The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer Early Detection provide recommendations for prostate cancer screening in healthy men who have elected to participate in an early detection program. The NCCN Guidelines focus on minimizing unnecessary procedures and limiting the detection of indolent disease. These NCCN Guidelines Insights summarize the NCCN Prostate Cancer Early Detection Panel's most significant discussions for the 2016 guideline update, which included issues surrounding screening in high-risk populations (ie, African Americans, BRCA1/2 mutation carriers), approaches to refine patient selection for initial and repeat biopsies, and approaches to improve biopsy specificity.

Androgen receptor (AR) mediates the growth of prostate cancer (PCa) throughout its course of development, including in abnormal splice variants (AR-SV)-driven advanced stage castration-resistant disease. AR stabilization by androgens makes it distinct from other steroid receptors, which are typically ubiquitinated and degraded by proteasomes after ligand binding. Thus, targeting AR in advanced PCa requires the development of agents that can sustainably degrade variant isoforms for effective therapy. Here we report the discovery and characterization of potent selective AR degraders (SARDs) that markedly reduce the activity of wildtype and splice variant isoforms of AR at sub-micromolar doses. Three SARDs (UT-69, UT-155, and (R)-UT-155) bind the amino-terminal transcriptional activation domain AF-1, which has not been targeted for degradation previously, with two of these SARD (UT-69 and UT-155) also binding the carboxy-terminal ligand binding domain. Despite different mechanisms of action, all three SARDs degraded wild-type AR and inhibited AR function, exhibiting greater inhibitory potency than the approved AR antagonists. Collectively, our results introduce a new candidate class of next-generation therapeutics to manage advanced PCa.

< 22 mmol/L), and proteinuria ( ≥ 1 + on dipstick testing). Multivariate logistic regression (MV) was used to identify risk factors for developing an eGFR of < 60 mL/ min/1.73 m 2 , a creatinine level of ≥ 2.0 mg/dL and MA. RESULTSOf the 749 patients, 499 had RN and 250 NSS; there were no significant demographic differences between the groups. After surgery a significantly greater proportion of the RN than the NSS group had a low eGFR (44.7% vs 16.0%, P < 0.001), MA (12.8% vs 7.2%, P = 0.02), proteinuria (22.2% vs 13.2%, P = 0.003) and elevated creatinine (14.2% vs 8.4%, P = 0.022). MV showed that diabetes mellitus (odds ratio 8.96, P = 0.002), RN (5.32, P < 0.001), hypertension (4.55, P = 0.003), a body mass index (BMI) of ≥ 30 kg/m 2 (3.51, P = 0.017), age ≥ 60 years (2.91, P = 0.015) and smoking (2.44, P = 0.014) were risk factors for developing a low eGFR; and that age ≥ 60 years (2.00, P = 0.019), diabetes mellitus (10, P < 0.001), hypertension (7.41, P = 0.002), smoking (5.29, P < 0.001) and RN (3.08, P < 0.001) were risk factors for developing an elevated creatinine level; and that being male (2.50, P = 0.019), age ≥ 60 years (3.13, P = 0.002), a BMI ≥ 30 (3.52, P < 0.001), RN (9.82, P < 0.001), preoperative eGFR < 60 (9.71, P < 0.001) and elevated creatinine (5.9, P = 0.008) were risk factors for developing MA. CONCLUSIONSPatients undergoing RN had significantly greater CRI, MA and proteinuria rates than a well-matched group undergoing NSS. In addition to RN, age ≥ 60 years, diabetes mellitus, hypertension and smoking were associated with progression to CRI after surgery. KEYWORDSchronic renal insufficiency, metabolic acidosis, proteinuria, nephron-sparing surgery, radical nephrectomy, RCC Study Type -Prognosis (case series) Level of Evidence 4

RESULTSIn all, 396 patients (median age 73.2 years; median BMI of 26.7 kg/m 2 at ADT initiation) were analysed. Of these, 59.1% were AfricanAmerican and 40.9% were Caucasian/other. At a median follow-up of 60.1 months, 36 (11.3%) patients developed NODM. In 77 patients with pre-existing DM, there was an increase of ≥ 10% in serum HbA1c or fasting glucose levels in 15 (19.5%) and 22 (28.6%), respectively. On multivariate analysis, a BMI of ≥ 30 kg/m 2 was associated with an increased risk of developing NODM (odds ratio 4.65, P = 0.031). Receipt of vitamin D had a protective effect (odds ratio 5.75, P = 0.017). CONCLUSIONSPatients receiving ADT for prostate cancer with or with no history of DM should have routine surveillance of glycaemic control, particularly when their BMI is ≥ 30 kg/m 2 , with appropriate preventive and treatment measures.

Many prostate cancers relapse due to the generation of chemoresistance rendering first-line treatment drugs like paclitaxel (PTX) ineffective. The present study aims to determine the role of miRNAs and Hedgehog (Hh) pathway in chemoresistant prostate cancer and to evaluate the combination therapy using Hh inhibitor cyclopamine (CYA). Studies were conducted on PTX resistant DU145-TXR and PC3-TXR cell lines and clinical prostate tissues. Drug sensitivity and apoptosis assays showed significantly improved cytotoxicity with combination of PTX and CYA. To distinguish the presence of cancer stem cell like side populations (SP), Hoechst 33342 flow cytometry method was used. PTX resistant DU145 and PC3 cells, as well as human prostate cancer tissue possess a distinct SP fraction. Nearly 75% of the SP cells are in the G0/G1 phase compared to 62% for non-SP cells and have higher expression of stem cell markers as well. SP cell fraction was increased following PTX monotherapy and treatment with CYA or CYA plus PTX effectively reduced their numbers suggesting the effectiveness of combination therapy. SP fraction cells were allowed to differentiate and reanalyzed by Hoechst staining and gene expression analysis. Post differentiation, SP cells constitute 15.8% of total viable cells which decreases to 0.6% on treatment with CYA. The expression levels of P-gp efflux protein were also significantly decreased on treatment with PTX and CYA combination. MicroRNA profiling of DU145-TXR and PC3-TXR cells and prostate cancer tissue from the patients showed decreased expression of tumor suppressor miRNAs such as miR34a and miR200c. Treatment with PTX and CYA combination restored the expression of miR200c and 34a, confirming their role in modulating chemoresistance. We have shown that supplementing mitotic stabilizer drugs such as PTX with Hh-inhibitor CYA can reverse PTX chemoresistance and eliminate SP fraction in androgen independent, metastatic prostate cancer cell lines.