Robert Wake

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.

The NCCN Guidelines for Prostate Cancer Early Detection provide recommendations for individuals with a prostate who opt to participate in an early detection program after receiving the appropriate counseling on the pros and cons. These NCCN Guidelines Insights provide a summary of recent updates to the NCCN Guidelines with regard to the testing protocol, use of multiparametric MRI, and management of negative biopsy results to optimize the detection of clinically significant prostate cancer and minimize the detection of indolent disease.

OBJECTIVE To investigate the incidence of and risk factors for developing chronic renal insufficiency (CRI), proteinuria and metabolic acidosis (MA) in patients treated with radical nephrectomy (RN) or nephron‐sparing surgery (NSS). PATIENTS AND METHODS We retrospectively reviewed 749 patients (mean age 57.7 years; mean follow‐up 6.4 years) who had RN or NSS for renal tumours between July 1987 and June 2006 at our institution. The demographics and outcomes were analysed and recorded. The primary outcome variable was the development of an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m 2 , with secondary outcomes being the development of a serum creatinine level of ≥2.0 mg/dL, MA (serum bicarbonate <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. RESULTS Of 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. CONCLUSIONS Patients 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.

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.

The NCCN Guidelines for Prostate Cancer Early Detection provide recommendations for men choosing to participate in an early detection program for prostate cancer. These NCCN Guidelines Insights highlight notable recent updates. Overall, the 2014 update represents a more streamlined and concise set of recommendations. The panel stratified the age ranges at which initiating testing for prostate cancer should be considered. Indications for biopsy include both a cutpoint and the use of multiple risk variables in combination. In addition to other biomarkers of specificity, the Prostate Health Index has been included to aid biopsy decisions in certain men, given recent FDA approvals.