Laurence Harewood

A case–control study of the androgen receptor gene CAG repeat polymorphism in Australian prostate carcinoma subjects

The development of prostate carcinoma is androgen‐dependent. The coding sequence of the androgen receptor (AR) gene contains a CAG repeat polymorphism that has been shown to influence AR activity in vitro. Studies of this polymorphism as a prostate carcinoma risk factor have been conflicting.

Upgrade in Gleason score between prostate biopsies and pathology following radical prostatectomy significantly impacts upon the risk of biochemical recurrence

Study Type – Prognosis (retrospective cohort)

Human Epithelial Basal Cells Are Cells of Origin of Prostate Cancer, Independent of CD133 Status

Normal prostatic epithelium is composed of basal and luminal cells. Prostate cancer can be initiated in both benign basal and luminal stem cells, but because basal cell markers are not expressed in patient tumors, the former result was unexpected. Since the cells of origin of prostate cancer are important therapeutic targets, we sought to provide further proof that basal stem cells have tumorigenic potential. Prostatic basal cells were enriched based on α2β1integrinhi expression and further enriched for stem cells using CD133 in nontumorigenic BPH‐1 cells. Human embryonic stem cells (hESCs) were also used as a source of normal stem cells. To test their tumorigenicity, we used two alternate stromal‐based approaches; (a) recombination with human cancer‐associated fibroblasts (CAFs) or (b) recombination with embryonic stroma (urogenital mesenchyme) and treated host mice with testosterone and 17β‐estradiol. Enriched α2β1integrinhi basal cells from BPH‐1 cells resulted in malignant tumor formation using both assays of tumorigenicity. Surprisingly, the tumorigenic potential did not reside in the CD133+ stem cells but was consistently observed in the CD133− population. CAFs also failed to induce prostatic tumors from hESCs. These data confirmed that benign human basal cells include cells of origin of prostate cancer and reinforced their importance as therapeutic targets. In addition, our data suggested that the more proliferative CD133− basal cells are more susceptible to tumorigenesis compared to the CD133+‐enriched stem cells. These findings challenge the current dogma that normal stem cells and cells of origin of cancer are the same cell type(s). STEM CELLS2012;30:1087–1096

Underestimation of Gleason score at prostate biopsy reflects sampling error in lower volume tumours.

Study Type – Diagnostic (case series)

The ability of prostate-specific antigen (PSA) density to predict an upgrade in Gleason score between initial prostate biopsy and prostatectomy diminishes with increasing tumour grade due to reduced PSA secretion per unit tumour volume.

Study Type – Diagnostic (exploratory cohort)

Positive surgical margins are a risk factor for significant biochemical recurrence only in intermediate‐risk disease

Study Type – Therapy (case series)

Prostate tumour volume is an independent predictor of early biochemical recurrence in a high risk radical prostatectomy subgroup

Aims: To assess if accurately determined tumour volume variables could serve as independent predictors of early biochemical recurrence in high risk prostate cancer patients who underwent radical prostatectomy. Methods: Tumour volume variables were calculated by digital planimetry in 269 prostatectomy specimens of patients with high risk prostate cancer. The associations to biochemical progression of tumour volume and clinicopathological variables, including age, pre-operative prostate specific antigen (PSA) levels, final Gleason score, pathological T stage, and surgical margins, were examined using univariate and multivariate Cox proportional hazards analyses. Results: Median tumour volume was 3.7 ml [interquartile range (IQR) 2.1–6.1 mL] and median follow-up time was 12 months (IQR 6–24 months). Biochemical recurrence occurred in 64 men (24%) during this period, with a median time to recurrence of 7.5 months (IQR 3.0–15.5 months). On univariate analysis all of the tumour volume variables were strongly correlated with the clinicopathological variables, as well as biochemical recurrence (p < 0.001). On multivariate analysis, we found that tumour volume variables served as independent predictors of PSA progression whilst other routinely reported pathological variables did not. Conclusion: Accurately assessing tumour volume in the high risk setting may aid in identifying patients at greatest risk of developing early biochemical recurrence and most in need of adjuvant therapy.

Does perineural invasion in a radical prostatectomy specimen predict biochemical recurrence in men with prostate cancer

INTRODUCTION The ability of perineural invasion (PNI) in radical prostatectomy (RP) specimens to predict biochemical recurrence (BCR) is unclear. This study investigates this controversial question in a large cohort. METHODS A retrospective analysis was undertaken of prospectively collected data from 1497 men who underwent RP (no neoadjuvant therapy) for clinically localized prostate cancer. The association of PNI at RP with other clinicopathological parameters was evaluated. The correlation of clinicopathological factors and BCR (defined as prostate-specific antigen [PSA] >0.2 ng/mL) was investigated with univariable and multivariable Cox regression analysis in 1159 men. RESULTS PNI-positive patients were significantly more likely to have a higher RP Gleason score, pT3 disease, positive surgical margins, and greater cancer volume (p < 0.0005). The presence of PNI significantly correlated with BCR on univariable (hazard ratio 2.30, 95% confidence interval 1.50-3.55, p < 0.0005), but not multivariable analysis (p = 0.602). On multivariable Cox regression analysis the only independent prognostic factors were preoperative PSA, RP Gleason score, pT-stage, and positive surgical margin status. These findings are limited by a relatively short follow-up time and retrospective study design. CONCLUSIONS PNI at RP is not an independent predictor of BCR. Therefore, routine reporting of PNI is not indicated. Future research should be targeted at the biology of PNI to increase the understanding of its role in prostate cancer progression.

Re-evaluating the biological significance of seminal vesicle invasion (SVI) in locally advanced prostate cancer

•  To examine the impact of seminal vesicle invasion (SVI) in patients with locally advanced (pT3) prostate cancer on clinical outcome. •  To explore the clinical association of SVI with metastatic disease. •  To distinguish between the possibilities that either seminal vesicles possess their own biological significance and represent a privileged staging site for systemic tumour cell dissemination, or that their invasion is a surrogate marker for an aggressive large‐volume poorly differentiated cancer.

Presence or absence of a positive pathological margin outperforms any other margin‐associated variable in predicting clinically relevant biochemical recurrence in Gleason 7 prostate cancer

The presence of a positive pathological margin is an independent risk factor for clinically significant disease recurrence only in intermediate‐risk disease when the a priori risk of micrometastatic disease is accounted for. The study examines patients with Gleason 7 prostate cancer to assess the relative importance of various margin‐related variables (focality, linear length, tumour grade at margin, presence of diathermy artifact and plane of tumour) with regard to biochemical recurrence. We found that the presence or absence of a positive pathological margin outperforms any other margin‐associated variable in predicting significant disease recurrence.