Background

Hospital rankings have become integral to the marketing strategies of many health care systems. Methodology used in compiling these lists appears highly flawed.

Objective

Improve on current hospital ranking systems and to develop a more meaningful measure of a urology department’s contribution to the field, we developed an academic ranking score (ARS) based on publicly available data.

Design, setting, and participants

An active faculty list was assembled for each department. A list of all publications from each department from 2005 to 2010 was then compiled. Only publications with faculty members as first or last author were considered. The ARS was then derived by identifying the number of publications within an institution, normalized by the impact factor of the peer-reviewed journal in which the publication appeared.

Measurements

The 2010 U.S. News and World Report (USNWR) urology list was reranked based on ARS and compared with the USNWR rank list. ARS was also calculated for several leading European urologic centers.

Results and limitations

A total of 6437 urologic publications were indexed to calculate the ARS. Two of the top three programs in the USNWR rankings dropped out of the top 10. The top 10 academically ranked programs increased or decreased an average of >5 positions (range: 0–17). No correlation was seen between programs ranked in the top 10 by USNWR and our objective ARS method (Spearman ρ: −0.1; p = 0.75). Because ARS only includes first- or last-author publications for faculty with clinical duties, ARS likely excludes basic science contributions and contributions from nonclinical faculty.

Conclusions

Ranking of urology departments through quantification of each program’s recent academic contribution, as captured by the ARS, differs substantially from rankings developed by USNWR. Integration of such objective measures into an overall urology program ranking system would replace current subjective opinions marred by historical biases with up-to-date merit-based assessments.

Background

Although case-control studies have identified numerous single nucleotide polymorphisms (SNPs) associated with prostate cancer, the clinical role of these SNPs remains unclear.

Objective

Evaluate previously identified SNPs for association with prostate cancer and accuracy in predicting prostate cancer in a large prospective population-based cohort of unscreened men.

Design, setting, and participants

This study used a nested case-control design based on the Malmö Diet and Cancer cohort with 943 men diagnosed with prostate cancer and 2829 matched controls. Blood samples were collected between 1991 and 1996, and follow-up lasted through 2005.

Measurements

We genotyped 50 SNPs, analyzed prostate-specific antigen (PSA) in blood from baseline, and tested for association with prostate cancer using the Cochran-Mantel-Haenszel test. We further developed a predictive model using SNPs nominally significant in univariate analysis and determined its accuracy to predict prostate cancer.

Results and limitations

Eighteen SNPs at 10 independent loci were associated with prostate cancer. Four independent SNPs at four independent loci remained significant after multiple test correction (p < 0.001). Seven SNPs at five independent loci were associated with advanced prostate cancer defined as clinical stage ≥T3 or evidence of metastasis at diagnosis. Four independent SNPs were associated with advanced or aggressive cancer defined as stage ≥T3, metastasis, Gleason score ≥8, or World Health Organization grade 3 at diagnosis. Prostate cancer risk prediction with SNPs alone was less accurate than with PSA at baseline (area under the curve of 0.57 vs 0.79), with no benefit from combining SNPs with PSA. This study is limited by our reliance on clinical diagnosis of prostate cancer; there are likely undiagnosed cases among our control group.

Conclusions

Only a few previously reported SNPs were associated with prostate cancer risk in the large prospective Diet and Cancer cohort in Malmö, Sweden. SNPs were less useful in predicting prostate cancer risk than PSA at baseline.

Background

Clear cell renal cell carcinoma (ccRCC) displays molecular and histologic heterogeneity. Previously described subsets of this disease, ccA and ccB, were defined based on multigene expression profiles, but it is unclear whether these subgroupings reflect the full spectrum of disease or how these molecular subtypes relate to histologic descriptions or gender.

Objective

Determine whether additional subtypes of ccRCC exist and whether these subtypes are related to von Hippel-Lindau (VHL) inactivation, hypoxia-inducible factor (HIF) 1 and 2 expression, tumor histology, or gender.

Design, setting, and participants

Six large, publicly available ccRCC gene expression databases were identified that cumulatively provided data for 480 tumors for meta-analysis via meta-array compilation.

Measurements

Unsupervised consensus clustering was performed on the meta-arrays. Tumors were examined for the relationship of multigene-defined consensus subtypes and expression signatures of VHL mutation and HIF status, tumor histology, and gender.

Results and limitations

Two dominant subsets of ccRCC were observed. However, a minor third cluster was revealed that correlated strongly with a wild type (WT) VHL expression profile and indications of variant histologies. When variant histologies were removed, ccA tumors naturally divided by gender. This technique is limited by the potential for persistent batch effect, tumor sampling bias, and restrictions of annotated information.

Conclusions

The ccA and ccB subsets of ccRCC are robust in meta-analysis among histologically conventional ccRCC tumors. A third group of tumors was identified that may represent a new variant of ccRCC. Within definitively clear cell tumors, gender may delineate tumors in such a way that it could have implications regarding current treatments and future drug development.

Background

Intracavernous injection of cultured adipose tissue-derived stem cells (ADSCs) effectively restores erectile function in cavernous nerve (CN) injured rats when administered at the time of injury. However, culturing exposes ADSCs to risks of contamination and dedifferentiation. Furthermore, the acute treatment paradigm precludes selecting the patient subset benefitting from the treatment the most.

Objectives

To explore the effect of uncultured autologous adipose-derived stromal vascular fraction (SVF) on improving erectile function in a rat model of CN injury when administered at the time of injury or four weeks post-injury.

Design, setting, and interventions

Sixty-three male Sprague-Dawley rats were randomly divided into three groups: intracavernous injection of saline immediately after CN crush (vehicle), intracavernous injection of SVF immediately after CN crush (immediate-treatment), intracavernous injection of SVF four weeks post-CN crush (delayed-treatment). Twenty-six animals underwent sham surgery (sham). Functional testing and histological analysis were performed 12 weeks post-CN crush or sham surgery.

Measurements

Intracavernous pressure (ICP) response to CN electrostimulation, histological examination of midpenile cross-sections.

Results

Intracavernous injection of SVF, either immediately, or four weeks post-CN injury, resulted in significantly increased ICP/mean arterial pressure (MAP) ratios compared with the vehicle-treated group. Both immediate and delayed treatment with SVF significantly increased expression of neuronal nitric oxide synthase (nNOS) and neurofilament (NF) in dorsal penile nerves compared to the vehicle group. Furthermore, smooth muscle content and smooth muscle/collagen ratio within corpus cavernosum were significantly improved in both SVF treatment groups compared to vehicle-treated rats.

Conclusions

Uncultured autologous SVF injected immediately or 4 weeks post-CN crush improved erectile function, promoted nerve regeneration and prevented fibrosis of the corpus cavernosum following CN injury. The clinical availability of routine SVF isolation devices merits testing autologous SVF therapy in penile rehabilitation studies following radical prostatectomy in the near future.

Background

Nocturia, a common complaint in aging men and women, is frequently cited as the cause of nocturnal awakenings leading to sleep loss, daytime fatigue, and reduced quality of life (QOL).

Objective

Investigate the association of nocturia with QOL and depressive symptoms among men and women.

Design, setting, and participants

A population-based epidemiologic survey of urologic symptoms among persons aged 30–79 yr. A multistage stratified cluster sample design was used to randomly sample 5503 residents of Boston, MA, USA.

Measurements

Nocturia was defined as a self-report of two or more voiding episodes nightly or having to get up to urinate more than once nightly “fairly often,” “usually,” or “almost always.” QOL was assessed using the physical and mental health component scores of the 12-Item Short-Form Survey (SF-12). Depression was assessed using the Center for Epidemiological Studies Depression Scale. Multiple linear and logistic regression methods were used to model the nocturia and QOL association and to control for confounders.

Results and limitations

Nocturia was associated with decreased SF-12 scores for both the physical and mental health components after multivariate adjustment. Nocturia was also associated with increased odds of depressive symptoms (men: adjusted odds ratio [OR]: 2.79; 95% confidence interval [CI], 1.81–4.31; women: adjusted OR: 1.80; 95% CI, 1.29–2.51). Among women who reported sleep interference due to urologic symptoms, nocturia was associated with a threefold increase in odds of depression. In this cross-sectional analysis, the temporal sequence of causality of the nocturia and depression association could not be assessed.

Conclusions

Nocturia is associated with decreased QOL and with an increased prevalence of depressive symptoms in both men and women.

Background

The pathophysiology of interstitial cystitis (IC) is unknown. Deficits in urothelial cell layers and autoimmune mechanisms may play a role.

Objective

To examine whether immunization of mice with recombinant mouse uroplakin II (rmUPK2), a bladder-specific protein, would provoke an autoimmune response sufficient to create an IC phenotype.

Design, setting, and participants

RmUPK2 complementary DNA was generated, transferred into a bacterial expression vector, and the generated protein was purified. Eight-week-old SWXJ female mice were immunized with rmUPK2 protein via subcutaneous injection of 200 µg of rmUPK2 protein in 200 µl of an emulsion.

Measurements

Mice were euthanized 5 wk after immunization. Axillary and inguinal lymph node cells were tested for antigen-specific responsiveness and cytokine production, serum isotype antibody titers against rmUPK2 were determined, and gene expression of inflammatory mediators was measured in the bladder and other organs. For functional analysis, mice were placed in urodynamic chambers for 24-h micturition frequency and total voided urine measurements.

Results and limitations

Immunization with rmUPK2 resulted in T-cell infiltration of the bladder urothelium and increased rmUPK2-specific serum antibody responses in the experimental autoimmune cystitis (EAC) mice models compared with controls. The ratio of bladder to body weight was increased in EAC mice. Quantitative reverse transcriptase polymerase chain reaction analysis showed elevated gene expression of tumor necrosis factor α, interferon γ, interleukin (IL)-17A, and IL-1β in bladder urothelium but not in other organs. Evaluation of 24-h micturition habits of EAC mice showed significantly increased urinary frequency (p < 0.02) and significantly decreased urine output per void (p < 0.021) when compared with control mice.

Conclusions

Our study showed that a bladder-specific autoimmune response sufficient to induce inflammation and EAC occurs in mice following immunization with rmUPK2. EAC mice displayed significant evidence of urinary frequency and decreased urine output per void. Further phenotype characterization of EAC mice should include evidence for pain and/or afferent hypersensitivity, and evidence of urothelial cell layer damage.

Background

Intracavernous (IC) injection of stem cells has been shown to ameliorate cavernous-nerve (CN) injury-induced erectile dysfunction (ED). However, the mechanisms of action of adipose-derived stem cells (ADSC) remain unclear.

Objectives

To investigate the mechanism of action and fate of IC injected ADSC in a rat model of CN crush injury.

Design, setting, and participants

Sprague-Dawley rats (n = 110) were randomly divided into five groups. Thirty-five rats underwent sham surgery and IC injection of ADSC (n = 25) or vehicle (n = 10). Another 75 rats underwent bilateral CN crush injury and were treated with vehicle or ADSC injected either IC or in the dorsal penile perineural space. At 1, 3, 7 (n = 5), and 28 d (n = 10) postsurgery, penile tissues and major pelvic ganglia (MPG) were harvested for histology. ADSC were labeled with 5-ethynyl-2-deoxyuridine (EdU) before treatment. Rats in the 28-d groups were examined for erectile function prior to tissue harvest.

Measurements

IC pressure recording on CN electrostimulation, immunohistochemistry of the penis and the MPG, and number of EdU-positive (EdU+) cells in the injection site and the MPG.

Results and limitations

IC, but not perineural, injection of ADSC resulted in significantly improved erectile function. Significantly more EdU+ ADSC appeared in the MPG of animals with CN injury and IC injection of ADSC compared with those injected perineurally and those in the sham group. One day after crush injury, stromal cell-derived factor-1 (SDF-1) was upregulated in the MPG, providing an incentive for ADSC recruitment toward the MPG. Neuroregeneration was observed in the group that underwent IC injection of ADSC, and IC ADSC treatment had beneficial effects on the smooth muscle/collagen ratio in the corpus cavernosum.

Conclusions

CN injury upregulates SDF-1 expression in the MPG and thereby attracts intracavernously injected ADSC. At the MPG, ADSC exert neuroregenerative effects on the cell bodies of injured nerves, resulting in enhanced erectile response.

Background

Two potential targets for preventing chronic lower urinary tract symptoms (LUTS) in older men are obesity and physical activity.

Objective

To examine associations of adiposity and physical activity with incident LUTS in community-dwelling older men.

Design, setting, and participants

The Osteoporotic Fractures in Men Study (MrOS) is a prospective cohort of men ≥65 yr of age. MrOS participants without LUTS and a history of LUTS treatment at baseline were included in this analysis.

Measurements

Adiposity was measured with body mass index (BMI), physical activity with the Physical Activity Scale for the Elderly (PASE) and self-report of daily walking, and LUTS with the American Urological Association Symptom Index.

Results and limitations

The mean age (standard deviation [SD]) of the 1695 participants was 72 (5) yr at baseline. At a mean (SD) follow-up of 4.6 (0.5) yr, 524 (31%) of men reported incident LUTS. In multivariate analyses, compared with men of normal weight at baseline (BMI <25 kg/m2), overweight (BMI: 25.0–29.9 kg/m2) and obese (≥30 kg/m2) men were 29% (adjusted odds ratio [ORadj]: 1.29; 95% confidence interval [CI], 1.00–1.68) and 41% (ORadj: 1.41; 95% CI, 1.03–1.93) more likely to develop LUTS, respectively. Men in the highest quartile of physical activity were 29% (ORadj: 0.71; 95% CI, 0.53–0.97) and those who walked daily 20% (ORadj: 0.80; 95% CI, 0.65–0.98) less likely than their sedentary peers to develop LUTS, adjusting for BMI. The homogeneous composition of MrOS potentially diminishes the external validity of these results.

Conclusions

In older men, obesity and higher physical activity are associated with increased and decreased risks of incident LUTS, respectively. Prevention of chronic urinary symptoms represents another potential health benefit of exercise in elderly men.

Background

Radiation therapy is commonly used to treat localized prostate cancer; however, representative data regarding treatment-related toxicities compared with conservative management are sparse.

Objective

To evaluate gastrointestinal (GI) toxicities in men treated with either primary radiation or conservative management for T1–T2 prostate cancer.

Design, setting, and participants

We performed a population-based cohort study, using Medicare claims data linked to the Surveillance Epidemiology and End Results data. Competing risk models were used to evaluate the risks.

Measurements

GI toxicities requiring interventional procedures occurring at least 6 mo after cancer diagnosis.

Results and limitations

Among 41 737 patients in this study, 28 088 patients received radiation therapy. The most common GI toxicity was GI bleeding or ulceration. GI toxicity rates were 9.3 per 1000 person-years after three-dimensional conformal radiotherapy, 8.9 per 1000 person-years after intensity-modulated radiotherapy, 5.3 per 1000 person-years after brachytherapy alone, 20.1 per 1000 person-years after proton therapy, and 2.1 per 1000 person-years for conservative management patients. Radiation therapy is the most significant factor associated with an increased risk of GI toxicities (hazard ratio [HR]: 4.74; 95% confidence interval [CI], 3.97–5.66). Even after 5 yr, the radiation group continued to experience significantly higher rates of new GI toxicities than the conservative management group (HR: 3.01; 95% CI, 2.06–4.39). Because our cohort of patients were between 66 and 85 yr of age, these results may not be applicable to younger patients.

Conclusions

Patients treated with radiation therapy are more likely to have procedural interventions for GI toxicities than patients with conservative management, and the elevated risk persists beyond 5 yr.

Background

Abiraterone acetate (AA) is an androgen biosynthesis inhibitor shown to prolong life in patients with castration-resistant prostate cancer (CRPC) already treated with chemotherapy. AA treatment results in dramatic declines in prostate-specific antigen (PSA) in some patients and no declines in others, suggesting the presence of molecular determinants of sensitivity in tumors.

Objective

To study the role of transmembrane protease, serine 2 (TMPRSS2)–v-ets erythroblastosis virus E26 oncogene homolog (ERG) fusion, an androgen-dependent growth factor, in circulating tumor cells (CTCs) as a biomarker of sensitivity to AA.

Design, setting, and participants

The predictive value of TMPRSS2-ERG status was studied in 41 of 48 men with postchemotherapy-treated CRPC enrolled in sequential phase 2 AA trials.

Intervention

Patients received AA 1000 mg daily and continuously.

Measurements

TMPRSS2-ERG status was characterized by a sensitive, analytically valid reverse transcription polymerase chain reaction assay in CTCs enriched from ethylene-diaminetetraacetic acid anticoagulated blood obtained prior to AA treatment. Outcomes were measured by PSA Working Group 1 criteria.

Results and limitations

Standard procedures for specimen acquisition, processing, and testing using the validated TMPRSS2-ERG assay on a multiplex platform gave intra-assay and interassay coefficients of variation <7%. TMPRSS2-ERG fusion was present in 15 of 41 patients (37%), who had a median baseline CTC count of 17 (interquartile range: 7–103 cells per 7.5 ml). A PSA decline ≥50% was observed in 7 of 15 patients (47%) with the fusion and in 10 of 26 patients (38%) without the fusion. Although limited by the low number of patients, a posttherapy CTC count of less than five per 7.5 ml was prognostic for longer survival relative to a CTC count five or more. TMPRSS2-ERG status did not predict a decline in PSA or other clinical outcomes.

Conclusions

Molecular profiles of CTCs with an analytically valid assay identified the presence of the prostate cancer–specific TMPRSS2-ERG fusion but did not predict for response to AA treatment. This finding demonstrates the role of CTCs as surrogate tissue that can be obtained in a routine practice setting.

Background

The optimal number of 3-wk docetaxel plus prednisone (DP) cycles for metastatic castration-resistant prostate cancer (mCRPC) is unclear.

Objective

A retrospective analysis of two clinical trials was performed to evaluate the association of the number of cycles with overall survival (OS).

Design, setting, and participants

An exploratory analysis compared outcomes of 332 men who received DP in the TAX-327 trial, which stipulated up to 10 cycles, and 220 men who received DP in CS-205, a randomized phase 2 trial comparing DP plus AT-101 (bcl-2 inhibitor) versus DP plus placebo, which allowed up to 17 cycles.

Measurements

Patients who completed 10 cycles of DP without progression in both trials were included. Men in both arms of CS-205 were combined for analysis, as no significant differences in outcomes were observed. OS was estimated from the date of cycle 10 docetaxel infusion.

Results and limitations

The number of men receiving 10 cycles was similar (p = 0.26) in the two trials (166 [50.0%] in TAX-327 vs 99 [45.0%] in CS-205; the latter group received a median of five additional cycles). Six- and 12-mo estimated survival after cycle 10 was 92.2% (95% confidence interval [CI], 86.9–95.4%) and 74.6% (CI, 67.2–80.5%) in TAX-327, compared with 92.8% (CI, 85.5–96.5) and 63.4% (CI, 51.8–72.9%) in CS-205. Subanalyses suggested that <10 cycles may have a negative impact and prostate-specific antigen (PSA) declines at cycle 10 may carry a favorable impact. The significance of continued PSA declines up to 17 cycles is unclear. Limitations of a retrospective analysis apply.

Conclusions

A survival benefit was not detected with >10 cycles of DP in men with mCRPC in this retrospective hypothesis-generating analysis.

Context

Androgen deprivation therapy (ADT) for prostate cancer (PCa) represents one of the most effective systemic palliative treatments known for solid tumors. Although clinical trials have assessed the role of ADT in patients with metastatic and advanced locoregional disease, the risk–benefit ratio, especially in earlier stages, remains poorly defined. Given the mounting evidence for potentially life-threatening adverse effects with short- and long-term ADT, it is important to redefine the role of ADT for this disease.

Objective

Review the published experience with currently available ADT approaches in various contemporary clinical settings of PCa and reported serious treatment-related adverse events. This review addresses the level of evidence associated with the use of ADT in PCa, focusing upon survival outcome measures. Furthermore, this paper discusses evolving approaches targeting androgen receptor signaling pathways and emerging evidence from clinical trials with newer compounds.

Evidence acquisition

A comprehensive review of the literature was performed, focusing on data from the last 10 yr (January 2000 to July 2011) and using the terms androgen deprivation, hormone treatment, prostate cancer and adverse effects. Abstracts from trials reported at international conferences held in 2010 and 2011 were also evaluated.

Evidence synthesis

Data from randomized controlled trials and population-based studies were analyzed in different clinical paradigms. Specifically, the role of ADT was evaluated in patients with nonmetastatic disease as the primary and sole treatment, in combination with radiation therapy (RT) or after surgery, and in patients with metastatic disease. The data suggest that in men with nonmetastatic disease, the use of primary ADT as monotherapy has not shown a benefit and is not recommended, while ADT combined with conventional-dose RT (<72 Gy) for patients with high-risk disease may delay progression and prolong survival. The postoperative use of ADT remains poorly evaluated in prospective studies. Likewise, there are no trials evaluating the role of ADT in patients with biochemical relapses after surgery or RT. In patients with metastatic disease, there is a clear benefit in terms of quality of life, reduction of disease-associated morbidity, and possibly survival. Treatment with bilateral orchiectomy, luteinizing hormone–releasing hormone agonist therapy, with and without antiandrogens has been associated with various serious adverse events, including cardiovascular disease, diabetes, and skeletal complications that may also affect mortality.

Conclusions

Although ADT is an effective treatment of PCa, consistent long-term benefits in terms of quality and quantity of life are predominantly evident in patients with advanced/metastatic disease or when ADT is used in combination with RT (<72 Gy) in patients with high-risk tumors. Implementation of ADT should be evidence based, with special consideration to adverse events and the risk–benefit ratio.

Background

The association between tumor complexity and postoperative complications after partial nephrectomy (PN) has not been well characterized.

Objective

We evaluated whether increasing renal tumor complexity, quantitated by nephrometry score (NS), is associated with increased complication rates following PN using the Clavien-Dindo classification system (CCS).

Design, setting, and participants

We queried our prospectively maintained kidney cancer database for patients undergoing PN from 2007 to 2010 for whom NS was available.

Interventions

All patients underwent PN.

Measurements

Tumors were categorized into low- (NS: 4–6), moderate- (NS: 7–9), and high-complexity (NS: 10–12) lesions. Complication rates within 30 d were graded (CCS: I–5), stratified as minor (CCS: I or 2) or major (CCS: 3–5), and compared between groups.

Results and limitations

A total of 390 patients (mean age: 58.0 ± 11.9 yr; 66.9% male) undergoing PN (44.6% open, 55.4% robotic) for low- (28%), moderate- (55.6%), and high-complexity (16.4%) tumors (mean tumor size: 3.74 ± 2.4 cm; median: 3.2 cm) from 2007 to 2010 were identified. Tumor size, estimated blood loss, and ischemia time all significantly differed (p < 0.0001) between groups; patient age, body mass index (BMI), and operative time were comparable. When stratified by CCS, minor and major complication rates for all patients were 26.7% and 11.5%, respectively. Minor complication rates were comparable (26.6 vs 24.9 vs 32.8%; p = 0.45), whereas major complication rates differed (6.4 vs 11.1 vs 21.9%; p = 0.009) among tumor complexity groups. Controlling for age, gender, BMI, type of surgical approach, operative duration, and tumor complexity, prolonged operative time (odds ratio [OR]: 1.01; confidence interval [CI], 1.0–1.02) and high tumor complexity (OR: 5.4; CI, 1.2–24.2) were associated with the postoperative development of a major complication. Lack of external validation is a limitation of this study.

Conclusions

Increasing tumor complexity is associated with the development of major complications after PN. This association should be validated externally and integrated into the decision-making process when counseling patients with complex renal tumors.

Background

PRX302 is a prostate specific antigen (PSA)–activated pore-forming protein toxin under development as a targeted approach for improving lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH) without affecting sexual function.

Objective

To evaluate the safety and efficacy of PRX302 in men with moderate to severe BPH.

Design, setting, and participants

Eligible subjects were refractory, intolerant, or unwilling to undergo medical therapies for BPH and had International Prostate Symptom Score (IPSS) ≥12, a quality of life (QoL) score ≥3, and prostate volumes between 30 and 80 g. Fifteen patients were enrolled in phase 1 studies, and 18 patients entered phase 2 studies.

Interventions

Subjects received intraprostatic injection of PRX302 into the right and left transition zone via a transperineal approach in an office-based setting. Phase 1 subjects received increasing concentrations of PRX302 at a fixed volume; phase 2 subjects received increasing volumes per deposit at a fixed concentration.

Measurements

IPSS, QoL, prostate volume, maximum flow rate (Qmax), International Index of Erectile Function, serum PSA levels, pharmacokinetics, and adverse events were recorded at 30, 60, 90, 180, 270, and 360 d after treatment with PRX302.

Results and limitations

Sixty percent of men in the phase 1 study and 64% of men in the phase 2 study treated with PRX302 had ≥30% improvement compared to baseline in IPSS out to day 360. Patients also experienced improvement in QoL and reduction in prostate volume out to day 360. Patients receiving ≥1 ml of PRX302 per deposit had the best response overall. PRX302 had no deleterious effect on erectile function. Adverse events were mild to moderate and transient in nature. The major study limitation was the small sample size.

Conclusions

The promising safety profile and evidence of efficacy in the majority of treated subjects in these phase 1 and 2 studies supports further development of PRX302 as a minimally invasive, targeted treatment for BPH.

Context

We have recently witnessed a rapid increase in the number of effective systemic agents for men with metastatic castration-resistant prostate cancer (CRPC), including novel hormonal therapies (abiraterone acetate and MDV3100), immunotherapies (sipu-leucel-T), chemotherapies (cabazitaxel), and bone microenvironment targeting agents (denosumab, radium 223). Given the increasing complexity of treatment decisions for this disease, major research and clinical priorities are (1) finding biomarkers that enable an understanding of the natural history and complex biology of this heterogeneous malignancy, (2) defining predictive biomarkers that identify men most likely to benefit from a given therapy, and (3) identifying biomarkers of early response or progression to optimize outcomes.

Objective

In this review, we discuss existing and potential biomarkers in CRPC and how they may currently inform prognosis, aid in treatment selection (predictive value), and relate to survival outcomes (surrogacy).

Evidence acquisition

PubMed-based literature searches and abstracts through September 2011 provided the basis for this literature review as well as expert opinion.

Evidence synthesis

We address blood and urine-based biomarkers such as prostate-specific antigen, lactate dehydrogenase, total and bone alkaline phosphatase and other bone turnover markers, hemoglobin, and circulating tumor cells in the context of prognosis, prediction, and patient selection for therapy. Given the inherent problems associated with defining progression-free survival in CRPC, the importance of biomarker development and the needed steps are highlighted. We place the discussion of bio-markers within the context of the design/intent of a trial and mechanism of action of a given systemic therapy. We discuss novel biomarker development and the pathway for surrogate or predictive biomarkers to become credentialed as useful tests that inform therapeutic decisions.

Conclusions

A greater understanding of biomarkers in CRPC permits a more personalized approach to care that maximizes benefit and minimizes harm and can inform clinical trials tailored to men most likely to derive benefit.

Background

Counseling patients with enhancing renal mass currently occurs in the context of significant uncertainty regarding tumor pathology.

Objective

We evaluated whether radiographic features of renal masses could predict tumor pathology and developed a comprehensive nomogram to quantitate the likelihood of malignancy and high-grade pathology based on these features.

Design, setting, and participants

We retrospectively queried Fox Chase Cancer Center’s prospectively maintained database for consecutive renal masses where a Nephrometry score was available.

Intervention

All patients in the cohort underwent either partial or radical nephrectomy.

Measurements

The individual components of Nephrometry were compared with histology and grade of resected tumors. We used multiple logistic regression to develop nomograms predicting the malignancy of tumors and likelihood of high-grade disease among malignant tumors.

Results and limitations

Nephrometry score was available for 525 of 1750 renal masses. Nephrometry score correlated with both tumor grade (p < 0.0001) and histology (p < 0.0001), such that small endophytic nonhilar tumors were more likely to represent benign pathology. Conversely, large interpolar and hilar tumors more often represented high-grade cancers. The resulting nomogram from these data offers a useful tool for the preoperative prediction of tumor histology (area under the curve [AUC]: 0.76) and grade (AUC: 0.73). The model was subjected to out-of-sample cross-validation; however, lack of external validation is a limitation of the study.

Conclusions

The current study is the first to objectify the relationship between tumor anatomy and pathology. Using the Nephrometry score, we developed a tool to quantitate the preoperative likelihood of malignant and high-grade pathology of an enhancing renal mass.

Background

Oncologic outcomes in men with radiation-recurrent prostate cancer (PCa) treated with salvage radical prostatectomy (SRP) are poorly defined.

Objective

To identify predictors of biochemical recurrence (BCR), metastasis, and death following SRP to help select patients who may benefit from SRP.

Design, setting, and participants

This is a retrospective, international, multi-institutional cohort analysis. There was a median follow-up of 4.4 yr following SRP performed on 404 men with radiation-recurrent PCa from 1985 to 2009 in tertiary centers.

Intervention

Open SRP.

Measurements

BCR after SRP was defined as a serum prostate-specific antigen (PSA) ≥0.1 or ≥0.2 ng/ml (depending on the institution). Secondary end points included progression to metastasis and cancer-specific death.

Results and limitations

Median age at SRP was 65 yr of age, and median pre-SRP PSA was 4.5 ng/ml. Following SRP, 195 patients experienced BCR, 64 developed metastases, and 40 died from PCa. At 10 yr after SRP, BCR-free survival, metastasis-free survival, and cancer-specific survival (CSS) probabilities were 37% (95% confidence interval [CI], 31–43), 77% (95% CI, 71–82), and 83% (95% CI, 76–88), respectively. On preoperative multivariable analysis, pre-SRP PSA and Gleason score at postradiation prostate biopsy predicted BCR (p = 0.022; global p < 0.001) and metastasis (p = 0.022; global p < 0.001). On postoperative multivariable analysis, pre-SRP PSA and pathologic Gleason score at SRP predicted BCR (p = 0.014; global p < 0.001) and metastasis (p < 0.001; global p < 0.001). Lymph node involvement (LNI) also predicted metastasis (p = 0.017). The main limitations of this study are its retrospective design and the follow-up period.

Conclusions

In a select group of patients who underwent SRP for radiation-recurrent PCa, freedom from clinical metastasis was observed in >75% of patients 10 yr after surgery. Patients with lower pre-SRP PSA levels and lower postradiation prostate biopsy Gleason score have the highest probability of cure from SRP.

Background

Partial adrenalectomy has recently been advocated to preserve unaffected adrenal tissue during resection of pheochromocytoma.

Objective

To describe a robot-assisted laparoscopic partial adrenalectomy (RALPA) technique and to report on early functional and oncologic outcomes.

Design, setting, and participants

From 2007 to 2010, 15 RALPA were performed on 12 consecutive patients with pheochromocytoma. Follow-up data of >1 yr are available on 11 procedures. Median follow-up for the entire cohort was 17.3 mo (range: 6–45).

Surgical procedure

Positioning and port placement is designed for adequate reach and visualization of the upper retroperitoneum. The plane between the adrenal cortex and pheochromocytoma pseudocapsule is identified visually and with laparoscopic ultrasound. The tumor is dissected away from normal adrenal cortex, preserving normal adrenal tissue.

Measurements

Preoperative, perioperative, pathologic, and functional outcomes data were analyzed.

Results and limitations

Fourteen of 15 cases were completed robotically. Among 15 procedures, 4 were performed on a solitary adrenal gland. Four cases required resection of multiple tumors (up to six) with two performed in a solitary gland. The mean age of the patients was 30 yr, and the mean body mass index was 27. The mean operative time was 163 min, the median estimated blood loss was 161 ml, and the median tumor size was 2.7 cm (range: 1.3–5.5). There was one conversion to an open procedure in a patient requiring reoperation on a solitary adrenal gland. One patient who underwent RALPA on a solitary adrenal gland required postoperative steroid supplementation at last follow-up. At a median follow-up of 17.3 mo (range: 6–45), there were no recurrences or metastatic events. Study limitations include small sample size and short follow-up.

Conclusions

RALPA for the treatment of pheochromocytoma is feasible and safe and provides encouraging functional and oncologic outcomes, even in patients with a solitary adrenal lesion or multiple ipsilateral lesions.

Background

Whether lower urinary tract symptoms (LUTS), including voiding, storage, and urinary incontinence, are affected by dietary micronutrients is uncertain.

Objective

To test the hypothesis that carotenoid, vitamin C, zinc, and calcium intakes are associated with LUTS and urinary incontinence in women.

Design, setting, and participants

During an observational, cross-sectional, population-based epidemiologic study of 2060 women (30–79 yr of age) in the Boston Area Community Health (BACH) survey (2002–2005), data were collected by validated food frequency questionnaire and in-person interviews and analyzed using multivariate regression.

Measurements

LUTS, storage, and voiding symptoms were assessed using the American Urological Association Symptom Index (AUASI) and a validated severity index for urinary incontinence.

Results and limitations

Women who consumed high-dose vitamin C from diet and supplements were more likely to report storage symptoms, especially combined frequency and urgency (>500 vs <50 mg/d; odds ratio [OR]: 3.42; 95% confidence interval [CI], 1.44–8.12). However, greater consumption of dietary vitamin C or β-cryptoxanthin was inversely associated with voiding symptoms (ptrend < 0.01). Both dietary and supplemental calcium were positively associated with storage symptoms (eg, supplement >1000 mg/d vs none; OR: 2.04; 95% CI, 1.35–3.09; ptrend = 0.0002). No consistent associations were observed for β-carotene, lycopene, or other carotenoids, although smokers using β-carotene supplements were more likely to report storage problems. Whether the observed associations represent direct causes of diet on LUTS is uncertain.

Conclusions

High-dose intakes of vitamin C and calcium were positively associated with urinary storage or incontinence, whereas vitamin C and β-cryptoxanthin from foods and beverages were inversely associated with voiding symptoms. Results indicate that micronutrient intakes may contribute to LUTS in dose-dependent and symptom-specific ways. Further study is needed to confirm these findings and their relevance to clinical treatment decisions.

Background

The role of malnutrition has not been well studied in patients undergoing surgery for renal cell carcinoma (RCC).

Objective

Our aim was to evaluate whether nutritional deficiency (ND) is an important determinant of survival following surgery for RCC.

Design, setting, and participants

A total of 369 consecutive patients underwent surgery for locoregional RCC from 2003 to 2008. ND was defined as meeting one of the following criteria: body mass index <18.5 kg/m2, albumin <3.5 g/dl, or preoperative weight loss ≥5% of body weight.

Intervention

All patients underwent radical or partial nephrectomy.

Measurements

Primary outcomes were overall and disease-specific mortality. Covariates included age, Charlson comorbidity index (CCI), preoperative anemia, tumor stage, Fuhrman grade, and lymph node status. Multivariate analysis was performed using a Cox proportional hazards model. Mortality rates were estimated using the Kaplan-Meier product-limit method.

Results and limitations

Eighty-five patients (23%) were categorized as ND. Three-year overall and disease-specific survival was 58.5% and 80.4% in the ND cohort compared with 85.4% and 94.7% in controls, respectively (p < 0.001). ND remained a significant predictor of overall mortality (hazard ratio [HR]: 2.41, 95% confidence interval [CI], 1.40–4.18) and disease-specific mortality (HR: 2.76; 95% CI, 1.17–6.50) after correcting for age, CCI, preoperative anemia, stage, grade, and nodal status. This study is limited by its retrospective nature.

Conclusions

ND is associated with higher mortality in patients undergoing surgery for locoregional RCC, independent of key clinical and pathologic factors. Given this mortality risk, it may be important to address nutritional status preoperatively and counsel patients appropriately.

Background

The relative importance of genetic and environmental factors for the occurrence of lower urinary tract symptoms (LUTS) is poorly understood.

Objective

To (1) estimate the prevalence of urinary incontinence (UI), overactive bladder (OAB), and other LUTS and (2) to assess the heritability of these symptoms.

Design, setting, and participants

Cross-sectional survey of LUTS in a national population-based cohort of Swedish twins 20–46 yr of age (n = 42 582) from the Swedish Twin Registry.

Measurements

Prevalence rates were determined and heritability of LUTS (in female twins) was assessed using indicators of twin similarity.

Results and limitations

A total of 25 364 twins completed the questionnaire (response rate: 59.6%). LUTS were more common in women (UI: 7%; OAB: 9%; nocturia: 61%; micturition frequency: 18%) than in men (UI: 1%; OAB: 5%; nocturia: 40%; micturition frequency: 11%), and prevalence increased with age. The strongest genetic effects were observed for UI, frequency, and nocturia. The lowest estimate for genetic effects was observed for OAB where environmental effects dominated, and more specifically shared family environment accounted for a third or more of the total variation. For stress UI, a fifth of the total variation in susceptibility to the disorder could be attributed to shared environment. Nonshared environmental effects were seen in the range of 45–65% for the various LUTS. The prevalence of LUTS was low in the men, and there were too few male cases to compute measures of similarity or heritability estimates.

Conclusions

This study provides robust evidence of a genetic influence for susceptibility to UI, frequency, and nocturia in women. In contrast, shared environmental factors seem more important for the predisposition to develop OAB, which may reflect familial patterns such as learning from parental behaviours.

Objectives:

We sought to evaluate the regulatory influence of endothelial nitric oxide (NO) on the basal functional states of the NO and RhoA/Rho-kinase signaling pathways in the penis employing endothelial NO synthase (eNOS) mutant mice and eNOS gene transfer technology.

Methods:

Four groups of mice were utilized: 1) wild type (WT), 2) eNOS gene deleted (eNOS −/−), 3) eNOS and neuronal NOS gene deleted (dNOS −/−), and 4) eNOS −/− mutant mice transfected intracavernosally with eNOS. Cyclic guanosine monophosphate (cGMP) concentration, protein kinase G (PKG) activity, activated RhoA, and Rho-kinase activity were determined in penes of WT and both mutant mouse groups. Constitutive NOS and PKG activities, RhoA, Rho-kinase-α and-β isoforms, and phosphorylated myosin light chain phosphatase target subunit (p-MYPT-1) expressions as well as Rho-kinase activity were determined in penes of eNOS−/− mice after eNOS gene transfer.

Results:

When compared with results in the WT penis, eNOS−/− and dNOS−/− mutant mouse penes had significant reductions in NOS activity, cGMP concentration, PKG activity, Rho-kinase activity and p-MYPT-1 expression (p<0.05) with no significant changes in activated RhoA or in RhoA and Rho-kinase-α and-β protein expressions. After eNOS gene transfer to penes of eNOS−/− mice, Rho-kinase-β and p-MYPT-1 expressions and total Rho-kinase activity were significantly increased from baseline levels (p<0.05).

Conclusions:

These data suggest that endothelial NO serves a role in the penis as a regulator of the basal signaling functions of the NO and RhoA/Rho-kinase erection mediatory pathways. These data offer new insight into the homeostasis of erection regulatory biology.

Context

The introduction of new lithotripters has increased problems associated with shock wave application. Recent studies concerning mechanisms of stone disintegration, shock wave focusing, coupling, and application have appeared that may address some of these problems.

Objective

To present a consensus with respect to the physics and techniques used by urologists, physicists, and representatives of European lithotripter companies.

Evidence acquisition

We reviewed recent literature (PubMed, Embase, Medline) that focused on the physics of shock waves, theories of stone disintegration, and studies on optimising shock wave application. In addition, we used relevant information from a consensus meeting of the German Society of Shock Wave Lithotripsy.

Evidence synthesis

Besides established mechanisms describing initial fragmentation (tear and shear forces, spallation, cavitation, quasi-static squeezing), the model of dynamic squeezing offers new insight in stone comminution. Manufacturers have modified sources to either enlarge the focal zone or offer different focal sizes. The efficacy of extracorporeal shock wave lithotripsy (ESWL) can be increased by lowering the pulse rate to 60–80 shock waves/min and by ramping the shock wave energy. With the water cushion, the quality of coupling has become a critical factor that depends on the amount, viscosity, and temperature of the gel. Fluoroscopy time can be reduced by automated localisation or the use of optical and acoustic tracking systems. There is a trend towards larger focal zones and lower shock wave pressures.

Conclusions

New theories for stone disintegration favour the use of shock wave sources with larger focal zones. Use of slower pulse rates, ramping strategies, and adequate coupling of the shock wave head can significantly increase the efficacy and safety of ESWL.

Background

Previous studies have shown that complications and biochemical recurrence rates after radical prostatectomy (RP) vary between different surgeons to a greater extent than might be expected by chance. Data on urinary and erectile outcomes, however, are lacking.

Objective

In this study, we examined whether between-surgeon variation, known as heterogeneity, exists for urinary and erectile outcomes after RP.

Design, setting, and participants

Our study consisted of 1910 RP patients who were treated by 1 of 11 surgeons between January 1999 and July 2007.

Intervention

All patients underwent RP at Memorial Sloan-Kettering Cancer Center.

Measurements

Patients were evaluated for functional outcome 1 yr after surgery. Multivariable random effects models were used to evaluate the heterogeneity in erectile or urinary outcome between surgeons, after adjustment for case mix (age, prostate-specific antigen, pathologic stage and grade, comorbidities) and year of surgery.

Results and limitations

We found significant heterogeneity in functional outcomes after RP (p < 0.001 for both urinary and erectile function). Four surgeons had adjusted rates of full continence <75%, whereas three had rates >85%. For erectile function, two surgeons in our series had adjusted rates <20%; another two had rates >45%. We found some evidence suggesting that surgeons’ erectile and urinary outcomes were correlated. Contrary to the hypothesis that surgeons “trade off” functional outcomes and cancer control, better rates of functional preservation were associated with lower biochemical recurrence rates.

Conclusions

A patient’s likelihood of recovering erectile and urinary function may differ depending on which of two surgeons performs his RP. Functional preservation does not appear to come at the expense of cancer control; rather, both are related to surgical quality.