Daniel Stevens

Prostate Cancer Tumour Features on Template Prostate-mapping Biopsies: Implications for Focal Therapy

Background Focal therapy is being offered as a viable alternative for men with localised prostate cancer (PCa), but it is unclear which men may be suitable. Objective To determine the proportion of men with localised PCa who are potentially suitable for focal therapy. Design, setting, and participants Our institutional transperineal template prostate-mapping (TTPM) biopsy registry of 377 men from 2006 to 2010 identified 291 consecutive men with no prior treatment. Intervention TTPM biopsies using a 5-mm sampling frame. Outcome measurements and statistical analysis Suitability for focal therapy required the cancer to be (1) unifocal, (2) unilateral, (3) bilateral/bifocal with at least one neurovascular bundle avoided, or (4) bilateral/multifocal with one dominant index lesion and secondary lesions with Gleason ≤3 + 3 and cancer core involvement ≤3 mm. Binary logistic regression modelling was used to determine variables predictive for focal therapy suitability. Results and limitations The median age was 61 yr, and the median prostate-specific antigen was 6.8 ng/ml. The median total was 29 cores, with a median of 8 positive cores. Of 239 of 291 men with cancer, 29% (70 men), 60% (144 men), and 8% (20 men) had low-, intermediate-, and high-risk PCa, respectively. Ninety-two percent (220 men) were suitable for one form of focal therapy: hemiablation (22%, 53 men), unifocal ablation (31%, 73 men), bilateral/bifocal ablation (14%, 33 men), and index lesion ablation (26%, 61 men). Binary logistic regression modelling incorporating transrectal biopsy parameters showed no statistically significant predictive variable. When incorporating TTPM parameters, only T stage was a significant negative predictor for suitability (p = 0.001) (odds ratio: 0.001 [95% confidence interval, 0.000–0.048]). Limitations of the study include potential selection bias caused by tertiary referral practise and lack of long-term results on focal therapy efficacy. Conclusions Focal therapy requires an accurate tool to localise individual cancer lesions. When such a test, TTPM biopsy, was applied to men with low- and intermediate-risk PCa, most of the men were suitable for a tissue preservation strategy.

The Utility of Molecular Imaging in Prostate Cancer

Prostate cancer is the commonest solid-organ cancer diagnosed in males and represents an important source of morbidity and mortality worldwide. Imaging plays a crucial role in diagnosing prostate cancer and informs the ongoing management of the disease at all stages. Several novel molecular imaging technologies have been developed recently that have the potential to revolutionise disease diagnosis and the surveillance of patients living with prostate cancer. These innovations include hyperpolarised MRI, choline PET/CT and PSMA PET/CT. The major utility of choline and PSMA PET/CT currently lies in their sensitivity for detecting early recurrence after radical treatment for prostate cancer and identifying discrete lesions that may be amenable to salvage therapy. Molecular imaging is likely to play a future role in characterising genetic and biochemical signatures in individual tumours, which may be of particular significance as cancer therapies move into an era of precision medicine.

Organ-Confined Prostate Cancer: Are We Moving Towards More or Less Radical Surgical Intervention?

Treatment possibilities for clinically localised prostate cancer include radical prostatectomy (RP), external beam radiotherapy, brachytherapy, focal therapy and active surveillance. Conflicting and methodologically flawed observational data from the last two decades have led to uncertainty as to the best oncological option. However, recently, there has been a series of high-quality studies that point to disease specific and overall survival advantages for those men undergoing RP. This article reviews the latest evidence and argues that at the current time, RP must be considered the gold standard treatment for the majority of men with clinically localised prostate cancer.

MP55-12 THE PROTON-ASSISTED AMINO ACID TRANSPORTER 4 (PAT4/SLC36A4) IS UP-REGULATED IN PROSTATE CANCER

INTRODUCTION AND OBJECTIVES: Cellular senescence occurs in response to sub-lethal stress after androgen deprivation therapy, radiation and chemotherapy whereby cells exit the cell cycle and develop distinct morphologic and biochemical characteristics. Senescence is a therapeutic approach, however potentially deleterious consequences make elimination of these cells important. The objective of this study was to determine whether the increased gluconeogenesis induced during senescence could be exploited to synergistically eliminate PCa cells using metformin (Met), an oral biguanide hyperglycemic approved for type II diabetes. METHODS: High throughput screening of small molecule collections identified two novel robust senescence inducing agents, AZQ (diaziquone) a quinone and AZD5438 a novel CDK inhibitor. Senescence was confirmed using beta-galactosidase staining, cell arrest and increased size by flow cytometry. mTOR a serine-threonine protein kinase activity was evaluated using western. PCa cells were seeded on 96-well plates, low(L) and high(H) AZQ (0.1 and 0.25 microM) or AZD 5438 (0.1 and 0.4 microM) concentrations administered and after 3 days of senescence induction Met (1 and 5mM) added. Cells were collected 24 and 72h later and stained with Hoechts to evaluate the cell number. CalcuSyn software (Biosoft, Cambridge, UK) modeled synergism. RESULTS: AZQ and AZD robustly increased beta-galactosidase staining, cell size and p27 and p16 induction in Du145, PC3, PPC1 cell lines. mTOR signaling through mTOR complex 1 significantly increased in AZQ-induced senescent cells. Used alone, AZD(L) and AZQ(L) demonstrate a 30% reduction in cell number and Met(L) alone 18%. Met after senescence induction (72h) decreased cell number 70% and 55% (AZD and AZQ respectively). CalcuSyn calculations revealed moderate synergistic effects with combinations of either AZD(H) or AZQ (L and H) and Met(L and H) at 24hr. A strong synergistic decrease in cell viability was demonstrated at 72h with AZQ(H) and Met(L) (CI1⁄4 0.267). CONCLUSIONS: Senescent cells targeted by metformin may offer an alternative treatment strategy for removing castrate-resistant PCa cells. Increased gluconeogenesis during senescence represents a novel ‘Achilles heel’ for these dormant/arrested cancer cells. mTOR activity is activated during the conversion of cells to senescence, and Met inhibition of this pathway is a putative mechanism. Our results suggest that combination treatment with a senescence-inducing drug and metformin may be a feasible targeted therapeutic approach.