Decision Regret in Patients with Localised Prostate Cancer: A Systematic Review and Meta-analysis.

CONTEXT: Treatment choice for localised prostate cancer remains a significant challenge for patients and clinicians, with uncertainty over decisions potentially leading to conflict and regret. There is a need to further understand the prevalence and prognostic factors of decision regret to improve patient quality of life. OBJECTIVE: To generate the best estimates for the prevalence of significant decision regret localised prostate cancer patients, and to investigate prognostic patient, oncological, and treatment factors associated with regret. EVIDENCE ACQUISITION: We performed a systematic search of MEDLINE, Embase, and PsychINFO databases including studies evaluating the prevalence or patient, treatment, or oncological prognostic factors in localised prostate cancer patients. A pooled prevalence of significant regret was calculated with the formal prognostic factor evaluation conducted per factor identified. EVIDENCE SYNTHESIS: Significant decision regret was present in a pooled 20% (95% confidence interval 16-23) of patients across 14 studies and 17883 patients. This was lower in active surveillance (13%), with little difference between those who underwent radiotherapy (19%) and those who underwent prostatectomy (18%). Evaluation of individual prognostic factors demonstrated higher regret in those with poorer post-treatment bowel, sexual, and urinary function; decreased involvement in the decision-making process; and Black ethnicity. However, evidence remains conflicting, with low or moderate certainty of findings. CONCLUSIONS: A significant proportion of men experience decision regret after a localised prostate cancer diagnosis. Monitoring those with increased functional symptoms and improving patient involvement in the decision-making process through education and decision aids may reduce regret. PATIENT SUMMARY: We looked at how common regret in treatment decisions is after treatment for early-stage prostate cancer and factors linked with this. We found that one in five regret their decision, with those who had experienced side effects or were less involved in the decision-making process more likely to have regret. By addressing these, clinicians could reduce regret and improve quality of life.

Risk of progression following a negative biopsy in prostate cancer active surveillance.

BACKGROUND: Currently, follow-up protocols are applied equally to men on active surveillance (AS) for prostate cancer (PCa) regardless of findings at their initial follow-up biopsy. To determine whether less intensive follow-up is suitable following negative biopsy findings, we assessed the risk of converting to active treatment, any subsequent upgrading, volume progression (>33% positive cores), and serious upgrading (grade group >2) for negative compared with positive findings on initial follow-up biopsy. METHODS: 13,161 men from 24 centres participating in the Global Action Plan Active Surveillance Prostate Cancer [GAP3] consortium database, with baseline grade group ≤2, PSA ≤ 20 ng/mL, cT-stage 1-2, diagnosed after 1995, and ≥1 follow-up biopsy, were included in this study. Risk of converting to treatment was assessed using multivariable mixed-effects survival regression. Odds of volume progression, any upgrading and serious upgrading were assessed using mix-effects binary logistic regression for men with ≥2 surveillance biopsies. RESULTS: 27% of the cohort (n = 3590) had no evidence of PCa at their initial biopsy. Over 50% of subsequent biopsies in this group were also negative. A negative initial biopsy was associated with lower risk of conversion (adjusted hazard ratio: 0.45; 95% confidence interval [CI]: 0.42-0.49), subsequent upgrading (adjusted odds ratio [OR]: 0.52; 95%CI: 0.45-0.62) and serious upgrading (OR: 0.74; 95%CI: 0.59-92). Radiological progression was not assessed due to limited imaging data. CONCLUSION: Despite heterogeneity in follow-up schedules, findings from this global study indicated reduced risk of converting to treatment, volume progression, any upgrading and serious upgrading among men whose initial biopsy findings were negative compared with positive. Given the low risk of progression and high likelihood of further negative biopsy findings, consideration should be given to decreasing follow-up intensity for this group to reduce unnecessary invasive biopsies.

Active Surveillance for Men Younger than 60 Years or with Intermediate-risk Localized Prostate Cancer. Descriptive Analyses of Clinical Practice in the Movember GAP3 Initiative.

Background: Active surveillance (AS) is a management option for men diagnosed with low-risk prostate cancer. Opinions differ on whether it is safe to include young men (≤60 yr) or men with intermediate-risk disease. Objective: To assess whether reasons for discontinuation, treatment choice after AS, and adverse pathology at radical prostatectomy (RP; N1, or ≥GG3, or ≥pT3) differ for men ≤60 yr or those with European Association of Urology (EAU) intermediate-risk disease from those for men >60 yr or those with EAU low-risk disease. Design setting and participants: We analyzed data from 5411 men ≤60 yr and 14 959 men >60 yr, 14 064 men with low-risk cancer, and 2441 men with intermediate-risk cancer, originating from the GAP3 database (21 169 patients/27 cohorts worldwide). Outcome measurements and statistical analysis: Cumulative incidence curves were used to estimate the rates of AS discontinuation and treatment choice. Results and limitations: The probability of discontinuation of AS due to disease progression at 5 yr was similar for men aged ≤60 yr (22%) and those >60 yr (25%), as well as those of any age with low-risk disease (24%) versus those with intermediate-risk disease (24%). Men with intermediate-risk disease are more prone to discontinue AS without evidence of progression than men with low-risk disease (at 1/5 yr: 5.9%/14.2% vs 2.0%/8.8%). Adverse pathology at RP was observed in 32% of men ≤60 yr compared with 36% of men >60 yr (p = 0.029), and in 34% with low-risk disease compared with 40% with intermediate-risk disease (p = 0.048). Conclusions: Our descriptive analysis of AS practices worldwide showed that the risk of progression during AS is similar across the age and risk groups studied. The proportion of adverse pathology was higher among men >60 yr than among men ≤60 yr. These results suggest that men ≤60 yr and those with EAU intermediate-risk disease should not be excluded from opting for AS as initial management. Patient summary: Data from 27 international centers reflecting daily clinical practice suggest that younger men or men with intermediate-risk prostate cancer do not hold greater risk for disease progression during active surveillance.

The vaccine journey for COVID-19: a comprehensive systematic review of current clinical trials in humans.

INTRODUCTION: Since December 2019, there has been an outbreak of a novel beta-Coronavirus (SARS-CoV-2) in Wuhan, China. On March 11, 2020, the World Health Organization (WHO) declared COVID-19 as a pandemic, with over 118,000 cases in more than 110 countries around the world. In response to the global Coronavirus disease 2019 (COVID-19) emergency, clinical trial research assessing the efficacy and safety of experimental vaccines to prevent COVID-19 are emerging at an unprecedented rate. The aim of this systematic review was to summarize the preliminary experiences and ongoing clinical trials of the major candidates and challenges of the vaccine strategies in humans. EVIDENCE ACQUISITION: After a-priori protocol registration with PROSPERO (181483), systematic research of the published literature was conducted on April 24, 2020, using Medline (via PubMed), Embase (via Ovid), and WHO databases. Moreover, to explore the more recent literature we also searched the preprint server medRxiv. Finally, we scrutinized the Cochrane COVID-19 study register and the COVID-19 section of ClinicalTrials.gov database to identify relevant ongoing clinical trials. Thereafter we selected the articles according to the PRISMA Guidelines. Animal or in-vitro experimental studies were excluded. Moreover editorials, commentaries, abstracts, reviews, book chapters, and articles not in English were not included. EVIDENCE SYNTHESIS: Our search identified 1359 published papers, 478 preprint articles and 367 ongoing clinical trials. Finally, only ten ongoing clinical trials met the inclusion criteria. Specifically, seven developed vaccines for the S protein of SARS-CoV-2 and three clinical trials assessed the protective role of BCG vaccine against COVID-19. The first group included phase I/II trials with different types of molecules (DNA or mRNA vaccine, bacterial plasmid or viral vectors), the latter were phase III/IV trials designed on the basis of a heterologous lymphocyte activation by the BCG vaccine. CONCLUSIONS: This new disease is pushing the scientific community to develop swiftly a safe and effective vaccine. Notwithstanding the limitations of our analysis, given by the absence of available results, we try to provide a comprehensive view of the ongoing clinical trials in humans. Our analysis reveals a worldwide effort of both scientists and enterprises to achieve one of the most challenging goals of our century.

Repurposing of drugs for COVID-19: a systematic review and meta-analysis.

INTRODUCTION: The aim of this systematic review was to evaluate the data currently available regarding the repurposing of different drugs for COVID-19 treatment. Participants with suspected or diagnosed COVID-19 were included in this study. The interventions that have been considered were repurposed drugs and comparators that included standard of care treatment or placebo. EVIDENCE ACQUISITION: We searched Ovid-MEDLINE, EMBASE, Cochrane library, clinical trial registration site in the UK(NIHR), Europe (clinicaltrialsregister.eu), US (ClinicalTrials.gov) and internationally (isrctn.com), and reviewed the reference lists of articles for eligible articles published up to April 22, 2020. All studies in English that evaluated the efficacy of the listed drugs were included. Cochrane RoB 2.0 and ROBINS-I tool were used to assess study quality. This systematic review adheres to the PRISMA guidelines. The protocol is available at PROSPERO (CRD42020180915). EVIDENCE SYNTHESIS: From 708 identified studies or clinical trials, 16 studies and 16 case reports met our eligibility criteria. Of these, 6 were randomized controlled trials (763 patients), 7 cohort studies (321 patients) and 3 case series (191 patients). Chloroquine (CQ) had a 100% discharge rate compared to 50% with lopinavir-ritonavir at day 14, however a trial has recommended against a high dosage due to cardiotoxic events. Hydroxychloroquine (HCQ) has shown no significant improvement in negative seroconversion rate which is also seen in our meta-analysis (P=0.68). Adverse events with HCQ have a significant difference compared to the control group (P=0.001). Lopinavir-ritonavir has shown no improvement in time to clinical improvement which is seen in our meta-analyses (P=0.1). Remdesivir has shown no significant improvement in time to clinical improvement but this trial had insufficient power. CONCLUSIONS: Due to the paucity in evidence, it is difficult to establish the efficacy of these drugs in the treatment of COVID-19 as currently there is no significant clinical effectiveness of the repurposed drugs. Further large clinical trials are required to achieve more reliable findings. A risk-benefit analysis is required on an individual basis to weigh out the potential improvement in clinical outcome and viral load reduction compared to the risks of the adverse events.

Feasibility and safety of radical prostatectomy for oligo-metastatic prostate cancer: the Testing Radical prostatectomy in men with prostate cancer and oligo-Metastases to the bone (TRoMbone) trial.

OBJECTIVES: To test the feasibility of randomisation to radical prostatectomy (RP) plus pelvic lymphadenectomy in addition to standard-of-care (SOC) systemic therapy in men with newly diagnosed oligo-metastatic prostate cancer. PATIENTS AND METHODS: A prospective, randomised, non-blinded, feasibility clinical trial with an embedded QuinteT Recruitment Intervention (QRI) to optimise recruitment was conducted in nine nationwide tertiary care centres undertaking high-volume robotic surgery. We aimed to randomise 50 men with synchronous oligo-metastatic prostate cancer within an 18-month recruitment period to SOC systemic therapy vs SOC plus RP (intervention arm). The main outcome measures were: ability to randomise patients, optimised by a QRI; EuroQoL five Dimensions five Levels (EQ-5D-5L) questionnaires to capture quality-of-life (QoL) data at baseline and 3 months post-randomisation; routine clinicopathological assessment to capture adverse events and prostate-specific antigen in both arms, plus standard perioperative parameters in the surgical arm. RESULTS: A total of 51 men were randomised within 14 months (one was subsequently deemed ineligible), with 60-83% accrual rate in centres that recruited at least two patients. All patients completed the trial follow-up; one patient in the intervention arm subsequently did not undergo the surgical intervention and one in the SOC arm refused all therapies. The QRI positively impacted recruitment. QoL data showed similarly high functioning in both study arms. Surgery for men with oligo-metastatic prostate cancer was found to be safe and had similar impact on early functional outcomes as surgery for standard indication. CONCLUSION: It is feasible to randomise men with synchronous oligo-metastatic prostate cancer to a surgical intervention in addition to standard systemic therapies. While surgery appeared safe with no substantial impact on QoL in this feasibility study, a large randomised controlled trial is now warranted to examine treatment effectiveness of this additional component in the multimodality management of oligo-metastatic prostate cancer.

Comparison of Characteristics, Follow-up and Outcomes of Active Surveillance for Prostate Cancer According to Ethnicity in the GAP3 Global Consortium Database.

BACKGROUND: Studies of active surveillance (AS) for prostate cancer (PCa) have focussed predominantly on Caucasian populations. Little is known about the experience of Asian men, while suitability for men of African descent has been questioned. OBJECTIVE: To compare baseline characteristics, follow-up, and outcomes for men on AS for PCa, according to ethnicity. DESIGN SETTING AND PARTICIPANTS: The study cohort included 13 centres from the GAP3 consortium that record ethnicity (categorised broadly as Caucasian/white, African/Afro-Caribbean/black, Asian, mixed/other, and unknown). Men with biopsy grade group >2, prostate-specific antigen (PSA) >20 ng/ml, T stage ≥cT3, or age >80 yr were excluded. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinical characteristics, follow-up schedules, outcome status, and reasons for discontinuation were compared across ethnic groups. Risk of upgrading, potential disease progression (grade group ≥3 or T stage ≥3), suspicious indications (any upgrading, number of positive cores >3, T stage ≥cT3, PSA >20 ng/ml, or PSA density >0.2 ng/ml/cc2), and conversion to treatment were assessed using mixed-effect regression models. RESULTS AND LIMITATIONS: The eligible cohort (n = 9158) comprised 83% Caucasian men, 6% men of African descent, 5% Asian men, 2% men of mixed/other ethnicity, and 4% men of unknown ethnicity. Risks of suspicious indicators (hazard ratio = 1.27; 95% confidence interval [CI] 1.12-1.45), upgrading (odds ratio [OR] = 1.40; 95% CI 1.14-1.71), and potential progression (OR = 1.46; 95% CI 1.06-2.01) were higher among African/black than among Caucasian/white men. Risk of transitioning to treatment did not differ by ethnicity. More Asian than Caucasian men converted without progression (42% vs 26%, p < 0.001). Heterogeneity in surveillance protocols and racial makeup limit interpretation. CONCLUSIONS: This multinational study found differences in the risk of disease progression and transitioning to treatment without signs of progression between ethnic groups. Further research is required to determine whether differences are due to biology, sociocultural factors, and/or clinical practice. PATIENT SUMMARY: This international study compared prostate cancer active surveillance outcomes by ethnicity. Risks of upgrading and disease progression were higher among African than among Caucasian men. Transitioning to treatment without progression was highest among Asian men. Understanding of these differences requires further investigation.

Erectile Function Following Surgery for Benign Prostatic Obstruction: A Systematic Review and Network Meta-analysis of Randomised Controlled Trials.

CONTEXT: Benign prostatic obstruction (BPO) is associated with sexual dysfunction. Furthermore, numerous BPO interventions may themselves impact sexual function. OBJECTIVE: To perform a systematic review with network meta-analysis to evaluate how BPO interventions affect erectile function. EVIDENCE ACQUISITION: Three databases were searched for randomised controlled trials (RCTs) comparing surgical interventions for BPO. The primary outcome was postoperative International Index of Erectile Function-5 (IIEF-5) score at ten time points up to 72 mo. A random-effects Bayesian network meta-analysis with meta-regression was performed. In comparison to monopolar transurethral resection (mTURP), the mean difference (MD) with 95% credible interval (CrI) and rank probability (rank p) were calculated for interventions. The mean baseline score was studied in meta-regression. τ2 values were used to quantify heterogeneity. EVIDENCE SYNTHESIS: A total of 48 papers (33 RCTs, 5159 patients, 16 interventions) were included. Prostatic urethral lift (PUL) ranked highest at 1 mo (MD 3.88, 95% CrI -0.47 to 8.25; rank p = 0.742), 6 mo (MD 2.43, 95% CrI -0.72 to 5.62; rank p = 0.581), 12 mo (MD 2.94, 95% CrI -0.26 to 6.12, rank p = 0.782), and 24 mo (MD 3.63, 95% CrI 0.14 to 7.11; rank p = 0.948), at which point statistical significance was reached. At time points up to 60 mo, there were no statistically significant comparisons for other interventions. Analyses were not possible at 18, 48, or 72 mo. ß did not reach statistical significance in meta-regression. τ2 was highest at 1 mo (0.56) and 60 mo (0.55). CONCLUSIONS: PUL ranked highly and resulted in erectile function improvement at 24 mo compared to mTURP, but direct evidence is lacking. We did not observe significant differences in erectile function following other interventions up to 60 mo. Owing to heterogeneity, our conclusions are weakest at 1 and 60 mo. Further RCTs comparing sexual function outcomes are recommended, such as PUL versus holmium laser or bipolar enucleation. PATIENT SUMMARY: Different surgical treatments can be used to treat benign enlargement of the prostate causing urinary problems. We compared the effects of various treatments on erectile function at time points up to 5 years after surgery. Compared to surgical removal of some of the prostate gland (transurethral resection of the prostate, TURP), a technique called prostatic urethral lift resulted in better erectile function scores at 24 months. However, other treatments did not differ in their effect on erectile function.

Guy's and St Thomas NHS Foundation active surveillance prostate cancer cohort: a characterisation of a prostate cancer active surveillance database.

BACKGROUND: The routine clinical use of serum prostatic specific antigen (PSA) testing has allowed earlier detection of low-grade prostate cancer (PCa) with more favourable characteristics, leading to increased acceptance of management by active surveillance (AS). AS aims to avoid over treatment in men with low and intermediate-risk PCa and multiple governing bodies have described several AS protocols. This study provides a descriptive profile of the Guy's and St Thomas NHS Foundation Trust (GSTT) AS cohort as a platform for future research in AS pathways in PCa. METHODS: Demographic and baseline characteristics were retrospectively collected in a database for patients at the GSTT AS clinic with prospective collection of follow-up data from 2012. Seven hundred eighty-eight men being monitored at GSTT with histologically confirmed intermediate-risk PCa, at least 1 follow-up appointment and diagnostic characteristics consistent with AS criteria were included in the profile. Descriptive statistics, Kaplan-Meier survival curves and multivariable Cox proportion hazards regression models were used to characterize the cohort. DISCUSSION: A relatively large proportion of the cohort includes men of African/Afro-Caribbean descent (22%). More frequent use of magnetic resonance imaging and trans-perineal biopsies at diagnosis was observed among patients diagnosed after 2012. Those who underwent trans-rectal ultrasound diagnostic biopsy received their first surveillance biopsy 20 months earlier than those who underwent trans-perineal diagnostic biopsy. At 3 years, 76.1% men remained treatment free. Predictors of treatment progression included Gleason score 3 + 4 (Hazard ratio (HR): 2.41, 95% Confidence interval (CI): 1.79-3.26) and more than 2 positive cores taken at biopsy (HR: 2.65, CI: 1.94-3.62). A decreased risk of progressing to treatment was seen among men diagnosed after 2012 (HR: 0.72, CI: 0.53-0.98). CONCLUSION: An organised biopsy surveillance approach, via two different AS pathways according to the patient's diagnostic method, can be seen within the GSTT cohort. Risk of patients progressing to treatment has decreased in the period since 2012 compared with the prior period with more than half of the cohort remaining treatment free at 5 years, highlighting that the fundamental aims of AS at GSTT are being met. Thus, this cohort is a good resource to investigate the AS treatment pathway.

Presentation, follow-up, and outcomes among African/Afro-Caribbean men on active surveillance for prostate cancer: experiences of a high-volume UK centre.

BACKGROUND: Experiences of African/Afro-Caribbean men on active surveillance (AS) for prostate cancer (PCa) in the United Kingdom (UK) are not well documented. We compared follow-up appointments, adherence, and clinical outcomes among African/Afro-Caribbean men on AS at a high-volume UK hospital with other ethnicities. METHODS: Men with confirmed low-intermediate risk Pca who attended the AS clinic (2005-2016) and had undergone ≥1 follow-up biopsy (n = 458) were included. Non-adherence (defined as >20% missed appointments), suspicion of disease progression (any upgrading, >30% positive cores, cT-stage > 3, PIRADS > 3), any upgrading from diagnostic biopsy and conversion to active treatment (prostatectomy, radiotherapy or hormone therapy) according to ethnicity (African/Afro-Caribbean versus other ethnicities) were assessed using multivariable regression analysis. RESULTS: Twenty-three percent of eligible men were recorded as African/Afro-Caribbean, while the remainder were predominantly Caucasian. African/Afro-Caribbean men had slightly lower PSA at diagnosis (median 5.0 vs. 6.0 ng/mL) and more positive cores at diagnosis (median 2 vs. 1). They had a substantially higher rate of non-attendance at scheduled follow-up visits (24% vs. 10%, p < 0.001). Adjusted analyses suggest African/Afro-Caribbean men may be at increased risk of disease progression (hazard ratio [HR]: 1.38; 95% confidence interval [CI] 0.99-1.91, P = 0.054) and upgrading (HR: 1.29; 95% CI 0.87-1.92, P = 0.305), though neither reached statistical significance. No difference in risk of conversion to treatment was observed between ethnic groups (HR: 1.03; 95% CI 0.64-1.47, P = 0.873). CONCLUSIONS: African/Afro-Caribbean men on AS for PCa in the UK are less likely to adhere to scheduled appointments, suggesting a more tailored service addressing their specific needs may be required. While African/Afro-Caribbean men were no more likely to convert to treatment than Caucasian/other men, findings of a potentially higher risk of disease progression signal the need for careful selection and monitoring of African/Afro-Caribbean men on AS. Larger prospective, multicentre studies with longer follow-up are required to provide more definitive conclusions.

Negative first follow-up prostate biopsy on active surveillance is associated with decreased risk of upgrading, suspicion of progression and converting to active treatment.

OBJECTIVE: To determine the risk of disease progression and conversion to active treatment following a negative biopsy while on active surveillance (AS) for prostate cancer (PCa). PATIENTS AND METHODS: Men on an AS programme at a single tertiary hospital (London, UK) between 2003 and 2018 with confirmed low-intermediate-risk PCa, Gleason Grade Group <3, clinical stage 30% positive cores, magnetic resonance imaging (MRI) Likert score >3/T3 or PSA level of >20 ng/mL. Conversion to treatment included radical or hormonal treatment. RESULTS: Among the 460 eligible patients, 23% had negative follow-up biopsy findings. The median follow-up was 62 months, with one to two repeat biopsies and two MRIs per patient during that period. Negative biopsy findings at first repeat biopsy were associated with decreased risk of converting to active treatment (hazard ration [HR] 0.18, 95% confidence interval [CI] 0.09-0.37; P < 0.001), suspicion of disease progression (HR 0.56, 95% CI: 0.34-0.94; P = 0.029), and upgrading (HR 0.48, 95% CI 0.23-0.99; P = 0.047). Data are limited by fewer men with multiple follow-up biopsies. CONCLUSION: A negative biopsy finding at the first scheduled follow-up biopsy among men on AS for PCa was strongly associated with decreased risk of subsequent upgrading, clinical or radiological suspicion of disease progression, and conversion to active treatment. A less intense surveillance protocol should be considered for this cohort of patients.

Targeted and systematic cognitive freehand-guided transperineal biopsy: is there still a role for systematic biopsy?

OBJECTIVES: To assess whether targeted cognitive freehand-assisted transperineal biopsies using a PrecisionpointTM device still require additional systematic biopsies to avoid missing clinically significant prostate cancer, and to investigate the benefit of a quadrant-only biopsy approach to analyse whether a quadrant or extended target of the quadrant containing the target only would have been equivalent to systematic biopsy. PATIENTS AND METHODS: Patients underwent combined systematic mapping and targeted transperineal prostate biopsies at a single institution. Biopsies were performed using the Precisionpoint device (Perineologic, Cumberland, MD, USA) under either local anaesthetic (58%, 163/282), i.v. sedation (12%, 34/282) or general anaesthetic (30%, 85/282). A mean (range) of 24 (5-42) systematic and 4.2 (1-11) target cores were obtained. Magnetic resonance imaging (MRI) scans were reported using the Likert scale. Clinically significant cancer was defined as Gleason 7 or above. Histopathological results were correlated with the presence of an MRI abnormality within a spatial quadrant and the other adjoining or non-adjoining (opposite) quadrants. Histological concordance with radical prostatectomy specimens was analysed. RESULTS: A total of 282 patients were included in this study. Their mean (range) age was 66.8 (36-80) years, median (range) prostate-specific antigen level 7.4 (0.91-116) ng/mL and mean prostate volume 45.8 (13-150) mL. In this cohort, 82% of cases (230/282) were primary biopsies and 18% (52/282) were patients on surveillance. In all, 69% of biopsies (195/282) were identified to have clinically significant disease (Gleason ≥3 + 4). Any cancer (Gleason ≥3 + 3) was found in 84% (237/282) of patients. Of patients with clinically significant disease, the target biopsies alone picked up 88% (171/195), with systematic biopsy picking up the additional 12% (24/195) that the target biopsies missed. This altered with Likert score; 73% of Likert score 3 disease was detected by target biopsy, 92% of Likert score 4 and 100% of Likert score 5. Target biopsies with additional same-quadrant-only systematic cores picked up 75% (18/24) of significant cancer that was missed on target only, found in the same quadrant as the target. CONCLUSION: Systematic biopsy is still an important tool when evaluating all patients referred for prostate biopsy, but the need is decreased with increasing suspicion on MRI. Patients with very high suspicion of prostate cancer (Likert score 5) may not require systematic cores, unless representative surrounding biopsies are required for other specific treatments (e.g. focal therapy, or operative planning). More prospective studies are needed to evaluate this in full.

The genetic landscapes of urological cancers and their clinical implications in the era of high-throughput genome analysis.

OBJECTIVE: With the advent of high-throughput genome analysis, we are increasingly able to sequence and hence understand the pathogenic processes underlying individual cancers. Recently, consortiums such as The Cancer Genome Atlas (TCGA) have performed large-scale projects to this end, providing significant amounts of information regarding the genetic landscapes of several cancers. PATIENTS AND METHODS: We performed a narrative review of studies from the TCGA and other major studies. We aimed to summarise data exploring the clinical implications of specific genetic alterations, both prognostically and therapeutically, in four major urological cancers. These were renal cell carcinoma, muscle-invasive bladder cancer/carcinoma, prostate cancer, and testicular germ cell tumours. RESULTS: With these four urological cancers, great strides have been made in the molecular characterisation of tumours. In particular, recent studies have focussed on identifying molecular subtypes of tumours with characteristic genetic alterations and differing prognoses. Other prognostic alterations have also recently been identified, including those pertaining to epigenetics and microRNAs. In regard to treatment, numerous options are emerging for patients with these cancers such as including immune checkpoint inhibition, epigenetic-based treatments, and agents targeting MAPK, PI3K, and DNA repair pathways. There are a multitude of trials underway investigating the effects of these novel agents, the results of which are eagerly awaited. CONCLUSIONS: As medicine chases the era of personalised care, it is becoming increasingly important to provide individualised prognoses for patients. Understanding how specific genetic alterations affects prognosis is key for this. It will also be crucial to provide highly targeted treatments against the specific genetics of a patient's tumour. With work performed by the TCGA and other large consortiums, these aims are gradually being achieved. Our review provides a succinct overview of this exciting field that may underpin personalised medicine in urological oncology.

Prostate cancer cells enhance interleukin-15-mediated expansion of NK cells.

OBJECTIVES: To identify cytokines that can activate and expand NK cells in the presence of prostate cancer cells in order to determine whether these agents may be useful in future intra-tumoural administration in pre-clinical and clinical prostate cancer trials. MATERIALS AND METHODS: Lymphocytes isolated from normal donor blood were set up in co-cultures with either cancer or non-cancerous prostate cell lines, together with each of the cytokines interleukin (IL)-2, IL-12, IL-15, interferon (IFN)-γ or IL-21 for a period of 7 days. Then, expansion of NK cells, NKT cells and CD8 T cells was measured by flow cytometry and compared with the expansion of the same cells in the absence of prostate cells. The cytotoxic activity of NK cells, as measured by perforin and tumour cell killing, was also assessed. NK cell receptors and their corresponding ligands on prostate tumour cells were analysed to determine whether any of these were modulated by co-culture. The role of the tumour-secreted heat shock proteins HSP90 and HSP70 in the expansion of NK cells in the co-cultures was also investigated because of their effects on NK and CD8 T-cell activation. RESULTS: We showed that, among a panel of cytokines known to cause NK cell activation and expansion, only IL-15 could actively induce expansion of NK, NKT and CD8 T cells in the presence of prostate cancer cell lines. Furthermore, the expansion of NK cells was far greater (up to 50% greater) in the presence of the cancer cells (LNCaP, PC3) than when lymphocytes were incubated alone. In contrast, non-cancerous cell lines (PNT2 and WPMY-1) did not exert any expansion of NK cells. The cytolytic activity of the NK cells, as measured by perforin, CD107a and killing of tumour cells, was also greatest in co-cultures with IL-15. Examination of NK cell receptors shows that NKG2D is upregulated to a greater degree in the presence of prostate cancer cells, compared with the upregulation with IL-15 in lymphocytes alone. However, blocking of NKG2D does not inhibit the enhanced expansion of NK cells in the presence of tumour cells. CONCLUSIONS: Among a panel of NK cell-activating cytokines, IL-15 was the only cytokine that could stimulate expansion of NK cells in the presence of prostate cancer cells; therefore IL-15 may be a good candidate for novel future intra-tumoural therapy of the disease.

Initial outcomes of local anaesthetic freehand transperineal prostate biopsies in the outpatient setting.

OBJECTIVES: To evaluate the histopathological outcomes, morbidity and tolerability of freehand transperineal (TP) prostate biopsies using the PrecisionPoint™ access system (Perineologic, Cumberland, MD, USA) under local anaesthetic (LA) in the day surgery and outpatient environments, as systematic and targeted biopsies can be taken with the potential for reduced morbidity, particularly sepsis. PATIENTS AND METHODS: In all, 176 patients underwent freehand TP prostate biopsies from May 2016 to November 2017. The procedure was carried out either under LA alone or with the addition of sedation. Magnetic resonance imaging (MRI) scans were reported using the Prostate Imaging-Reporting and Data System (PI-RADS), version 2. Tolerability was assessed using a visual analogue scale pain score for each procedural stage. Histopathological outcomes and complications were recorded. RESULTS: The mean (range) age was 65 (36-83) years, median (range) prostate-specific antigen level was 7.9 (0.7-1374) ng/mL, and the mean (range) prostate volume 45 (15-157) mL. Biopsies were taken under LA alone (160 patients, 90%) or under LA with sedation (16, 9%). The main indication for biopsy was primary diagnosis (88.6%). In all, 91 (52%) patients underwent systematic TP biopsies (mean 24.2 cores). Cognitive MRI-targeted biopsies alone were performed in 45 patients (26%; mean 6.8 cores), and 40 (23%) had both systematic and target biopsies (mean 27.9 cores). Of the 75 patients who had primary systematic biopsies alone, 46 (61%) were positive, and 28/46 (60.9%) were diagnosed with clinically significant disease (Gleason ≥3+4). VAS pain scores were greatest during LA administration. There were five complications (2.8%, Clavien-Dindo Grade I/II). No patients developed urosepsis. CONCLUSIONS: Freehand TP biopsies using the PrecisionPoint access system is a safe, tolerable and effective method for systematic and targeted biopsies under LA in the outpatient setting. It has replaced transrectal biopsies in our centre and has potential to transform practice.

IL-15 Upregulates Telomerase Expression and Potently Increases Proliferative Capacity of NK, NKT-Like, and CD8 T Cells.

Interleukin-15 (IL-15) is a cytokine that has been shown to expand CD8 T cell and natural killer (NK) cell populations, and therefore has potential for potentiating adoptive immune cell therapy for cancer. Previously, IL-15 has been shown to induce proliferation of CD8 memory T cells through activation of telomerase. Here, we investigated whether telomerase is also activated during the IL-15 mediated proliferation of NK and NKT-like (CD56+CD3+) cells. We also examined the extent that each of the three signaling pathways known to be stimulated by IL-2/IL-15 (JAK-STAT, PI3K-AKT Ras-RAF/MAPK) were activated and involved in the telomerase expression in the three cell types NK, NKT, or CD8 T cells. To assess cell proliferation and doubling, peripheral blood mononuclear cells (PBMCs) or isolated NK, NKT-like or CD8 T cells were incubated with varying concentrations of IL-15 or IL-2 for 7 days. CD8 T, NK, and NKT cell expansion was determined by fluorophore-conjugated antibody staining and flow cytometry. Cell doubling was investigated using carboxyfluorescein-succinimidyl-ester (CFSE). Telomerase expression was investigated by staining cells with anti-telomerase reverse transcriptase (anti-TERT). Telomerase activity in CD56+ and CD8 T cells was also measured via Telomerase Repeat Amplification Protocol (TRAP). Analysis of cellular expansion, proliferation and TERT expression concluded that IL-15 increased cellular growth of NK, NKT, and CD8 T cells more effectively than IL-2 using low or high doses. IL-15, increased TERT expression in NK and NKT cells by up to 2.5 fold, the same increase seen in CD8 T cells. IL-2 had effects on TERT expression only at high doses (100-1000 ng/ml). Proteome profiling identified that IL-15 activated selected signaling proteins in the three pathways (JAK-STAT, PI3K-AKT, Ras-MAPK) known to mediate IL-2/IL-15 signaling, more strongly than IL-2. Evaluation by signaling pathway inhibitors revealed that JAK/STAT and PI3K/AKT pathways are important in IL-15's ability to upregulate TERT expression in NK and NKT cells, whereas all three pathways were involved in CD8 T cell TERT expression. In conclusion, this study shows that IL-15 potently stimulates TERT upregulation in NK and NKT cells in addition to CD8 T cells and is therefore a valuable tool for adoptive cell therapies.

Imaging modalities aiding nerve-sparing during radical prostatectomy.

Nerve-sparing robot-assisted radical prostatectomy has decreased the post-surgical complications of prostate surgery, but has not eliminated it. The ability to view the microstructure will enable better surgical decisions and lead to better post-surgical outcomes. An ideal imaging modality should provide rapid image acquisition, be low cost, and be specific to the tissue being examined. This article aims to review the current literature to compare three main techniques: multiphoton microscopy (MPM), optical coherence tomography, and confocal microscopy, to see which of these techniques may be best applied in surgical procedures in the future. Embase and Medline were used as the primary databases. Combinations of various key words were used while researching the literature. These included: "Radical prostatectomy," "nerve-sparing," "nerve mapping," "multiphoton microscopy," "Confocal microscopy," and "Optical Coherence Tomography." Thereafter, the relevant results were selected and used in the review. Although optical coherence tomography is a low cost and compact modality, it lacks cellular resolution, while confocal microscopy offers great cellular resolution but lacks depth. MPM, on the other hand, provides sufficient depth and produces high-resolution images. The limitation of MPM is its lack of portability, however the advent of dual-modality MPM may be a way forward.

A Single Educational Seminar Increases Confidence and Decreases Dropout from Active Surveillance by 5 Years After Diagnosis of Prostate Cancer.

BACKGROUND: Researchers remain divided on the major causes of dropout from active surveillance (AS), with rates of up to 38% among men with no evidence of prostate cancer (PC) progression. OBJECTIVE: To develop and evaluate an educational intervention in terms of adherence to AS among men with low- to intermediate-risk PC. DESIGN, SETTING, AND PARTICIPANTS: We first carried out focus group discussions with men who had remained on and dropped out of AS to inform an intervention to increase adherence to AS. A total of 255 consecutive men who had selected AS were then recruited to either standard care (written information and access to a nurse specialist) or standard care and the intervention. INTERVENTION: An educational seminar was designed by patients and clinicians including information on imaging, biopsy techniques, understanding pathology, large AS cohorts - mortality and morbidity risk and diet and lifestyle advice. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The proportion of men dropping out of AS for reasons other than disease progression was assessed at 1 and 5yr after AS selection using multivariate logistic regression. RESULTS AND LIMITATIONS: Common themes influencing decision-making by men on AS were identified: (1) clinical consistency; (2) information; and (3) lifestyle advice. Addition of an educational seminar led to significantly fewer men dropping out of AS: at 1 and 5yr the dropout rate was 25% and 42%, respectively, in the standard care group, compared to 11% and 22% (p=0.001) in the intervention group. In the intervention group, 18 men failed to attend the seminar. CONCLUSIONS: The AS dropout rate was halved following a single educational seminar delivered to groups of men with intermediate- or low-risk PC, even at 5yr. PATIENT SUMMARY: Men on active surveillance (AS) for prostate cancer feel more supported when provided with an educational seminar within 3 mo of their treatment choice. The seminar halved the number of men dropping-out of AS, even at 5yr.