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We report on the electrostatic trapping of neutral SrF molecules. The molecules are captured from a cryogenic buffer-gas beam source into the moving traps of a 4.5-m-long traveling-wave Stark decelerator. The SrF molecules in X^{2}Σ^{+}(v=0,N=1) state are brought to rest as the velocity of the moving traps is gradually reduced from 190  m/s to zero. The molecules are held for up to 50 ms in multiple electric traps of the decelerator. The trapped packets have a volume (FWHM) of 1  mm^{3} and a velocity spread of 5(1)  m/s, which corresponds to a temperature of 60(20) mK. Our result demonstrates a factor 3 increase in the molecular mass that has been Stark decelerated and trapped. Heavy molecules (mass>100  amu) offer a highly increased sensitivity to probe physics beyond the standard model. This work significantly extends the species of neutral molecules of which slow beams can be created for collision studies, precision measurement, and trapping experiments.

A measurement of the magnitude of the electric dipole moment of the electron (eEDM) larger than that predicted by the Standard Model (SM) of particle physics is expected to have a huge impact on the search for physics beyond the SM. Polar diatomic molecules containing heavy elements experience enhanced sensitivity to parity (P) and time-reversal (T)-violating phenomena, such as the eEDM and the scalar-pseudoscalar (S-PS) interaction between the nucleons and the electrons, and are thus promising candidates for measurements. The NL-eEDM collaboration is preparing an experiment to measure the eEDM and S-PS interaction in a slow beam of cold BaF molecules [P. Aggarwal et al., Eur. Phys. J. D 72, 197 (2018)]. Accurate knowledge of the electronic structure parameters, W d and W s , connecting the eEDM and the S-PS interaction to the measurable energy shifts is crucial for the interpretation of these measurements. In this work, we use the finite field relativistic coupled cluster approach to calculate the W d and W s parameters in the ground state of the BaF molecule. Special attention was paid to providing a reliable theoretical uncertainty estimate based on investigations of the basis set, electron correlation, relativistic effects, and geometry. Our recommended values of the two parameters, including conservative uncertainty estimates, are 3.13 ±0.12×10 24 Hzecm for W d and 8.29 ± 0.12 kHz for W s .

A supersonic beam source for SrF and BaF molecules is constructed by combining the expansion of carrier gas (a mixture of 2% SF 6 and 98% argon) from an Even-Lavie valve with laser ablation of a barium/strontium metal target at a repetition rate of 10 Hz. Molecular beams with a narrow translational velocity spread are produced at relative values of Δv/v = 0.053(11) and 0.054(9) for SrF and BaF, respectively. The relative velocity spread of the beams produced in our source is lower in comparison with the results from other metal fluoride beams produced in supersonic laser ablation sources. The rotational temperature of BaF is measured to be 3.5 K. The source produces 6 × 10 8 and 10 7 molecules per steradian per pulse in the X 2 Σ + (ν = 0, N = 1) state of BaF and SrF molecules, respectively, a state amenable to Stark deceleration and laser cooling.

The NL-eEDM collaboration is building an experimental setup to search for the permanent electric dipole moment of the electron in a slow beam of cold barium fluoride molecules [NL-eEDM Collaboration, Eur. Phys. J. D 72, 197 (2018)]. Knowledge of the molecular properties of BaF is thus needed to plan the measurements and, in particular, to determine the optimal laser-cooling scheme. Accurate and reliable theoretical predictions of these properties require the incorporation of both high-order correlation and relativistic effects in the calculations. In this work, theoretical investigations of the ground and lowest excited states of BaF and its lighter homologs, CaF and SrF, are carried out in the framework of the relativistic Fock-space coupled cluster and multireference configuration interaction methods. Using the calculated molecular properties, we determine the Franck-Condon factors (FCFs) for the A 2 Π 1/2 →X 2 Σ 1/2 + transition, which was successfully used for cooling CaF and SrF and is now considered for BaF. For all three species, the FCFs are found to be highly diagonal. Calculations are also performed for the B 2 Σ 1/2 + →X 2 Σ 1/2 + transition recently exploited for laser-cooling of CaF; it is shown that this transition is not suitable for laser-cooling of BaF, due to the nondiagonal nature of the FCFs in this system. Special attention is given to the properties of the A' 2 Δ state, which in the case of BaF causes a leak channel, in contrast to CaF and SrF species where this state is energetically above the excited states used in laser-cooling. We also present the dipole moments of the ground and excited states of the three molecules and the transition dipole moments (TDMs) between the different states. Finally, using the calculated FCFs and TDMs, we determine that the A 2 Π 1/2 →X 2 Σ 1/2 + transition is suitable for transverse cooling in BaF.

Rationale, Aims and Objectives: A physician-led clinic for the preoperative optimization and management of high-risk surgical patients was implemented in a South Australian public hospital in 2008. This study aimed to estimate the costs and effects of the clinic using a mixed retrospective and prospective observational study design., Method: Alternative propensity score estimation methods were applied to retrospective routinely collected administrative and clinical data, using weighted and matched cohorts. Supplementary survey-based prospective data were collected to inform the analysis of the retrospective data and reduce potential unmeasured confounding., Results: Using weighted cohorts, clinic patients had a significantly longer mean length of stay and higher mean cost. With the matched cohorts, reducing the calliper width resulted in a shorter mean length of stay in the clinic group, but the costs remained significantly higher. The prospective data indicated potential unmeasured confounding in all analyses other than in the most tightly matched cohorts., Conclusions: The application of alternative propensity-based approaches to a large sample of retrospective data, supplemented with a smaller sample of prospective data, informed a pragmatic approach to reducing potential observed and unmeasured confounding in an evaluation of a physician-led preoperative clinic. The need to generate tightly matched cohorts to reduce the potential for unmeasured confounding indicates that significant uncertainty remains around the effects of the clinic. This study illustrates the value of mixed retrospective and prospective observational study designs but also underlines the need to prospectively plan for the evaluation of costs and effects alongside the implementation of significant service innovations., (© 2016 John Wiley & Sons, Ltd.)

Circulating microRNAs (miRNAs) are emerging as useful non-invasive markers of disease. The objective of this study was to use a mouse model of prostate cancer as a tool to discover serum miRNAs that could be assessed in a clinical setting. Global miRNA profiling identified 46 miRNAs at significantly altered levels (p ≤ 0.05) in the serum of TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice with advanced prostate cancer compared to healthy controls. A subset of these miRNAs with known human homologues were validated in an independent cohort of mice and then measured in serum from men with metastatic castration-resistant prostate cancer (mCRPC; n = 25) or healthy men (n = 25). Four miRNAs altered in mice, mmu-miR-141, mmu-miR-298, mmu-miR-346 and mmu-miR-375, were also found to be at differential levels in the serum of men with mCRPC. Three of these (hsa-miR-141, hsa-miR-298 and hsa-miR-375) were upregulated in prostate tumors compared with normal prostate tissue, suggesting that they are released into the blood as disease progresses. Moreover, the intra-tumoral expression of hsa-miR-141 and hsa-miR-375 were predictors of biochemical relapse after surgery. This study is the first to demonstrate that specific serum miRNAs are common between human prostate cancer and a mouse model of the disease, highlighting the potential of such models for the discovery of novel biomarkers., (Copyright © 2011 UICC.)

The response of prostate cells to androgens reflects a combination of androgen receptor (AR) transactivation and transrepression, but how these two processes differ mechanistically and influence prostate cancer risk and disease outcome remain elusive. Given recent interest in targeting AR transrepressive processes, a better understanding of AR/corepressor interaction and responses is warranted. Here, we used transactivation and interaction assays with wild-type and mutant ARs, and deletion AR fragments, to dissect the relationship between AR and the corepressor, silencing mediator for retinoic acid and thyroid hormone receptors (SMRT). We additionally tested how these processes are influenced by AR agonist and antagonist ligands, as well as by variation in the polyglutamine tract in the AR amino terminal domain (NTD), which is encoded by a polymorphic CAG repeat in the gene. SMRT was recruited to the AR ligand binding domain by agonist ligand, and as determined by the effect of strategic mutations in activation function 2 (AF-2), requires a precise conformation of that domain. A distinct region of SMRT also mediated interaction with the AR-NTD via the transactivation unit 5 (TAU5; residues 315-538) region. The degree to which SMRT was able to repress AR increased from 17% to 56% as the AR polyglutamine repeat length was increased from 9 to 42 residues, but critically this effect could be abolished by increasing the SMRT:AR molar ratio. These data suggest that the extent to which the CAG encoded polyglutamine repeat influences AR activity represents a balance between corepressor and coactivator occupancy of the same ligand-dependent and independent AR interaction surfaces. Changes in the homeostatic relationship of AR to these molecules, including SMRT, may explain the variable penetrance of the CAG repeat and the loss of AR signaling flexibility in prostate cancer progression., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To determine the prevalence of, and associated risk factors for, voiding and storage lower urinary tract symptoms (LUTS) in a population-based sample of Australian men., Methods: Data were collected from 1,103 men randomly selected, community-dwelling men, as part of the Florey Adelaide Male Ageing Study, after exclusion of men with prostate or bladder cancer or prior surgery to either organ. The presence of LUTS was assessed using the International Prostate Symptom Score. Urine flow was measured via flow meter. Demographic, clinical, and bio-psychosocial data were collected by questionnaire., Results: The prevalence of total, storage, and voiding LUTS was 18.1, 28.0 and 12.6%, respectively. The most common storage symptoms were frequency (12.3%), nocturia (9.9%) and urgency (8.1%), and voiding symptoms were weak stream (8.5%), intermittency (5.4%), incomplete emptying (5.1%) and straining (2.4%). There were linear associations between storage LUTS and increased abdominal fat mass, plasma glucose and low HDL cholesterol (components of the metabolic syndrome), obstructive sleep apnoea (OSA) risk, and retirement. Voiding symptoms were associated with a previous diagnosis of benign prostatic enlargement (BPH), mean peak urine flow, total energy intake, elevated risk of OSA, erectile dysfunction, physician-diagnosed thyroid dysfunction and higher household income., Conclusions: The close association of storage LUTS with the metabolic syndrome, and of both storage and voiding LUTS with OSA, suggest that these conditions should be considered in men presenting with LUTS.

Background: Epigenetic alterations are common in prostate cancer, yet how these modifications contribute to carcinogenesis is poorly understood. We investigated whether specific histone modifications are prognostic for prostate cancer relapse, and whether the expression of epigenetic genes is altered in prostate tumorigenesis., Methods: Global levels of histone H3 lysine-18 acetylation (H3K18Ac) and histone H3 lysine-4 dimethylation (H3K4diMe) were assessed immunohistochemically in a prostate cancer cohort of 279 cases. Epigenetic gene expression was investigated in silico by analysis of microarray data from 23 primary prostate cancers (8 with biochemical recurrence and 15 without) and 7 metastatic lesions., Results: H3K18Ac and H3K4diMe are independent predictors of relapse-free survival, with high global levels associated with a 1.71-fold (P < 0.0001) and 1.80-fold (P = 0.006) increased risk of tumor recurrence, respectively. High levels of both histone modifications were associated with a 3-fold increased risk of relapse (P < 0.0001). Epigenetic gene expression profiling identified a candidate gene signature (DNMT3A, MBD4, MLL2, MLL3, NSD1, and SRCAP), which significantly discriminated nonmalignant from prostate tumor tissue (P = 0.0063) in an independent cohort., Conclusions: This study has established the importance of histone modifications in predicting prostate cancer relapse and has identified an epigenetic gene signature associated with prostate tumorigenesis., Impact: Our findings suggest that targeting the epigenetic enzymes specifically involved in a particular solid tumor may be a more effective approach. Moreover, testing for aberrant expression of epigenetic genes such as those identified in this study may be beneficial in predicting individual patient response to epigenetic therapies., (©2010 AACR.)

Background: Knowledge of preanalytic conditions that biospecimens are subjected to is critically important because novel surgical procedures, tissue sampling, handling, and storage might affect biomarker expression or invalidate tissue samples as analytes for some technologies., Methods: We investigated differences in RNA quality, gene expression by quantitative real-time PCR, and immunoreactive protein expression of selected prostate cancer biomarkers between tissues from retropubic radical prostatectomy (RRP) and robot-assisted laparoscopic prostatectomy (RALP). Sections of tissue microarray of 23 RALP and 22 RRP samples were stained with antibodies to androgen receptor (AR) and prostate-specific antigen (PSA) as intersite controls, and 14 other candidate biomarkers of research interest to three laboratories within the Australian Prostate Cancer BioResource tissue banking network. Quantitative real-time PCR was done for AR, PSA (KLK3), KLK2, KLK4, and HIF1A on RNA extracted from five RALP and five RRP frozen tissue cores., Results: No histologic differences were observed between RALP and RRP tissue. Biomarker staining grouped these samples into those with increased (PSA, CK8/18, CKHMW, KLK4), decreased (KLK2, KLK14), or no change in expression (AR, ghrelin, Ki67, PCNA, VEGF-C, PAR2, YB1, p63, versican, and chondroitin 0-sulfate) in RALP compared with RRP tissue. No difference in RNA quality or gene expression was detected between RALP and RRP tissue., Conclusions: Changes in biomarker expression between RALP and RRP tissue exist at the immunoreactive protein level, but the etiology is unclear., Impact: Future studies should account for changes in biomarker expression when using RALP tissues, and mixed cohorts of RALP and RRP tissue should be avoided.

The androgen receptor (AR) is an important signaling molecule in multiple tissues, yet its mode of action and cell-specific activities remain enigmatic. AR function has been best studied in the prostate, in which it is essential for growth and homeostasis of the normal organ as well as each stage of cancer development. Investigation of mechanisms responsible for continued AR action that evolve during prostate cancer progression or after hormonal management of the disease have been instructive in defining AR signaling pathways. In the current paper, we use sequence similarity and the collocation of somatic mutations in prostate cancer to define residues 501-535 of the AR amino-terminal domain as an important mediator of receptor function. Specifically, the 501-535 region is required for optimal interaction of the amino-terminal domain with both the p160 coactivator, nuclear receptor coactivator-2, and the AR-ligand binding domain in the amino/carboxyl (N/C) interaction. The N/C interaction is decreased by deletion of the 501-535 region but is distinct from deletion of the (23)FQNLF(27) peptide in that it does not affect the capacity of the AR to activate transcription from a chromatin integrated reporter or recruitment of the receptor to androgen-responsive loci in vivo. Collectively, we have been able to outline two classes of N/C-deficient AR variant that are divergent in their capacity to act in a chromatin context, thereby further defining the interplay between N/C interaction and coregulator recruitment via multiple receptor domains. These mechanisms are likely to be key determinants of the cell and promoter specific activities of the AR.

Background: Previous studies from our laboratory demonstrated a strong association between an elevated level of chondroitin sulfate (CS) in peritumoral stroma and PSA-relapse in patients with early stage disease. In this study we determined whether CS levels could predict overall survival in men diagnosed with advanced prostate cancer subsequently treated by orchiectomy alone., Methods: CS was localized in archived prostatic tissues by immunohistochemistry, and the level of CS expression as measured by video image analysis was compared in cohorts of 157 and 60 men with early stage or advanced disease, respectively., Results: The CS levels in the peritumoral stroma of patients without relapse after treatment for early stage disease was significantly reduced compared to levels in prostate tissue from patients who either relapsed (P = 0.003) or were diagnosed with advanced prostate cancer (P < 0.00001). There was no difference between the median CS level in the peritumoral prostatic stroma of early stage patients that relapsed after treatment and patients diagnosed with advanced prostate cancer. Increased CS levels (P < 0.0001) and high Gleason score (P < 0.0001) were associated with an increased rate of PSA-relapse in the cohort of patients with early stage disease. However, neither CS level nor Gleason score alone or in combination could predict survival outcome in patients with advanced prostate cancer following androgen deprivation therapy., Conclusions: Although peritumoral CS levels and Gleason score are strong predictors of relapse-free survival in early stage prostate cancer patients, neither peritumoral CS levels nor Gleason score can predict survival outcome in patients with advanced disease., (2009 Wiley-Liss, Inc.)

Objective: To describe trends in prostate-specific antigen (PSA) testing, prostate cancer incidence and mortality in New South Wales., Design and Setting: Descriptive analysis using routinely collected data of observed trends in PSA testing from 1989 to 2006, and prostate cancer cases and deaths from 1972 to 2005 in NSW., Main Outcome Measures: Age-standardised and age-specific rates and joinpoint regression to identify changes in trends; projected trends observed before the introduction of PSA testing to quantify its impact on incidence and mortality rates., Results: The number of PSA tests per year more than doubled between 1994 and 2006. Age-standardised incidence of prostate cancer peaked in 1994, fell by 10.0% per year to 1998 and then increased by 4.9% per year from 2001 to 2005. An estimated 19 602 (43%) more men than expected from preceding trends were diagnosed with prostate cancer between 1989 and 2005 after PSA testing was introduced. The incidence of recorded advanced prostate cancer at diagnosis fell from 13.0 per 100,000 men in 1987-1991 to 7.0 per 100,000 men in 2002-2005. The age-standardised mortality from prostate cancer increased by 3.6% per year between 1984 and 1990 and then fell by 2.0% per year to 2005., Conclusions: There was a sustained increase in prostate cancer incidence in NSW after PSA testing was introduced. While falls in the incidence of advanced disease at diagnosis and mortality from prostate cancer after 1993 are consistent with a benefit from PSA testing, other explanations cannot be excluded.

The glycosaminoglycan chondroitin sulfate is significantly increased in the peritumoral stroma of prostate tumors compared with normal stroma and is an independent predictor of prostate-specific antigen (PSA) relapse following radical prostatectomy. In this study, we determined whether specific alterations in the sulfation pattern of glycosaminoglycan chains in clinically organ-confined prostate cancer are associated with PSA relapse. Immunoreactivity to distinct glycosaminoglycan disaccharide epitopes was assessed by manually scoring the staining intensity in prostate tissues from patients with benign prostatic hyperplasia (n = 19), early-stage cancer (cohort 1, n = 55 and cohort 2, n = 275), and advanced-stage cancer (n = 20). Alterations to glycosaminoglycans in benign and malignant prostate tissues were determined by cellulose acetate chromatography and high-pressure liquid chromatography. Glycosaminoglycan disaccharide epitopes were localized to the peritumoral stroma of clinically localized prostate cancer. The level of immunostaining for unsulfated disaccharides (C0S) in the peritumoral stroma, but not for 4-sulfated (C4S) or 6-sulfated disaccharides (C6S), was significantly associated with the rate of PSA relapse following radical prostatectomy. High levels of C0S immunostaining were determined to be an independent predictor of PSA relapse (1.6-fold, P = 0.020). Advanced-stage prostate cancer tissues exhibited reduced electrophoretic mobility for chondroitin sulfate and increased unsulfated disaccharides when compared with benign prostatic hyperplasia tissues, whereas the sulfated disaccharide levels were unaffected. The level of C0S immunostaining in the peritumoral stroma is an independent determinant of PSA failure in clinically localized prostate cancer. Specific alterations to chondroitin sulfate side chains occurring during tumor development may be a crucial step for disease progression in prostate cancer.

Background: In this study, we investigated the expression of HER-2/neu and AR in clinically organ-confined prostate cancer to determine whether alterations in these signaling pathways contribute to the development of metastatic disease., Methods: HER-2/neu and AR immunoreactivity were evaluated in archived prostatic tissues obtained from 53 men with clinically organ-confined disease who underwent radical prostatectomy. Associations between AR and HER-2/neu immunostaining and disease outcome were determined., Results: Seventy percent (37/53) of tumors exhibited high levels of HER-2/neu immunostaining and 68% (36/53) of tumors had elevated AR levels. Patients with high levels of both HER-2/neu and AR had the highest rate of PSA failure (56%, 15/27) compared with no PSA failures amongst seven patients with low levels of both HER-2/neu and AR (log rank statistic 7.69, P = 0.021). Concurrent high levels of HER-2/neu and AR expression were significantly associated with high pathological stage (P = 0.027) and development of metastatic disease (P = 0.022)., Conclusions: These findings support the notion that both the HER-2/neu and AR signaling pathways may contribute to development of metastatic disease. The subset of prostate tumors with increased HER-2/neu and AR levels may benefit from treatment strategies that target both signaling pathways., ((c) 2008 Wiley-Liss, Inc.)

Although the androgen receptor (AR) is accepted as the major determinant of prostate cancer cell survival throughout disease progression, it is currently unclear how the receptor sustains genomic signaling under conditions of systemic androgen ablation. Here, we show that the evolutionarily conserved Hsp70/Hsp90 cochaperone, small glutamine-rich tetratricopeptide repeat containing protein alpha (alphaSGT), interacts with the hinge region of the human AR in yeast and mammalian cells. Overexpression and RNA interference revealed that alphaSGT acts to (a) promote cytoplasmic compartmentalization of the AR, thereby silencing the receptors basal/ligand-independent transcriptional activity, (b) regulate the sensitivity of receptor signaling by androgens, and (c) limit the capacity of noncanonical ligands to induce AR agonist activity. Immunofluorescence, coactivator, and chromatin immunoprecipitation analyses strongly suggest that these effects of alphaSGT on AR function are mediated by interaction in the cytoplasm and are distinct from the receptors response to classic coregulators. Quantitative immunohistochemical analysis of alphaSGT and AR levels in a cohort of 32 primary and 64 metastatic human prostate cancers revealed dysregulation in the level of both proteins during disease progression. The significantly higher AR/alphaSGT ratio in metastatic samples is consistent with the sensitization of prostate tumor cells to androgen signaling with disease progression, particularly in a low-hormone environment. These findings implicate alphaSGT as a molecular rheostat of in vivo signaling competence by the AR, and provide new insight into the determinants of androgen sensitivity during prostate cancer progression.

Previous studies have demonstrated that high levels of hyaluronan (HA) and the chondroitin sulfate proteoglycan, versican in the peritumoral stroma are associated with metastatic spread of clinical prostate cancer. In vitro integration of HA and versican into a pericellular sheath is a prerequisite for proliferation and migration of vascular smooth muscle cells. In this study, a particle exclusion assay was used to determine whether human prostate cancer cell lines are capable of assembling a pericellular sheath following treatment with versican-containing medium and whether formation of a pericellular sheath modulated cell motility. PC3 and DU145, but not LNCaP cells formed prominent polarized pericellular sheaths following treatment with prostate fibroblast-conditioned medium. The capacity to assemble a pericellular sheath correlated with the ability to express membranous HA receptor, CD44. HA and versican histochemical staining were observed surrounding PC3 and DU145 cells following treatment with prostatic fibroblast-conditioned medium. The dependence on HA for integrity of the pericellular sheath was demonstrated by its removal following treatment with hyaluronidase. Purified versican or conditioned medium from Chinese hamster ovary K1 cells overexpressing versican V1, but not conditioned medium from parental cells, promoted pericellular sheath formation and motility of PC3 cells. Using time lapse microscopy, motile PC3 cells treated with versican but not non-motile cells exhibited a polar pericellular sheath. Polar pericellular sheath was particularly evident at the trailing edge but was excluded from the leading edge of PC3 cells. These studies indicate that prostate cancer cells recruit stromal components to remodel their pericellular environment and promote their motility.

Background: Proteoglycans are structural and informational molecules important during embryogenesis and organ maturation. Maturation of the prostate is influenced by androgens and estrogens, but changes in the relative spatiotemporal expression of steroid receptors and proteoglycans during hormonal change are unexplored., Methods: Guinea pig prostate was used to define hormone-induced changes in the expression of androgen (AR) and estrogen (ER(alpha)) receptors, chondroitin sulfate (CS) glycosaminoglycan and core proteins of versican and syndecan-1. Tissue locations of AR, ER(alpha), CS and the proteoglycans versican and syndecan-1 were determined by immunohistochemistry. Cellular content of ER(alpha) and syndecan-1 was assessed visually. Versican, CS56 epitope, and AR were quantified by image analysis., Results: AR expression within prostate epithelial and stromal cell nuclei decreased following castration and increased following treatment of castrate animals with dihydrotestosterone (DHT). ER(alpha) expression was restricted to prostate stromal cell nuclei and decreased during puberty, and following treatment of castrate animals with DHT. Versican was present in periacinar stroma immediately peripheral to basal epithelial cells, fibromuscular stromal tissue bands surrounding acinar units, and loose fibrovascular connective tissue interspersed between individual acini. Versican and native CS expression decreased (>10-fold) in periacinar stroma during puberty and following administration of DHT to castrated animals. Expression of syndecan-1 was restricted to fibromuscular cells of prostate stroma, and remained constant during puberty and hormone manipulation., Conclusions: ER(alpha), versican core protein and CS side chain epitopes are negatively regulated in prostate stromal tissue by DHT, whilst AR levels are positively regulated., ((c) 2006 Wiley-Liss, Inc.)

Background: Although up to 30% of men who undergo radical prostatectomy for clinically organ-confined prostate cancer will relapse with disseminated disease, currently it is not possible to predict these patients., Methods: Androgen receptor (AR) immunoreactivity in stromal and epithelial compartments of tumor foci was evaluated by video image analysis in 53 radical prostatectomy specimens. Kaplan-Meier and Cox Regression analyses were used to determine whether AR immunostaining was related to rate and risk of relapse, respectively., Results: Ninety-eight percent (52/53) of the tumors contained AR positive malignant epithelial cells. Kaplan-Meier analysis indicated that patients with high AR levels (>64% AR positive nuclear area) in the malignant epithelial cells or low AR levels (

In this study, we examined whether versican, a recognized anti-cell adhesive molecule for various mesenchymal and nerve cell types, influences prostate cancer cell adhesion to extracellular matrix components. Prostate cancer cell adhesion to fibronectin, a major component of the stromal extracellular matrix was inhibited by versican-rich conditioned medium (CM) from cultured human prostatic fibroblasts. In contrast, cancer cell attachment to laminin, a component of basement membranes, was not affected by the same CM. Consistent with versican being the active inhibitory factor in the CM, the integrity of chondroitin sulfate side chains and an ability to bind the RGD (Arg-Gly-Asp) peptide sequence of fibronectin were essential for the inhibition of prostate cancer cell attachment to fibronectin. Subsequent studies with versican purified from human prostate fibroblast CM confirmed its anti-adhesive activity. We conclude that versican is an important modulator of tumor cell attachment to the interstitial stromal matrix of the prostate, the latter being an essential step in cancer cell motility and local invasion of the prostatic stroma.

Objective: To assess the value of preoperative symptom score assessment and pressure-flow measurement in men undergoing transurethral prostatectomy (TURP)., Patients and Methods: In a prospective study, 95 men (mean age 74.3 years) scheduled for TURP because of their lower urinary tract symptoms, flow rates and urinary residual volumes were assessed using the self-administered International Prostate Symptom Score (IPSS) and urodynamic pressure-flow studies. At 3 months after TURP the patients were reassessed with a flow rate measurement and the IPSS. The baseline IPSS and urodynamic values were analysed with respect to the endpoints of the study, flow rate and IPSS after TURP, and the improvements thereof, respectively., Results: There were significant improvements in mean IPSS (- 10.87 points) and peak flow rate (+ 7.06 mL/s) 3 months after TURP. Classifying the patients into subgroups with distinctly different initial values for IPSS, flow rate, residual urine volume and degree of obstruction (as expressed by Abrams-Griffiths number) showed that the flow rate and degree of obstruction influenced the improvement in flow rate but not in symptoms after TURP. Symptom improvement was only related to the initial level of symptoms. In a multivariate analysis, only age was an independent predictor of the outcome variables of flow rate and symptoms., Conclusions: Clinical decision-making remains a valid instrument for selecting patients for TURP. Both the IPSS and pressure-flow assessment are useful to exclude patients who are unlikely to benefit from TURP. Age is an important predictor of the improvement in symptoms and flow rates after TURP for the lower urinary tract symptom complex associated with benign prostatic enlargement.

Hyperuricosuria has long been documented as a predisposing factor to calcium oxalate (CaOx) stone pathogenesis. However, its mechanism is still without sound scientific foundation. Previously, we showed that hyperuricosuria, simulated by the addition of dissolved sodium urate, promotes the crystallization of CaOx. In the present study, we demonstrate that the urate's effect on the crystallization is attributable to its salting out CaOx from solution. Furthermore, analysis of urines revealed that their metastable limit decreased with increases in the product of the prevailing concentrations of calcium and urate: this has implications for CaOx stone genesis. We also outline anti-salting out strategies for future research for the prevention and/or treatment of CaOx calculi.

Consistent with both the development of the normal prostate gland and prostate tumorigenesis being dependent on testicular androgens, targeting the androgen-signaling axis (i.e., androgen ablation therapy) remains the predominant treatment regime for patients with metastatic prostate cancer. Although there is a very good initial response to androgen ablation, these treatments are essentially palliative. Recent evidence suggests that treatment failure may not result from a loss of androgen signaling but, rather, from the acquisition of genetic changes that lead to aberrant activation of the androgen-signaling axis. A consistent finding is that androgen receptor (AR) gene mutations, present in metastatic prostate cancer and in human prostate cancer cell lines as well as in xenograft and other animal models, result in decreased specificity of ligand-binding and inappropriate receptor activation by estrogens, progestins, adrenal androgens, glucocorticoids and/or AR antagonists. Because a significant proportion of missense mutations in the AR gene reported in prostate cancer collocate to the signature sequence and AF-2, two discrete regions of the ligand-binding domain critical for androgen signaling, we recently proposed that collocation of mutations identified in prostate cancer would identify additional regions of the AR important in receptor function. This approach led to the identification of a four-amino acid region at the boundary of the hinge and ligand-binding domains of the receptor that forms half of a potential protein-protein binding site. AR gene mutations have also been identified that collocate to areas in the DNA-binding domain, to the NH(2)-terminal transactivation domain, and to the hinge region in prostate tumors. In nearly every case, missense mutations in the AR gene identified in prostate cancer that collocate to discrete regions of the receptor contribute to altered androgen signaling and provide a potential mechanism to explain the reemergence of tumor growth during the course of hormone ablation therapies.

The external appearance of urinary calcium oxalate (CaOx) crystals suggests that they are solid, homogeneous structures, despite their known association with proteins. Our aim was to determine whether proteins comprising the organic matrix of CaOx crystals are superficial or intracrystalline in order to clarify the role of urinary proteins in the formation of kidney stones. CaOx crystals were precipitated from centrifuged and filtered, or ultrafiltered, healthy human urine. They were then treated with dilute NaOH to remove bound proteins, partially demineralized with EDTA, or fractured and subjected to limited proteolysis before examination by low-resolution scanning electron microscopy or field emission scanning electron microscopy. Crystals precipitated from centrifuged and filtered urine had a complex interior network of protein distributed throughout the mineral phase, which appeared to comprise closely packed subcrystalline particles stacked in an orderly array among an amorphous organic matrix. This ultrastructure was not evident in crystals deposited in the absence of macromolecules, which were completely solid. This is the first direct evidence that crystals generated from cell-free systems contain significant amounts of protein distributed throughout a complex internal cribriform ultrastructure. Combined with mineral erosion in the acidic lysosomal environment, proteins inside CaOx crystals would render them susceptible to attack by urinary and intracellular renal proteases and facilitate their further dissolution or disruption into small particles and ions for removal by exocytosis. The findings also have broader ramifications for industry and the materials sciences, as well as the development and resorption of crystals in biomineralization systems throughout nature., (Copyright 2001 Academic Press.)

The androgen receptor (AR), a member of the steroid receptor superfamily of nuclear transcription factors, mediates androgen signaling in diverse target tissues. Here we report AR gene mutations identified in human prostate cancer and the autochthonous transgenic adenocarcinoma of the mouse prostate model that colocate to residues (668)QPIF(671) at the boundary of the hinge and ligand-binding domain, resulting in receptors that exhibit 2- to 4-fold increased activity compared with wild-type AR in response to dihydrotestosterone, estradiol, progesterone, adrenal androgens, and the AR antagonist, hydroxyflutamide, without an apparent effect on receptor levels, ligand binding kinetics, or DNA binding. The expression of these or similar variants could explain the emergence of hormone refractory disease in a subset of patients. Homology modeling indicates that amino acid residues (668)QPIF(671) form a ridge bordering a potential protein-protein interaction surface. The naturally occurring AR gene mutations reported in this study result in decreased hydrophobicity of this surface, suggesting that altered receptor-protein interaction mediates the precocious activity of the AR variants.

The ultimate aim of our research is to understand the role of macromolecules in the formation of human kidney stones, particularly their interactions with calcium oxalate (CaOx) crystals. The invariable association of stones with proteins raises the possibility that proteins play a role in their formation, similar to the role of proteins in healthy biomineralization. Do these proteins induce mineralization? Are they merely a response to the disease process? Or are they protective molecules that were overwhelmed by mineral supersaturation? A protein of particular interest is fragment 1 (F1) of prothrombin. We have shown that mRNA for prothrombin is present in the kidney. Because the F1 fragment of prothrombin present in urine is slightly different from that found in the blood, we refer to this protein as "urinary prothrombin fragment 1" (UPTF1). Available evidence suggests that the kidney manufactures the protein for protection against stone disease and that the protein has a directive role in stone formation. We now have evidence that proteins are interred within CaOx crystals precipitated from human urine, where it is distributed in continuous channels. These proteins could facilitate crystal deconstruction and removal after attachment to the renal epithelium and endocytosis. We suspect that the formation of CaOx crystals in the urine is a normal process designed to permit harmless disposal of an excess of calcium, oxalate, or both. The incorporation of proteins provides a second line of defense against stone formation by enabling the destruction and removal of retained crystals. Understanding the basic molecular strategies by which plants produce protein-containing CaOx crystals may provide insight into human CaOx stone formation.

Incidentally discovered adrenal masses often pose a diagnostic challenge in the asymptomatic patient. The majority represent functional adrenal adenomas but primary or secondary malignancy must be considered. Bilateral incidentalomas are rare, and a case of asymptomatic bilateral adrenal melanoma metastases is presented. The diagnostic and treatment strategies relevant to this clinical problem are presented and discussed., (Copyright 2000 S. Karger AG, Basel)

Objectives: To identify predictors of poor symptomatic improvement after transurethral resection of the prostate (TURP), we investigated mucosal cell abnormalities in men about to undergo this procedure, and any association between these abnormalities and pre- and postoperative urinary tract symptoms., Methods: Bladder lavages were obtained from patients undergoing TURP for outflow obstruction during 1995 to 1996 at the Repatriation General Hospital. Pressure flow studies were obtained preoperatively, and International Prostate Symptom Scores and flow rates were obtained preoperatively and 3 months and 2 years postoperatively. Cells from bladder washings were examined flow-cytometrically for Tn antigen expression and DNA cell cycle parameters., Results: Of 192 patients recruited, 145 met the inclusion criteria. The frequency of Tn antigen expression, aneuploidy, and tetraploid aneuploidy in bladder mucosal cell washings in this group was comparable to a previous study. Weak, statistically significant associations were found between S-phase fraction and the initial International Prostate Symptom Score irrespective of whether total S-phase fraction cell numbers or categories were used. The trend of each of these associations was consistent (ie, patients with higher S-phase fraction values had more severe symptoms, poorer quality of life, and lower flow rates). The association was maintained at 3 months postoperatively but not at 2 years. Potential confounding factors did not explain the association., Conclusions: Bladder mucosal cell abnormalities can be found in men selected to undergo TURP to relieve obstruction and are associated with poor short-term symptomatic outcome. Further studies are needed to confirm these findings, in particular any association between higher mucosal cell proliferation rates and the presence of lower urinary tract symptoms.

Objective: To determine the natural course of patients with subjectively disappointing early results after transurethral prostatectomy (TURP), who experience prolonged discomfort and an initial deterioration in symptoms., Patients and Methods: A consecutive series of 127 patients undergoing urodynamic studies and TURP were assessed 3 months after surgery using symptom scores and measurements of urinary flow rate; 107 patients reported improved symptom and quality-of-life scores, but 20 did not improve, with no change or a deterioration. These 20 patients were followed for several months using symptom scores, and measurements of flow rates and residual urine volumes. Baseline variables, including preoperative urodynamic studies, were compared between those who improved and those who did not., Results: Over a mean (range) follow-up of 10.6 (6-15) months, all those initially not improving showed spontaneous improvement in all three variables with no further treatment and eventually achieved the same significant degree of improvement as those who improved soon after TURP. Preoperatively, those initially not improving had mean lower symptom scores, more bladder irritability and less obstruction than did those who improved., Conclusion: A significant proportion (approximately 15%) of patients with obstructive symptoms will experience considerable symptomatic discomfort for a prolonged period after an uncomplicated TURP and will not gain the full symptomatic benefit from the procedure until 6-9 months afterward.

Objective: To investigate the prevalence of erectile dysfunction (ED) in the South Australian community, and the influence of demographic and other risk factors., Design: Survey by mailed questionnaire (based on the University of California, Los Angeles prostate cancer index) of a subset (men who agreed to participate) of a probability sample of the South Australian community who completed a multiuser interview survey., Participants and Setting: Men over the age of 40 in South Australia., Main Outcome Measures: Sexual desire, orgasm, ability to have an erection, adequacy (firmness) of erections for intercourse, frequency of erections when wanted, frequency of intercourse, nocturnal or morning erections, and history of prostate surgery; total sexual function score based on these., Results: 612 men (86.7%) agreed to answer the sexual function survey; 427 (69.8%) returned questionnaires. ED was strongly correlated with age in all seven domains of sexual function. Erections inadequate for intercourse affected 3% of 40-49-year-olds, increasing to 64% of 70-79-year-olds. The frequency of intercourse considered normal for age by men 50-69 years was 1-6 times weekly; the disparity between this and reported frequency increased in men over 60 years, as did the difference between sexual desire and potency. A history of vigorous exercise was protective across all ages. High triglyceride levels, blood pressure medication and non-cancer surgery for prostate disease were independent predictors of poor sexual function at older ages. High cholesterol level was an independent predictor of impotence., Conclusions: We found similar or higher levels of ED than in comparable overseas studies. Disparity between potency and desire was greatest, and hence the age group in whom demand for treatment may be highest, in those 60 years and older. Cardiovascular risk factors were predictors of ED in these older men, suggesting that prevention may benefit sexual function. Non-cancer prostate surgery may be a greater contributor to ED than previously realised.

The disease course of localized prostate cancer is highly variable, and patients potentially curable by aggressive management are not readily identified by current clinical practice. Chondroitin sulfate (CS) glycosaminoglycan is a candidate biomarker as elevated levels of CS in peritumoral stroma of prostate cancer have been associated with prostate-specific antigen (PSA) failure. Immunoreactive CS was measured using image analysis of archived radical prostatectomy tissues, obtained from 157 men with a median of 47 months (range, 16-111 months) clinical follow-up. CS level, Gleason score, and preoperative serum PSA levels were independent predictors of PSA failure by Cox's multivariate analysis. Patients with low CS levels had significantly fewer PSA failures after radical prostatectomy than patients with high levels of CS (Kaplan-Meier plot; 32% PSA failures at 5 years for CS mean integrated absorbance cut point < 7.0 versus 50% for CS > or = 7.0, P = 0.0001). In the subgroup of patients with preoperative serum PSA levels < 10 ng/ml, CS was particularly useful in discriminating retrospectively those patients most suited for surgery (Kaplan-Meier plot; 14% PSA failures at 5 years for CS mean integrated absorbance cut point < 7.0 versus 47% for CS > or = 7.0, P = 0.0001). We conclude that measurements of CS level can assist in predicting patient outcome after surgery. Additionally, our data suggest that the combination of CS and PSA measurements may improve outcome prediction for patients with intermediate Gleason scores.

Objective: To determine the prevalence and other characteristics of self-reported blood testing (prostate-specific antigen [PSA]) for prostate cancer in the community., Design: Interview-based prevalence study., Participants and Setting: 695 men aged 40 years and over in the Spring 1996 South Australian Health Omnibus survey of a probability sample of 3011 households, weighted to reflect the age and sex distribution of the South Australian population., Outcome Measures: Number of men who had a PSA test in the preceding 12 months; number of first tests; the person initiating and performing the test; knowledge of the next step if test result abnormal; number of men visiting doctor for lower urinary tract symptoms in the preceding 12 months., Results: 20.3% of participants reported having a PSA test in the preceding 12 months; 62.1% were first tests. Prevalence of testing was highest in the age group 70-79 years (35.8%). Most tests were initiated by the general practitioner (41.2%) and by patients (35.7%). Of those tested, 45.3% had inadequate knowledge of the next step. Visiting a doctor for urinary symptoms was significantly associated with PSA testing (P < 0.001): 47.7% of men who visited a doctor for urinary symptoms had been tested compared with only 17.4% of those who did not visit the doctor for this problem. Only age and visiting a doctor for urinary symptoms were significant independent predictors of having a PSA test., Conclusions: Investigation of lower urinary tract symptoms contributed substantially to PSA testing, and those tested did not adequately understand the consequences. Our findings suggest a need for a better framework for PSA testing in general practice, including all important elements of decision-making, such as evidence and patient preference, as well as the means to ensure adequate patient counselling before testing.

An abnormally raised 24-h urinary excretion of calcium has long been regarded as a common feature of calcium stone disease. However, hypercalciuria can be defined only by reference to a range of values measured in a representative population of individuals who have never suffered from stone disease. To date, there have been significant flaws in all published studies reporting normal ranges for daily urinary calcium excretion. There is no doubt that additional, carefully performed and documented investigations need to be undertaken to establish what is truly abnormal for a given population; the persistent use of arbitrarily defined limits may be hindering rather than helping to unravel the role of calcium in the pathogenesis of calcium stones.

Patients with clinically localized prostate cancer who might be cured by aggressive management are not easily identified using current clinical information. Additional, more accurate, biomarkers of tumor behavior need to be identified to improve clinical outcome. Our previous studies indicated that the concentration of the glycosaminoglycan chondroitin sulfate in prostatic stroma might be a useful biomarker of disease progression in early-stage prostate cancer. In this study, two chondroitin sulfate proteoglycans, versican and decorin, were investigated. Versican and decorin were immunolocalized to the periacinar and peritumoral fibromuscular stroma in sections of nonmalignant and malignant human prostate tissues. Video image measurements indicated that the concentrations of both proteoglycans were increased in the prostatic tissue of men with early-stage prostate cancer compared with tissue from men without cancer (P = 0.0006). Cox's univariate analysis indicated that increases in versican concentration but not in that of decorin were associated with increased risk of prostate-specific antigen (PSA) progression. Versican concentration was compared with other clinical or biological features of prognosis in two-variable regression analyses. Versican and serum PSA concentrations were independent predictors of PSA progression. Versican was a stronger prognostic factor than tumor grade, and it could predict outcome for patients with moderately differentiated tumors. Patients with low versican concentration had significantly better progression-free survival than patients with high levels of versican (Kaplan-Meier plot, 89% versus 27% PSA progression-free at 5 years, respectively; P = 0.0001). We conclude that the measurement of prostatic concentrations of versican, a molecule with reported anticellular adhesive properties, may be a useful marker of disease progression in patients with early-stage prostate cancer and that further study of versican in other patient cohorts is warranted.

Purpose: To determine the cellular distribution and levels of immunohistochemical staining for apolipoprotein D (Apo-D), prostate specific antigen (PSA) and androgen receptor (AR) in early stage prostate cancers., Materials and Methods: Cellular distribution of Apo-D, PSA and AR in 30 stage A/B prostate cancers and in non-malignant glandular tissue contained in the same sections was detected immunohistochemically, and staining was evaluated by computerized video image analysis., Results: Staining for Apo-D (percentage positive cellular area) was significantly increased in tumor cells of early stage prostate cancers compared with non-malignant glandular tissue. PSA and AR were present at high levels in both early stage prostate tumors and non-malignant prostate., Conclusions: Malignant transformation in the prostate is associated with increased cellular levels of Apo-D.

While there has been widespread recent interest in men's health issues, and prostate cancer in particular, there have been few studies to determine which issues are important from the viewpoint of men themselves. This study was undertaken to identify genitourinary issues of concern to older men. A series of 19 focus groups involved 137 men and 14 women from a broad demographic background. Men expressed consistent concern about urinary symptoms, prostate cancer and sexual function. They revealed misunderstanding and a desire for more information about all issues. Urinary symptoms had a high impact on quality of life that could be made worse by environmental constraints such as working conditions and availability of toilets. Prostate cancer was a concern in all groups, even those at low risk, and men believed that screening for prostate cancer should be offered. Men believed sexuality was not recognised as an issue of concern to older people. Potential barriers to health action included stoicism, not talking about health issues and poor relationships with doctors. The study suggests a substantial need for community and professional education and for health promotion focused on preventable morbidity.

This study investigates the prevalence and determinants of prostate cancer screening in the South Australian community. An interview-based survey of a probability sample of the SA population (N = 3,016) in 1995 addressed previous PSA testing, beliefs about vulnerability to prostate cancer and efficacy of screening, presence of uncomplicated lower urinary tract symptoms (LUTS) and sociodemographic variables. Of 736 men, 40 years and over with no history of prostate cancer, 24.7% (182/736) reported ever having had a test and 53.9% (397) reported an intention to test; 74% (547) agreed that prostate cancer could be cured if detected early, while only 14.9% (109) believed they were unlikely to suffer from prostate cancer. In a logistic regression model, visit to a doctor for (but not presence of) LUTS was a strong, independent predictor of participation in PSA testing (OR 9.0, 95% CI 5.0, 16.0). Beliefs, occupation and education were not. In a similar model examining intention to test, belief in vulnerability to prostate cancer was the strongest predictor (OR 3.32, 95% CI 1.9, 5.9), followed by doctor visit for urinary symptoms. These data are consistent with widespread PSA testing and with seeking treatment for LUTS being a major determinant of previous testing. NHMRC Clinical Guidelines for LUTS recommend against PSA testing for investigation of uncomplicated LUTS. Implementation of those guidelines may therefore have a significant effect on PSA testing rates. Belief in personal vulnerability to prostate cancer remains a significant component of reported future testing, suggesting a focus for community education.

Purpose: This study was designed to evaluate prospectively the results of pelvic floor physiotherapy with the aid of biofeedback in a heterogeneous group of patients with intractable constipation., Methods: Biofeedback was used to treat 19 patients (age range, 16-78 (median, 63) years) with intractable constipation. Assessment, using visual linear analog scales of symptoms, was performed prospectively by an independent researcher. Biofeedback was performed by a physiotherapist, and patients were required to attend six sessions on an outpatient basis. The cause of constipation was heterogeneous, with no specific disorder being implicated on testing with anal manometry, defecating proctography, and colonic transit time., Results: At six weeks, there was a median 27 percent (range, -8-93 percent) improvement in symptom scores. At six months, there was a median 23 percent (range, -54-64 percent) improvement in symptom scores. These were statistically significant compared with the scores at outset, six weeks (P = 0.0006), and six months (P = 0.012). However, only two (12.5 percent) patients at the six-month follow-up had an improvement of greater than 50 percent in their symptoms., Conclusion: Biofeedback is not recommended in the management of constipation.

Objective: To determine the prevalence of troublesome lower urinary tract symptoms (LUTS) in men and women in the community., Design: Interview-based prevalence survey., Setting: Metropolitan and rural communities in South Australia, September, 1995., Subjects: Probability sample of 1204 men and 1686 women (aged over 18 years) weighted to reflect the age and sex distribution of the South Australian population., Data Collected: Presence of storage (irritative) and voiding (obstructive) symptoms, based on the International Prostate Symptom Score questionnaire; satisfaction with urinary condition (quality-of-life measure); and visits to a doctor for urinary symptoms in the preceding 12 months., Results: The prevalence of one or more troublesome LUTS was 26% (318/1204) for men and 39% (662/1686) for women (all ages) and 48% (314/649) for men and women over 65. The most common troublesome symptoms in men and women were nocturia and frequency. Symptoms were significantly age-related in men, but less so in women, in whom symptom prevalence exceeded 30% for all age groups. Ten per cent of men (123/1204) and 15% of women (249/1686) had visited a doctor for a urinary problem in the previous 12 months. Nine per cent of men (104/1204) and 16% of women (274/1686) were substantially dissatisfied with their urinary condition. Symptom prevalence and dissatisfaction with urinary condition were significantly associated with visiting the doctor (P < 0.0001), but only 28% (88/318) of men and 27% (179/662) of women with troublesome LUTS saw a doctor, and 63% (65/104) of men and 59% (162/274) of women dissatisfied with their urinary condition did not seek medical help., Conclusions: Although the prevalence of troublesome LUTS in the community is high, the number of people whose quality of life is substantially affected is much lower. The impact of these symptoms upon quality of life is a major reason for patients to see a doctor, yet many who are "bothered" by the symptoms do not do so.

Purpose: We determined the reliability of the International Prostate Symptom Score (I-PSS) in predicting the outcome of transurethral prostatectomy and, therefore, how useful it can be in patient selection for surgery., Materials and Methods: A prospective trial was done of 105 consecutive patients undergoing transurethral prostatectomy at our institution. Patients were assessed with the I-PSS before and 3 months after surgery. Flow rates and preoperative residual volumes also were measured., Results: There was significant postoperative improvement in all parameters of the symptom score and a change in symptom profile. Symptoms remaining with the greatest scores at 3 months postoperatively were frequency, urgency and nocturia. A significant correlation was found between I-PSS and quality of life before and after transurethral prostatectomy, and between postoperative improvement in flow rates and change in I-PSS. Patients with a greater preoperative I-PSS gained the most symptomatic benefit. The positive predictive value of a significant postoperative improvement of at least 7 I-PSS points depended on the preoperative I-PSS criteria applied. With a preoperative I-PSS of more than 17 the positive predictive value was 87% with a corresponding negative predictive value of 71%., Conclusions: The preoperative I-PSS predicted a symptomatic improvement of more than 7 points with high sensitivity. The predictive value depends on the definition of significant improvement (magnitude of I-PSS change) and the level of I-PSS symptoms defined as sufficient to warrant transurethral prostatectomy.

Curative therapies for clinically localized prostate cancer have significant morbidity, and those patients who might be cured by aggressive management are not easily identified using current clinical information. Better biomarkers of tumor behavior need to be identified to improve clinical outcome. Chondroitin sulfate (CS), a glycosaminoglycan, may be a potentially useful biomarker as it is known to influence cell growth and differentiation and might influence malignant progression. In this study, CS was immuno-localized to the periacinar and peritumoral fibromuscular stromal tissue of nonmalignant and malignant prostates. The CS concentration was increased in the prostate tissue of men with early-stage prostate cancer compared with tissue from men without cancer (P < 0.0001). Using Cox's univariate analysis, CS concentration, tumor grade, preoperative serum prostate-specific antigen (PSA), extracapsular extension of disease, positive surgical margins, and patient age were associated with an increased risk of PSA failure. The CS concentration was compared with the other features in two-variable regression analyses. CS and preoperative serum PSA concentrations were independent predictors of PSA failure. CS was a stronger prognostic feature than tumor grade and could predict outcome for patients with moderately differentiated tumors. Patients with a low CS concentration had significantly better progression-free survival following radical prostatectomy than patients with high levels of CS (Kaplan-Meier plot, 91% versus 49% PSA progression free at 5 years, respectively, P = 0.0038). Only postoperative pathological indices (extracapsular extension, surgical margins) were stronger predictors than CS. We conclude that measurement of prostatic CS concentrations at diagnosis may allow stratification of patients with early-stage prostate cancer for adjunctive or alternate therapies.

Objectives: A pooled analysis of all available randomized trials with 2-year follow-up data with finasteride and placebo was undertaken to further investigate recent observations that finasteride use may reduce the occurrence of acute urinary retention (AUR) and benign prostatic hyperplasia (BPH)-related surgical intervention., Methods: Occurrences of AUR and surgical intervention were examined by treatment group in a pooled series of 4222 men with moderately symptomatic BPH., Results: In total, 81 occurrences of AUR were reported, 24 (1.1%) of 2113 in the finasteride group and 57 (2.7%) of 2109 in the placebo group. The hazard ratio was consistent in all three studies, with a 57% decrease in the hazard rate for occurrence of AUR with finasteride compared with that for placebo present in the pooled data set over the 2-year study period (P < 0.001). Additionally, 227 surgical interventions were recorded over the 2-year study period, 89 (4.2%) of 2113 in the finasteride group and 138 (6.5%) of 2109 in the placebo group. The hazard ratio was consistent across the three studies, with a 34% reduction in the hazard rate for occurrence of surgery with finasteride compared with that for placebo (P < 0.002). Overall, there was 35% reduction in the two BPH-related end points (ie, AUR or surgery)., Conclusions: Treatment with finasteride for up to 2 years more than halves the frequency of AUR and reduces surgical intervention by over one third relative to placebo in patients with moderate BPH. This is the first demonstration that long-term medical therapy can reduce clinically significant end points such as AUR or surgery, and these data have important implications for the long-term management of patients with BPH.