FOCUS ON 10 TH ANNIVERSARY
VIEWPOINT
Looking forward, looking back—10 years in urology Maarten Albersen, Rufus Cartwright, Peter Choyke, S. Larry Goldenberg, Howard Goldman, Nathan Lawrentschuk, W. Marston Linehan, Declan Murphy, Harris Nagler, Peter Scardino, Linda Shortliffe, Arnulf Stenzl and Dan Theodorescu Abstract | When Nature Reviews Urology launched in 2004, the field of urology was vastly different to that which we work in today, and the past 10 years have seen the field change immensely. As a specialty on the forefront of cutting-edge innovation, urologists are often the first to embrace new technologies and ideas. In this Viewpoint, members of the Nature Reviews Urology advisory board were asked what they thought was the most important change, issue or innovation in urology in the past 10 years, and what they expected to be the most important in the next decade. Here are their opinions. Albersen, M. et al. Nat. Rev. Urol. 11, 649–655 (2014); published online 28 October 2014; doi:10.1038/nrurol.2014.263
Maarten Albersen University Hospitals Leuven, Belgium
For me personally, erectile dysfunction (ED) following radical prostatectomy has been a focus of interest and research during the past 10 years. In spite of the hype surround ing nerve-sparing techniques (both robotassisted and retropubic), we are still faced with high numbers of patients who are affected by this complication. In the past 10 years, clinical research efforts have been focussed on reducing nerve-injury-induced cavernosal fibrosis, while basic scientists have seen a surge in regenerative medicine techniques, such as stem-cell treatment, aimed at improving nerve recovery and Competing interests
H.G. declares that he is a member of the speakers’ bureau for Allergan, Medtronic and Uroplasty, and that he has acted as a consultant for Allergan, Astellas, Medtronic and Uroplasty. P.S. declares that he is a scientific advisor to OPKO Diagnostics, who are developing a commercial assay for the 4KScore®developed at Memorial Sloan–Kettering. A.S. declares that has acted as a consultant for Alere, and as a speaker and consultant for Ipsen and Janssen. His institution receives research grants from Amgen, Immatics Biotechnologies GmbH, Karl Storz and Novartis, and is involved in clinical studies with Bayer, CureVac, Immatics Biotechnologies GmbH and Johnson & Johnson. The other authors declare no competing interests.
regeneration after injury. 10 years ago, in 2004, the first stem-cell study successfully targeting cavernous-nerve-injury-induced ED in rats was conducted by Bochinski et al.1 at UCSF. 10 years later, several clinical trials are running to investigate this therapy in human patients, and the first abstract on a phase I trial investigating safety of stemcell injection in prostate cancer patients was presented at the EAU 2014 by Rene Yiou from France.2 However, several large-scale trials—such the PIVOT trial3 and the PRIAS project4—carried out during the past decade have also made us more aware of the fact that a large proportion of patients with organconfined prostate cancer, in whom nervesparing surgery would be an oncologically safe option, do not always need surgery immediately and we can, therefore, spare our patients the adverse effects of surgery by adopting an active surveillance strategy. One of the biggest changes we might see over the next 10 years in this field is based on these recent trials, with the outcome that we might be doing fewer prostatectomies for organ-confined tumours. This change in approach will be in favour of active surveillance strategies and emerging local ized therapies, which target the tumour rather than the whole organ and are, there fore, associated with smaller risks in terms of complications such as incontinence and ED (in the case of prostate cancer). In those
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patients who will be surgically treated for prostate cancer, I personally believe we will see a shift towards the selection of patients with locally advanced tumours, in which the role of surgery is becoming more and more apparent. As nerve sparing will then become even more challenging, and as we have seen generally disappointing results with the use of oral therapies for penile rehabilitation, we will need to further develop more potential regenerative therapies for nerve recovery and regeneration in the near future. The results of the first stem-cell trials are eagerly awaited and might bring hope to patients suffering from postprostatectomy ED in the coming decade.
Rufus Cartwright Imperial College London, UK
Evidence-based medicine has recently been under attack as promoting a ‘one size fits all’ approach to investigation and treatment. Some would also argue that truly systematic approaches to evidence synthesis have yet to be applied to guidance from the major uro logical societies. But, despite these concerns, the rise of evidence-based medicine over the past decade and the availability of evidencebased guidelines have transformed the working practices of urologists. Although practice variation remains rife, at least uro logists now have somewhere to turn for a best estimate of an effect size, and a con sensus view about any treatment options. The easy availability of evidence summaries has not only helped urologists navigate an impossibly expanded literature, but also revolutionized patient‑led decision making. Genetics has been being claimed as “the next big thing” in all medical fields for at least the past 25 years. Although the fruits of the Human Genome Project have been slow to translate to practice, over the past decade (the so-called GWAS era), new discoveries in urological genetic epidemiology have multiplied exponentially, spreading steadily from urological oncology right across the field. Aspects of the genetic architecture of most common urological conditions have now been established. Over the next 10 years huge resources will be spent to under stand the functional consequences of new VOLUME 11 | NOVEMBER 2014 | 649
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PERSPECTIVES The contributors* Maarten Albersen Maarten Albersen is a senior resident in urology and postdoctoral research fellow in the Department of Urology at the University Hospitals Leuven, Belgium. He obtained his MD in 2006 from Leuven University and afterwards enrolled in residency in surgery and urology. In 2012 he completed his PhD training, based on stem-cell work done in Leuven and at the University of California, San Francisco. His research focuses on regenerative treatment options for sexual dysfunctions and pathophysiological mechanisms of erectile dysfunction and Peyronie’s disease. He is the chair of the scientific committee of the European Society for Sexual Medicine, advisory board member for Nature Reviews Urology and assistant editor for the Journal of Sexual Medicine. Rufus Cartwright Rufus Cartwright is a UK Medical Research Council-funded research fellow who is working on the genetic epidemiology of incontinence and prolapse at Imperial College London, UK. He completed his MD(res) degree at King’s College London, on the assessment of overactive bladder symptoms. He is the chair of the International Urogynecological Association Fellows Committee, and trainee editor for urogynaecology at BJOG: An International Journal of Obstetrics & Gynaecology. Peter Choyke Peter L. Choyke is the Chief of the Molecular Imaging Program of the National Cancer Institute, Bethesda, MD, USA. Dr Choyke graduated from Jefferson Medical College in Philadelphia, and received training in Diagnostic Radiology at Yale University and the University of Pennsylvania. His research is focused on imaging of genitourinary malignancies and targeted imaging probes, and developing novel molecular imaging agents for cancer. S. Larry Goldenberg Larry Goldenberg received his medical degree from the University of Toronto and became a Fellow of the Royal College of Surgeons in 1984. He is currently the Stephen A. Jarislowski Professor of Urologic Sciences at UBC and the Mohammed Mohseni Chair in Men’s Health. He is the founding Executive Director of the Vancouver Prostate Centre. In 2009 he created the Men’s Health Initiative of BC and in 2014 he founded and became Chairman of the Canadian Men’s Health Foundation. He has been recognized for his contributions to Canadian health care by being inducted into the Order of British Columbia and the Order of Canada. Howard Goldman Howard B. Goldman is a Professor of Surgery (Urology) at the Cleveland Clinic Lerner College
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of Medicine, Cleveland, OH, USA, and part of the Center for Female Pelvic Medicine and Reconstructive Surgery within the Glickman Urologic and Kidney Institute. He is also the Director of Quality and Patient Safety within the Institute. He is a well-known lecturer and researcher in the areas of incontinence, prolapse, and neuromodulation with a specific interest in cost-effective care. He currently serves as an assistant editor for the Journal of Urology and on the editorial boards of several other journals, including Nature Reviews Urology.
Nathan Lawrentschuk Nathan Lawrentschuk is a urological surgeon and urologic oncologist at the University of Melbourne Department of Surgery and Ludwig Institute for Cancer Research at the Austin Hospital, Melbourne, Australia. He has published over 170 peer-reviewed publications and book chapters and presented at multiple international meetings. He completed a PhD in kidney cancer research and later a Society of Urologic Oncology Fellowship, which involved additional training in robotic, laparoscopic and open cancer surgery at the University of Toronto, Canada. His interests range from Greenlight laser prostatectomy for BPH through to cystectomies with neobladders and penile preservation surgery. W. Marston Linehan W. Marston Linehan, MD received his internship, residency and fellowship training Duke University Medical Center. He began his career at the National Cancer Institute in 1982, where he is currently Urologist-inCharge and Chief of the Urologic Oncology Branch, National Cancer Institute. He has had a long standing interest in identification of the genetic basis of cancer of the kidney. By studying patients and families with kidney cancer, he and his colleagues identified the VHL gene (von Hippel-Lindau and clear cell renal carcinoma), the gene for Hereditary Papillary Renal Carcinoma (MET oncogene) the FLCN gene (Birt Hogg Dubé syndrome), the gene for TFE3 kidney cancer and described the germline fumarate hydratase and succinate dehydrogenase B/C/D mutations in North American families with hereditary leiomyomatosis renal cell carcinoma (HLRCC) and SDH-RCC. He and his colleagues have also defined the methods for clinical management these hereditary forms of kidney cancer. Declan Murphy Declan G. Murphy is urologic oncologist & Director of Robotic Surgery at the Peter MacCallum Cancer Centre, Head of Uro‑Oncology at the Royal Melbourne Hospital and Honorary Clinical Associate Professor at the University of Melbourne, Australia. He has previously been consultant urological surgeon at Guys & St Thomas’ NHS Foundation Trust
in London where he underwent his specialist urology training. He has published extensively in the field of minimally-invasive urology, and is a consulting editor at European Urology and Director of the Melbourne Uro-Oncology Training Programme. His other interests include multimedia surgical education and social media in health care.
Harris Nagler Harris M. Nagler is Physician-in-Chief at Mount Sinai Beth Israel Medical Center NY, USA, where he is also Chair of the Sol and Margaret Berger Department of Urology. Prof. Nagler is also Senior Associate Dean for Clinical Affairs and Professor of Urology at the Icahn School of Medicine at Mount Sinai. His clinical practice focuses on male infertility, impotence and general urology. Peter Scardino Peter T. Scardino is Chair of the Department of Surgery and Head of the Prostate Cancer Programme at Memorial Sloan–Kettering Cancer Center, NY, USA. He served as Editorin-Chief of Nature Clinical Practice Urology from its launch in 2004, until its rebrand as Nature Reviews Urology in 2009. Linda Shortliffe Linda Shortliffe earned her medical degree at Stanford University in Palo Alto. She is currently the Stanley McCormick Memorial Professor, past Chair of the Department of Urology at Stanford University and past Chief of Paediatric Urology at Lucile Packard Children’s Hospital. Arnulf Stenzl Arnulf Stenzl is Director of the Department of Urology, University of Tübingen Medical School, Germany. He has authored or co-authored more than 300 publications and scientific papers in peer-reviewed journals, and is a member of numerous public and privately initiated steering committees and advisory boards on a variety of urological topics. He has been the chairman of the Scientific Congress Office of the European Association of Urology since 2012. Dan Theodorescu Dan Theodorescu is Director of the University of Colorado Comprehensive Cancer Center and Professor of Urology and Pharmacology. He has focussed his career on translational bladder cancer biology, using computational biology to discover genes that drive this and other cancers, while providing novel biomarkers and therapeutic targets that serve as the foundation for personalized therapeutic approaches currently tested in clinical trials. His experience as a practising surgeon provides him with insights that help direct his research to make the most impact on human health. *The contributors are listed in alphabetical order.
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FOCUS ON 10 TH ANNIVERSARY susceptibility genes. At last we should finally see the clinical benefits of these studies, including the introduction of reliable bio markers, effective screening strategies, tar geted prevention efforts, and hopefully a wide range of stratified approaches to both surgery and pharmacotherapy.
Peter Choyke National Institutes of Health, USA
10 years ago the field began to realize that overtreatment of prostate cancer was a burgeoning problem, owing to a combina tion of PSA screening and random biopsies that detected inconsequential low-grade tumours and missed high-grade tumours outside the usual template. Investigators around the world began to use MRI to detect cancers, rather than just for staging. Realizing that detection by imaging was not sufficient, a number of solutions for image-guided biopsies—including in gantry MRI biopsies and MRI–ultrasonography fusion biopsies—were invented. These tech niques have now entered the marketplace and have become a widely available techno logy that is revolutionizing the way pros tate cancer is detected. These advances in image-based detection should increase the confidence with which men are placed on active surveillance protocols and increase the detection of aggressive tumours that are missed by random biopsies. Determining which patients should be treated and how intense the treatment should be for prostate cancer based on genomic data obtained from image-guided biopsies will be a big issue over the next decade in urology. Currently, the biopsy sample is evaluated using the Gleason grading system, and although this is an important prognostic biomarker, it must be acknowledged that it is almost 50 years old, and new and cost-effective genomic technologies are emerging. However, which genes of the 20,000 or so are important? The ability to accurately prognosticate a specific prostate cancer will depend on obtain ing a good sample of the tumour from an image-guided biopsy and a genomic profile looking for driver mutations that indicate a more aggressive biology. Because prostate cancer is generally slow growing, it will take some time to identify which mutations are associated with bad outcomes; determining which mutations portend a poor outcome will be a major issue in urology over the next 10 years.
S. Larry Goldenberg University of British Columbia, Canada
Over the course of the past 10 years we have continued to witness a distancing from the Halstedian approach to cancer surgery of large ‘slashes’ (“bigger cut, bigger surgeon”) to a world awash in very minimally invasive approaches (LESS) and active surveillance of lesions in the prostate, kidney, penis and bladder. With what might still be consid ered quite primitive tools for predicting tumour biology, we have convinced many patients not to rush into aggressive thera pies with the promise of decreased morbid ity and preserved quality of life. Our need to improve our diagnostic and prognostic tools has stimulated the global expansion of biobanking, research into diagnostic blood and urine biomarkers, imaging tools, and genomics.
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10 years ago, in 2004, the first stem-cell study successfully targeting cavernous-nerveinjury-induced ED in rats was conducted…
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While much of urology has focused on ‘technopoly science’ over the past decade, the future will witness the resurgence of the urologic surgeon–scientist striving towards a better understanding of tumour biology. In parallel to seeking better tech nical methods of performing an existing therapeutic procedure (illustrated by the rise of robotics and image-guided thera pies), I believe that we will fine-tune our ‘smart screening’ approaches and use of chemopreventive options in betterdefined, high-risk populations, and we will find better and more targeted or precision therapeutic procedures based on ‘big data’, ‘omics’ science, and molecular imaging (MRI, PET scanning). All of our scien tific progress will be facilitated by global partners hips. Our digital world will see further exciting fusions of engineering, science, and medicine. One example will be the application of machine-l earning methodologies to the development of automated and more accurate interpreta tion of digitized imaging and pathology. This development will enrich the infor mation that can be gleaned from digital information that is beyond the human eye to perceive. Above all, we will adopt a
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‘humanomics’ approach to medicine with patients and families participating more and more in their health-care decisions, an increase in patient-originated research ideas, ethical population-based attention to ‘value in medicine’ issues, and to new directions in informatics.
Howard Goldman Cleveland Clinic, USA
Although much has changed within the subspecialty of female urology in the past decade, controversies continue about specific issues, and further improvements should be expected in the coming years. The debate about synthetic transvaginal prolapse mesh has generated significant medicolegal activity in many countries, and its use has declined in certain locales. Unfortunately, although the use of widepore polypropylene mesh as midurethral sling material has been endorsed by many reputable societies, the controversy regarding the transvaginal prolapse mesh has spilled over and in some places placed the use of synthetic midurethral slings in jeopardy. Over the next few years these concerns should settle down, as synthetic slings have clearly been recognized as safe and effective. Despite this, the search for non-meshbased alternatives for the treatment of stress urinary incontinence continues. Exciting research using autologous muscle cells to help repair the female periurethral muscles has been reported. Furthermore, stem cells and their secretome products have been demonstrated to help repair childbirthrelated pelvic-floor injuries in animal models. The hope that proteins produced by stem cells could somehow help prevent pelvic floor injury after vaginal delivery and thus prevent pelvic floor disorders is actively being researched and holds the promise of a complete paradigm shift in the management of these patients.
Nathan Lawrentschuk University of Melbourne, Australia
Nature Reviews Urology has become a journal that many people in the field of urology enjoy reading. The simple reason is that it has been able to focus on relevant topics time and again, meaning that it is well read and cited appropriately, with thoughtful selection of authors by the VOLUME 11 | NOVEMBER 2014 | 651
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PERSPECTIVES
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The next decade will see kidney cancer move towards becoming fundamentally a nonsurgical disease, with the development of therapies targeting specific kidney‑cancer‑gene pathways…
It’s a SCREAM! Edvard Munchs masterpiece is stolen from the Munch Museumin Norway
Lifestyle guru found guilty of lying about a suspicious sale of shares in the drug company ImClone
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NEWS
November 2004
NATURE PUBLISHING GROUP LAUNCHES CLINICAL UROLOGY REVIEWS JOURNAL November 2004, London NPG has launched a Urology journal, as part of the clinical expansion of its Reviews titles. Publishing high-quality, commissioned Reviews, opinion pieces, News & Views and in-house Research Highlights, the journal will be published monthly and is proud to announce Peter Scardino as launch Editor-In Chief.
Top 10 articles
from 2004 in NCPU 1 Mechanisms of disease: central nervous system involvement in overactive bladder syndrome Karl-Erik Andersson
2 Technology insight: novel ureteral stent materials and designs Ben H. Chew & John D. Denstedt 3 New theories in interstitial cystitis Toby C. Chai & Susan Keay
ENTERTAINMENT NEWS Double Dubya! Number 1 songs in the UK in George W. Bush elected for a November 2004 included second term ‘Just Lose It’ by Eminem, in office ‘I’ll Stand By You’ by Girls Aloud, and ‘Vertigo’ by U2; in the USA, Usher and Alicia Keys spent 6 weeks at number 1 over November 2004 with ‘My Boo’, which is, disappointingly, not about bladder outlet obstruction
Films released in November 2004 include Disney’s ‘The Incredibles’, ‘The Polar Express’, and urology-themed biopic ‘Kinsey’, featuring Liam Neeson as the famous sexologist
4 Diagnosis and management of patients with overactive bladder syndrome and abnormal detrusor activity Michelle Jo Semins & Michael B. Chancellor
5 The value of radiotherapy in treating recurrent prostate cancer after radical prostatectomy Andrew J. Stephenson & Kevin M. Slawin
6 Treatment of chronic prostatitis Richard B. Alexander
7 Surgical intervention in patients with metastatic renal cancer: current status of metastasectomy and cytoreductive nephrectomy Paul Russo
8 Current views on evaluation, management, and gender assignment of the intersex infant Caleb P. Nelson & John P. Gearhart
9 Erectile dysfunction and priapism Derek J. Bochinski, Robert C. Dean & Tom F. Lue
10 Early cystectomy for clinical stage T1 bladder cancer Brent K. Hollenbeck & James E. Montie
editorial staff and strong support from the Advisory Board. Above all, the key to success has been to recognize that the field of urology is moving faster than many others with regards to management and technology. This makes Reviews impor tant but they must be fresh and succinct. At one end of the spectrum we have had a rush towards the use of robotics5 yet at the other, a push for conservatism with active surveillance for low-risk prostate cancer.6 The future holds more change for uro logy, as we are pressured to manage our shrinking health resources—how will we justify our outcomes without high-quality data? Will all of the technologies survive or will they become cheaper as competi tors arise? Will conservatism become even more accepted, leading to less surgery? How will radiation remain relevant to urology? What new technologies will make surgery 652 | NOVEMBER 2014 | VOLUME 11
NPG
more consistent and accurate? What drugs will help us achieve better results? Finally, above all, patient outcomes and individual ized medicine are likely to dominate, and Nature Reviews Urology will be there to document it all and expand its readership to help us comprehend the changes that confront us all.
W. Marston Linehan National Cancer Institute, USA
The past decade has brought both dra matic advances in our understanding of the genetic and biochemical basis of kidney cancer as well as historic changes in therapy for patients with this disease. The development of novel therapeu tic approaches targeting the VHL/HIF pathway led to the approval by the FDA of
seven agents, including sorafenib (2005), sunitinib (2006), temsirolimus (2007), everolimus (2009), bevacizumab plus interferon (2009), pazopanib (2009) and axitinib (2012), which have revolution ized the management of patients with advanced kidney cancer. Although most patients eventually progress and many will die of this disease, the impressive clinical responses seen in up to 45% of patients with advanced kidney cancer provide hope that more effective forms of therapy will be developed in the future. Novel insights into the genetic basis of kidney cancer came with the identification of mutations in chro matin remodeling genes such as PBRM1, BAP1, SETD2 and KDM5C.7,8 The finding of extensive genomic heterogeneity raised new issues about the evolution of clear cell renal cell carcinoma (ccRCC) as well as profound questions about the develop ment of targeted therapeutic approaches for this disease. The next decade will see dramatic changes in the management of kidney cancer. With the widespread availability of high-throughput next-generation sequenc ing, clinical decisions will be driven by genotype instead of histology; biopsy of a small renal tumour with mutation of a gene such as VHL, for example, would lead to management by active surveillance until the tumour reaches a certain size (such as 3 cm), at which time therapy would be recommended. Detection of a small renal mass with, for example, a fumarate hydra tase (FH) gene mutation or a TFE3 fusion translocation, on the other hand, would lead to more immediate management. The next decade will see kidney cancer move towards becoming fundamentally a nonsurgical disease, with the development of therapies targeting specific kidney-cancer-gene path ways, such as VHL, MET, TFE3, TSC, PTEN and FH. The management of localized kidney cancer will change from surgical to systemic therapy and the role of the urologic surgeon will change from recommending surgery to managing genomic analysis and treatment with targeted therapy. www.nature.com/nrurol
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FOCUS ON 10 TH ANNIVERSARY Declan Murphy Peter MacCallum Cancer Centre, Australia
Although I tried hard not to, I could not answer this question without mention ing robotic surgery! In 2004 I was midway through my urology training programme at Guy’s Hospital in London and laparoscopic radical prostatectomy was very much in vogue. We actually installed our first da Vinci© robot at Guy’s that year but I remained very focused on training in conventional laparo scopic radical prostatectomy. We had a view that the robot just added time and cost to this procedure and that it would in time become a white elephant. I had my epiphany during my Fellowship with Professor Tony Costello in Melbourne in 2007, when it became clear to me that the robotic technique was going to prevail. Although there remain unresolved issues about cost and which procedures might be most appropriate for the robot, it has become very clear to me over the past 10 years that robotic prostatectomy is the standardof-care for men who choose to have surgery for localized prostate cancer. I can’t see that changing in the next decade. One of our biggest challenges is to fully embrace multidisciplinary working and sub speciality practice. Urology is a very broad, multi-organ, multi-faceted specialty—there is enough in there for four or five full special ties by anyone else’s standards. I think we need to ensure best outcomes for our patients by managing them in multidisciplinary net works, where patients are managed by those most expert in managing individual condi tions. Another big change I foresee is the way in which we interact with our peers, our patients, and our professional resources. This will change utterly. The sweeping influ ence of social and digital media offers both unprecedented opportunities and consid erable challenges for health professionals. There is no point trying to pretend that the huge communication changes that are sweeping across our society will not impact on the staid world of medicine. I think we must embrace all of these changes in order to not just better serve our patients and realize our professional ambitions, but also to enjoy what we do even more.
Harris Nagler Beth Israel Medical Center, USA
Over the past 10 years the use of assisted reproductive techniques (ART), in particular
in vitro fertilization (IVF), has dramatically increased. Over the same time period, the live birth success rates have nearly doubled. The Centers for Disease Control (CDC) reported that ART resulted in nearly 62,000 babies born in 2012 in the United States, comprising a record 1.5% of all live births.9 As ART has become disseminated, the use of IVF has increasingly been accepted as an almost routine option for many couples. Another important development related to men’s health has been the explosive increase in testosterone replacement ther apy (TRT) for hypogonadism treatment. A recent JAMA study showed that TRT use in men increased from 0.81% to 2.91% from 2001 to 2011. 10 The paper also reported, unfortunately, that nearly 25% of new TRT users had not had serum testosterone levels measured over the prior year. TRT, like any medical intervention, is associated with risks that must be weighed against the highly publicized potential quality of life and clinical health benefits. We believe that it is critical that urologists assess patients with signs and/or symptoms of testosterone deficiency and only treat after appropriate discussion of risks, benefits and alterna tives. If treatment is initiated patients must be appropriately monitored; failure to do the above would be inconsistent with patient safety best practices.
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Exciting research using autologous muscle cells to help repair the female periurethral muscles has been reported
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We live in an ever-changing environment that has the potential to expose individuals to known and unknown agents that could have adverse effects on fertility. By extrapolating current environmental and lifestyle trends in male reproductive health risk factors, we can consider potential challenges and opportuni ties over the next 10 years. One needs only to walk down the street to recognize the penetration of mobile phones into everyday life. The United Nations reported an increase in cell phone accounts from 6 to 7.3 billion over a recent 1-year period;11 radiofrequency electromagnetic radiation from phones has been reported to impact semen analysis parameters.12 This observation has not been confirmed by others, but the widespread use in general and especially in younger boys does raise concern regarding potential impact on reproductive potential. The FDA
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reported opioid prescriptions increased from 174 to 257 million from 2000–2009.13 Although chronic opioid exposure is deleteri ous to spermatogenesis and testosterone con centration,14 recently enacted federal and state regulations and educational programs might stabilize or reverse this trend. On the other hand, other risk factors for impaired male fertility that have significantly declined in the past decade include cigarette smoking, alcohol consumption, and airborne pollutant concentrations15 and, if these patterns hold, they represent good news as they relate to male reproductive potential going forward. Research to further define environmental factors that affect male fertility is needed to help mitigate their effects.
Peter Scardino Memorial Sloan–Kettering Cancer Center, USA
The most significant change in urology over the past 10 years has been the wide spread introduction of a more conservative approach to the management of early-stage prostate cancer, based on the recognition that low-grade (Gleason 6) cancers rarely metastasize and have a long natural history, and that most men, even young men, with Gleason 6 cancers do not need immediate definitive therapy and can be safely observed in an active surveillance programme. This approach was strengthened by the PIVOT randomized trial3 showing no difference in 12-year survival rates between men with low-risk prostate cancer treated with radical prostatectomy versus observation, and was further reinforced by the US Preven tive Services Task Force’s recommendation against PSA screening based on their assess ment that screening could lead to more harm than good.16 Acceptance of the fact that the adverse effects of definitive treatment of lowrisk prostate cancers are not accompanied by a benefit in survival or disease progression has been an important shift in the field. At the same time, robot-assisted radical pros tatectomy failed to improve cancer control or functional outcomes compared with the traditional open procedure, despite the early exaggerated claims. These widely touted benefits have been refuted by properly con ducted multi-institutional and populationbased comparative effectiveness studies.17–19 Robotic techniques offer a new way of per forming prostate cancer surgery, but they involve similar adverse effects on function and no better cancer control, compared with other forms of radical therapy. VOLUME 11 | NOVEMBER 2014 | 653
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PERSPECTIVES The greatest change in the field over the next 10 years will be driven by the avail ability of preoperative and intraoperative molecular imaging of cancers. These new imaging techniques will change cancer surgery from a Halstedian radical approach (remove as much as possible to have the best chance of curing the cancer) to more indi vidualized ‘smart surgery’ directed at the actual extent of cancer present. Preopera tive imaging could substantially improve focal ablation or resection of cancer in the kidney, and could make focal ablation of clinically significant prostate cancer both feasible and effective—approaches that promise substantial reduction in morbid ity and fewer adverse effects on quality of life. Preoperative imaging advances will be driven by improvements in MRI and, even more so, in PET scanning. Intraoperative molecular imaging with optical-labeled probes will alter our approach to lympha denectomy for cancer, allowing us to limit the dissection to involved nodes, greatly simplifying the operation. Optical imaging will help to reduce morbidity by identify ing cancer at the surgical margins, making surgery more effective and enabling us to tailor each procedure to the known extent of the cancer, improving the rate of complete resection and reducing collateral damage to normal structures and deleterious effects on postoperative function and morbidity. Rapid advances in the genomic characteriza tion of cancers will provide more targets for imaging probes to be used before and during surgery. These technological improvements will most likely be more adaptable to robotassisted surgery than to open techniques, which may finally provide a definitive advantage to the robotic approach.
Linda Shortliffe Stanford University Medical Center, USA
When we began using MRI for imaging hydronephrosis in rats in 1992, we made our own rat body coil and defended slow MRI as potentially useful for imaging the urinary tract. Over the past decade, computational technology enabling fast MRI imaging has made MRI the imaging modality of choice for many studies. Examination of delayed radiation effects from the atomic bomb, moreover, has made MRI the modality of choice for complex genitourinary and other evaluations in children and foetuses. The inherent MRI qualities of enhanced tissue and anatomical definition, and ability to 654 | NOVEMBER 2014 | VOLUME 11
measure differential relative renal function and drainage without ionizing radiation, make MRI an important genitourinary imaging tool for clinical management. 3D imaging and anatomical reconstructions resulting from advanced computational capacities in both computed tomography and MRI eliminate much of the ‘differential’ from diagnoses. Over the next decade as imaging techno logy progresses further into cellular and molecular levels, even more of the ‘differ ential’ will be solved and this will allow us to focus upon disease stratification and prognostic factors: further personalization of medicine.
Arnulf Stenzl Eberhard Karls University Tübingen, Germany
Apart from minimization of pelvic and retroperitoneal surgery, the past 10 years have seen exciting new developments of first-line and second-line systemic treat ment in urologic tumours’ big three: pros tate cancer, urothelial cancer and RCC. The taxanes docetaxel and cabazitaxel, the adrenal hormone blocker abiraterone, the androgen-receptor (AR)-blocker enzalu tamide and the α‑emitter alpharadin have completely changed our treatment algor ithm of castration-resistant prostate cancer (CRPC).20–24 A whole range of new drugs targeting kinase inhibitors and inhibiting vascular endothelial growth factors has markedly increased survival rates in meta static RCC. Urothelial cancer—albeit not as dramatically—has seen new substances approved for second-line chemot herapy such as vinflunine.25 This new armamentar ium of systemic drug application has led to some partially unresolved questions not only about timing, sequence and combination of these drugs among each other, but also about their incorporation into treatment strategies involving surgical interventions and radiotherapy. In the future, surgical ablation of tumour(s) must focus on destruction and/or removal of the tumorous region itself instead of the whole tumour-bearing organ. One way to achieve this goal will be functional imaging using new tracers precisely deline ating those malignancies, which should be selectively destroyed. Currently explored is the application of photodynamic sensitizers or nanoparticles into a tumourous region. With external activation using optical or physical radiation, selective destruction of
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The future holds more change for urology, as we are pressured to manage our shrinking health resources…
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tumour with minimal adverse effects on surrounding parenchyma or other struc tures (such as nerves) would be possible. Despite exciting new developments in sys temic treatment over the past decade, cure is still rare in recurrent advanced or meta static prostate, renal cell and urothelial cancer. Immunotherapy—which actually has a long history in treating RCC and bladder cancer—has recently been (re-) explored for metastatic prostate and kidney tumours, either sequentially or in combina tion with chemotherapy. Synergism of the different mode of action of immunotherapy with conventional chemotherapy might add to overall survival and could also create a long-lasting effect exceeding that of chemo therapy, by permanently reducing immune tolerance to tumour cells.
Dan Theodorescu University of Colorado Cancer Center, USA
Urology has always been a technology-rich surgical specialty. From the advent of the first cystoscopes, through resectoscopes, lasers for use in both benign and malig nant diseases to lithotripters and laparo scopy, urologists have sometimes been the pioneers and almost always eager adopt ers of new technology. This technological progress has dramatically accelerated in the past decade with the development of better endoscopic instruments, widespread adop tion of digital imaging technology for both endoscopic and noninvasive patient assess ments and remote servo operated laparo scopic (robotic) surgery. These advances have come together to form a “perfect storm of progress” for our field in the past decade, leading our inexorable march towards minimally invasive treatment of urological disease. For most urological conditions, we are now positioned to treat with minimal morbidity, reduced length of hospital stay (or no stay) and improved convalescence. The field of urology is poised for trans formation in the next decade, facilitated by a culture of early and avid new technology adopters. This tectonic shift will be primar ily driven by the genetic revolution, which has provided us the molecular blueprints of the human host and of many of the diseases www.nature.com/nrurol
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FOCUS ON 10 TH ANNIVERSARY and conditions we treat. In no area is this truer than in cancer, where the elucidation of the driver mutations has led, and will be progressively leading, to more targeted agents that can reduce tumour growth and, in many cases, convert aggressive dis eases that limit survival to chronic diseases that patients can live with rather than die from. This will also lead to a new practical definition of what cancer really is, at least from the lay perspective, and a reduction in the fear and psychological burden that diagnosis will mean to individual patients. The genomic knowledge of pathobiology will also bring with it the ability to predict risk and diagnose diseases early and non invasively. Predicting risk of developing certain diseases years and decades before they are detected, then detecting them non invasively with molecular-based urine or blood tests that can also prognosticate and predict response to therapy, and coupling this with minimally invasive surgical pro cedures when required, will be the next urological revolution. Department of Urology, University Hospitals Leuven, Herestraat 49, Leuven 3000, Belgium (M.A.). Imperial College London, Institute of Reproductive and Developmental Biology, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK (R.C.). The Molecular Imaging Program, NCI, NIH, 10 Center Drive, Building 10, Room B3B69, Bethesda, MD 20892 USA (P.C.). University of British Columbia, Department of Urologic Sciences, Level 6, 2775 Laurel Street, Vancouver, BC V5Z 1M9, Canada (S.L.G.). Glickman Urological and Kidney Institute, The Cleveland Clinic, Q10‑1, 9500 Euclid Avenue, Cleveland, OH 44195, USA (H.G.). University of Melbourne, Department of Surgery and Ludwig Institute for Cancer Research, Austin Hospital, Suite 5, 210 Burgundy Street, Heidelberg, VIC 3084, Australia (N.L.). Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Building 10, CRC Room 1‑5940, Bethesda, MD 20892, USA (W.M.L.). Division of Cancer Surgery, Peter MacCallum Cancer Centre, East Melbourne, VIC 3003, Australia (D.M.). Beth Israel Medical Center, 10 Union Square East, Suite 3A, New York, NY 10003, USA (H.N.).
Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA (P.S.). Department of Urology, S287, 300 Pasteur Drive, Stanford, CA 94305‑5118, USA (L.S.). Department of Urology, University Clinic of Urology, Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany (A.S.). University of Colorado Comprehensive Cancer Center, MS F‑434, 13001 East 17th Place, Aurora, CO 80045, USA (D.T.). Correspondence to: Nature Reviews Urology Editorial Office [email protected] 1.
Bochinski, D. et al. The effect of neural embryonic stem cell therapy in a rat model of cavernosal nerve injury. BJU Int. 94, 904–909 (2004). 2. Yiou, R. et al. Intra-cavernous injection of bone marrow stem cells is well tolerated and improve erectile function in patients with postprostatectomy erectile dysfunction: Preliminary results of a phase I-II clinical trial. Abstract 599. Presented at the 29th Annual EAU Congress (2014). 3. Wilt, T. J. et al. Radical prostatectomy versus observation for localized prostate cancer. N. Engl. J. Med. 367, 203–213 (2012). 4. Bul, M. et al. Active surveillance for low-risk prostate cancer worldwide: the PRIAS study. Eur. Urol. 63, 597–603 (2013). 5. Sridhar, A. N. et al. Image-guided robotic interventions for prostate cancer. Nat. Rev. Urol. 10, 452–462 (2013). 6. Lawrentschuk, N. & Klotz, L. Active surveillance for low-risk prostate cancer: an update. Nat. Rev. Urol. 8, 312–320 (2011). 7. Varela, I. et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542 (2011). 8. The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013). 9. Centers for Disease Control and Prevention. Assisted Reproductive Technology [online], http://www.cdc.gov/ART (2014). 10. Baillargeon, J. et al. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern. Med. 173, 1465–1466 (2013). 11. International Telecommunication Union. The world in 2013: ICT facts and figures [online], http://www.itu.int/en/ITU-D/Statistics/ Documents/facts/ICTFactsFigures2013-e.pdf (2014). 12. Agarwal, A. et al. Effect of cell phone usage on semen analysis in men attending infertility clinic: an observational study. Fertil. Steril. 89, 124–128 (2008).
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13. US Food and Drug Administration. Outpatient Prescription Opioid Utilization in the U. S. Years 2000–2009 [online], http://www.fda.gov/ downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/ AnestheticAndLifeSupportDrugs AdvisoryCommittee/UCM220950.pdf (2014). 14. Fronczak, C. M., Kim, E. D. & Barqawi, A. B. The insults of illicit drug use on male fertility. J. Androl. 33, 515–528 (2012). 15. Barazani, Y. et al. Lifestyle, environment, and reproductive health. Urol. Clin. N. Am. 41, 55–66 (2013). 16. Moyer, V. A. U.S. Preventive Services Task Force Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann. Intern. Med. 157, 120–134 (2012). 17. Barry, M. J., Gallagher, P. M., Skinner, J. S. & Fowler, F. J. Jr. Adverse effects of roboticassisted laparoscopic versus open radical retropubic prostatectomy among a nationwide sample of Medicare-age men. J. Clin. Oncol. 30, 513–513 (2012). 18. Tewari, A. et al. Positive surgical margin and perioperative complication rates of primary surgical treatments for prostate cancer: a systematic review and meta-analysis comparing retropubic, laparoscopic, and robotic prostatectomy. Eur. Urol. 62, 1–15 (2012). 19. Gandaglia, G. et al. Comparative effectiveness of robot-assisted and open radical prostatectomy in the postdissemination era. J. Clin. Oncol. 32, 1419–1426 (2014). 20. Tannock, I. F. et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N. Engl. J. Med. 351, 1502–1512 (2004). 21. de Bono, J. S. et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castrationresistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 376, 1147–1154 (2010). 22. Attard, G. et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J. Clin. Oncol. 27, 3742–3748 (2008). 23. Scher, H. I. et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl. J. Med. 367, 1187–1197 (2012). 24. Parker, C. et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N. Engl. J. Med. 369, 213–223 (2013). 25. Stenzl, A. et al. Treatment of muscle-invasive and metastatic bladder cancer: update of the EAU guidelines. Eur. Urol. 59, 1009–1018 (2011). Acknowledgements H.N. would like to thank Doron Stember for his assistance with his contribution to this article.
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VIEWPOINT
Looking forward, looking back—10 years in urology Maarten Albersen, Rufus Cartwright, Peter Choyke, S. Larry Goldenberg, Howard Goldman, Nathan Lawrentschuk, W. Marston Linehan, Declan Murphy, Harris Nagler, Peter Scardino, Linda Shortliffe, Arnulf Stenzl and Dan Theodorescu Abstract | When Nature Reviews Urology launched in 2004, the field of urology was vastly different to that which we work in today, and the past 10 years have seen the field change immensely. As a specialty on the forefront of cutting-edge innovation, urologists are often the first to embrace new technologies and ideas. In this Viewpoint, members of the Nature Reviews Urology advisory board were asked what they thought was the most important change, issue or innovation in urology in the past 10 years, and what they expected to be the most important in the next decade. Here are their opinions. Albersen, M. et al. Nat. Rev. Urol. 11, 649–655 (2014); published online 28 October 2014; doi:10.1038/nrurol.2014.263
Maarten Albersen University Hospitals Leuven, Belgium
For me personally, erectile dysfunction (ED) following radical prostatectomy has been a focus of interest and research during the past 10 years. In spite of the hype surround ing nerve-sparing techniques (both robotassisted and retropubic), we are still faced with high numbers of patients who are affected by this complication. In the past 10 years, clinical research efforts have been focussed on reducing nerve-injury-induced cavernosal fibrosis, while basic scientists have seen a surge in regenerative medicine techniques, such as stem-cell treatment, aimed at improving nerve recovery and Competing interests
H.G. declares that he is a member of the speakers’ bureau for Allergan, Medtronic and Uroplasty, and that he has acted as a consultant for Allergan, Astellas, Medtronic and Uroplasty. P.S. declares that he is a scientific advisor to OPKO Diagnostics, who are developing a commercial assay for the 4KScore®developed at Memorial Sloan–Kettering. A.S. declares that has acted as a consultant for Alere, and as a speaker and consultant for Ipsen and Janssen. His institution receives research grants from Amgen, Immatics Biotechnologies GmbH, Karl Storz and Novartis, and is involved in clinical studies with Bayer, CureVac, Immatics Biotechnologies GmbH and Johnson & Johnson. The other authors declare no competing interests.
regeneration after injury. 10 years ago, in 2004, the first stem-cell study successfully targeting cavernous-nerve-injury-induced ED in rats was conducted by Bochinski et al.1 at UCSF. 10 years later, several clinical trials are running to investigate this therapy in human patients, and the first abstract on a phase I trial investigating safety of stemcell injection in prostate cancer patients was presented at the EAU 2014 by Rene Yiou from France.2 However, several large-scale trials—such the PIVOT trial3 and the PRIAS project4—carried out during the past decade have also made us more aware of the fact that a large proportion of patients with organconfined prostate cancer, in whom nervesparing surgery would be an oncologically safe option, do not always need surgery immediately and we can, therefore, spare our patients the adverse effects of surgery by adopting an active surveillance strategy. One of the biggest changes we might see over the next 10 years in this field is based on these recent trials, with the outcome that we might be doing fewer prostatectomies for organ-confined tumours. This change in approach will be in favour of active surveillance strategies and emerging local ized therapies, which target the tumour rather than the whole organ and are, there fore, associated with smaller risks in terms of complications such as incontinence and ED (in the case of prostate cancer). In those
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patients who will be surgically treated for prostate cancer, I personally believe we will see a shift towards the selection of patients with locally advanced tumours, in which the role of surgery is becoming more and more apparent. As nerve sparing will then become even more challenging, and as we have seen generally disappointing results with the use of oral therapies for penile rehabilitation, we will need to further develop more potential regenerative therapies for nerve recovery and regeneration in the near future. The results of the first stem-cell trials are eagerly awaited and might bring hope to patients suffering from postprostatectomy ED in the coming decade.
Rufus Cartwright Imperial College London, UK
Evidence-based medicine has recently been under attack as promoting a ‘one size fits all’ approach to investigation and treatment. Some would also argue that truly systematic approaches to evidence synthesis have yet to be applied to guidance from the major uro logical societies. But, despite these concerns, the rise of evidence-based medicine over the past decade and the availability of evidencebased guidelines have transformed the working practices of urologists. Although practice variation remains rife, at least uro logists now have somewhere to turn for a best estimate of an effect size, and a con sensus view about any treatment options. The easy availability of evidence summaries has not only helped urologists navigate an impossibly expanded literature, but also revolutionized patient‑led decision making. Genetics has been being claimed as “the next big thing” in all medical fields for at least the past 25 years. Although the fruits of the Human Genome Project have been slow to translate to practice, over the past decade (the so-called GWAS era), new discoveries in urological genetic epidemiology have multiplied exponentially, spreading steadily from urological oncology right across the field. Aspects of the genetic architecture of most common urological conditions have now been established. Over the next 10 years huge resources will be spent to under stand the functional consequences of new VOLUME 11 | NOVEMBER 2014 | 649
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PERSPECTIVES The contributors* Maarten Albersen Maarten Albersen is a senior resident in urology and postdoctoral research fellow in the Department of Urology at the University Hospitals Leuven, Belgium. He obtained his MD in 2006 from Leuven University and afterwards enrolled in residency in surgery and urology. In 2012 he completed his PhD training, based on stem-cell work done in Leuven and at the University of California, San Francisco. His research focuses on regenerative treatment options for sexual dysfunctions and pathophysiological mechanisms of erectile dysfunction and Peyronie’s disease. He is the chair of the scientific committee of the European Society for Sexual Medicine, advisory board member for Nature Reviews Urology and assistant editor for the Journal of Sexual Medicine. Rufus Cartwright Rufus Cartwright is a UK Medical Research Council-funded research fellow who is working on the genetic epidemiology of incontinence and prolapse at Imperial College London, UK. He completed his MD(res) degree at King’s College London, on the assessment of overactive bladder symptoms. He is the chair of the International Urogynecological Association Fellows Committee, and trainee editor for urogynaecology at BJOG: An International Journal of Obstetrics & Gynaecology. Peter Choyke Peter L. Choyke is the Chief of the Molecular Imaging Program of the National Cancer Institute, Bethesda, MD, USA. Dr Choyke graduated from Jefferson Medical College in Philadelphia, and received training in Diagnostic Radiology at Yale University and the University of Pennsylvania. His research is focused on imaging of genitourinary malignancies and targeted imaging probes, and developing novel molecular imaging agents for cancer. S. Larry Goldenberg Larry Goldenberg received his medical degree from the University of Toronto and became a Fellow of the Royal College of Surgeons in 1984. He is currently the Stephen A. Jarislowski Professor of Urologic Sciences at UBC and the Mohammed Mohseni Chair in Men’s Health. He is the founding Executive Director of the Vancouver Prostate Centre. In 2009 he created the Men’s Health Initiative of BC and in 2014 he founded and became Chairman of the Canadian Men’s Health Foundation. He has been recognized for his contributions to Canadian health care by being inducted into the Order of British Columbia and the Order of Canada. Howard Goldman Howard B. Goldman is a Professor of Surgery (Urology) at the Cleveland Clinic Lerner College
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of Medicine, Cleveland, OH, USA, and part of the Center for Female Pelvic Medicine and Reconstructive Surgery within the Glickman Urologic and Kidney Institute. He is also the Director of Quality and Patient Safety within the Institute. He is a well-known lecturer and researcher in the areas of incontinence, prolapse, and neuromodulation with a specific interest in cost-effective care. He currently serves as an assistant editor for the Journal of Urology and on the editorial boards of several other journals, including Nature Reviews Urology.
Nathan Lawrentschuk Nathan Lawrentschuk is a urological surgeon and urologic oncologist at the University of Melbourne Department of Surgery and Ludwig Institute for Cancer Research at the Austin Hospital, Melbourne, Australia. He has published over 170 peer-reviewed publications and book chapters and presented at multiple international meetings. He completed a PhD in kidney cancer research and later a Society of Urologic Oncology Fellowship, which involved additional training in robotic, laparoscopic and open cancer surgery at the University of Toronto, Canada. His interests range from Greenlight laser prostatectomy for BPH through to cystectomies with neobladders and penile preservation surgery. W. Marston Linehan W. Marston Linehan, MD received his internship, residency and fellowship training Duke University Medical Center. He began his career at the National Cancer Institute in 1982, where he is currently Urologist-inCharge and Chief of the Urologic Oncology Branch, National Cancer Institute. He has had a long standing interest in identification of the genetic basis of cancer of the kidney. By studying patients and families with kidney cancer, he and his colleagues identified the VHL gene (von Hippel-Lindau and clear cell renal carcinoma), the gene for Hereditary Papillary Renal Carcinoma (MET oncogene) the FLCN gene (Birt Hogg Dubé syndrome), the gene for TFE3 kidney cancer and described the germline fumarate hydratase and succinate dehydrogenase B/C/D mutations in North American families with hereditary leiomyomatosis renal cell carcinoma (HLRCC) and SDH-RCC. He and his colleagues have also defined the methods for clinical management these hereditary forms of kidney cancer. Declan Murphy Declan G. Murphy is urologic oncologist & Director of Robotic Surgery at the Peter MacCallum Cancer Centre, Head of Uro‑Oncology at the Royal Melbourne Hospital and Honorary Clinical Associate Professor at the University of Melbourne, Australia. He has previously been consultant urological surgeon at Guys & St Thomas’ NHS Foundation Trust
in London where he underwent his specialist urology training. He has published extensively in the field of minimally-invasive urology, and is a consulting editor at European Urology and Director of the Melbourne Uro-Oncology Training Programme. His other interests include multimedia surgical education and social media in health care.
Harris Nagler Harris M. Nagler is Physician-in-Chief at Mount Sinai Beth Israel Medical Center NY, USA, where he is also Chair of the Sol and Margaret Berger Department of Urology. Prof. Nagler is also Senior Associate Dean for Clinical Affairs and Professor of Urology at the Icahn School of Medicine at Mount Sinai. His clinical practice focuses on male infertility, impotence and general urology. Peter Scardino Peter T. Scardino is Chair of the Department of Surgery and Head of the Prostate Cancer Programme at Memorial Sloan–Kettering Cancer Center, NY, USA. He served as Editorin-Chief of Nature Clinical Practice Urology from its launch in 2004, until its rebrand as Nature Reviews Urology in 2009. Linda Shortliffe Linda Shortliffe earned her medical degree at Stanford University in Palo Alto. She is currently the Stanley McCormick Memorial Professor, past Chair of the Department of Urology at Stanford University and past Chief of Paediatric Urology at Lucile Packard Children’s Hospital. Arnulf Stenzl Arnulf Stenzl is Director of the Department of Urology, University of Tübingen Medical School, Germany. He has authored or co-authored more than 300 publications and scientific papers in peer-reviewed journals, and is a member of numerous public and privately initiated steering committees and advisory boards on a variety of urological topics. He has been the chairman of the Scientific Congress Office of the European Association of Urology since 2012. Dan Theodorescu Dan Theodorescu is Director of the University of Colorado Comprehensive Cancer Center and Professor of Urology and Pharmacology. He has focussed his career on translational bladder cancer biology, using computational biology to discover genes that drive this and other cancers, while providing novel biomarkers and therapeutic targets that serve as the foundation for personalized therapeutic approaches currently tested in clinical trials. His experience as a practising surgeon provides him with insights that help direct his research to make the most impact on human health. *The contributors are listed in alphabetical order.
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FOCUS ON 10 TH ANNIVERSARY susceptibility genes. At last we should finally see the clinical benefits of these studies, including the introduction of reliable bio markers, effective screening strategies, tar geted prevention efforts, and hopefully a wide range of stratified approaches to both surgery and pharmacotherapy.
Peter Choyke National Institutes of Health, USA
10 years ago the field began to realize that overtreatment of prostate cancer was a burgeoning problem, owing to a combina tion of PSA screening and random biopsies that detected inconsequential low-grade tumours and missed high-grade tumours outside the usual template. Investigators around the world began to use MRI to detect cancers, rather than just for staging. Realizing that detection by imaging was not sufficient, a number of solutions for image-guided biopsies—including in gantry MRI biopsies and MRI–ultrasonography fusion biopsies—were invented. These tech niques have now entered the marketplace and have become a widely available techno logy that is revolutionizing the way pros tate cancer is detected. These advances in image-based detection should increase the confidence with which men are placed on active surveillance protocols and increase the detection of aggressive tumours that are missed by random biopsies. Determining which patients should be treated and how intense the treatment should be for prostate cancer based on genomic data obtained from image-guided biopsies will be a big issue over the next decade in urology. Currently, the biopsy sample is evaluated using the Gleason grading system, and although this is an important prognostic biomarker, it must be acknowledged that it is almost 50 years old, and new and cost-effective genomic technologies are emerging. However, which genes of the 20,000 or so are important? The ability to accurately prognosticate a specific prostate cancer will depend on obtain ing a good sample of the tumour from an image-guided biopsy and a genomic profile looking for driver mutations that indicate a more aggressive biology. Because prostate cancer is generally slow growing, it will take some time to identify which mutations are associated with bad outcomes; determining which mutations portend a poor outcome will be a major issue in urology over the next 10 years.
S. Larry Goldenberg University of British Columbia, Canada
Over the course of the past 10 years we have continued to witness a distancing from the Halstedian approach to cancer surgery of large ‘slashes’ (“bigger cut, bigger surgeon”) to a world awash in very minimally invasive approaches (LESS) and active surveillance of lesions in the prostate, kidney, penis and bladder. With what might still be consid ered quite primitive tools for predicting tumour biology, we have convinced many patients not to rush into aggressive thera pies with the promise of decreased morbid ity and preserved quality of life. Our need to improve our diagnostic and prognostic tools has stimulated the global expansion of biobanking, research into diagnostic blood and urine biomarkers, imaging tools, and genomics.
‘‘
10 years ago, in 2004, the first stem-cell study successfully targeting cavernous-nerveinjury-induced ED in rats was conducted…
’’
While much of urology has focused on ‘technopoly science’ over the past decade, the future will witness the resurgence of the urologic surgeon–scientist striving towards a better understanding of tumour biology. In parallel to seeking better tech nical methods of performing an existing therapeutic procedure (illustrated by the rise of robotics and image-guided thera pies), I believe that we will fine-tune our ‘smart screening’ approaches and use of chemopreventive options in betterdefined, high-risk populations, and we will find better and more targeted or precision therapeutic procedures based on ‘big data’, ‘omics’ science, and molecular imaging (MRI, PET scanning). All of our scien tific progress will be facilitated by global partners hips. Our digital world will see further exciting fusions of engineering, science, and medicine. One example will be the application of machine-l earning methodologies to the development of automated and more accurate interpreta tion of digitized imaging and pathology. This development will enrich the infor mation that can be gleaned from digital information that is beyond the human eye to perceive. Above all, we will adopt a
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‘humanomics’ approach to medicine with patients and families participating more and more in their health-care decisions, an increase in patient-originated research ideas, ethical population-based attention to ‘value in medicine’ issues, and to new directions in informatics.
Howard Goldman Cleveland Clinic, USA
Although much has changed within the subspecialty of female urology in the past decade, controversies continue about specific issues, and further improvements should be expected in the coming years. The debate about synthetic transvaginal prolapse mesh has generated significant medicolegal activity in many countries, and its use has declined in certain locales. Unfortunately, although the use of widepore polypropylene mesh as midurethral sling material has been endorsed by many reputable societies, the controversy regarding the transvaginal prolapse mesh has spilled over and in some places placed the use of synthetic midurethral slings in jeopardy. Over the next few years these concerns should settle down, as synthetic slings have clearly been recognized as safe and effective. Despite this, the search for non-meshbased alternatives for the treatment of stress urinary incontinence continues. Exciting research using autologous muscle cells to help repair the female periurethral muscles has been reported. Furthermore, stem cells and their secretome products have been demonstrated to help repair childbirthrelated pelvic-floor injuries in animal models. The hope that proteins produced by stem cells could somehow help prevent pelvic floor injury after vaginal delivery and thus prevent pelvic floor disorders is actively being researched and holds the promise of a complete paradigm shift in the management of these patients.
Nathan Lawrentschuk University of Melbourne, Australia
Nature Reviews Urology has become a journal that many people in the field of urology enjoy reading. The simple reason is that it has been able to focus on relevant topics time and again, meaning that it is well read and cited appropriately, with thoughtful selection of authors by the VOLUME 11 | NOVEMBER 2014 | 651
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PERSPECTIVES
‘‘
The next decade will see kidney cancer move towards becoming fundamentally a nonsurgical disease, with the development of therapies targeting specific kidney‑cancer‑gene pathways…
It’s a SCREAM! Edvard Munchs masterpiece is stolen from the Munch Museumin Norway
Lifestyle guru found guilty of lying about a suspicious sale of shares in the drug company ImClone
’’
NEWS
November 2004
NATURE PUBLISHING GROUP LAUNCHES CLINICAL UROLOGY REVIEWS JOURNAL November 2004, London NPG has launched a Urology journal, as part of the clinical expansion of its Reviews titles. Publishing high-quality, commissioned Reviews, opinion pieces, News & Views and in-house Research Highlights, the journal will be published monthly and is proud to announce Peter Scardino as launch Editor-In Chief.
Top 10 articles
from 2004 in NCPU 1 Mechanisms of disease: central nervous system involvement in overactive bladder syndrome Karl-Erik Andersson
2 Technology insight: novel ureteral stent materials and designs Ben H. Chew & John D. Denstedt 3 New theories in interstitial cystitis Toby C. Chai & Susan Keay
ENTERTAINMENT NEWS Double Dubya! Number 1 songs in the UK in George W. Bush elected for a November 2004 included second term ‘Just Lose It’ by Eminem, in office ‘I’ll Stand By You’ by Girls Aloud, and ‘Vertigo’ by U2; in the USA, Usher and Alicia Keys spent 6 weeks at number 1 over November 2004 with ‘My Boo’, which is, disappointingly, not about bladder outlet obstruction
Films released in November 2004 include Disney’s ‘The Incredibles’, ‘The Polar Express’, and urology-themed biopic ‘Kinsey’, featuring Liam Neeson as the famous sexologist
4 Diagnosis and management of patients with overactive bladder syndrome and abnormal detrusor activity Michelle Jo Semins & Michael B. Chancellor
5 The value of radiotherapy in treating recurrent prostate cancer after radical prostatectomy Andrew J. Stephenson & Kevin M. Slawin
6 Treatment of chronic prostatitis Richard B. Alexander
7 Surgical intervention in patients with metastatic renal cancer: current status of metastasectomy and cytoreductive nephrectomy Paul Russo
8 Current views on evaluation, management, and gender assignment of the intersex infant Caleb P. Nelson & John P. Gearhart
9 Erectile dysfunction and priapism Derek J. Bochinski, Robert C. Dean & Tom F. Lue
10 Early cystectomy for clinical stage T1 bladder cancer Brent K. Hollenbeck & James E. Montie
editorial staff and strong support from the Advisory Board. Above all, the key to success has been to recognize that the field of urology is moving faster than many others with regards to management and technology. This makes Reviews impor tant but they must be fresh and succinct. At one end of the spectrum we have had a rush towards the use of robotics5 yet at the other, a push for conservatism with active surveillance for low-risk prostate cancer.6 The future holds more change for uro logy, as we are pressured to manage our shrinking health resources—how will we justify our outcomes without high-quality data? Will all of the technologies survive or will they become cheaper as competi tors arise? Will conservatism become even more accepted, leading to less surgery? How will radiation remain relevant to urology? What new technologies will make surgery 652 | NOVEMBER 2014 | VOLUME 11
NPG
more consistent and accurate? What drugs will help us achieve better results? Finally, above all, patient outcomes and individual ized medicine are likely to dominate, and Nature Reviews Urology will be there to document it all and expand its readership to help us comprehend the changes that confront us all.
W. Marston Linehan National Cancer Institute, USA
The past decade has brought both dra matic advances in our understanding of the genetic and biochemical basis of kidney cancer as well as historic changes in therapy for patients with this disease. The development of novel therapeu tic approaches targeting the VHL/HIF pathway led to the approval by the FDA of
seven agents, including sorafenib (2005), sunitinib (2006), temsirolimus (2007), everolimus (2009), bevacizumab plus interferon (2009), pazopanib (2009) and axitinib (2012), which have revolution ized the management of patients with advanced kidney cancer. Although most patients eventually progress and many will die of this disease, the impressive clinical responses seen in up to 45% of patients with advanced kidney cancer provide hope that more effective forms of therapy will be developed in the future. Novel insights into the genetic basis of kidney cancer came with the identification of mutations in chro matin remodeling genes such as PBRM1, BAP1, SETD2 and KDM5C.7,8 The finding of extensive genomic heterogeneity raised new issues about the evolution of clear cell renal cell carcinoma (ccRCC) as well as profound questions about the develop ment of targeted therapeutic approaches for this disease. The next decade will see dramatic changes in the management of kidney cancer. With the widespread availability of high-throughput next-generation sequenc ing, clinical decisions will be driven by genotype instead of histology; biopsy of a small renal tumour with mutation of a gene such as VHL, for example, would lead to management by active surveillance until the tumour reaches a certain size (such as 3 cm), at which time therapy would be recommended. Detection of a small renal mass with, for example, a fumarate hydra tase (FH) gene mutation or a TFE3 fusion translocation, on the other hand, would lead to more immediate management. The next decade will see kidney cancer move towards becoming fundamentally a nonsurgical disease, with the development of therapies targeting specific kidney-cancer-gene path ways, such as VHL, MET, TFE3, TSC, PTEN and FH. The management of localized kidney cancer will change from surgical to systemic therapy and the role of the urologic surgeon will change from recommending surgery to managing genomic analysis and treatment with targeted therapy. www.nature.com/nrurol
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FOCUS ON 10 TH ANNIVERSARY Declan Murphy Peter MacCallum Cancer Centre, Australia
Although I tried hard not to, I could not answer this question without mention ing robotic surgery! In 2004 I was midway through my urology training programme at Guy’s Hospital in London and laparoscopic radical prostatectomy was very much in vogue. We actually installed our first da Vinci© robot at Guy’s that year but I remained very focused on training in conventional laparo scopic radical prostatectomy. We had a view that the robot just added time and cost to this procedure and that it would in time become a white elephant. I had my epiphany during my Fellowship with Professor Tony Costello in Melbourne in 2007, when it became clear to me that the robotic technique was going to prevail. Although there remain unresolved issues about cost and which procedures might be most appropriate for the robot, it has become very clear to me over the past 10 years that robotic prostatectomy is the standardof-care for men who choose to have surgery for localized prostate cancer. I can’t see that changing in the next decade. One of our biggest challenges is to fully embrace multidisciplinary working and sub speciality practice. Urology is a very broad, multi-organ, multi-faceted specialty—there is enough in there for four or five full special ties by anyone else’s standards. I think we need to ensure best outcomes for our patients by managing them in multidisciplinary net works, where patients are managed by those most expert in managing individual condi tions. Another big change I foresee is the way in which we interact with our peers, our patients, and our professional resources. This will change utterly. The sweeping influ ence of social and digital media offers both unprecedented opportunities and consid erable challenges for health professionals. There is no point trying to pretend that the huge communication changes that are sweeping across our society will not impact on the staid world of medicine. I think we must embrace all of these changes in order to not just better serve our patients and realize our professional ambitions, but also to enjoy what we do even more.
Harris Nagler Beth Israel Medical Center, USA
Over the past 10 years the use of assisted reproductive techniques (ART), in particular
in vitro fertilization (IVF), has dramatically increased. Over the same time period, the live birth success rates have nearly doubled. The Centers for Disease Control (CDC) reported that ART resulted in nearly 62,000 babies born in 2012 in the United States, comprising a record 1.5% of all live births.9 As ART has become disseminated, the use of IVF has increasingly been accepted as an almost routine option for many couples. Another important development related to men’s health has been the explosive increase in testosterone replacement ther apy (TRT) for hypogonadism treatment. A recent JAMA study showed that TRT use in men increased from 0.81% to 2.91% from 2001 to 2011. 10 The paper also reported, unfortunately, that nearly 25% of new TRT users had not had serum testosterone levels measured over the prior year. TRT, like any medical intervention, is associated with risks that must be weighed against the highly publicized potential quality of life and clinical health benefits. We believe that it is critical that urologists assess patients with signs and/or symptoms of testosterone deficiency and only treat after appropriate discussion of risks, benefits and alterna tives. If treatment is initiated patients must be appropriately monitored; failure to do the above would be inconsistent with patient safety best practices.
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Exciting research using autologous muscle cells to help repair the female periurethral muscles has been reported
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We live in an ever-changing environment that has the potential to expose individuals to known and unknown agents that could have adverse effects on fertility. By extrapolating current environmental and lifestyle trends in male reproductive health risk factors, we can consider potential challenges and opportuni ties over the next 10 years. One needs only to walk down the street to recognize the penetration of mobile phones into everyday life. The United Nations reported an increase in cell phone accounts from 6 to 7.3 billion over a recent 1-year period;11 radiofrequency electromagnetic radiation from phones has been reported to impact semen analysis parameters.12 This observation has not been confirmed by others, but the widespread use in general and especially in younger boys does raise concern regarding potential impact on reproductive potential. The FDA
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reported opioid prescriptions increased from 174 to 257 million from 2000–2009.13 Although chronic opioid exposure is deleteri ous to spermatogenesis and testosterone con centration,14 recently enacted federal and state regulations and educational programs might stabilize or reverse this trend. On the other hand, other risk factors for impaired male fertility that have significantly declined in the past decade include cigarette smoking, alcohol consumption, and airborne pollutant concentrations15 and, if these patterns hold, they represent good news as they relate to male reproductive potential going forward. Research to further define environmental factors that affect male fertility is needed to help mitigate their effects.
Peter Scardino Memorial Sloan–Kettering Cancer Center, USA
The most significant change in urology over the past 10 years has been the wide spread introduction of a more conservative approach to the management of early-stage prostate cancer, based on the recognition that low-grade (Gleason 6) cancers rarely metastasize and have a long natural history, and that most men, even young men, with Gleason 6 cancers do not need immediate definitive therapy and can be safely observed in an active surveillance programme. This approach was strengthened by the PIVOT randomized trial3 showing no difference in 12-year survival rates between men with low-risk prostate cancer treated with radical prostatectomy versus observation, and was further reinforced by the US Preven tive Services Task Force’s recommendation against PSA screening based on their assess ment that screening could lead to more harm than good.16 Acceptance of the fact that the adverse effects of definitive treatment of lowrisk prostate cancers are not accompanied by a benefit in survival or disease progression has been an important shift in the field. At the same time, robot-assisted radical pros tatectomy failed to improve cancer control or functional outcomes compared with the traditional open procedure, despite the early exaggerated claims. These widely touted benefits have been refuted by properly con ducted multi-institutional and populationbased comparative effectiveness studies.17–19 Robotic techniques offer a new way of per forming prostate cancer surgery, but they involve similar adverse effects on function and no better cancer control, compared with other forms of radical therapy. VOLUME 11 | NOVEMBER 2014 | 653
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PERSPECTIVES The greatest change in the field over the next 10 years will be driven by the avail ability of preoperative and intraoperative molecular imaging of cancers. These new imaging techniques will change cancer surgery from a Halstedian radical approach (remove as much as possible to have the best chance of curing the cancer) to more indi vidualized ‘smart surgery’ directed at the actual extent of cancer present. Preopera tive imaging could substantially improve focal ablation or resection of cancer in the kidney, and could make focal ablation of clinically significant prostate cancer both feasible and effective—approaches that promise substantial reduction in morbid ity and fewer adverse effects on quality of life. Preoperative imaging advances will be driven by improvements in MRI and, even more so, in PET scanning. Intraoperative molecular imaging with optical-labeled probes will alter our approach to lympha denectomy for cancer, allowing us to limit the dissection to involved nodes, greatly simplifying the operation. Optical imaging will help to reduce morbidity by identify ing cancer at the surgical margins, making surgery more effective and enabling us to tailor each procedure to the known extent of the cancer, improving the rate of complete resection and reducing collateral damage to normal structures and deleterious effects on postoperative function and morbidity. Rapid advances in the genomic characteriza tion of cancers will provide more targets for imaging probes to be used before and during surgery. These technological improvements will most likely be more adaptable to robotassisted surgery than to open techniques, which may finally provide a definitive advantage to the robotic approach.
Linda Shortliffe Stanford University Medical Center, USA
When we began using MRI for imaging hydronephrosis in rats in 1992, we made our own rat body coil and defended slow MRI as potentially useful for imaging the urinary tract. Over the past decade, computational technology enabling fast MRI imaging has made MRI the imaging modality of choice for many studies. Examination of delayed radiation effects from the atomic bomb, moreover, has made MRI the modality of choice for complex genitourinary and other evaluations in children and foetuses. The inherent MRI qualities of enhanced tissue and anatomical definition, and ability to 654 | NOVEMBER 2014 | VOLUME 11
measure differential relative renal function and drainage without ionizing radiation, make MRI an important genitourinary imaging tool for clinical management. 3D imaging and anatomical reconstructions resulting from advanced computational capacities in both computed tomography and MRI eliminate much of the ‘differential’ from diagnoses. Over the next decade as imaging techno logy progresses further into cellular and molecular levels, even more of the ‘differ ential’ will be solved and this will allow us to focus upon disease stratification and prognostic factors: further personalization of medicine.
Arnulf Stenzl Eberhard Karls University Tübingen, Germany
Apart from minimization of pelvic and retroperitoneal surgery, the past 10 years have seen exciting new developments of first-line and second-line systemic treat ment in urologic tumours’ big three: pros tate cancer, urothelial cancer and RCC. The taxanes docetaxel and cabazitaxel, the adrenal hormone blocker abiraterone, the androgen-receptor (AR)-blocker enzalu tamide and the α‑emitter alpharadin have completely changed our treatment algor ithm of castration-resistant prostate cancer (CRPC).20–24 A whole range of new drugs targeting kinase inhibitors and inhibiting vascular endothelial growth factors has markedly increased survival rates in meta static RCC. Urothelial cancer—albeit not as dramatically—has seen new substances approved for second-line chemot herapy such as vinflunine.25 This new armamentar ium of systemic drug application has led to some partially unresolved questions not only about timing, sequence and combination of these drugs among each other, but also about their incorporation into treatment strategies involving surgical interventions and radiotherapy. In the future, surgical ablation of tumour(s) must focus on destruction and/or removal of the tumorous region itself instead of the whole tumour-bearing organ. One way to achieve this goal will be functional imaging using new tracers precisely deline ating those malignancies, which should be selectively destroyed. Currently explored is the application of photodynamic sensitizers or nanoparticles into a tumourous region. With external activation using optical or physical radiation, selective destruction of
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The future holds more change for urology, as we are pressured to manage our shrinking health resources…
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tumour with minimal adverse effects on surrounding parenchyma or other struc tures (such as nerves) would be possible. Despite exciting new developments in sys temic treatment over the past decade, cure is still rare in recurrent advanced or meta static prostate, renal cell and urothelial cancer. Immunotherapy—which actually has a long history in treating RCC and bladder cancer—has recently been (re-) explored for metastatic prostate and kidney tumours, either sequentially or in combina tion with chemotherapy. Synergism of the different mode of action of immunotherapy with conventional chemotherapy might add to overall survival and could also create a long-lasting effect exceeding that of chemo therapy, by permanently reducing immune tolerance to tumour cells.
Dan Theodorescu University of Colorado Cancer Center, USA
Urology has always been a technology-rich surgical specialty. From the advent of the first cystoscopes, through resectoscopes, lasers for use in both benign and malig nant diseases to lithotripters and laparo scopy, urologists have sometimes been the pioneers and almost always eager adopt ers of new technology. This technological progress has dramatically accelerated in the past decade with the development of better endoscopic instruments, widespread adop tion of digital imaging technology for both endoscopic and noninvasive patient assess ments and remote servo operated laparo scopic (robotic) surgery. These advances have come together to form a “perfect storm of progress” for our field in the past decade, leading our inexorable march towards minimally invasive treatment of urological disease. For most urological conditions, we are now positioned to treat with minimal morbidity, reduced length of hospital stay (or no stay) and improved convalescence. The field of urology is poised for trans formation in the next decade, facilitated by a culture of early and avid new technology adopters. This tectonic shift will be primar ily driven by the genetic revolution, which has provided us the molecular blueprints of the human host and of many of the diseases www.nature.com/nrurol
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FOCUS ON 10 TH ANNIVERSARY and conditions we treat. In no area is this truer than in cancer, where the elucidation of the driver mutations has led, and will be progressively leading, to more targeted agents that can reduce tumour growth and, in many cases, convert aggressive dis eases that limit survival to chronic diseases that patients can live with rather than die from. This will also lead to a new practical definition of what cancer really is, at least from the lay perspective, and a reduction in the fear and psychological burden that diagnosis will mean to individual patients. The genomic knowledge of pathobiology will also bring with it the ability to predict risk and diagnose diseases early and non invasively. Predicting risk of developing certain diseases years and decades before they are detected, then detecting them non invasively with molecular-based urine or blood tests that can also prognosticate and predict response to therapy, and coupling this with minimally invasive surgical pro cedures when required, will be the next urological revolution. Department of Urology, University Hospitals Leuven, Herestraat 49, Leuven 3000, Belgium (M.A.). Imperial College London, Institute of Reproductive and Developmental Biology, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK (R.C.). The Molecular Imaging Program, NCI, NIH, 10 Center Drive, Building 10, Room B3B69, Bethesda, MD 20892 USA (P.C.). University of British Columbia, Department of Urologic Sciences, Level 6, 2775 Laurel Street, Vancouver, BC V5Z 1M9, Canada (S.L.G.). Glickman Urological and Kidney Institute, The Cleveland Clinic, Q10‑1, 9500 Euclid Avenue, Cleveland, OH 44195, USA (H.G.). University of Melbourne, Department of Surgery and Ludwig Institute for Cancer Research, Austin Hospital, Suite 5, 210 Burgundy Street, Heidelberg, VIC 3084, Australia (N.L.). Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Building 10, CRC Room 1‑5940, Bethesda, MD 20892, USA (W.M.L.). Division of Cancer Surgery, Peter MacCallum Cancer Centre, East Melbourne, VIC 3003, Australia (D.M.). Beth Israel Medical Center, 10 Union Square East, Suite 3A, New York, NY 10003, USA (H.N.).
Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA (P.S.). Department of Urology, S287, 300 Pasteur Drive, Stanford, CA 94305‑5118, USA (L.S.). Department of Urology, University Clinic of Urology, Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany (A.S.). University of Colorado Comprehensive Cancer Center, MS F‑434, 13001 East 17th Place, Aurora, CO 80045, USA (D.T.). Correspondence to: Nature Reviews Urology Editorial Office [email protected] 1.
Bochinski, D. et al. The effect of neural embryonic stem cell therapy in a rat model of cavernosal nerve injury. BJU Int. 94, 904–909 (2004). 2. Yiou, R. et al. Intra-cavernous injection of bone marrow stem cells is well tolerated and improve erectile function in patients with postprostatectomy erectile dysfunction: Preliminary results of a phase I-II clinical trial. Abstract 599. Presented at the 29th Annual EAU Congress (2014). 3. Wilt, T. J. et al. Radical prostatectomy versus observation for localized prostate cancer. N. Engl. J. Med. 367, 203–213 (2012). 4. Bul, M. et al. Active surveillance for low-risk prostate cancer worldwide: the PRIAS study. Eur. Urol. 63, 597–603 (2013). 5. Sridhar, A. N. et al. Image-guided robotic interventions for prostate cancer. Nat. Rev. Urol. 10, 452–462 (2013). 6. Lawrentschuk, N. & Klotz, L. Active surveillance for low-risk prostate cancer: an update. Nat. Rev. Urol. 8, 312–320 (2011). 7. Varela, I. et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542 (2011). 8. The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013). 9. Centers for Disease Control and Prevention. Assisted Reproductive Technology [online], http://www.cdc.gov/ART (2014). 10. Baillargeon, J. et al. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern. Med. 173, 1465–1466 (2013). 11. International Telecommunication Union. The world in 2013: ICT facts and figures [online], http://www.itu.int/en/ITU-D/Statistics/ Documents/facts/ICTFactsFigures2013-e.pdf (2014). 12. Agarwal, A. et al. Effect of cell phone usage on semen analysis in men attending infertility clinic: an observational study. Fertil. Steril. 89, 124–128 (2008).
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13. US Food and Drug Administration. Outpatient Prescription Opioid Utilization in the U. S. Years 2000–2009 [online], http://www.fda.gov/ downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/ AnestheticAndLifeSupportDrugs AdvisoryCommittee/UCM220950.pdf (2014). 14. Fronczak, C. M., Kim, E. D. & Barqawi, A. B. The insults of illicit drug use on male fertility. J. Androl. 33, 515–528 (2012). 15. Barazani, Y. et al. Lifestyle, environment, and reproductive health. Urol. Clin. N. Am. 41, 55–66 (2013). 16. Moyer, V. A. U.S. Preventive Services Task Force Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann. Intern. Med. 157, 120–134 (2012). 17. Barry, M. J., Gallagher, P. M., Skinner, J. S. & Fowler, F. J. Jr. Adverse effects of roboticassisted laparoscopic versus open radical retropubic prostatectomy among a nationwide sample of Medicare-age men. J. Clin. Oncol. 30, 513–513 (2012). 18. Tewari, A. et al. Positive surgical margin and perioperative complication rates of primary surgical treatments for prostate cancer: a systematic review and meta-analysis comparing retropubic, laparoscopic, and robotic prostatectomy. Eur. Urol. 62, 1–15 (2012). 19. Gandaglia, G. et al. Comparative effectiveness of robot-assisted and open radical prostatectomy in the postdissemination era. J. Clin. Oncol. 32, 1419–1426 (2014). 20. Tannock, I. F. et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N. Engl. J. Med. 351, 1502–1512 (2004). 21. de Bono, J. S. et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castrationresistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 376, 1147–1154 (2010). 22. Attard, G. et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J. Clin. Oncol. 27, 3742–3748 (2008). 23. Scher, H. I. et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl. J. Med. 367, 1187–1197 (2012). 24. Parker, C. et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N. Engl. J. Med. 369, 213–223 (2013). 25. Stenzl, A. et al. Treatment of muscle-invasive and metastatic bladder cancer: update of the EAU guidelines. Eur. Urol. 59, 1009–1018 (2011). Acknowledgements H.N. would like to thank Doron Stember for his assistance with his contribution to this article.
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