Lipid pathway deregulation in advanced prostate cancer

The link between prostate cancer (PC) development and lipid metabolism is well established, with AR intimately involved in a number of lipogenic processes involving SREBP1, PPARG, FASN, ACC, ACLY and SCD1. Recently, there is growing evidence implicating the role of obesity and peri-prostatic adipose tissue (PPAT) in PC aggressiveness and related mortality, suggesting the importance of lipid pathways in both localised and disseminated disease. A number of promising agents are in development to target the lipogenic axis in PC, and the likelihood is that these agents will form part of combination drug strategies, with targeting of multiple metabolic pathways (e.g. FASN and CPT1), or in combination with AR pathway inhibitors (SCD1 and AR)

Peri-prostatic fat volume measurement as a predictive tool for castration resistance in advanced prostate cancer

Background: Obesity and aggressive prostate cancer (PC) may be linked, but how local peri-prostatic fat relates to tumour response following androgen deprivation therapy (ADT) is unknown. Objective: To test if peri-prostatic fat volume (PPFV) predicts tumour response to ADT. Design, setting, and participants: We performed a retrospective study on consecutive patients receiving primary ADT. From staging pelvic magnetic resonance imaging scans, the PPFV was quantified with OsirixX 6.5 imaging software. Statistical (univariate and multivariate) analysis were performed using R Version 3.2.1. Results and limitations: Of 224 consecutive patients, 61 with advanced (≥T3 or N1 or M1) disease had (3-mm high resolution axial sections) pelvic magnetic resonance imaging scan before ADT. Median age = 75 yr; median PPFV = 24.8 cm3 (range, 7.4–139.4 cm3). PPFV was significantly higher in patients who developed castration resistant prostate cancer (CRPC; n = 31), with a median of 37.9 cm3 compared with 16.1 cm3 (p < 0.0001, Wilcoxon rank sum test) in patients who showed sustained response to ADT (n = 30). Multivariate analysis using Cox proportional hazards models were performed controlling for known predictors of CRPC. PPFV was shown to be independent of all included factors, and the most significant predictor of time to CRPC. Using our multivariate model consisting of all known factors prior to ADT, PPFV significantly improved the area under the curve of the multivariate models receiver operating characteristic analysis. The main study limitation is a relatively small cohort to account for multiple variables, necessitating a future large-scale prospective analysis of PPFV in advanced PC. Conclusions: PPFV quantification in patients with advanced PC predicts tumour response to ADT

AMP-activated protein kinase (AMPK) as a potential therapeutic target independent of PI3K/Akt signaling in prostate cancer

Depletion of cellular energy activates the AMP-activated protein kinase (AMPK) to favor energy-producing catabolic processes during tumorigenesis. Using a panel of in vitro cell lines and resected tumors, we investigated the therapeutic value of manipulating AMPK in prostate cancer (PC). Phospho-AMPK expression was significantly elevated in human PC cells and clinical PC samples. In clinical PC, we observed a trend for increasing phospho-AMPK with increasing Gleason sum score; Phospho-AMPK expression was associated with phospho-ACC (p=0.0023). Using the paired PC3 and PC3M cells to model progressive androgen-independent PC, treatment with either 5-aminoimidazole-4-carboxamide riboside (AICAR) or A-769662 suppressed proliferation, migration and invasion in both cell lines, and down-regulated mTOR and P70S6Ki levels regardless of the Akt status. Involvement of AMPK was confirmed by Compound C (AMPK inhibitor) and siRNA-mediated AMPK silencing. Despite similar functional responses in PC3 and PC3M cells, AMPK activation resulted in sustained phospho-Akt activation in PC3M cells, but not in PC3 cells. This prompted the addition of the PI3K inhibitor LY-294002 to AICAR treatment of PC3M cells in a proliferation assay. Interestingly, we found no synergistic effects upon combined treatment. Collectively, these findings support AMPK as a potential therapeutic target independent of PI3K/Akt signalling

Development of the Lymphoedema Genito-Urinary Cancer Questionnaire

The aim of this study was to develop a patient self-report tool to detect symptoms of genital and lower limb lymphoedema in male survivors of genitourinary cancer. The study incorporated the views of patients and subject specialists (lymphoedema and urology) in the design of a patient questionnaire based on the literature. Views on comprehensiveness, relevance of content, ease of understanding and perceived acceptability to patients were collated. The findings informed the development of the next iteration of the questionnaire. The overall view of participants was that the development and application of such a tool was of great clinical value and the Lymphoedema Genito- Urinary Cancer Questionnaire (LGUCQ) has significant potential for further development as a research tool to inform prevalence of this under-reported condition

Decision-analytic cost-effectiveness model to compare prostate cryotherapy to androgen deprivation therapy for treatment of radiation recurrent prostate cancer

Objective: To determine the cost-effectiveness of salvage cryotherapy (SC) in men with radiation recurrent prostate cancer (RRPC). Design: Cost-utility analysis using decision analytic modelling by a Markov model. Setting and methods: Compared SC and androgen deprivation therapy (ADT) in a cohort of patients with RRPC (biopsy proven local recurrence, no evidence of metastatic disease). A literature review captured published data to inform the decision model, and resource use data were from the Scottish Prostate Cryotherapy Service. The model was run in monthly cycles for RRPC men, mean age of 70 years. The model was run over the patient lifetime, to assess changes in patient health states and the associated quality of life, survival and cost impacts. Results are reported in terms of the discounted incremental costs and discounted incremental quality-adjusted life years (QALYs) gained between the 2 alternative interventions. Probabilistic sensitivity analysis used a 10 000 iteration Monte Carlo simulation. Results: SC has a high upfront treatment cost, but delays the ongoing monthly cost of ADT. SC is the dominant strategy over the patient lifetime; it is more effective with an incremental 0.56 QALY gain (95% CI 0.28 to 0.87), and less costly with a reduced lifetime cost of £29 719 (€37 619) (95% CI −51 985 to −9243). For a ceiling ratio of £30 000, SC has a 100% probability to be cost-effective. The cost neutral point was at 3.5 years, when the upfront cost of SC (plus any subsequent cumulative cost of side effects and ADT) equates the cumulative cost in the ADT arm. Limitations of our model may arise from its insensitivity to parameter or structural uncertainty. Conclusions: The platform for SC versus ADT cost-effective analysis can be employed to evaluate other treatment modalities or strategies in RRPC. SC is the dominant strategy, costing less over a patient's lifetime with improvements in QALYs

A review on the interactions between the tumour microenvironment and androgen receptor signaling in prostate cancer

Prostate cancer growth is controlled by androgen receptor signaling via both androgen-dependent and androgen-independent pathways. Furthermore, the prostate is an immune competent organ with inflammatory changes both within the systemic and local environment contributing to the reprogramming of the prostatic epithelium with consistently elevated lymphocyte infiltration and pro-inflammatory cytokines being found in prostate cancer. The crosstalk between the tumour microenvironment and androgen receptor signaling is complex with both pro-tumorigenic and anti-tumourigenic roles observed. However, despite an increase in immune checkpoint inhibitors and inflammatory signaling blockades available for a range of cancer types, we are yet to see substantial progress in the treatment of prostate cancer. Therefore, this review aims to summarize the tumour microenvironment and its impact on androgen receptor signaling in prostate cancer

Grid-based cognitive diagnostic prostatic biopsies without transrectal ultrasound imaging

No abstract available

A cohort analysis of patients receiving neoadjuvant androgen deprivation therapy prior to robot-assisted laparoscopic prostatectomy during the Covid-19 pandemic

Objectives: The purpose of this study was to investigate localised prostate cancer treated with or without neoadjuvant androgen deprivation therapy prior to robot-assisted laparoscopic prostatectomy, and the impact of Covid-19 treatment disruption, on clinico-pathologic outcomes. Patients and methods: Data was retrospectively collected from 124 consecutive patients treated with robot-assisted laparoscopic prostatectomy between November 2019–September 2020. Sixty-two patients were treated before 13 March 2020 (historic cohort) and 62 afterwards (covid cohort). Thirty-seven patients in the covid cohort additionally received neoadjuvant androgen deprivation therapy (mean duration of 3 months) consisting of bicalutamide 150 mg once a day for 4 weeks, with leuprolide 3.75 mg monthly injections commencing after week 1, up until the date of surgery. Results: Statistical analysis found no difference in peri-operative measures and length of stay for patients treated with or without neoadjuvant androgen deprivation therapy. Patients with delayed surgical treatment offered neoadjuvant androgen deprivation therapy showed a trend towards a reduction in positive surgical margins (p=0.134), N1 disease (p=0.424) and pathological down-staging (50% patients with pT2 disease). Patients within the covid cohort experienced significantly increased detectable prostate-specific antigen levels (p<0.007). Conclusion: Our study demonstrated that a three-month duration of neoadjuvant androgen deprivation therapy prior to robot-assisted laparoscopic prostatectomy may improve pathological outcomes but this time-frame is inadequate to influence detectable prostate-specific antigen levels. Covid-19-related treatment delays led to significantly increased detectable prostate-specific antigen levels. Level of evidence: 2b

Psychometric evaluation of the Chinese version of the subjective happiness scale: Evidence from the Hong Kong FAMILY cohort

BACKGROUND: With China's rapid economic growth in the past few decades, there is currently an emerging focus on happiness. Cross-cultural validity studies have indicated that the four-item Subjective Happiness Scale (SHS) has high internal consistency and stable reliability. However, the psychometric characteristics of the SHS in broader Chinese community samples are unknown. PURPOSE: We evaluated the factor structure and psychometric properties of the SHS in the Hong Kong general population. METHODS: The Chinese SHS was derived using forward-backward translation. Of the Cantonese-speaking participants aged >/=15 years, 2,635 were randomly selected from the random sample component of the FAMILY Cohort, a territory-wide cohort study in Hong Kong. In addition to the SHS, a single-item overall happiness scale, the Patient Health Questionnaire-9 (PHQ-9), the Family Adaptation, Partnership, Growth, Affection, Resolve (APGAR) scale, and the Medical Outcomes Study 12-item short-form version 2 (SF-12) mental and physical health scales were administered. RESULTS: Exploratory and confirmatory factor analyses supported a single factor with high loadings for the four SHS items. Multiple group analyses indicated factor invariance across sex and age groups. Cronbach's alpha was 0.82, and 2-week test-retest reliability (n = 191) was 0.70. The SHS correlated significantly with single-item overall happiness (Spearman's rho [rho] = 0.57), Family APGAR (rho = 0.26), PHQ-9 (rho = -0.34), and mental health-related quality of life (rho = 0.40) but showed a lower correlation with physical health (rho = 0.15). A regression model that included the PHQ-9 and Family APGAR scores explained 37 % of the variance in SF-12 mental health scores; adding the SHS raised the variance explained to 41 %. CONCLUSIONS: Our results support the reliability and validity of the SHS as a relevant component in the measurement battery for mental well-being in a Chinese general population.published_or_final_versio

A functional genomics screen reveals a strong synergistic effect between docetaxel and the mitotic gene DLGAP5 that is mediated by the androgen receptor

Based on a molecular classification of prostate cancer using gene expression pathway signatures, we derived a set of 48 genes in critical pathways that significantly predicts clinical outcome in all tested patient cohorts. We tested these genes in a functional genomics screen in a panel of three prostate cancer cell lines (LNCaP, PC3, DU145), using RNA interference. The screen revealed several genes whose knockdown caused strong growth inhibition in all cell lines. Additionally, we tested the gene set in the presence of docetaxel to see whether any gene exhibited additive or synergistic effects with the drug. We observed a strong synergistic effect between DLGAP5 knockdown and docetaxel in the androgen-sensitive line LNCaP, but not in the two other androgen-independent lines. We then tested whether this effect was connected to androgen pathways and found that knockdown of the androgen receptor by si-RNA attenuated the synergy significantly. Similarly, androgen desensitized LNCaP-AI cells had a higher IC50 to docetaxel and did not exhibit the synergistic interaction. Short-term exposure to enzalutamide did not significantly alter the behaviour of parental LNCaP cells. An immunofluorescence analysis in LNCaP cells suggests that under the double insult of DLGAP5 knockdown and docetaxel, cells predominantly arrest in metaphase. In contrast, the knockdown of the androgen receptor by siRNA appears to assist cells to progress through metaphase in to anaphase, even in the presence of docetaxel. Our data suggest that DLGAP5 has a unique function in stabilizing spindle formation and surviving microtubule assault from docetaxel, in an androgen-regulated cell cycle system