Expression of Small Noncoding RNAs in Urinary Exosomes Classifies Prostate Cancer into Indolent and Aggressive Disease.

PURPOSE: This is the first report of the development and performance of a platform that interrogates small noncoding RNAs (sncRNA) isolated from urinary exosomes. The Sentinel™ PCa Test classifies patients with prostate cancer from subjects with no evidence of prostate cancer, the miR Sentinel CS Test stratifies patients with prostate cancer between those with low risk prostate cancer (Grade Group 1) from those with intermediate and high risk disease (Grade Group 2-5), and the miR Sentinel HG Test stratifies patients with prostate cancer between those with low and favorable intermediate risk prostate cancer (Grade Group 1 or 2) and those with high risk (Grade Group 3-5) disease. MATERIALS AND METHODS: sncRNAs were extracted from urinary exosomes of 235 participants and interrogated on miR 4.0 microarrays. Using proprietary selection and classification algorithms, informative sncRNAs were selected to customize an interrogation OpenArray™ platform that forms the basis of the tests. The tests were validated using a case-control sample of 1,436 subjects. RESULTS: The performance of the miR Sentinel PCa Test demonstrated a sensitivity of 94% and specificity of 92%. The Sentinel CS Test demonstrated a sensitivity of 93% and specificity of 90% for prediction of the presence of Grade Group 2 or greater cancer, and the Sentinel HG Test demonstrated a sensitivity of 94% and specificity of 96% for the prediction of the presence of Grade Group 3 or greater cancer. CONCLUSIONS: The Sentinel PCa, CS and HG Tests demonstrated high levels of sensitivity and specificity, highlighting the utility of interrogation of urinary exosomal sncRNAs for noninvasively diagnosing and classifying prostate cancer with high precision.

Primary urethral carcinoma: A Surveillance, Epidemiology, and End Results data analysis identifying predictors of cancer-specific survival.

OBJECTIVES: Primary urethral carcinoma (PUC) is rare, accounting for <1% of genitourinary malignancies. Current knowledge regarding is founded upon tertiary care centers reporting their experiences. We aim to identify factors predictive of outcomes using a nationwide registry database. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results-18 registries database was queried for cases of PUC ranging between 2004 and 2010. To identify PUC cases, ICD-O site code C68.0 was used as a filter, hence identifying PUC with histologic subtypes including urothelial carcinoma (UC), squamous cell carcinoma (SCC), and adenocarcinoma (AC). Tumor characteristics were compared using log-rank analysis, and survival outcomes were compared using Cox proportional hazards models. RESULTS: A total of 419 PUC cases were identified, 250 (59.7%) male and 169 (40.3%) female patients. The most common histology in men was UC (134, 53.6%), followed by SCC (87, 34.8%) and AC (29, 11.6%). The most common histology in women was AC (79, 46.7%), followed by SCC (43, 25.4%) and UC (42, 24.9%). Log-rank analysis illustrated significant difference in cancer-specific survival (CSS) for T-stage, N-stage, M-stage, and stage of PUC with all histological variants combined (P < 0.001). Multivariate Cox proportional hazards model demonstrated that stage and age were significant for survival, with a risk ratio of 1.033 (95% confidence interval [CI], 1.020-1.046)/year of increased age (P < 0.001) and 3.71 (95% CI, 2.72-5.05) for patients with regional or distant spread. CONCLUSIONS: Knowledge of patient and tumor characteristics that influences survival is paramount in dictating management. The present study illustrates that age and stage are factors significantly associated with CSS in PUC.

Surgical Management of Female Voiding Dysfunction.

Surgical intervention for female voiding dysfunction is common, involving a single or multifaceted approach affecting multiple organ systems in the pelvis. Surgical success relies on knowledge of surgical history, anatomic approaches, and judicious use of supports or materials. Owing to the varied repairs used over the last few decades, it is important for the general surgeon to understand both current and historic approaches. This understanding will help in planning future pelvic surgery as well as in evaluating current ramifications of prior surgery.

Comparison of fracture risk assessment tool score to bone mineral density for estimating fracture risk in patients with advanced prostate cancer on androgen deprivation therapy.

OBJECTIVE: To estimate the risk of fracture (Fracture Risk Assessment Tool [FRAX] algorithm) because of the development of osteoporosis in prostate cancer patients undergoing androgen deprivation therapy (ADT) for patients who would otherwise not have been identified for treatment by the T score. METHODS: This study includes men undergoing ADT for prostate cancer at our urology group. Clinical data were collected via chart review. Subjects were evaluated for fracture risk using country specific (for the United States of America) World Health Organization's FRAX. The FRAX calculations were then compared to fracture risk as determined by T score, for a subset of our cohort that received dual-energy X-ray absorptiometry. RESULTS: Our cohort consisted of 613 patients on ADT, 94 of which had a dual-energy X-ray absorptiometry scan. The FRAX algorithm identified 61.6% patients requiring therapy without bone mass density (BMD), 46.8% with BMD, and 19.14% with T score alone. In addition, positive correlation was found between FRAX with and without BMD as well as T score and FRAX with BMD and without BMD. CONCLUSION: Our data indicate that many patients who were not found at significant risk for fracture with T score were in fact found to be at risk with the FRAX calculation. The largest proportion of patients was found to be at risk through the FRAX calculation without BMD, followed by FRAX with BMD, followed by T score alone. The utility of FRAX is beneficial in identifying patients that may benefit from effective bone-tropic treatment modalities.

Current status of pelvic lymph node dissection in prostate cancer.

Pelvic lymph node dissection (PLND) is presently considered the gold standard for the detection of lymph node invasion in prostate cancer (PCa) patients. Controversy exists over the adequate extent of PLND for patients at different stages of PCa and over the therapeutic value of the procedure. The most recent consensus advocates extended PLND (ePLND) in a patient with Gleason score ≥7 and serum prostate-specific antigen >10 ng/ml who is undergoing radical prostatectomy. Critics claim more aggressive dissection is associated with an increase in complications, hospitalization time, and cost. The present review examines the debate of limited versus ePLND, and discusses the potential value of the latter for patients with PCa. Furthermore, it examines the utility of robotic-assisted surgery in performing PLNDs with both comparable oncological outcomes and comparable complication rates. The literature has reported promising results that support both diagnostic and therapeutic benefits of ePLND. However, prospective, multi-center, long-term studies are necessary to alleviate criticism of the increased risk of complications and costs of performing PLND.

Developing a successful robotics program.

PURPOSE OF REVIEW: Advancements in the robotic surgical technology have revolutionized the standard of care for many surgical procedures. The purpose of this review is to evaluate the important considerations in developing a new robotics program at a given healthcare institution. RECENT FINDINGS: Patients' interest in robotic-assisted surgery has and continues to grow because of improved outcomes and decreased periods of hospitalization. Resulting market forces have created a solid foundation for the implementation of robotic surgery into surgical practice. Given proper surgeon experience and an efficient system, robotic-assisted procedures have been cost comparable to open surgical alternatives. Surgeon training and experience is closely linked to the efficiency of a new robotics program. Formally trained robotic surgeons have better patient outcomes and shorter operative times. Training in robotics has shown no negative impact on patient outcomes or mentor learning curves. SUMMARY: Individual economic factors of local healthcare settings must be evaluated when planning for a new robotics program. The high cost of the robotic surgical platform is best offset with a large surgical volume. A mature, experienced surgeon is integral to the success of a new robotics program.

Intramuscular VEGF activates an SDF1-dependent progenitor cell cascade and an SDF1-independent muscle paracrine cascade for cardiac repair.

The skeletal muscle is endowed with an impressive ability to regenerate after injury, and this ability is coupled to paracrine production of many trophic factors possessing cardiovascular benefits. Taking advantage of this humoral capacity of the muscle, we recently demonstrated an extracardiac therapeutic regimen based on intramuscular delivery of VEGF-A(165) for repair of the failing hamster heart. This distal organ repair mechanism activates production from the injected hamstring of many trophic factors, among which stromal-derived factor-1 (SDF1) prominently mobilized multi-lineage progenitor cells expressing CXCR4 and their recruitment to the heart. The mobilized bone marrow progenitor cells express the cardiac transcription factors myocyte enhancer factor 2c and GATA4 and several major trophic factors, most notably IGF1 and VEGF. SDF1 blockade abrogated myocardial recruitment of CXCR4(+) and c-kit(+) progenitor cells with an insignificant effect on the hematopoietic progenitor lineage. The knockdown of cardiac progenitor cells led to deprivation of myocardial trophic factors, resulting in compromised cardiomyogenesis and angiogenesis. However, the VEGF-injected hamstring continued to synthesize cardioprotective factors, contributing to moderate myocardial tissue viability and function even in the presence of SDF1 blockade. These findings thus uncover two distinct but synergistic cardiac therapeutic mechanisms activated by intramuscular VEGF. Whereas the SDF1/CXCR4 axis activates the progenitor cell cascade and its trophic support of cardiomyogenesis intramuscularly, VEGF amplifies the skeletal muscle paracrine cascade capable of directly promoting myocardial survival independent of SDF1. Given that recent clinical trials of cardiac repair based on the use of marrow-mobilizing agents have been disappointing, the proposed dual therapeutic modality warrants further investigation.

Cone degeneration following rod ablation in a reversible model of retinal degeneration.

PURPOSE: Amphibian retinas regenerate after injury, making them ideal for studying the mechanisms of retinal regeneration, but this leaves their value as models of retinal degeneration in question. The authors asked whether the initial cellular changes after rod loss in the regenerative model Xenopus laevis mimic those observed in nonregenerative models. They also asked whether rod loss was reversible. METHODS: The authors generated transgenic X. laevis expressing the Escherichia coli enzyme nitroreductase (NTR) under the control of the rod-specific rhodopsin (XOP) promoter. NTR converts the antibiotic metronidazole (Mtz) into an interstrand DNA cross-linker. A visually mediated behavioral assay and immunohistochemistry were used to determine the effects of Mtz on the vision and retinas of XOPNTR F1 tadpoles. RESULTS: NTR expression was detected only in the rods of XOPNTR tadpoles. Mtz treatment resulted in rapid vision loss and near complete ablation of rod photoreceptors by day 12. Müller glial cell hypertrophy and progressive cone degeneration followed rod cell ablation. When animals were allowed to recover, new rods were born and formed outer segments. CONCLUSIONS: The initial secondary cellular changes detected in the rodless tadpole retina mimic those observed in other models of retinal degeneration. The rapid and synchronous rod loss in XOPNTR animals suggested this model may prove useful in the study of retinal degeneration. Moreover, the regenerative capacity of the Xenopus retina makes these animals a valuable tool for identifying the cellular and molecular mechanisms at work in lower vertebrates with the remarkable capacity of retinal regeneration.