The Role of Individual-Level Socioeconomic Status on Nursing Home Placement Accounting for Neighborhood Characteristics.

OBJECTIVE: Independent living is desirable for many older adults. Although several factors such as physical and cognitive functions are important predictors for nursing home placement (NHP), it is also reported that socioeconomic status (SES) affects the risk of NHP. In this study, we aimed to examine whether an individual-level measure of SES is associated with the risk of NHP after accounting for neighborhood characteristics. DESIGN: A population-based study (Olmsted County, Minnesota, USA). SETTING AND PARTICIPANTS: Older adults (age 65+ years) with no prior history of NHP. METHODS: Electronic health records (EHR) were used to identify individuals with any NHP between April 1, 2012 (baseline date) and April 30, 2019. Association between the (HOUsing-based index of SocioEconomic Status (HOUSES) index, an individual-level SES measure based on housing characteristics of current residence, and risk of NHP was tested using random effects Cox proportional hazard model adjusting for area deprivation index (ADI), an aggregated SES measure that captures neighborhood characteristics, and other pertinent confounders such as age and chronic disease burden. RESULTS: Among 15,031 older adults, 3341 (22.2%) experienced NHP during follow-up period (median: 7.1 years). At baseline date, median age was 73 years old with 55% female persons, 91% non-Hispanic Whites, and median number of chronic conditions of 4. Accounting for pertinent confounders, the HOUSES index was strongly associated with risk of NHP (hazard ratio 1.89; 95% confidence interval 1.66‒2.15 for comparing the lowest vs highest quartiles), which was not influenced by further accounting for ADI. CONCLUSIONS AND IMPLICATIONS: This study demonstrates that an individual-level SES measure capturing current individual-specific socioeconomic circumstances plays a significant role for predicting NHP independent of neighborhood characteristics where they reside. This study suggests that older adults who are at higher risk of NHP can be identified by utilizing the HOUSES index and potential individual-level intervention strategies can be applied to reduce the risk for those with higher risk.

Molecular Profile Changes in Patients with Castrate-Resistant Prostate Cancer Pre- and Post-Abiraterone/Prednisone Treatment.

We identified resistance mechanisms to abiraterone acetate/prednisone (AA/P) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the Prostate Cancer Medically Optimized Genome-Enhanced Therapy (PROMOTE) study.We analyzed whole-exome sequencing (WES) and RNA-sequencing data from 83 patients with metastatic biopsies before (V1) and after 12 weeks of AA/P treatment (V2). Resistance was determined by time to treatment change (TTTC).At V2, 18 and 11 of 58 patients had either short-term (median 3.6 months; range 1.4-4.5) or long-term (median 29 months; range 23.5-41.7) responses, respectively. Nonresponders had low expression of TGFBR3 and increased activation of the Wnt pathway, cell cycle, upregulation of AR variants, both pre- and posttreatment, with further deletion of AR inhibitor CDK11B posttreatment. Deletion of androgen processing genes, HSD17B11, CYP19A1 were observed in nonresponders posttreatment. Genes involved in cell cycle, DNA repair, Wnt-signaling, and Aurora kinase pathways were differentially expressed between the responder and non-responder at V2. Activation of Wnt signaling in nonresponder and deactivation of MYC or its target genes in responders was detected via SCN loss, somatic mutations, and transcriptomics. Upregulation of genes in the AURKA pathway are consistent with the activation of MYC regulated genes in nonresponders. Several genes in the AKT1 axis had increased mutation rate in nonresponders. We also found evidence of resistance via PDCD1 overexpression in responders. IMPLICATIONS: Finally, we identified candidates drugs to reverse AA/P resistance: topoisomerase inhibitors and drugs targeting the cell cycle via the MYC/AURKA/AURKB/TOP2A and/or PI3K_AKT_MTOR pathways.

Screening Postoperative Hemoglobin after Robot-Assisted Radical Prostatectomy-Frequently Used, but Is It Necessary?

INTRODUCTION: Robot-assisted radical prostatectomy is associated with low rates of postoperative transfusion and hemorrhage. At our institution the decision to obtain screening hemoglobin testing after uncomplicated robot-assisted radical prostatectomy is left to surgeon discretion. It is unknown whether this testing represents high value care. We assessed the prevalence and clinical utility of hemoglobin testing after uncomplicated robot-assisted radical prostatectomy. METHODS: We retrospectively reviewed patients undergoing robot-assisted radical prostatectomy between 2002 and 2016. Patients transfused intraoperatively were excluded. Demographic and perioperative data were reviewed. In patients requiring blood transfusion and/or with hemorrhage clinical signs/symptoms of anemia were reviewed. The primary endpoint was rate of routine postoperative hemoglobin testing. Secondary endpoints included rates of postoperative transfusion and hemorrhage, rates of signs/symptoms of anemia in patients transfused postoperatively and/or with hemorrhage. RESULTS: A total of 3,405 patients were identified of whom 73.8% (2,514) underwent postoperative hemoglobin testing. Mean change relative to preoperative hemoglobin was -2.7±1.0 gm/dl with 10.2% (256) and 3.5% (87) experiencing a decrease in hemoglobin 4 gm/dl or greater and postoperative hemoglobin 10 gm/dl or less, respectively. Of patients undergoing at least 1 postoperative hemoglobin test subsequent testing was prompted for 13.4% (337). Of patients transfused (1.7%, 58) and/or with postoperative hemorrhage (1.5%, 48) with records available for review (46), 95.7% (44) had clinical signs/symptoms of anemia. CONCLUSIONS: Our results suggest that routine hemoglobin testing after uncomplicated prostatectomy should be performed when clinically indicated rather than as routine practice.

Impact of metabolic syndrome on functional outcomes and complications of surgical treatment of prostate cancer.

BACKGROUND: Metabolic syndrome (MetS) has a negative impact on functional recovery and complications after many surgical procedures. AIM: To assess the role of Mets on functional outcomes and complications after radical prostatectomy (RP) for prostate cancer. PATIENTS AND METHODS: Complete data were collected from 5758 patients, undergoing RP at a single referral centers in a 10-year period and the presence of MetS before surgery was ascertained in 17.7% of them using a modified version of the IDF-AHA/NHLBI criteria. Outcomes included 1-year continence and potency rates, early (≤90 days) and late (>90 days) complications. RESULTS: Postoperative continence (no pads) was significantly less likely in MetS patients (75.4% vs 82.6%, P < .01), despite no difference in preoperative continence. Erections with or without therapy were reached in 55.8% of non-MetS and 41.8% of MetS patients (P < .01), in this case a significant difference in preoperative function was seen. No differences in early and late complications, except for wound infections (5.8% vs 3.9%, P < .01) were observed. CONCLUSIONS: In the present study RP was safe from the complications standpoint in MetS patients, but the presence of the syndrome was a significant risk factor for post-RP incontinence and impotence.

A Prospective Correlation of Tissue Histopathology With Nucleic Acid Yield in Metastatic Castration-Resistant Prostate Cancer Biopsy Specimens.

OBJECTIVE: To determine histopathologic, exome, and transcriptome nucleic acid material yield from prospectively collected metastatic tissue biopsy specimens in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Patients with mCRPC initiating abiraterone acetate therapy underwent 2 serial metastatic site core needle biopsies after study activation on May 17, 2013. Multiple cores were obtained, and from each core, 1- to 2-mm segments were separated and formalin fixed for histopathologic examination. Tumor purity was determined for DNA and RNA from the rest of the biopsy specimen. RNA quality was assessed by calculation of an RNA integrity number and a DV200 score. RESULTS: A total of 89 patients underwent 172 uniformly processed core needle biopsies (89 on visit 1 and 83 on visit 2) between May 30, 2013, and September 10, 2015. Metastatic sites biopsied included bone (131), lymph nodes (31), liver (5), lung (3), and pelvic soft tissues (2). Of the 172 biopsy specimens, 85 (49%) had at least one of the multiple cores positive for tumor on histopathologic examination (53 of 88 [60%] from visit 1 and 32 of 83 [39%] from visit 2; P=.006). Metastatic carcinoma was observed in 50 of 130 bone lesion specimens (38%), compared to 35 of 41 nonbone specimens (85%) (P<.001). More than 10% tumoral DNA purity was observed in 89% and 80% of visit 1 and visit 2 biopsy specimens, respectively. Similarly, more than 10% tumor RNA purity was observed in 79% of visit 1 vs 59% for visit 2 (P=.008). In all, 134 of 172 procedures (78%) yielded tumor material either by histopathologic or nucleic acid purity analysis. CONCLUSION: This study found that biopsy specimens from mCRPC sites yield adequate histopathologic, exome, and transcriptome material in most, but not all, cases. This finding has relevance for future genome sequencing studies on the introduction of targeted therapeutic agents. TRIAL REGISTRATION: clinicaltrials.gov Identifier: 01953640.

Role of Metabolic Syndrome on Perioperative and Oncological Outcomes at Radical Prostatectomy in a Low-risk Prostate Cancer Cohort Potentially Eligible for Active Surveillance.

BACKGROUND: Metabolic syndrome (MetS) is considered a potential risk factor for adverse outcomes after radical prostatectomy (RP). Furthermore, studies about the effect of MetS on low-risk prostate cancer (PCa) and its implications in active surveillance (AS) are limited. OBJECTIVE: To investigate the role of MetS (using International Diabetes Federation-American Heart Association/National Heart, Lung, and Blood Institute criteria) on perioperative and oncological outcomes after RP in low-risk PCa and in a subgroup potentially eligible for AS. DESIGN, SETTING, AND PARTICIPANTS: A total of 3662 patients treated with RP for low-risk PCa and further stratified as very low risk (VLR) PCa-prostate-specific antigen density of ≤0.15ng/ml/cm3, ≤2 cores involved, and no core with >50% cancer involvement-at a tertiary referral hospital were identified. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes analyzed were pathological outcomes, perioperative complications, biochemical failure (BCF), and overall survival. Pathological outcomes and complications were analyzed with logistic regression models. Kaplan-Meier curves and Cox proportional hazards models were used to analyze survival outcomes. RESULTS AND LIMITATIONS: In univariate/multivariate analyses, MetS was associated with upgrading and positive surgical margins in the entire cohort, upgrading only in the VLR group. In Kaplan-Meier analysis, MetS patients had a higher rate of overall death (p<0.0001) and BCF (p=0.03) for MetS patients. In the VLR group, no differences were found for BCF (p=0.064). Further, in Cox proportional hazards models, MetS was not associated with BCF (hazard ratio=1.23; 95% confidence interval [CI]=0.95-1.60, p=0.12). MetS patients had a higher rate of complications compared with non-MetS patients (23.7% vs 19.7%; p=0.01). In multivariate analysis, MetS was associated with a higher rate of complications (odds ratio=1.24, 95% CI=1.04-1.49, p=0.018) but did not impact the rate of major ones. This study is limited by its retrospective design. CONCLUSIONS: In low-risk PCa treated with RP but potentially eligible for AS, MetS impacted perioperative and pathological outcomes, suggesting further study of MetS in patients undergoing AS. PATIENT SUMMARY: Metabolic syndrome negatively impacts perioperative and pathological outcomes in low-risk prostate cancer patients treated with radical prostatectomy but potentially eligible for active surveillance, in a large American single-center cohort. These findings suggest the need for a more cautious approach to low-risk prostate cancer in patients with metabolic syndrome.

Impact of metabolic syndrome on oncologic outcomes at radical prostatectomy.

PURPOSE: The associations between metabolic syndrome (MetS) and prostate cancer (CaP) outcomes following radical prostatectomy (RP) are not clear. This study aims to understand the role of MetS in influencing oncological outcomes at RP. MATERIALS AND METHODS: Patients who underwent RP for CaP at our institution from 2000 to 2010 were identified; MetS prior to RP was ascertained with a modified version of the IDF-AHA/NHLBI using ICD-9 codes. Histopathological outcomes included surgical margins, pathological stage, and Gleason score (GS) upgrading. Long-term outcomes included biochemical recurrence (BCR), local recurrence, systemic progression, and CaP-specific mortality. Multivariable adjusted logistic regression and Cox proportional hazards regression assessed the association between MetS status and histopathological and long-term outcomes, respectively. RESULTS: Of 8,504 RP patients, 1,054 (12.4%) had MetS at the time of RP. MetS patients were older, had higher biopsy GS, but lower pre-op prostatic specific antigen (PSA), higher pathological GS, and larger prostate volume. Adjusted logistic regression suggested an association between MetS and positive margins (odds ratio [OR] = 1.22, P = 0.025) and GS upgrading (OR = 1.28, P = 0.002). There was evidence of an increased risk of local recurrence (hazard ratio [HR] = 1.33, P = 0.037) and CaP-specific mortality (HR = 1.58, P < 0.001) for MetS patients. There was no evidence to suggest an association with BCR or systemic progression. CONCLUSION: Men with MetS are at higher risk of GS upgrade and positive surgical margins at surgery, local recurrence, and CaP-specific mortality. Pathological stage, BCR, and systemic progression were not associated with MetS. Our data may be useful in patients' counseling, especially when active surveillance is an option.

Long-term Follow-up of a Matched Cohort Study Evaluating the Role of Adjuvant Radiotherapy for Organ-confined Prostate Cancer With a Positive Surgical Margin.

OBJECTIVE: To evaluate if adjuvant radiation therapy (ART) is associated with improved long-term oncologic outcomes for pT2N0R1 prostate cancer (PCa). METHODS: Men with pT2N0 PCa and a single positive surgical margin following radical prostatectomy and pelvic lymphadenectomy were identified (1987-1996). Men who received ART were matched 1:1 to men who did not receive ART based on age, year of surgery, Gleason score, preoperative prostate-specific antigen, site of positive surgical margin, and DNA ploidy. Biochemical recurrence (BCR), local recurrence, distant metastasis, and overall survival (OS) were compared between groups in time-to-event analyses. RESULTS: The cohort included 152 men (76 per group) with a median follow-up of 20 years (interquartile range 19,22). ART was associated with a lower cumulative incidence of BCR (25% vs 52%; P <.001) and local recurrence (3% vs 12%; P = .03), but no significant differences in cumulative incidence of distant metastasis (10% vs 7%; P = .44) or in probability of OS (56% vs 68%; P = .08) at 20 years. In competing risks models, receipt of ART was associated with reduced risks of BCR (hazard ratio [HR] = 0.40; 95% confidence interval [CI] 0.23-0.70; P <.001) and local recurrence (HR = 0.21; 95% CI .05-0.98; P = .05), but not distant metastasis (HR = 1.56; 95% CI 0.51-4.75; P = .43). In the Cox model, ART was not associated with improved OS (HR = 1.56; 95% CI 0.94-2.57; P = .08). CONCLUSION: ART was associated with reduced risks of BCR and local recurrence for men with pT2N0R1 PCa. However, ART was not significantly associated with metastasis-free or OS benefits, as recurrences in these patients generally followed an indolent trajectory with 20 years of median follow-up.

Androgen Receptor Variant AR-V9 Is Coexpressed with AR-V7 in Prostate Cancer Metastases and Predicts Abiraterone Resistance.

Purpose: Androgen receptor (AR) variant AR-V7 is a ligand-independent transcription factor that promotes prostate cancer resistance to AR-targeted therapies. Accordingly, efforts are under way to develop strategies for monitoring and inhibiting AR-V7 in castration-resistant prostate cancer (CRPC). The purpose of this study was to understand whether other AR variants may be coexpressed with AR-V7 and promote resistance to AR-targeted therapies.Experimental Design: We utilized complementary short- and long-read sequencing of intact AR mRNA isoforms to characterize AR expression in CRPC models. Coexpression of AR-V7 and AR-V9 mRNA in CRPC metastases and circulating tumor cells was assessed by RNA-seq and RT-PCR, respectively. Expression of AR-V9 protein in CRPC models was evaluated with polyclonal antisera. Multivariate analysis was performed to test whether AR variant mRNA expression in metastatic tissues was associated with a 12-week progression-free survival endpoint in a prospective clinical trial of 78 CRPC-stage patients initiating therapy with the androgen synthesis inhibitor, abiraterone acetate.Results: AR-V9 was frequently coexpressed with AR-V7. Both AR variant species were found to share a common 3' terminal cryptic exon, which rendered AR-V9 susceptible to experimental manipulations that were previously thought to target AR-V7 uniquely. AR-V9 promoted ligand-independent growth of prostate cancer cells. High AR-V9 mRNA expression in CRPC metastases was predictive of primary resistance to abiraterone acetate (HR = 4.0; 95% confidence interval, 1.31-12.2; P = 0.02).Conclusions: AR-V9 may be an important component of therapeutic resistance in CRPC. Clin Cancer Res; 23(16); 4704-15. ©2017 AACR.

Factors affecting egg production in the selfing mangrove rivulus (Kryptolebias marmoratus).

The mangrove rivulus, Kryptolebias marmoratus, is one of two known vertebrate species with preferentially self-fertilizing hermaphrodites. Males also exist, and can outcross with hermaphrodites. Outcrossing events vary across wild populations and occur infrequently in laboratory settings. This study sought to add dimension to our understanding of mangrove rivulus reproductive habits by probing the effects of male presence on hermaphroditic unfertilized egg production. Specifically, we quantified egg production of solitary hermaphrodites compared to hermaphrodites exposed to males and exposed to other hermaphrodites. Hermaphrodites tended to produce more fertilized eggs in the presence of males but unfertilized eggs were produced relatively rarely and did not vary significantly among treatments. The probability that hermaphrodites would produce eggs changed as a function of genetic dissimilarity with their partner and in a season-dependent manner. In the fall, the probability of laying eggs decreased as a function of increased genetic dissimilarity, regardless of the sex of the partner. In the winter/spring, however, the probability of laying eggs increased markedly with increased genetic dissimilarity, regardless of the sex of the partner. Our findings indicate that reproductive decisions are modulated by factors beyond male presence, and we discuss a number of alternative hypotheses that should be tested in future studies.

The Incremental Role of Magnetic Resonance Imaging for Prostate Cancer Staging before Radical Prostatectomy.

In the present report we aimed to analyze the incremental value of preoperative magnetic resonance imaging (MRI), in addition to clinical variables and clinically-derived nomograms, in predicting outcomes radical prostatectomy (RP). All Mayo Clinic RP patients who underwent preoperative 1.5-Tesla MRI with endo-rectal coil from 2003 to 2013 were identified. Clinical and histopathological variables were used to calculate Partin estimates and Cancer of the Prostate Risk Assessment (CAPRA) score. MRI results in terms of extracapsular extension (ECE), seminal vesicle invasion (SVI), and lymph-node invasion (N+) were recorded. Using RP pathology as gold standard, we developed multivariate logistic regression models based on clinical variables, Partin Tables, and CAPRA score, and assessed their predictive accuracy before and after the addition of MRI results. Five hundred and one patients were included. MRI + clinical models outperformed clinical-based models alone for all outcomes. Comparing Partin and Partin + MRI predictive models, the areas under the curve were 0.61 versus 0.73 for ECE, 0.75 versus 0.82 for SVI, and 0.82 versus 0.85 for N+. Comparing CAPRA and CAPRA + MRI models, the areas under the curve were 0.69 versus 0.77 for ECE, 0.75 versus 0.83 for SVI, and 0.82 versus 0.85 for N+. Our data show that MRI can improve clinical-based models in prediction of nonorgan confined disease, particularly for ECE and SVI. PATIENT SUMMARY: Magnetic resonance imaging, together with clinical information, can be useful in preoperative assessment before radical prostatectomy.

Oncological outcomes following radical prostatectomy for patients with pT4 prostate cancer

ABSTRACT Objectives: Radical prostatectomy (RP) for locally advanced prostate cancer may reduce the risk of metastasis and cancer-specific death. Herein, we evaluated the outcomes for patients with pT4 disease treated with RP. Materials and methods: Among 19,800 men treated with RP at Mayo Clinic from 1987 to 2010, 87 were found to have pT4 tumors. Biochemical recurrence (BCR)-free survival, systemic progression (SP) free survival and overall survival (OS) were estimated using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazards regression models were used to assess the association of clinic-pathological features with outcome. Results: Median follow-up was 9.8 years (IQR 3.6, 13.4). Of the 87 patients, 50 (57.5%) were diagnosed with BCR, 30 (34.5%) developed SP, and 38 (43.7%) died, with 11 (12.6%) dying of prostate cancer. Adjuvant androgen deprivation therapy was administered to 77 men, while 32 received adjuvant external beam radiation therapy. Ten-year BCR-free survival, SP-free survival, and OS was 37%, 64%, and 70% respectively. On multivariate analysis, the presence of positive lymph nodes was marginally significantly associated with patients' risk of BCR (HR: 1.94; p=0.05), while both positive lymph nodes (HR 2.96; p=0.02) and high pathologic Gleason score (HR 1.95; p=0.03) were associated with SP. Conclusions: Patients with pT4 disease may experience long-term survival following RP, and as such, when technically feasible, surgical resection should be considered in the multimodal treatment approach to these men.

Oncological outcomes following radical prostatectomy for patients with pT4 prostate cancer.

OBJECTIVES: Radical prostatectomy (RP) for locally advanced prostate cancer may reduce the risk of metastasis and cancer-specific death. Herein, we evaluated the outcomes for patients with pT4 disease treated with RP. MATERIALS AND METHODS: Among 19,800 men treated with RP at Mayo Clinic from 1987 to 2010, 87 were found to have pT4 tumors. Biochemical recurrence (BCR)-free survival, systemic progression (SP) free survival and overall survival (OS) were estimated using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazards regression models were used to assess the association of clinic-pathological features with outcome. RESULTS: Median follow-up was 9.8 years (IQR 3.6, 13.4). Of the 87 patients, 50 (57.5%) were diagnosed with BCR, 30 (34.5%) developed SP, and 38 (43.7%) died, with 11 (12.6%) dying of prostate cancer. Adjuvant androgen deprivation therapy was administered to 77 men, while 32 received adjuvant external beam radiation therapy. Tenyear BCR-free survival, SP-free survival, and OS was 37%, 64%, and 70% respectively. On multivariate analysis, the presence of positive lymph nodes was marginally significantly associated with patients' risk of BCR (HR: 1.94; p=0.05), while both positive lymph nodes (HR 2.96; p=0.02) and high pathologic Gleason score (HR 1.95; p=0.03) were associated with SP. CONCLUSIONS: Patients with pT4 disease may experience long-term survival following RP, and as such, when technically feasible, surgical resection should be considered in the multimodal treatment approach to these men.

Determining the frequency of pathogenic germline variants from exome sequencing in patients with castrate-resistant prostate cancer.

OBJECTIVES: To determine the frequency of pathogenic inherited mutations in 157 select genes from patients with metastatic castrate-resistant prostate cancer (mCRPC). DESIGN: Observational. SETTING: Multisite US-based cohort. PARTICIPANTS: Seventy-one adult male patients with histological confirmation of prostate cancer, and had progressive disease while on androgen deprivation therapy. RESULTS: Twelve patients (17.4%) showed evidence of carrying pathogenic or likely pathogenic germline variants in the ATM, ATR, BRCA2, FANCL, MSR1, MUTYH, RB1, TSHR and WRN genes. All but one patient opted in to receive clinically actionable results at the time of study initiation. We also found that pathogenic germline BRCA2 variants appear to be enriched in mCRPC compared to familial prostate cancers. CONCLUSIONS: Pathogenic variants in cancer-susceptibility genes are frequently observed in patients with mCRPC. A substantial proportion of patients with mCRPC or their family members would derive clinical utility from mutation screening. TRIAL REGISTRATION NUMBER: NCT01953640; Results.

Standardizing the Definition of Biochemical Recurrence after Radical Prostatectomy-What Prostate Specific Antigen Cut Point Best Predicts a Durable Increase and Subsequent Systemic Progression?

PURPOSE: Multiple definitions of biochemical recurrence for prostate cancer exist after radical prostatectomy, and variation continues in prostate cancer outcome reporting and secondary treatment initiation. We reviewed long-term prostatectomy outcomes to assess the most appropriate prostate specific antigen cut point that predicts future disease progression. MATERIALS AND METHODS: We identified 13,512 patients with cT1-2N0M0 prostate cancer who underwent radical prostatectomy between 1987 and 2010. Single prostate specific antigen cut points of 0.2, 0.3, 0.4 and 0.5 ng/ml or greater, as well as confirmatory prostate specific antigen value definitions of 0.2 ng/ml or greater followed by prostate specific antigen greater than 0.2 ng/ml and 0.4 ng/ml or greater followed by prostate specific antigen greater than 0.4 ng/ml were tested. Continued prostate specific antigen increase after a designated cut point definition was estimated using cumulative incidence. The strength of association between biochemical recurrence definitions and subsequent systemic progression were analyzed using Cox proportional hazard models and the O'Quigley event based R(2) test. RESULTS: At a median postoperative followup of 9.1 years (IQR 4.9-14.3) a detectable prostate specific antigen developed in 5,041 patients and systemic progression developed in 512. After reaching the prostate specific antigen cut point of 0.2, 0.3 and 0.4 ng/ml, the percentage of patients experiencing a continued prostate specific antigen increase over 5 years was 61%, 67% and 74%, respectively, plateauing at 0.4 ng/ml. The strongest association between biochemical recurrence and systemic progression occurred using a single prostate specific antigen cut point of 0.4 ng/ml or greater (HR 36, R(2) 0.92). CONCLUSIONS: A prostate specific antigen cut point of 0.4 ng/ml or greater reflects the threshold at which a prostate specific antigen increase becomes durable and shows the strongest correlation with subsequent systemic progression. Consideration should be given to using a prostate specific antigen of 0.4 ng/ml or greater as the standard biochemical recurrence definition after radical prostatectomy.

Patient-reported Functional Outcomes Following Open, Laparoscopic, and Robotic Assisted Radical Prostatectomy Performed by High-volume Surgeons at High-volume Hospitals.

BACKGROUND: Functional outcomes following radical prostatectomy (RP) have received increased focus with dissemination of minimally invasive approaches. OBJECTIVE: To examine contemporary patient-reported functional outcomes following open RP. (ORP), laparoscopic RP, (LRP), and robotic assisted RP (RARP) performed by high-volume surgeons at high-volume hospitals. DESIGN, SETTINGS, AND PARTICIPANTS: This was a retrospective cohort study of 1686 men with cT1-cT2 prostate cancer treated with ORP (n=441), LRP (n=156), or RARP (n=1089) by high-volume surgeons (annual volume ≥25 cases) at two academic centers from 2009 to 2012. Surveys containing the Expanded Prostate Cancer Index Composite urinary and sexual domains were administered at a median of 30.5 mo postoperatively. INTERVENTIONS: ORP, LRP, and RARP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Bother with overall urinary and sexual function was examined and stratified by surgical technique. Logistic regression models evaluated the associations of clinicopathologic features with survey responses. RESULTS AND LIMITATIONS: In total, 6.4% of men reported a moderate or big problem with overall urinary function (ORP 5.8%, LRP 5.1%, RARP 6.8%; p=0.62), whereas 37.3% reported a moderate or big problem with overall sexual function (ORP 37.2%, LRP 36.1%, RARP 37.5%; p=0.95). On multivariable analysis, older age at surgery (odds ratio [OR]: 1.08; p<0.0001) was associated with overall urinary bother, whereas older age at surgery (OR: 1.03; p=0.005), preoperative erectile dysfunction treatment (OR: 2.22; p<0.0001), greater prostate volume (OR: 1.01; p=0.02), and RP Gleason score (7 vs 6: OR: 0.96; p=0.004; 8-10 vs 6: OR: 2.25; p=0.0006) were associated with overall sexual bother. Surgical technique was not associated with either functional outcome. Limitations included selection bias and a retrospective design. CONCLUSIONS: In this study of high-volume surgeons at high-volume hospitals, patients reported excellent functional outcomes independent of surgical technique. These results have implications for patient counseling. PATIENT SUMMARY: In this study of high-volume surgeons at high-volume hospitals, patients reported excellent outcomes for urinary and sexual function following radical prostatectomy regardless of surgical technique.

Mutational Landscapes of Sequential Prostate Metastases and Matched Patient Derived Xenografts during Enzalutamide Therapy.

Developing patient derived models from individual tumors that capture the biological heterogeneity and mutation landscape in advanced prostate cancer is challenging, but essential for understanding tumor progression and delivery of personalized therapy in metastatic castrate resistant prostate cancer stage. To demonstrate the feasibility of developing patient derived xenograft models in this stage, we present a case study wherein xenografts were derived from cancer metastases in a patient progressing on androgen deprivation therapy and prior to initiating pre-chemotherapy enzalutamide treatment. Tissue biopsies from a metastatic rib lesion were obtained for sequencing before and after initiating enzalutamide treatment over a twelve-week period and also implanted subcutaneously as well as under the renal capsule in immuno-deficient mice. The genome and transcriptome landscapes of xenografts and the original patient tumor tissues were compared by performing whole exome and transcriptome sequencing of the metastatic tumor tissues and the xenografts at both time points. After comparing the somatic mutations, copy number variations, gene fusions and gene expression we found that the patient's genomic and transcriptomic alterations were preserved in the patient derived xenografts with high fidelity. These xenograft models provide an opportunity for predicting efficacy of existing and potentially novel drugs that is based on individual metastatic tumor expression signature and molecular pharmacology for delivery of precision medicine.

A mixed-methods feasibility trial of protein kinase C iota inhibition with auranofin in asymptomatic ovarian cancer patients.

PURPOSE: This trial was undertaken (1) to determine the feasibility of enrolling asymptomatic ovarian cancer patients with CA-125 elevation in a trial with the protein kinase C iota (PKCι) inhibitor auranofin and (2) to understand patients' perceptions of CA-125 monitoring. METHODS: Asymptomatic ovarian cancer patients with CA-125 elevation received 3 mg auranofin orally twice per day and were evaluated. The patients participated in interviews about CA-125 monitoring. RESULTS: Ten patients were enrolled in slightly over 6 months, exceeding our anticipated accrual rate. Four manifested stable CA-125 levels for 1 month or longer. The median progression-free survival was 2.8 months (95% CI: 1.3-3.8); auranofin was well tolerated. One patient had baseline and monthly CA-125 levels of 5,570, 6,085, 3,511, and 2,230 U/ml, respectively, stopped auranofin because of radiographic progression at 3 months, and manifested an increase in CA-125 to 7,168 U/ml approximately 3 months later. Patient interviews revealed (1) the important role of CA-125 in cancer monitoring, (2) ardent advocacy of CA-125 testing, and (3) an evolution toward CA-125 assuming a life of its own. CONCLUSIONS: This study showed the feasibility of enrolling asymptomatic ovarian cancer patients with CA-125 elevation in a trial with auranofin. One patient had a decline in CA-125, suggesting that PKCι inhibition merits further study in ovarian cancer.

Effect of metformin on prostate cancer outcomes after radical prostatectomy.

OBJECTIVE: Recent studies have shown a relative risk reduction in the incidence of prostate cancer in patients taking metformin. However, there are conflicting findings on the effect of metformin on established cases of prostate cancer. In this study we evaluated the effect of metformin on survival and pathologic outcomes in established prostate cancer. MATERIALS AND METHODS: We retrospectively identified 12,052 patients who underwent radical prostatectomy between 1997 and 2010 at Mayo Clinic. Among these, 885 (7.3%) were diabetics, including 323 taking and 562 not taking metformin. Kaplan-Meier method was utilized to calculate rates of biochemical recurrence (BCR), systemic progression (SP), and all-cause mortality (ACM). Cox models were used to estimate the metformin hazard ratio (HR) adjusted for clinical and pathologic variables. RESULTS AND CONCLUSIONS: Median follow-up was 5.1 years. In univariate analysis, metformin HR (95% confidence intervals) was not significant for BCR (1.13 [0.84, 1.52]; P = 0.40), SP (1.37 [0.69, 2.72]; P = 0.37), and ACM (1.32 [0.84, 2.05]; P = 0.23). After adjusting for covariates of interest, the HRs for metformin among diabetics remained nonsignificant for BCR (0.91 [0.67, 1.24]; P = 0.55), SP (0.83 [0.39, 1.74]; P = 0.62); and ACM (1.16 [0.73, 1.86]; P = 0.53). No significant difference was seen between metformin users and nonusers in the final pathologic Gleason score (P = 0.33), stage (P = 0.1), rate of positive surgical margins (P = 0.29), or tumor volume (P = 0.76). Metformin use was not associated with a risk reduction in BCR, SP, or ACM. Besides presenting survival data, our results describing metformin's effect on final pathology are unique.