Advancing research capacity within British urology – a joint BAUS and RCS England two-day workshop

Abstract

This year’s British Association of Urological Surgeons (BAUS) Section of Academic Urology Annual Meeting took place on 1–2 December at The Royal College of Surgeons of England in London. Day 1, chaired by Robert Pickard, was dedicated to clinical trials in urology, celebrating our achievements, addressing the challenges, and exploring ways to advance practice through research. Day 2 consisted of presentations of on-going research work taking place across the United Kingdom (UK) and Ireland together with a ‘Dragon’s Den’, where trainees pitched ideas for research projects that could be taken forward by a national urology trainees research collaborative

Purpose of Meeting Day 1

The purpose of Day 1 was to launch the contribution from Urology UK to the Royal College of Surgeons of England (RCSEng) Clinical Research Initiative (https://www.rcseng.ac.uk/surgeons/research/surgical-research/surgical-clinical-trials). This initiative aims to increase surgical clinical research and ensure that the results are translated to improved patient care. Funding of £15,000 has been generously agreed from BAUS, the Trustees of BJU International Ltd, and The Urology Foundation to support the RCSEng clinical research leads; Mark Emberton (oncology) and Robert Pickard (Benign), to increase the number of urologists acting as principal investigators (PIs) for clinical trials and to ensure that all urology patients are offered participation in clinical research.

Presentations

Setting the scene: BAUS

Mark Speakman, president of BAUS, opened the morning. In his introduction he explained that the BAUS Section of Academic Urology was formed in 2007 to promote expansion of high-quality academic urology, to facilitate interactions between academic clinicians in the UK and Ireland and to act as a forum for discussion of clinical research. It has grown to 244 members, including 94 trainees, fulfilling its aim to nurture future academic urologists. He highlighted that BAUS research priorities involved ‘Cinderella’ topics such as pelvic pain and urinary tract infection (UTI) as well as life-threatening disease such as prostate cancer.

Mr Speakman put the research role of BAUS and its Academic Section into historical perspective, reminding us of the debt we owe to natural philosophers of the Age of Enlightenment: Robert Boyle, Humphrey Davy, and Michael Faraday. Not only do we share the same purpose – to reform society using reason, to challenge ideas grounded in tradition and faith, and to advance knowledge through the scientific method – but we also share the same methods, by clearly stating principles, using correct logic to arrive at conclusions, testing the conclusions against evidence, and then revising the principles in the light of that evidence.

Setting the scene: RCSEng

Dion Morton, director of clinical research at RCSEng, addressed the practical aspects of developing a trials culture in surgery and the role of RCSEng in the process. Less than 2% of government research funding goes into surgical areas despite a third of hospital admissions involving surgery. He highlighted the concern that clinical research in surgery is lacking, pointing out there were 10 times fewer active studies across all surgical specialties in 2011 than in cardiology alone! Professor Morton then introduced the new RCS Clinical Research Initiative: collaboration between the RCS, National Institute for Health Research (NIHR), Cancer Research UK and the Rosetrees Trust. This collaboration has established a network of surgical trials units and surgical research champions across the UK to support new studies across all surgical specialities, ensure innovations are introduced quickly and help reduce variation in care. The program is overseen by an independent steering committee (CRISC) chaired by Sir Michael Rawlins. To gain broad leadership, 16 surgical specialty leads have been appointed with the specific remit to develop new trials and establish clinical networks including patients. Prof Morton introduced Mark Emberton and Robert Pickard as the newly appointed specialty leads for urology, and expressed his hope that the recent success in clinical trial funding and completion run both by consultants and trainees in general surgery can be replicated in urology (Figure 1).

Figure 1.

A clinical academic career in urology

To explore what makes a successful clinical academic, Mark Emberton chaired a discussion among three clinical academic colleagues: Dr Louise Dickinson, Ms Caroline Moore and Mr Hashim Ahmed. All three pursued research in urology, all three succeeded in it, yet each of them did it in his or her own unique way. Dr Dickinson explained how her experience as one of the first academic clinical fellows (ACF) provided opportunities and an environment for exposure to research during clinical training. Having organised a European Consensus Meeting on magnetic resonance imaging (MRI) for prostate cancer and then coordinated a large, multicentre study of focal high-intensity focused ultrasound (HIFU), she was able to develop academic expertise in a focused area and has pursued it further by starting radiology training following her PhD. Ms Moore confessed that she began with an MD ‘as a mean of obtaining a urology training number’. However, having been awarded her MD and the number, she chose to continue her research and with determined persuasion she created her own clinical lectureship. In contrast, Mr Ahmed decided early on an academic career and followed a more traditional pathway through a research fellow post, a Medical Research Council (MRC) Clinician Doctoral Research Fellowship, to his current MRC Clinician Scientist Award. Yet he too encountered similar difficulties and prejudices juggling the challenges of combining research with surgical training. Mark Emberton reflected that these stories from three different individuals show that whilst there is no one recipe for academic success, core ingredients are scepticism, inquisitiveness and drive for clinical and academic excellence.

Conducting clinical research as a full-time National Health Service (NHS) clinician

The challenges of achieving results as a research-active NHS consultant were explored by John McGrath and Sam McClinton. They explained that whilst ample opportunities exist, there are multiple hurdles to overcome in to successfully lead clinical research whether NIHR-funded trials, researcher-led studies, or commercial projects. The ethos, experience, credibility and performance of one’s centre, along with navigating the research regulatory arena, can be some of the generic challenges to set up a research unit. Mr McGrath observed that priorities of your employer can easily lie elsewhere and involvement in research can attract criticism, with clinical work always being the trump card. Additionally, local funding can be too small to be meaningful, and the peaks and troughs in funding can be difficult to weather. Research must be a team effort rather than an individual venture, with support from the NHS organisation, patients, and most importantly departmental colleagues being crucial to success. With time always at a premium, Prof McClinton listed ways to make the experience easier and more effective, by being realistic, by planning around one’s own clinical and commitments and source of funding, and by seeking help, both from one’s mentor and the wider team.

Effective research from drawing board to delivery

To conclude the morning talks, Vicki Barber, Rebecca Lewis and Wendy Robson brought together the various points raised throughout the day, focusing on what makes an effective and successful clinical research team. Dr Barber, clinical trials unit manager in Oxford who is supported by the RCS Initiative, introduced the ‘strategies for trial enrolment and participant study’ STEPS, a joint NIHR Human Tissue Authority (HTA)/MRC project which concluded that the three factors successful trials share are: being a cancer or drug trial, having interventions only available inside the trial, and having a dedicated trial manager. A quote from Peter Davidson from the NETSCC emphasised the funder’s perspective, that ‘it is vital that a person leading a trial has good management leadership skills rather than merely energy and scientific curiosity’. Dr Barber encouraged the triallists to seek input from the surgical trials units Prof Morton spoke so keenly about, as an invaluable source of not only expertise, continuity and stability, but also infrastructure, quality assurance, information technology (IT) and statistical input. Ms Lewis, senior trials manager at the Institute of Cancer Research, explained how a collaborative and pragmatic approach to implementation of trial design into clinical care was required. Trials had to fit the scope and paradigm of the current practice and target population, minimising the burden on the patients and teams. Every trial was a learning experience that could be translated to improving running of the next study. Wendy Robson, leader of the urology and renal clinical research team at Freeman Hospital, Newcastle upon Tyne, used real examples to illustrate aspects of trial design that bring either joy or heartsink to an NHS research nurse. The key is a good balance between the needs of the research question and the needs of the patients involved. Effective leadership from the local PI with clearly defined responsibilities and time frames are essential together with clear trial documentation. Things to avoid include lack of flexibility in time points, patient questionnaire overload, burdensome distracting ‘sub-studies’ and data collected ‘because you can’ rather than required for primary analysis. All three speakers emphasised the need for timely, two-way communication between trial designers and those who deliver clinical research to allow completion to time and target and speedy implementation of clinically-relevant results.

Summary

These varied talks emphasised the will and enthusiasm to drive advancement in urology patient care through clinical research and demonstrated that much was already being done. The challenge will be to improve on this platform and spread the message through all UK urology departments.

Discussion group I

Aligning trial design to the clinical problem

Framing the problem

During the afternoon of Day 1, delegates split into two discussion groups. The first discussion led by Mark Emberton centred on trial design and was facilitated by contributions from five invited experts: Dr Clare Relton, Professor John Norrie, Dr Jan van der Meulen, Dr Emma Hall and Dr Susan Dutton. The task was to fit the research design to the ‘value’ of the answer for any given research question with the need to explore alternatives to the ‘gold standard’: the randomised controlled trial (RCT). The opening statement from Prof Emberton that ‘all research comes from a hunch that something isn’t quite right and could be improved’ led the audience to consider examples of challenging research questions.

A worked example

To focus discussion, the research question ‘Can extended lymphadenectomy with prostatectomy compared to radical prostatectomy alone improve morbidity and mortality in men with intermediate risk localised prostate cancer?’ was introduced. Defining the study population, standardising the technique for lymphadenectomy and ensuring comparable surgical expertise were listed as some of the design issues the researcher was likely to face. The panel and the audience agreed that setting strict inclusion and exclusion criteria, common practice for regulatory drug trials, led to poor recruitment and selection bias. The trial population would tend to consist of patients likely to gain maximum effect, whilst excluding minorities, those hard to reach, and those at greater risk of harm. This could lead to disparities between the target and populations, resulting in a study result lacking generalisability to routine care. The decision whether to keep the intervention simple, i.e. surgical and controllable, or more generalised, i.e. complex but potentially beneficial to more patients, was another challenge given to the audience. Potential for contamination of the results by requiring treatment by two specialists was suggested as a reason for keeping things simple. It was commented that undertaking single-centre trials of treatments in different populations by different research teams leads to clinical and statistical heterogeneity which hampers meta-analysis of the results and makes translation to clinical care uncertain; much better to have just one large definitive study.

For study outcome measures, the panel and the audience were agreed that ambiguity should be avoided by making the outcomes clear and specific. One-dimensional outcomes were considered rare and unlikely in surgical research, and so the primary outcomes could include morbidity, quality of life, recurrence-free survival and overall survival. End-points should be relevant and acceptable to the patients, something that can be demonstrated by involvement of patient groups in trial design at an early stage. Whilst it was widely acknowledged that failure to recruit to target has implications for the power and generalisability of trial results, the panel questioned whether for many circumstances the existing evidence could be used to answer the research question. The audience pointed out that in the example of lymphadenectomy with radical prostatectomy, data from single-centre case series and small studies were already available. With clinical practice constantly evolving, data from large trials begun 10 years ago may be invalid to current practice. Patients and their circumstances also evolve over time, affecting the clinical decisions made. With progress in care over time often reducing the value of large trial results, new approaches are needed to fit the research design to the ‘value’ and urgency of the answer.

Dr Clare Relton’s example from a systematic review (Ross et al. J Clin Epidemiol 1999; 52: 1143–1156), stating that ‘most common reason given by patients and clinicians for not participating in clinical trials is related to concerns about information and consent’ sparked a discussion on the issues surrounding ethics and consent. She further challenged the audience to the concept of: ‘Random allocation is something “done” to all, whilst random selection ‘happens’ to some’. It was pointed out that unlike patients receiving routine care, patients consenting to participation in clinical trials are fully informed pre-randomisation about treatments they may or may not receive, or that their treatment will be decided by chance. Some members of the audience suggested that patients need to be consented for randomisation only if their allocated treatment was different from usual care, as by prospectively informing people we change the way they act. Mr Jan Nawrocki felt that this is contrary to routine clinical practice, where available options are explained and advice is given on the best course of action. The audience agreed that whilst this is the case in elective circumstances, it may not strictly apply to clinical trials. Mr Nawrocki further remarked on the new General Medical Council (GMC) definition of consent, implying that patients now request treatment and the clinicians consent to provide it. The panel concluded that consent is a marriage of a transaction and a dialogue.

Alternative trial designs

Prof Emberton expanded further on alternative trial designs which could be more suited to the ‘value’ and immediacy of the answer. The examples given by the audience included cluster randomisation, embedding clinical trials into observational registries and cohort studies, and more pragmatic design in line with current practice, such as Zelen’s randomised consent design. The impact of these alternatives was debated, with the audience feeling strongly negative about cluster randomisation, raising further concerns around ethics, patient preferences and consent. When further questioned by Prof Emberton about ways of making it easier to design a publishable study, the audience mentioned adaptive, pragmatic and non-inferior design methods. The panel agreed that in the current constantly evolving world where new markers and treatments emerge regularly, the setting and the objectives of a study may change with time, requiring an adaptive pragmatic design. Recruiting heterogeneous populations and focusing on effectiveness rather than efficacy of the intervention, pragmatic trials have high external validity and can immediately inform practical health care decision making if analysed by an experienced researcher. However, their external validity can be limited to specific health care settings. Prof John Norrie quoted, as an example, a study his team recently published (Brittenden et al. N Engl J Med 2014; 371: 1218), which, although relevant to UK practice, received criticism from the United States (US) audience, who could not extrapolate its findings. Lastly, in studies where use of a superiority trial against a placebo control may be considered unethical, non-inferiority trials were suggested as an alternative, but were heavily criticised by the panel due to large sample requirements and the risk of progression to an inferiority trial.

Dr Relton then introduced the ‘cohort multiple randomised controlled trial’ (cmRCT) design (Relton et al. BMJ 2010; 340: c1066) as an innovative approach that rethinks the nature and infrastructure of pragmatic RCTs, how trial populations are identified, concept of randomisation, and the time and content of information given to the patient. The cmRCTs’ design allows recruitment of large observational cohorts of patients with regularly measured outcomes. This then provides the resource for multiple trials (both concurrent and subsequent) over time, thus saving time and cost. The audience saw the potential of such design, especially in studies where large populations are recruited and suggested that in a study cohort of 20,000, one could collaborate with research groups to formulate 20 different hypotheses and conduct 20 parallel trials. For each trial only some patients from all eligible individuals within the cmRCT cohort are randomly selected and offered the intervention. Direct comparison can be made of the outcomes in the randomly selected patients with others in the cohort having standard care. On recruitment to the cmRCT cohort, patients consent only to being followed up for life, periodically filling in questionnaires, being approached if new recruitment becomes available, and having their biographical data safely stored. Further participation in the ‘nested’ trials then requires additional consent. Prof Emberton felt that the beauty of this method is that everyone carries on doing what they are doing (non-disruptive), few get selected, but all have a chance of being approached giving equity of access. There is a limitation that a standard care comparator is required and this risks non-acceptance and non-compliance among those with high preference against the intervention under test.

Summary

Looking into the future, the audience concluded the session by identifying our main challenge to be the advancement of robust cancer registries, which would reflect changes in patients’ clinical status, e.g. progressing from one stage of disease to another, thus allowing the researchers to identify those potentially eligible for new trials.

Discussion group II

Delivering effective patient recruitment

The second discussion group was chaired by Rob Pickard and looked at various factors that may encourage or prevent recruitment at a local level to clinical trials in urology. Experts with ‘on-the-ground’ experience including presentations from John McGrath, Rebecca Lewis and Wendy Robson, and contributions from Sam McClinton and Rachel Stephenson, helped facilitate the discussion under specific headings.

Local feasibility

Discussion established that it is vital that individual departments make realistic predictions about the numbers of people they are likely to be able to recruit in a specified time period before agreeing to act as a local trial site. It is important to realise that only a relatively small proportion (≈25%) of the total local patient population eligible for the trial is likely to be recruited. This prediction must take into account the local resources available. Delegates both from trial management and clinical research teams agreed it is harmful all round if local feasibility is not established at the start.

Identify support

The NIHR infrastructure provides considerable support across England for all NHS organisations. The main difficulty is accessing it for a specific study. The clinical research team members emphasised the need to engage with the relevant local NIHR clinical network (LCRN) lead. The LCRN also provide training, particularly Good Clinical Practice (GCP). John McGrath pointed out it is important to have buy-in from clinical colleagues that recruitment to trials was a routine part of departmental business.

Local set-up

Trials come with a fair amount of administrative paperwork both in set- up and continuation. The trial managers, clinicians and research teams present emphasised the importance of keeping good records of permissions to carry out the research and continued documentation of progress of the trial locally. All agreed that the headache of inspections and audits is best relieved by proper record keeping from the start.

Identification of eligible patients

Wendy Robson emphasised the importance of mapping out the journey of patients eligible for a trial and working out the best time and place to approach them. This involves collaboration with the clinical team and an easy line of communication with the research nurse. Rapid responsiveness by the research nurse team and ready availability of trial documents for interested patients is also very important. The difficulty of identifying patients who present ‘out of hours’ was highlighted and possible solutions, such as ensuring that on-call medical staff were all GCP trained, discussed.

Recruitment, retention and follow-up

The difficulty of recruiting to trials where the treatment options being tested were already available in the NHS was acknowledged and a number of strategies to ensure that patients were given a fair picture of the uncertainties that generated the need for the trial were put forward. The importance of approaching the patient at the right time and of ensuring that all clinicians were able to express the uncertainty of current practice was emphasised. Another workable option is for clinicians to ‘cross-refer’ patients eligible for a trial to the main clinician to get a consistency of approach. Hand-in-hand with this was the advantage of using various promotional materials to ensure clinicians, support staff and patients maintain awareness of the trial. This is also helped by regular meetings and updates to all involved.

Measuring and maintaining activity

All present acknowledged that success in recruitment breeds further success and additionally is the main measure by which NHS organisations and individual departments are judged. High recruitment brings more resources to the NHS organisation through the NIHR accrual-related support and additional LCRN-funded research staff. Unfortunately this extra support may not fully filter down to department level so it is an important part of the PI’s job to help emphasise the importance of success in a recruiting to a particular trial and encourage the team. Friendly competition between units was thought to be helpful but sharing strategies that helped increase recruitment would be best in the longer term.

Summary

The conclusions of the wide-ranging discussion were that successful and satisfying local involvement in multi-centre trials can be achieved, but does require effort, often unsung, and knowing where to get help, advice and support. It was felt that the BAUS website would be a good forum to provide generic advice and points of contact to help individuals and departments new to clinical trial work.

Purpose of meeting Day 2: Tuesday 2 December 2014

Introduction

The second day of the meeting chaired by Mr Vincent Gnanapragasam and Professor Robert Pickard was the BAUS Academic Section of Urology Annual Research Meeting and was a highly successful event. More than 50 delegates took part in an exciting day of presentations and discussions with the inclusion of two new features: the inaugural BAUS Academic Section of Urology Research Prize, and a ‘Dragons’ Den’ style competition for urology trainees seeking to set up collaborative regional or national studies in line with one of the strategies of the RCSEng Clinical Research Initiative.

Summary of the day

More than 40 abstracts were presented and these were all of a high calibre. The top 10 scoring abstracts were selected for podium presentation, while the remainder were presented as posters in three sessions. Podium presentations were judged by a panel of experts and the BAUS 2014 Academic Research Prize was awarded to Alexander Laird from Edinburgh. The presenters of the best posters judged from each of the three ‘poster rounds’ were Marcus Cumberbatch, Robert Foley and Elsie Ellimah Mensah. Many congratulations to these prize winners for their achievement. All the abstracts of the podium and poster presentations are included as part of this report. The ‘Dragons’ Den’-style session was a new feature organised by Ben Lamb, in which trainees were invited to submit ideas for collaborative regional or national audit, service development and research. After extensive debate around the criteria of ‘do-ability’ and maximising trainee involvement, the panel of ‘Surgical Dragons’ declared Taimur Shah as the winner for the project entitled ‘Role of inflammatory markers in ureteric colic and UK Stone Nomogram’.

Concluding remarks

The judges and participants were all highly impressed by the quality of the research being undertaken by the urology trainees and this augurs well for the future of academic research in urology. There was general agreement that this format was encouraging participation and would be taken forward to the next annual meeting and the Academic Section prize and the Dragons’ Den will remain as features.

Abstracts of prize-winning presentations

BAUS 2014 academic research prize winner

9. A retrospective cohort study of multi-molecular heterogeneity in renal cancer with the identification of NEFM promoter methylation as an independent marker of cancer-specific survival

A Laird, D Sproul, GD Stewart, FC O’Mahony, ACP Riddick, M O’Donnell, RR Meehan and DJ Harrison

Background: Genetic intra-tumoural heterogeneity (genetic ITH) has been described in renal cell cancer (RCC) and may limit clinical translation of prognostic biomarkers. There has been no assessment of ITH at other molecular levels. We aimed to define and compare proteomic, transcriptomic and DNA methylation ITH in RCC and identify potential prognostic biomarkers.

Methods: Tissue sampling was performed from multiple areas of primary tumours from 23 RCC patients (cohort 1) for intra-tumoural proteomic, transcriptomic and DNA methylation heterogeneity analysis. ITH was assessed using the ANOVA test and by comparison of unsupervised hierarchical clustering. Identification and validation of prognostic differentially methylated regions (DMR) was performed on three cohorts, two database and one experimental (cohort 2 TCGA, n = 154; cohort 3 Edinburgh, n = 46; cohort 4 CGP, n = 194).

Results: RCC exhibits protein, gene expression and methylation ITH. Protein ITH is greater than transcriptomic and methylation ITH (mean variance (MV (IQR)) 0.08 (0.08), 0.07 (0.04), 0.07 (0.05) respectively; p < 0.0001). Methylation ITH (MV 0.08 (0.05)) is significantly less than inter-patient variance of methylation (20.9 (8.5), p < 0.0001). There were 322 DMRs between recurrent and non-recurrent patients in cohort 2 but only five DMRs were validated in cohort 3. NEFM gene promoter methylation was the only DMR independently associated with cancer-specific survival (mean CSS; unmethylated-NEFM = 107months, methylated-NEFM = 49 months; p < 0.001: HR 1.8 (1.1–3.0); p = 0.02). This was confirmed on cohort 4.

Conclusion: RCC intra-tumoural protein heterogeneity is significantly greater than methylation and gene-expression ITH. While methylation ITH exists, its occurrence is significantly less than inter-patient variance. This led us to investigate methylation associated prognostic markers in RCC and we found promoter methylation of NEFM is associated with poorer cancer specific survival independent of tumour stage, grade and node status.

‘Best in session’ poster presentations

2. messengerRNA (mRNA) export and cancer

M Cumberbatch, N Viphakone, M Livingstone, P Heath, M Dickman, JWF Catto and SA Wilson

Introduction: Cancer/testis antigens (CTAs) are expressed in human germ cells, but are aberrantly expressed in cancers. Their restricted expression in normal tissues and ability to elicit an immune response in patients makes them promising targets for customized immunotherapies. However, 70% of the CTAs known have no defined function. Here, we report that the CTA gene LUZP4/CT-8/HOM-TES-85 encodes a canonical messenger RNA (mRNA) export adaptor.

Materials and methods: Experimental approaches included bioinformatics, Western blotting, quantitative polymerase chain reactions, immunoprecipitations, RNA interference (RNAi), and cell-survival assays.

Results: LUZP4 is an RNA-binding protein that integrates into the transcription/export complex and interacts directly with the RNA helicase UAP56 and the mRNA export receptor NXF1. We demonstrate that LUZP4 functionally complements an RNAi-mediated depletion of the canonical mRNA export adaptor ALYREF by rescuing the global mRNA export pathway and restoring cellular growth.

We found that the presence of the LUZP4 protein in cancer cells is associated with low levels of the ALYREF protein and vice versa. We observed this inverted correlation expression in 80% of the cancer cell lines tested, which included bladder cancers. Furthermore, LUZP4 supports transport of transcripts required for cancer cell growth and tissue invasion, confirmed by a dramatic reduction of cancer cells proliferation upon knockdown of LUZP4 by RNAi.

Conclusions: This study assigns a function to a member of the poorly characterized CTA family. It defines the CTA LUZP4 gene as an mRNA export adaptor used by some cancer cells to sustain cell proliferation and suggests that LUZP4 could be a therapeutic target.

12. Prostate cancer risk stratification: A prospective multi-institutional study

R Foley, DJ Lundon, DJ Galvin and RWG Watson

Introduction: The decision to proceed to biopsy of the prostate in the investigation of prostate cancer is a difficult one. In order to make this decision, it is imperative that clinicians make the best use of the clinical information available, including prostate-specific antigen (PSA), digital rectal exam (DRE) and family history. We assessed the potential clinical benefit of the Prostate Cancer Prevention Trial risk calculator (PCPT-rc) in order to inform the decision for prostate biopsy in an Irish cohort of men.

Patients and methods: A total of 251 men were prospectively enrolled in a clinical trial in which blood samples were taken pre-biopsy. Their clinical information was used to derive their risk according to the PCPT-rc and this was compared to a base model consisting of PSA, DRE and family history. Receiver-operating characteristic (ROC) curves as well as decision curve analysis was undertaken to ascertain the clinical utility of the PCPT-rc.

Result: The areas under the ROC curve for the PCPT-rc and the base model were 0.70 and 0.63 respectively for the prediction of prostate cancer and 0.72 and 0.69 for the prediction of Gleason ⩾7 disease. Decision curve analysis demonstrated a significant net benefit for the PCPT-rc in the diagnosis of Gleason ⩾7 disease in the 20–45% risk threshold range.

Conclusion: Despite an increase in predictive accuracy, the PCPT-rc has significant room for improvement and requires the integration of novel biomarkers – such as pro(–2)PSA, currently under investigation in this cohort – which could help improve its clinical relevance.

25. ‘Blood in Pee’ Campaign 2013: Did this lead to an increase in bladder and kidney cancer diagnosis?

E Ellimah Mensah, AHH Hughes-Hallett, JV Vale and EM Mayer

Introduction: The Department of Health’s ‘Blood in Pee’ campaign was rolled out to raise awareness of visible haematuria as a potential symptom of bladder and kidney cancer and promote early diagnosis. This study aimed to determine if the campaign led to an increase in haematuria referrals and whether this translated to an increase in new bladder and kidney cancer diagnosis.

Methods: Data were collected for new two-week-wait referrals to a single Trust’s one-stop haematuria clinic during February 2012 to June 2014 and also new renal and transitional cell cancer diagnosis over the same period. Paired t-test analysis compared pre-campaign (February 2013–September 2013) and post-campaign (October 2013–March 2014) cohorts. Referrals and diagnosis numbers for February 2012–January 2013 were used for baseline comparison.

Results: There was an increase in the number of haematuria referrals in the post-campaign, compared with the pre-campaign, period (p = 0.065). There was no associated increase in urothelial or renal cancer diagnosis (p = 0.47).

Conclusions: In this cohort, the 2013 ‘Pee in Urine’ campaign led to an increase in rapid access referrals but did not translate into an increase in new renal/bladder cancer diagnoses. The increase in referrals was short lived and three months post-campaign, referral rates returned to baseline (February 2012–January 2013). It can be said that the campaign achieved its aim of raising awareness of the symptoms of bladder and kidney cancers, although short lived, but did not translate to a greater number of cases being diagnosed; a second roll-out of this campaign has been planned for October–November 2014.

‘Dragons’ Den’ winner

2. Role of inflammatory markers in ureteric colic and UK Stone Nomogram

T Shah

Background: There is conflicting evidence on the role of raised inflammatory markers in acute ureteric colic with some showing an improved stone passage rate whilst others claiming a lower rate with an increased need for intervention. Additionally, the latest US and European guidelines quote a 68% ureteral stone passage rate for stones <5 mm and 47% for stones between 5 mm and 10 mm. There appears to be varying UK practice on stones between 5 mm and 10 mm, and I would like to propose a single-arm prospective study to determine the impact of inflammatory markers on patient outcome along with sepsis, stone passage and intervention rates. The creation of such a prospective cohort of patients may also allow the development of a UK/BAUS nomogram to better individualise patient care and determine who may benefit from early intervention versus observation.

Primary question: Role of inflammatory markers (WBC, Neutrophils, CRP) in relation to ureteric colic outcomes including rates of sepsis and need for intervention.

Secondary questions: Spontaneous stone passage rates with medically expulsive therapy at varying stone sizes.

Creation of a prospective database to assess secondary factors such as Hounsfield units, comorbidities (diabetes), pain score, previous history of stones to eventually create a nomogram.

Paper Session 1: Professor Rob Pickard, Mr Derek Rosario, Mr Richard Bryan and Professor Noel Clarke

Tuesday, 2 December 0920-1105

1. Identification and diagnostic performance of a small RNA within the PCA3 and BMCC1 gene locus that potentially targets mRNA

K Pang, S Miah, I Rehman, R Clarke, R Stoehr, M Lavin, ES Martens-Uzunova, RA Gardiner, FC Hamdy and JWF Catto

Introduction: Prostate cancer antigen-3 (PCA3) is a non-coding RNA (ncRNA), with unknown function, upregulated in prostate cancer (PCa) used to stratify biopsy. Long ncRNAs may be processed into smaller active species. We hypothesised this role for PCA3 and searched for short-RNAs (sh-RNA) within this gene.

Methods: We computed RNA hairpins within the BMCC1 gene (encompasses PCA3) and searched a prostate transcriptome, generated through deep sequencing, for RNAs derived from these hairpins. We measure their expression using qPCR in three cohorts: PCa tissues (n = 60), exfoliated urinary cells (cancer, n = 484; control, n = 166) and cell lines (n = 22). We used in silico predictions and RNA knock-up to identify potential mRNA targets of the sh-RNAs.

Results: We predicted 13 hairpins, including PCA3-shRNA2, which was the majority species expressed in a prostate transcriptome. PCA3-shRNA2 is located within intron 1 of PCA3 and appears regulated by androgens. Expression of PCA3-shRNA2 was upregulated in malignant prostatic tissues (T-test p < 0.01), exfoliated urinary cells from men with PCa (13- to 273-fold change, T-test p < 0.003) and closely correlated to PCA3 expression (r = 0.84 to 0.93, p < 0.001). PCA3-shRNA2 (C-index 0.75–0.81) and PCA3 (C-index 0.78) could identify the presence of cancer from urinary samples of most men. Following PCA3-shRNA2 knock-down, altered expression of several mRNAs in PCa cell line DU145, including COPS2, SOX11, WDR48, TEAD1 and Noggin, was identified. SOX11 expression was reduced in urine samples from men with PCa (p = 0.03).

Conclusion: We identified a short-RNA transcribed from the PCA3 gene, whose expression is upregulated in PCa, and may target mRNAs implicated in PCa biology.

2. Assessment of urinary interleukin-6 as a marker for urinary tract infection in patient with lower urinary tract symptoms

T Brenton, K Gill and Malon JG

Introduction: When assessing patients with lower urinary tract symptoms (LUTS), exclusion of UTI is a mandatory first step. Current tests to exclude infection have been widely discredited by many groups. There is need for novel, rapid and accurate tests for UTI. Interleukin-6 (IL-6) is an acute phase protein which is produced during bacterial invasion and poses an attractive alternative.

Methods: This was a blinded, controlled observational study. Forty-seven patients presenting to specialist urodynamics clinic with LUTS were included as were 10 healthy controls. Patients completed validated questionnaires and provided a catheter specimen of urine and normal controls provided meticulous MSU samples. Pyuria and urothelial cells were counted by immediate light microscopy of fresh unspun urine. The urine was cultured on selective chromogenic agar and aliquots of spun urine were stored at −80^oC. Urine concentration was determined by spot urine creatinine measurement. IL-6 concentrations were determined using a commercial high-sensitivity ELISA.

Results: IL-6 was significantly raised in the patient group when compared to controls. Within the patient group, IL-6 was significantly higher in urine samples with ⩾ 10 leucocytes (p = 0.001) and in those that were positive for bacterial growth (p = 0.006).

Conclusions: This preliminary study confirms the potential for urinary IL-6 as a screening test for UTI in patients with LUTS. IL-6 was found to be significantly higher in patients with LUTS, pyuria and positive MSU cultures. IL-6 provides a more sensitive alternative to current tests used to screen for urine infection and this study substantiates the potential urinary IL-6 holds as a biomarker in UTIs.

3. Response of scaffold materials designed for treatment of stress urinary incontinence (SUI) and pelvic organ prolapse (POP) to distension

C Hillary, S Roman, NI Osman, AJ Bullock, SM MacNeil and CR Chapple

Introduction: Polypropylene mesh is commonly used for stress incontinence and prolapse surgery; however, serious complications associated with these meshes are currently under investigation by regulators. Mesh erosion through tissues may occur as a result of a mismatch between the mechanical properties of this mesh and the host tissues. Other more elastic polyurethane polymer materials have shown promise recently for hernia repair (Takanari K et al. J Tissue Eng Regen Med. Epub ahead of print 27 December 2013).

Aim: To develop electrospun biodegradable polyurethane materials for stress urinary incontinence (SUI) and pelvic organ prolapse (POP).

Materials and methods: Poly-L-lactic acid (PLLA), polyurethanes and composites of the two, were electrospun to form monofilament, microfibrous scaffolds. All materials were subjected to mechanical testing (Bose electroforce tensiometer) before and after seven days of static or dynamic distension (Ebers bioreactor) and compared to commercial polypropylene mesh (PP) and healthy paravaginal tissues. Adipose-derived stem cells were cultured on each scaffold, with cell viability and total collagen production assessed (AlamarBlue and Sirius red assay, respectively) up to 14 days in vitro.

Results: PP was the strongest material and became much stiffer after dynamic loading; however, PP, PLLA and co-polymers of polyurethane and PLLA all deformed irreversibly following seven days of dynamic distension. Only polyurethane scaffolds successfully withstood dynamic distension. However, scaffolds containing PLLA resulted in greater cell viability and total collagen production as compared to polyurethanes alone.

Conclusions: Polyurethanes possess more appropriate mechanical properties than polypropylene. Methods of fabrication can be investigated to combine polypropylene and PLLA in order to increase cell proliferation without affecting mechanical appropriateness.

4. Ectodomain shedding in bladder cancer

H Regan, H Abbas, SJ Pirrie, AJ Devall, KK Cheng, MP Zeegers, ND James, MA Knowles, DG Ward and RT Bryan

Introduction and objectives: Better biomarkers must be discovered to develop clinically useful urine tests for bladder cancer.

Materials and methods: We used shotgun proteomics and bioinformatics to identify the proteins secreted and shed by eight bladder cancer cell lines with and without PMA and marimastat. Lists of candidate markers were generated. Candidates were evaluated by ELISA in >400 urine samples from bladder cancer patients and non-urothelial cancer controls.

Results: We identified >2000 proteins released by bladder cancer cell lines. Many integral plasma membrane proteins were detected in ultracentrifuged conditioned media and the levels of approximately 60% of these were lower in the presence of marimastat, indicating that the ectodomains of many proteins are subject to metalloprotease-mediated shedding from the surface of bladder cancer cells. The most abundant secreted proteases included MMPs 1, 2, 19 and 13 and urokinase-type and tissue-type plasminogen activators; the most abundant cell surface proteases were ADAM10, ADAM9, matriptase and MMP14. Two proteins released as soluble ectodomains, EpCAM and EGFR, are elevated in the urine of patients with aggressive disease and both are independent prognostic indicators of bladder cancer-specific survival with HRs of 1.76 and 2.89, respectively.

Conclusions: Measuring urinary EGFR and EpCAM may represent a simple and useful approach for fast-tracking the investigation and treatment of those patients with the most aggressive bladder cancers. Whilst it may seem counterintuitive to consider measuring integral membrane proteins in urine, many are released in soluble form from bladder cancer cell lines and might have biomarker utility.

5. Mapping of inguinal lymph nodes drainage in penile carcinoma to optimise oncological safety of lymphadenectomy

S Omorphos andAM Muneer

Introduction: Management of lymph nodes in clinically node-negative patients (cN0) with penile carcinoma is controversial. Radical inguinal lymphadenectomy causes significant morbidity and may be an overtreatment in up to 80% of these patients. It’s been proposed that penile carcinoma never metastasises below the saphenofemoral junction (SFJ) hence zones inferior to SFJ could be spared at the time of lymphadenectomy to minimise procedure-associated morbidity.

Patients and methods: Sixty-three patients with penile cancer and cN0 underwent single-photon emission computerised tomography (SPECT) for sentinel nodes (SLN) localisation. A uroradiologist distributed SLN into relevant zones in the groin by analysing coronal SPECT images, using Rouvière’s classification; superficial inguinal lymph nodes are divided into five anatomical zones, bounded by horizontal and vertical lines from the SFJ. Nodes were classified using three distinct approaches to avoid observational bias.

Results: All three approaches demonstrated that the majority of SLNs lie in the upper zones, above the SFJ: Zone I (38.5%), II (32.8%) and V (26.0%). Most importantly, we are the first to report that SLN can occur in the inferior zones: Zone III and IV (0.7%–3.1%).

Conclusion: Our findings are important and may partly explain the high recurrence rate following the modified lymphadenectomy approach, which typically does not include the inferior zones. Therefore these regions should not be overlooked during radical treatment, otherwise oncological safety maybe compromised.

Paper Session 2: Professor Rob Pickard, Mr Derek Rosario, Mr Richard Bryan and Professor Noel Clarke

Tuesday, 2 December 1145-1330

6. Identifying potential therapeutic targets in the metabolic pathway of sphingosine-1-phosphate for urothelial carcinoma of the bladder

A Mercado, S Baker, F Radvanyi, J Hinley, J Pearson, F Marchant, E Castellon and J Southgate

Introduction: Urothelial carcinoma (UC) of the bladder is characterised by high recurrence rates. The quality of life of these patients is impaired by rigorous surveillance regimens that place undue pressure on health care resources. Current adjuvant therapies to reduce recurrence and progression are suboptimal. Sphingosine-1-phosphate (S1P) is formed by phosphorylation of sphingosine by sphingosine kinase-1 (SPHK1) and promotes proliferative and anti-apoptotic effects. Altered sphingolipid metabolism has been described in several cancers, with overexpression of SPHK1 and down-regulation of enzymes that dephosphorylate (SGPP1 and SGPP2) or degrade (SGPL1) S1P. The role of S1P metabolism in normal human urothelial (NHU) cells and whether its deregulation contributes to the development and progression of UC of the bladder is unknown.

Materials and methods: Expression analyses from RNA profile databases of NHU cells and human UC samples were validated by reverse-transcriptase polymerase chain reaction in NHU and UC-derived cell lines. SK1-I is a specific inhibitor of SPHK1 and its effect on cell viability, proliferation and apoptosis was assessed.

Results: SPHK1 was over-expressed in muscle-invasive UC and SGPP2 down-regulated at all stages of UC. Cells with proliferative phenotypes were characterised by increased SPHK1 and reduced SGPP2 expression in comparison to quiescent/differentiated NHU cells. Pharmacological inhibition of SPHK1 caused a reduction in cell culture biomass in all cell lines, mainly due to a reduction in cell proliferation.

Conclusion: S1P metabolism may play a role in the regulation of urothelial cell proliferation and its manipulation may offer a new strategy for the treatment of UC.

7. Assessing synergy between Wnt, Pi3 Kinase and Ras pathways in human and murine prostate cancer

M Jefferies, AC Cox, V Menier, A Clarke and H Kynaston

Introduction: The spectrum of genetic mutations in prostate cancer (PCa) is diverse, with tumour heterogeneity revealing a low rate of recurrent lesions in many genes. However, recurrent alterations in certain signalling pathways such as Wnt, PI3Kinase and Ras do predominate. The precise roles of these pathways and the interplay between them remain poorly understood.

Material and methods: A total of 317 prostate samples from 245 patients were used to construct a tissue micro-array (TMA). Immunohistochemistry was used to quantify expression levels of different antibodies associated with each signalling pathway. To assess deregulation of these pathways in the mouse we generated mice harbouring deletion of Pten and activated mutations in beta-catenin and k-ras.

Results: The expression levels of Wnt, PI3 Kinase and Ras are increased in human PCa when compared to normal (p < 0.0001). Using principal components analysis for markers of all three pathways, we were able to separate the samples based on Gleason grade, with high-risk samples clustering together with greater expression levels. To assess this synergy further, we have shown that mice harbouring deregulation of a greater number of pathways develop more aggressive tumours with a reduced survival.

Conclusion: There is synergy between the three signalling pathways (Wnt, PI3 Kinase and Ras) both in human and murine PCa. Future work will assess further molecular relationships between these pathways aiming to identify the driver molecule or pathway in initiation and progression of PCa. This work will help stratify patients based on pathway analysis permitting the use of targeted therapies.

8. A cohort study of 18,352 men with advanced prostate cancer treated with up to 15 years follow-up shows a survival benefit for those who received radical therapy on top of standard care

P Sooriakumaran, T Nyberg, O Akre, G Steineck and P Wiklund

Importance: If local therapy of the primary tumour in metastatic prostate cancer improved survival, this would herald a paradigm shift in treatment.

Objective: The objective of this research is to determine whether radical therapy locally directed to the primary tumour in men with likely or definite metastatic prostate cancer improves survival.

Design: An observational cohort study of 18,352 men with likely or definite metastatic prostate cancer (PSA > 50) treated by initial radical therapy (radical prostatectomy or radiation therapy) or initial androgen-deprivation therapy, and followed for up to 15 years.

Setting: The PCBaSe dataset provides information on >98% of patient and tumour characteristics of virtually all prostate cancer cases in Sweden diagnosed since 1998. We identified men with PSA > 50 ng/ml, and compared prostate cancer and other-cause mortality between radically treated and androgen-deprivation groups. We matched treatment cohorts for PSA, clinical stage, M-stage, tumour grade, Charlson comorbidity index, age, and year of diagnosis, and repeated comparative effectiveness analyses.

Exposures: One group received initial therapy with either radical prostatectomy or radiation therapy, and the other group received initial androgen deprivation.

Main outcomes and measures: We compared competing risks adjusted prostate cancer mortality, calculating crude, traditional (multivariable) adjusted, and propensity score adjusted subdistribution hazard ratios for comparisons between the treatment groups.

Results: Prostate cancer mortality was substantially greater in the androgen-deprivation group compared to the radically treated one, in unmatched (9062/17,602 = 51.5% vs 86/750 = 11.5%, respectively) and matched (177/575 = 30.8% vs 71/575 = 12.3%, respectively) cohorts. Among the matched cohorts, androgen deprivation was associated with a nearly three-fold increase in risk of prostate cancer death compared with locally directed radical therapy (2.87; 95% CI 2.16–3.82). Multiple sensitivity analyses suggested the findings were robust.

Conclusions and relevance: This is the largest and most comprehensive population-based observational study to address the efficacy of radical therapy in men with likely metastatic or micro-metastatic prostate cancer. The results indicate a survival benefit for locally directed radical treatment in men with metastatic prostate cancer and provide a strong rationale to consider a randomised controlled trial in this setting.

10. CYR61 as a novel therapeutic target in muscle invasive bladder cancer

R Robinson, M Brown, MW Lau, VK Sangar, VAC Ramani and NW Clarke

Aims: CYR61 (cysteine-rich angiogenic inducer 61) was identified through Oncomine® as a putative treatment target in bladder cancer. It is implicated in aggressive cancer cell behaviour in a number of tumour types; however, its role in bladder cancer is unknown. This study evaluated the role of CYR61 in bladder cancer, using cell line models and an outcome-linked tissue microarray (TMA).

Methods: siRNA knockdown of CYR61 was performed during proliferation, migration, invasion and chemo-sensitivity assays in the high-grade J82 and T24 cell lines. A TMA was constructed using the cystectomy specimens of 567 MIBC patients. Cellular expression of CYR61 was correlated with outcome using IHC staining of TMA sections and automated image-analysis.

Results: CYR61 knockdown significantly reduced T24 proliferation (p < 0.01) associated with loss of vimentin expression. Knockdown combined with IC₅₀ cisplatinum significantly reduced proliferation in both cell lines compared to IC₅₀ cisplatinum alone (p < 0.0001). Hepatocyte growth factor (HGF) induced migration and both HGF and FCS induced Matrigel® invasion was significantly reduced (p < 0.01) by knockdown in both cell lines.

Across the TMA, 84% of tumours demonstrated intermediate/high CYR61 expression compared to 62% of normal controls (p < 0.01). Intermediate/high vs. negative/low expression was associated with significantly reduced overall (median 33 vs. >72 months) and cancer-specific (39 vs. >72 months) survival following cystectomy. Expression was an independent predictor of survival, HR 1.493 (p = 0.030, Cox regression).

Conclusions: CYR61 promotes an aggressive MIBC phenotype and knockdown reverses features of EMT and increases chemo-sensitivity. Clinical cohort correlation confirms CYR61 to be a promising MIBC treatment target.

Posters Round 1: Mr Ghulam Nabi and Professor Jenny Southgate

Tuesday, 2 December 1105-1145

1. Hypoxic hangovers for the urothelium

A Radford, A Pilborough, N Ahmad, R Subramaniam and J Southgate

Introduction: End-stage bladder disease culminates in contracted bladders that cannot function adequately or safely. More than 11,000 surgical procedures are carried out annually to increase capacity and compliance in such bladders (Department of Health, 2013). Urothelial cells harvested from diseased bladders have a compromised capacity to propagate or differentiate in vitro (Subramaniam et al. J Urol 2011; 186: 2014–2020). We hypothesise that urothelial cells undergo epigenetic modification in response to hypoxia in a disease environment.

Materials and methods: Evidence of hypoxia in diseased bladder specimens was sought using immunohistochemistry. A disease model, using the chemical hypoxic mimetic deferoxamine mesylate (DFO), was established to investigate whether hypoxia affected the capacity for normal human urothelial (NHU) cell cultures to form a functional urothelial barrier, as monitored by transepithelial electrical resistance.

Results: HIF 1-α was prominent in high-pressure end-stage bladder disease specimens. Hypoxia, mimicked by the application of DFO, had a detrimental impact on the ability of NHU cells to form a functional barrier in vitro (1732 ± 425 vs 4960 ± 701 Ω.cm²; p < 0.01 n = 9). Compromised capacity for barrier development persisted following removal of DFO for 12 days (658 ± 186 vs 1641 ± 496 Ω.cm²; p < 0.01 n = 9).

Conclusions: HIF-1α expression in situ is indicative of a role for hypoxia in end-stage bladder disease. Our in vitro model indicates that hypoxia effects long-term heritable changes in urothelial cell phenotype. End-stage bladder disease is a candidate for autologous tissue engineering replacement and the use of epigenetic-modifying treatments may improve the efficacy of autologous urothelial cells for such solutions.

3. N6-Methyladenosine mRNA methylation in common human cancers: Identifying a potential role in androgen-resistance within prostate cancer

K Pang, MG Cumberbatch, SA Wilson and JWF Catto

Introduction: The identification of >12,000 N6-methyadeonisine (m6A)-methylated human mRNAs, and the reversibility of this modification point towards novel epigenetic mechanisms. We compared expressions of mRNAs reported to undergo m6A-methyation in common cancers: prostate, bladder, renal, breast, lung, colorectal, ovarian and gastric cancer.

Methods: mRNA expression microarray datasets for eight common cancers were extracted from Array-Express. mRNAs were stratified according to malignant expression (if T-test p < 0.001) in cancer compared to normal/benign samples, or in castrate-resistant PCa (CRPC) versus androgen-sensitive (AS) PCa, then sub-stratified according to their reported susceptibility to undergo m6A-methylation. Methylated mRNAs were ranked according to their frequency of aberrant expression within multiple datasets and annotated functionally using gene-enrichment software.

Results: We extracted 47 datasets: seven comparing PCa and benign prostate hyperplasia (BPH), and two comparing CRPC and AS-PCa. The total (range) number of cancer samples vs control were, n = 2405 (10–226), n = 1435 (4–294), respectively; PCa, n = 292 (11–68), n = 294 (8-71); and CRPC, n = 39 (10–29), n = 32 (10–22). Between 26.3% and 59.4% of aberrantly expressed mRNAs were susceptible to m6A-methylation (PCa, 37.6–54.6% and CRPC, 56.2–58.2%). We found 689 genes whose transcripts are reported to undergo m6A-methylation shared in all cancers from >1 dataset per cancer type; 138 genes shared in >5/7 PCa datasets; 127 genes shared in both CRPC datasets. Key genes include PTEN, EZH2, HDAC1, TP53, CAV1, TIMP3, GSTP1, DAPK1 and BCL2.

Conclusion: We reported the distribution of aberrantly expressed m6A-mRNAs in eight common cancers. In vitro studies evaluating this and identifying roles of these m6A-methylated mRNAs in PCa/CRPC would allow further investigation into therapeutic agents.

4. DNA copy number aberrations and potential candidate driver genes in HPV-positive and HPV-negative penile carcinoma

S La-Touche, C Lemetre, M Lambros, E Stankiewicz, C Ng, B Weigelt, C Corbishley, N Watkin, DM Berney and JS Reis-Filho

Introduction: Penile squamous cell carcinoma (PSCC) is a rare disease and somatic genetic aberrations have yet to be characterised. We hypothesised that human papillomavirus (HPV) status and clinico-pathological features might correlate with gene copy aberrations. We sought to determine gene copy number aberrations in a large series of PSCCs and to define their correlations with HPV status, subtype, grade, stage and nodal status.

Materials and methods: DNA was extracted from 70 formalin-fixed paraffin embedded PSCCs micro-dissected samples and subjected to polymerase chain reaction-based HPV assessment and genotyping using the INNO-LiPA HPV Genotyping Extra Assay and microarray-based comparative genomic hybridixation using a 32K Bacterial Artificial Chromosome array platform.

Results: Recurrent gains were observed in chromosomes 1p13.3–q44 (88%), 3p12.3–q29 (86%), 5p15.33–p11 (67%), 8p12–q24.3 (84%) and 11p12.3–q14.1 (39%). Amplifications of 5p15.33–p11 and 11p14.1–p12 were found in seven (11%) and four (6%) cases, respectively. Losses were observed in chromosomes 2q33–q37.3 (86%), 3p26.3–q11.1 (83%) and 11q12.2–q25 (81%). These loci encompassed several potential candidate driver genes, including PRKCI, LAMP3, PIK3CA, SKP2, CLDN1, CPT1A and CCND1.

Gene copy number losses and gains were similar throughout the cohort, but using multi-Fisher’s exact test adjusted for multiple comparisons, statistically significant differences were observed in specific loci, between HPV-positive and negative tumours, tumour subtype, grade and nodal status.

Conclusion: This study demonstrates correlations between clinico-pathological variables and genetic changes in PSCC, which could play an important role in its natural history and progression, as well as potential driver genes, which may feature in molecular pathways for existing therapeutic agents.

5. Patient-derived, first-generation xenografts of prostate cancers: Promising tools for predicting drug responses for personalised chemotherapy

R Beekharry, MLL Labarthe-Last, MS Simms, VM Mann, NJM Maitland and AC Collins

Introduction: The treatment of advanced prostate cancer remains disappointing and is hindered by the lack of relevant preclinical models to improve development of effective therapeutic strategies. The limitations of current preclinical models are increasingly cited as a key cause of the low success rate of oncological drug development. Early passages of freshly generated xenografts are possibly better predictors of response and may better represent the heterogeneity seen in prostate cancer than either cell lines or murine allografts.

Objectives: The objective of this research is to determine if primary tumour xenografts represent the clinical heterogeneity of human prostate cancer and to assess their ability to predict clinical outcome and sensitivity to standard of care therapy.

Material and methods: Tumour fragments from patients undergoing curative surgery or channel resection for prostate cancer were implanted into immunodeficient mice within 24 hours of surgery. Once serially transplantable xenografts were achieved, tumour pieces were engrafted into flanks of mice. When tumours reached 5 mm³, mice were randomised and treated with (a) docetaxel (20 mg/kg) or vehicle control, (b) flutamide, placebo or an androgen-loaded diet.

Results: Tumour outgrowth was observed from 38 of 121 (31%) implanted prostate cancers, with 19 stable lines generated. The ability to engraft correlated with advanced disease (r = 0.22; p < 0.05). Patients who had undergone androgen ablation therapy were significantly more likely to engraft compared with no-xenograft patients. Not all of the patient-derived xenografts responded to docetaxel, which is consistent with clinical data. Preliminary data suggest that these xenografts are refractory to anti-androgen.

Conclusions: Patient-derived xenografts may serve as important preclinical models. Tumours that engraft are more aggressive and may be more representative of cancer with a higher propensity to relapse.

6. CD8 T cells inhibit the IL-15-induced cytotoxic activity of NK cells toward tumour cells in the prostate cancer microenvironment

O Elhage, C Sakellariou, RA Smith, C Galustian and P Dasgupta

Introduction: The prostate cancer microenvironment is highly immunosuppressive and immune-effector cells entering it are rendered inactive: However, we have shown that IL-15 can enhance NK-cell expansion and tumour cell killing in a prostate cancer (PCa)-lymphocyte-co-culture model. In this study, we investigated the effects of depleting CD56+ cells (NK and NKT-cells) and CD8-T cells on IL-15-mediated effector-cell-induced PCa-cell killing, and expansion of CD8, and CD56-cells respectively within the co-co-cultures.

Methods: Lymphocytes were isolated from whole blood, and depleted of CD56 or CD8-T cells, followed by a seven-day co-culture with LNCaP and PC3 PCa lines. Effector-cell expansion and PCa-cell killing were then examined with flow-cytometry using antibody-markers for CD3, CD56 and CD8-T cells, and annexin and propidium-iodide, respectively.

Results: IL-15 expanded NK cells by up to 255% and CD8-T cells by 33% in PCa-lymphocyte co-cultures(n =5, p < 0.05). NK cell expansion was not affected by depleting CD8-T cells and CD8-T cell expansion was not affected by depleting CD56+ cells before co-culture. With IL-15 present, up to 64% PCa cell death occurred: No PCa-cell cytotoxicity occurred with CD56+-depleted lymphocytes. However, when CD8-T cells were depleted, PCa-cell killing was enhanced by up to 27%(n = 5, p < 0.05).

Conclusions: IL-15 mediates NK-cell and CD8-T cell expansion in PCa-lymphocyte co-cultures. This is not affected by removal of CD8-T cells or CD56+ cells, respectively. However, CD8-T-cell depletion enhances NK-cell-mediated PCa-cell killing, suggesting that CD8-T cells hinder CD56+ cell activity. This is important in the context of anti-cancer immunotherapy, indicating that CD8-T cells may hinder PCa-cell killing by NK cells.

7. The role of fabricated oestradiol releasing synthetic scaffolds for the treatment of stress urinary incontinence (SUI) and pelvic organ prolapse (POP)

C Hillary, NI Osman, AJ Bullock, S MacNeil and CR Chapple

Introduction: Stress incontinence (SUI) and prolapse (POP) are common conditions with debilitating consequences. Reduced local collagen expression has been reported for some patients (Jackson et al., Lancet 1996; 347: 1658–1661) and oestradiol therapy can improve local collagen content (Rahn et al., J Clin Endocrinol Metab 2014; 99: 3728–3736).

Aim: The aim of this research is to produce materials that release oestradiol in a controlled fashion to promote collagen expression.

Materials and methods: Adipose-derived stem cell (ADSC) viability was measured to determine therapeutic concentrations of 17βEstradiol. These were incorporated into PLLA solutions and electrospun to form the surface of a microporous bilayer scaffold, with polyurethane forming the base layer. Oestradiol release was measured fluorimetrically. ADSC were cultured on scaffolds, with cell viability and total collagen production measured (AlamarBlue and Sirius red assay, respectively) after 14 days’ culture. Young’s modulus and ultimate tensile strength of materials were also calculated (Bose electroforce tensiometer) before and after 14 days of culture.

Results: Oestradiol was released in a dose-dependent fashion over a five-month period. A physiological concentration of oestradiol significantly increased the viability and total collagen production of cells cultured on these scaffolds. Scaffolds became stronger yet more elastic following 14 days of cell culture, which is comparable to the strength and elasticity of healthy paravaginal tissues.

Conclusions: Oestradiol can be incorporated into scaffolds and is released as fibres break down. Addition of oestradiol increases collagen production of cells and may therefore improve the initial wound-healing implant integration, which now needs to be studied in vivo.

8. Shock-wave lithotripsy (SWL), for the treatment of solitary unilateral kidney stones, results in changes to inflammatory and phagocytic leucocyte biomarkers

A Moyes, I Shergill, SJ T-Wright, J Banwell, S Mushtaq, M Abdulmajed and SF Hughes

Introduction: Recent evidence from Wales (UK) suggests that surgical intervention to treat complications (such as infection and acute kidney injury) posed by kidney stones is increasing. The aim of this study was to test the hypothesis that shock-wave lithotripsy (SWL), for the treatment of solitary unilateral kidney stones, results in changes to specific inflammatory and phagocytic leucocyte biomarkers.

Materials and methods: Ten patients undergoing SWL for solitary unilateral kidney stones were recruited (n = 10). From patients (six male and four female), aged between 31 and70 years (median, 50 years) venous blood samples were collected pre-operatively (baseline), at 30 minutes, 120 minutes and 240 minutes post-operatively. Specific inflammatory biomarkers (IL-6, IL-10 and TNF-α) and phagocytic leucocytes (monocytes and neutrophils) were measured by ELISA kits and an automated blood analyser.

Results: SWL result in similar changes of inflammatory and phagocytic leucocyte biomarkers, which is suggestive of increased inflammatory reactions post-operatively. Specifically, IL-6 concentrations increased (three-fold) from baseline at 240 minutes post-operatively (p ⩽ 0.01). Following SWL, increased changes to monocyte and neutrophils concentrations were observed (p < 0.001 andp = 0.003, respectively). Trends of increasing IL-10 and TNF-α concentration were observed following SWL; these were, however, non-significant.

Conclusion: IL-6 and leucocyte cell numbers peaked between 120 and 240 minutes post-operatively. It is proposed that the data provided by these markers would provide a more clinically relevant assessment of the extent of inflammation due to surgery. Ultimately, the specific inflammatory and phagocytic leucocyte biomarkers assessed here may have important diagnostic potential in detecting possible complications (e.g. infection) occurring post-operatively.

9. An analysis of the occupational risk factors for developing bladder cancer amongst the population of South Yorkshire

S Jolly

Introduction: Contemporary data suggest 10% of bladder cancer (BC) arises through occupational exposure. Incidence of BC varies significantly between regions within the UK. Yorkshire – renowned for its heavy metals industry – has higher rates of BC compared to other regions with similar smoking rates. We wanted to look at our own population and the patient-reported risk of task-specific exposure to carcinogens to understand our population’s comparatively higher risk of developing BC.

Patients and methods: We conducted prospective data collection through questionnaires administered to patients diagnosed with BC at our centre over the past 10 years. Details obtained included occupation, daily tasks and exposure to carcinogens, smoking history and patient demographics. Information on tumour grade, stage, recurrence and mortality was also collated.

Results: We have data from 528 patients to date: 117 (22%) women and 411 (78%) men. Being a current/ex-smoker conferred a significant risk of higher grade and stage on diagnosis (n = 421, p = 0.015 and p = 0.026, respectively). Risk of developing T1/Tis disease was significantly higher in patients with exposure to cadmium (n = 62, p = 0.046), heavy metal exposure (n = 211, p = 0.025) and dyes and solvents (n = 191, p = 0.037). Patients exposed to PAHs were significantly more likely to have high-grade disease (n = 232, p = 0.002), as were those exposed to dyes and solvents (n = 191, p = 0.021).

Conclusion: BC is locally an important cause of cancer morbidity and mortality. We have been able to gather important data on our population’s industrial carcinogen exposure that facilitates clinical decision-making and patient counselling. Data collection with control cases is ongoing.

10. Active surveillance in men with pure Gleason 6 disease on transperineal template prostate mapping biopsies

Y Shanmugabavan, M Valerio, C Anele, A Freeman, C Jameson, M Emberton and HU Ahmed

Introduction: There is level 1 evidence that patients with low-grade prostate cancer should be managed with active surveillance. The aim was to determine transition-to-treatment and histological progression rates in men with Gleason 6 confirmed by TPM biopsies who entered a surveillance programme.

Methods: From January 2004 to December 2011, patients with Gleason 3+3 on TPM biopsies were included. Follow-up consisted of PSA every three to six months and histological verification in clinical suspicion of disease progression.

Results: Seventy-eight men with mean age 61 years (SD±6) and mean PSA 6.8 ng/ml (SD 4.3) were included. A median number of two cores (0–18) were positive with mean maximum percentage of cancer core was 25% (SD±19%). At a median follow-up of 33 months (6–84), 17% (13/78) had a biopsy for suspicion of disease progression: two of 13 were negative, five of 13 confirmed Gleason 6, and six of 13 had grade progression to Gleason 7. Twenty-two per cent (17/38) patients opted for active treatment after a median follow-up of 30 months (range 14–63). Reasons for treatment were histological upgrading (7.7%), radiological progression (6.4%) and personal choice (7.7%).

Conclusions: The use of TPM biopsy as a first-line tool to select candidates for surveillance may have considerable clinical utility. First, transition rates to treatment are low in men on surveillance following Gleason 6 disease verified by TPM biopsy. Second, our study also shows histological disease progression was found in 8% of this group. Whilst this proportion is close to the grade mis-attribution of TPM biopsy, some of these cases may have demonstrated true grade progression.

Posters Round 2: Professor Sam McClinton and Mr Prasanna Sooriakumaran

Tuesday, 2 December 1330-1430

11. Targeting the DNA damage response pathways in prostate cancer can be synthetically lethal

H Dev, M Asim, C Massie, K Wadhwa, T Helleday and D Neal

Introduction: The inhibition of poly(ADP-ribose)polymerase 1 (PARP1) leads to double-stranded breaks (DSBs), and is synthetically lethal in BRCA1/2-deficient cells. We investigate the ability to reproduce this therapeutic effect in prostate cancers which often possess functional BRCA1/2, through the dual inhibition of PARP1 and the DSB-sensor protein, ataxia-telangiectasia-mutated (ATM).

Methods: A dual combination of ATM and PARP1 inhibition using KU55933 and olaparib respectively was compared to their use as single agents or DMSO, in a non-neoplastic immortalised and castrate-resistant prostate cancer (CRPC) cell line (RWPE and C42) across a range of assays: confluence-based proliferation, cell viability, and colony-forming assays; flow-cytometry-based cell cycle analysis; γH2X and RAD51 formation by fluorescence microscopy and Western blot; homologous recombination was measured using a direct-repeat-green-fluorescent-protein reporter assay (Nakanishi, 2011). In vivo drug effects were evaluated by subcuticular C42-LM (luciferin-expressing) xenografts established in NOD-SCID mice; and ex vivo, a novel patient-derived CRPC tissue assay was designed and used with Ki-67/cleaved-caspase-3 immunohistochemical analysis after five days of drug treatments.

Results: The combinatorial effect of PARP1 and ATM inhibition are synthetically lethal in prostate cancer cells, in vivo and ex vivo, with minimal effects in benign prostate cell lines. The combination therapy results in a reduction in γH2X and RAD51 assembly, significantly less homologous recombination and greater G2/M arrest than with each inhibitor alone.

Discussion: We describe a new mechanism of synthetic lethality through which the potentiation of stalled replication forks using PARP inhibition and the abrogation of DSB repair with ATM inhibition results in prostate cancer-selective reduction in growth.

13. Management of new red patches identified at flexible cystoscopy: Do we need to biopsy everyone?

S Omorphos and SJ Jain

Introduction: To date there is no standardised management for new red patches at diagnostic cystoscopy. The decision whether to refer for rigid cystoscopy and biopsy is entirely clinician dependent.

Aims and objectives: We investigated our detection rate of malignancy in newly identified red patches. Secondary objectives were: cost-analysis of the management and evaluation of clinician seniority in the decision to biopsy.

Method: We conducted a retrospective analysis of bladder biopsies performed after detection of new red patches at flexible cystoscopy over a 24-month period, December 2011 to November 2013.

Results: Fifty five of the 4205 flexible cystoscopies had red patches without obvious bladder tumour and underwent subsequent bladder biopsy (1.31%).The mean age at biopsy was 59.38 years (range 24–89 years). Malignancy was found in three patients (5.45%) Two patients had carcinoma in situ (CIS) and one had papillary tumour (G1pTa). The incidence per year of detecting malignancy secondary to red patches was 5.45%. Referrals for biopsy by grade were 15 and 40, for consultants and urology trainees, respectively. This audit shows a potential cost-saving of approximately 50% and avoidance of unnecessary GA investigation if patients with low suspicion of malignancy were to have a repeat flexible cystoscopy rather than rigid cystoscopy and biopsy.

Conclusion: To avoid the potential dilemma of repeating flexible cystoscopy versus rigid cystoscopy and biopsy, we propose a cost-effective algorithm to help standardise the management of new red patches, enabling an accurate and cost-effective diagnosis.

14. Single-centre experience of performing dynamic sentinel lymph node biopsy as a delayed procedure in penile cancer

S Omorphos and AM Muneer

Introduction: The technique of dynamic sentinel lymph node biopsy (DSNB) offers a minimally invasive approach to stage the inguinal lymph nodes in patients with penile cancer with clinically impalpable nodes. The aim of this study is to investigate the diagnostic accuracy and outcomes of performing DSNB in patients who have already undergone surgery for primary penile cancer.

Methods: A cohort of 92 consecutive patients diagnosed with penile cancer and with unilateral or bilateral impalpable inguinal lymph nodes who had already undergone primary resection of the penile tumour (stage ⩾ T1, grade ⩾ G2) was studied. An intradermal injection of ^99mTc-nanocolloid was performed just proximal to the previous resection scar followed by planar lymphoscintigraphy and SPECT to localise the sentinel lymph node (SLN). Intraoperatively, the SLN was identified using a combination of patent blue dye and a γ-probe. Radical inguinal lymphadenectomy was performed only if the SLN was positive for micrometastatic disease following histological analysis.

Results: DSNB was undertaken in 165 groins with a non-visualisation rate of 4.8% (eight of 165 groins). The SLN was positive for micrometastatic disease in nine groins (5.5%) from a total of eight patients (8.7%). One patient developed regional recurrence in a pre-pubic lymph node after excision of bilateral negative SLN (1.1%). The three-year disease-specific survival for patients with negative and positive SLN was 98.8% and 87.5%, respectively (p = 0.042). Using DSNB, occult lymph node metastases in penile cancer can be detected with a sensitivity of 88.9% and specificity of 100%.

Conclusions: This study demonstrates that DSNB is feasible as a delayed procedure using a combination of planar lymphoscintigraphy and SPECT to localise the SLN.

15. Migrants from countries that have a higher incidence of urolithiasis tend to retain this increased risk in London

J Cook, BW Lamb, J Lettin and S Graham

Introduction: Little is known about the risk of urolithiasis within an ethnically diverse population living in the same area. We sought to identify the ethnicity of a cohort of patients presenting with renal colic over a six-month period and to assess whether the risk of stone formation varies by ethnic group.

Patients and Methods: Data on a cohort of 100 consecutive patients presenting to our emergency department with acute renal colic were collected retrospectively. Data were extracted from electronic patient record review, trust data and the 2011 census.

Risk ratios were calculated and comparisons between groups were made with Chi-squared test using SPSS.

Result: The odds of being Turkish (odds ratio (OR) 6.57, 95% confidence interval (CI) 3.31–13.04, p < 0.001), Bulgarian (OR 4.94, CI 1.82–13.44, p = 0.001), Romanian (OR 4.53, CI 2.10–9.77, p < 0.001), Indian (OR 2.42, CI 1.17–4.98, p = 0.013) or Pakistani (OR 2.25, CI 1.38–3.67, p = 0.001) were significantly more likely among the colic than the local population.

The odds of being Black-Caribbean (OR 0.27, CI 0.07–1.07, p = 0.045), Black-African (OR 0.27, CI 0.07–1.07, p = 0.046) or White-British (OR 0.44, CI 0.30–0.66, p < 0.001) were significantly lower among the colic population.

The odds of being Lithuanian or Polish were not statistically significant.

Conclusion: This study shows that migrants from countries known to have higher incidence of urolithiasis tend to retain this increased risk once in London. Such ethnic groups may benefit from targeted intervention to reduce the incidence of stone disease. Further research is needed with greater numbers in a range of populations.

16. The clinical utility of transperineal template prostate mapping biopsy

Y Shanmugabavan, A Freeman, C Jameson, M Valerio, M Emberton and HU Ahmed

Introduction: Template biopsies are increasingly used to risk stratify prostate cancer. Our aim was to evaluate the impact on clinical decision-making when using transperineal template prostate mapping (TPM) biopsy following a prior standard trans-rectal ultrasound (TRUS) biopsy.

Materials and methods: Our TPM registry database of 557 men had 424 men diagnostic standard TRUS biopsy. The management recommendation after each biopsy result was ascertained from medical records that were recorded prospectively prior to TPM.

Results: Median age, mean PSA (pre-TPM) and mean PSA (post-TPM) was 63years (range 40–83), 7.6 ng/ml and 8.8 ng/ml, respectively. 225/424 (53%) transitioned to higher risk cancer, 57/424 (13%) transitioned to lower risk and 142/424 (34%) had no change in risk category following TPM. After TPM, 73/ 142 (51%) had a change in recommendation from active surveillance to active treatment. A total of 83/224 (20%) had a change in the type of active treatment they were offered and 169/369 (46%) had no change in treatment recommendation made. Eighteen men, who were offered active treatment or surveillance, were discharged after their TPM due to a ‘no cancer’ diagnosis.

Conclusion: TPM biopsies, when compared to TRUS biopsies, carry significant clinical utility by directly affecting management recommendations made to men with prostate cancer.

17. Whole-gland HIFU in the treatment of radiorecurrent prostate cancer

T Shah, A Kanthabalan, N McCartan, Y Fatola, A Freeman, M Arya, M Emberton and HU Ahmed

Background: Treatment options for radio-recurrent prostate cancer are either androgen-deprivation therapy or salvage prostatectomy with its significant morbidity. Whole-gland high-intensity focused ultrasound (HIFU) might have a role in this setting.

Methods: Fifty-two men from our HIFU registry underwent whole-gland HIFU following histological confirmation of localised disease following prior external beam radiotherapy (2005–2012).

Progression was defined as either biochemical recurrence using the ASTRO-Phoenix criteria (prostate serum antigen (PSA) >nadir+2 ng/ml) or start of hormone therapy/second-line treatments or development of metastases.

Results: Median age, pretreatment serum PSA, and biopsy Gleason score was 68 years (range 56-78), 5.79 ng/ml (range 0.2–49), and 7 (range 6-9), respectively. Median follow-up was 61 months (range 2.5–100). Thirty-three of 52 (63%) achieved a PSA nadir of ⩽0.5 ng/ml. Thirteen of 52 (25%) patients had a nadir >0.5 ng/ml. Six of 52 (12%) did not achieve a nadir (PSA non-responders).

Overall, one-, three- and five-year progression-free survival (PFS) (composite) rates were 71%, 31% and 17%, respectively.

When comparing patients with PSA nadir ⩽0.5 ng/ml, PSA nadir >0.5 and PSA non-responders, a statistically significant difference in PFS was seen (p < 0.05). Three-year PFS in each group was 42%, 15% and 0%, respectively.

Early in the learning curve, between 2005 and 2007, four of 52 (7.5%) developed recto-urethral fistulae. Intervention for bladder outlet obstruction was needed in 28/52 (54%).

Conclusions: Whole-gland salvage HIFU carries significant morbidity. Our oncological outcomes for this high-risk group (with few selection criteria) in whom 30–50% may have micro-metastases at presentation, were promising. Focal salvage ablation may reduce toxicity whilst retaining benefits of treating these men.

18. Surgical margin parameters affect biochemical recurrence after robotic-assisted prostatectomy

H Dev, P Wiklund, V Patel, D Parashar, K Palmer, T Nyberg, D Skarecky, D Neal, T Ahlering and P Sooriakumaran

Introduction: Robotic-assisted laparoscopic radical prostatectomy (RARP) is a current standard treatment for localised prostate cancer, and treatment failure is defined by biochemical recurrence (BCR). Open prostatectomy series identify positive surgical margins (PSM) as predictors of cancer recurrence. We assess patients with localised prostate cancer treated with RARP across three high-volume institutions, and assess the impact of margin parameters on BCR.

Methods: De-identifiable clinical and pathological data was collected for more than 4000 patients with three or more years follow-up. Three statistical models were employed to evaluate the effect of margin parameters on recurrence: crude rates, traditional multivariable Cox regression and a propensity-adjusted model.

Results: Ten per cent of men with negative margins developed recurrence compared with 37% of men with a PSM (HR = 1.81, 95% CI: 1.47–2.22). Multifocality and length ⩾3 mm carried greater risk of BCR than negative margin cases. Considering only the PSM cohort, multivariable Cox regression revealed only apical margins significantly predicted BCR relative to basal margins (HR = 2.03, 95% CI: 1.01–4.09). In contrast there was no statistically significant difference in BCR rates for postero-lateral margins (HR = 1.62, 95% CI: 0.84–3.11). Propensity-adjusted modelling was used to confirm this smaller effect of postero-lateral margins compared with apical margins.

Conclusions: PSM lengths which are ⩾3 mm, and to a lesser extent multifocality in general, are predictive of BCR. Surprisingly, compared with open prostatectomy series, postero-lateral margins are less likely to result in BCR than apical PSMs.

19. The utility and financial implications of repeat post-vasectomy semen analysis

V Kasivisvanathan, O Nehikhare, A Kadirvelarasan, Y Ali, N Golban, T Malthouse, Y Ali, B Challacombe, P Hegarty and M Shabbir

Background: Guidelines on post-vasectomy semen analysis (PVSA) are highly variable. EAU and AUA recommend a single PVSA at 12 weeks whereas the British Andrology Society recommends two PVSAs at 16 and 18–20 weeks.

We aimed to evaluate the utility of repeating semen analysis in patients undergoing bilateral vasectomy.

Methods: Data for all patients undergoing vasectomy between January 2007 and May 2013 at a single institution were identified from electronic records. Patients were typically asked to provide two semen samples at 12 and 16 weeks. Agreement in failure to obtain azoospermia between samples was identified. Univariate and multivariate analysis to identify risk factors for failure to obtain azoospermia at 16–18 weeks were identified.

Results: A total of 190 men submitted PVSAs at both 12–14 weeks and 16–18 weeks. In these men first and second samples agreed in 148/190 (78%) of cases. The PVSA at 12–14 weeks failed to show azoospermia in 67/190 (35%) whereas at 16–18 weeks, 49/190 (26%) failed to show azoospermia. This difference of 9% (95% CI 2%–17%) was statistically significant (p = 0.008). Surgical occlusion technique (p = 0.995), primary surgeon seniority (p = 0.995), presence of an assistant (p = 0.9) or anaesthetic type (p = 0.878) did not influence failure to obtain azoospermia at 16 weeks on multivariate analysis. A single sample PVSA at 16–18 weeks would have saved £12,367.

Conclusions: Twelve to 14 weeks may be an unnecessarily early time for a PVSA. A single 16- to 18-week sample would allow clearance of a greater proportion of men, would have important cost saving implications and may alleviate anxiety and increase patient compliance.

20. The changing profile of occupational bladder cancer: A meta-analysis of exposures reported to increase risk

M Cumberbatch and JWF Catto

Introduction: Bladder cancer (BC) is a common disease arising following occupational carcinogen exposure. Whilst improvements in workplace hygiene have reduced exposure to many carcinogens, contemporary data suggest 10% of BCs arise through occupational exposure.

Materials and methods: We searched for articles published or in press up to October 2012 reporting original data on occupational risk for BC in adults. For meta-analysis we combined risk estimates in a random-effects model. We used adjusted risk estimates when reported.

Results: Our search identified 215 eligible manuscripts reporting 40 occupational classes with increased BC risk. Meta-analysis, using 231,627 cases and 4.76 million matched controls, confirmed an elevated incidence risk for 36 classes and BC-related mortality risk in eight. The greatest incidence and mortality risks were in tobacco (SIR 1.72, 95% CI 1.37–2.15) and glass workers, respectively (SMR 8.07, 95% CI 2.07–31.50).

Conclusions: Improvements in workplace hygiene have reduced risks in many industries and changed the profile of occupations with increased BC risk. The largest improvements have resulted from changes in manufacturing (e.g. rubber industries) or technology (e.g. printing). Reductions in BC risk for clerical and recreational/bar staff are anticipated as a consequence of legislation to prohibit workplace cigarette smoking. Little reduction in BC risk was seen in industries where the carcinogens are unknown (e.g. painters), exposure is uncontrolled (e.g. diesel fume inhalation in drivers) or have not been replaced (electrical workers exposed to polychlorinated biphenyls and heavy metals). Our limitations are that reports mostly stratify workers by job title not occupational task.

Posters Round 3: Professor Prokar Dasgupta and Mr Erik Mayer

Tuesday, 2 December 1600-1640

21. The role of tobacco smoke in bladder and kidney carcinogenesis: A comparison of exposures and meta-analysis of incidence and mortality risks

M Cumberbatch, C La Vecchia, JWF Catto, F Real and N Malats

Introduction: Tobacco smoke is a common carcinogen implicated in the aetiology of bladder cancer (BC) and renal cancer (RC). Here we examine the relationship between tobacco consumption and the natural history of BC and RC, and assess whether cessation alleviates the risk of disease.

Materials and methods: We searched the PubMed database for original manuscripts in English, using the string terms ‘tobacco smoking’ AND ‘bladder cancer’, OR ‘tobacco smoking’ AND ‘kidney cancer’ up to August 2013 in compliance with PRISMA standards approach. A meta-analysis of risks was performed using a random-effects model in the STATA statistical suite.

Results: We identified 2683 papers, of which 129 fulfilled the inclusion criteria. Ever tobacco smoke inhalation increases the incidence of both BC (relative risk (RR) 4.08, CI 3.76 to 3.76) and RC (RR 2.74, CI 2.5 to 3.13). BC incidence in current smokers is greater than that of ex-smokers (RR 12.84 (±95% CI) and 4.72 (±95% CI), respectively). Current smokers have a greater RR for BC than RC (RR 12.84 (±95% CI) and 2.79 (±95% CI), respectively). Mortality rates are higher in ever smokers compared to non-smokers but there is no significant difference between current and ex-smokers. There is an increased BC recurrence risk in ever-smokers. Smoking pipes and cigars carries an increased risk but has been less intensively studied than cigarettes. Second-hand smoking (SHS) is a risk factor.

Conclusions: Our outcomes are consistent with current literature. The role of tobacco in RC needs more study.

22. PROGENY: The Prostate Cancer Genomic Heterogeneity Study

Y Shanmugabavan, M Hung, R Scott, A Rowan, A Freeman, A El-Shater Bosaily, Y Hu, M Gerlinger, C Swanton and HU Ahmed

Introduction: Prostate cancer has known intra-tumour heterogeneity. Metastases were shown to arise from one lesion. It is unknown whether the metastatic clone arises from one region within a prostate cancer lesion. Whilst whole-mount specimens provide tissue for investigating heterogeneity, the low incidence of metastases in this group means linkage of genomic changes in the prostate to metastases is not possible. The NCRN PROGENY study aims to investigate inter- and intra-tumour heterogeneity using accurate image-fusion transperineal prostate-targeted biopsies. Here we report the clinical outcomes of the pilot phase.

Materials and methods: Men with an elevated PSA and a lesion on multi-parametric MRI (mpMRI) underwent targeted transperineal biopsy under. Each diagnostic core was associated with another core taken for deep genomic sequencing. Blood samples were taken to measure cell-free plasma DNA.

Results: Of 23 men, the mean age was 70 (54–81) years. The mean PSA was 68.5 ng/ml (3.66–157.7 ng/ml). The mpMRI stage was T3a in 10, T3b in 10 and T4 in 3 men, respectively; six men were identified with metastases on mpMRI. Three men had intermediate and 20 men high-risk disease. Gleason grade was 3+4 (n = 3), 4+3 (n = 7), 4+4 (n = 3), 4+5 (n = 6) and 5+4 (n = 1). Maximum cancer core length was mean 7 mm (range 0.5–16). Imaging and genomic correlation is currently under way.

Conclusion: The PROGENY trial will determine the association of clinical and imaging factors to histological and genomic heterogeneity, and with time, to metastases and treatment failure. Our results demonstrate targeted biopsies accurately diagnose and depict the grade heterogeneity in a lesion.

23. Segmental ureterectomy for upper tract urothelial carcinoma appears to be oncologically sound

H Dev, M Kuet, H Copley, S Poo, J Armitage and S Connolly

Introduction: Segmental ureteric resection for upper tract urothelial cancer (UTUC) is confined to imperative cases (e.g. solitary kidney) due to concerns about cancer multifocality and ipsilateral recurrence. We retrospectively analysed our experience of nephroureterectomy (NU) to determine how many patients could have safely benefitted from segmental resection.

Methods: We identified patients undergoing NU in the last 15 years. Pre-operative evaluation included excretory-phase computed urography, endourological evaluation and urine cytology and/or biopsy. Pathology reports were scrutinised for tumour variables. ‘Suitability for segmental ureterectomy’ criteria were: unifocal lesions within mid or distal third ureter; tumour length ⩽50 mm; tumour grade<‘high-grade’ G2; and ipsilateral renal function estimated >20% total renal function.

Results: A total of 133 patients were identified, and NU was undertaken for unifocal (92) or multifocal (39) disease. Seven cases (5%) fulfilled our criteria. The NU specimen in all cases confirmed unifocal disease. Final UTUC stage was pT0, pTa, pT1 in one (dysplasia), three, and three cases, respectively. No positive surgical margins were identified. Upgrading occurred in 2 cases. A significant rise in creatinine occurred in all seven cases, with mean pre- and post-operative creatinine of 94 µmol/l and 157 µmol/l (paired t-test = 9.55; p < 0.0001).

Conclusion: Segmental ureterectomy appears feasible and oncologically safe, although confined to a small group of patients. Benefit of such treatment should be sought from a prospective randomised trial, which will almost certainly require multicentre collaboration due to the small numbers involved.

24. Does focal high-intensity focused ultrasound have a role in treating localised prostate cancer in the elderly?

S Guillaumier, N McCartan, Y Fatola, L Dickinson, K Shah, A Freeman, RG Hindley, M Emberton and HU Ahmed

Introduction: There is an increase in the ageing population leading a significant proportion of men diagnosed with prostate cancer being over 75 years of age. Misconceptions regarding treating the elderly are still rife. The body of evidence that has recently emerged shows that this cohort of patients should be offered the same curative therapies as their counterparts. This study looks at the feasibility of focal high-intensity focused ultrasound (HIFU) in treating localised prostate cancer in those aged over 75 years of age.

Materials and methods: Our independent academic HIFU registry incorporates a total of 60 patients who were diagnosed with low-, intermediate- and high-risk localised adenocarcinoma of the prostate, stage T2a–T3aN0M0 and treated with focal HIFU using Sonablate500, between 2004 and 2014. We divided the patient cohort into those who were treated within the remit of a trial protocol, and those who were not.

Results: As biochemical failure is difficult to define, we looked at the medium-term transition rates to redo HIFU, local salvage and systemic therapy (Table 1).

Table 1.

Characteristics of patient group.

	Total patients	Redo HIFU	Salvage radiotherapy	Salvage ADT	Radical prostatectomy
Focal HIFU (trial)	7	2 (28.5%)	0 (0%)	0 (0%)	0 (0%)
Focal HIFU (registry)	53	5 (9.4%)	1 (1.9%)	4 (7.5%)	0 (0%)

HIFU: high-intensity focused ultrasound; ADT: androgen-deprivation therapy.

Table 2 outlines the complication rates associated with focal HIFU.

Table 2.

Outcomes.

	Acute urinary retention	Urinary tract infection	Epididymo-orchitis	Urethro-rectal fistula	Pad-free at last follow-up
Focal HIFU (trial)	0 (0%)	0 (0%)	0 (0%)	0 (0%)	7/7 (100%)
Focal HIFU (registry)	4/5 (7.5%)	3 (5.7%)	0 (0%)	0 (0%)	52/53 (98%)

HIFU: high-intensity focused ultrasound.

Conclusions: Focal HIFU has been shown to be both feasible and effective in the elderly population. It is a safe modality of treatment to use in this patient cohort with a low complication profile. Long-term studies are, however, necessary.

26. Erosion of penile prosthesis in patients with erectile dysfunction and diabetes

M Christodoulidou and I Pearce

Introduction: Complications of penile prosthetic surgery are well documented but erosion is less frequently reported in literature. Patients with diabetes have microvascular disease and neuropathy and therefore have a theoretically increased risk of erosion. The primary objective in this systematic review was to determine whether patients with diabetes are more susceptible to erosion of a penile implant compared to other patient cohorts.

Patients and methods: We conducted a systematic review searching through the Medline database from 1960 to 2014 using keywords ‘penile prosthesis(es)’, ‘penile implant(s)’ and ‘diabetes’. We identified 73 articles and screened for eligibility and incidence of erosion.

Results: We identified seven publications reporting erosion on Medline and other sources. One case series reported that diabetes was a risk factor in 39% of their erosion occurrence. Two case series though reported erosion with an incidence of 0–0.5% in patients with diabetes. All three case series reported a higher incidence of erosion in patients with vasculogenic erectile dysfunction. We also identified four case reports reporting erosion and gangrene of the penis glans in patients with diabetes.

Conclusion: Erosion occurrence is rare in literature but it remains a mystery whether this is truly rare or whether this information is not published as frequently. There is not enough evidence to support that patients with diabetes have a higher risk of erosion of their penile implant. It is therefore important that cases with erosion are entered on an International Audit database to allow the future study and possible prevention of this occurrence.

27. Guidance on the initial assessment of sterile pyuria – based on a Delphi Consensus Process

J Manley, J Rees, F Carter, B Patel, R Persad and E Jefferies

Introduction: Sterile pyuria is the presence of leucocytes in the urine without any demonstrable urine infection. It is a common finding and often results in referral to secondary care for investigation. There is a wide differential of factors related to the finding, including: specimen collection, previous treatment, and urological or systemic pathology. Despite this, there is a paucity of published evidence with regards to the assessment and management of sterile pyuria, and no national guidelines.

The objective was to create a consensus statement and guidelines on the initial investigation of a patient with sterile pyuria.

Methods: A modified Delphi method was used, consisting of a two-round questionnaire to a panel of experts (n = 59) from numerous fields (urologists, general practitioners with special interest in urology, renal physicians and microbiologists) with specialist input regarding questionnaire development. Following each round the results were reported to the panel members, comparing their answer with that of the panel and any additional comments. Any statement reaching 70% agreement became the consensus statement.

Results: Statements were formulated in a total of 22 subdivided aspects of the condition (total questions, n = 76). A consensus was reached on greater than 85% of statements regarding the optimal investigative technique and modalities.

Conclusion: The outstanding statements will be discussed at a panel meeting, and the results form the basis of a guideline for the initial investigation of sterile pyuria in primary care.

28. How to do proper positioning of ureteric stent in antegrade insertion?

M Aboelmagd

Introduction: In case of unilateral or bilateral obstructive uropathy and failure of retrograde insertion of double J ureteric stent, antegrade double J insertion is recommended.

There is a problem in the proper positioning of antegrade ureteric stent with the use of ordinary guide wires. The upper J tip of double J stent is difficult to adjust well in the proper position.

To our knowledge there are no reports mentioning the use of specific types of guide wire except what we have: the straight or J tip guide wire. We designed a special type of guide wire to be circular, floppy and straight ended, which is very helpful for the proper positioning of the upper J tip of ureteric stent.

Materials and methods: Between September 2013 and August 2014, specially designed guide wire was used in the insertion of antegrade double J stent in 15 cases where it is difficult to properly position the of upper J tip using ordinary guide wire. The outcome was to compare the ease of proper positioning of the upper J tip by using specially designed guide wire and an ordinary one.

Results: In all cases, the use of the specially designed guide wire showed ease of proper positioning of the upper J end of double D ureteric stent in comparison to the use of ordinary guide wire, which led to bad positioning of either the upper ureter or even in the kidney parenchyma.

Conclusions: The use of the specially designed guide wire is considered a good option to overcome the difficulties in the proper positioning of the double J ureteric stent during antegrade insertion.

Idea and innovation: Introduction of our new guide wire with a circular, floppy and straight end was very helpful in the proper positioning of the upper J tip of the ureteric stent during antegrade insertion.

Description of idea: During antegrade insertion of the double J using of our guide wire, the upper end of double J ureteric stent coils when it reaches the proper position in the renal pelvis while the circular part of guide wire remains inside the upper J tip of the stent. At this moment in our hand, the guide wire remains inside the stent, the threads are still attached to the stent and the pusher was not removed.

If the upper J end of the stent with the floppy, circular part of the guide wire inside is in the narrow space as in the upper ureter or in kidney parenchyma, the coiled shape will not occur, thereby indicating the improper positioning of the double J stent.

29. Is the risk of infection of penile prostheses in patients with diabetes higher compared to other patient cohorts? A systematic review

M Christodoulidou and I Pearce

Introduction: Up to 50% of patients with diabetes experience some level of erectile dysfunction. This has led to the increased use of implants in this group as the final definitive procedure. Despite diabetes still remaining a controversial risk factor for penile prosthesis infection, we believe this risk has declined over the decades with device improvement and surgical expertise. The primary objective of this review was to determine whether the presence of diabetes increases the risk of prosthesis infection.

Patients and methods: We performed a systematic review searching through the Medline database from 1960 to 2014, using keywords: ‘penile prosthesis(es)’, ‘penile implant(s)’ and ‘diabetes’. We identified 61 case series for analysis.

Results: Case series reporting a higher infection rate in patients with diabetes date from the 1970s to 1990s with a rate of 5.5% to 20% containing a small cohort of patients. In the 1990s larger case series reported a lower infection rate in patients with diabetes compared to patients with paraplegia, pelvic trauma and on steroids but still reported an infection rate as high as 10.6%. With the implementation of antibiotic-coated implants in 2001, infection rates declined to 2% in patients with diabetes. With the latest ‘no-touch’ technique, the infection rate was 0.46%, which was not statistically significant.

Conclusion: There is no doubt that penile prosthesis surgery is a safe and appropriate definitive option for patients with organic erectile dysfunction. In specialised, high-volume centres, there is no statistical difference in the infection rates between patients with and without diabetes.

30. Exercise to prevent hip fracture in prostate cancer survivors undergoing androgen-deprivation therapy

S Allison

Introduction: Hip fractures are a common and serious problem in men receiving androgen-deprivation therapy (ADT) for prostate cancer treatment, leading to a poor quality of life and premature death. Maintenance of optimum bone health during ADT is therefore important in the management of this patient population. Regular exercise is an effective lifestyle approach for improving and maintaining bone health, so has the potential to reduce fracture risk in prostate cancer patients on ADT.

Materials: The ideal exercise prescription for maintaining bone health in prostate cancer patients during ADT might include impact exercises that provide an optimal loading regimen to target bone at the hip and can be easily incorporated into daily routine. In older men, a population also at high risk of fracture, we showed that high-impact exercises were effective for increasing bone mineral density at the femoral neck (Allison et al. Bone 2013; 53: 321–328). However, it is currently unclear whether men on ADT for prostate cancer treatment can respond to or tolerate this type and intensity of exercise.

Conclusions: In collaboration with colleagues at Imperial College (Department of Surgery and Cancer), the plan is to now develop an exercise prescription and evaluate its feasibility and influence on bone health in men with prostate cancer undergoing ADT. Findings from this work will help to develop national guidelines to extend the quality and quantity of life in prostate cancer patients on ADT, by maintaining optimal bone health and reducing fracture risk.

Dragons Den – Urology’s Got Talent Proposals: Professor Rob Pickard, Mr John Kelly and Mr Tom Pinkney

Tuesday, 2 December 1430-1600

1. Can a smartphone application improve patient safety by reducing the incidence of forgotten ureteric stents?

N Arumainayagam, M Mikhail, W Cook, H Gresty, A Shamsuddin and R Dasgupta

Charing Cross Hospital, Imperial College Healthcare NHS Trust

In modern urological care, ‘forgotten ureteric stents’ still occur, resulting in harm to patients and financial burden to health care systems.

We have developed a novel smartphone application (Stentbook^TM) to quickly upload stent information on insertion, and log stent removal at a later date, again using the application. Stentbook^TM triggers an automated email to the clinician and SMS message when a stent is not logged out, in a given timeframe set by the clinician. The application aims to provide a safety net, hopefully minimising the risk of the ‘forgotten stent’, and making the process of entering stent information simple for the clinician, without the need to log into a computer.

The population to be investigated are patients undergoing urological or radiological stent insertion over a six-month period. The intervention proposed is the use of the Stentbook^TM application. The comparator group will be patients undergoing stent insertion without use of the smartphone application to act as a safety net. The outcome will be the number of overdue or forgotten stents in each group.

Implementing our study at a trainee level across multiple sites will not require additional resources or funding, and if successful may improve patient safety.

3. A trainee-led multicentre observational study of patients presenting acutely with malignant ureteric obstruction

Trainee:

N Campain (clinical fellow, Royal Devon and Exeter NHS Trust)

Supervisor:

JS McGrath (consultant urological surgeon, Royal Devon and Exeter NHS Trust)

Patients: All patients across participating centres presenting with acute ureteric obstruction secondary to malignancy, or suspected malignancy, that require intervention with either percutaneous nephrostomy or endoscopically placed ureteric stent. All consecutive patients presenting through the urology unit for a period of one month should be considered eligible.

Intervention: Patient cohorts will consist of three groups, with management according to usual clinical care.

Percutaneous nephrosotomy

Endoscopic ureteric stent

No intervention (for example, if patient declined, medically unfit, not clinically appropriate)

Comparator: This will be a prospective observational case series study of patients presenting with malignant, or suspected malignant, ureteric obstruction. Patients will receive treatment according to usual clinical care and will not require randomisation to any intervention. As such this is a non-comparator study, designed to answer a real-world clinical question.

Outcomes:

Primary outcomes are:

Initial success/failure rate of each procedure (successful placement of percutaneous nephrostomy or ureteric stent)

Improvement of renal function (measured at two weeks following intervention)

Clinical outcome at three months (patient alive or dead)

Secondary outcomes are:

Number of patients requiring further radiological intervention (for example antegrade stent or change of nephrostomy/ureteric stent)

Number of patients undergoing surgery for ureteric obstruction

Numbers of patients requiring palliative care

Hypothesis:

In pelvic malignancy, patients presenting with acute ureteric obstruction may achieve better renal function with percutaneous nephrostomy compared to ureteric stent placement.