG fusion mRNA and PCA3 mRNA, were measured by quantitative reverse-transcription polymerase chain reaction. RESULTS Of the 528 patients from whom expressed prostatic secretions were collected 216 were eligible for active surveillance under NCCN guidelines. Variable selection on logistic regression identified 2 models, including one featuring types III and VI TMPRSS2:ERG variants, and one featuring 2 secretion capacity biomarkers. Of the 2 high performing models the secretion capacity model was most effective for detecting cases in this group that were up-staged or up-staged plus upgraded. It decreased the risk of up-staging in patients with a negative test almost eightfold and decreased the risk of up-staging plus upgrading about fivefold while doubling the prevalence of up-staging in the positive test group. CONCLUSIONS Noninvasive expressed prostatic secretion testing may improve patient acceptance of active surveillance by dramatically reducing the presence of occult risk factors among those eligible for active surveillance under NCCN guidelines.

Emerging Utility of Urinary Cell-free Nucleic Acid Biomarkers for Prostate, Bladder, and Renal Cancers

CONTEXT By 2020 the estimated incidence of genitourinary (GU) cancers (prostate, bladder, and kidney) will be over 2 million worldwide and responsible for ∼800 000 deaths. Current diagnosis and monitoring methods of GU cancer patients are often invasive and/or lack sensitivity and specificity. Given the utility of blood-based cell-free nucleic acid (cfNA) biomarkers, the development of urinary cfNA biomarkers may improve the sensitivity of urine assays utilizing urine sediment for GU cancers. This review of urinary cfNA in GU cancers identifies the current stage of research, potential clinical utility, and the next steps needed to enter clinical use. OBJECTIVE To critically evaluate the literature of urinary cfNA in GU cancers for clinical utility in diagnosis, screening, and precision medicine. Furthermore, the strategy for future efforts to discover potential new urinary cfNA biomarkers will be described. EVIDENCE ACQUISITION A PubMed database (2006 to current) search was performed according to Preferred Reporting Items for Systemic Review and Meta-analysis using key Medical Subject Headings terms. Additional studies were obtained by cross-referencing from the literature. EVIDENCE SYNTHESIS The collective research publications in urinary cfNA of GU cancers present a promising alternative liquid biopsy approach compared with blood biopsies and urine sediment, particularly for early-stage GU diseases. CONCLUSIONS Urinary cfNA as a liquid biopsy holds potential for a more sensitive alternative to blood biopsies and urine sediment-based tests for clinical use in GU cancers. Not only does urinary cfNA offer advantages including the potential for more frequent testing, monitoring, and home use, but also has applications in early-stage GU cancers. PATIENT SUMMARY In this review, we evaluated the current status of urinary cell-free nucleic acid in genitourinary cancers. We identified the potential advantages of urinary cell-free nucleic acid over blood and urine sediment and its clinical use in genitourinary cancer.

Robotic Radical Cystectomy and Urinary Diversions: Complications and Outcomes

It is incumbent upon urological surgeons who perform robotic assisted radical cystectomy and urinary diversion to critically analyze the complications, functional outcomes and oncological outcomes in order to confirm that it offers no decrease in benefit over traditional open surgery. The surgery can have significant morbidity, so minimizing these complications is and always has been an undisputed goal. Reports from the Pasadena Consensus Panel and the International Robotic Cystectomy Consortium have helped to analyze the literature, review the submitted data, and focus on current issues. This information allowed surgeons from around the world to combine their data to provide optimal care to those patients with invasive urothelial carcinoma. This chapter is a summary of those systematic reviews and recommendations.

2110 DISTINGUISHING PROSTATE CANCER FROM BENIGN PROSTATIC HYPERPLASIA BY NANODEVICE DETECTION OF BIOMARKERS ASSOCIATED WITH REACTIVE STROMA

INTRODUCTION AND OBJECTIVES: Reactive stroma (RS) has been shown to be a predictor of biochemical free recurrence in prostate cancer (Ayala et al. 2003;9:2003), however molecular markers of the stromal response have not yet been successfully applied in prognosis. We recently demonstrated that a thioredoxin-targeted nanodevice selectively binds to RS in frozen tumor sections (Singer et al. Nanomedicine 2011;6:659). Thioredoxin was used as the targeting ligand because it is involved in reductive pathways associated with the wound response mounted by the stroma. Our objective was to compare the stromal binding of the Thioredoxin-targeted nanodevice in benign prostatic hyperplasia (BPH) versus prostate cancer (PCa) to determine whether or not they could be distinguished using a stromal marker. METHODS: A fluorescein-labeled nanodevice (ND-Trx3) that displays 3 copies of the bacterial Thioredoxin (Trx) as a cellular targeting ligand was generated as described previously (Singer, Nanoletters). Robotic-Assisted radical prostatectomy tissue for frozen sections was obtained from 45 patients. Serial sections were incubated with varying concentrations of nanodevice in PBS and 1% BSA. Binding fluorescence was observed at 100x with a Zeiss Observer microscope and images of the entire tumor section were obtained by rastertiling of individual pictures. A numerical grading system was given as the level of nanodevice fluorescence in the stroma. 1 was a lightly visible signal, 2was a moderately intense visible signal and 3 was a bright and intense signal within the RS. Slides where then reviewed by a blinded pathologist. RESULTS: Specimens were collected from 45 patients with Gleason sums ranging 6-to-10. Adjacent serial sections were stained with ND-Trx3, Trichome and H&E. We compared the stromal binding of the ND-Trx3 in BPH vs. PCa to determine whether or not they could be distinguished using a stromal marker .18 slides contained PCa and 17 only contained BPH. There is a strong correlation p 0.0182 between the intensity of nanodevice binding to the stroma and the presence of PCa compared to BPH (Figure 1). The conditional power of the current sample size (N 33) is 91%. CONCLUSIONS: Thioredoxin-linked reductive pathways associated with the wound response may provide useful biomarkers of PCa.