Archive for category: Article of the Week

Editorial: Semen Proteome Alterations in the Smoking Male

Infertility affects 15% of couples, with male factor infertility influencing half of such couples [1]. Multiple environmental risk factors for male infertility have been identified, including: diet, exposure to pollution, and multiple substance abuses, e.g. alcohol, tobacco, marijuana, opiates [2].

In this issue of BJUI, the study of Antoniassi et al. [3] makes an important contribution to the literature regarding the impact of a particular environmental factor, smoking, on male factor infertility. Standard semen analysis does not have strong sensitivity or specificity for male factor infertility given that it only examines sperm. Guzick et al. [4] demonstrated this in a study that showed extensive overlap in the sperm motility, concentration, and morphology in the male partners of fertile and infertile couples. Given this, multiple aspects of functional sperm testing have been added to standard semen analysis. Proteins added to the semen by the male accessory sex organs play a vital role in male reproductive capacity, providing nourishment and protection to spermatozoa. Batruch et al. [5] identified >2300 proteins in the semen of both fertile and infertile men using mass spectrometry. The physiological role of most of these proteins is unknown. Proteomics identifies the protein complement present in the semen using mass spectrometry. Sharma et al. [6] reported that the proteome of men with reactive oxygen species present is altered and that the absence of certain proteins may impair the neutralization of oxidative stress in semen. Prior studies have shown that the protein complement of the semen is different in men with clinical varicocoeles [7].

While the concern about the impact of smoking on male reproductive health is well documented, the effect that it has on the semen proteome is unknown. Antoniassi et al. [3] compared the semen proteome in both non-smoking and smoking men who presented to their laboratory for semen analysis. Given that patients rather than volunteers were used in this study, one cannot easily generalize the study findings to the general male population. After testing the samples for mitochondrial activity, acrosome function, and DNA integrity, the samples underwent liquid chromatography/mass spectroscopy to analyze the proteome. Sperm from smokers showed lesser sperm integrity, higher DNA fragmentation rates, and a lower percentage of intact mitochondria. The investigators demonstrated that smoking causes changes in the semen proteome. In smoking men one protein was absent, 27 proteins were under-represented, and six were over-represented. This study [3] provides some insight into how certain proteins may impact fertility. The protein S100A9 is overexpressed in smoking men and is associated with chronic inflammation, which corresponds with the fact that smokers frequently exhibit leukocytospermia. Mammoglobin B, the protein absent in men who smoke, is involved in the binding of steroid hormones; therefore, it is conceivable that its absence inhibits the ability of sperm to respond to sex hormones. you can find more info on Theihcc.com around these and other steroids.

This study [3] establishes that, among men who present for fertility evaluation, smokers have an altered proteome compared to non-smokers. This highlights the need for a greater understanding of how the semen proteome interacts with cellular elements. Further studies that examine the proteome of smokers and non-smokers with no history of infertility are warranted.

 

Kenneth J. DeLay and Wayne J.G. Hellstrom

 

Department of Urology, Tulane University School of Medicine, New Orleans, LA, USA

 

References

 

1 Sabanegh E Jr, Agarwal A. Male infertility. In Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA eds, Campbell-Walsh Urology10th edn, Philadelphia, PA: Elsevier Saunders: 2011

 

2 Barazani Y, Katz BF, Nagler HM, Stember DS. Lifestyle, environment, and male reproductive health. Urol Clin North Am 2014; 41: 5566

 

3 AntoniassiMP, Intasqui P, Camargo M et al.Analysisofthefunctionaaspects and seminal plasma proteomic proleofspermfromsmokers. BJU Int 2016; 118: 81422

 

4 GuzickDS, Overstreet JW, Factor-Litvak P et al.Spermmorphologymotility, and concentration in fertile and infertile men. NEnglJMed2001; 345: 138893

 

 

6 Sharma R, Agarwal A, Mohanty G et al. Proteomic analysis of seminal uid from men exhibiting oxidative stress. Reprod Biol Endocrinol 2013; 11: 85.

 

7 Zylbersztejn DS, Andreoni C, Del Giudice PT et al. Proteomic analysis of seminal plasma in adolescents with and without varicocele. Fertil Steril 2013; 99: 928

 

Video: The Effect of Smoking on Sperm Functional Quality and Seminal Plasma Proteomic Profile

Analysis of the functional aspects and seminal plasma proteomic profile of sperm from smokers

Mariana Pereira Antoniassi*, Paula Intasqui*, Mariana Camargo*, Daniel Suslik
Zylbersztejn*, Valdemir Melechco Carvalho, Karina H. M. Cardozo† and Ricardo
Pimenta Bertolla*
*Department of Surgery, Division of Urology, Human Reproduction Section, Sao Paulo Federal University, Fleury Group, and Hospital Sao Paulo, Sao Paulo, Brazil

Objective

To evaluate the effect of smoking on sperm functional quality and seminal plasma proteomic profile.

Patients and Methods

Sperm functional tests were performed in 20 non-smoking men with normal semen quality, according to the World Health Organization (2010) and in 20 smoking patients. These included: evaluation of DNA fragmentation by alkaline Comet assay; analysis of mitochondrial activity using DAB staining; and acrosomal integrity evaluation by PNA binding. The remaining semen was centrifuged and seminal plasma was used for proteomic analysis (liquid chromatography-tandem mass spectrometry). The quantified proteins were used for Venn diagram construction in Cytoscape 3.2.1 software, using the PINA4MS plug-in. Then, differentially expressed proteins were used for functional enrichment analysis of Gene Ontology categories, Kyoto Encyclopedia of Genes and Genomes and Reactome, using Cytoscape software and the ClueGO 2.2.0 plug-in.

aotm-nov-1-results

Results

Smokers had a higher percentage of sperm DNA damage (Comet classes III and IV; P < 0.01), partially and fully inactive mitochondria (DAB classes III and IV; P = 0.001 and P = 0.006, respectively) and non-intact acrosomes (P < 0.01) when compared with the control group. With respect to proteomic analysis, 422 proteins were identified and quantified, of which one protein was absent, 27 proteins were under-represented and six proteins were over-represented in smokers. Functional enrichment analysis showed the enrichment of antigen processing and presentation, positive regulation of prostaglandin secretion involved in immune response, protein kinase A signalling and arachidonic acid secretion, complement activation, regulation of the cytokine-mediated signalling pathway and regulation of acute inflammatory response in the study group (smokers).

Conclusion

In conclusion, cigarette smoking was associated with an inflammatory state in the accessory glands and in the testis, as shown by enriched proteomic pathways. This state causes an alteration in sperm functional quality, which is characterized by decreased acrosome integrity and mitochondrial activity, as well as by increased nuclear DNA fragmentation.

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Article of the Week: Complications and QoL in patients undergoing CU with single stoma or IC after RC

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 discussing the paper.

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

Complications and quality of life in elderly patients with several comorbidities undergoing cutaneous ureterostomy with single stoma or ileal conduit after radical cystectomy

Nicola Longo*, Ciro Imbimbo*, Ferdinando Fusco*, Vincenzo Ficarra, Francesco Mangiapia*, Giuseppe Di Lorenzo, Massimiliano Creta§, Vittorio Imperatore§ and Vincenzo Mirone*

 

*Department of Neurosciences, Sciences of Reproduction and Odontostomatology, University Federico II of Naples, Naples, Urology Department, University of Udine, Udine, Oncology Department, University Federico II of Naples, and §Urology Unit, Buon Consiglio Fatebenefratelli Hospital, Naples, Italy

 

Read the full article

Objectives

To compare peri-operative outcomes and quality of life (QoL) in a series of elderly patients with high comorbidity status who underwent single stoma cutaneous ureterostomy (CU) or ileal conduit (IC) after radical cystectomy (RC).

Patients and Methods

The clinical records of patients aged >75 years with an American Society of Anesthesiologists (ASA) score >2 who underwent RC at a single institution between March 2009 and March 2014 were retrospectively analysed. After RC, all patients included in the study received an IC urinary diversion or a CU with single stoma urinary diversion. Preoperative clinical characteristics as well as intra- and postoperative outcomes were evaluated and compared between the two groups. In addition, the Bladder Cancer Index (BCI) was used to assess QoL.

aotw-oct-5-results

Results

A total of 70 patients were included in the final comparative analyses. Of these, 35 underwent IC diversion and 35 CU single stoma diversion. The two groups were similar with regard to age, gender, ASA score, type of indication and pathological features. Operating times (P < 0.001), estimated blood loss (P < 0.001), need for intensive care unit stay (P = 0.01), time to drain removal (P < 0.001) and length of hospital stay (P < 0.001) were significantly higher in patients undergoing IC diversion. The number of patients with intra- (P = 0.04) and early postoperative (P = 0.02) complications was also significantly higher among those undergoing IC diversion. Interestingly, the mean BCI scores were overlapping in the two groups.

Conclusions

The present results show that CU with a single stoma can represent a valid alternative to IC in elderly patients with relevant comorbidities, reducing peri-operative complications without a significant impairment of QoL.

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Editorial: Cutaneous Ureterostomy: ‘Back to the Future’

An increasingly ageing and frail population undergoing cystectomy and urinary diversion has rekindled interest in urinary diversions with a lower risk of peri-operative complications, such as cutaneous ureterostomy (CU).

The study in this issue of BJUI by Longo et al. [1] compares complications and quality of life in elderly patients with high comorbidities (American Society of Anesthesiologists [ASA] physical status score 3–4 and Charlson Comorbidity Index [CCI] ~5) receiving either an ileal conduit (IC) or a CU with a single stoma. Although the IC group had longer surgery, greater intra-operative blood loss, a higher number of patients needing intensive care monitoring, a longer time to drain removal and a longer hospital stay, as well as a higher number of intra- and early postoperative complications, the intensive care unit length of stay and quality of life did not differ.

Complication rates are high for cystectomy and urinary diversion, especially in the frail elderly population with comorbidities [2]. Most studies are retrospective and the reported complication rates differ largely. Few centres have compared IC with CU and, probably as a result of selection biases, the results vary [3, 4]. Obvious advantages of CU are the reduced length of surgery and the lack of a bowel anastomosis, and peritoneal lesions can be minimized or omitted, thus reducing the risk of postoperative ileus (POI), a common complication after urinary diversion. These advantages were confirmed in the present study, with prolonged POI observed in 25.7% in the IC group vs 5.7% in the CU group and the duration of surgery being 226 min in the IC group vs 150 min in the CU group. Interestingly, there was no difference in major complications classified as Clavien–Dindo grades III–IV, with the exception of urinary leakage from the uretero-ileal anastomosis (14.2%).

Somewhat surprisingly, 42.8% of patients with IC required a blood transfusion compared with 17.1% with UC. The main blood loss usually takes place during cystectomy, whereas blood loss during urinary diversion is minimal [5]. The authors explain this through bleeding from the mesenteric vessels associated with isolating a bowel segment for IC, an occurrence not commonly observed in our experience or in other published reports. Overall the transfusion rate seems high, but this is highly dependent on the preoperative haemoglobin level/anaemia and the haemoglobin level set for transfusion, which differs between centres.

One of the main problems with CU is ureteric obstruction, especially of the left ureter. The rationale behind this is the more extensive mobilization of the left ureter to enable its transfer to the right side, which can result in ischaemic lesions of the distal ureter. Stenosis and kinking of the ureters when passing through the abdominal wall can also lead to obstruction. For these reasons, many patients have long-term ureteric stents. In the present study, the ureteric stents were changed every month. Foreign bodies in the urinary tract can cause problems such as upper urinary tract infections, stent encrustation and nephrolithiasis [3]. To reduce these problems, meticulous care of the CU and frequent changes of the silicone JJ stent with antibiotic prophylaxis are generally recommended. A cost assessment would be of interest to determine the long-term cost of regular stent changes compared with the management of a higher rate of peri-operative complications in patients receiving an IC. Tubeless approaches have been described, and one study reported less ureteric obstruction with deferred stent removal after surgery [6].

The Bladder Cancer Index score as a measure of quality of life did not differ between groups. Quality of life questionnaires assessing urinary diversion have inherent problems. When comparing leakage (frequency of leakage) and control (amount of leakage) in a patient with an IC or a CU, it is not surprising that there is no difference. However, the need for regular hospital visits to change the stents, which can be bothersome for patients, especially the frail and dependent elderly or those with problems travelling, because of the need to transport the necessary aides (stoma bags, pads, catheters), are rarely addressed in questionnaires.

Cutaneous ureterostomy, which is being rediscovered, belongs in the armamentarium of every surgeon performing cystectomy. However, each type of urinary diversion has its pros and cons, and careful selection is necessary to balance benefits against risks in an effort to offer the best individual option to the older and frail patient.

Read the full article

 

Fiona C. Burkhard* and Patrick Y. Wuethrich

 

*Department of Urology, University Hospital Bern, Inselspital Anna Seiler-Haus, Bern, Switzerland and Department of Anaesthesiology and Pain Medicine, University Hospital Bern, Bern, Switzerland

 

References

 

Video: Complications and QoL in patients undergoing CU with single stoma or IC after RC

Complications and quality of life in elderly patients with several comorbidities undergoing cutaneous ureterostomy with single stoma or ileal conduit after radical cystectomy

Nicola Longo*, Ciro Imbimbo*, Ferdinando Fusco*, Vincenzo Ficarra, Francesco Mangiapia*, Giuseppe Di Lorenzo, Massimiliano Creta§, Vittorio Imperatore§ and Vincenzo Mirone*
*Department of Neurosciences, Sciences of Reproduction and Odontostomatology, University Federico II of Naples, Naples, Urology Department, University of Udine, Udine, Oncology Department, University Federico II of Naples, and §Urology Unit, Buon Consiglio Fatebenefratelli Hospital, Naples, Italy
Read the full article

Objectives

To compare peri-operative outcomes and quality of life (QoL) in a series of elderly patients with high comorbidity status who underwent single stoma cutaneous ureterostomy (CU) or ileal conduit (IC) after radical cystectomy (RC).

Patients and Methods

The clinical records of patients aged >75 years with an American Society of Anesthesiologists (ASA) score >2 who underwent RC at a single institution between March 2009 and March 2014 were retrospectively analysed. After RC, all patients included in the study received an IC urinary diversion or a CU with single stoma urinary diversion. Preoperative clinical characteristics as well as intra- and postoperative outcomes were evaluated and compared between the two groups. In addition, the Bladder Cancer Index (BCI) was used to assess QoL.

aotw-oct-5-results

Results

A total of 70 patients were included in the final comparative analyses. Of these, 35 underwent IC diversion and 35 CU single stoma diversion. The two groups were similar with regard to age, gender, ASA score, type of indication and pathological features. Operating times (P < 0.001), estimated blood loss (P < 0.001), need for intensive care unit stay (P = 0.01), time to drain removal (P < 0.001) and length of hospital stay (P < 0.001) were significantly higher in patients undergoing IC diversion. The number of patients with intra- (P = 0.04) and early postoperative (P = 0.02) complications was also significantly higher among those undergoing IC diversion. Interestingly, the mean BCI scores were overlapping in the two groups.

Conclusions

The present results show that CU with a single stoma can represent a valid alternative to IC in elderly patients with relevant comorbidities, reducing peri-operative complications without a significant impairment of QoL.

Read more articles of the week

Article of the Week: Patient expectations of sexual function following RP

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 survey of patient expectations regarding sexual function following radical prostatectomy

Serkan Deveci*,, Geoffrey T. Gotto*, Byron Alex*, Keith OBrien* and John P. Mulhall*

 

*Department of Urology, Memorial Sloan Kettering Cancer Center, New York, NY, USA, and Department of Urology, Medical School of Acibadem University, Istanbul, Turkey

 

Read the full article

Objective

To assess the understanding of patients, who had previously undergone radical prostatectomy (RP), about their postoperative sexual function, as clinical experience suggests that some RP patients have unrealistic expectations about their long-term sexual function.

Patients and Methods

Patients presenting within 3 months of their open RP or robot-assisted laparoscopic prostatectomy (RALP) were questioned about the sexual function information that they had received preoperatively. Patients were questioned about erectile function (EF), postoperative ejaculatory status, orgasm, and postoperative penile morphology changes. Statistical analyses were performed to assess for differences between patients who underwent open RP vs RALP.

octaotw4-results

Results

In all, 336 consecutive patients (from nine surgeons) with a mean (SD) age of 64 (11) years had the survey instrument administered (216 underwent open RP and 120 underwent RALP). There were no significant differences in patient age or comorbidity profiles between the two groups. Only 38% of men had an accurate recollection of their nerve-sparing status. The mean (SD) elapsed time after RP at the time of postoperative assessment was 3 (2) months. RALP patients expected a shorter EF recovery time (6 vs 12 months, P = 0.02), a higher likelihood of recovery back to baseline EF (75% vs 50%, P = 0.01), and a lower potential need for intracavernosal injection therapy (4% vs 20%, P = 0.01). Almost half of all patients were unaware that they were rendered anejaculatory by their surgery. None of the RALP patients and only 10% of open RP patients recalled being informed of the potential for penile length loss (P < 0.01) and none were aware of the association between RP and Peyronie’s disease.

Conclusions

Patients who have undergone RP have largely unrealistic expectations about their postoperative sexual function.

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Editorial: Managing expectations after radical prostatectomy; time to change

There have been numerous advances in the management of prostate cancer. Developments in imaging, surgical and radiotherapy technology, and pathological grading, have led to improvements in the diagnosis and management of this common malignancy. Such progress has translated to earlier diagnosis and improved disease-specific outcomes.

With improved outcomes comes increased attention on life after treatment. Survivorship in cancer has been an area of increasing focus. The aim; to live as healthy and as good a quality of life for as long as possible after diagnosis, by managing the consequences of the cancer and its treatment. In prostate cancer, the functional impact of surgery on quality of life can be considerable, especially given the falling age at first presentation. The consequences of treatment are often the reason patients’ select one form of therapy over another.

Both sexual function and urinary continence can be significantly affected after radical prostatectomy (RP). Despite numerous consequences of surgery on sexual function, the greatest focus in publications is erectile dysfunction (ED). The quoted incidence in published studies can vary from 20% to 90%, depending on whether the return of ‘normal’ erectile function is classed as the return of spontaneous erections, a ‘return to baseline function’, or functional recovery only with pharmacological assistance. This lack of agreed definition of ED after RP hampers progress by underestimating the impact of surgery and making an uneven playing field when comparing studies.

The tendency for surgeons and studies to focus solely on erectile function, when there are so many changes in sexual function after RP, does not give patients a realistic expectation of the impact of surgery on their life after treatment. Patients should be made aware 100% will experience some change in their sexual function after surgery. Patients should be aware of all the possible risks, including;

  1. ED: All will develop a degree of ED after any RP and should be aware that their risk is dependent on their baseline function, comorbidity, and nerve-spare status. They should be made aware of the protracted time course for recovery, even when the nerves are spared, the need for possible injection therapy, and the possible future dependence on some form of therapy to achieve functional erections in the long-term.
  2. Changes in ejaculation: All patients should be made aware of the loss of ejaculation as a permanent feature, and the impact this will have on their natural fertility. They should also be aware that some develop climacturia, and the possible risk of ejaculatory pain.
  3. Changes to penile size/shape: Patients should be aware of the possible reduction in penile length after RP, and the increased risk of developing Peyronie’s disease after RP, which can further impact their sexual function.

With high profile advances such as the rise of robot-assisted RP (RARP), much has been made of the improved view of local anatomy, and ability to manoeuvre within the confined space. The expectation that this translates to improved functional outcome existed way before any studies had been conducted to show any benefit. It is of no surprise, therefore, that patients’ expectations of outcomes after RP have been unrealistically raised by such technologies.

In this month’s BJUI, Deveci et al. [1] present their survey looking at patient expectations of sexual function after RP. In this study, patients who had undergone RP (open or robot-assisted) in the last 3 months were asked to recall the counselling they had received about possible changes in sexual function preoperatively. The comprehensive approach of this study examined patients’ expectations in all the different facets of sexual function, including erectile function, expected time to full recovery of erections, the possible need for intracavernosal injections (ICI), changes in ejaculation including intensity, pain, and climacturia, and awareness of penile length changes and risk of postoperative Peyronie’s disease.

Compared with those undergoing open RP, patient’s expectations after RARP were greater, with more expecting a shorter recovery time (6 vs 12 months, P = 0.02), a higher expectation of a recovery back to baseline erectile function (75% vs 50%, P = 0.01), and lower expected need for ICI (4% vs 20%, P = 0.01) [1]. This greater expectation of newer technology leads to greater regret, and a greater need to manage expectations preoperatively [1, 2].

In addition to the misconceptions on erectile function, ~50% were unaware of the risk of anejaculation, <10% were aware of changes to penile length, and none were aware of risks of developing Peyronie’s disease after RP.

While the Deveci et al. [1] study does have flaws, primarily the lack of ability to differentiate between what patients were exactly told before RP by the nine different operating surgeons, and what could be recalled after RP, it does highlight an important point. No matter what patients were told before surgery, within 3 months of surgery their recollection and understanding of its possible impact on sexual function was poor. Previous studies have highlighted this disparity between clinician’s recall of discussions on the consequences of surgery and patient recall. In one study, while 100% of clinicians felt they had adequately addressed patients concerns on ED, <30% of patients felt the issues had been adequately addressed [3].

Effective management of patients’ expectations of the possible consequences of RP preoperatively allows for better informed consent, a realistic expectation of outcome and time course for recovery, better compliance with postoperative treatments for ED, and less regret of the initial surgical approach.

Given the limited time in consultations, there is not enough time to address all the possible consequences of surgery in detail. When being diagnosed with cancer, often the last thing on the patients mind is sexual function a year down the line. The more important issue at first is coming to terms with the cancer diagnosis, and just making it through the surgery. In addition, one has to wonder if it is fitting for the oncological surgeon to discuss the functional consequences, possible outcomes and their management when other specialists will manage this in the future. A discussion of sexual consequences of surgery is very different coming from the robotic surgeon, rather than the andrologist who would see them after.

The most ideal approach would be for all patients to see an andrologist and continence specialist before RP or be seen in preoperative ‘survivorship’ seminars, based on discussing possible consequences and optimising functional recovery after treatment. Such seminars should be run by the teams involved in managing sexual function and continence postoperatively. Patients should be given a simple, one page sheet outlining the possible consequences of their intended treatment, be that radiotherapy or surgery, on sexual function and continence. In the same way that patients are given a key contact for their cancer care, they should have access to a key contact for their functional recovery. In addition to follow-up visits with the operating surgeon, focusing on the oncological outcome, a separate follow-up based on functional outcome with an andrologist and continence specialist would focus on functional recovery.

There has been a drive to develop high-volume cancer centres of excellence, with pooled resources to allow excellence in imaging, pathology, as well as surgical and non-surgical treatments. The most utopian approach would see these centres also having andrology and continence specialists focused on the management of all postoperative functional consequences, including the ability to undertake penile implant and artificial sphincter surgery as required.

The progress in developing such an infrastructure has been slow. Research on optimising functional recovery has not been as extensive as the focus on diagnosis and treatment in prostate cancer, which can dominate many urology journals and meetings. This imbalance needs to be addressed, to provide not only the best treatment for prostate cancer, but also the best management of the consequences of treatment, aimed at improving quality of life after surgery.

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Majid Shabbir
Guys Hospital, London, UK

 

References

 

1 Deveci S, Gotto GT, Alex B, OBrien K, Mulhall JP. A survey of patient

 

2 Schroeck FR, Krupski TL, Sun L et al. Satisfaction and regret after open

 

3 Crawford ED, Bennett CL, Stone NN et al. Comparison of perspectives

 

Article of the Week: Prevalence of the HOXB13 G84E mutation in Danish men undergoing radical prostatectomy and its correlations with prostate cancer risk and aggressiveness

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.

Prevalence of the HOXB13 G84E mutation in Danish men undergoing radical prostatectomy and its correlations with prostate cancer risk and aggressiveness

Tine M. Storebjerg*,,, Søren Høyer, Pia Kirkegaard§, Flemming Bro§, the LuCamp Study Group, Torben F. Ørntoft, Michael Borre* and Karina D. Sørensen

 

Departments of*Urology Pathology, Aarhus University Hospital, Department of Molecular Medicine, Aarhus University Hospital, §Research Unit for General Practice and Research Centre for Cancer Diagnosis in Primary Care, Aarhus University, Aarhus, and Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care, Copenhagen, Denmark

 

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Objectives

To determine the prevalence of the HOXB13 G84E mutation (rs138213197) in Danish men with or without prostate cancer (PCa) and to investigate possible correlations between HOXB13 mutation status and clinicopathological characteristics associated with tumour aggressiveness.

Materials and Methods

We conducted a case–control study including 995 men with PCa (cases) who underwent radical prostatectomy (RP) between 1997 and 2011 at the Department of Urology, Aarhus University Hospital, Denmark. As controls, we used 1622 healthy men with a normal prostate specific antigen (PSA) level.

Results

The HOXB13 G84E mutation was identified in 0.49% of controls and in 2.51% of PCa cases. The mutation was associated with a 5.12-fold increased relative risk (RR) of PCa (95% confidence interval [CI] 2.26–13.38; P = 13 × 10−6). Furthermore, carriers of the risk allele were significantly more likely to have a higher PSA level at diagnosis (mean PSA 19.9 vs 13.6 ng/mL; P = 0.032), a pathological Gleason score ≥7 (83.3 vs 60.9%; P = 0.032), and positive surgical margins (56.0 vs 28.5%; P = 0.006) than non-carriers. Risk allele carriers were also more likely to have aggressive disease (54.2 vs 28.6%; P = 0.011), as defined by a preoperative PSA ≥20 ng/mL, pathological Gleason score ≥ (4+3) and/or presence of regional/distant disease. At a mean follow-up of 7 months, we found no significant association between HOXB13mutation status and biochemical recurrence in this cohort of men who underwent RP.

octaotw3-results

Conclusions

This is the first study to investigate the HOXB13 G84E mutation in Danish men. The mutation was detected in 0.49% of controls and in 2.51% of cases, and was associated with 5.12-fold increased RR of being diagnosed with PCa. In our RP cohort, HOXB13 mutation carriers were more likely to develop aggressive PCa. Further studies are needed to assess the potential of HOXB13 for future targeted screening approaches.

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Editorial: HOXB13 mutations and prostate cancer risk

For the first time, Storebjerg et al. [1] describe the prevalence of the HOXB13 G84E mutation in a Danish population and its association with prostate cancer risk and features indicative of clinically aggressive disease in a cohort of men undergoing radical prostatectomy. In this study, the prostate cancer risk mutation was seen in 0.49% of controls with an ~5-fold increase in risk of prostate cancer among carriers. The homeobox transcription factor gene HOXB13, is located on the long arm of chromosome 17 (17q21), and belongs to a superfamily of genes considered critical to animal embryonic development, characterised by a highly-conserved DNA-binding domain. In 2012, our research team described the association of a rare recurrent HOXB13 mutation, substituting adenine for guanine in the second position of codon 84 resulting in the replacement of glycine by glutamic acid, with prostate cancer and found that the carrier frequency was ~20-times higher among men with early onset disease and multiple affected close relatives compared with men presumed without disease [2]. Since then, numerous studies have confirmed this association with estimates of risk overall varying from ~3 to 9-fold, and generally a greater risk seen among men diagnosed before the age of 60 years and among those with a positive family history of disease among first-degree relatives [3]. The G84E mutation is almost exclusively found in men of Northern European descent with evidence suggesting that it is a relatively recent (circa 1790s) founder mutation in the population, and considered to be of moderate penetrance (estimated lifetime risk among carriers 35–65%) [4]. The same germline mutation has also been preliminarily reported to be associated with cancers of the breast, colon, bladder, and leukaemia, but requires further investigation [5, 6].

The findings from this study [1], both for the prevalence of the mutation, as well as its magnitude of association with prostate cancer, are comparable to prior reports in Northern European populations. Furthermore, among the 995 cases, the mutation frequency was significantly associated with features predictive of progression after surgery (high PSA level, positive surgical margins, higher pathological Gleason score, and non-organ confined disease) suggesting that genetic evaluation of men with a strong family history would identify a subset of men that would benefit from early screening and intervention in the same manner as are male carriers of known founder mutations in BRCA2[7]. The observation between HOXB13 and clinical features indicative of aggressive disease has been less consistent compared with studies of risk overall and the exact mechanism whereby the gene contributes to malignant progression in the prostate is not well-understood. There is some suggestion that the gene may operate both as a tumour suppressor, as early studies reported its suppression of androgen receptor activity, and as an oncogene as HOXB13 overexpression has been seen in androgen-independent tumours [8].

Currently, most countries (including the USA) do not recommend use of PSA screening for men at average risk for prostate cancer. However, given the significant risk of prostate cancer in men carrying a single copy of the HOXB13 G84E allele, should these male mutation carriers be screened for prostate cancer with PSA testing and DRE? If so, how do we identify these men and at what age should testing commence? Unfortunately, many G84E carriers may not be identified by family history, which raises the question about when is the risk of disease significant enough to warrant population level testing? As Nordic countries, including Denmark, have a higher frequency of HOXB13 G84E allele in the general population, research directed toward understanding the benefit of genetic testing followed by prostate cancer early detection strategies should be considered.

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Kathleen A. Cooney* and Jennifer L. Beebe-Dimmer

 

*Departments of Internal Medicine and Urology, The University of Michigan, Comprehensive Cancer Center, Ann Arbor, and Department of Oncology, Wayne State University School of Medicine, Karmanos Cancer Institute, Detro it, MI, USA

 

References

 

 

2 Ewing CM, Ray AM, Lange EM et al. Germline mutations in HOXB13 and prostate-cancer risk. N Engl J Med 2012; 366: 1419

 

3 Beebe-Dimmer JL, Isaacs WB, Zuhlke KA et al. Prevalence of the HOXB13 G84E prostate cancer risk allele in men treated with radical prostatectomy. BJU Int 2014; 113: 8305

 

 

5 Alanee S, Couch F, OftK. Association of a HOXB13 variant with breast cancer. N Engl J Med 2012; 367: 4801

 

6 Beebe-Dimmer JL, Hathcock M, Yee C et al. The HOXB13 G84E mutation is associated with an increased risk for prostate cancer and other malignancies. Cancer Epidemiol Biomarkers Prev 2015; 24: 136672

 

7 National Comprehensive Cancer Network (NCCN), NCCN Clinical Practice Guidelines in Oncology. Genetic/Familial High-risk Assessment: Breast and Ovarian (Version 2.2015). Available at: https://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed 12-27-2015

 

8 Shah N, Sukumar S. The Hox genes and their roles in oncogenesis. Nat Rev Cancer 2010; 10: 36171

 

Article of the Week: Predictive value of negative 3T multiparametric MRI of the prostate on 12-core biopsy results

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.

 

Predictive value of negative 3T multiparametric magnetic resonance imaging of the prostate on 12-core biopsy results

James S. Wysock, Neil Mendhiratta, Fabio Zattoni, Xiaosong Meng, Marc Bjurlin,
William C. Huang, Herbert Lepor, Andrew B. Rosenkrantz* and Samir S. Taneja
Department of Urology, and *Department of Radiology, NYU Langone Medical Center, New York, NY, USA

 

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Objectives

To evaluate the cancer detection rates for men undergoing 12-core systematic prostate biopsy with negative prebiopsymultiparametric magnetic resonance imaging (mpMRI) results.

 

Materials and Methods

Clinical data from consecutive men undergoing prostate biopsy who had undergone prebiopsy 3T mpMRI from December 2011 to August 2014 were reviewed from an institutional review board-approved prospective database. Men with negative prebiospy mpMRI results (negMRI) before biopsy were identified for the present analysis. Clinical features, cancer detection rates and negative predictive values were summarized.

 

Results

Seventy five men with negMRI underwent systematic 12-core biopsy during the study period. In the entire cohort, men with no previous biopsy, men with previously negative biopsy and men enrolled in active surveillance protocols, the overall cancer detection rates were 18.7, 13.8, 8.0 and 38.1%, respectively, and the detection rates for Gleason score (GS) ≥7 cancer were 1.3, 0, 4.0 and 0%, respectively. The NPVs for all cancers were 81.3, 86.2, 92.0, and 61.9, and for GS ≥7 cancer they were 98.7, 100, 96.0 and 100%, respectively.

 

Conclusions

A negative prebiopsy mpMRI confers an overall NPV of 82% on 12-core biopsy for all cancer and 98% for GS ≥7 cancer. Based on biopsy indication, these findings assist in prebiopsy risk stratification for detection of high-risk disease and may provide guidance in the decision to pursue biopsy.

 

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