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Editorial: Does cold exposure cause nocturia?

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We have all experienced that changing from a warm environment to a colder external temperature may provoke a sudden compelling desire to void. This feeling fits quite well with part of the definition of urgency following the International Continence Society definition. Consequently, it is logical to suspect that cold exposure during daytime may influence bladder behaviour and hence contribute to nocturia episodes. These Japanese authors [1] performed a cross-sectional analysis as part of a community based cohort study in 1127 home-dwelling volunteers aged ≤60 years. Living room and bedroom temperatures were measured for 48 h and the participants completed voiding charts and nocturnal urine collection, but were excluded if >12 h were spent outside their house. The mean age of the participants was ≈72 years and nocturia was present in 30.8%. A decrease in daytime indoor temperature of 1 °C was associated with a higher odds ratio for nocturia and this was independent of outdoor temperature and other potential confounders. Furthermore, the association was independent of nocturnal urine production and hence reflect a direct effect on bladder behaviour, probably due to detrusor overactivity. However, a change of indoor temperature modified nocturia in only 29.3% of participants, and varied significantly in individuals. Nevertheless, these findings could be used as a population approach to reduce the prevalence of nocturia and hence the eventual impact on quality of life and morbidity that is known to go together with nocturia.

Read the full article
Philip Van Kerrebroeck, Professor of Urology
Department of Urology, Maastricht University Medical Centre, Maastricht, The Netherlands

 

References
1 Saeki K, Obayashi K, Kurumatani N. Indoor cold exposure and nocturia: a cross-sectional analysis of the HEIJO-KYO study. BJU Int 2016; 117: 829–35

 

 

Editorial: PSMA-targeted imaging of PCa – the best is yet to come

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In recent years there has been increasing interest in imaging recurrent or metastatic prostate cancer with positron-emission tomography (PET) radiotracers targeting prostate-specific membrane antigen (PSMA [1]). The majority of this work has been performed using urea-based small molecules labelled with gallium-68 (68Ga). Within this class of radiotracers, 68Ga-PSMA-11 (also known as 68Ga-PSMA-HBED-CC) has been the most widely studied. In this month’s edition of BJUI, van Leeuwen et al. [2] report on the clinical utility of 68Ga-PSMA-11 PET/CT in men with rising PSA levels after radical prostatectomy being considered for salvage radiation therapy. In their study, 70 patients with negative conventional imaging findings and a median PSA of 0.2 ng/mL (all <1 ng/mL) were imaged with 68Ga-PSMA-11 PET/CT prior to initiating treatment. On PSMA-targeted PET/CT, 53 lesions were detected in 38 (54%) patients. Perhaps most significant among their findings was that 28.6% of men had radiotracer uptake outside of the prostatic fossa leading to a major change in clinical management. In total, these data demonstrate the great potential of PSMA-targeted imaging, particularly in men with biochemically recurrent prostate cancer.

While a great deal of encouraging data with 68Ga-PSMA-11 has appeared in the medical literature, it is worth noting that several other small molecules that offer potential advantages over this agent have seen early clinical development. For example, PSMA-617 makes use of the DOTA chelation moiety in place of HBED-CC, allowing for a scaffold that can accommodate both diagnostic 68Ga and therapeutic lutetium-177 (177Lu) [3]. Additionally, our group has focused on fluorine-18 (18F)-labelled urea-based small molecules targeting PSMA, most recently 18F-DCFPyL [4]. 18F-labelled small molecules offer several potential advantages over those labelled with 68Ga. These include more favourable dosimetry allowing for higher injected radiotracer doses and lower-energy emitted positrons that have shorter path lengths to annihilation and therefore higher intrinsic spatial resolution [5]. Notably, a recent direct comparison of 68Ga-PSMA-11 and 18F-DCFPyL performed by Dietlein et al. [6] seems to confirm these advantages, having observed a higher rate of lesion detection as well as superior mean tumour-to-background ratios with the radiofluorinated compound. An additional advantage of 18F-labelled compounds is related to their longer half-life for radionuclide decay (109 vs 68 min for 68Ga). Given this difference, agents incorporating 68Ga typically require an on-site generator for radiotracer production, whereas 18F-based radiotracers can be produced en masse at a central site with a cyclotron and then delivered to remote locations via pre-existing distribution infrastructure (e.g. PETNET in the USA). Table 1 summarizes several relevant differences in the physical properties of 68Ga and 18F.

Table 1. Comparison of gallium-68 and fluorine-18
Radionuclide 68Ga 18F
Half-life, min 68 109
Method of production Generator Cyclotron
Average positron energy, keV 836.0 249.3
Average path length in soft tissue, mm 8.1 2.4
Positron yield per 100 disintegrations 89.14 96.86

 

In summary, these are exceptionally exciting times for the study of PSMA-targeted imaging of prostate cancer. With continued radiotracer development and accompanying well-designed clinical trials, there is no doubt we can drastically improve the care of men with prostate cancer.

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Michael A. Gorin*, Martin G. Pomper† and Steven P. Rowe†

 

*The James Buchanan Brady Urological Institute and Department of Urology, and †Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA

 

References

 

1 Lutje S, Heskamp S, Cornelissen AS et al. PSMA ligands for radionuclide imaging and therapy of prostate cancer: clinical status. Theranostics 2015; 5: 1388–401

 

2 van Leeuwen PJ, Stricker P, Hruby G et al. 68Ga-PSMA has a high detection rate of prostate cancer recurrence outside the prostatic fossa in patients being considered for salvage radiation treatment. BJU Int 2016; 117: 732–9

 

3 Afshar-Oromieh A, Hetzheim H, Kratochwil C et al. The theranostic PSMA ligand PSMA-617 in the diagnosis of prostate cancer by PET/CT: biodistribution in humans, radiation dosimetry, and first evaluation of tumor lesions. J Nucl Med 2015; 56: 1697–705

 

4 Szabo Z, Mena E, Rowe SP et al. Initial Evaluation of [(18)F]DCFPyL for Prostate-Specific Membrane Antigen (PSMA)-Targeted PET Imaging of Prostate Cancer. Mol Imaging Biol 2015; 17: 565–74
5 Sanchez-Crespo A. Comparison of Gallium-68 and Fluorine-18 imaging characteristics in positron emission tomography. Appl Radiat Isot 2013; 76: 55–62

 

6 Dietlein M, Kobe C, Kuhnert G et al. Comparison of [18F]DCFPyL and [68Ga]Ga-PSMA-HBED-CC for PSMA-PET imaging in patients with relapsed prostate cancer. Mol Imaging Biol 2015; 17: 575–84

 

Editorial: Unmasking roles of the peripheral endocannabinoid system associated with bladder overactivity

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Identifying regulatory roles of peripheral endocannabinoid systems for bladder function is a highly intricate task; nonetheless, in this issue of BJUI, a research report by Aizawa et al. [1] shows functional evidence for a role of fatty acid amide hydrolase (FAAH) in improving bladder overactivity induced by prostaglandin E2 (PGE2) in rats. By systemically blocking FAAH with URB937, an inhibitor of FAAH that does not penetrate the CNS, the authors found that afferent nerve activity and bladder cystometric parameters decreased in a rat overactive bladder model induced by intravesical perfusion of PGE2. Confirmation that ≈80% of dorsal root neurones at the Lumbar-6 dorsal root ganglia co-express FAAH and cannabinoid receptors 1 and 2 (CB1, CB2), emphasises the role of the peripheral endocannabinoid system during bladder overactivity induced by increased activity of C-fibres during PGE2 application.

Because FAAH catabolises CB ligands rapidly, a key regulatory role for pain perception was initially proposed [2]. Now, we recognise that the peripheral endocannabinoid system participates in both normal physiology and pathological conditions of the heart, liver, immune system, bone, skin, skeletal muscle, reproduction, and gastrointestinal tract [3]. The participation of the endocannabinoid system in regulating lower urinary tract function has been less studied; however, research evidence suggest an important regulatory role at different levels of the micturition reflex [4]. The study of Aizawa et al. [1] is important because it shows that the rat urinary bladder can be affected by the catabolism of endogenous ligands for CB1 and CB2 during systemic FAAH inhibition in conditions of bladder overactivity induced by PGE2. However, the experiments were performed in conditions where the urothelial cell layer was disturbed with the intravesical application of protamine sulphate. Although this seems to be the best approach to induce bladder overactivity with PGE2, it disturbs the sensory role of the urothelium for monitoring the urinary bladder filling status [5]. Thus, an alternative model for bladder overactivity requires an evaluation of an FAAH inhibitor. Supporting this suggestion, a recent report by Wang et al. [6] shows that intravesical application of a CB1agonist decreases bladder overactivity induced by intravesical nerve growth factor (NGF) in mice with an intact urothelial layer. Additionally, NGF did not induce bladder overactivity in knockout mice for the FAAH enzyme, reinforcing the suggestion for Aizawa et al. [1] about testing the peripherally-restricted inhibition of FAAH with URB937 in urothelium-intact rats.

The above comments and references recommend the performance of a pre-clinical evaluation of the endocannabinoid system using FAAH inhibitors to treat, for instance, neurogenic bladder overactivity in rats with spinal cord injury. Naturally, this overactive bladder model will prove to be more complicated and challenging to evaluate, but the results may provide overwhelming support for a rigorous assessment of the use of cannabinoids to treat urinary bladder dysfunction in humans [3]. At the mechanistic level it would be interesting to know at what part(s) of the micturition reflex is FAAH regulating bladder function. How significant is the catabolism of endogenous CB1/CB2 receptors during the storage and contraction phases of either normal or altered micturition? While the current study of Aizawa et al. [1] contributes to a deeper knowledge of the cannabinoid system in bladder dysfunction, additional studies are required to determine whether systemic inhibition of FAAH improves C-fibre mediated bladder sensory pathways in other animal models of detrusor and bladder overactivity.

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Alvaro Munoz, Assistant Research Professor of Urology
Departments of Regenerative Medicine and Urology, Houston Methodist Research Institut e and Houston Methodist Hospital, Houston, TX, USA

 

References

 

1 Aizawa N, Gandaglia G, Hedlund P et al. URB937, a peripherally restricted inhibitor for fatty acid amide hydrolase, reduces prostaglandin E2-induced bladder overactivity and hyperactivity of bladder mechano-afferent nerve fibres in rats. BJU Int 2016; 117: 821–8

 

2 Cravatt BF, Demarest K, Patricelli MP et al. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci USA 2001; 98: 9371–6

 

3 Maccarrone M, Bab I, Bıro T et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci 2015; 36: 277–96

 

4 Hedlund P. Cannabinoids and the endocannabinoid system in lower urinary tract function and dysfunction. Neurourol Urodyn 2014; 33: 46–53

 

5 Birder L, Andersson KE. Urothelial signaling. Physiol Rev 2013; 93: 653–80

 

6 Wang ZY, Wang P, Bjorling DE. Activation of cannabinoid receptor 1 inhibits increased bladder activity induced by nerve growth factor. Neurosci Lett 2015; 589: 19–24

 

Editorial: The vexing problem of UAB in children – a viable alternative

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Underactive bladder, as defined by the International Children’s Continence Society (ICCS; impaired detrusor contractility that leads to low voiding frequency (<3 voids/day), hesitancy, incomplete bladder emptying, and high post-void residual urine volumes (PVRs) that may produce UTI and urinary incontinence) has been a vexing problem for many paediatric providers to manage.

Antimuscarinic and α-agonist drugs have not proven effective to warrant their recommendation, and urotherapy, which demystifies the condition and tries to teach children to void often, take the time to urinate, use correct posture, and promote dietary habits that seem to adjudicate fluid intake, resulting in appropriate urine production and regular bowel movements, have not fully solved the problems in all patients. More invasive therapies, i.e., percutaneous tibial nerve stimulation, intravesical electrical stimulation, and sacral neuromodulation provide some improvement in mollifying symptoms but long-term responses do not seem to be sustainable. Intermittent catheterisation, which immediately achieves bladder emptying on a timely schedule, is often a therapy that children and their parents prefer to avoid. All these management options with their varying responses have left patients resigned as their symptoms persist and their parents frustrated.

Kajbafzadeh et al. [1], in a study reported in this issue of the Journal, have clearly shown the value and potential promise of interferential electrical stimulation (IFES) for non-neuropathic underactive bladder in children. IFES changes bladder dynamics so that urinary frequency, bladder contractility, and PVRs improve to the extent that incontinence, both daytime and night-time, as well as UTIs, resolve. Although it is time consuming, as one would expect all therapies that reverse pathological processes might be, the promise that long-term responses remain salient is a testament to its worthiness. As a reference, Kajbafzadeh et al. [2] recently published similar responses in a randomised clinical trial of children with primary monosymptomatic enuresis, using standard urotherapy (as used in this current study [1]) with and without IFES, which revealed statistically significant improvement in enuretic episodes, both initially and after 1 year in those children treated with IFES. In a previous randomly allocated report of 30 children with myelomeningocele and detrusor overactivity, IFES was substantially effective in 20 vs 10 who were ‘sham controlled’ [3].

The authors [1] do indicate deficiencies in their study, the most glaring of which is the absence of a ‘sham’ group of children who should have ‘received’ IFES treatment without any actual ES. In clinical practice this is almost impossible to achieve. Long-term urodynamic data would also have been helpful in solidifying these responses when compared to pre-treatment investigations but again having families assent to a study that involves catheterising their child for this purpose is nearly impossible.

The authors did not comment on the improvement in bowel function these children may experience in the immediate period after treatment or in the long-term, but given the emphasis on better toileting it is presumed lower gastrointestinal function would have been helped as well. In addition, the authors [1] have left us wondering if these improved toileting habits changed the propensity towards UTIs over time. Nor have they expressed any improvement in behavioural issues as a result of this programme, or what effect, if any, has occurred regarding school performance and social interaction. It is now up to these pioneers, as well as future investigators, to lead the way to engage a child’s entire milieu and his family responses, to the acceptability of this treatment programme. Looking beyond just the immediacy of an IFES regimen and its effects on the urinary and gastrointestinal systems will surely tell us if this management schema truly has large scale merit for a wider cohort. That kind of communication would surely be an impetus for scientifically minded clinicians to delve into the ‘whys’ of its positive pathophysiological effects.

I commend the authors for their exceptional work and desire to find an effective, minimally invasive treatment that has long-term sustainability. The gauntlet has been dropped, only to be picked up by others (or these same providers) to address and answer the additional concerns and questions posed by this editorial.

Read the full article
Stuart B. Bauer
Department of Urology, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA, 02115, USA

 

References

 

1 Kajbafzadeh AM, Sharifi-Rad L, Ladi-Seyedian SS, Mozafarpour S. Transcutaneous interferential electrical stimulation for the management of non-neuropathic underactive bladder in children: a randomised clinical trial. BJU Int 2016; 117: 793–800

 

2 Kajbafzadeh AM, Sharifi-Rad L, Mozafarpour S, Ladi-Seyedian SS. Efficacy of transcutaneous interferential electrical stimulation in treatment of children with primary nocturnal enuresis: a randomized clinical trial. Pediatr Nephrol 2015; 30: 1139–45

 

3 Kajbafzadeh AM, Sharifi-Rad L, Baradaran N, Nejat F. Effect of pelvic floor interferential electrostimulation on urodynamic parameters and incontinency of children with myelomeningocele and detrusor overactivity. Urology 2009; 74: 324–9

 

Editorial: Some like it safe

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Since the implementation of ureteroscopy (URS) about 100 years ago, technological as well as peri-operative management improvements have made URS the treatment of choice for ureteric and renal stones. Depending on stone location and size, stone-free rates of up to 100% have been reported in combination with low peri-operative complications and short hospital stay. Endoscopic therapy of stone disease, e.g. (primary) URS, reflects the zeitgeist: minimally invasive, fast, efficient and economic. There is, however, still a lack of consensus on the question of preoperative stenting in stone management strategies. The underlying aim of preoperative stenting is to cause passive dilation of the ureter, allowing easier access to the upper urinary tract during a secondary URS.

In the current issue of the BJUI, Assimos et al. [1] report higher stone-free rates, as well as fewer complications, with the use of a JJ stent before URS in patients with renal stones, and their article, therefore, supports the previously reported findings of retrospective series with observational, multicentre evidence [2]. Their findings do not, however, corroborate improved outcomes for prestented patients with ureteric stones [1]. Notably, more stents overall were placed in the presence of renal stones compared with ureteric stones (36.4 vs 11.9%). Primary URS may not always be feasible because of anatomical abnormalities, a narrow ureteric lumen, complex ureteric path or previous instrumentation [3]. In such cases, further manipulation risking trauma and potentially long-term stricture formation should be avoided and ureteric stent placement is necessary before further therapy. Indeed, it is possible that renal stone treatment may be associated with increased ureteric manipulation; therefore, passive ureteric dilation might be helpful and facilitate endocopic access to the renal pelvis. A direct elective prestenting in these patients followed by a secondary URS, therefore, warrants discussion. Although prestenting is an additional procedure, it has the potential to lower healthcare costs by decreasing complications rates, operating time and re-operation rates, especially for large proximal stones [4].

Routine preoperative stenting is not necessarily recommended by current guidelines [5]; however, the management of pre-URS stent placement is left to institutional and international practice patterns. Indeed, as shown in Figs 1 and 2 of the present paper [1], the incidence of preoperative JJ stenting varied tremendously by country. Whereas the large majority of patients with ureteric (88.1%) as well as renal (63.6%) stones were treated without a stent, in Germany, for example, >50% of patients were stented before URS. Also in China, Chile, Egypt and Israel, a higher percentage of patients with ureteric stones primarily received a JJ stent.

The use of stents is known to cause discomfort, pain and urinary symptoms, and therefore can represent significant health problems for the patient. These negatively affect daily activities, work capacity and quality of life [6]. Other disadvantages of a stenting may be higher costs associated with the need for interval procedure(s) and additional hospital stay(s). In addition, as recently reported, preoperative ureteric stent placement was not an independent predictor of stone-free status after flexible URS for renal stone removal [7].

Although there is no consensus or definite recommendation for pre-URS stenting, it should be considered and discussed with the patient when obtaining preoperative consent, especially for purely elective, non-urgent cases and in the presence of renal stones.

Long-term outcomes will show whether or not pre-URS stenting makes a difference with regard to the formation of ureteric strictures. Finally, surgical strategies need to weigh carefully the benefits to the patients and improved outcomes against cost-effectiveness.

Read the full article
Atiqullah Aziz, and Marianne Schmid
Department of Urology, University Medical Centre Hamburg- Eppendorf, Hamburg, Germany

 

References

 

1 Assimos D, Crisci A, Culkin D et al. Preoperative JJ stent placement in ureteric and renal stone treatment: results from the Clinical Research Office of Endourological Society (CROES) ureteroscopy (URS) Global Study. BJU Int 2016; 117: 648–54

 

2 Netsch C, Knipper S, Bach T, Herrmann TR, Gross AJ. Impact of preoperative ureteral stenting on stone-free rates of ureteroscopy for nephroureterolithiasis: a matched-paired analysis of 286 patients. Urology 2012; 80: 1214–9

 

3 Cetti RJ, Biers S, Keoghane SR. The difficult ureter: what is the incidence of pre-stenting? Ann R Coll Surg Engl 2011; 93: 31–3

 

4 Chu L, Farris CA, Corcoran AT, Averch TD. Preoperative stent placement decreases cost of ureteroscopy. Urology 2011; 78: 309–13 

 

5 Turk C, Petřík A, Sarica K et al. EAU guidelines on interventional treatment for urolithiasis. Eur Urol 2015; doi: 10.1016/j.eururo.2015. 07.041. [Epub ahead of print]

 

6 Joshi HB, Newns N, Stainthorpe A, MacDonagh RP, Keeley FX Jr, Timoney AG. Ureteral stent symptom questionnaire: development and validation of a multidimensional quality of life measure. J Urol 2003; 169: 1060–4

 

7 Ito H, Sakamaki K, Kawahara T et al. Development and internal validation of a nomogram for predicting stone-free status after flexible ureteroscopy for renal stones. BJU Int 2015; 115: 446–51

 

May Editorial: The Current Hot Topics in Functional Urology

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BJUI-May-2015-cover_smallFor some time, the challenge represented by managing the overactive bladder (OAB) has been dominant in functional urology research. The introduction of new therapies has galvanised the area, with mirabegron showing strong promise for many patients as a monotherapy. In addition, the potential for combined therapy using mirabegron with established antimuscarinics has recently been reported for urgency urinary incontinence [1]. Now that the place of onabotulinum-A injections in refractory cases is firmly established, management options have clearly taken a step forward in recent years. However, there remain people for whom even the more comprehensive current options are inadequate or intolerable. The need for basic science research remains a priority, in the hope of translation into clinical options. In this month’s BJUI, Aizawa et al. [2] report responses in an animal model to an inhibitor of fatty acid amide hydrolase, showing how exploiting the endocannabinoid pathway might be a translational focus for entirely new approaches in OAB. They consider an issue that is very important in developing clinical options, which is that the systems regulating bladder function are also fundamental in other organs, such as the CNS. As the compound they studied does not cross the blood–brain barrier, the potential generation of CNS adverse effects is reduced, which would be important for its potential as a new therapy.

OAB is a symptom syndrome based on storage-type LUTS [3]. Increasingly the field of functional urology is recognising the large number of people who present with voiding and post-micturition LUTS yet do not have BOO. Currently, there are no satisfactory treatment options for affected people and the symptoms can have considerable impact. Frustratingly, current diagnostic methods rely on urodynamic testing to establish whether the presence of detrusor underactivity explains voiding LUTS in an individual patient. Recently, the profession has established a move towards using symptoms to categorise the clinical need in patients [4]. Accordingly, the International Continence Society has established a working group to generate terminology for underactive bladder (UAB), which will report this year, including a symptom-based definition. A symptomatic diagnosis would be very helpful to enable therapy development to proceed without the need for urodynamic testing. Also, in this month’s BJUI, Kajbafzadeh et al. [5] report a clinical trial in UAB using transcutaneous interferential electrical stimulation in children. The treatment was delivered in the context of the rather laborious process currently required for managing this difficult problem, namely diet and fluid manipulation, scheduled voiding, toilet training, and pelvic floor and abdominal muscles relaxation training. The electrical stimulation was demonstrably beneficial, and included responses for the highly troublesome symptom of nocturnal enuresis. The comparatively straightforward nature of this therapeutic approach potentially makes it a valuable tool for dealing with a notoriously difficult problem.

Marcus J. Drake, Senior Lecturer
School of Clinical Sciences, University of Bristol, Bristol, UK

 

References

 

1 Drake MJ, Chapple C, Esen AA et al. Efficacy and safety of mirabegron add-on therapy to solifenacin in incontinent overactive bladder patients with an inadequate response to initial 4-week solifenacin monotherapy: a randomised double-blind multicentre phase 3B study (BESIDE). Eur Urol 2016; [Epub ahead of print]. DOI: 10.1016/j.eururo.2016.02.030

 

2 Aizawa N, Gandaglia G, Hedlund P et al. URB937, a peripherally restricted inhibitor for fatty acid amide hydrolase, reduces prostaglandin E2-induced bladder overactivity and hyperactivity of bladder mechano-afferent nerve fibres in rats. BJU Int 2016; 117: 821–8

 

3 Abrams P, Cardozo L, Fall M et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub- committee of the International Continence Society. Neurourol Urodyn 2002; 21: 167–78

 

4 Chapple CR, Osman NI , Birder L et al. The underactive bladder: a new clinical concept? Eur Urol 2015; 68: 351–3

 

5 Kajbafzadeh AM, Sharifi-Rad L, Ladi-Seyedian SS, Mozafarpour S. Transcutaneous interferential electrical stimulation for the management of non-neuropathic underactive bladder in children: a randomised clinical trial. BJU Int 2016; 117: 793–800

 

Editorial: To PSA or not to PSA?

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Family history (FH) has long been known to increase a man’s risk of developing prostate cancer (PCa); there is an approximately twofold increased risk with an affected father and a threefold increased risk with an affected brother [1]. Furthermore, FH may increase the risk of more aggressive disease for family members, although results of studies in the PSA screening era have been inconsistent [2, 3]. Using FH as a risk factor, the present analysis of the Swiss arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC) conducted by Randazzo et al. [4] sought to determine whether men with a positive FH of PCa, followed up by PSA screening every 4 years, would have a higher risk of having more aggressive disease.

As expected, the present results show that a significantly higher proportion of men with a FH were diagnosed with PCa compared with those with a negative FH; however, there was no difference in the frequency of more aggressive disease amongst men with a FH, therefore, while FH information can be used to identify men at highest risk of PCa, it does not appear to identify those who are most likely to harbour clinically significant disease.

One reason that a positive FH may not be associated with aggressiveness in the present study is that it has been previously established that PSA screening is associated with a migration towards lower grade and stage disease. It may not be surprising, therefore, that the PSA screened arm may have less aggressive disease. What we ultimately want to understand is whether unscreened men with a FH present with more aggressive disease. This question may have been better addressed by comparing those with a positive FH undergoing screening with those with a positive FH not undergoing screening. Previous studies conducted in this fashion suggested a difference in PCa mortality among men with a positive FH [5]. Unfortunately, these data were not available in the ERSPC. Future studies that continue to evaluate this question may elucidate whether FH predisposes to more aggressive disease.

Another factor that may have impeded the results of the present study is that men aged <55 years were not included in ERSPC. It is possible that FH predisposes to more aggressive cancers earlier in life, in men as young as 40 years. There is evidence that relative risk and risk for early-onset disease increases when a father or brother is diagnosed at a younger age, <60 years [6]. Future studies incorporating this younger cohort of men should therefore be conducted.

Until it has been clarified whether men with a positive FH of PCa are at risk of more aggressive disease, PSA screening strategies that begin at young ages should be used. In this fashion, it will be possible to selectively test populations of men at highest risk of developing PCa. Once these men have been screened, clinicians will be able to distinguish men with aggressive disease from those with more indolent disease. We believe that this shifts the focus to a different question: to treat or not to treat? Future research should continue to focus on methods of identifying those men who will go on to develop aggressive disease. Until then, men with low grade disease should continue to be followed by active surveillance [3].

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Christina G. Selkirk* and Brian T. Helfand†
*Center for Medical Genetics, Department of Medicine, NorthShore University Health System, and †John and Carol Walter Center for Urological Health, Department of Surgery, NorthShor e University HealthSystem, Chicago, IL, USA

 

References

 

1 Kicinski M, Vangronsveld J, Nawrot TS. An epidemiological reappraisal of the familial aggregation of prostate cancer: a meta-analysis. PLoS One 2011; 6: e27130

 

2 Kupelian PA, Kupelian VA, Witte JS, Macklis R, Klein EA. Family history of prostate cancer in patients with localized prostate cancer: an independent predictor of treatment outcome. JCO 1997; 15: 1478–80

 

3 Selkirk CG, Wang CH, Lapin B, Helfand BT. Family history of prostate cancer in men being followed by active surveillance does not increase risk of being diagnosed with high-grade disease. Urology 2015; 85: 742–7

 

4 Randazzo M, Muller A, Carlsson S et al. A positive family history as a risk factor for prostate cancer in a population-based study with organised prostate-specific antigen screening: results of the Swiss European Randomised Study of Screening for Prostate Cancer (ERSPC, Aarau). BJU Int 2016; 117: 576–83

 

5 Liss MA, Chen H, Hemal S et al. Impact of family history on prostate cancer mortality in white men undergoing prostate specific antigen based screening. J Urol 2015; 193: 75–9

 

6 Madersbacher S, Alcaraz A, Emberton M et al. The influence of family history on prostate cancer risk: implications for clinical management. BJUI 2011; 107: 716–21

 

Editorial: Be better with public health campaigns (and taxpayers’ money)

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In this month’s issue of the BJUI, Hughes-Hallette et al. [1] report on the impact of a mass media public health campaign for gross haematuria. The authors performed a retrospective analysis evaluating the effectiveness of the ‘Be Clear on Cancer: “Blood in the pee”’ campaign. Similar campaigns for colorectal cancer have shown increased referrals and cost, without increasing the number of cancer diagnoses [2, 3]. In the current study [1], cancer diagnosis similarly did not rise. The two questions that therefore needs to be asked are:

  1. Is gross i.e. visible haematuria a predictor for urological malignancy?
  2. Does a mass media public health campaign constitue an effective means of improving early diagnosis of cancer?

Recent data from large integrative datasets have shown that visible haematuria is a significant predictor for bladder cancer [4, 5]. If gross haematuria is a predictor for urological malignancy, however, why did the authors [1] fail to find an increase in diagnosis of urological malignancy in their study? While the authors indicate that the study may have been underpowered, and that the use of an unlinked dataset may have interfered with proper accounting of cancer incidence, one must also consider that mass media outreach may not be an effective method for cancer outreach.

The ‘Be Clear on Cancer’ campaign involved the use of television adverts, print media and ‘out of home’ advertisements. Using this method, patients who are at risk of renal and bladder cancer, i.e. men, those aged >50 years, and smokers, are targeted as frequently as non-smoking teenagers. This type of mass media outreach programme is analogous to traditional advertising, where the message is often diluted and ineffective. While the ‘Be Clear on Cancer’ campaign is a worthy endeavour, the data do not seem to support the use of taxpayers’ money given its ineffective nature. A novel approach to visible haematuria may be to encourage GPs to ask patients about visible, painless haematuria, much as they would ask about chest pain or blood pressure. This would create a more focussed and durable outreach programme that would reduce the number of non-oncological referrals. As stewards of taxpayers’ money, we must be careful of how public funds are spent. The next generation of mass media outreach may require a combination of traditional media in addition to, social media and targeted advertising [6]. Although the ‘Be Clear on Cancer’ campaign did not appear to achieve its intended goals at this time, we must continue to refine and create new interactive approaches to improve the diagnosis and treatment of urological malignancies.

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Casey K. Ng
Department of Urology, Southern California Permanente Medical Group, Pasadena, and USC Institute of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

 

References

 

1 Hughes-Hallett A, Browne D, Mensah E, Vale J, Mayer E. Assessing the impact of mass media public health campaigns. Be Clear on Cancer ‘blood in pee’: a case in point. BJU Int 2016; 117: 570–75

 

2 Peacock O, Clayton S, Atkinson F, Tierney GM, Lund JN. ‘Be Clear on Cancer’: the impact of the UK National Bowel Cancer Awareness Campaign. Colorectal Dis 2013; 15: 963–7

 

3 Bethune R, Marshall MJ, Mitchell SJ et al. Did the ‘Be Clear on Bowel Cancer’ public awareness campaign pilot result in a higher rate of cancer detection? Postgrad Med J 2013; 89: 390–3

 

4 Jung H, Gleason JM, Loo RK, Patel HS, Slezak JM, Jacobsen SJ. Association of hematuria on microscopic urinalysis and risk of urinary tract cancer. J Urol 2011; 185: 1698–703

 

5 Loo RK, Lieberman SF, Slezak JM et al. Stratifying risk of urinary tract malignant tumors in patients with asymptomatic microscopic hematuria. Mayo Clin Proc 2013; 88: 129–38

 

6 Freeman B, Potente S, Rock V, McIver J. Social media campaigns that make a difference: what can public health learn from the corporate sector and other social change marketers? Public Health Res Pract 2015; 25: e2521517

 

Editorial: New possibilities for urinary molecular diagnostics

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Fusion of androgen-driven serine protease transmembrane protease (TMPRSS) and oncogenic erythroblast transformation-specific-related gene (ERG) genes is a specific alteration in human prostate cancer and many studies have been performed in order to analyse its role as a biomarker or, even more interestingly, as a tumour promoter [1]. Recently, Nguyen et al. [1] demonstrated that ERG activates the Yes-associated protein 1 (YAP1) transcriptional programme thus inducing prostate carcinogenesis. YAP is a transcriptional coactivator involved in regulation of many biological processes. Thus, there is increasing evidence showing that ERG is causally involved in prostate cancer development. Since the original publication by Tomlins et al. [2], in which the gene fusion was discovered, researchers have addressed numerous scientific questions in order to reveal importance of the TMPRSS:ERG fusion in prostate cancer. This is particularly important because several other proteins have been proposed as prostate tumour markers; however, many of them cannot be used in clinical practice. The reasons for that are related to differences in sampling of tissues and methodologies. Thus, biomarker research will in future probably be restructured on the basis of standardisation of experimental procedures. Biomarker research work related to the TMPRSS:ERG fusion appears to be more advanced. In addition to tissue diagnostics, studies on detection of ERG may be performed in urine as evidenced in the paper by Pal et al. [3]. Moreover, the authors for the first time show that exfoliated urinary cells can be used to identify patients with prostate cancer by detection of positive ERG samples. The authors used nested PCR and urinary immunocytochemistry and fluorescence in situ hybridisation in this study. As the TMPRSS:ERG fusion is detectable in ≈50% of prostate cancer specimens, the data presented in the study published in this issue of BJUI are of considerable interest.

Combining the use of TMPRSS:ERG detection and other markers in urine should further improve diagnostics of prostate cancer. Another tumour marker, prostate cancer antigen 3 (PCA3), is frequently used in prostate cancer diagnostics. In urine, TMPRSS:ERG urinary transcript detection is superior to PSA and PCA3 for identifying patients with cancer [4]. The results support data recently published according to which the determination of urine TMPRSS2:ERG together with PCA3 may be used for a more individualised prostate cancer risk assessment [5].

As the authors state in the paper [3], differences between results of some marker studies on TMPRSS:ERG detection may be a consequence of the appearance of less common isoforms, which are not detectable by all assays.

In summary, Pal et al. [3] show for the first time that patients with prostate cancer could be identified by immunocytochemistry on the basis of detection of ERG in exfoliated urine cells. In addition, the authors [3] also show that the appearance of ERG in exfoliated urine cells is associated with a bad prognosis. Indirectly, the present paper [3], supports the concept that the presence of TMPRSS:ERG regulates various cellular events leading to increased migration and proliferation of prostate cancer cells [6]. It is expected that further improvements in urinary molecular diagnostics based on the presence of TMPRSS:ERG will be achieved in the near future. However, clinicians should also be aware that, despite its high specificity, there are limitations of methodology used in this paper, in particular a large proportion of tumours may remain undetected and not all cancers exfoliate into the urine.

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Zoran Culig
Experimental Urology, Department of Urology, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, A-6020, Austria

 

References

 

1 Nguyen LT, Tretiakova MS, Silvis MR et al. ERG activates the YAP1 transcriptional program and induces the development of age-related prostate tumors. Cancer Cell 2015; 27: 797–808

 

2 Tomlins SA, Rhodes DR, Perner S et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005; 310: 644–8
3 Pal RP, Kockelbergh RC, Pringle JH et al. Immunocytochemical detection of ERG expression in exfoliated urinary cells identifies with specificity patients with prostate cancer. BJU Int 2016; 117: 686–96

 

4 Leyten GH, Hessels D, Jannink SA et al. Prospective multicentre evaluation of PCA3 and TMPRSS2-ERG gene fusions as diagnostic and prognostic urinary biomarkers for prostate cancer. Eur Urol 2014; 65: 534–42

 

5 Tomlins SA, Day JR, Lonigro RJ et al. Urine TMPRSS2:ERG plus PCA3 for individualized prostate cancer risk assessment. Eur Urol 2015; [Epub ahead of print] DOI: 10.1016/j.eururo.2015.04.039

 

6 Washington MN, Weigel NL. 1(alpha),25-dihydroxyvitamin D3 inhibits growth of VCaP prostate cancer cells despite inducing the growth-promoting TMPRSS2:ERG gene fusion. Endocrinology 2010; 151: 1409–17

 

Divided by more than a common language

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CaptureAt its simplest, hypogonadism manifests as (abnormally) low testosterone levels, which require effective clinical intervention; however, there is little or no consensus on the definition, diagnosis and treatment of the condition. Indeed, at least in the USA, the issue of the (ab)use of testosterone replacement has been under the microscope because of a hypothesis, albeit flawed, linking it to increased cardiovascular risk. The need for consensus on the management of hypogonadism is increasing almost in front of our eyes as a result of the link with the metabolic dysfunction associated with the increase in diabetes and/or obesity in the general population. With this background, an international panel representing the disciplines involved in the management of hypogonadism was convened; the output of the group, in terms of definition and patient management, is reported in this month’s issue of BJUI [1].

Apparently, the need for effective intervention is more critical than one would necessarily assume. Not only is there a hypogonadism ‘epidemic’, linked to the fattening of our population, but there is no globally approved treatment for secondary hypogonadism (2HG) i.e. that form not associated with testicular failure. Epidemiologists warn that 2HG is in fact the predominant clinical representation, being roughly six times as common as primary hypogonadism.

The conclusions of the recent consensus panel are neither more nor less appropriate nor scholarly than those of other groups, e.g. the Endocrine Society, BAUS, AUA or SMSNA, but their value is as a timely reminder that unless there is clinical consensus on the disorder it is practically impossible to design regulatory authority-proof clinical trials to ensure drug approval. Ironically the most effective treatment strategy in many instances would be lifestyle intervention, but we all know how compliant men are when diet and exercise are recommended.

Returning to drug treatment, the panel does emphasize the critical importance of distinguishing between the different aetiologies of primary hypogonadism and 2HG. Although testosterone replacement therapy is usually appropriate in the treatment of primary hypogonadism, it may be inappropriate in the treatment of 2HG. Because of negative feedback in this situation testosterone replacement can reduce spermatogenesis and testicular function. This clinical phenomenon is exemplified by the phase III data from two clinical trials presented by Kim et al. [2] in this issue of BJUI. Compared with placebo, testosterone replacement produced substantial reductions in spermatogenesis and testicular function. Bearing in mind that many men with androgen deficiency may well wish to preserve fertility, testosterone replacement could therefore in fact be counterproductive. The trials by Kim et al. also showed that, by comparison, the selective, centrally active, oestrogen antagonist, enclomiphene, could normalize testosterone levels while maintaining testicular function and spermatogenesis.

In many ways, assuming eventual regulatory approval, enclomiphene could represent the optimum therapy for 2HG, preferably as an adjunct to lifestyle modification, i.e. dietary manipulation and exercise. Unfortunately, at least in the USA, the regulatory authority appear not to recognize 2HG as a condition that merits treatment. Pressure from the clinical community could influence this attitude.

Michael G. Wyllie, BJUI Consulting Editor, Sexual Medicine
Stratton House, Shenington, Banbury, Oxfordshire, UK

 

References

 

1 Dean J, Maggi M, de Boer J-B et al. Diagnosing secondary hypogonadism: important consequences for fertility and reversibility. BJU Int 2016; 117: 551–4

 

2 Kim ED, McCullough A, Kaminetsky J. Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement. BJU Int 2016; 117: 677–85

 

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