Impact of the COVID-19 pandemic on the diagnosis and treatment of men with prostate cancer.

OBJECTIVE: To determine the impact of the COVID-19 pandemic on diagnostic and treatment activity in 2020 across hospital providers of prostate cancer (PCa) care in the English National Health Service. METHODS: Diagnostic and treatment activity between 23 March (start of first national lockdown in England) and 31 December 2020 was compared with the same calendar period in 2019. Patients newly diagnosed with PCa were identified from national rapid cancer registration data linked to other electronic healthcare datasets. RESULTS: There was a 30.8% reduction (22 419 vs 32 409) in the number of men with newly diagnosed PCa in 2020 after the start of the first lockdown, compared with the corresponding period in 2019. Men diagnosed in 2020 were typically at a more advanced stage (Stage IV: 21.2% vs 17.4%) and slightly older (57.9% vs 55.9% ≥ 70 years; P < 0.001). Prostate biopsies in 2020 were more often performed using transperineal (TP) routes (64.0% vs 38.2%). The number of radical prostatectomies in 2020 was reduced by 26.9% (3896 vs 5331) and the number treated by external beam radiotherapy (EBRT) by 14.1% (9719 vs 11 309). Other changes included an increased use of EBRT with hypofractionation and reduced use of docetaxel chemotherapy in men with hormone-sensitive metastatic PCa (413 vs 1519) with related increase in the use of enzalutamide. CONCLUSION: We found substantial deficits in the number of diagnostic and treatment procedures for men with newly diagnosed PCa after the start of the first lockdown in 2020. The number of men diagnosed with PCa decreased by about one-third and those diagnosed had more advanced disease. Treatment patterns shifted towards those that limit the risk of COVID-19 exposure including increased use of TP biopsy, hypofractionated radiation, and enzalutamide. Urgent concerted action is required to address the COVID-19-related deficits in PCa services to mitigate their impact on long-term outcomes.

Urinary incontinence and use of incontinence surgery after radical prostatectomy: a national study using patient-reported outcomes.

OBJECTIVES: To investigate whether patient-reported urinary incontinence (UI) and bother scores after radical prostatectomy (RP) result in subsequent intervention with UI surgery. PATIENTS AND METHODS: Men diagnosed with prostate cancer in the English National Health Service between April 2014 and January 2016 were identified. Administrative data were used to identify men who had undergone a RP and those who subsequently underwent a UI procedure. The National Prostate Cancer Audit database was used to identify men who had also completed a post-treatment survey. These surveys included the Expanded Prostate Cancer Composite Index (EPIC-26). The frequency of subsequent UI procedures, within 6 months of the survey, was explored according to EPIC-26 UI scores. The relationship between 'good' (≥75) or 'bad' (≤25) EPIC-26 UI scores and perceptions of urinary bother was also explored (responses ranging from 'no problem' to 'big problem' with respect to their urinary function). RESULTS: We identified 11 290 men who had undergone a RP. The 3-year cumulative incidence of UI surgery was 2.5%. After exclusions, we identified 5165 men who had also completed a post-treatment survey after a median time of 19 months (response rate 74%). A total of 481 men (9.3%) reported a 'bad' UI score and 207 men (4.0%) also reported that they had a big problem with their urinary function. In all, 47 men went on to have UI surgery within 6 months of survey completion (0.9%), of whom 93.6% had a bad UI score. Of the 71 men with the worst UI score (zero), only 11 men (15.5%) subsequently had UI surgery. CONCLUSION: In England, there is a significant number of men living with severe, bothersome UI after RP, and an unmet clinical need for UI surgery. The systematic collection of patient-reported outcomes could be used to identify men who may benefit from UI surgery.

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.

Is the Toxicity of Salvage Prostatectomy Related to the Primary Prostate Cancer Therapy Received?

PURPOSE: To compare the toxicity profile and oncological outcome of salvage radical prostatectomy following focal therapy versus salvage radical prostatectomy after radiation therapies (external beam radiation therapy or brachytherapy). MATERIALS AND METHODS: Data concerning all men undergoing salvage radical prostatectomy for recurrent prostate cancer after either focal therapy, external beam radiation therapy or brachytherapy were retrospectively collected from 4 high volume surgical centers. The primary outcome measure of the study was toxicity of salvage radical prostatectomy characterized by any 30-day postoperative Clavien-Dindo complication rate, 12-month continence rate and 12-month potency rate. The secondary outcome was oncological outcome after salvage radical prostatectomy including positive margin rate and 12-month biochemical recurrence rate. Biochemical recurrence was estimated using Kaplan-Meier methods and significant differences were calculated using a log rank test. Median followup was 29.5 months. RESULTS: Between April 2007 and September 2018, 185 patients underwent salvage radical prostatectomy of whom 95 had salvage radical prostatectomy after focal therapy and 90 had salvage radical prostatectomy after radiation therapy (external beam radiation therapy or brachytherapy). Salvage radical prostatectomy after radiation therapy was associated with a significantly higher 30-day Clavien-Dindo I-IV complication rate (34% vs 5%, p <0.001). At 12 months following surgery, patients undergoing salvage radical prostatectomy after focal therapy had significantly better continence (83% pad-free vs 49%) while potency outcomes were similar (14% vs 11%). Men undergoing salvage radical prostatectomy after radiation therapy had a significantly higher stage and grade of disease together with a higher positive surgical margin rate (37% vs 13%, p=0.001). The 3-year biochemical recurrence after focal therapy was 35% compared to 32% after radiation therapy (p=0.76). In multivariable analysis, men undergoing salvage radical prostatectomy after focal therapy experienced a higher risk of biochemical recurrence (HR 0.36, 95% CI 0.16-0.82, p=0.02). CONCLUSIONS: This multicenter study demonstrates the toxicity of salvage radical prostatectomy in terms of perioperative complications and long-term urinary continence recovery is dependent on initial primary prostate cancer therapy received with men undergoing salvage radical prostatectomy after focal therapy experiencing lower postoperative complication rates and better urinary continence outcomes.

Outcomes of the RAFT trial: robotic surgery after focal therapy.

OBJECTIVES: To report toxicity of treatment observed in men participating in the Robotic surgery After Focal Therapy (RAFT) clinical trial. PATIENTS AND METHODS: Men were eligible for this prospective single group interventional study if they had histologically confirmed recurrent/residual prostate adenocarcinoma following primary FT. The short-form Expanded Prostate Cancer Index Composite (EPIC-26) measured prior to salvage robotic prostatectomy (S-RARP) and 3-monthly post-operatively together with Clavien-Dindo complications (I-IV). Secondary outcomes included biochemical recurrence-free survival (BCFS) following surgery and need for salvage treatment after surgery. This study is registered with ClinicalTrials.gov NCT03011606. RESULTS: Twenty-four men were recruited between February 2016 and September 2018. 1 patient withdrew from the trial after consenting and before S-RARP. 23 men completed 12-month post S-RARP follow-up. Median EPIC-26 urinary continence scores initially deteriorated after 3 months (82.4 vs 100) but there was no statistically significant difference from baseline at 12 months (100 vs 100, P = 0.31). Median lower urinary tract symptom scores improved after 12 months compared to baseline (93.8 vs 87.5, P = 0.01). At 12 months, 19/23 (83%) were pad-free and 22/23 (96%) required 0/1 pads. Median sexual function subscale scores deteriorated and remained low at 12 months (22.2 vs 58.3, P < 0.001). Utilising a minimally important difference of nine points, at 12 months after surgery 17/23 (74%) reported urinary continence to be 'better' or 'not different' to pre-operative baseline. The corresponding figure for sexual function (utilising a minimally important difference of 12 points) was 7/23 (30%). There was no statistically significant difference on median bowel/hormonal subscale scores. Only a single patient had a post-operative complication (Clavien-Dindo Grade I). BCFS at 12 months after surgery was 82.6% (95% confidence interval [CI]: 60.1-93.1%) while 4/23 (17%) received salvage radiation. CONCLUSIONS: The RAFT clinical trial suggests toxicity of surgery after FT is low, with good urinary function outcomes, albeit sexual function deteriorated overall. Oncological outcomes at 12 months appear acceptable.

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.

The management impact of 68gallium-tris(hydroxypyridinone) prostate-specific membrane antigen (68Ga-THP-PSMA) PET-CT imaging for high-risk and biochemically recurrent prostate cancer.

PURPOSE: To determine the impact on clinical management of patients with high-risk (HR) prostate cancer at diagnosis and patients with biochemical recurrence (BCR) using a new kit form of 68Ga-prostate-specific membrane antigen (PSMA), namely tris(hydroxypyridinone) (THP)-PSMA, with positron emission tomography-computed tomography (PET-CT). METHODS: One hundred eighteen consecutive patients (50 HR, 68 BCR) had management plans documented at a multidisciplinary meeting before 68Ga-THP-PSMA PET-CT. Patients underwent PET-CT scans 60-min post-injection of 68Ga-THP-PSMA (mean 159 ± 21.2 MBq). Post-scan management plans, Gleason score, prostate-specific antigen (PSA) and PSA doubling time (PSAdt) were recorded. RESULTS: HR group: 12/50 (24%) patients had management changed (9 inter-modality, 3 intra-modality). Patients with PSA < 20 µg/L had more frequent management changes (9/26, 34.6%) compared with PSA > 20 µg/L (3/24, 12.5%). Gleason scores > 8 were associated with detection of more nodal (4/16, 25% vs 5/31, 16.1%) and bone (2/16, 12.5% vs 2/31, 6.5%) metastases. BCR group: Clinical management changed in 23/68 (34%) patients (17 inter-modality, 6 intra-modality). Forty out of 68 (59%) scans were positive. Positivity rate increased with PSA level (PSA < 0.5 µg/L, 0%; PSA 0.5-1.0 µg/L, 35%; PSA 1.0-5.0 µg/L, 69%; PSA 5.0-10.0 µg/L, 91%), PSAdt of < 6 months (56% vs 45.7%) and Gleason score > 8 (78.9% vs 51.2%). CONCLUSIONS: 68Ga-THP-PSMA PET-CT influences clinical management in significant numbers of patient with HR prostate cancer pre-radical treatment and is associated with PSA. Management change also occurs in patients with BCR and is associated with PSA and Gleason score, despite lower scan positivity rates at low PSA levels < 0.5 µg/L.

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.

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.

Comparison of complications after transrectal and transperineal prostate biopsy: a national population-based study.

OBJECTIVES: To assess the complications of transrectal (TR) compared to transperineal prostate (TP) biopsies. PATIENTS AND METHODS: Men diagnosed with prostate cancer between 1 April 2014 and 31 March 2017 in England were identified in the National Prostate Cancer Audit. Administrative hospital data were then used to categorize the type of prostate biopsy and subsequent complications requiring hospital admission. Administrative hospital data were used to identify patients staying overnight immediately after biopsy and those readmitted separately for hospital admissions because of sepsis, urinary retention or haematuria. Procedure-related mortality and total length of hospital stay within 30 days were also recorded. Generalized linear models were used to calculate adjusted risk differences (aRDs). RESULTS: A total of 73 630 patients undergoing prostate biopsy were identified. Those undergoing TP biopsy (n = 13 723) were more likely to have an overnight hospital stay (12.3% vs 2.4%; aRD 9.7%, 95% confidence interval [CI] 7.1-12.3), were less likely to be readmitted because of sepsis (1.0% vs 1.4%; aRD -0.4%, CI -0.6 to -0.2), and were more likely to be readmitted with urinary retention (1.9% vs 1.0%; aRD 1.1%, CI 0.7-1.4) than those undergoing a TR biopsy (n = 59 907). There were no significant differences in the risk of haematuria or mortality. CONCLUSIONS: Our results showed that TP biopsy had a lower risk of readmission for sepsis but a higher risk of readmission for urinary retention than TR biopsy. Use of the TP route would prevent one readmission for sepsis in 278 patients at the cost of three additional patients readmitted for urinary retention.

Diabetes in day case general and vascular surgery: A multicentre regional audit.

BACKGROUND: People with Diabetes Mellitus (DM) are at increased risk of postoperative complications if their HbA1C readings are not well controlled. In the UK, there are clear national guidelines requiring all people with DM to have HbA1C blood testing within 6months before undergoing surgery and that these readings should be below 69 mmol/mol if this is safe to achieve. The aim of this study was to determine whether hospitals in the region were compliant with the guidelines. METHODS: Data were prospectively collected from seven hospitals across the East of England region from 1st October 2017 to 31st March 2018 (6 months) in all people with DM undergoing elective day case procedures in General and Vascular surgery for benign disease. RESULTS: A total of 181 people with DM were included in the study, of whom 77.9% were male patients and the median age was 63 years. The three most commonly performed operations were laparoscopic cholecystectomy (20.9%, n = 38/181), inguinal hernia repair (20.4%, n = 37/181) and umbilical/para-umbilical hernia repair (11.0%, n = 20/181). In keeping with the national guidelines, only 86.7% (n = 157/181) of patients had an HbA1C tested within 6 months prior to their surgery date. Of the patients who had a preoperative HbA1C, 14 (n = 14/157, 8.9%) had an HbA1C ≥ 69 mmol/mol, and 12 (n = 12/14, 85.7%) of these proceeded to surgery without optimisation of their HbA1C. CONCLUSION: A significant proportion of people with diabetes undergoing elective day case procedures in our region do not have HbA1C testing within 6 months of their procedure as recommended by the national guidelines. In patients who do have a high HbA1C, the majority still undergo surgery without adequate control of their DM. Greater awareness amongst healthcare workers and robust pathways are required for this vulnerable group of patients if we are to reduce the risk of developing postoperative complication rates.

Impact of cancer service centralisation on the radical treatment of men with high-risk and locally advanced prostate cancer: A national cross-sectional analysis in England.

In many countries, specialist cancer services are centralised to improve outcomes. We explored how centralisation affects the radical treatment of high-risk and locally advanced prostate cancer in the English NHS. 79,085 patients diagnosed with high-risk and locally advanced prostate cancer in England (April 2014 to March 2016) were identified in the National Prostate Cancer Audit database. Poisson models were used to estimate risk ratios (RR) for undergoing radical treatment by whether men were diagnosed at a regional co-ordinating centre ('hub'), for having surgery by the presence of surgical services on-site, and for receiving high dose-rate brachytherapy (HDR-BT) in addition to external beam radiotherapy by its regional availability. Men were equally likely to receive radical treatment, irrespective of whether they were diagnosed in a hub (RR 0.99, 95% CI 0.91-1.08). Men were more likely to have surgery if they were diagnosed at a hospital with surgical services on site (RR 1.24, 1.10-1.40), and more likely to receive additional HDR-BT if they were diagnosed at a hospital with direct regional access to this service (RR 6.16, 2.94-12.92). Centralisation of specialist cancer services does not affect whether men receive radical treatment, but it does affect treatment modality. Centralisation may have a negative impact on access to specific treatment modalities.

Impact of patient choice and hospital competition on patient outcomes after prostate cancer surgery: A national population-based study.

BACKGROUND: Policies that encourage patient choice and hospital competition have been introduced across several countries with the purpose of improving the quality of health care services. The objective of the current national cohort study was to analyze the correlation between choice and competition on outcomes after cancer surgery using prostate cancer as a case study. METHODS: The analyses included all men who underwent prostate cancer surgery in the United Kingdom between 2008 and 2011 (n = 12,925). Multilevel logistic regression was used to assess the effect of a radical prostatectomy center being located in a competitive environment (based on the number of centers within a threshold distance) and being a successful competitor (based on the ability to attract patients from other hospitals) on 3 patient-level outcomes: postoperative length of hospital stay >3 days, 30-day emergency readmissions, and 2-year urinary complications. RESULTS: With adjustment for patient characteristics, men who underwent surgery in centers located in a stronger competitive environment were less likely to have a 30-day emergency readmission, irrespective of the type or volume of procedures performed at each center (odds ratio, 0.46; 95% confidence interval, 0.36-0.60; P = .005). Men who received treatment at centers that were successful competitors were less likely to have a length of hospital stay >3 days (odds ratio, 0.49; 95% confidence interval, 0.25-0.94; P = .02). CONCLUSIONS: The current results suggest for the first time that hospital competition improves short-term outcomes after prostate cancer surgery. Further evaluation of the potential role of patient choice and hospital competition is required to inform health service design in contrast to the role of top-down-driven approaches, which have focused on centralization of services.

Sustained expression of miR-26a promotes chromosomal instability and tumorigenesis through regulation of CHFR.

MicroRNA 26a (miR-26a) reduces cell viability in several cancers, indicating that miR-26a could be used as a therapeutic option in patients. We demonstrate that miR-26a not only inhibits G1-S cell cycle transition and promotes apoptosis, as previously described, but also regulates multiple cell cycle checkpoints. We show that sustained miR-26a over-expression in both breast cancer (BC) cell lines and mouse embryonic fibroblasts (MEFs) induces oversized cells containing either a single-large nucleus or two nuclei, indicating defects in mitosis and cytokinesis. Additionally, we demonstrate that miR-26a induces aneuploidy and centrosome defects and enhances tumorigenesis. Mechanistically, it acts by targeting G1-S transition genes as well as genes involved in mitosis and cytokinesis such as CHFR, LARP1 and YWHAE. Importantly, we show that only the re-expression of CHFR in miR-26a over-expressing cells partially rescues normal mitosis and impairs the tumorigenesis exerted by miR-26a, indicating that CHFR represents an important miR-26a target in the regulation of such phenotypes. We propose that miR-26a delivery might not be a viable therapeutic strategy due to the potential deleterious oncogenic activity of this miRNA.

Robot-assisted radical prostatectomy vs laparoscopic and open retropubic radical prostatectomy: functional outcomes 18 months after diagnosis from a national cohort study in England.

BACKGROUND: Robot-assisted radical prostatectomy (RARP) has been rapidly adopted without robust evidence comparing its functional outcomes against laparoscopic radical prostatectomy (LRP) or open retropubic radical prostatectomy (ORP) approaches. This study compared patient-reported functional outcomes following RARP, LRP or ORP. METHODS: All men diagnosed with prostate cancer in England during April - October 2014 who underwent radical prostatectomy were identified from the National Prostate Cancer Audit and mailed a questionnaire 18 months after diagnosis. Group differences in patient-reported sexual, urinary, bowel and hormonal function (EPIC-26 domain scores) and generic health-related quality of life (HRQoL; EQ-5D-5L scores), with adjustment for patient and tumour characteristics, were estimated using linear regression. RESULTS: In all, 2219 men (77.0%) responded; 1310 (59.0%) had RARP, 487 (21.9%) LRP and 422 (19.0%) ORP. RARP was associated with slightly higher adjusted mean EPIC-26 sexual function scores compared with LRP (3·5 point difference; 95% CI: 1.1-5.9, P=0.004) or ORP (4.0 point difference; 95% CI: 1.5-6.5, P=0.002), which did not meet the threshold for a minimal clinically important difference (10-12 points). There were no significant differences in other EPIC-26 domain scores or HRQoL. CONCLUSIONS: It is unlikely that the rapid adoption of RARP in the English NHS has produced substantial improvements in functional outcomes for patients.

National cohort study comparing severe medium-term urinary complications after robot-assisted vs laparoscopic vs retropubic open radical prostatectomy.

OBJECTIVES: To evaluate the occurrence of severe urinary complications within 2 years of surgery in men undergoing either robot-assisted radical prostatectomy (RARP), laparoscopic radical prostatectomy (LRP) or retropubic open radical prostatectomy (ORP). PATIENTS AND METHODS: We conducted a population-based cohort study in men who underwent RARP (n = 4 947), LRP (n = 5 479) or ORP (n = 6 873) between 2008 and 2012 in the English National Health Service (NHS) using national cancer registry records linked to Hospital Episodes Statistics, an administrative database of admissions to NHS hospitals. We identified the occurrence of any severe urinary or severe stricture-related complication within 2 years of surgery using a validated tool. Multi-level regression modelling was used to determine the association between the type of surgery and occurrence of complications, with adjustment for patient and surgical factors. RESULTS: Men undergoing RARP were least likely to experience any urinary complication (10.5%) or a stricture-related complication (3.3%) compared with those who had LRP (15.8% any or 5.7% stricture-related) or ORP (19.1% any or 6.9% stricture-related). The impact of the type of surgery on the occurrence of any urinary or stricture-related complications remained statistically significant after adjustment for patient and surgical factors (P < 0.01). CONCLUSION: Men who underwent RARP had the lowest risk of developing severe urinary complications within 2 years of surgery.

Metformin and longevity (METAL): a window of opportunity study investigating the biological effects of metformin in localised prostate cancer.

BACKGROUND: Metformin is a biguanide oral hypoglycaemic agent commonly used for the treatment of type 2 diabetes mellitus. In addition to its anti-diabetic effect, metformin has also been associated with a reduced risk of cancer incidence of a number of solid tumours, including prostate cancer (PCa). However, the underlying biological mechanisms for these observations have not been fully characterised in PCa. One hypothesis is that the indirect insulin lowering effect may have an anti-neoplastic action as elevated insulin and insulin like growth factor - 1 (IGF-1) levels play a role in PCa development and progression. In addition, metformin is a potent activator of activated protein kinase (AMPK) which in turn inhibits the mammalian target of rapamycin (mTOR) and other signal transduction mechanisms. These direct effects can lead to reduced cell proliferation. Given its wide availability and tolerable side effect profile, metformin represents an attractive potential therapeutic option for men with PCa. Hence, the need for a clinical trial investigating its biological mechanisms in PCa. METHODS: METAL is a randomised, placebo-controlled, double-blind, window of opportunity study investigating the biological mechanism of metformin in PCa. 100 patients with newly-diagnosed, localised PCa scheduled for radical prostatectomy will be randomised 1:1 to receive metformin (1 g b.d.) or placebo for four weeks (+/- 1 week) prior to prostatectomy. Tissue will be collected from both diagnostic biopsy and prostatectomy specimens. The primary endpoint is the difference in expression levels of markers of the Fatty acid synthase (FASN)/AMPK pathway pre and post treatment between the placebo and metformin arms. Secondary endpoints include the difference in expression levels of indicators of proliferation (ki67 and TUNEL) pre and post treatment between the placebo and metformin arms. METAL is currently open to recruitment at Guy's and St Thomas' Hospital and the Royal Marsden Hospital, London. DISCUSSION: This randomised placebo-controlled double blinded trial of metformin vs. placebo in men with localised PCa due to undergo radical prostatectomy, aims to elucidate the mechanism of action of metformin in PCa cells, which should then enable further larger stratification trials to take place. TRIAL REGISTRATION: EudraCT number 2014-005193-11 . Registered on September 09, 2015.

Quantifying severe urinary complications after radical prostatectomy: the development and validation of a surgical performance indicator using hospital administrative data.

OBJECTIVES: To develop and validate a surgical performance indicator based on severe urinary complications that require an intervention within 2 years of radical prostatectomy (RP), identified in hospital administrative data. PATIENTS AND METHODS: Men who underwent RP between 2008 and 2012 in England were identified using hospital administrative data. A transparent coding framework based on procedure codes was developed to identify severe urinary complications which were grouped into 'stricture', 'incontinence' and 'other'. Their validity as a performance indicator was assessed by evaluating the consistency with diagnosis codes and association with patient and surgical characteristics. Kaplan-Meier methods were used to assess time to first occurrence and multivariable logistic regression was used to estimate adjusted odds ratios (ORs) for patient and surgical characteristics. RESULTS: A total of 17 299 men were included, of whom 2695 (15.6%) experienced at least one severe urinary complication within 2 years. High proportions of men with a complication had relevant diagnosis codes: 86% for strictures and 93% for incontinence. Urinary complications were more common in men from poorer socio-economic backgrounds (OR comparing lowest with highest quintile: 1.45; 95% confidence interval [CI] 1.26-1.67) and in those with prolonged length of hospital stay (OR 1.54, 95% CI 1.40-1.69), and were less common in men who underwent robot-assisted surgery (OR 0.65, 95% CI 0.58-0.74). CONCLUSION: These results show that severe urinary complications identified in administrative data provide a medium-term performance indicator after RP. They can be used for research assessing outcomes of treatment methods and for service evaluation comparing performance of prostate cancer surgery providers.