The effect of reef morphology on coral recruitment at multiple spatial scales.

Coral reefs are in decline worldwide, making it increasingly important to promote coral recruitment in new or degraded habitat. Coral reef morphology-the structural form of reef substrate-affects many aspects of reef function, yet the effect of reef morphology on coral recruitment is not well understood. We used structure-from-motion photogrammetry and airborne remote sensing to measure reef morphology (rugosity, curvature, slope, and fractal dimension) across a broad continuum of spatial scales and evaluated the effect of morphology on coral recruitment in three broadcast-spawning genera. We also measured the effect of other environmental and biotic factors such as fish density, adult coral cover, hydrodynamic larval import, and depth on coral recruitment. All variables combined explained 72% of coral recruitment in the study region. Coarse reef rugosity and curvature mapped at ≥2 m spatial resolution-such as large colonies, knolls, and boulders-were positively correlated with coral recruitment, explaining 22% of variation in recruitment. Morphology mapped at finer scales (≤32 cm resolution) was not significant. Hydrodynamic larval import was also positively related to coral recruitment in Porites and Montipora spp., and grazer fish density was linked to significantly lower recruitment in all genera. In addition, grazer density, reef morphology, and hydrodynamic import had differential effects on coral genera, reflecting genus-specific life history traits, and model performance was lower in gonochoric species. Overall, coral reef morphology is a key indicator of recruitment potential that can be detected by remote sensing, allowing potential larval sinks to be identified and factored into restoration actions.

Untapped policy avenues to protect coral reef ecosystems.

Coral reefs are experiencing severe decline, and urgent action is required at local and global scales to curb ecosystem loss. Establishing new regulations to protect corals, however, can be time consuming and costly, and it is therefore necessary to leverage existing legal instruments, such as policies originally designed to address terrestrial rather than marine activities, to prevent coral reef degradation. Focusing on the United States, but drawing on successful examples worldwide, we present actionable pathways to increase coral protections under legislation that was originally designed to advance clean freshwater, safe drinking water, and emergency management. We identify specific legal policies and procedures (e.g., industrial permit limits, nonpoint source management incentives, and floodplain restoration programs) that can curb coral reef pollution and can be extended to other countries with similar regulations in place. Coral reef practitioners should consider a broad array of currently underused, actionable, and intersecting environmental policies that can be applied to mitigate coral stress.

Nontuberculous Mycobacteria Show Differential Infectivity and Use Phospholipids to Antagonize LL-37.

Comparisons of infectivity among the clinically important nontuberculous mycobacteria (NTM) species have not been explored in great depth. Rapid-growing mycobacteria, including Mycobacterium abscessus and M. porcinum, can cause indolent but progressive lung disease. Slow-growing members of the M. avium complex are the most common group of NTM to cause lung disease, and molecular approaches can now distinguish between several distinct species of M. avium complex including M. intracellulare, M. avium, M. marseillense, and M. chimaera. Differential infectivity among these NTM species may, in part, account for differences in clinical outcomes and response to treatment; thus, knowing the relative infectivity of particular isolates could increase prognostication accuracy and enhance personalized treatment. Using human macrophages, we investigated the infectivity and virulence of nine NTM species, as well as multiple isolates of the same species. We also assessed their capacity to evade killing by the antibacterial peptide cathelicidin (LL-37). We discovered that the ability of different NTM species to infect macrophages varied among the species and among isolates of the same species. Our biochemical assays implicate modified phospholipids, which may include a phosphatidylinositol or cardiolipin backbone, as candidate antagonists of LL-37 antibacterial activity. The high variation in infectivity and virulence of NTM strains suggests that more detailed microbiological and biochemical characterizations are necessary to increase our knowledge of NTM pathogenesis.

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.

HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer: a retrospective, multicohort study.

BACKGROUND: HSD3B1 (1245A>C) has been mechanistically linked to castration-resistant prostate cancer because it encodes an altered enzyme that augments dihydrotestosterone synthesis from non-gonadal precursors. We postulated that men inheriting the HSD3B1 (1245C) allele would exhibit resistance to androgen-deprivation therapy (ADT). METHODS: In this multicohort study, we determined HSD3B1 genotype retrospectively in men treated with ADT for post-prostatectomy biochemical failure and correlated genotype with long-term clinical outcomes. We used data and samples from prospectively maintained prostate cancer registries at the Cleveland Clinic (Cleveland, OH, USA; primary study cohort) and the Mayo Clinic (Rochester, MN, USA; post-prostatectomy and metastatic validation cohorts). In the post-prostatectomy cohorts, patients of any age were eligible if they underwent prostatectomy between Jan 1, 1996, and Dec 31, 2009 (at the Cleveland Clinic; primary cohort), or between Jan 1, 1987, and Dec 31, 2011 (at the Mayo Clinic; post-prostatectomy cohort) and were treated with ADT for biochemical failure or for non-metastatic clinical failure. In the metastatic validation cohort, patients of any age were eligible if they were enrolled at Mayo Clinic between Sept 1, 2009, and July 31, 2013, with metastatic castration-resistant prostate cancer. The primary endpoint was progression-free survival according to HSD3B1 genotype. We did prespecified multivariable analyses to assess the independent predictive value of HSD3B1 genotype on outcomes. FINDINGS: We included and genotyped 443 patients: 118 in the primary cohort (who underwent prostatectomy), 137 in the post-prostatectomy validation cohort, and 188 in the metastatic validation cohort. In the primary study cohort, median progression-free survival diminished as a function of the number of variant alleles inherited: 6·6 years (95% CI 3·8-not reached) in men with homozygous wild-type genotype, 4·1 years (3·0-5·5) in men with heterozygous variant genotype, and 2·5 years (0·7 to not reached) in men with homozygous variant genotype (p=0·011). Relative to the homozygous wild-type genotype, inheritance of two copies of the variant allele was predictive of decreased progression-free survival (hazard ratio [HR] 2·4 [95% CI 1·1-5·3], p=0·029), as was inheritance of one copy of the variant allele (HR 1·7 [1·0-2·9], p=0·041). Findings were similar for distant metastasis-free survival and overall survival. The effect of the HSD3B1 genotype was independently confirmed in the validation cohorts. INTERPRETATION: Inheritance of the HSD3B1 (1245C) allele that enhances dihydrotestosterone synthesis is associated with prostate cancer resistance to ADT. HSD3B1 could therefore potentially be a powerful genetic biomarker capable of distinguishing men who are a priori likely to fare favourably with ADT from those who harbour disease liable to behave more aggressively, and who therefore might warrant early escalated therapy. FUNDING: Prostate Cancer Foundation, National Institutes of Health, US Department of Defense, Howard Hughes Medical Institute, American Cancer Society, Conquer Cancer Foundation of the American Society of Clinical Oncology, Cleveland Clinic Research Programs Committee and Department of Radiation Oncology, Gail and Joseph Gassner Development Funds.

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.

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.

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.

Blood type, lymphadenectomy and blood transfusion predict venous thromboembolic events following radical prostatectomy with pelvic lymphadenectomy.

PURPOSE: Venous thromboembolic events are the most common nonoperative complication after radical prostatectomy and they represent the most common cause of death within 30 days of surgery. While effective mechanical and chemoprophylaxis exists, such prophylaxis may also be associated with increased complications. To identify venous thromboembolic event risk factors and, thereby, facilitate targeted prophylaxis we characterized clinicopathological variables associated with these events in patients undergoing radical prostatectomy. MATERIALS AND METHODS: We reviewed the records of 18,472 consecutive patients who underwent radical prostatectomy with pelvic lymphadenectomy for prostate cancer at our institution from 1987 to 2010. Patients were followed postoperatively for complications. Venous thromboembolic events within 30 days of surgery were recorded. Logistic regression models were used to analyze clinicopathological variables associated with venous thromboembolic events. RESULTS: We identified symptomatic venous thromboembolic events in 271 patients (1.4%). This diagnosis was not associated with preoperative body mass index, prostate specific antigen, Gleason score or cancer recurrence. However, the diagnosis was significantly associated with nonO blood type (OR 1.98, p = 0.004), an increasing number of lymph nodes removed (OR 1.05, p = 0.035) and blood transfusion (OR 1.30, p = 0.02). Patients with venous thromboembolic events were significantly more likely to die within 30 days of surgery (3.0% vs 0%, p <0.001). CONCLUSIONS: Blood type, pelvic lymphadenectomy extent and blood transfusion are significant risk factors for symptomatic venous thromboembolic event before radical prostatectomy plus pelvic lymph node dissection. These data should be used for patient counseling, particularly in regard to obviating lymphadenectomy in patients at low risk and for individualizing prophylaxis for venous thromboembolic event in patients at higher risk.

Recruitment strategies and consent rates in a national prospective colorectal cancer screening cohort: results from year 1 of the Voyage Study.

OBJECTIVE: To identify the optimal incentive protocol for maximising participation while managing study costs during the Voyage trial. DESIGN: Prospective cohort (Voyage trial) of colorectal cancer (CRC) incidence and mortality outcomes in individuals screened with multitarget stool DNA (mt-sDNA) served as the population. A subset was randomised to receive postage stamps as a pre-consent incentive, or as a post-consent incentive after completion of the consent and questionnaire. Descriptive statistics from year 1 are reported. RESULTS: During year 1 of the Voyage trial, a total of 600 258 individuals with mt-sDNA orders received at Exact Sciences Laboratories were randomly selected and invited to participate. Of those, 26 429 (4.4%) opted in, 14 365 of whom (54.3%) consented. The opt-in and consent samples were similar to the target population with respect to sex but differed by geographic residence and age (p<0.001). For the embedded incentive experiment, 2333 were randomised to the pre-incentive arm, while 2342 were randomised to the post-incentive arm. Overall consent rate in the incentive trial was 56.4% (60.9% for the pre-consent incentive arm (1421/2333) vs 52.0% for the post-consent incentive arm (1217/2342), p<0.001). Cost reduction was observed for the pre-consent incentive group, and higher response rates were seen among older versus younger individuals. CONCLUSIONS: Pre-consent incentive option was associated with a higher participation rate and lower costs and was used for the remainder of study recruitment. CRC incidence and mortality vary with age; thus, adjusting for differential participation by age and region will be important in analyses of Voyage data. TRIAL REGISTRATION NUMBER: NCT04124406.

Well-Child Visits for Early Detection and Management of Maternal Postpartum Hypertensive Disorders.

Importance: Innovative approaches are needed to address the increasing rate of postpartum morbidity and mortality associated with hypertensive disorders. Objective: To determine whether assessing maternal blood pressure (BP) and associated symptoms at time of well-child visits is associated with increased detection of postpartum preeclampsia and need for hospitalization for medical management. Design, Setting, and Participants: This is a pre-post quality improvement (QI) study. Individuals who attended the well-child visits between preimplementation (December 2017 to December 2018) were compared with individuals who enrolled after the implementation of the QI program (March 2019 to December 2019). Individuals were enrolled at an academic pediatric clinic. Eligible participants included birth mothers who delivered at the hospital and brought their newborn for well-child check at 2 days, 2 weeks, and 2 months. A total of 620 individuals were screened in the preintervention cohort and 680 individuals were screened in the QI program. Data was analyzed from March to July 2022. Exposures: BP evaluation and preeclampsia symptoms screening were performed at the time of the well-child visit. A management algorithm-with criteria for routine or early postpartum visits, or prompt referral to the obstetric emergency department-was followed. Main Outcome and Measures: Readmission due to postpartum preeclampsia. Comparisons across groups were performed using a Fisher exact test for categorical variables, and t tests or Mann-Whitney tests for continuous variables. Results: A total of 595 individuals (mean [SD] age, 27.2 [6.1] years) were eligible for analysis in the preintervention cohort and 565 individuals (mean [SD] age, 27.0 [5.8] years) were eligible in the postintervention cohort. Baseline demographic information including age, race and ethnicity, body mass index, nulliparity, and factors associated with increased risk for preeclampsia were not significantly different in the preintervention cohort and postintervention QI program. The rate of readmission for postpartum preeclampsia differed significantly in the preintervention cohort (13 individuals [2.1%]) and the postintervention cohort (29 individuals [5.6%]) (P = .007). In the postintervention QI cohort, there was a significantly earlier time frame of readmission (median [IQR] 10.0 [10.0-11.0] days post partum for preintervention vs 7.0 [6.0-10.5] days post partum for postintervention; P = .001). In both time periods, a total of 42 patients were readmitted due to postpartum preeclampsia, of which 21 (50%) had de novo postpartum preeclampsia. Conclusions and Relevance: This QI program allowed for increased and earlier readmission due to postpartum preeclampsia. Further studies confirming generalizability and mitigating associated adverse outcomes are needed.

Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population.

PURPOSE: Patients with locally advanced prostate cancer after radical prostatectomy are candidates for secondary therapy. However, this higher risk population is heterogeneous. Many cases do not metastasize even when conservatively managed. Given the limited specificity of pathological features to predict metastasis, newer risk prediction models are needed. We report a validation study of a genomic classifier that predicts metastasis after radical prostatectomy in a high risk population. MATERIALS AND METHODS: A case-cohort design was used to sample 1,010 patients after radical prostatectomy at high risk for recurrence who were treated from 2000 to 2006. Patients had preoperative prostate specific antigen greater than 20 ng/ml, Gleason 8 or greater, pT3b or a Mayo Clinic nomogram score of 10 or greater. Patients with metastasis at diagnosis or any prior treatment for prostate cancer were excluded from analysis. A 20% random sampling created a subcohort that included all patients with metastasis. We generated 22-marker genomic classifier scores for 219 patients with available genomic data. ROC and decision curves, competing risk and weighted regression models were used to assess genomic classifier performance. RESULTS: The genomic classifier AUC was 0.79 for predicting 5-year metastasis after radical prostatectomy. Decision curves showed that the genomic classifier net benefit exceeded that of clinical only models. The genomic classifier was the predominant predictor of metastasis on multivariable analysis. The cumulative incidence of metastasis 5 years after radical prostatectomy was 2.4%, 6.0% and 22.5% in patients with low (60%), intermediate (21%) and high (19%) genomic classifier scores, respectively (p<0.001). CONCLUSIONS: Results indicate that genomic information from the primary tumor can identify patients with adverse pathological features who are most at risk for metastasis and potentially lethal prostate cancer.

Interaction of adjuvant androgen deprivation therapy with patient comorbidity status on overall survival after radical prostatectomy for high-risk prostate cancer.

BACKGROUND: To evaluate the impact of adjuvant hormonal therapy after radical prostatectomy on overall survival in high-risk prostate cancer patients, stratified by comorbidity status. METHODS: We identified 1247 patients who underwent radical prostatectomy from 1988 to 2004 for high-risk prostate cancer, as defined by National Comprehensive Cancer Network classification. Comorbidity status was stratified by Charlson Comorbidity Index as 0, 1 or >2, as well as by the presence or absence of cardiovascular disease. Overall survival was estimated by the Kaplan-Meier method, and compared within each comorbidity category/adjuvant hormonal therapy strata with the log-rank test. RESULTS: Median patient age was 65 years, and the median postoperative follow up was 11.2 years. In total, 419 patients (34%) received adjuvant hormonal therapy. The distribution of Charlson Comorbidity Index was 0, 1 and ≥ 2 in 861 (69%), 244 (20%) and 142 (11%) patients, respectively. The 10-year overall survival for patients who received adjuvant hormonal therapy versus those who did not was 75% versus 82% (P=0.54) for patients with Charlson Comorbidity Index=0, 72% versus 76% (P=0.83) with Charlson Comorbidity Index=1, and 70% versus 68% (P=0.33) with Charlson Comorbidity Index ≥ 2. Meanwhile, 155 (12%) patients had cardiovascular disease, and the 10-year overall survival for patients with cardiovascular disease who received adjuvant hormonal therapy was 72%, compared with 76% without adjuvant hormonal therapy (P=0.97). On multivariate analysis, receipt of adjuvant hormonal therapy was not associated with non-prostate cancer mortality (P=0.24). CONCLUSIONS: Adjuvant hormonal therapy after radical prostatectomy for high-risk prostate cancer does not increase non-prostate cancer mortality, even among patients with multiple comorbidities. Additional studies are warranted to determine optimal multimodal treatment approach for high-risk patients.

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.

20-Year survival after radical prostatectomy as initial treatment for cT3 prostate cancer.

UNLABELLED: Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Despite a lack of randomised controlled trials, most men with locally advanced prostate cancer are recommended to undergo external beam radiotherapy (EBRT), often combined with long-term androgen-deprivation therapy (ADT). Many of these men are not offered radical prostatectomy (RP) by their treating urologist. Additionally, it is know that EBRT with long-term ADT does provide good cancer control (88% at 10 years). We have previously published intermediate-term follow-up of a large series of men treatment with RP for cT3 prostate cancer. We report long-term follow-up of a large series of men treated with RP as primary treatment for cT3 prostate cancer. Our study shows that with long-term follow-up RP provides excellent oncological outcomes even at 20 years. While most men do require a multimodal treatment approach, many men can be managed successfully with RP alone. OBJECTIVE: • To present long-term survival outcomes after radical prostatectomy (RP) for patients with cT3 prostate cancer, as the optimal treatment for patients with clinical T3 prostate cancer is debated. PATIENTS AND METHODS: • We identified 843 men who underwent RP for cT3 tumours between 1987 and 1997. • Survival was estimated using the Kaplan-Meier method. • Cox proportional hazards regression models were used to evaluate the association of clinicopathological features with outcome RESULTS: • The median (range) postoperative follow-up was 14.3 (0.1-23.5) years. • Down-staging to pT2 disease occurred in 26% (223/843) at surgery. • Local recurrence-free, systemic progression-free and cancer-specific survival for men with cT3 prostate cancer after RP was 76%, 72%, and 81%, respectively, at 20 years. • On multivariate analysis, increasing RP Gleason score (hazard ratio [HR] 1.8; P = 0.01), non-diploid chromatin content (HR 1.8; P = 0.01), positive surgical margins (HR 2.1; P = 0.007), and seminal vesicle invasion (HR 2.1; P = 0.005) were associated with a significant risk of prostate cancer death, while a more recent year of surgery was associated with a decreased risk of cancer-specific mortality (HR 0.88; P = 0.01) CONCLUSIONS: • RP affords accurate pathological staging and may be associated with durable cancer control for cT3 prostate cancer, with 20 years of follow-up presented here. • RP as part of a multimodal treatment strategy therefore remains a viable treatment option for patients with cT3 tumours.

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.

The impact of positive surgical margins on mortality following radical prostatectomy during the prostate specific antigen era.

PURPOSE: The presence of a positive surgical margin at radical prostatectomy has been linked to an increased risk of postoperative biochemical recurrence. We evaluated the impact of margin status on subsequent clinical progression and mortality. MATERIALS AND METHODS: We reviewed the records of 11,729 patients who underwent prostatectomy between 1990 and 2006. Survival was estimated for patients with vs without a positive margin and compared using the log rank test. Cox proportional hazards regression models were used to analyze the impact of margin status on survival. RESULTS: Overall 3,651 (31.1%) men were identified with a positive margin. Median postoperative followup was 8.2 years (IQR 4.4, 12.1). The 10-year biochemical recurrence-free rate for patients with and without a positive margin was 56% and 77%, respectively (p <0.001), while 10-year local recurrence-free survival was 89% vs 95% (p <0.001). Margin status also stratified systemic progression-free survival (93% vs 97%, p <0.001), cancer specific survival (96% vs 99%, p <0.001) and overall survival (83% vs 88%, p <0.001). On multivariate analysis the presence of a positive margin was associated with increased risk of biochemical recurrence (HR 1.63, 95% CI 1.47-1.80, p <0.0001), local recurrence (HR 1.78, 95% CI 1.45-2.19, p <0.0001) and receipt of salvage therapy (HR 1.79, 95% CI 1.58-2.02, p <0.0001) but was not a significant predictor of systemic progression (p = 0.95), cancer specific death (p = 0.15) or overall mortality (p = 0.16). CONCLUSIONS: The presence of a positive margin increased the risk of biochemical recurrence, local recurrence and the need for salvage treatment but was not independently associated with systemic progression, cancer specific death or overall mortality. These results should be considered when evaluating patients for adjuvant therapy.

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.