Circulating microRNAs combined with PSA for accurate and non-invasive prostate cancer detection.

The dosage of prostate-specific antigen (PSA), an easily evaluable and non-invasive biomarker, has made early detection of prostate cancer (PCa) possible. However, it leads to high percentages of unnecessary biopsies and may miss aggressive tumors in men with PSA levels below 4 ng/ml. Therefore, we propose to combine circulating microRNAs (miRs) with PSA, to improve the diagnostic route for PCa. Plasma miR profiling identified candidate diagnostic miRs in a discovery cohort of 60 tumors and 60 controls (men with benign prostatic hyperplasia or healthy donors). Linear models with an empirical Bayesian approach and multivariate penalized logistic regression were applied to select tumor-associated miRs and/or clinical variables. A classifier was developed and tested on a validation cohort of 68 tumors and 174 controls consecutively collected, where miRs were evaluated by quantitative real-time polymerase chain reaction. A classifier based on miR-103a-3p, let-7a-5p and PSA could detect both overall and clinically significant tumors better than PSA alone, even in 50-69 years aged men with PSA ≤ 4 ng/ml. Even in the validation cohort, the classifier performed better than PSA alone in terms of specificity and positive predictive value, allowing to correctly identify eight out of nine tumors undetected by PSA, including three high-risk and three tumors in 50-69 years old men. Of carriers of non-malignant lesions with PSA in the 4-16 ng/ml interval, who may avoid unnecessary biopsies, 34% were correctly identified. Coupling two circulating miRs with PSA could be a useful strategy to diagnose clinically significant PCa and avoid an important fraction of unnecessary biopsies.

Prostate cancer treatment in renal transplant recipients: a systematic review.

The aim of this review was to summarize the current evidence and to highlight the main issues future research needs to address regarding prostate cancer (PCa) treatment in renal transpant recipients (RTRs). We conducted a search of AMED, Medline and Embase up to 17 November 2016 to investigate oncological and functional outcomes of PCa treatment in RTR. Type and use/protocols of immunosuppression and peri-operative antibiotic drugs were also assessed. The search was implemented manually. Exclusion criteria were absence of full text or absence of information that allowed us to differentiate oncological and/or functional outcomes of each therapeutic approach used. We included 241 patients from 27 retrospective studies published between 1991 and 2016; seven of the studies were case-control and 20 were case series. We also considered nine case reports published between 1999 and 2016. Follow-up ranged from 1 to 120 months. PCa was organ-confined, with Gleason score ≤6 in 75.2% and 60.4% of patients. Surgery was the most frequent treatment used (n = 186), for which cancer-specific (CSS) and overall survival (OS) rates were both 96.8%. Functional outcomes, including continence and erectile function, and complications were less frequently reported and were generally similar to those reported for radical prostatectomy (RP) in non-RTRs. Other treatment methods in the patients included in the review were radiotherapy (RT) ± androgen deprivation therapy (ADT; n = 34; OS 88.2%; CSS 88.2%), ADT alone (n = 14; OS 42.9%; CSS 64.3%), brachytherapy (BT; n = 11; OS and CSS 100%), watchful waiting (n = 4) and active surveillance (n = 1). Overall no treatment-related graft loss occurred. Immunosuppression and antibiotic schemes were poorly reported and inconsistent. Outcomes of PCa treatment in RTRs are encouraging and do not appear to be inferior to those of non-RTR. RP was the most commonly assessed approach, whilst RT, BT and ADT were less frequent. Immunosuppression and antibiotic use were poorly reported and highly variable. High-quality studies are needed because the current level of evidence is low, and our results should therefore be interpreted with caution.

Predicting survival in node-positive prostate cancer after open, laparoscopic or robotic radical prostatectomy: A competing risk analysis of a multi-institutional database.

OBJECTIVES: To investigate cancer-specific mortality and other-cause mortality in prostate cancer patients with nodal metastases. METHODS: The study included 411 patients treated with radical prostatectomy and pelvic lymph node dissection for prostate cancer with lymph node metastases at 10 tertiary care centers between 1995 and 2014. Kaplan-Meier analyses were used to assess cancer-specific mortality-free survival rates at 8 years' follow up in the overall population, and after stratifying patients according to clinical and pathological parameters. Uni- and multivariable competing risk Cox regression analyses were used to assess cancer-specific mortality and other-cause mortality. Finally, cumulative-incidence plots were generated for cancer-specific mortality and other-cause mortality after stratifying patients according to the number of positive lymph nodes and the median age at surgery, according to the competing risks method. RESULTS: Men with prostate-specific antigen ≤40 ng/mL and those with one to three positive lymph nodes showed higher cancer-specific mortality-free survival estimates as compared with their counterparts with prostate-specific antigen >40 ng/mL and >3 metastatic lymph nodes, respectively (all P < 0.001). At multivariable Cox regression analyses, preoperative prostate-specific antigen >40 ng/mL, >3 lymph node metastases and pathological Gleason score 8-10 were all independent predictors of cancer-specific mortality (all P-values ≤0.001). On competing risk analysis, when patients were stratified according to the number of positive lymph nodes (namely, ≤3 vs >3), the 8-year cancer-specific mortality rates were 27.4% versus 44.8% for patients aged <65 years, and 15.2% versus 52.6% for patients aged ≥65 years, respectively. CONCLUSIONS: Three positive lymph nodes represent the best prognostic cut-off in node-positive prostate cancer patients. In those individuals with >3 positive lymph nodes, the overall mortality rate is completely related to prostate cancer in young patients.

Oncological outcomes of salvage radical prostatectomy for recurrent prostate cancer in the contemporary era: A multicenter retrospective study.

BACKGROUND: Salvage radical prostatectomy (sRP) historically yields poor functional outcomes and high complication rates. However, recent reports on robotic sRP show improved results. Our objectives were to evaluate sRP oncological outcomes and predictors of positive margins and biochemical recurrence (BCR). METHODS: We retrospectively collected data of sRP for recurrent prostate cancer after local nonsurgical treatment at 18 tertiary referral centers in United States, Australia and Europe, from 2000 to 2016. SM and BCR were evaluated in a univariate and multivariable analysis. Overall and cancer-specific survival were also assessed. RESULTS: We included 414 cases, 63.5% of them performed after radiotherapy. Before sRP the majority of patients had biopsy Gleason score (GS) ≤7 (55.5%) and imaging negative or with prostatic bed involvement only (93.3%). Final pathology showed aggressive histology in 39.7% (GS ≥9 27.6%), with 52.9% having ≥pT3 disease and 16% pN+. SM was positive in 29.7%. Five years BCR-Free, cancer-specific survival and OS were 56.7%, 97.7% and 92.1%, respectively. On multivariable analysis pathological T (pT3a odds ratio [OR] 2.939, 95% confidence interval [CI] 1.469-5.879; ≥pT3b OR 2.428-95% CI 1.333-4.423) and N stage (pN1 OR 2.871, 95% CI 1.503-5.897) were independent predictors of positive margins. Pathological T stage ≥T3b (OR 2.348 95% CI 1.338-4.117) and GS (up to OR 7.183, 95% CI 1.906-27.068 for GS >8) were independent predictors for BCR. Limitations include the retrospective nature of the study and limited follow-up. CONCLUSIONS: In a contemporary series, sRP showed promising oncological control in the medium term despite aggressive pathological features. BCR risk increased in case of locally advanced disease and higher GS. Future studies are needed to confirm our findings.

The impact of warmed and humidified CO2 insufflation during robotic radical prostatectomy: Results of a randomized controlled trial.

BACKGROUND: Cool and dry gas insufflation during laparoscopy induces hypothermia and cytokine increase, with significant perioperative morbidity. Our aim was to assess if warmed and humidified CO2 insufflation with HumiGard™ device can achieve significant benefits over standard insufflation in terms of risk of hypothermia, cytokine response, blood gases, and intra- and postoperative parameters, in the setting of robot-assisted radical prostatectomy (RARP). METHODS: This was a prospective, randomized controlled clinical trial. Sixty-four patients with prostate cancer undergoing RARP were randomized to receive warmed and humidified CO2 insufflation with HumiGard device, plus hot air warming blanket (treatment group, H + WB), or standard CO2 insufflation, plus hot air warming blanket (control group, WB). Body core temperature (BCT), plasma levels of IL-6 and TNF-α, pain scores, and intraoperative parameters were recorded. The data were analyzed according to the Bayesian paradigm. RESULTS: Intraoperative BCT increased in both groups during surgery, with a statistically significant difference favoring group H + WB, ending at 0.2°C higher on average than group WB. No difference across groups was shown for cytokine levels. Blood gas parameters were not affected by warmed CO2 insufflation. No statistical differences were noted for pain scores and the other intra- and postoperative parameters. CONCLUSIONS: During RARP, warm and humidified CO2 insufflation with the HumiGard device was more effective than the standard CO2 insufflation in maintaining the patient's heat homeostasis, even if the difference was minimal. No imbalances were detected on blood gas analyses. No benefit could be shown in terms of cytokine levels and pain scores.

Proton pump inhibitors promote the growth of androgen-sensitive prostate cancer cells through ErbB2, ERK1/2, PI3K/Akt, GSK-3ß signaling and inhibition of cellular prostatic acid phosphatase.

Prostate cancer (PCa) is one of the most common cancer in men. Although hormone-sensitive PCa responds to androgen-deprivation, there are no effective therapies for castration-resistant PCa. It has been recently suggested that proton pump inhibitors (PPIs) may increase the risk of certain cancers; however, association with PCa remains elusive. Here, we evaluated the tumorigenic activities of PPIs in vitro, in PCa cell lines and epithelial cells from benign prostatic hyperplasia (BPH) and in vivo, in PCa mice xenografts. PPIs increased survival and proliferation, and inhibited apoptosis in LNCaP cells. These effects were attenuated or absent in androgen-insensitive DU-145 and PC3 cells, respectively. Specifically, omeprazole (OME) promoted cell cycle progression, increased c-Myc expression, ErbB2 activity and PSA secretion. Furthermore, OME induced the phosphorylation of MAPK-ERK1/2, PI3K/Akt and GSK-3ß, and blunted the expression and activity of cellular prostatic acid phosphatase. OME also increased survival, proliferation and PSA levels in BPH cells. In vivo, OME promoted tumor growth in mice bearing LNCaP xenografts. Our results indicate that PPIs display tumorigenic activities in PCa cells, suggesting that their long-term administration in patients should be carefully monitored.

A Review on the Management of Small Renal Masses: Active Surveillance Versus Surgery.

Despite the rise of small renal tumour (SRMs) diagnosis and related surgeries, death rate of kidney cancer is increasing, suggesting a non-optimal management of SRMs. Active Surveillance (AS) for kidney cancer was introduced to deal with this paradox. However, incertitude remains on whether and when AS can replace surgery in selected patients. We performed a literature search, reviewed and discussed the evidence in favour of AS or surgery for SRMs. Histopathology and natural history of SRMs, including the percentage of benign tumours amongst SRMs, tumour growth rate, life expectancy of SRMs patients being generally older, and current results of AS series seem to support its use in selected groups. However, kidney cancer is a heterogeneous entity, metastasis and ≥T3a status can be found also for SRMs and no biomarkers or other parameters are available to identify lethal SRMs. Despite the recent improvement in the diagnostic and prognostic work through imaging modalities, renal biopsies and nomograms, the interpretation of a survival plot subjectively is still not possible. The majority of AS studies are retrospective and extensive level 1 evidence cohorts with long term follow up are lacking. No unanimity is present regarding inclusion and exclusion criteria to undergo AS, follow up timings and AS exit criteria. Surgery is the only definitive treatment and remains the current standard. A better understanding of kidney cancer biology and SRMs behaviour is needed to clarify the role of AS and its indications.

Cell-cycle Progression-score Might Improve the Current Risk Assessment in Newly Diagnosed Prostate Cancer Patients.

OBJECTIVE: To assess whether cell-cycle progression (CCP)-score (Prolaris) can improve the current risk assessment in newly diagnosed prostate cancer (PCa) patients. CCP-score is a well-validated prognostic assay predictive of PCa death, biochemical recurrence, and progression. METHODS: We evaluated CCP-score at biopsy in 52 patients newly diagnosed with PCa who underwent radical prostatectomy. CCP-score was calculated as average RNA expression of 31 CCP genes, normalized to 15 housekeeping genes. The predictive ability of CCP-score was assessed in univariate and multivariate analyses, and compared to that of Ki-67 levels and traditional clinical variables including prostate-specific antigen, Gleason score, stage, and percentage of positive cores at biopsy. RESULTS: In spite of an overall good accuracy in attributing the correct risk class, 7 high-risk and 13 intermediate-risk patients were misclassified by the Prolaris test. On analysis of variance, mean CCP-score significantly differed across different risk classes based on pathologic results (-1.2 in low risk, -0.444 in intermediate risk, 0.208 in high risk). CCP-score was a significant predictor of high-risk PCa both on univariate and multivariate analyses, after adjusting for clinical variables. Combining CCP-score and the European Association of Urology clinical risk assessment improved the accuracy of risk attribution by around 10%, up to 87.8%. CCP-score was a significant predictor of biochemical recurrence, but only on univariate analysis. CONCLUSION: The CCP-score might provide important new information to risk assessment of newly diagnosed PCa in addition to traditional clinical variables. A correct risk attribution is essential to tailor the best treatment for each patient.