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Article of the Month: Enclomiphene for Secondary Hypogonadism – Restoration not Replacement

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Every Month the Editor-in-Chief selects an Article of the Month from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

The second post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Andrew McCullough, discussing his paper.

If you only have time to read one article this week, it should be this one.

Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement

Edward D. Kim, Andrew McCullough* and Jed Kaminetsky†

 

University of Tennessee Graduate School of Medicine, Knoxville, TN
*Urological Institute of Northeastern, New York, NY, USA, and †University Urology Associates, New York, NY, USA

 

Read the full article

 

Enclomiphene-infographic_sm

Click on image for full size infographic

Objectives

To determine the effects of daily oral doses of enclomiphene citrate compared with Low T gel treatment, luteinising hormone (LH), follicle-stimulating hormone (FSH), and sperm counts in men with secondary hypogonadism.

Patients and Methods

  • selective oestrogen receptor modulator

Two parallel randomised, double-blind, double-dummy, placebo-controlled, multicentre, phase III studies were undertaken to evaluate two doses of enclomiphene citrate vs testosterone gel (Low T androgel1.62%) on TT, LH, FSH, and sperm counts in overweight men aged 18–60 years with secondary hypogonadism. Men were screened and enrolled in the trials (ZA-304 and ZA-305). All enrolled men had early morning serum TT levels in the low or low normal range (≤300 ng/dL; ≤10.4 nmol/L) and had low or normal LH (<9.4 IU/L) levels measured on two separate occasions 2–10 days apart. Serum samples were obtained over the course of the study to determine relevant hormone levels at baseline and after 16 weeks of treatment. Men provided semen samples twice to enroll at the beginning and twice at the end of the study.

AprAOTM

Results

TT levels increased between baseline and after 16 weeks of treatment in all the treatment groups. FSH and LH levels increased in the enclomiphene citrate groups and decreased in the testosterone gel group at 16 weeks. Enclomiphene citrate maintained sperm concentration in the normal range over the treatment period, while there was a marked reduction in spermatogenesis in the testosterone gel group.

Conclusions

Enclomiphene citrate consistently increased serum TT, LH and FSH, restoring normal levels of serum TT. Enclomiphene citrate treatment maintained sperm concentrations in the normal range. The effects on TT were also seen with testosterone replacement via testosterone gel but sperm counts were not maintained.

Read more articles of the week

Video: Restoration not Replacement – Enclomiphene for Secondary Hypogonadism

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Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement

Edward D. Kim, Andrew McCullough* and Jed Kaminetsky†

 

University of Tennessee Graduate School of Medicine, Knoxville, TN
*Urological Institute of Northeastern, New York, NY, USA, and †University Urology Associates, New York, NY, USA

 

Read the full article

Objectives

To determine the effects of daily oral doses of enclomiphene citrate compared with topical testosterone gel treatment on serum total testosterone (TT), luteinising hormone (LH), follicle-stimulating hormone (FSH), and sperm counts in men with secondary hypogonadism.

Patients and Methods

Two parallel randomised, double-blind, double-dummy, placebo-controlled, multicentre, phase III studies were undertaken to evaluate two doses of enclomiphene citrate vs testosterone gel (AndroGel®1.62%) on TT, LH, FSH, and sperm counts in overweight men aged 18–60 years with secondary hypogonadism. Men were screened and enrolled in the trials (ZA-304 and ZA-305). All enrolled men had early morning serum TT levels in the low or low normal range (≤300 ng/dL; ≤10.4 nmol/L) and had low or normal LH (<9.4 IU/L) levels measured on two separate occasions 2–10 days apart. Serum samples were obtained over the course of the study to determine relevant hormone levels at baseline and after 16 weeks of treatment. Men provided semen samples twice to enroll at the beginning and twice at the end of the study.

AprAOTM

Results

TT levels increased between baseline and after 16 weeks of treatment in all the treatment groups. FSH and LH levels increased in the enclomiphene citrate groups and decreased in the testosterone gel group at 16 weeks. Enclomiphene citrate maintained sperm concentration in the normal range over the treatment period, while there was a marked reduction in spermatogenesis in the testosterone gel group.

Conclusions

Enclomiphene citrate consistently increased serum TT, LH and FSH, restoring normal levels of serum TT. Enclomiphene citrate treatment maintained sperm concentrations in the normal range. The effects on TT were also seen with testosterone replacement via testosterone gel but sperm counts were not maintained.

Read more articles of the week

Article of the Week: FH as a risk factor for PCa

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Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

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)

Marco Randazzo*,†, Alexander Muller*, Sigrid Carlsson‡,§, Daniel Eberli*, Andreas

 

Huber, Rainer Grobholz**, Lukas Manka††, Ashkan Mortezavi*, Tullio Sulser*, Franz Recker† and Maciej Kwiatkowski†,††

 

*Department of Urology, University Hospital Zurich, Zurich, †Department of Urology, Cantonal Hospital Aarau, Aarau, Switzerland, ‡Department of Surgery (Urology Service), Memorial Sloan Kettering Cancer Center, New York, NY, USA, §Department of Urology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden, Department of Laboratory Medicine, **Department of Pathology, Cantonal Hospital Aarau, Aarau, Switzerland, and ††Department of Urology, Academic Hospital Braunschweig, Braunschweig, Germany

 

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Objective

To assess the value of a positive family history (FH) as a risk factor for prostate cancer incidence and grade among men undergoing organised prostate-specific antigen (PSA) screening in a population-based study.

Subjects and Methods

The study cohort comprised all attendees of the Swiss arm of the European Randomised Study of Screening for Prostate Cancer (ERSPC) with systematic PSA level tests every 4 years. Men reporting first-degree relative(s) diagnosed with prostate cancer were considered to have a positive FH. Biopsy was exclusively PSA triggered at a PSA level threshold of 3 ng/mL. The primary endpoint was prostate cancer diagnosis. Kaplan–Meier and Cox regression analyses were used.

Results

Of 4 932 attendees with a median (interquartile range, IQR) age of 60.9 (57.6–65.1) years, 334 (6.8%) reported a positive FH. The median (IQR) follow-up duration was 11.6 (10.3–13.3) years. Cumulative prostate cancer incidence was 60/334 (18%, positive FH) and 550/4 598 (12%, negative FH) [odds ratio 1.6, 95% confidence interval (CI) 1.2–2.2, P = 0.001). In both groups, most prostate cancer diagnosed was low grade. There were no significant differences in PSA level at diagnosis, biopsy Gleason score or Gleason score on pathological specimen among men who underwent radical prostatectomy between both groups. On multivariable analysis, age (hazard ratio [HR] 1.04, 95% CI 1.02–1.06), baseline PSA level (HR 1.13, 95% CI 1.12–1.14), and FH (HR 1.6, 95% CI 1.24–2.14) were independent predictors for overall prostate cancer incidence (all P < 0.001). Only baseline PSA level (HR 1.14, 95% CI 1.12–1.16, P < 0.001) was an independent predictor of Gleason score ≥7 prostate cancer on prostate biopsy. The proportion of interval prostate cancer diagnosed in-between the screening rounds was not significantly different.

AOTW4Apr

Conclusion

Irrespective of the FH status, the current PSA-based screening setting detects the majority of aggressive prostate cancers and missed only a minority of interval cancers with a 4-year screening algorithm. Our results suggest that men with a positive FH are at increased risk of low-grade but not aggressive prostate cancer.

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Editorial: To PSA or not to PSA?

/2 Comments/by

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].

Read the full article
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

 

Article of the Week: Be Clear on Cancer – Blood in Pee

/1 Comment/by

Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Mr. Archie Hughes-Hallett,, discussing his paper.

If you only have time to read one article this week, it should be this one.

Assessing the impact of mass media public health campaigns. ‘Be Clear on Cancer: Blood in Pee’ a case in point

Archie Hughes-Hallett*, Daisy Browne†, Elsie Mensah*, Justin Vale*† and Erik Mayer*†‡

 

*Department of Surgery and Cancer, Imperial College London, †Department of Urology, Imperial College Healthcare Trust, and ‡Institute of Global Health Innovation, Imperial College London, London, UK

 

Read the full article

Objectives

To assess the impact on suspected cancer referral burden and new cancer diagnosis of Public Health England’s recent Be Clear on Cancer ‘blood in pee’ mass media campaign.

Methods

A retrospective cohort study design was used. For two distinct time periods, August 2012 to May 2013 and August 2013 to May 2014, all referrals of patients deemed to be at risk of urological cancer by the referring primary healthcare physician to Imperial College NHS Healthcare Trust were screened. Data were collected on age and sex and whether the referral was for visible haematuria, non-visible haematuria or other suspected urological cancer. In addition to referral data, hospital episode data for all new renal cell (RCC) and upper and lower tract transitional cell carcinoma (TCC), as well as testicular and prostate cancer diagnoses for the same time periods were obtained.

Results

Over the campaign period and the subsequent 3 months, the number of haematuria referrals increased by 92% (P = 0.013) when compared with the same period a year earlier. This increase in referrals was not associated with a significant corresponding rise in cancer diagnosis; instead changes of 26.8% (P = 0.56) and −3.3% (P = 0.84) were seen in RCC and TCC, respectively.

AOTW2Apr

 

Conclusions

This study has shown that the Be Clear on Cancer ‘blood in pee’ mass media campaign significantly increased the number of new suspected cancer referrals, but there was no significant change in the diagnosis of target cancers across a large catchment. Mass media campaigns are expensive, require significant planning and appropriate implementation and, while the findings of this study do not challenge their fundamental objective, more work needs to be done to understand why no significant change in target cancers was observed. Further consideration should also be given to the increased referral burden that results from these campaigns, such that pre-emptive strategies, including educational and process mapping, across primary and secondary care can be implemented.

Read more articles of the week

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.

Read the full article
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

 

Video: Be Clear on Cancer – Blood in Pee

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Assessing the impact of mass media public health campaigns. ‘Be Clear on Cancer: Blood in Pee’ a case in point

Archie Hughes-Hallett*, Daisy Browne†, Elsie Mensah*, Justin Vale*† and Erik Mayer*†‡

 

*Department of Surgery and Cancer, Imperial College London, †Department of Urology, Imperial College Healthcare Trust, and ‡Institute of Global Health Innovation, Imperial College London, London, UK

 

Read the full article

Objectives

To assess the impact on suspected cancer referral burden and new cancer diagnosis of Public Health England’s recent Be Clear on Cancer ‘blood in pee’ mass media campaign.

Methods

A retrospective cohort study design was used. For two distinct time periods, August 2012 to May 2013 and August 2013 to May 2014, all referrals of patients deemed to be at risk of urological cancer by the referring primary healthcare physician to Imperial College NHS Healthcare Trust were screened. Data were collected on age and sex and whether the referral was for visible haematuria, non-visible haematuria or other suspected urological cancer. In addition to referral data, hospital episode data for all new renal cell (RCC) and upper and lower tract transitional cell carcinoma (TCC), as well as testicular and prostate cancer diagnoses for the same time periods were obtained.

Results

Over the campaign period and the subsequent 3 months, the number of haematuria referrals increased by 92% (P = 0.013) when compared with the same period a year earlier. This increase in referrals was not associated with a significant corresponding rise in cancer diagnosis; instead changes of 26.8% (P = 0.56) and −3.3% (P = 0.84) were seen in RCC and TCC, respectively.

AOTW2Apr

Conclusions

This study has shown that the Be Clear on Cancer ‘blood in pee’ mass media campaign significantly increased the number of new suspected cancer referrals, but there was no significant change in the diagnosis of target cancers across a large catchment. Mass media campaigns are expensive, require significant planning and appropriate implementation and, while the findings of this study do not challenge their fundamental objective, more work needs to be done to understand why no significant change in target cancers was observed. Further consideration should also be given to the increased referral burden that results from these campaigns, such that pre-emptive strategies, including educational and process mapping, across primary and secondary care can be implemented.

Read more articles of the week

Article of the Week: Immunocytochemical expression of ERG in urine identifies prostate cancer

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Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Immunocytochemical detection of ERG expression in exfoliated urinary cells identifies with high specificity patients with prostate cancer

Raj P. Pal*†, Roger C. Kockelbergh†, John Howard Pringl e*, Lara Cresswell‡, Roger
Hew§, John P. Dormer§, Colin Cooper, John Kilian Mellon†, Julian G. Barwell** and Edward J. Hollox**

 

*Department of Cancer Studies and Molecular Medicine, University of Leicester, †Department of Urology, ‡Department of Cytogenetics, §Department of Cellular Pathology, University Hospitals of Leicester NHS Trust, Leicester, Department of Cancer Genetics, University of East Anglia, Norwich, and **Department of Genetics, University of Leicester, Leicester, UK

 

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Objectives

To evaluate the immunocytochemical detection of ERG protein in exfoliated cells as a means of identifying patients with prostate cancer (PCa) before prostate biopsy.

Materials and Methods

Urine samples (30 mL) were collected after digital rectal examination (DRE) from 159 patients with an elevated age-specific prostate-specific antigen (PSA) and/or an abnormal DRE who underwent prostate biopsy. In all cases, exfoliated urinary cells from half of the urine sample underwent immunocytochemical assessment for ERG protein expression. Exfoliated cells in the remaining half underwent assessment ofTMPRSS2:ERG status using either nested reverse-transcriptase (RT)-PCR (151 cases) or fluorescence in situ hybridization (FISH; eight cases). Corresponding tissue samples were evaluated using FISH to determine chromosomal gene fusion tissue status and immunohistochemistry (IHC) to determine ERG protein expression. Results were correlated with clinicopathological variables.

Results

The sensitivity and specificity of urinary ERG immunocytochemistry (ICC) for PCa were 22.7 and 100%, respectively. ERG ICC results correlated with advanced tumour grade, stage and higher serum PSA. In comparison, urine TMPRSS2:ERG transcript analysis had 27% sensitivity and 98% specificity for PCa detection. On tissue IHC, ERG staining was highly specific for PCa. In all, 52% of cancers harboured foci of ERG staining; however, only 46% of cancers that were found to have ERG overexpression were positive on urine ICC. The ERG ICC results showed strong concordance with urinary RT-PCR and FISH, and tissue IHC and FISH.

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Conclusion

This is the first study to show that cytological gene fusion detection using ICC is feasible and identifies patients with adverse disease markers. ERG ICC was highly specific, but this technique was less sensitive than RT-PCR.

Read more articles of the week

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.

Read the full article
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

 

Article of the Week: Using The PHI to improve Prostate Cancer Risk Assessment

/by

Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Mr. Robert Foley, discussing his paper.

If you only have time to read one article this week, it should be this one.

Improving Multivariable Prostate Cancer Risk Assessment Using The Prostate Health Index

Robert W. Foley*†, Laura Gorman*, Neda Sharifi‡, Keefe Murphy§, Helen Moore‡, Alexandra V. Tuzova**, Antoinette S. Perry**, T. Brendan Murphy§, Dara J. Lundon*††† and R. William G. Watson*†

 

*Conway Institute of Biomolecular and Biomedical Research, University College Dublin, †UCD School of Medicine and Medical Science, University College Dublin, ‡Department of Biochemistry, Beaumont Hospital, §UCD School of Mathematical Sciences, University College Dublin, Insight Centre for Data Analytics, University College Dublin, **Prostate Molecular Oncology, Institute of Molecular Medicine, Trinity College Dublin, and ††Department of Urology, Mater Misericordiae University Hospital, Dublin, Ireland

 

Read the full article

Objectives

To analyse the clinical utility of a prediction model incorporating both clinical information and a novel biomarker, p2PSA, in order to inform the decision for prostate biopsy in an Irish cohort of men referred for prostate cancer assessment.

Patients and Methods

Serum isolated from 250 men from three tertiary referral centres with pre-biopsy blood draws was analysed for total prostate-specific antigen (PSA), free PSA (fPSA) and p2PSA. From this, the Prostate Health Index (PHI) score was calculated (PHI = (p2PSA/fPSA)*√tPSA). The men’s clinical information was used to derive their risk according to the Prostate Cancer Prevention Trial (PCPT) risk model. Two clinical prediction models were created via multivariable regression consisting of age, family history, abnormality on digital rectal examination, previous negative biopsy and either PSA or PHI score, respectively. Calibration plots, receiver-operating characteristic (ROC) curves and decision curves were generated to assess the performance of the three models.

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Results

The PSA model and PHI model were both well calibrated in this cohort, with the PHI model showing the best correlation between predicted probabilities and actual outcome. The areas under the ROC curve for the PHI model, PSA model and PCPT model were 0.77, 0.71 and 0.69, respectively, for the prediction of prostate cancer (PCa) and 0.79, 0.72 and 0.72, respectively, for the prediction of high grade PCa. Decision-curve analysis showed a superior net benefit of the PHI model over both the PSA model and the PCPT risk model in the diagnosis of PCa and high grade PCa over the entire range of risk probabilities.

Conclusion

A logical and standardized approach to the use of clinical risk factors can allow more accurate risk stratification of men under investigation for PCa. The measurement of p2PSA and the integration of this biomarker into a clinical prediction model can further increase the accuracy of risk stratification, helping to better inform the decision for prostate biopsy in a referral population.

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