Comparing Patient-reported Functional Outcomes After Radical Prostatectomy in Historical and Contemporary Practice.

PURPOSE: Modifications to surgical technique, particularly the widespread adoption of robotic surgery, have been proposed to improve functional recovery after prostate cancer surgery. However, rigorous comparison of men in historical vs contemporary practice to evaluate the cumulative effect of these changes on urinary and sexual function after radical prostatectomy is lacking. MATERIALS AND METHODS: We compared prospectively collected patient-reported urinary and sexual function from historical (PROSTQA [Prostate Cancer Outcomes and Satisfaction With Treatment Quality Assessment study], n=235) and contemporary (MUSIC-PRO [Michigan Urological Surgery Improvement Collaborative Patient Reported Outcome] registry, n=1,215) cohorts at the University of Michigan to understand whether modern techniques have resulted in functional improvements for men undergoing prostate cancer surgery. RESULTS: We found significant differences in baseline function, with better urinary (median [IQR]; 100 [93.8-100] vs 93.8 [85.5-100], P < .001) and sexual scores (median [IQR]; 83.3 [66.7-100] vs 74.4 [44.2-87.5], P < .001) prior to treatment in PROSTQA compared to MUSIC-PRO patients, respectively. There was no statistically significant difference in the pattern of urinary incontinence recovery after surgery from 6-24 months between groups (P = .14). However, men in the contemporary MUSIC-PRO group did have significantly better recovery of sexual function compared to men in the historical PROSTQA group (P < .0001). Further, we found that contemporary practice consists of men with more unfavorable demographic and clinical characteristics compared to historical practice. CONCLUSIONS: Our results demonstrate that the widespread alterations in prostate cancer surgery over the past 2 decades have yielded improvements in sexual, but not urinary, function recovery.

Use of the MyProstateScore Test to Rule Out Clinically Significant Cancer: Validation of a Straightforward Clinical Testing Approach.

PURPOSE: The MyProstateScore test was validated for improved detection of clinically significant (grade group ≥2) prostate cancer relative to prostate specific antigen based risk calculators. We sought to validate an optimal MyProstateScore threshold for clinical use in ruling out grade group ≥2 cancer in men referred for biopsy. MATERIALS AND METHODS: Biopsy naïve men provided post-digital rectal examination urine prior to biopsy. MyProstateScore was calculated using the validated, locked multivariable model including only serum prostate specific antigen, urinary prostate cancer antigen 3 and urinary TMPRSS2:ERG. The MyProstateScore threshold approximating 95% sensitivity for grade group ≥2 cancer was identified in a training cohort, and performance was measured in 2 external validation cohorts. We assessed the 1) overall biopsy referral population and 2) population meeting guideline based testing criteria (ie, prostate specific antigen 3-10, or <3 with suspicious digital rectal examination). RESULTS: Validation cohorts were prospectively enrolled from academic (977 patients, median prostate specific antigen 4.5, IQR 3.1-6.0) and community (548, median prostate specific antigen 4.9, IQR 3.7-6.8) settings. In the overall validation population (1,525 patients), 338 men (22%) had grade group ≥2 cancer on biopsy. The MyProstateScore threshold of 10 provided 97% sensitivity and 98% negative predictive value for grade group ≥2 cancer. MyProstateScore testing would have prevented 387 unnecessary biopsies (33%), while missing only 10 grade group ≥2 cancers (3.0%). In 1,242 patients meeting guideline based criteria, MyProstateScore ≤10 provided 96% sensitivity and 97% negative predictive value, and would have prevented 32% of unnecessary biopsies, missing 3.7% of grade group ≥2 cancers. CONCLUSIONS: In a large, clinically pertinent biopsy referral population, MyProstateScore ≤10 provided exceptional sensitivity and negative predictive value for ruling out grade group ≥2 cancer. This straightforward secondary testing approach would reduce the use of more costly and invasive procedures after screening with prostate specific antigen.

Glypican-1 as a target for fluorescence molecular imaging of bladder cancer.

OBJECTIVES: To investigate whether anti-glypican-1 antibody Miltuximab conjugated with near-infrared dye IRDye800CW can be used for in vivo fluorescence imaging of urothelial carcinoma. METHODS: The conjugate, Miltuximab-IRDye800CW, was produced and characterized by size exclusion chromatography and flow cytometry with glypican-1-expressing cells. Balb/c nude mice bearing subcutaneous urothelial carcinoma xenografts were intravenously injected with Miltuximab-IRDye800CW or control IgG-IRDye800CW and imaged daily by fluorescence imaging. After 10 days, tumors and major organs were collected for ex vivo study of the conjugate biodistribution, including its accumulation in the tumor. RESULTS: The intravenous injection of Miltuximab-IRDye800CW to tumor-bearing mice showed its specific accumulation in the tumors with the tumor-to-background ratio of 12.7 ± 2.4, which was significantly higher than that in the control group (4.6 ± 0.9, P < 0.005). The ex vivo imaging was consistent with the in vivo findings, with tumors from the mice injected with Miltuximab-IRDye800CW being significantly brighter than the organs or the control tumors. CONCLUSIONS: The highly specific accumulation and retention of Miltuximab-IRDye800CW in glypican-1-expressing tumors in vivo shows its high potential for fluorescence imaging of urothelial carcinoma and warrants its further investigation toward clinical translation.

Clinicopathological characterisation of renal cell carcinoma in young adults: a contemporary update and review of literature.

AIMS: Renal cell carcinomas are relatively rare in children and young adults. While well characterised in adults, the morphological and molecular characterisation of these tumours in young patients is relatively lacking. The objective of this study was to explore the spectrum of renal cell carcinoma (RCC) subtypes in children and young adults and to determine their clinico-pathological, immunohistochemical and molecular characteristics by evaluating a large retrospective cohort of renal cell carcinoma patients age 30 years or younger. METHODS AND RESULTS: Sixty-eight cases with confirmed diagnosis of renal cell carcinoma at age 30 years or younger were identified at our institution. Clear cell carcinoma accounted for the most common subtype seen in this age group. Translocation renal cell carcinoma and rare familial syndrome subtypes such as succinate dehydrogenase deficient renal cell carcinoma and tuberous sclerosis complex-associated renal cell carcinoma were found relatively more frequently in this cohort. Despite applying the 2016 WHO classification criteria, a high proportion of the tumours in our series remained unclassified. CONCLUSIONS: Our results suggest that renal cell carcinoma in children and young adults is a relatively rare disease that shares many histological similarities to renal cell carcinoma occurring in adults and yet demonstrate some unique clinical-pathological differences. Microphthalmia-associated transcription (MiT) family translocation RCC and rare familial syndrome subtypes are relatively more frequent in the paediatric and adolescent age groups than in adults. Clear cell RCC still accounted for the most common subtype seen in this age group. MiT family translocation RCC patients presented with advanced stage disease and had poor clinical outcomes. The large and heterogeneous subgroup of unclassified renal cell carcinoma contains phenotypically distinct tumours with further potential for future subcategories in the renal cell carcinoma classification.

Anatomical patterns of recurrence following biochemical relapse after post-prostatectomy salvage radiation therapy: a multi-institutional study.

OBJECTIVES: To characterise the frequency and detailed anatomical sites of failure for patients receiving post-radical prostatectomy (RP) salvage radiation therapy (SRT). PATIENTS AND METHODS: A multi-institutional retrospective study was performed on 574 men who underwent SRT between 1986 and 2013. Anatomical recurrence patterns were classified as lymphotrophic (lymph nodes only), osteotrophic (bone only), or multifocal if both were present. Isolated first failure sites were defined as sites of initial clinically detected recurrence that remained isolated for at least 3 months. RESULTS: The median follow-up after SRT was 6.8 years. The 8-year rates of local, regional, and distant failure for patients undergoing SRT were 2%, 6%, and 21%, respectively. Of the 22% men (128 of 574) who developed a clinically detectable recurrence, 17%, 50%, and 31% were lymphotrophic, osteotrophic, and multifocal, respectively. The trophic nature of metastases was prognostic for distant metastases-free survival (DMFS) and prostate cancer-specific survival (PCSS); the 10-year rates of DMFS were 18%, 5%, and 7% (P < 0.01), and PCSS were 78%, 68%, and 56% (P < 0.01), for lymphotrophic, osteotrophic, and multifocal failure patterns, respectively. CONCLUSIONS: We demonstrate that trophism for metastatic site has significant prognostic impact on PCSS in men treated with SRT. Radiographic local failure is an uncommon event after SRT when compared to historical data of patients treated with surgery monotherapy. However, distant failure remains a challenge in this patient population and warrants further therapeutic investigation.

Age, Gender and R.E.N.A.L. Nephrometry Score do not Improve the Accuracy of a Risk Stratification Algorithm Based on Biopsy and Mass Size for Assigning Surveillance versus Treatment of Renal Tumors.

PURPOSE: A previously published risk stratification algorithm based on renal mass biopsy and radiographic mass size was useful to designate surveillance vs the need for immediate treatment of small renal masses. Nonetheless, there were some incorrect assignments, most notably when renal mass biopsy indicated low risk malignancy but final pathology revealed high risk malignancy. We studied other factors that might improve the accuracy of this algorithm. MATERIALS AND METHODS: For 202 clinically localized small renal masses in a total of 200 patients with available R.E.N.A.L. (radius, exophytic/endophytic, nearness of tumor to collecting system or sinus, anterior/posterior, hilar tumor touching main renal artery or vein and location relative to polar lines) nephrometry score, preoperative renal mass biopsy and final pathology we assessed the accuracy of management assignment (surveillance vs treatment) based on the previously published risk stratification algorithm as confirmed by final pathology. Logistic regression was used to determine whether other factors (age, gender, R.E.N.A.L. score, R.E.N.A.L. score components and nomograms based on R.E.N.A.L. score) could improve assignment. RESULTS: Of the 202 small renal masses 53 (26%) were assigned to surveillance and 149 (74%) were assigned to treatment by the risk stratification algorithm. Of the 53 lesions assigned to surveillance 25 (47%) had benign/favorable renal mass biopsy histology while in 28 (53%) intermediate renal mass biopsy histology showed a mass size less than 2 cm. Nine of these 53 masses (17%) were incorrectly assigned to surveillance in that final pathology indicated the need for treatment (ie intermediate histology and a mass greater than 2 cm or unfavorable histology). Final pathology confirmed a correct assignment in all 149 masses assigned to treatment. None of the additional parameters assessed improved assignment with statistical significance. CONCLUSIONS: Age, gender, R.E.N.A.L. nephrometry score, R.E.N.A.L. score components and nomograms or combinations of these factors do not improve the predictive performance of a small renal mass management risk stratification algorithm based on renal mass biopsy and radiographic mass size.

Prognostic Value of Percent Gleason Grade 4 at Prostate Biopsy in Predicting Prostatectomy Pathology and Recurrence.

PURPOSE: The importance of primary Gleason grade among men with Gleason score 7 disease has been well-defined. However, this dichotomization may oversimplify the continuous spectrum of absolute percent Gleason grade 4 disease (G4%). In this study we report the prognostic value of G4% in cancer related outcomes of men undergoing radical prostatectomy. MATERIALS AND METHODS: Patients who underwent radical prostatectomy for clinically localized Gleason 6-8 prostate cancer from 2005 to 2013 were included in the study. G4% was determined as biopsy tumor length containing Gleason pattern 4/total tumor length, which performed better than alternative quantifications of pattern 4 involvement. G4% was correlated with time to biochemical recurrence and presence of adverse radical prostatectomy pathology, defined as primary Gleason 4 or pT3 or greater, by multivariable Cox and logistic regressions. RESULTS: Of 1,691 patients 517 (30.6%) had adverse pathological features and 86 (5.6%) experienced biochemical recurrence. On multivariable analyses G4% was a significant predictor of adverse pathology (OR 1.04, 95% CI 1.03-1.05) and time to biochemical recurrence (HR 1.02, CI 1.01-1.03). G4% was also a significant independent predictor of adverse pathology in subsets of patients with Gleason score 7 (OR 1.05, 95% CI 1.03-1.06), 3+4 (OR 1.06, 95% CI 1.04-1.08) and 4+3 cancer (OR 1.05, 95% CI 1.03-1.06). We found a significantly increased risk of adverse pathology at potentially meaningful G4% thresholds (1% to 10% vs 20% to 30%). CONCLUSIONS: The incremental percentage of Gleason grade 4 disease in biopsy specimens is an important predictor of adverse pathology and biochemical recurrence across the entire range of G4% disease. Accounting for G4% can improve risk assessment even among those patients with Gleason 3+4 or 4+3 cancer and may help inform patient counseling.

Independent surgical validation of the new prostate cancer grade-grouping system.

OBJECTIVE: To report the independent prognostic impact of the new prostate cancer grade-grouping system in a large external validation cohort of patients treated with radical prostatectomy (RP). PATIENTS AND METHODS: Between 1994 and 2013, 3 694 consecutive men were treated with RP at a single institution. To investigate the performance of and validate the grade-grouping system, biochemical recurrence-free survival (bRFS) rates were assessed using Kaplan-Meier tests, Cox-regression modelling, and discriminatory comparison analyses. Separate analyses were performed based on biopsy and RP grade. RESULTS: The median follow-up was 52.7 months. The 5-year actuarial bRFS for biopsy grade groups 1-5 were 94.2%, 89.2%, 73.1%, 63.1%, and 54.7%, respectively (P < 0.001). Similarly, the 5-year actuarial bRFS based on RP grade groups was 96.1%, 93.0%, 74.0%, 64.4%, and 49.9% for grade groups 1-5, respectively (P < 0.001). The adjusted hazard ratios for bRFS relative to biopsy grade group 1 were 1.98, 4.20, 5.57, and 9.32 for groups 2, 3, 4, and 5, respectively (P < 0.001), and for RP grade groups were 2.09, 5.27, 5.86, and 10.42 (P < 0.001). The five-grade-group system had a higher prognostic discrimination compared with the commonly used three-tier system (Gleason score 6 vs 7 vs 8-10). CONCLUSIONS: In an independent surgical cohort, we have validated the prognostic benefit of the new prostate cancer grade-grouping system for bRFS, and shown that the benefit is maintained after adjusting for important clinicopathological variables. The greater predictive accuracy of the new system will improve risk stratification in the clinical setting and aid in patient counselling.

What couples say about their recovery of sexual intimacy after prostatectomy: toward the development of a conceptual model of couples' sexual recovery after surgery for prostate cancer.

INTRODUCTION: Interventions designed to help couples recover sexual intimacy after prostatectomy have not been guided by a comprehensive conceptual model. AIM: We examined a proposed biopsychosocial conceptual model of couples' sexual recovery that included functional, psychological, and relational aspects of sexuality, surgery-related sexual losses, and grief and mourning as recovery process. METHODS: We interviewed 20 couples preoperatively and 3 months postoperatively. between 2010 and 2012. Interviews were analyzed with Analytic Induction qualitative methodology, using NVivo software. Paired t-tests described functional assessment data. Study findings led to a revised conceptual model. MAIN OUTCOME MEASURES: Couples' experiences were assessed through semi-structured interviews; male participants' sexual function was assessed with the Expanded Prostate Cancer Index Composite and female participants' sexual function with the Female Sexual Function Index. RESULTS: Preoperatively, 30% of men had erectile dysfunction (ED) and 84% of partners were postmenopausal. All valued sexual recovery, but worried about cancer spread and surgery side effects. Faith in themselves and their surgeons led 90% of couples to overestimate erectile recovery. Postoperatively, most men had ED and lost confidence. Couples' sexual activity decreased. Couples reported feeling loss and grief: cancer diagnosis was the first loss, followed by surgery-related sexual losses. Couples' engagement in intentional sex, patients' acceptance of erectile aids, and partners' interest in sex aided the recovery of couples' sexual intimacy recovery. Unselfconscious sex, not returning to erectile function baseline, was seen as the end point. Survey findings documented participants' sexual function losses, confirming qualitative findings. CONCLUSIONS: Couples' sexual recovery requires addressing sexual function, feelings about losses, and relationship simultaneously. Perioperative education should emphasize the roles of nerve damage in ED and grief and mourning in sexual recovery.

The nanochannel delivery system for constant testosterone replacement therapy.

INTRODUCTION: The goal of testosterone replacement is to provide long-term physiological supplementation at sufficient levels to mitigate the symptoms of hypogonadism. AIM: The objective of this work is to determine if the implantable nanochannel delivery system (nDS) can present an alternative delivery strategy for the long-term sustained and constant release of testosterone. METHODS: A formulation of common testosterone esters (F1) was developed to enable nanochannel delivery of the low water soluble hormone. In vivo evaluation of testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels by liquid chromatography/mass spectrometry and a multiplex assay, respectively, in castrated Sprague-Dawley rats implanted with nDS-F1 implants or polymeric pellets was performed over a 6-month period. The percent of testosterone concentrations observed that fell within the normal range of testosterone levels for each animal was calculated and used to compare the study groups. MAIN OUTCOME MEASURES: Sustain release of testosterone in vivo for over 6 months. RESULTS: The subcutaneous release of F1 from nDS implants exhibited sustained in vivo release kinetics and attained stable clinically relevant plasma testosterone levels. Plasma LH and FSH levels were significantly diminished in nDS-F1 implant-treated animals, confirming biological activity of the released testosterone. CONCLUSIONS: In conclusion, we demonstrate that nDS-F1 implants represents a novel approach for the treatment of male hypogonadism. Further studies will be performed in view of translating the technology to clinical use.

Screening for Prostate Cancer-Beyond Total PSA, Utilization of Novel Biomarkers.

Urology has been beset by several major trends that have shifted the entire paradigm for prostate cancer screening. These stem from a backlash against overdiagnosis and overtreatment due to prostate-specific antigen (PSA)-based screening efforts and have led national societies to modify their guidelines. More importantly, the public outcry has shifted the focus of early detection from an effort to diagnose any and all prostate cancers to an effort to diagnose clinically significant prostate cancers at an early stage. This review provides an update on contemporary biomarkers for prostate cancer that may be used to supplement PSA-based screening approaches.

Metabolomic profiling identifies biochemical pathways associated with castration-resistant prostate cancer.

Despite recent developments in treatment strategies, castration-resistant prostate cancer (CRPC) is still the second leading cause of cancer-associated mortality among American men, the biological underpinnings of which are not well understood. To this end, we measured levels of 150 metabolites and examined the rate of utilization of 184 metabolites in metastatic androgen-dependent prostate cancer (AD) and CRPC cell lines using a combination of targeted mass spectrometry and metabolic phenotyping. Metabolic data were used to derive biochemical pathways that were enriched in CRPC, using Oncomine concept maps (OCM). The enriched pathways were then examined in-silico for their association with treatment failure (i.e., prostate specific antigen (PSA) recurrence or biochemical recurrence) using published clinically annotated gene expression data sets. Our results indicate that a total of 19 metabolites were altered in CRPC compared to AD cell lines. These altered metabolites mapped to a highly interconnected network of biochemical pathways that describe UDP glucuronosyltransferase (UGT) activity. We observed an association with time to treatment failure in an analysis employing genes restricted to this pathway in three independent gene expression data sets. In summary, our studies highlight the value of employing metabolomic strategies in cell lines to derive potentially clinically useful predictive tools.

Exploring the role of the partner in couples' sexual recovery after surgery for prostate cancer.

BACKGROUND: Prostate cancer survivors' post-surgery sexual problems are well documented and long lasting. Partners' distress in this context leads to psychological morbidity which is poorly understood. Given the prevalence of prostate cancer diagnoses in older men, partners' distress represents a public health concern. This study elucidates an important aspect of partners' distress which has hitherto been undocumented. It can lead to further research and health-care provisions that will support couples in prostate cancer survivorship towards improved mental health and health outcomes. PURPOSE: Partner sexual function has been viewed as a factor in men's erectile function recovery after prostatectomy for prostate cancer. However, patients' and partners' perceptions on the role of the partner in couples' sexual recovery has not been studied. We wanted to understand those perceptions and to see whether their perceptions were congruent. METHODS: Men and partners were recruited from a previous study and interviewed separately about the role of the partner. Interview transcripts were analyzed using grounded theory with the help of NVivo software. RESULTS: Ten men and nine partners participated; most were more than 1 year past surgery. Men were 62, and partners were 58 years old on average. Nine men had erectile dysfunction. Six female partners were post-menopausal, and a participating male partner had post-prostatectomy erectile dysfunction. Men and partners agreed that partners provide emotional and logistical support. Both perceived the partner's own sexual interest, not function, as critical to the couple's sexual recovery. Some men felt pressured by partners' initiative, feeling insecure about sexual performance. Men were unaware of partners' sexual needs or needs for support. Partners expressed those needs but were unsure of what kind of support they needed. CONCLUSION: Partners' sexual and support needs during couples' sexual recovery after prostatectomy should be acknowledged and addressed as a legitimate aspect of research and care for men recovering from prostatectomy.

Analyzing the Current State and Visibility of Diversity, Equity, and Inclusion Initiatives at Urology Residency Programs.

OBJECTIVE: To analyze AUA urology residency program websites to determine visibility of diversity, equity, and inclusion (DEI) initiatives. There is growing interest in DEI initiatives by urology applicants, and in recent years, urology programs have invested in efforts to promote DEI. METHODS: All ACGME-accredited urology residency program with a website were assessed. Military programs were excluded. A DEI Score Card was developed using published pillars of DEI, including five domains: departmental inclusion, pipeline growth, departmental education, community engagement, and faculty demographics. Program Doximity rank, address, and surrounding demographics were collected to determine predictors of investing in DEI. RESULTS: One hundred forty-one urology residency websites were included for analysis. Only 40.7% of programs referenced DEI on their webpage, and 21.4% offered funded mentorship opportunities. Department education and community engagement were the least popular initiatives. The Western, Northeastern, and North Central sections had the highest DEI total score with wide variation across domains. Mention of DEI was not associated with program's county-level social vulnerability or percent minority but was associated with being a top 50 program (OR=4.0; 95% CI 1.8, 8.9; P = .0007). CONCLUSION: Less than half of academic urology programs' websites referenced DEI initiatives. Using a DEI score card, our study shows that investment in DEI varies widely by AUA section, and greater investment is positively correlated with program rank. Our DEI score card serves as a tool that programs can use to assess their current DEI investment, identify areas for improvement, and ensure existing initiatives are visible to applicants.

Integrative multi-region molecular profiling of primary prostate cancer in men with synchronous lymph node metastasis.

Localized prostate cancer is frequently composed of multiple spatially distinct tumors with significant inter- and intra-tumoral molecular heterogeneity. This genomic diversity gives rise to many competing clones that may drive the biological trajectory of the disease. Previous large-scale sequencing efforts have focused on the evolutionary process in metastatic prostate cancer, revealing a potential clonal progression to castration resistance. However, the clonal origin of synchronous lymph node (LN) metastases in primary disease is still unknown. Here, we perform multi-region, targeted next generation sequencing and construct phylogenetic trees in men with prostate cancer with synchronous LN metastasis to better define the pathologic and molecular features of primary disease most likely to spread to the LNs. Collectively, we demonstrate that a combination of histopathologic and molecular factors, including tumor grade, presence of extra-prostatic extension, cellular morphology, and oncogenic genomic alterations are associated with synchronous LN metastasis.

Development and Validation of an 18-Gene Urine Test for High-Grade Prostate Cancer.

Importance: Benefits of prostate cancer (PCa) screening with prostate-specific antigen (PSA) alone are largely offset by excess negative biopsies and overdetection of indolent cancers resulting from the poor specificity of PSA for high-grade PCa (ie, grade group [GG] 2 or greater). Objective: To develop a multiplex urinary panel for high-grade PCa and validate its external performance relative to current guideline-endorsed biomarkers. Design, Setting, and Participants: RNA sequencing analysis of 58 724 genes identified 54 markers of PCa, including 17 markers uniquely overexpressed by high-grade cancers. Gene expression and clinical factors were modeled in a new urinary test for high-grade PCa (MyProstateScore 2.0 [MPS2]). Optimal models were developed in parallel without prostate volume (MPS2) and with prostate volume (MPS2+). The locked models underwent blinded external validation in a prospective National Cancer Institute trial cohort. Data were collected from January 2008 to December 2020, and data were analyzed from November 2022 to November 2023. Exposure: Protocolized blood and urine collection and transrectal ultrasound-guided systematic prostate biopsy. Main Outcomes and Measures: Multiple biomarker tests were assessed in the validation cohort, including serum PSA alone, the Prostate Cancer Prevention Trial risk calculator, and the Prostate Health Index (PHI) as well as derived multiplex 2-gene and 3-gene models, the original 2-gene MPS test, and the 18-gene MPS2 models. Under a testing approach with 95% sensitivity for PCa of GG 2 or greater, measures of diagnostic accuracy and clinical consequences of testing were calculated. Cancers of GG 3 or greater were assessed secondarily. Results: Of 761 men included in the development cohort, the median (IQR) age was 63 (58-68) years, and the median (IQR) PSA level was 5.6 (4.6-7.2) ng/mL; of 743 men included in the validation cohort, the median (IQR) age was 62 (57-68) years, and the median (IQR) PSA level was 5.6 (4.1-8.0) ng/mL. In the validation cohort, 151 (20.3%) had high-grade PCa on biopsy. Area under the receiver operating characteristic curve values were 0.60 using PSA alone, 0.66 using the risk calculator, 0.77 using PHI, 0.76 using the derived multiplex 2-gene model, 0.72 using the derived multiplex 3-gene model, and 0.74 using the original MPS model compared with 0.81 using the MPS2 model and 0.82 using the MPS2+ model. At 95% sensitivity, the MPS2 model would have reduced unnecessary biopsies performed in the initial biopsy population (range for other tests, 15% to 30%; range for MPS2, 35% to 42%) and repeat biopsy population (range for other tests, 9% to 21%; range for MPS2, 46% to 51%). Across pertinent subgroups, the MPS2 models had negative predictive values of 95% to 99% for cancers of GG 2 or greater and of 99% for cancers of GG 3 or greater. Conclusions and Relevance: In this study, a new 18-gene PCa test had higher diagnostic accuracy for high-grade PCa relative to existing biomarker tests. Clinically, use of this test would have meaningfully reduced unnecessary biopsies performed while maintaining highly sensitive detection of high-grade cancers. These data support use of this new PCa biomarker test in patients with elevated PSA levels to reduce the potential harms of PCa screening while preserving its long-term benefits.

Gleason pattern 5 is the strongest pathologic predictor of recurrence, metastasis, and prostate cancer-specific death in patients receiving salvage radiation therapy following radical prostatectomy.

BACKGROUND: The presence of Gleason pattern 5 (GP5) at radical prostatectomy (RP) has been associated with worse clinical outcome; however, this pathologic variable has not been assessed in patients receiving salvage radiation therapy (SRT) after a rising prostate-specific antigen level. METHODS: A total of 575 patients who underwent primary RP for localized prostate cancer and subsequently received SRT at a tertiary medical institution were reviewed retrospectively. Primary outcomes of interest were biochemical failure (BF), distant metastasis (DM), and prostate cancer-specific mortality (PCSM), which were assessed via univariate analysis and Fine and Grays competing risks multivariate models. RESULTS: On pathologic evaluation, 563 (98%) patients had a documented Gleason score (GS). The median follow-up post-SRT was 56.7 months. A total of 60 (10.7%) patients had primary, secondary, or tertiary GP5. On univariate analysis, the presence of GP5 was prognostic for BF (hazard ratio [HR] 3.3; P < .0001), DM (HR:11.1, P < .0001), and PCSM (HR:8.8, P < .0001). Restratification of the Gleason score to include GP5 as a distinct entity resulted in improved prognostic capability. Patients with GP5 had clinically worse outcomes than patients with GS8(4+4). On multivariate analysis, the presence of GP5 was the most adverse pathologic predictor of BF (HR 2.9; P < .0001), DM (HR 14.8; P < .0001), and PCSM (HR 5.7; P < .0001). CONCLUSION: In the setting of SRT for prostate cancer, the presence of GP5 is a critical pathologic predictor of BF, DM, and PCSM. Traditional GS risk stratification fails to fully utilize the prognostic capabilities of individual Gleason patterns among men receiving SRT post-RP.

Certificate of need programs, intensity modulated radiation therapy use and the cost of prostate cancer care.

PURPOSE: Certificate of need programs are a primary mechanism to regulate the use and cost of health care services at the state level. The effect of certificate of need programs on the use of intensity modulated radiation therapy and the increasing costs of prostate cancer care is unknown. We compared the use of intensity modulated radiation therapy and change in prostate cancer health care costs in regions with vs without active certificate of need programs. MATERIALS AND METHODS: This population based, observational study using SEER (Surveillance, Epidemiology, and End Results)-Medicare linked data from 2002 through 2009 was comprised of 13,814 men treated for prostate cancer in 3 regions with active certificate of need programs (CON Yes) vs 44,541 men treated for prostate cancer in 9 regions without active certificate of need programs (CON No). We assessed intensity modulated radiation therapy use relative to other prostate cancer definitive therapies and overall prostate cancer health care costs with respect to certificate of need status. RESULTS: In propensity score adjusted analyses, intensity modulated radiation therapy use increased from 2.3% to 46.4% of prostate cancer definitive therapies in CON Yes regions vs 11.3% to 41.7% in CON No regions from 2002 to 2009. Furthermore, we observed greater intensity modulated radiation therapy use with time in CON Yes vs No regions (p <0.001). Annual cost growth did not differ between CON Yes vs No regions (p = 0.396). CONCLUSIONS: Certificate of need programs were not effective in limiting intensity modulated radiation therapy use or attenuating prostate cancer health care costs. There remains an unmet need to control the rapid adoption of new, more expensive therapies for prostate cancer that have limited cost and comparative effectiveness data.

Characterization of nanochannel delivery membrane systems for the sustained release of resveratrol and atorvastatin: new perspectives on promoting heart health.

Novel drug delivery systems capable of continuous sustained release of therapeutics have been studied extensively for use in the prevention and management of chronic diseases. The use of these systems holds promise as a means to achieve higher patient compliance while improving therapeutic index and reducing systemic toxicity. In this work, an implantable nanochannel drug delivery system (nDS) is characterized and evaluated for the long-term sustained release of atorvastatin (ATS) and trans-resveratrol (t-RES), compounds with a proven role in managing atherogenic dyslipidemia and promoting cardioprotection. The primary mediators of drug release in the nDS are nanofluidic membranes with hundreds of thousands of nanochannels (up to 100,000/mm(2)) that attain zero-order release kinetics by exploiting nanoconfinement and molecule-to-surface interactions that dominate diffusive transport at the nanoscale. These membranes were characterized using gas flow analysis, acetone diffusion, and scanning and transmission electron microscopy (SEM, TEM). The surface properties of the dielectric materials lining the nanochannels, SiO(2) and low-stress silicon nitride, were further investigated using surface charge analysis. Continuous, sustained in vitro release for both ATS and t-RES was established for durations exceeding 1 month. Finally, the influence of the membranes on cell viability was assessed using human microvascular endothelial cells. Morphology changes and adhesion to the surface were analyzed using SEM, while an MTT proliferation assay was used to determine the cell viability. The nanochannel delivery approach, here demonstrated in vitro, not only possesses all requirements for large-scale high-yield industrial fabrication, but also presents the key components for a rapid clinical translation as an implantable delivery system for the sustained administration of cardioprotectants.