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.

Informed prostate cancer risk-adjusted testing: a new paradigm.

• Currently there is significant confusion and polarisation about prostate cancer screening for both patients and physicians alike. • We propose a risk-adjusted testing programme, which would lead to fewer patients who need to be tested and treated to save a life and also eliminate inappropriate prostate-specific antigen testing in the elderly and patients with severe co-morbidities where there is no clear benefit.

Examining the 'gold standard': a comparative critical analysis of three consecutive decades of monopolar transurethral resection of the prostate (TURP) outcomes.

What's known on the subject? and What does the study add? Transurethral resection of the prostate (TURP) remains the dominant and definitive treatment for lower urinary tract symptoms due to benign prostatic hyperplasia (LUTS-BPH), but the widespread use of medical therapies (particularly monotherapies) for rapid symptom improvement has meant that the most common indication for TURP has shifted to moderate-severe medical therapy refractory LUTS to, coupled with abnormal objective parameters, or when complications arise. Patients undergoing TURP as part of contemporary randomised controlled trials are not older but have a larger preoperative prostate volume and reduced major morbidity compared with large cohort studies from successive past eras. Delayed surgery because of prolonged medical monotherapy may explain a higher reported failure to void rate, possibly because of negative impact on detrusor function from unrelieved obstruction. This study examined contemporary TURP for significant changes, specifically regarding prostate size, operative parameters, and outcomes, compared with two preceding decades. Electronic databases PubMed, EMBASE & Cochrane collaboration were searched for English literature on prospective randomized controlled trials, published between 1997 and 2007 using keywords "transurethral resection" and "prostate". Monopolar TURP (M-TURP) cohort data of each study were selectively pooled for analysis, weighting studies according to patient numbers. Where possible, pooled post-operative outcomes data were compared with two large cohort landmark studies of successive preceding decades. A total of 3470 patients from 67 studies were included. Mean patient age (67 years) was unchanged, while mean pre-operative prostate volume of 47.6 g was greater than previously reported. Mean resected prostate tissue (25.8 g) with a resection time of 38.5 minutes suggested improved resection efficiency. A statistically significantly reduced transfusion rate and increased urinary tract infection (UTI) rate were reported. Hospital stay (3.6 days) and initial catheterisation duration (2.5 days) were similar, but post-operative urinary retention rate was slightly higher (6.8%). Contemporary RCTs of M-TURP showed larger prostate volume, and reduced major morbidity, compared with large cohort studies from successive past eras. The higher reported failure to void rate, may possibly reflect worse detrusor function at time of TURP. Delaying surgery by prolonged medical monotherapy may compound this. Trials methodology in this area requires quality improvement and standardisation in future.

Comparative analysis of three risk assessment tools in Australian patients with prostate cancer.

UNLABELLED: What's known on the subject? and What does the study add? Prognostic tools, such as the Cancer of the Prostate Risk Assessment (CAPRA) score and the 1998 Kattan and 2006 Stephenson nomograms, predicting biochemical recurrence after radical prostatectomy are widely used for treatment decision making and counselling patients. However, tools derived in certain cohorts tend to perform less well when they are applied to populations that are dissimilar in terms of population or disease characteristics, health systems or treatment practices. Some of the loss in accuracy of a prognostic tool is a consequence of unknown factors and hence the performance of a tool when applied to a different population is unknown and largely unpredictable. This study validates these widely used tools in South Australian patients treated at three public hospitals. All three tools discriminated well according to risk of recurrence in these patients. However, when compared against observed rates of recurrence, it was found that predictions of recurrence varied widely between the three tools, suggesting that their use in counselling patients on such risk may not be appropriate. Interestingly, the oldest of the three tools (Kattan 1998) was the best predictor of absolute risk of recurrence. In the paper, this is linked to later adoption of updated Gleason grading, among other factors. SUMMARY: In many countries, prognostic tools, which draw on the experience of thousands of patients with cancer, are used to predict cancer outcomes, but accuracy varies. This paper compares the accuracy of three widely used tools predicting prostate cancer recurrence after surgery in Australian patients. The results show that all tools were good at predicting which patients were most likely to experience recurrence and which were least. However, prediction of absolute risk varied and the oldest tool was the most accurate. OBJECTIVE: • To compare performance of the CAPRA score and two commonly used risk assessment nomograms, the 1998 Kattan and the 2006 Stephenson, in an untested Australian cohort. PATIENTS AND METHODS: • We present data on 635 men from the South Australian Prostate Cancer Clinical Outcomes Database who underwent radical prostatectomy between January 1996 and May 2009 and had all required variables for predicting biochemical recurrence (BCR). • BCR was defined as prostate-specific antigen ≥ 0.2 ng/mL or secondary treatment for a rising prostate-specific antigen. • Accuracy was evaluated using Harrell's concordance index, plotting calibration curves, and constructing decision analysis curves. RESULTS: • Concordance indices were high for all three tools: 0.791, 0.787 and 0.744 for the 2006 Stephenson nomogram, CAPRA score and 1998 Kattan nomogram respectively. • At 3 years, calibration of the tools (agreement between predicted and observed BCR-free probability) was close to ideal for the 1998 Kattan nomogram, whereas the 2006 Stephenson model underestimated and the CAPRA model overestimated BCR-free probability. • The 1998 Kattan and 2005 CAPRA tools performed better than the 2006 Stephenson nomogram across a wide range of threshold probabilities using decision curve analysis. CONCLUSION: • All three tools discriminate between patients' risk effectively. • Absolute estimates of risk are likely to vary widely between tools, however, suggesting that models should be validated and, if necessary, recalibrated in the population to which they will be applied. • Recent development does not mean a nomogram is more accurate for use in a particular population.

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.

Assessment of laparoscopic suturing skills of urology residents: a pan-European study.

BACKGROUND: It has been acknowledged that standardised training programmes are needed to improve laparoscopic training of urologic trainees. Previous studies have suggested that simulator-based laparoscopic training can improve performance during real laparoscopic procedures. OBJECTIVE: To determine if there are performance differences for the completion of a simulated laparoscopic suturing task among urology residents based on their postgraduate year of training (PGY). DESIGN, SETTING, AND PARTICIPANTS: Using a validated scoring checklist, two independent observers objectively scored the completion of a standardised laparoscopic suturing task in a bench-top laparoscopic box trainer. PGY and previous exposure to laparoscopic surgery and laparoscopic simulated training was obtained from self-administered questionnaires. Data acquisition was undertaken at the European Urological Residents Education Programme (EUREP) 2007, run by the European School of Urology, and included a pan-European cohort of 201 urology residents. MEASUREMENTS: Reliability among those rating the suturing tasks was excellent (Cronbach's α=0.83). Each resident was scored for the suturing task. Residents were categorised into three groups based on their PGY status (junior [n=8]; intermediate [n=37]; senior [n=156]). The Kruskal-Wallis test was used to measure trend across the PGY; the Mann-Whitney U test was used to determine variation among categorised PGY groups. RESULTS AND LIMITATIONS: Laparoscopic suturing skill was significantly different across PGY levels (p=0.032), and between junior residents and both intermediate and senior residents (p=0.008 and p=0.012, respectively). There was no significant difference between intermediate and senior residents (p=0.697). Only 12% of participants rated their existing volume of laparoscopic operative cases as sufficient, while 55% of participants had no regular opportunities, and 32% of participants had not performed laparoscopic procedures as primary surgeon. Most residents (96%) reported the use of laparoscopic simulators to be beneficial in training, although current European training programmes appear to provide <50% of residents with the opportunity to train with them. CONCLUSIONS: A discernable relationship existed between the score obtained for a laparoscopic suturing task and year of resident training. Modular simulator training as part of a formal training programme may help to overcome some of the shortfall in residents' exposure to laparoscopic procedures as primary surgeon.

A prospective study analysing the effect of pain on probe insertion, and the biopsy strategy, on the patients' perception of pain during TRUS-guided biopsy of the prostate.

OBJECTIVES: PSA testing has led to an increasing number of TRUS-guided biopsies being performed. These are well tolerated in the majority, but a minority of men find the procedure unacceptably painful. We have studied a cohort of men undergoing TRUS guided prostate biopsy to ascertain whether the biopsy strategy, or pain on probe insertion, can assist in predicting those who men most likely to suffer severe pain during prostate biopsy. METHODS: 162 men (screened and symptomatic) between 47 and 86 years of age (mean age 61.7 yrs) who attended for TRUS and biopsy were studied. The number of cores taken were governed by TRUS volume, less than and equal to or=40cc =12 cores. Each completed a 10-point visual analogue pain score (VAS) immediately after procedure. All men were asked to describe their pain, on insertion of the TRUS probe, followed by the first and the last biopsy. All biopsies were taken with an 18G spring-loaded Tru-cut disposable needle. Severe pain (score of 8-10) was deemed unacceptable. RESULTS: 22% (36/162) of the men biopsied experienced unacceptable pain in one or more of the three categories. There was a higher incidence of severe pain in those undergoing 12 cores compared to 7-11, or a standard sextant strategy (p=0.05, Chi-squared for linear trend). Severe pain was experienced by 6% (9/162) of men during probe insertion. Of this group 78% (7/9) also went on to find biopsies unacceptably painful, compared to 19% (29/152) of those who did not experience severe pain for probe insertion (p<0.0001, exact test for two independent proportions). CONCLUSIONS: Approximately 1 in 5 men experience unacceptable pain at some time during TRUS biopsy of the prostate. A high proportion of men (78%) in whom insertion of the TRUS probe was unacceptably painful, found subsequent biopsies equally painful. With trend towards saturation biopsies the need for predicting group of men who will need local/general anaesthesia is ever-increasing.