ETS1 induces transforming growth factor ß signaling and promotes epithelial-to-mesenchymal transition in prostate cancer cells.

Expression of the transcriptional regulator, E26 transformation-specific 1 (ETS1), is elevated in human prostate cancers, and this is associated with more aggressive tumor behavior and a rapid progression to castrate-resistant disease. Multiple ETS1 isoforms with distinct biological activities have been characterized and in 44 matched nonmalignant and malignant human prostate specimens, messenger RNAs for two ETS1 isoforms, ETS1p51 and ETS1p42, were detected, with ETS1p51 levels significantly lower in prostate tumor compared to matched nonmalignant prostate tissues. In contrast, ETS1p51 protein, the only ETS1 isoform detected, was expressed at significantly higher levels in malignant prostate. Analysis of epithelial-to-mesenchymal transition (EMT)-associated genes regulated following overexpression of ETS1p51 in the LNCaP prostate cancer cell line predicted promotion of transforming growth factor ß (TGFß) signaling and of EMT. ETS1p51 overexpression upregulated cellular levels of the EMT transcriptional regulators, ZEB1 and SNAIL1, resulted in reduced expression of the mesenchymal marker vimentin with concomitantly elevated levels of claudin 1, an epithelial tight junction protein, and increased prostate cancer cell migration and invasion. ETS1p51-induced activation of the pro-EMT TGFß signaling pathway that was predicted in polymerase chain reaction arrays was verified by demonstration of elevated SMAD2 phosphorylation following ETS1p51 overexpression. Attenuation of ETS1p51 effects on prostate cancer cell migration and invasion by inhibition of TGFß pathway signaling indicated that ETS1p51 effects were in part mediated by induction of TGFß signaling. Thus, overexpression of ETS1p51, the predominant ETS1 isoform expressed in prostate tumors, promotes an EMT program in prostate cancer cells in part via activation of TGFß signaling, potentially accounting for the poor prognosis of ETS1-overexpressing prostate tumors.

The Impact of Prostate Cancer Zonal Origin on Pathological Parameters at Radical Prostatectomy and Subsequent Biochemical Failure.

PURPOSE: We assessed the impact of prostatic zone tumor origin on pathological prognostic features and subsequent biochemical outcomes after radical prostatectomy. MATERIALS AND METHODS: A total of 7,051 patients who underwent radical prostatectomy between September 1998 and December 2016 in Western Australia were divided into a high grade group, defined as Gleason sum 4 + 3, 8 and 9 or greater and ISUP (International Society of Urological Pathology) groups 3, 4 and 5, and a low grade group, defined as Gleason sum 6 or less and 3 + 4, and ISUP groups 1 and 2. The t-test and the Pearson chi-square test were used to evaluate differences between transition zone and peripheral/central zone cancer. The Kaplan-Meier method with the log rank test was used to determine differences in biochemical recurrence-free survival at 5 years in patients with high grade disease. Univariate and multivariable Cox proportional hazard regression analyses were performed. Model calibration was determined by the internal validation method. RESULTS: High grade transition zone cancer was associated with significantly increased prostate specific antigen, tumor volume and incidence of positive surgical margins but a lower incidence of intraductal carcinoma, extraprostatic spread, seminal vesicle invasion, lymph node involvement and biochemical failure after radical prostatectomy. Patients with low grade prostate cancer had excellent biochemical recurrence-free survival regardless of tumor origin. The high grade multivariable model had a c-index of 0.78 and improved predictive accuracy, particularly for high grade transition zone disease. CONCLUSIONS: Transition zone tumor origin independently and positively impacts biochemical outcomes of high grade prostate cancer. A high grade postoperative prognostic model including transition zone tumor origin as an independent predictor was developed and predictive accuracy was significantly improved in patients with high grade, transition zone disease.

The Australian laparoscopic non robotic radical prostatectomy experience - analysis of 2943 cases (USANZ supplement).

OBJECTIVES: To analyse the Australian experience of high-volume Fellowship-trained Laparoscopic Radical Prostatectomy (LRP) surgeons. MATERIALS AND METHODS: 2943 LRP cases were performed by nine Australian surgeons. The inclusion criteria were a prospectively collected database with a minimum of 100 consecutive LRP cases. The surgeons' LRP experience commenced at various times from July 2003 to September 2009. Data were analysed for demographic, peri-operative, oncological and functional outcomes. RESULTS: The mean age of patients were 61.5 years and mean preoperative PSA 7.4 ng/ml. Mean operating time was 168 minutes with conversion to open surgery in 0.5% and a blood transfusion rate of 1.1%. Overall mean length of stay was 2.5 days. 73.6% of pathological specimens were pT2 and 86.3% had Gleason Score >7. Overall positive surgical margins (PSM) occurred in 15.9% with pT2 PSM 9.8%, pT3a PSM 30.8% and pT3b PSM 39.2%. Mean urinary continence at 12 months was 91.4% (data available from five surgeons). Mean 12 months potency after bilateral nerve spare was 47.2% (data available from four surgeons). Biochemical recurrence occurred in 10.6% (mean follow up 17 months). CONCLUSION: The Australian experience of Fellowship trained surgeons performing LRP demonstrates favourable peri-operative, oncological and functional outcomes in comparison to published data for open, laparoscopic and robotic assisted radical prostatectomy. In our Australian centres, LRP remains an acceptable minimally invasive surgical treatment for prostate cancer despite the increasing use of robotic assisted surgery.

Prostate carcinoma with positive margins at radical prostatectomy: role of tumour zonal origin in biochemical recurrence.

OBJECTIVE: To assess the influence of tumour zonality on biochemical recurrence (BCR) after radical prostatectomy (RP) with a histologically confirmed positive surgical margin (PSM). PATIENTS AND METHODS: Data from 382 patients that underwent RP with either transition zone (TZ) or peripheral zone (PZ) tumours involving PSMs between 1998 and 2010 were retrieved from the Abbott West Australian Prostatectomy Database. Statistical analysis was used to evaluate the relationship of various tumour clinicopathological parameters, e.g. zonal origin of tumour, tumour volume, Gleason score, and stage to the development of BCR RESULTS: There were 51 TZ and 331 PZ tumours with PSMs identified. The TZ tumours compared with PZ tumours were larger (median 5.67 vs 3.64 mL, P < 0.001), more frequently lower grade (Gleason score 6 33% vs 5%, P < 0.01), organ confined (51% vs 35.6%, P = 0.073), and preferentially involved the bladder neck (49% vs 6%, P < 0.001). Tumour zonality was not associated with BCR for the entire cohort. TZ and PZ tumours had similar 5-year BCR-free survival rates (58% vs 63%, P = 0.691) and comparable time to development of BCR (14.4 vs 19.2 months, P = 0.346). On univariate analysis, preoperative PSA level, PSM at the bladder neck, tumour volume, Gleason score (P < 0.001) and tumour stage were independent predictors of BCR for the entire cohort. On multivariate analysis tumour volume and Gleason score retained significance as independent predictors of BCR. Tumour zonality was not directly associated with BCR. Of the patients who received adjuvant therapy, the incidence of BCR was similar for TZ and PZ tumours (58% vs 67%, P = 0.077), although TZ tumours failed significantly earlier (mean 4.4 vs 16.4 months, P = 0.037). CONCLUSIONS: PSA recurrence in patients with histologically confirmed PSMs after RP is independent of the zonal location of the index tumour. However, tumour zonal origin may have an indirect influence on PSA relapse, as TZ tumours tend to be of large volume and more likely involve the bladder neck margin, both risk factors for BCR. Bladder neck margin involvement is associated with higher rates of BCR than other sites of PSMs. The preoperative identification of TZ tumours might aid surgical planning with appropriate alteration of RP technique to incorporate wider surgical margins at the bladder neck. Adjuvant radiotherapy appears to be associated with adverse outcome for TZ tumours, a novel finding which warrants further investigation.

Review of renal cell carcinoma with rhabdoid features with focus on clinical and pathobiological aspects.

Rhabdoid morphology in renal cell carcinoma (RCC) may, like sarcomatoid change, be perceived as a type of dedifferentiation, and is a poor prognostic factor. Histologically, rhabdoid neoplastic cells are round to polygonal cells with globular eosinophilic cytoplasmic inclusions and eccentric vesicular nuclei and enlarged nucleoli. All types of RCC, including clear cell, papillary, chromophobe, collecting duct carcinoma, renal medullary carcinoma, acquired cystic disease-associated RCC, ALK-positive renal cancer and unclassified RCC, may display a variably prominent rhabdoid phenotype. Immunohistochemically, the cytoplasm of rhabdoid cells shows positivity for vimentin and/or cytokeratin. Ultrastructurally, cytoplasmic whorls/aggregates of intermediate filaments correspond to light microscopically observed inclusions. Genetically, a previous report suggests that combined loss of BAP1 and PBRM1 may be associated with rhabdoid morphology. As with sarcomatoid change, pathologists should describe, estimate and state the proportion of tumor cells with a rhabdoid phenotype in the routine pathology report of RCC.

Regulation of expression of deoxyhypusine hydroxylase (DOHH), the enzyme that catalyzes the activation of eIF5A, by miR-331-3p and miR-642-5p in prostate cancer cells.

The enzyme deoxyhypusine hydroxylase (DOHH) catalyzes the activation of eukaryotic translation initiation factor (eIF5A), a protein essential for cell growth. Using bioinformatic predictions and reporter gene assays, we have identified a 182-nt element within the DOHH 3'-untranslated region (3'-UTR) that contains a number of target sites for miR-331-3p and miR-642-5p. Quantitative RT-PCR studies demonstrated overexpression of DOHH mRNA and underexpression of miR-331-3p and miR-642-5p in several prostate cancer cell lines compared with normal prostate epithelial cells. Transient overexpression of miR-331-3p and/or miR-642-5p in DU145 prostate cancer cells reduced DOHH mRNA and protein expression and inhibited cell proliferation. We observed synergistic growth inhibition with the combination of miR-331-3p and miR-642-5p and mimosine, a pharmacological DOHH inhibitor. Finally, we identified a significant inverse relationship between the expression of miR-331-3p or miR-642-5p and DOHH in a cohort of human prostate cancer tissues. Our results suggest a novel role for miR-331-3p and miR-642-5p in the control of prostate cancer cell growth via the regulation of DOHH expression and eIF5A activity.

Intraductal carcinoma of the prostate: precursor or aggressive phenotype of prostate cancer?

BACKGROUND: Although the term "intraductal carcinoma of the prostate" (IDC-P) was introduced almost 40 years ago, there is still the lack of appreciation that this entity represents a clinically aggressive disease that continues to be misreported under the diagnostic category of high grade prostatic intraepithelial neoplasia (HGPIN). METHODS: Recent data obtained from histological, molecular, and clinical studies were reviewed to demonstrate that IDC-P significantly differs from HGPIN, and has a major impact in terms of diagnosis, prognosis and therapy of prostate cancer (PCa). RESULTS: HGPIN is the only accepted precursor of PCa. Its diagnosis in prostate biopsies has no prognostic implications, and does not dictate therapeutic decisions. By contrast, IDC-P correlates with a worse pathological and clinical outcome. IDC-P differs from HGPIN by distinct histological and molecular features. Recent clinical studies report that IDC-P is associated with neoadjuvant androgen deprivation therapy (ADT) and, chemotherapy (CT) failure as well as early disease recurrence after external beam radiation. Finally, IDC-P is associated with TMPRSS2-ERG gene fusion, which was reported to be regulated by estrogens and their receptors. CONCLUSIONS: IDC-P is an aggressive phenotype of prostate cancer and predicts poor response to ADT, CT, and external beam radiation. IDC-P should be separated from HGPIN and should be reported in prostate biopsies and prostatectomy specimens.

Percutaneous core biopsy of small renal mass lesions: a diagnostic tool to better stratify patients for surgical intervention.

OBJECTIVES: To further validate the safety and diagnostic accuracy of percutaneous core biopsy in small renal masses ([SRMs]≤4 cm) in response to the rising prevalence of renal 'incidentalomas'. To determine the value of percutaneous core biopsy in its ability to influence the choice of intervention or surveillance for the management of SRMs. PATIENTS AND METHODS: We collected data on the incidence of benign, malignant and non-diagnostic samples from 268 SRM (clinical T1a) biopsies performed at our institution between 1998 and 2009. The diagnostic accuracy of biopsy in small renal lesions was examined in cases proceeding to nephrectomy. Follow-up on the remaining non-surgical cases was performed. RESULTS: SRMs (≤4 cm, clinical T1a) constituted 59% of all renal lesions diagnosed; 80% of these biopsies were diagnostic and 20% were non-diagnostic. Of the diagnostic samples, 74% were malignant and 26% were benign. Thirty-three percent (17 of the initial 52) non-diagnostic samples underwent re-biopsy, with 94% yielding a histological diagnosis on repeat sampling. Fifty-eight percent of our diagnostic masses underwent nephrectomy, returning a renal biopsy accuracy rate of 100% for identifying lesions as benign or malignant. Of the 98 observed masses, 49% were benign, 28% malignant and 23% were non-diagnostic. In 63% of these cases, size remained stable in the follow-up period. CONCLUSIONS: Percutaneous core biopsy continues to provide an accurate and safe tool for preoperative tissue diagnosis of SRMs and should be offered to patients before considering surgical intervention. With regard to both benign and malignant T1a renal lesions, in select patient groups, those electing to undergo observation may expect favourable short- to medium-term outcomes.

Zonal origin of prostate cancer: comparison of long-term outcomes after radical prostatectomy.

PURPOSE: To assess the impact of zonal origin on positive bladder neck (BN) margins and prostate-specific antigen (PSA) failure or early adjuvant therapy in the patients with complete long-term follow-up after radical prostatectomy (RP). METHODS: A set of 4512 men were identified who underwent RP in Western Australia (WA) from March 2000 to December 2016 and had complete long-term follow-up. The t-test, Pearson chi-square test and Kaplan-Meier method with the log-rank test were used to evaluate differences between the transition zone (TZ) and peripheral/central zone (PZ/CZ) cancer. Univariate and multivariable Cox proportional hazard regression models were applied to assess parameters on PSA failure and early treatment. RESULTS: The positive BN margin rate for TZ cancer fell significantly over the study period. However, BN margin rates increased for PZ/CZ cancer over the time. Data of 4512 patients with median follow-up of 9.1 years confirmed that the high-risk TZ tumours with negative margins had a significant lower rate of PSA failure or early treatment compared to those high-risk PZ/CZ tumours with negative margins. CONCLUSION: Prostate cancer zonal origin significantly impacts long-term biochemical outcomes in high-risk and margin-negative patients. BN invasion with margin involvement is more frequent in the TZ cancer and can be reduced by pre-operative identification of cancer zonal origin and adjustment of surgical procedures.

Cytoprotective mitochondrial chaperone TRAP-1 as a novel molecular target in localized and metastatic prostate cancer.

Molecular chaperones of the heat shock protein-90 (Hsp90) family promote cell survival, but the molecular requirements of this pathway in tumor progression are not understood. Here, we show that a mitochondria-localized Hsp90 chaperone, tumor necrosis factor receptor-associated protein-1 (TRAP-1), is abundantly and ubiquitously expressed in human high-grade prostatic intraepithelial neoplasia, Gleason grades 3 through 5 prostatic adenocarcinomas, and metastatic prostate cancer, but largely undetectable in normal prostate or benign prostatic hyperplasia in vivo. Prostate lesions formed in genetic models of the disease, including the transgenic adenocarcinoma of the mouse prostate and mice carrying prostate-specific deletion of the phosphatase tensin homolog tumor suppressor (Pten(pc-/-)), also exhibit high levels of TRAP-1. Expression of TRAP-1 in nontransformed prostatic epithelial BPH-1 cells inhibited cell death, whereas silencing of TRAP-1 in androgen-independent PC3 or DU145 prostate cancer cells by small interfering RNA enhanced apoptosis. Targeting TRAP-1 with a novel class of mitochondria-directed Hsp90 inhibitors, ie, Gamitrinibs, caused rapid and complete killing of androgen-dependent or -independent prostate cancer, but not BPH-1 cells, whereas reintroduction of TRAP-1 in BPH-1 cells conferred sensitivity to Gamitrinib-induced cell death. These data identify TRAP-1 as a novel mitochondrial survival factor differentially expressed in localized and metastatic prostate cancer compared with normal prostate. Targeting this pathway with Gamitrinibs could be explored as novel molecular therapy in patients with advanced prostate cancer.

A new preoperative nomogram to predict minimal prostate cancer: accuracy and error rates compared to other tools to select patients for active surveillance.

PURPOSE: We designed and fully evaluated the performance of a nomogram to identify patients with prostate cancer who may be suitable for active surveillance. MATERIALS AND METHODS: We developed a nomogram to predict the probability of minimal prostate cancer (total tumor volume less than 0.5 cc, organ confined disease and no Gleason pattern 4 or 5) using preoperative data on 2,525 Australian patients who underwent radical prostatectomy. Accuracy and error rates at multiple probability cutoffs were compared with those of contemporary Epstein criteria and the Prostate Cancer Research International: Active Surveillance trial inclusion criteria when applied to these patients. High risk disease was defined as 1 or more adverse characteristics (including positive surgical margins, seminal vesicle invasion, extracapsular extension, 50% or greater Gleason pattern 4/5 and/or tumor volume 4.0 cc or greater) at radical prostatectomy. RESULTS: Minimal cancer was confirmed in 152 men (6.0%) at prostatectomy. The bootstrap corrected predictive accuracy of our nomogram was 93.3% vs 89.1% and 91.0% for Prostate Cancer Research International: Active Surveillance and Epstein criteria, respectively. For men with a nomogram derived minimal cancer probability of 0% to 4.9%, 5.0% to 19.9%, 20.0% to 34.9%, 35.0% to 49.9% and 50.0% to 71.0% the rate of high risk disease was 70.8%, 37.8%, 22.4%, 9.0% and 3.8%, respectively. In contrast, the rate of high risk disease for men who met Prostate Cancer Research International: Active Surveillance and Epstein criteria were 17.1% and 13.9%, respectively. CONCLUSIONS: A detailed breakdown of the expected rates of false-positive results and high risk disease associated with the nomogram derived probability of minimal cancer would provide more complete information to clinicians and patients on which to base therapeutic clinical decisions for presumed early stage prostate cancer.

Inverted papilloma of the urinary tract.

OBJECTIVES: • To compare the clinical and pathological details of inverted papilloma (IP) of the urinary tract diagnosed in Western Australia with those published. • To determine whether urinary tract IP requires post-treatment cystoscopic follow-up. PATIENTS AND METHODS: • Clinical and pathological details were summarized for 41 cases of IP of the urinary tract diagnosed in Western Australia between 1998 and 2010. • Publications on IP of the urinary tract were reviewed and summarized. RESULTS: • IP of the urinary tract is a rare benign tumour most commonly diagnosed in older men presenting with haematuria or symptoms of lower urinary tract obstruction. • IP is most frequently identified in the bladder neck or trigone as a polypoid growth with a smooth surface. • The major differential diagnosis is transitional cell carcinoma (TCC) with an inverted growth pattern, with differentiation based mainly on morphological criteria. • Treatment involves transurethral resection for lower urinary tract lesions whereas upper urinary tract IPs are resected by ureteroscopy, percutaneous endoscopy, partial ureterectomy or nephroureterectomy. • IP is weakly associated with a history of TCC and with increased risk of concomitant or subsequent TCC. CONCLUSIONS: • Based on the association with TCC, post-treatment follow-up for IP of the urinary tract should include cystoscopic follow-up.

A post-radical-prostatectomy nomogram incorporating new pathological variables and interaction terms for improved prognosis.

OBJECTIVE: To evaluate new variables in prostate pathology reporting including, the per cent of Gleason patterns 4 and/or 5 (% 4/5), presence or absence of intraductal carcinoma of the prostate (IDCP), tumour volume and the prostatic zone of tumour origin as predictors of post-radical-prostatectomy (RP) biochemical recurrence (BCR). To develop an optimal postoperative nomogram for patients with prostate cancer. PATIENTS AND METHODS: Our study cohort was 1939 eligible patients from the Abbott West Australian Prostatectomy Database. Multivariate Cox proportional hazard regression models were developed to predict BCR which was defined as prostate-specific antigen (PSA) ≥ 0.2 ng/mL. Our models and the 2009 Kattan postoperative nomogram were compared in terms of discrimination and calibration, with internal validation of our final model performed using bootstrapping methods. Our final model is presented as a nomogram. RESULTS: The Kattan nomogram was accurate in discriminating our patients according to risk (concordance index: 0.791) but calibration analysis indicated underestimation of patient risk, particularly for high-risk disease. Our nomogram incorporates % 4/5, IDCP and prostate weight plus interaction terms between % 4/5, positive surgical margins and extracapsular extension, giving improved predictive accuracy (concordance index: 0.828) and calibration. CONCLUSIONS: Nomograms that predict risk of BCR defined as PSA ≥ 0.4 ng/mL may not be optimal for patient cohorts where BCR is defined as PSA ≥ 0.2 ng/mL. If our findings are validated in other populations, current post-RP nomograms may be improved to a modest degree by incorporating the new variables prostate weight, IDCP and % 4/5, and by considering interactions between predictive variables.

Redefining the Concept of Clinically Insignificant Prostate Cancer.

OBJECTIVE: To assess the risk of biochemical recurrence (BCR) in small low-grade prostate tumors following radical prostatectomy (RP), which are defined as clinically insignificant based on the existing criteria developed by Stamey and Epstein. MATERIALS AND METHODS: We identified 3784 men who underwent RP in Western Australia from September 1998 to March 2019. These patients had a Gleason sum (GS) of ≤6 or 3+4, prostate confined and negative margins. Pathological data analysis was performed using logistic regression modeling. RESULTS: Median follow-up was 96.8 months. BCR occurred in 110 men (2.91%). There was no statistical difference in the rates of failure for patients with a tumor volume <0.5 mL vs 0.5-2.0 mL when comparing (i) those with Gleason 6, or (ii) those with Gleason 3+4. Furthermore, there was no statistical difference in rates of failure when comparing patients with a tumor volume of ≤2 mL vs >2 mL when the percentage of Gleason pattern 4 was ≤20%. However, once the percentage of Gleason pattern 4 increased to 30%, there was a significant increase in BCR in the larger tumors (> 2 mL). CONCLUSION: This study did not support either Stamey's or Epstein's criteria of insignificant cancer based on volumes of less than 0.5 mL, GS <7 and confined margin negative disease. No risk free cancer was identified, as all groups demonstrated some risk of BCR. This study redefines the entity of insignificant cancer as rather "low risk" cancer and expands its scope to include smaller tumors with minor Gleason pattern 4 components.

Fifteen-year analysis of prostate biopsies in Western Australia including recent impact of multiparametric magnetic resonance imaging.

BACKGROUND: The number of men undergoing prostate biopsy and subsequent cancer detection rates has changed significantly over the past 15 years. We aim to evaluate changes in the diagnostic pathway of prostate cancer between 2003 and 2018. METHODS: A total of 13 844 Western Australian biopsy-naive men were assessed to determine trends in age, prostate-specific antigen levels, number of core samples, positive cores and tumour grade (Gleason) between 2003 and 2018. Further, in 2018, the impact of pre-biopsy multiparametric magnetic resonance imaging (mpMRI) was also assessed. RESULTS: Between 2003 and 2012, the number of men undergoing biopsy increased from 1445 to 3100. During this time, the prostate cancer detection rate (%) remained unchanged. However, in 2018, 2042 men underwent prostate biopsy (reduction of 34.1%) and the detection rate increased to 72.6%. The incidence of low-grade cancer (Gleason score <7) increased from 28.1% in 2003 to 36.2% in 2012, but it decreased significantly to 15.1% by 2018. High-grade cancer (Gleason score >7) declined from 21.3% in 2003 to 15.2% in 2012 but then increased to 35.7% in 2018. The use of mpMRI in 2018 improved the detection rate of high-grade cancer. However, its specificity remains low (29.7%) and a considerable proportion of low Prostate Imaging Reporting and Data System score lesions was later diagnosed with cancer unsuitable for active surveillance. CONCLUSION: In recent years, there has been a significant increase in the diagnosis high-grade cancer and a reduction in cancer suitable for active surveillance. mpMRI identifies high-grade tumours but is not a reliable alternative to prostate biopsy.

Influence of 16S rDNA primer sequence mismatches on the spectrum of bacterial genera detected in prostate tissue by universal eubacterial PCR.

BACKGROUND: Propionibacterium sp. and Staphylococcus spp. are the most frequent bacteria cultured from prostatectomy specimens but are seldom detected by universal eubacterial PCR. MATERIALS AND METHODS: We obtained from GenBank representative 16S rRNA gene sequences from Propionibacterium sp., Staphylococcus spp. and from 34 bacterial genera that were recently detected in prostate tissues using universal eubacterial PCR. We compared these 16S rDNA sequences with the universal eubacterial 16S PCR primer sets chosen for detection of bacterial DNA in prostate tissues. RESULTS: We show that failure to detect DNA from Propionibacterium sp. and Staphylococcus spp. in prostate tissues is strongly associated with the presence of mismatches near the 3' termini of the 16S rDNA primer sets used. CONCLUSIONS: The choice of 16S PCR primers may play an important role in determining the spectrum of bacterial genera detected in prostate tissue by universal eubacterial PCR.

The value of preoperative needle core biopsy for diagnosing benign lesions among small, incidentally detected renal masses.

PURPOSE: We determined the safety and accuracy of preoperative needle core biopsy for diagnosing benign lesions among small incidental asymptomatic renal masses. MATERIALS AND METHODS: Between February 2000 and December 2007 we received a total of 235 preoperative core biopsies from 222 less than 5 cm incidental renal masses. Biopsy results were correlated with surgical specimen final pathology findings or with patient followup if surgery was avoided. RESULTS: Of the 235 biopsies 184 (78%) were diagnostic, whereas 51 (22%) were nondiagnostic due to insufficient material or contents of only normal, inflammatory, fibrotic or necrotic tissue, or blood clot. Diagnostic biopsies revealed 138 malignant (75%) and 46 benign (25%) lesions. Of these patients 108 (59%) underwent renal surgery, which showed a 100% biopsy accuracy rate for distinguishing malignant from benign lesions and a 98% rate for determining histological tumor type. Followup with radiological imaging was performed for 59 lesions in patients with nondiagnostic biopsies or benign masses and for 16 low grade malignant tumors in elderly patients. Lesions remained stable in 61 cases, showed minor size changes in 9 and resolved in 5. No patient has shown symptoms or required renal surgery to date. Significant biopsy related complications were noted in only 2 patients (0.9%). CONCLUSIONS: We found that needle core biopsy was a safe and accurate technique for distinguishing between malignant and benign tumors in small asymptomatic incidentally detected renal masses. Biopsy of small tumors is associated with a relatively high rate of technical biopsy failure, although this may be addressed by adopting improved biopsy techniques, as discussed.

Central zone carcinoma of the prostate gland: a distinct tumor type with poor prognostic features.

PURPOSE: The central zone of the prostate gland is a region rarely associated with carcinoma. To our knowledge central zone tumors have not previously been compared to carcinoma originating in the peripheral or transition zone of the prostate gland. MATERIALS AND METHODS: All 2,010 radical prostatectomy cases seen at our institution from October 1998 to December 2006 were reviewed to identify tumor zonal origin. Central zone carcinoma was characterized and compared with tumors of other zones. RESULTS: Zonal origin was determined in a total of 2,494 tumors in 1,703 cases. Of the tumors 63 (2.5%) were of central zone origin with 59 of the 63 representing the index or main tumor. Comparative analysis of a defined subset of 726 cases showed that central zone cancers were significantly more aggressive than peripheral or transition zone cancers with a far greater risk of extracapsular extension, seminal vesicle invasion and positive surgical margins. Escape from the gland was often via the ejaculatory ducts and seminal vesicles. Kaplan-Meier analysis confirmed that the probability of post-prostatectomy biochemical failure was double that of tumors of the other zones with a far more rapid rate of failure. Multivariate Cox regression analysis identified Gleason grade, positive margins, extracapsular extension, tumor volume and preoperative serum prostate specific antigen as the major contributors to this poor prognosis, rather than specific zonal origin. CONCLUSIONS: To our knowledge this study provides the first characterization and comparative analysis of central zone carcinoma, identifying these tumors as a rare but highly aggressive form of prostate carcinoma with a distinct route of spread from the gland that contrasts with tumors of other zones. Preoperative identification is currently hampered by the avoidance of biopsy targeting the central zone. However, if recognized preoperatively, aggressive intervention may possibly improve the currently bleak outlook.

The antibody response to Propionibacterium acnes is an independent predictor of serum prostate-specific antigen levels in biopsy-negative men.

OBJECTIVE: To investigate whether the serum titres of Propionibacterium acnes antibodies in patients undergoing prostate biopsy are associated with prostate cancer or markers of prostate disease, including serum prostate-specific antigen (PSA) levels. PATIENTS AND METHODS: The cell wall-associated proteins from P. acnes types IA, IB and II were extracted and characterized by Western blotting and immunoblotting. We developed an enzyme-linked immunosorbent assay (ELISA) based on extracted proteins to determine the anti-P. acnes antibody titres in the sera of 68 patients undergoing prostate biopsy. Correlations between these titres and multiple markers of prostate disease were investigated. RESULTS: In patients with biopsies negative for cancer, a high anti-P. acnes antibody titre was associated with high serum PSA levels (>or=10.0 ng/mL, P = 0.04), and multiple linear regression analysis identified antibody titre as the predominant independent predictor of serum PSA level (P = 0.03). The titre was positively correlated with patient age, prostate volume and aggressive inflammation, suggesting an involvement with benign prostatic hyperplasia (BPH). However in patients with histologically detected cancer, the volume of cancer in the biopsy cores was the predominant independent predictor of serum PSA (P = 0.01). CONCLUSIONS: These results support our hypothesis that P. acnes might be involved in the development of inflammation-related prostate diseases, in particular with BPH. Our ELISA might be valuable for identifying P. acnes infection of the prostate gland in patients with elevated serum PSA levels but a negative biopsy, and might identify men at risk of developing clinical BPH. However, an investigation with more patients is needed to confirm these preliminary findings.

miR-331-3p and Aurora Kinase inhibitor II co-treatment suppresses prostate cancer tumorigenesis and progression.

RNA-based therapeutics could represent a new avenue of cancer treatment. miRNA 331-3p (miR-331-3p) is implicated in prostate cancer (PCa) as a putative tumor suppressor, but its functional activity and synergy with other anti-tumor agents is largely unknown. We found miR-331-3p expression in PCa tumors was significantly decreased compared to non-malignant matched tissue. Analysis of publicly available PCa gene expression data sets showed miR-331-3p expression negatively correlated with Gleason Score, tumor stage, lymph node involvement and PSA value, and was significantly down regulated in tumor tissue relative to normal prostate tissue. Overexpression of miR-331-3p reduced PCa cell growth, migration and colony formation, as well as xenograft tumor initiation, proliferation and survival of mice. Microarray analysis identified seven novel targets of miR-331-3p in PCa. The 3'-untranslated regions of PLCγ1 and RALA were confirmed as targets of miR-331-3p, with mutation analyses confirming RALA as a direct target. Expression of miR-331-3p or RALA siRNA in PCa cells reduced RALA expression, proliferation, migration and colony formation in vitro. RALA expression positively correlated with Gleason grade in two separate studies, as well as in a PCa tissue microarray. Co-treatment using siRALA with an Aurora Kinase inhibitor (AKi-II) decreased colony formation of PCa cells while the combination of AKi-II with miR-331-3p resulted in significant reduction of PCa cell proliferation in vitro and PCa xenograft growth in vivo. Thus, miR-331-3p directly targets the RALA pathway and the addition of the AKi-II has a synergistic effect on tumor growth inhibition, suggesting a potential role as combination therapy in PCa.