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To increase the rate of minimally invasive hysterectomy (MIH) in patients with large uteri. The rate of MIH was evaluated at a single institution. A before-and-after single-phase quality improvement project was undertaken by implementing a bundle of preoperative assessment and surgery performed by a team with MIH expertise. Community-focused academic tertiary healthcare center. Women aged 18 years or older undergoing hysterectomy. Patients with malignant pathology and those with missing data were excluded. At this county hospital, a group approach practice is implemented where patients undergo a single "faculty exam" to determine the route of hysterectomy. The physician deciding on the surgical approach may not be the one performing surgery. This can lead to discrepancies between the preoperative plan and the actual surgery, and a high "conversion rate" if the surgeon is not comfortable performing MIH for large uteri. To address this, the quality intervention (QI) involved a group of surgeons with MIH expertise conducting both the preoperative examinations and surgeries for uteri larger than 16 weeks size. A total of 833 patients underwent hysterectomy during the study period. Of these, 722 (86.7%) had surgery before, and 111 (13.3%) after the QI. Patient characteristics did not significantly differ between cohorts. Following the QI, a significantly higher proportion of patients underwent MIH (91% vs 73%, P<0.0001). There was no significant difference in uterine weight (513g vs 424g, P= 0.06) or complication rate (11% vs 14%, P=0.33). The rate of same-day discharge significantly increased post-intervention (56% vs 69.3%, P<0.001). More importantly, in the cohort of patients with uteri >500 grams/16weeks, the rate of MIH increased from 36.9% to 75.8% after the QI, p<0.001. A QI was implemented to increase access to MIH for patients with large uteri. This intervention may lead to sustainable and significant improvements in surgical outcomes in this population. [ABSTRACT FROM AUTHOR]

Abstract Background Steroid Responsive Meningitis-Arteritis (SRMA) is a common cause of inflammation of the canine central nervous system (CNS). To investigate if transforming growth factor beta 1 (TGF-β1), interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) are involved in the production of excessive immunoglobulin A (IgA), the induction of acute phase proteins and in the development of a systemic necrotizing vasculitis, characteristic of SRMA, these three signalling proteins were evaluated. Results Cerebrospinal fluid (CSF) and serum samples of dogs during the acute phase of SRMA (SRMA) were tested for IL-6, VEGF and TGF- β1. Results were compared to those of dogs affected with SRMA during treatment (SRMA Th) and during relapse (SRMA R), to dogs with other meningoencephalomyelitides (ME), with miscellaneous non-inflammatory diseases of the CNS (CNS-Mix), with idiopathic epilepsy (IE), with systemic inflammatory diseases (Syst. Infl.) and with healthy dogs (Healthy). Concentrations of IL-6 and VEGF in CSF were significantly elevated in the SRMA group compared to the other disease categories (p 1 were increased in SRMA group, but statistically significant differences were found only in comparison with Healthy and CNS-Mix groups. No differences were detected in the serum concentrations of TGF-β1 between the different groups. In untreated SRMA patients, a positive correlation (rSpear = 0.3549; P = 0.0337) between concentrations of TGF-β1 and IgA concentration was found in CSF, while concentrations of IL-6 and VEGF in CSF positively correlated with the degree of pleocytosis (rSpear = 0.8323; P Spear = 0.5711; P = 0.0166, respectively). Conclusions Our results suggest that these three signalling proteins are biomarkers of disease activity in SRMA. VEGF might play an important role in the development of a systemic arteritis. TGF-β1 is considered to be involved in the excessive IgA production, while IL-6 in the pleocytosis. The combined intrathecal increase of TGF-β1 and IL-6 detected in SRMA could possibly force CD4 progenitors to differentiate towards the newly described Th17 lymphocyte subset and enhance the autoimmune response.

Abstract Background Steroid-responsive meningitis-arteritis (SRMA) is a systemic inflammatory disease affecting young adult dogs and a potential large animal model for neutrophilic meningitis. Similarities between SRMA and infectious central nervous system (CNS) diseases in lymphocyte subsets suggest an infectious origin. Toll-like receptors (TLRs) are pattern recognition receptors playing an important role in innate immunity. Due to their ability to recognize both self and non-self antigens, we hypothesize that TLRs are among the key factors for the induction of the inflammatory process in SRMA and provide an indirect hint on the etiology of the disease. Methods The expression profile of cell surface TLRs (TLR2, TLR4 and TLR5) and intracellular TLRs (TLR3 and TLR9) of canine leukocytes was analyzed by immunophenotyping and subsequent flow cytometric measurements. Experiments were performed on cerebrospinal fluid (CSF) and peripheral blood (PB) samples of dogs affected with SRMA during the acute phase (n = 14) as well as during treatment (n = 23) and compared with those of dogs with bacterial meningitis (n = 3), meningoencephalitis of unknown etiology (n = 6), neoplasia of the central nervous system (n = 6) and a group of dogs with miscellaneous neurological diseases (n = 9). Two additional control groups consisted of dogs with pyogenic infections (n = 13) and of healthy dogs (n = 6). Results All examined groups showed a high percentage of TLR2, TLR4 and TLR5 positive PB polymorphonuclear cells (PMNs) in comparison to healthy dogs. Very high values of TLR9 positive PB PMNs were detected in acute SRMA. Only a few similarities were found between SRMA patients and dogs with pyogenic infections, both groups were characterized by high expression of TLR4 positive PB monocytes. Glucocorticosteroid therapy reduced TLR2, TLR4 and TLR9 expression in PB monocytes. Conclusions A relatively high expression of TLR4 and TLR9 in acute SRMA suggests that these two receptors might be involved in the inflammatory process in SRMA, enhancing the autoimmune reaction. Systematic CSF cell analysis for TLRs can be performed in future treatment studies in larger animals, such as dogs.

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., Competing Interests: Competing interests: KJY, REC, CRK, EJK, JLSS, JAG and JEO are employees of Mayo Clinic and received funding for this study through a grant from Exact Sciences Corporation. BK and JJL are employees and shareholders of Exact Sciences. At the start of the work herein, LJFR was an employee of the Mayo Clinic, whereby she offered scientific input to Exact Sciences for research studies through a contracted services agreement between Mayo Clinic and Exact Sciences Corporation. During the writing of this manuscript, she became a full-time employee of Exact Sciences Corporation. Currently, she is an employee of Mayo Clinic only., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The aromatic compound ( E )-anethol is widely used in the flavor, fragrance, and medicinal industries. This compound is commonly produced through steam distillation of fennel, star anise, and anise seed. Given the cost of production, these natural and authentic essential oils are commonly adulterated with lower-cost natural materials or synthetic alternatives. The current study investigates essential oil profiles (gas chromatography/mass spectrometry) and stable isotope ratios (gas chromatography/isotope ratio mass spectrometry) of the abundant compound ( E )-anethol in both authentic reference standards ( n = 15) and commercially available samples ( n = 30). This multifaceted analytical approach establishes techniques for ensuring the authenticity of essential oil sources of ( E )-anethol and was then used to evaluate the current essential oil market sources of ( E )-anethol. These findings report that adulteration of ( E )-anethol-containing natural products takes various forms, and a multifaceted analytical approach is recommended for authentication. Of the commercial samples analyzed for this report, 27% were adulterated.

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., (Copyright © 2023 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Two species within the Lamiaceae (mint) family, Agastache urticifolia and Monardella odoratissima , are aromatic plants that are native to the Intermountain Region (USA). Essential oil produced through steam distillation was examined to establish the essential oil yield and both the achiral and chiral aromatic profiles of both plant species. The resulting essential oils were analyzed by GC/MS, GC/FID, and MRR (molecular rotational resonance). For A. urticifolia and M. odoratissima , achiral essential oil profiles were largely composed of limonene (71.0%, 27.7%), trans -β-ocimene (3.6%, 6.9%), and pulegone (15.9%, 4.3%), respectively. Between the two species, eight chiral pairs were analyzed and, interestingly, the dominant enantiomer (calculated as ee%) of limonene and pulegone switched between the two species. Where enantiopure standards were not commercially available, MRR was used as a reliable analytical technique for chiral analysis. This study verifies the achiral profile for A. urticifolia and, for the first time to the authors' knowledge, establishes the achiral profile for M. odoratissima and chiral profile for both species. Additionally, this study confirms the utility and practicality of using MRR for determining chiral profiles in essential oils.

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&#95;AKT&#95;MTOR pathways., (©2022 The Authors; Published by the American Association for Cancer Research.)

Osmorhiza occidentalis Torr. is an essential-oil-bearing plant in the Apiaceae family. Volatile oil was produced through steam distillation ( n = 3) of the above ground plant parts and was analyzed by gas chromatography (GC/FID, GC/MS), and gas chromatography/isotope ratio mass spectrometry (GC/IRMS) to establish the essential oil composition and stable isotope profile. The resulting essential oils were found to be comprised of 33 volatile compounds. Prominent volatile compounds include methyl chavicol (avg. 61.6%), ( Z )-β-ocimene (avg. 14.7%), sabinene (avg. 10.5%), and γ-terpinene (avg. 2.8%). Stable isotope values were determined for prominent volatile compounds, including methyl chavicol, ( Z )-β-ocimene, sabinene, and γ-terpinene. Values for δ 2 H range from -393.479 (avg. sabinene) to -171.516 (avg. methyl chavicol). Those for δ 13 C range from -35.957 (avg. methyl chavicol) to -30.820 (avg. ( Z )-β-ocimene). The essential oil yield was 0.12% ( w/w ). The current study establishes for the first time, to the best knowledge of the authors, the essential oil yield, essential oil composition, and stable isotope profile of prominent volatile compounds extracted from the above-ground portions of O. occidentalis . These results provide insight into the volatile chemical composition produced by the plant and provide fundamental data for substantiation of ethnobotanical applications.

Ocimum campechianum Mill. (Peruvian basil) is an essential oil-bearing plant of the Lamiaceae family. Volatile oil produced through steam distillation of Peruvian basil was examined to establish the aromatic and stable isotope profiles of samples ( n = 9) from three different cultivated plots in Peru. The resulting essential oils were analyzed by GC/FID, GC/MS, and GC/IRMS. In accordance with findings from other researchers, multiple chemotypes, defined by the most abundant aromatic compounds, exist within these populations. Overall, 55% of samples are the eugenol chemotype (values ranging 15.4-30.2%), 33% are the methyl eugenol chemotype (values ranging 68.1-68.7%), and a single sample is a mixture of both chemotypes, containing high levels of both eugenol (38.1%) and methyl eugenol (8.6%). Stable isotope ratios, δ 2 H and δ 13 C, performed on prominent compounds provide supporting data for distinguishing chemotypes. Complete aromatic profiles, stable isotope ratios, and essential oil yield are established for each sample. This study confirms the existence of multiple chemotypes and, for the first time, to the author's best knowledge, establishes stable isotope ratios for O. campechianum essential oil, which proves a useful tool in further investigating plant metabolism and determining essential oil authenticity.

Trophic state indexes (TSI) guide management strategies regarding eutrophication control worldwide. Such indexes usually consider chlorophyll-a (Chl-a), total phosphorus (TP), and Secchi disk depth (SDD) as independent variables for estimating aquatic productivity and the degree of impairment. TSIs for each of these components are frequently averaged to produce a single TSI value associated with a trophic state classification (e.g., oligotrophic, mesotrophic, or eutrophic). The potential divergence among equations and classification systems originally developed for temperate lakes or tropical/subtropical reservoirs might be particularly relevant in the tropics, where there is a lack of data and the use of equations originally developed for temperate systems may be inappropriate. We calculated two widely used TSIs for temperate lakes (TSI temp ) or tropical reservoirs (TSI trop ) and explored the deviations among TSI components in Brazilian reservoirs. When applied to our tropical/subtropical reservoirs, the TSI temp provided a conservative approach, with lower limits anticipating increasing trophic state classification. TSI components for Chl-a and SDD significantly deviated for both sets of equations, and these discrepancies were related to turbidity, water temperature, and cyanobacterial biomass. For TSI temp , but not for TSI trop , TSI values in relation to Chl-a and TP were also significantly different. All such deviations have important management implications especially when Chl-a, TP, and SDD are averaged in a single TSI, representing loss of information and less useful trophic state classifications. Our results demonstrate that tropical water bodies may respond to drivers of eutrophication differently than temperate systems, highlighting the need for more data to better inform management of these understudied ecosystems. As managers collect data from more tropical water bodies, regional models may offer even better understanding of factors influencing trophic state., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Lavandula angustifolia Mill. (lavender) is an essential-oil-bearing plant in the Lamiaceae family. Volatile oil produced through the steam distillation of lavender was examined to establish the essential oil yield and aromatic profile from each portion of the plant-namely, the corolla, calyx, leaf, and whole flowering top. The resulting essential oils were analyzed by GC-FID and GC-MS. The different plant parts generally shared similar compounds but in varying relative percentages. Aromatic profiles of the whole flowering top and calyx were similar, with prominent compounds being linalool acetate (34.3%, 32.0%), linalool (26.5%, 32.9%), lavandulyl acetate (5.6%, 4.9%), terpinen-4-ol (5.3%, 7.0%), and ( Z )-β-ocimene (4.5%, 5.4%), respectively. Aromatic profiles for the corolla and leaf were unique. Prominent aromatic compounds of the corolla included linalool acetate (18.4%), linalool (10.8%), epi-α-cadinol (10.0%), borneol (7.3%), and lavandulyl acetate (6.3%). Prominent aromatic compounds of the leaf included epi-α-cadinol (19.8%), γ-cadinene (11.0%), borneol (6.0%), caryophyllene oxide (4.9%), and bornyl acetate (4.8%). Complete profiles and essential oil yields of corolla, calyx, leaf, and whole flowering top were established. This study establishes the influence the corolla, calyx, and leaf exert on the aromatic profile of the whole flowering top and provides insight into authentication of lavender essential oil.

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.

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., (© 2019 Wiley Periodicals, Inc.)

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/cm 3 , ≤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., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

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.

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., (Copyright © 2018. Published by Elsevier Inc.)

Objective: To examine the occurrence of psychosocial risk factors among expectant fathers whose female partners were enrolled in prenatal home visiting services., Design: Cross-sectional, exploratory, quantitative design., Sample: Expectant father-mother pairs were recruited from two urban home visiting programs to participate in a randomized controlled trial of a father advocate intervention. The study sample consisted of 66 father-mother pairs who completed structured interviews at baseline, before randomization., Measurements: Participants were interviewed using a structured questionnaire. This study focused on their responses related to 11 psychosocial risk factors, as measured by the Brief Risk Overview (BRO) for men and the Prenatal Risk Overview (PRO) for pregnant women., Results: Moderate- or high-risk classification of psychosocial risk factors was prevalent among expectant fathers. The risk factors that fathers reported were diverse, related to their basic needs, social support, mental health, and substance use; risk factors frequently co-occurred. Fathers' and mothers' total risk scores, calculated as a composite of all 11 risk factors, were significantly correlated., Conclusions: Expectant fathers who have a partner enrolled in home visiting would benefit from psychosocial risk screening. Addressing fathers' risk factors may improve paternal health, their involvement in parenting, and the well-being of their partners and children., (© 2018 Wiley Periodicals, Inc.)

Background: Genomic aberrations have been identified in metastatic castration-resistant prostate cancer (mCRPC), but molecular predictors of resistance to abiraterone acetate/prednisone (AA/P) treatment are not known., Patients and Methods: In a prospective clinical trial, mCRPC patients underwent whole-exome sequencing (n = 82) and RNA sequencing (n = 75) of metastatic biopsies before initiating AA/P with the objective of identifying genomic alterations associated with resistance to AA/P. Primary resistance was determined at 12 weeks of treatment using criteria for progression that included serum prostate-specific antigen measurement, bone and computerized tomography imaging and symptom assessments. Acquired resistance was determined using the end point of time to treatment change (TTTC), defined as time from enrollment until change in treatment from progressive disease. Associations of genomic and transcriptomic alterations with primary resistance were determined using logistic regression, Fisher's exact test, single and multivariate analyses. Cox regression models were utilized for determining association of genomic and transcriptomic alterations with TTTC., Results: At 12 weeks, 32 patients in the cohort had progressed (nonresponders). Median study follow-up was 32.1 months by which time 58 patients had switched treatments due to progression. Median TTTC was 10.1 months (interquartile range: 4.4-24.1). Genes in the Wnt/β-catenin pathway were more frequently mutated and negative regulators of Wnt/β-catenin signaling were more frequently deleted or displayed reduced mRNA expression in nonresponders. Additionally, mRNA expression of cell cycle regulatory genes was increased in nonresponders. In multivariate models, increased cell cycle proliferation scores (≥ 50) were associated with shorter TTTC (hazard ratio = 2.11, 95% confidence interval: 1.17-3.80; P = 0.01)., Conclusions: Wnt/β-catenin pathway activation and increased cell cycle progression scores can serve as molecular markers for predicting resistance to AA/P therapy., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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 ., (©2017 American Association for Cancer Research.)

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., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

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., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Conflicts of Interest: None declared., (Copyright® by the International Brazilian Journal of Urology.)

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., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

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., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

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.

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., (© 2014 S. Karger AG, Basel.)

Nationally, death rates from prescription opioid pain reliever (OPR) overdoses quadrupled during 1999-2010, whereas rates from heroin overdoses increased by <50%. Individual states and cities have reported substantial increases in deaths from heroin overdose since 2010. CDC analyzed recent mortality data from 28 states to determine the scope of the heroin overdose death increase and to determine whether increases were associated with changes in OPR overdose death rates since 2010. This report summarizes the results of that analysis, which found that, from 2010 to 2012, the death rate from heroin overdose for the 28 states increased from 1.0 to 2.1 per 100,000, whereas the death rate from OPR overdose declined from 6.0 per 100,000 in 2010 to 5.6 per 100,000 in 2012. Heroin overdose death rates increased significantly for both sexes, all age groups, all census regions, and all racial/ethnic groups other than American Indians/Alaska Natives. OPR overdose mortality declined significantly among males, persons aged <45 years, persons in the South, and non-Hispanic whites. Five states had increases in the OPR death rate, seven states had decreases, and 16 states had no change. Of the 18 states with statistically reliable heroin overdose death rates (i.e., rates based on at least 20 deaths), 15 states reported increases. Decreases in OPR death rates were not associated with increases in heroin death rates. The findings indicate a need for intensified prevention efforts aimed at reducing overdose deaths from all types of opioids while recognizing the demographic differences between the heroin and OPR-using populations. Efforts to prevent expansion of the number of OPR users who might use heroin when it is available should continue.

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: It remains unclear whether the hemodilution effect of body mass index (BMI) on PSA levels translates to inappropriate prostate cancer (PCa) screening in obese men. To address this, we conducted two nested case-control studies within prospective cohorts of men undergoing radical prostatectomy for newly diagnosed PCa., Methods: We identified 1817 men with BMI 30 kg m(-2) (cases) and 1244 men with BMI <25 kg m(-2) (controls) who underwent surgery to treat PCa at Mayo Clinic in Rochester between 2000 and 2009. Cases and controls were frequency matched on age and PSA level. In a similar manner, we identified 206 cases and 133 controls treated at Mayo Clinic in Florida between 2006 and 2011. We employed logistic regression models to evaluate the association of pathologic features of aggressiveness with obesity status., Results: After adjusting for age and PSA level, we noted that obese men in the Rochester population are more likely to present with Gleason grade 8-10 tumors (OR= 1.50; 95% CI 1.14-1.96; P=0.003) and pT3, pT4, pTxN+ stage disease (OR=1.30; 95% CI 1.05-1.62). We noted a similar association seminal vesicle involvement (OR= 1.41; 95% CI 1.03-1.92; P=0.03). Results from the smaller Florida population supported these same associations but did not achieve conventional statistical significance., Conclusions: Obese men present with more aggressive PCa tumors compared with non-obese men of similar age and PSA screening values. If confirmed, this would support the need to explore PSA-based screening in obese men to possibly account for a hemodilution effect.

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., (© 2012 The Japanese Urological Association.)

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., (© 2012 THE AUTHORS. BJU INTERNATIONAL © 2012 BJU INTERNATIONAL.)

We tested the hypothesis that nitric oxide (NO) and vasodilating prostaglandins (PGs) contribute independently to hypoxic vasodilatation, and that combined inhibition would reveal a synergistic role for these two pathways in the regulation of peripheral vascular tone. In 20 healthy adults, we measured forearm blood flow (Doppler ultrasound) and calculated forearm vascular conductance (FVC) responses to steady-state (SS) isocapnic hypoxia (O₂ saturation ~85%). All trials were performed during local α- and β-adrenoceptor blockade (via a brachial artery catheter) to eliminate sympathoadrenal influences on vascular tone and thus isolate local vasodilatory mechanisms. The individual and combined effects of NO synthase (NOS) and cyclooxygenase (COX) inhibition were determined by quantifying the vasodilatation from rest to SS hypoxia, as well as by quantifying how each inhibitor reduced vascular tone during hypoxia. Three hypoxia trials were performed in each subject. In group 1 (n = 10), trial 1, 5 min of SS hypoxia increased FVC from baseline (21 ± 3%; P < 0.05). Infusion of N(G)-nitro-L-arginine methyl ester (L-NAME) for 5 min to inhibit NOS during continuous SS hypoxia reduced FVC by -33 ± 3% (P < 0.05). In Trial 2 with continuous NOS inhibition, the increase in FVC from baseline to SS hypoxia was similar to control conditions (20 ± 3%), and infusion of ketorolac for 5 min to inhibit COX during continuous SS hypoxia reduced FVC by -15 ± 3% (P < 0.05). In Trial 3 with combined NOS and COX inhibition, the increase in FVC from baseline to SS hypoxia was abolished (~3%; NS vs. zero). In group 2 (n = 10), the order of NOS and COX inhibition was reversed. In trial 1, five minutes of SS hypoxia increased FVC from baseline (by 24 ± 5%; P < 0.05), and infusion of ketorolac during SS hypoxia had minimal impact on FVC (-4 ± 3%; NS). In Trial 2 with continuous COX inhibition, the increase in FVC from baseline to SS hypoxia was similar to control conditions (27 ± 4%), and infusion of L-NAME during continuous SS hypoxia reduced FVC by -36 ± 7% (P < 0.05). In Trial 3 with combined NOS and COX inhibition, the increase in FVC from baseline to SS hypoxia was abolished (~3%; NS vs. zero). Our collective findings indicate that (1) neither NO nor PGs are obligatory to observe the normal local vasodilatory response from rest to SS hypoxia; (2) NO regulates vascular tone during hypoxia independent of the COX pathway, whereas PGs only regulate vascular tone during hypoxia when NOS is inhibited; and (3) combined inhibition of NO and PGs abolishes local hypoxic vasodilatation (from rest to SS hypoxia) in the forearm circulation of healthy humans during systemic hypoxia.

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., (2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

This paper describes the construction of a combinatorial artificial receptor array (CARA) and the application of the array to differentiation of proteins based on their binding patterns. Microarrays displaying 5035 unique binding environments were prepared using a library of 19 small molecule building blocks. Each building block was equipped with a carboxylic acid handle, allowing mixtures of the building blocks to be spotted onto the surface of an amine functionalized glass slide for covalent immobilization as subunits of the binding environments. This strategy employs the microarray surface as the receptor synthesis platform, which allows for flexibility in array preparation and agility in application. An advantage of the CARA strategy is the enormous flexibility it enables in the construction of alternate microarray configurations, which facilitates rapid access to the breadth and depth of binding space. Four fluorescently labeled proteins, ubiquitin, myoglobin, alpha-1-acid glycoprotein and lysozyme, were incubated with the arrays to demonstrate the reproducibility of binding and the level of differentiation that can be achieved. The binding environments are stable, scalable, and adaptable to other formats.

Age-related increases in oxidative stress impair endothelium-dependent vasodilatation in humans, leading to the speculation that endothelial dysfunction contributes to impaired muscle blood flow and vascular control during exercise in older adults. We directly tested this hypothesis in 14 young (22 +/- 1 years) and 14 healthy older men and women (65 +/- 2 years). We measured forearm blood flow (FBF; Doppler ultrasound) and calculated vascular conductance (FVC) responses to single muscle contractions at 10, 20 and 40% maximum voluntary contraction (MVC) before and during ascorbic acid (AA) infusion, and we also determined the effects of AA on muscle blood flow during mild (10% MVC) continuous rhythmic handgrip exercise. For single contractions, the peak rapid hyperaemic responses to all contraction intensities were impaired approximately 45% in the older adults (all P < 0.05), and AA infusion did not impact the responses in either age group. For the rhythmic exercise trial, FBF (approximately 28%) and FVC (approximately 31%) were lower (P = 0.06 and 0.05) in older versus young adults after 5 min of steady-state exercise with saline. Subsequently, AA was infused via brachial artery catheter for 10 min during continued exercise. AA administration did not significantly influence FBF or FVC in young adults (1-3%; P = 0.24-0.59), whereas FBF increased 34 +/- 7% in older adults at end-exercise, and this was due to an increase in FVC (32 +/- 7%; both P < 0.05). This increase in FBF and FVC during exercise in older adults was associated with improvements in vasodilator responses to acetylcholine (ACh; endothelium dependent) but not sodium nitroprusside (SNP; endothelium independent). AA had no effect on ACh or SNP responses in the young. We conclude that acute AA administration does not impact the observed age-related impairment in the rapid hyperaemic response to brief muscle contractions in humans; however, it does significantly increase muscle blood flow during continuous dynamic exercise in older adults, and this is probably due (in part) to an improvement in endothelium-dependent vasodilatation.

Recent evidence suggests that adenosine triphosphate (ATP) can inhibit vasoconstrictor responses to endogenous noradrenaline release via tyramine in the skeletal muscle circulation, similar to what is observed in contracting muscle. Whether this involves direct modulation of postjunctional alpha-adrenoceptor responsiveness, or is selective for alpha(1)- or alpha(2)-receptors remains unclear. Therefore, in Protocol 1, we tested the hypothesis that exogenous ATP can blunt direct postjunctional alpha-adrenergic vasoconstriction in humans. We measured forearm blood flow (FBF; Doppler ultrasound) and calculated the vascular conductance (FVC) responses to local intra-arterial infusions of phenylephrine (alpha(1)-agonist) and dexmedetomidine (alpha(2)-agonist) during moderate rhythmic handgrip exercise (15% maximum voluntary contraction), during a control non-exercise vasodilator condition (adenosine), and during ATP infusion in eight young adults. Forearm hyperaemia was matched across all conditions. Forearm vasoconstrictor responses to direct alpha(1)-receptor stimulation were blunted during exercise versus adenosine (DeltaFVC = -11 +/- 3% versus -39 +/- 5%; P< 0.05), and were abolished during ATP infusion (-3 +/- 2%). Similarly, vasoconstrictor responses to alpha(2)-receptor stimulation were blunted during exercise versus adenosine (-13 +/- 4% versus -40 +/- 8%; P< 0.05), and were abolished during ATP infusion (-4 +/- 4%). In Prototol 2 (n = 10), we tested the hypothesis that graded increases in ATP would reduce alpha(1)-mediated vasoconstriction in a dose-dependent manner compared with vasodilatation evoked via adenosine. Forearm vasoconstrictor responses during low dose adenosine (-38 +/- 3%) and ATP (-33 +/- 2%) were not significantly different from rest (-40 +/- 3%; P> 0.05). In contrast, vasoconstrictor responses during moderate (-22 +/- 6%) and high dose ATP (-8 +/- 5%) were significantly blunted compared with rest, whereas the responses during adenosine became progressively greater (moderate = -48 +/- 4%, P = 0.10; high = -53 +/- 6%, P< 0.05). We conclude that exogenous ATP is capable of blunting direct postjunctional alpha-adrenergic vasoconstriction, that this involves both alpha(1)- and alpha(2)-receptor subtypes, and that this is graded with ATP concentrations. Collectively, these data are consistent with the conceptual framework regarding how muscle blood flow and vascular tone are regulated in contracting muscles of humans.

Purpose: To investigate the impact of body mass index (BMI) on pathologic and functional outcomes after robot-assisted laparoscopic prostatectomy (RALP)., Patients and Methods: We evaluated 400 consecutive patients who underwent RALP at the Mayo Clinic between 2002 and 2006. Patients were categorized as normal weight (BMI <25 kg/ m(2), n = 94), overweight (BMI 25-29.9 kg/m(2), n = 187), and obese (BMI >or=30 kg/m(2), n = 119). Clinicopathologic features of the groups were compared, and logistical regression analysis was used to assess the associations of BMI with pathologic and functional outcomes after RALP., Results: Overweight and obese patients were more likely to have pT(3/4) disease (P = 0.0024) and pathologic Gleason 7 to 10 cancers (P < 0.0001). Overall, 9/94 (9.6%) normal-weight patients had a positive surgical margin (SM), compared with 25/187 (13.4%) overweight patients and 21/119 (17.6%) obese men (P = 0.087). On multivariate analysis, however, increasing BMI was not significantly associated with an increased risk of positive SM (odds ratio 1.12, 95% confidence interval 0.72-1.76, P = 0.61). In addition, although obese men had longer operative times (P = 0.049) and greater intraoperative blood loss (P = 0.04), we found no association between BMI and transfusion requirement (P = 0.34), length of hospital stay (P = 0.54), or the rates of early (P = 0.37) or late (P = 0.86) complications. Moreover, in those patients with follow-up available at 1 year after RALP, obesity did not impact the return of continence (P = 0.62) or potency (P = 0.13)., Conclusion: BMI was not an independent predictor of positive SM, complications, incontinence, or erectile dysfunction after RALP. These data suggest that RALP may offer equivalent margin rates and functional outcomes for patients across BMI.

We tested the hypothesis that aging is associated with an impaired contraction-induced rapid vasodilation in healthy adults. We reasoned that employing single contractions of a small muscle mass would allow us to isolate the local rapid vasodilatory responses independent of systemic hemodynamic and sympathetic neural influences on forearm hemodynamics. We measured forearm blood flow (Doppler ultrasound) and arterial blood pressure (Finapres) on a beat-by-beat basis and calculated the changes in forearm vascular conductance (DeltaFVC) in response to forearm contractions in 18 young (24 +/- 1 yr) and 13 older (62 +/- 2 yr) healthy subjects. Single, 1-s dynamic forearm contractions were performed with the experimental arm slightly above heart level at 5, 10, 20, and 40% of the subjects' maximal voluntary contraction (MVC) in random order. In general, muscle contractions evoked a rapid increase in FVC that reached a peak within approximately four to five cardiac cycles postcontraction in both age groups. At 5% MVC, there were no significant age-related differences in contraction-induced forearm vasodilation. However, the peak vasodilatory responses were impaired approximately 40-45% in older adults at 10, 20, and 40% MVC, as were the total vasodilatory responses (area under curve approximately 40-50%; all P < 0.05). Additionally, the immediate vasodilation (first cardiac cycle postcontraction) for the 20% and 40% MVC trials was also impaired approximately 50% with age (P < 0.05). There were no significant age-group differences in MVC or forearm fat-free mass, and these variables were not correlated with local vasodilation within a given exercise intensity. Under the experimental conditions employed, the blunted responses with age reflect impaired local contraction-induced rapid vasodilation.

We tested the hypothesis that mechanical deformation of forearm blood vessels via acute increases in extravascular pressure elicits rapid vasodilatation in humans. In healthy adults, we measured forearm blood flow (Doppler ultrasound) and calculated forearm vascular conductance (FVC) responses to whole forearm compressions and isometric muscle contractions with the arm above heart level. We used several experimental protocols to gain insight into how mechanical factors contribute to contraction-induced rapid vasodilatation. The findings from the present study clearly indicate that acute increases in extravascular pressure (200 mmHg for 2 s) elicit a significant rapid vasodilatation in the human forearm (peak DeltaFVC approximately 155%). Brief, 6 s sustained compressions evoked the greatest vasodilatation (DeltaFVC approximately 260%), whereas the responses to single (2 s) and repeated compressions (five repeated 2 s compressions) were not significantly different (DeltaFVC approximately 155% versus approximately 115%, respectively). This mechanically induced vasodilatation peaks within 1-2 cardiac cycles, and thus is dissociated from the temporal pattern normally observed in response to brief muscle contractions ( approximately 4-7 cardiac cycles). A non-linear relation was found between graded increases in extravascular pressure and both the immediate and peak rapid vasodilatory response, such that the responses increased sharply from 25 to 100 mmHg, with no significant further dilatation until 300 mmHg (maximal DeltaFVC approximately 185%). This was in contrast to the linear intensity-dependent relation observed with muscle contractions. Our collective findings indicate that mechanical influences contribute largely to the immediate vasodilatation (first cardiac cycle) observed in response to a brief, single contraction. However, it is clear that there are additional mechanisms related to muscle activation that continue to cause and sustain vasodilatation for several more cardiac cycles after contraction. Additionally, the potential contribution of mechanical influences to the total contraction-induced hyperaemia appears greatest for low to moderate intensity single muscle contractions, and this contribution becomes less significant for sustained and repeated contractions. Nevertheless, this mechanically induced vasodilatation could serve as a feedforward mechanism to increase muscle blood flow at the onset of exercise, as well as in response to changes in contraction intensity, prior to alterations in local vasodilating substances that influence vascular tone.