Knockdown of the cochaperone SGTA results in the suppression of androgen and PI3K/Akt signaling and inhibition of prostate cancer cell proliferation.

Solid tumors have an increased reliance on Hsp70/Hsp90 molecular chaperones for proliferation, survival and maintenance of intracellular signaling systems. An underinvestigated component of the chaperone system is the tetratricopeptide repeat (TPR)-containing cochaperone, which coordinates Hsp70/Hsp90 involvement on client proteins as well as having diverse individual actions. A potentially important cochaperone in prostate cancer (PCa) is small glutamine-rich TPR-containing protein alpha (SGTA), which interacts with the androgen receptor (AR) and other critical cancer-related client proteins. In this study, the authors used small interfering RNA coupled with genome-wide expression profiling to investigate the biological significance of SGTA in PCa and its influence on AR signaling. Knockdown of SGTA for 72 hr in PCa C4-2B cells significantly altered expression of >1,900 genes (58% decreased) and reduced cell proliferation (p < 0.05). The regulation of 35% of 5α-dihydrotestosterone (DHT) target genes was affected by SGTA knockdown, with gene-specific effects on basal or DHT-induced expression or both. Pathway analysis revealed a role for SGTA in p53, generic PCa and phosphoinositol kinase (PI3K) signaling pathways; the latter evident by a reduction in PI3K subunit p100ß levels and decreased phosphorylated Akt. Immunohistochemical analysis of 64 primary advanced PCa samples showed a significant increase in the AR:SGTA ratio in cancerous lesions compared to patient-matched benign prostatic hyperplasia tissue (p < 0.02). This study not only provides insight into the biological actions of SGTA and its effect on genome-wide AR transcriptional activity and other therapeutically targeted intracellular signaling pathways but also provides evidence for PCa-specific alterations in SGTA expression.

Abnormal PSA tests--delays in referral.

BACKGROUND: The main benefit of prostate specific antigen (PSA) testing is to help detect prostate cancer at an early, curable stage. Delays between the first abnormal PSA test and biopsy can undermine that benefit, but have not yet been studied. We investigated delays before biopsy together with associated PSA increases as an indicator of disease progression. METHODS: We identified 241 patients with a primary care referral because of an elevated PSA result (>4 ng/mL) and no previous prostate biopsy. Prostate specific antigen results and intervals between PSA testing, specialist clinic referral, appointment and biopsy were stratified by age. RESULTS: Median times between first abnormal PSA, referral, consultation and biopsy were modest but associated with increases in PSA. Extended delays (>20 months) between first abnormal PSA and referral occurred in 25% of younger men. A PSA result less than 10 ng/mL was the best predictor of a delay to refer. DISCUSSION: Rising PSA and possible cancer progression during investigation for prostate cancer suggest that prompt care is advisable.

Prostate cancer, the PSA test and academic detailing in Australian general practice: an economic evaluation.

OBJECTIVES: To evaluate whether introduction of a national education program for GPs to improve decision making relating to the use of prostate specific antigen (PSA) testing for screening represents 'value-for-money' from the perspective of the Australian Government. METHODS: The annual equivalent costs and consequences of a proposed national program in steady state operation are estimated for Australia using 1996 as the reference year. Because of the controversy about the efficacy of screening using PSA testing, two scenarios are modelled. Uncertainty in the model is examined using Monte Carlo simulation methods. RESULTS: In scenario one, our model predicts that the national program would cost dollars 12.5 million (gross) or dollars 6.6 million (net), would reduce the burden of disease by 4.7% of total DALYs due to prostate cancer in those aged 70 and over, with no loss of life and an incremental cost effectiveness ratio (ICER) of dollars 16,000/DALY (gross) and dollars 8,500/DALY (net). In scenario two, the proposed program would cost dollars 12.5 million (gross) or dollars 7.1 million (net), would reduce the burden of disease by 3.1% of total, increase by 44 the prostate cancer deaths at an ICER of dollars 24,000/DALY (gross) and dollars 14,000/DALY (net). CONCLUSIONS: These findings, with an overall health benefit at moderate cost and acceptable ICER, support the case for consideration of a national education program on the assumption that prostate cancer screening over age 70 does not reduce mortality. A larger Australian study currently being conducted should provide stronger evidence on the value of implementing a full national program.

Stromal androgen receptor regulates the composition of the microenvironment to influence prostate cancer outcome.

Androgen receptor (AR) signaling in stromal cells is important in prostate cancer, yet the mechanisms underpinning stromal AR contribution to disease development and progression remain unclear. Using patient-matched benign and malignant prostate samples, we show a significant association between low AR levels in cancer associated stroma and increased prostate cancer-related death at one, three and five years post-diganosis, and in tissue recombination models with primary prostate cancer cells that low stromal AR decreases castration-induced apoptosis. AR-regulation was found to be different in primary human fibroblasts isolated from adjacent to cancerous and non-cancerous prostate epithelia, and to represent altered activation of myofibroblast pathways involved in cell cycle, adhesion, migration, and the extracellular matrix (ECM). Without AR signaling, the fibroblast-derived ECM loses the capacity to promote attachment of both myofibroblasts and cancer cells, is less able to prevent cell-matrix disruption, and is less likely to impede cancer cell invasion. AR signaling in prostate cancer stroma appears therefore to alter patient outcome by maintaining an ECM microenvironment inhibitory to cancer cell invasion. This paper provides comprehensive insight into AR signaling in the non-epithelial prostate microenvironment, and a resource from which the prognostic and therapeutic implications of stromal AR levels can be further explored.

Prostate-specific antigen (PSA) rate of decline post external beam radiotherapy predicts prostate cancer death.

BACKGROUND AND PURPOSE: To assess the association between PSA velocity (PSAV) in the first 24 months after external beam radiotherapy (EBRT) and prostate cancer-specific mortality (PCSM) and all cause mortality. MATERIALS AND METHODS: All eligible patients in the South Australian (SA) Prostate Cancer Clinical Outcomes registry were followed. 848 Patients treated by definitive EBRT with more than one PSA recorded in the two year post-treatment were included. We calculated PSAV by linear regression. RESULTS: The mean number of PSA measurements in the 2year period was 4.4 (SD1.9). The median PSAVs across quartiles (Q1-Q4) were -4.17, -1.29, -0.38 and 0.20ng/ml/yr. In multivariable analysis, a U-shaped relationship was seen between PSAV and PCSM with Q1-Q4 hazard ratios (HR) being 3.82 (1.46-10.00), 3.07 (1.10-8.58), 1, 5.15 (1.99-13.30) respectively. HR for all cause mortality in a similar model were 1.79 (1.07-2.98), 1.55 (0.93-2.59), 1.00 and 1.74 (1.04-2.90) for Q1 to Q4 respectively. A rapid PSA decline in the first year was a strong predictor of PCSM. However, in the second year PSA increase was positively associated with PCSM. CONCLUSION: A rapid decline in PSA in the first year following EBRT is positively associated with PCSM. This may be a useful early indicator of the need for additional therapies.

Communicating prostate cancer risk: what should we be telling our patients?

Until definitive evidence of the effectiveness of prostate cancer screening is available, most guidelines advocate that men make their own decisions about testing, after being fully informed. A man's perception of his personal risk is a key element in the decision-making process. In this decision-making, the current routine use of population risk estimates may be misleading. Risk estimates need to be relevant to the man making the choice. In particular, they should be age-specific and, where possible, include adjustments for known risk factors such as family history. As an example, although the population risk of lung cancer mortality is twice that of prostate cancer, for a non-smoking man with a family history of prostate cancer the direction of this comparison would be reversed. A man aged 50 diagnosed with prostate cancer has a greater likelihood (60%) of dying prematurely (before 80 years) from prostate cancer than a man diagnosed when aged 70 (38%). This can be attributed to the longer time available for the prostate cancer to progress, and the increased effect of competing causes of death among older men. This suggests that the oft-used statement "men are more likely to die with prostate cancer than from prostate cancer" is misleading, particularly for men diagnosed in their 50s or 60s. Decisions need to be made by men based on the best possible understanding of their personal vulnerability, and the individualisation of risk provides a more realistic appraisal of potential threat posed by the disease.

Effectiveness of off-line and web-based promotion of health information web sites.

The relative effectiveness of off-line and web-based promotional activities in increasing the use of health information web sites by target audiences were compared. Visitor sessions were classified according to their method of arrival at the site (referral) as external web site, search engine, or "no referrer" (i.e., visitor arriving at the site by inputting URL or using bookmarks). The number of Australian visitor sessions correlated with no referrer referrals but not web site or search-engine referrals. Results showed that the targeted consumer group is more likely to access the web site as a result of off-line promotional activities. The properties of target audiences likely to influence the effectiveness of off-line versus on-line promotional strategies include the size of the Internet using population of the target audience, their proficiency in the use of the Internet, and the increase in effectiveness of off-line promotional activities when applied to locally defined target audiences.

Meeting the information needs of Australian men with prostate cancer by way of the internet.

OBJECTIVES: To assess the information preferred by Australian men for a prostate cancer website, to establish such a website, and to assess whether the first 2 years of use of the website reflected those needs. Successful patient information programs must be relevant to the target group's needs. METHODS: In phase 1, we surveyed Australian prostate cancer support group members asking for the preferred functions and content of an Australian website. In phase 2, a website was developed (http://www.prostatehealth.org.au) with the requested content derived from a urology service, state Cancer Councils, and medical directory and support group organizations. In phase 3, usage patterns of the site were analyzed using Web-Trends software for the first 2 years (2000 to 2002). RESULTS: The phase 1 survey of 54 men (response rate 69.2%) showed the most preferred pages were understanding diagnosis/understanding treatment (59%), on-line help-line (49%), and news sections (44%) with listings of Australian support groups (22%). Credible, up-to-date Australian-oriented content was requested. In phase 2, the site developed had five searchable databases with requested medical content from a urology service, support group and treatment center listings, and an on-line help-line run by a cancer council. In phase 3, after 2 years of operation, the site averaged 150,000 hits and 15,000 page views per month, with 46% of visitors from Australian domains. Most visited sections closely followed the needs assessment. CONCLUSIONS: Needs assessment is an important precursor to targeted web-based education programs. Nonmedical, community-based information is important to men with prostate cancer, as is information on diagnosis and treatment.

Coping with prostate cancer: a quantitative analysis using a new instrument, the centre for clinical excellence in urological research coping with cancer instrument.

OBJECTIVES: To assess the reliability (internal and interrater) and validity (concurrent) of a new interview measure for assessing patients' ability to cope with cancer, the Centre for Clinical Excellence in Urological Research Coping with Cancer Instrument (CCCI), and to determine whether there is an underlying structure to the various coping strategies used by patients with prostate cancer. METHODS: Eighty patients with prostate cancer were interviewed using the CCCI. The participants also completed measures of quality of life and anxiety and depression. RESULTS: The psychometric properties of the CCCI were acceptable. Factor analysis revealed that coping with prostate cancer can be described along five dimensions: positive problem solving (fighting against the illness, seeking information); self-reliance (developing a lay explanation, distrusting doctors); emotional availability (not withdrawing from others); distress (brooding, self-pity); and solace (taking alcohol or drugs to improve mood). These coping styles were correlated with age, quality of life, self-reported prostate-specific antigen level, and measures of anxiety and depression. CONCLUSIONS: The results of the present study have led to a greater understanding of the underlying coping styles used by patients with prostate cancer. Although some of these are similar to those found in other cancer populations, others, such as self-reliance and solace, represent unique and potentially clinically significant responses to prostate cancer diagnosis and treatment. A larger scale longitudinal study is needed to determine the wider clinical implications associated with each coping style.