The Use of Biomarkers in Prostate Cancer Screening and Treatment.

Prostate cancer screening and diagnosis has been guided by prostate-specific antigen levels for the past 25 years, but with the most recent US Preventive Services Task Force screening recommendations, as well as concerns regarding overdiagnosis and overtreatment, a new wave of prostate cancer biomarkers has recently emerged. These assays allow the testing of urine, serum, or prostate tissue for molecular signs of prostate cancer, and provide information regarding both diagnosis and prognosis. In this review, we discuss 12 commercially available biomarker assays approved for the diagnosis and treatment of prostate cancer. The results of clinical validation studies and clinical decision-making studies are presented. This information is designed to assist urologists in making clinical decisions with respect to ordering and interpreting these tests for different patients. There are numerous fluid and biopsy-based genomic tests available for prostate cancer patients that provide the physician and patient with different information about risk of future disease and treatment outcomes. It is important that providers be able to recommend the appropriate test for each individual patient; this decision is based on tissue availability and prognostic information desired. Future studies will continue to emphasize the important role of genomic biomarkers in making individualized treatment decisions for prostate cancer patients.

Upgrading and upstaging at radical prostatectomy in the post-prostate-specific antigen screening era: an effect of delayed diagnosis or a shift in patient selection?

Prostate cancer management changed in recent times given the recommendation against prostate-specific antigen screening, adherence to active surveillance, and "cytoreductive" surgery. We hypothesized that radical prostatectomy (RP) findings changed as well. All consecutive RPs (n=1348) and first time prostate needle biopsies (n=1719) in a period of 9 years were reviewed. The cohort was separated into 3 groups: (1) from May 2006 to April 2009, (2) from May 2009 to April 2012, and (3) from May 2012 to April 2015. The number of RPs decreased 15% from 551 in group 1 to 476 in group 2 and decreased a further 35% to 311 in group 3. Pure Gleason 6 (grade group 1) decreased from 46% in group 1 to 24% in group 2 (P<.001) to 12% in group 3 (P<.001). Gleason score 4+3=7 (grade group 3) increased from 9.8% in group 1 to 13.4% in group 2 (P=.07) to 20.6% in group 3 (P=.01). Gleason score 8, 9, or 10 (grade groups 4 and 5) increased from 0.9% in group 1 to 8.4% in group 2 (P<.001) to 13.2% in group 3 (P=.04). Pathologic stage pT3 or above increased from 15.5% in group 1 to 29.2% in group 2 (P<.01) to 38.3% in group 3 (P=.01). In needle biopsies, there was no difference in number of cancer diagnoses, number of positive cores, or distribution of grades among 3 groups. More patients with low-risk disease are opting for active surveillance, and patients with high-risk disease are offered cytoreductive surgery. Lack of similar changes in needle biopsies suggests that a decrease in screening is not playing a role in the changes seen at RPs.

Targeted imaging of urothelium carcinoma in human bladders by an ICG pHLIP peptide ex vivo.

Bladder cancer is the fifth most common in incidence and one of the most expensive cancers to treat. Early detection greatly improves the chances of survival and bladder preservation. The pH low insertion peptide (pHLIP) conjugated with a near-infrared fluorescent dye [indocyanine green (ICG)] targets low extracellular pH, allowing visualization of malignant lesions in human bladder carcinoma ex vivo. Cystectomy specimens obtained after radical surgery were immediately irrigated with nonbuffered saline and instilled with a solution of the ICG pHLIP construct, incubated, and rinsed. Bladders were subsequently opened and imaged, the fluorescent spots were marked, and a standard pathological analysis was carried out to establish the correlation between ICG pHLIP imaging and white light pathological assessment. Accurate targeting of bladder lesions was achieved with a sensitivity of 97%. Specificity is 100%, but reduced to 80% if targeting of necrotic tissue from previous transurethral resections or chemotherapy are considered as false positives. The ICG pHLIP imaging agent marked high-grade urothelial carcinomas, both muscle invasive and nonmuscle invasive. Carcinoma in situ was accurately diagnosed in 11 cases, whereas only four cases were seen using white light, so imaging with the ICG pHLIP peptide offers improved early diagnosis of bladder cancers and may also enable new treatment alternatives.

Intravesical Hemostatic Clip Migration After Robotic Prostatectomy: Case Series and Review of the Literature.

INTRODUCTION: The Weck Hem-o-lok™ Ligating clip is a routinely used hemostatic tool in robotic and laparoscopic surgery. It has been the practice in our institution to use such clips for hemostasis of the vascular bundles during robotic prostatectomy. Migration of such clips has been reported in the literature as single case reports. In this study, we present a case series of intravesical Weck clip extrusions presenting as bladder calculi. Such events have led to a change in our practice, and more research is needed to assess the impact of this change. MATERIALS AND METHODS: A retrospective chart review was conducted over the period 2006-2011. Patients included in the study required cystoscopic intervention for removal of encrusted or impacted Weck clips. Primary data points included type of intervention required, time to presentation, and number of presentations. Postoperative anastomotic leak, duration of postoperative hospital stay, and initial operative time were also investigated. RESULTS: Out of 570 total men undergoing robotic-assisted laparoscopic radical prostatectomy (RALRP), eight required return to the operating room for clip extraction (1.4%). Extraction methods included laser lithotripsy, blunt litholapaxy, and grasper extraction. Men experiencing clip migration were hospitalized for a longer period of time (7.6 days vs. 2.1 days, P < .01) and they required more blood transfusions (1.4 units vs. 0.05 units, P < .01) than men who did not experience clip migration. The most common site for clip intrusion was the bladder neck. Average time to presentation was 1.75 years. DISCUSSION: Weck clip migration is a recognized complication of robotic-assisted radical prostatectomy. Men with recurrent urinary tract infection, bothersome voiding symptoms, or hematuria following RALRP should be considered for cystoscopic evaluation. Increased length of hospital stays and the need for a larger volume blood transfusion following prostatectomy were significant predictors of clip migration. More research is needed to determine if implemented changes to our surgical technique have mitigated these risks.

A prostatic intraepithelial neoplasia-dependent p27 Kip1 checkpoint induces senescence and inhibits cell proliferation and cancer progression.

Transgenic expression of activated AKT1 in the murine prostate induces prostatic intraepithelial neoplasia (PIN) that does not progress to invasive prostate cancer (CaP). In luminal epithelial cells of Akt-driven PIN, we show the concomitant induction of p27(Kip1) and senescence. Genetic ablation of p27(Kip1) led to downregulation of senescence markers and progression to cancer. In humans, p27(Kip1) and senescence markers were elevated in PIN not associated with CaP but were decreased or absent, respectively, in cancer-associated PIN and in CaP. Importantly, p27(Kip1) upregulation in mouse and human in situ lesions did not depend upon mTOR or Akt activation but was instead specifically associated with alterations in cell polarity, architecture, and adhesion molecules. These data suggest that a p27(Kip1)-driven checkpoint limits progression of PIN to CaP.