Showing papers in "Nature Reviews Urology in 2017"

Oxidative stress and male infertility

Abstract: Male infertility accounts for up to half of the infertility cases and affects 13–15% couples worldwide. An optimal level of reactive oxygen species is crucial for maintaining spermatogenesis and sperm functions. However, excessive production of reactive oxygen species may cause oxidative stress. Oxidative stress has been identified as one of the major risk factors which affects the fertilizing potential of spermatozoa. Oxidative stress occurs due to excessive production of ROS and causes germ cell DNA damage, sperm fragility and defects in motility, culminating in infertility. Poor sperm quality and DNA damage may also result in pregnancy loss. This article highlights the significance of ROS in human male fertility and that of oxidative stress in infertility.

WNT signalling in prostate cancer

Abstract: Genome sequencing and gene expression analyses of prostate tumours have highlighted the potential importance of genetic and epigenetic changes observed in WNT signalling pathway components in prostate tumours - particularly in the development of castration-resistant prostate cancer. WNT signalling is also important in the prostate tumour microenvironment, in which WNT proteins secreted by the tumour stroma promote resistance to therapy, and in prostate cancer stem or progenitor cells, in which WNT-β-catenin signals promote self-renewal or expansion. Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of β-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression. Some WNT signalling inhibitors are in phase I trials, but they have yet to be tested in patients with prostate cancer.

Oligometastatic prostate cancer: definitions, clinical outcomes, and treatment considerations

Abstract: The oligometastatic state has been proposed as an intermediate stage of cancer spread between localized disease and widespread metastases. With improvements in diagnostic modalities such as functional imaging, oligometastatic prostate cancer is being diagnosed with greater frequency than ever before. Furthermore, the paradigm for treatment of advanced prostate cancers is shifting toward a more aggressive approach. Many questions surround the understanding of the process and consequences of oligometastasis, meaning that the contemporary literature offers a wide variety of definitions of oligometastatic prostate cancer. Until genomic data exist to provide a biological component to the definition of oligometastatic disease, a clinical diagnosis made on the basis of up to five extrapelvic lesions is reasonable for use. Retrospective studies suggest that interventions such as radical prostatectomy and local or metastasis-directed radiotherapy can be performed in the metastatic setting with minimal risk of toxic effects. These therapies seem to decrease the need for subsequent palliative interventions, but insufficient data are available to draw reliable conclusions regarding their effect on survival. Thus, a protocol for clinicians to manage the patient presenting with oligometastatic prostate cancer would be a useful clinical tool.

Position paper: Rationale for the treatment of Wilms tumour in the UMBRELLA SIOP-RTSG 2016 protocol.

Abstract: The Renal Tumour Study Group of the International Society of Paediatric Oncology (SIOP-RTSG) has developed a new protocol for the diagnosis and treatment of childhood renal tumours, the UMBRELLA SIOP-RTSG 2016 (the UMBRELLA protocol), to continue international collaboration in the treatment of childhood renal tumours. This protocol will support integrated biomarker and imaging research, focussing on assessing the independent prognostic value of genomic changes within the tumour and the volume of the blastemal component that survives preoperative chemotherapy. Treatment guidelines for Wilms tumours in the UMBRELLA protocol include recommendations for localized, metastatic, and bilateral disease, for all age groups, and for relapsed disease. These recommendations have been established by a multidisciplinary panel of leading experts on renal tumours within the SIOP-RTSG. The UMBRELLA protocol should promote international collaboration and research and serve as the SIOP-RTSG best available treatment standard.

New and developing diagnostic technologies for urinary tract infections

Abstract: Timely and accurate identification and determination of the antimicrobial susceptibility of uropathogens is central to the management of UTIs. Urine dipsticks are fast and amenable to point-of-care testing, but do not have adequate diagnostic accuracy or provide microbiological diagnosis. Urine culture with antimicrobial susceptibility testing takes 2-3 days and requires a clinical laboratory. The common use of empirical antibiotics has contributed to the rise of multidrug-resistant organisms, reducing treatment options and increasing costs. In addition to improved antimicrobial stewardship and the development of new antimicrobials, novel diagnostics are needed for timely microbial identification and determination of antimicrobial susceptibilities. New diagnostic platforms, including nucleic acid tests and mass spectrometry, have been approved for clinical use and have improved the speed and accuracy of pathogen identification from primary cultures. Optimization for direct urine testing would reduce the time to diagnosis, yet these technologies do not provide comprehensive information on antimicrobial susceptibility. Emerging technologies including biosensors, microfluidics, and other integrated platforms could improve UTI diagnosis via direct pathogen detection from urine samples, rapid antimicrobial susceptibility testing, and point-of-care testing. Successful development and implementation of these technologies has the potential to usher in an era of precision medicine to improve patient care and public health.

Varicocele and male infertility

Abstract: The link between varicoceles and male infertility has been a matter of debate for more than half a century. Varicocele is considered the most common correctable cause of male infertility, but some men with varicoceles are able to father children, even without intervention. In addition, improvements in semen quality after varicocelectomy do not always result in spontaneous pregnancy. Studies regarding possible pathophysiological mechanisms behind varicocele-induced infertility have tried to address these controversies. Oxidative stress seems to be a central mechanism; however, no single theory is able to explain the differential effect of varicoceles on infertility. As a consequence, careful patient selection for treatment based on couple fertility status, varicocele grade, and semen quality is critical for achieving a chance of a subsequent pregnancy. A substantial amount of data on the effects of varicocelectomy has been gathered, but inadequate study design and considerable heterogeneity of available studies mean that these data are rarely conclusive. Current evidence suggests a beneficial effect of varicocelectomy on semen quality and pregnancy outcomes in couples with documented infertility only if the male partner has a clinically palpable varicocele and affected semen parameters.

Antimicrobial-resistant sexually transmitted infections: gonorrhoea and Mycoplasma genitalium.

Abstract: Gonorrhoea andMycoplasma genitaliuminfections are evolving to be exceedingly difficult to treat or untreatable. Unemo and Jensen provide an overview and discussion of prevalence data, diagnostics, current treatment recommendations and potential future therapies of these infections, highlighting priorities to retain their treatability. The emergence of antimicrobial resistance (AMR) is a major concern worldwide and already compromises treatment effectiveness and control of several bacterial sexually transmitted infections (STIs). Neisseria gonorrhoeae and Mycoplasma genitalium are evolving into so-called superbugs that can become resistant, both in vitro and clinically, to essentially all antimicrobials available for treatment, causing exceedingly difficult-to-treat or untreatable STIs and threatening global public health. Widespread AMR in these bacteria is likely to persist and even worsen in the future, owing to the high number of infections, widespread and uncontrolled use of antimicrobials, limited surveillance of AMR and clinical failures, as well as the extraordinary capacity of these bacteria to develop AMR. This development would not only result in an increased prevalence of N. gonorrhoeae and M. genitalium infections but also in a considerably increasing number of severe complications affecting reproductive health. To combat this threat, clinicians need to be aware of the current guidelines on diagnostic procedures, recommended treatment regimens, as well as therapeutic options for multidrug-resistant bacteria. AMR testing needs to be more frequently performed, inform treatment decisions and elucidate how AMRs compromise treatment effectiveness, guiding research for effective future therapies.

The effect of the USPSTF PSA screening recommendation on prostate cancer incidence patterns in the USA

Abstract: In 2012, the United States Preventive Services Task Force issued a Grade D recommendation for PSA screening — in essence, a recommendation for cessation of prostate cancer screening in all US men. In this Review, the authors discuss the effect of this statement on prostate cancer incidence and dynamics, as well as changes in attitudes to screening of patients and health-care providers in the USA.

Characteristics and Clinical Significance of Histological Variants of Bladder Cancer

Abstract: The clinical relevance of variant histology in urinary bladder cancer has been increasing, resulting in new classifications of urothelial cancers by the WHO in 2016 and highlighting the importance of an accurate morphological description of pathological specimens for the therapeutic management of patients with bladder cancer. In the past 10 years evidence for the clinical relevance of variant histology in urinary bladder cancer has been increasing. This increase has resulted in new classifications of urothelial cancers by the WHO in 2016, highlighting the importance of an accurate morphological description of pathological specimens for the therapeutic management of patients with bladder cancer. The rising awareness of the importance of an accurate pathological report manifests itself in the increasing prevalence of reporting of variant histology in daily practice. Histological variants can generally be divided into urothelial and nonurothelial. Urothelial variants often have similar features that also have specific morphological phenotypes, whereas nonurothelial variants have independent features. Overall, histological variants follow a more aggressive clinical course than conventional urothelial carcinoma, but conclusive data on their effect on survival are currently lacking. The clinical relevance of variant histology can manifest at three different levels: diagnostic, as identification is challenging and misinterpretation is not uncommon; prognostic, for patient risk stratification and outcome estimation; and therapeutic, as particular variants could be responsive to specific treatment strategies. An accurate morphological description of histological variants is necessary for patient consultation and therapy planning. Moreover, the association of variant histology with specific mutation patterns promises to be helpful in discovering targeted therapeutic approaches based on specific molecular pathways.

Microfluidics for sperm analysis and selection

Abstract: Infertility is a growing global health issue with far-reaching socioeconomic implications. A downward trend in male fertility highlights the acute need for affordable and accessible diagnosis and treatment. Assisted reproductive technologies are effective in treating male infertility, but their success rate has plateaued at ∼33% per cycle. Many emerging opportunities exist for microfluidics - a mature technology in other biomedical areas - in male infertility diagnosis and treatment, and promising microfluidic approaches are under investigation for addressing male infertility. Microfluidic approaches can improve our fundamental understanding of sperm motion, and developments in microfluidic devices that use microfabrication and sperm behaviour can aid semen analysis and sperm selection. Many burgeoning possibilities exist for engineers, biologists, and clinicians to improve current practices for infertility diagnosis and treatment. The most promising avenues have the potential to improve medical practice, moving innovations from research laboratories to clinics and patients in the near future.

Semen quality in the 21st century.

Abstract: Although semen quality is an important determinant of fertility, defining clear thresholds for normal ranges has proven difficult. According to 'time to pregnancy' studies, fecundity starts to decline when sperm concentrations fall below 30-55 × 106/ml, whereas the WHO criterion for normal values is currently 15 × 106/ml. Multiple studies over the past 15 years have reported median sperm concentrations of 41-55 × 106/ml in young men (mean age 18-21 years) from the general population, suggesting that many of them have suboptimal semen quality. Sperm numbers remain fairly constant between 19 and 29 years of age, which points to the importance of developmental effects. Discussion on whether population semen quality has declined has continued for decades, as regional differences in trends have been noted. The reasons for poor semen quality and adverse trends are not well established, but some associations suggest a causal relationship, for example, with maternal smoking during pregnancy. The role of chemical exposures leading to endocrine disruption and detrimental reproductive effects has been in the focus of research during the past 20 years. Identification of exposures that affect fertility could provide opportunities for effective prevention of reproductive health problems.

The current evidence on statin use and prostate cancer prevention: are we there yet?

Abstract: An increasing amount of data supports an inverse association between statin use and cancer risk. The findings for prostate cancer, particularly advanced disease, are the most promising of all cancers studied. Use of these agents seems to also be associated with improved prostate- cancer-specific survival, particularly in men undergoing radiotherapy, suggesting usefulness of statins in secondary and tertiary prevention. Some study results might be influenced by increased PSA screening and health-conscious behaviour in statin users but these factors are unlikely to completely account for observed beneficial effects. The epidemiological evidence is supported by preclinical studies that show that statins directly inhibit prostate cancer development and progression in cell-based and animal-based models. The antineoplastic effect of statins might arise from a number of cholesterol-mediated and non-cholesterol-mediated mechanisms that affect pathways essential for cancer formation and progression. Understanding these mechanisms is instrumental in drug discovery research for the development of future prostate cancer therapeutics, as well as in designing clinical trials to test a role for statins in prostate cancer prevention. Currently, sufficient data are lacking to support the use of statins for the primary prevention of prostate cancer and further research is clearly warranted. Secondary and tertiary prevention trials in men who have been diagnosed with prostate cancer might soon be performed.

The evolution of brachytherapy for prostate cancer.

Abstract: Brachytherapy (BT), using low-dose-rate (LDR) permanent seed implantation or high-dose-rate (HDR) temporary source implantation, is an acceptable treatment option for select patients with prostate cancer of any risk group. The benefits of HDR-BT over LDR-BT include the ability to use the same source for other cancers, lower operator dependence, and - typically - fewer acute irritative symptoms. By contrast, the benefits of LDR-BT include more favourable scheduling logistics, lower initial capital equipment costs, no need for a shielded room, completion in a single implant, and more robust data from clinical trials. Prospective reports comparing HDR-BT and LDR-BT to each other or to other treatment options (such as external beam radiotherapy (EBRT) or surgery) suggest similar outcomes. The 5-year freedom from biochemical failure rates for patients with low-risk, intermediate-risk, and high-risk disease are >85%, 69-97%, and 63-80%, respectively. Brachytherapy with EBRT (versus brachytherapy alone) is an appropriate approach in select patients with intermediate-risk and high-risk disease. The 10-year rates of overall survival, distant metastasis, and cancer-specific mortality are >85%, <10%, and <5%, respectively. Grade 3-4 toxicities associated with HDR-BT and LDR-BT are rare, at <4% in most series, and quality of life is improved in patients who receive brachytherapy compared with those who undergo surgery.

Landmarks in the treatment of muscle-invasive bladder cancer.

Abstract: Muscle-invasive bladder cancer is an aggressive disease associated with high morbidity and mortality. Radical cystectomy is the mainstay of treatment and has evolved since the first reported cystectomy in 1887 to include pelvic lymph node dissection and the creation of increasingly sophisticated urinary diversions, such as neobladders and pouches, which enable patients to maintain continence. Pioneering work in the 1970s established the therapeutic activity of cisplatin in patients with bladder cancer and resulted in the introduction of cisplatin-based neoadjuvant chemotherapy, which led to the first improvement in survival outcomes in decades. Other notable advances include the development of bladder-sparing protocols, which combine surgery, chemotherapy, and radiotherapy. Molecular profiling of bladder cancer has helped to enhance our understanding of tumour biology and identify several therapeutic targets, such as programmed death (PD-1) and its ligand programmed cell death ligand 1 (PD-L1). Over the past 3 years, immune checkpoint inhibitors targeting the PD-1-PD-L1 axis have demonstrated the ability to achieve durable objective responses in trials of patients with metastatic disease. If the current momentum continues, immunotherapy is poised to change the landscape of muscle-invasive bladder cancer treatment, promising improved survival outcomes for patients with this disease.

BCG-unresponsive non-muscle-invasive bladder cancer: recommendations from the IBCG.

Abstract: Intravesical immunotherapy with live attenuated BCG remains the standard of care for patients with high-risk and intermediate-risk non-muscle-invasive bladder cancer (NMIBC). Most patients initially respond, but recurrence is frequent and progression to invasive cancer is a concern. No established and effective intravesical therapies are available for patients whose tumours recur after BCG, representing a clinically important unmet need. Development and discovery of treatment options for BCG-unresponsive NMIBC is a high priority in order to decrease the morbidity, burden of health-care expenditures, and mortality related to bladder cancer. This Review of treatment options after BCG failure focuses on principles of optimal management emerging therapies, thus enabling a synthesis of recommendations for management for such patients.

Risk factors for cryptorchidism.

Abstract: Undescended testis - known as cryptorchidism - is one of the most common congenital abnormalities observed in boys, and is one of the few known risk factors for testicular cancer. The key factors that contribute to the occurrence of cryptorchidism remain elusive. Testicular descent is thought to occur during two hormonally-controlled phases in fetal development - between 8-15 weeks (the first phase of decent) and 25-35 weeks gestation (the second phase of descent); the failure of a testis to descend permanently is probably caused by disruptions to one or both of these phases, but the causes and mechanisms of such disruptions are still unclear. A broad range of putative risk factors have been evaluated in relation to the development of cryptorchidism but their plausibility is still in question. Consistent evidence of an association with cryptorchidism exists for only a few factors, and in those cases in which evidence seems unequivocal the factor is likely to be a surrogate for the true causal exposure. The relative importance of each risk factor could vary considerably between mother-son pairs depending on an array of genetic, maternal, placental and fetal factors - all of which could vary between regions. Thus, the role of causative factors in aetiology of cryptorchidism requires further research.

Radiotherapy for renal cell carcinoma: Renaissance of an overlooked approach

Abstract: Conventional radiotherapy previously had a limited role in the definitive treatment of renal cell carcinoma (RCC), owing to the disappointing outcomes of several trials and the perceived radioresistance of this type of cancer. In this context, radiotherapy has been relegated largely to the palliation of symptoms in patients with metastatic disease, with variable rates of response. Following the availability of newer technologies that enable safe delivery of high-dose radiotherapy, stereotactic ablative radiotherapy (SABR) has become increasingly used in patients with RCC. Preclinical evidence demonstrates that RCC cells are sensitive to ablative doses of radiotherapy (≥8-10 Gy). Trials in the setting of intracranial and extracranial oligometastases, as well as primary RCC, have demonstrated excellent tumour control using this approach. Additionally, an awareness of the capacity of high-dose radiation to stimulate antitumour immunity has resulted in novel combinations of SABR with immunotherapies. Here we describe the historical application of conventional radiotherapy, the current biological understanding of the effects of radiation, and the clinical evidence supporting the use of ablative radiotherapy in RCC. We also explore emerging opportunities to combine systemic targeted agents or immunotherapies with radiation. Radiotherapy, although once an overlooked approach, is moving towards the forefront of RCC treatment.

The evolving genomic landscape of urothelial carcinoma

Abstract: Large-scale, next-generation sequencing collaborations have identified drivers and vulnerabilities of urothelial carcinoma. In this Review, the authors discuss the mutational landscape of urothelial carcinoma, including specific mutations in pathways and driver genes and describe how the next generation of therapies will be based on patient-specific targetable mutations observed in individual tumours.

Telomeres and telomerase in prostate cancer development and therapy

Abstract: Aberrations in telomere biology are among the earliest events in prostate cancer tumorigenesis and continue during tumour progression. Substantial telomere shortening occurs in prostate cancer cells and high-grade prostatic intraepithelial neoplasia. Not all mechanisms of telomere shortening are understood, but oxidative stress from local inflammation might accelerate prostatic telomere loss. Critically short telomeres can drive the accumulation of tumour-promoting genomic alterations; however, continued telomere erosion is unsustainable and must be mitigated to ensure cancer cell survival and unlimited replication potential. Prostate cancers predominantly maintain telomeres by activating telomerase, but alternative mechanisms of telomere extension can occur in metastatic disease. Telomerase activity and telomere length assessment might be useful in prostate cancer diagnosis and prognosis. Telomere shortening in normal stromal cells has been associated with prostate cancer, whereas variable telomere lengths in prostate cancer cells and telomere shortening in cancer-associated stromal cells correlated with lethal disease. Single-agent telomerase-targeted treatments for solid cancers were ineffective in clinical trials but have not been investigated in prostate cancer and might be useful in combination with established regimens. Telomere-directed strategies have not been explored as extensively. Telomere deprotection strategies have the advantage of being effective in both telomerase-dependent and telomerase-independent cancers. Disruption of androgen receptor function in prostate cancer cells results in telomere dysfunction, indicating telomeres and telomerase as potential therapeutic targets in prostate cancer.

Circulating tumour cells as biomarkers of prostate, bladder, and kidney cancer.

Abstract: Circulating tumour cells (CTCs) have been studied as biomarkers of a number of urological cancers, although the data are strongest in prostate cancer. CTCs have potential clinical applications in early cancer detection, disease staging, monitoring for recurrence, prognostication, and therapy selection, and might help identify which patients are most likely to respond to androgen-pathway targeted therapies for prostate cancer. In this Review, Gorin and colleagues consider the evidence for a role of CTCs in prostate, bladder, and kidney cancer, and discuss their potential clinical applications. Circulating tumour cells (CTCs) have been studied as biomarkers of a number of solid malignancies. Potential clinical applications for CTC analysis include early cancer detection, disease staging, monitoring for recurrence, prognostication, and to aid in the selection of therapy. In the field of urologic oncology, CTCs have been most widely studied as prognostic biomarkers of castration-resistant prostate cancer. Additionally, emerging data support a role for CTCs to help identify which patients are most likely to respond to novel androgen-pathway targeted therapies, such as abiraterone and enzalutamide. CTCs have also been studied as predictive biomarkers of bladder cancer, in particular as a means to identify patients whose disease has been clinically understaged. Less is known regarding CTCs in kidney cancer; this has been attributed to the fact that a minority of renal tumours express EpCAM, the epithelial cell surface protein commonly used by CTC assays for positive cell selection. However, alternative approaches using markers specific for kidney cancer are being explored.

An overview of female-to-male gender-confirming surgery

Abstract: Gender dysphoria is estimated to occur in approximately 25 million people worldwide, and can have severe psychosocial sequelae Medical and surgical gender transition can substantially improve quality-of-life outcomes for individuals with gender dysphoria Individuals seeking to undergo female-to-male (FtM) transition have various surgical options available for gender confirmation, including facial and chest masculinization, body contouring, and genital surgery The World Professional Association for Transgender Health guidelines should be met before the patient undergoes surgery, to ensure that gender-confirming surgery is appropriate and indicated Chest masculinization and metoidioplasty or phalloplasty are the most common procedures pursued, and both generally result in high levels of patient satisfaction Phalloplasty, with a resultant aesthetic and sensate phallus along with implantable prosthetic, can take upwards of a year to accomplish, and is associated with a considerable risk of complications Urethral complications are most frequent, and can be addressed with revision procedures A number of scaffolds, implants, and prostheses are now in development to improve outcomes in FtM patients

The potential of organoids in urological cancer research.

Abstract: Technical advances in the development of organoid systems enable cell lines, primary adult cells, or stem or progenitor cells to develop into diverse, multicellular entities, which can self-renew, self-organize, and differentiate. These 3D organoid cultures have proven to be of value in increasing our understanding of the biology of disease and offer the potential of regenerative and genetic therapies. The successful application of 3D organoids derived from adult tissue into urological cancer research can further our understanding of these diseases and could also provide preclinical cancer models to realize the precision medicine paradigm by therapeutic screening of individual patient samples ex vivo. Kidney organoids derived from induced pluripotent stem cells provide personalized biomarkers, which can be correlated with genetic and clinical information. Organoid models can also improve our comprehension of aspects of particular diseases; for example, in prostate cancer, 3D organoids can aid in the identification of tumour-initiating cells from an epithelial cell lineage. Furthermore, kidney organoid differentiation from human pluripotent stem cells enables gene editing to model disease in kidney tubular epithelial cells. State-of-the-art human organoid cultures have potential as tools in basic and clinical research in renal, bladder, and prostatic diseases.

Functional urological disorders: a sensitized defence response in the bladder-gut-brain axis.

Abstract: Functional urological and gastrointestinal disorders are interrelated and characterized by a chronic course and considerable treatment resistance. Urological disorders associated with a sizeable functional effect include overactive bladder (OAB), interstitial cystitis/bladder pain syndrome (IC/BPS), and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Poor treatment outcomes might be attributable to untreated underlying psychological and psychiatric disorders, as the co-occurrence of functional urological and gastrointestinal disorders with mood and anxiety disorders is common. The hypothetical bladder-gut-brain axis (BGBA) is a useful framework under which this interaction can be studied, suggesting that functional disorders represent a sensitized response to earlier threats such as childhood adversity or previous traumatic events, resulting in perceived emotional and bodily distress - the symptoms of functional disorders. Psychological and physical stress pathways might contribute to such alarm falsification, and neuroticism could be a risk factor for the co-occurrence of functional disorders and affective conditions. Additionally, physical threat - either from external sources or internal sources such as infection - might contribute to alarm falsification by influencing body-brain crosstalk on homeostasis and, therefore, affecting mood, cognition, and behaviour. Multidisciplinary research and an integrated care approach is, therefore, required to further elucidate and remediate functional urological and gastrointestinal polymorphic phenotypes.

The role of GATA2 in lethal prostate cancer aggressiveness

Abstract: The endothelial transcription factor GATA2 has been reported to have a key role in driving prostate cancer aggressiveness. GATA2 overexpression in prostate cancer increases cellular motility and invasiveness, proliferation, tumorigenicity, and resistance to standard therapies. Thus, GATA2 is a highly attractive target for the development of novel treatments against lethal prostate cancer. Advanced prostate cancer is a classic example of the intractability and consequent lethality that characterizes metastatic carcinomas. Novel treatments have improved the survival of men with prostate cancer; however, advanced prostate cancer invariably becomes resistant to these therapies and ultimately progresses to a lethal metastatic stage. Consequently, detailed knowledge of the molecular mechanisms that control prostate cancer cell survival and progression towards this lethal stage of disease will benefit the development of new therapeutics. The transcription factor endothelial transcription factor GATA-2 (GATA2) has been reported to have a key role in driving prostate cancer aggressiveness. In addition to being a pioneer transcription factor that increases androgen receptor (AR) binding and activity, GATA2 regulates a core subset of clinically relevant genes in an AR-independent manner. Functionally, GATA2 overexpression in prostate cancer increases cellular motility and invasiveness, proliferation, tumorigenicity, and resistance to standard therapies. Thus, GATA2 has a multifaceted function in prostate cancer aggressiveness and is a highly attractive target in the development of novel treatments against lethal prostate cancer.

Pathophysiology and management of urinary tract endometriosis

Abstract: Endometriosis predominantly affects the pelvic reproductive organs but can also affect the urinary tract. A number of theories for the pathogenesis of endometriosis have been suggested, but the exact mechanisms remain elusive. Endometriotic lesions can be found on both the ureter and bladder, and the optimal therapeutic approach depends on the extent, depth, and location of these lesions. Medical approaches, including hormonal therapies such as GnRH agonists and oral contraceptives, tend to be a temporary measure, but can be useful in a preoperative setting or if the patient is unsuitable for surgery, and are also useful as a postoperative treatment. If surgical resection is deemed appropriate, laparoscopic management with or without robotic assistance of urological endometriosis is feasible and advisable. Newer techniques, such as nerve-sparing surgery, might help to decrease the risk of urinary complications following resection of deeply infiltrating endometriosis.

Patient-derived xenografts as in vivo models for research in urological malignancies.

Abstract: Lack of appropriate models that recapitulate the complexity and heterogeneity of urological tumours precludes most of the preclinical reagents that target urological tumours from receiving regulatory approval. Patient-derived xenograft (PDX) models are characterized by direct engraftment of patient-derived tumour fragments into immunocompromised mice. PDXs can maintain the original histology, as well as the molecular and genetic characteristics of the source tumour. Thus, PDX models have various advantages over conventional cell-line-derived xenograft (CDX) and other models, which has resulted in an increase in the use of urological tumour PDXs in the analysis of tumour biology and, importantly, for drug development and treatment decisions in personalized medicine. PDX models of urological malignancies have great potential to be used for both basic and clinical research, but limitations exist and need to be overcome. In particular, several agents targeting the immune system have shown promising results in kidney and bladder cancer; however, establishing PDX models in mice with an intact immune system so that an immune response against the tumour is triggered is important to investigate these new therapeutics. Moreover, international collaboration to share PDX models is essential for research concerning fatal urological tumours.

Expert consensus document: Semantics in active surveillance for men with localized prostate cancer — results of a modified Delphi consensus procedure

Abstract: Active surveillance (AS) is broadly described as a management option for men with low-risk prostate cancer, but semantic heterogeneity exists in both the literature and in guidelines. To address this issue, a panel of leading prostate cancer specialists in the field of AS participated in a consensus-forming project using a modified Delphi method to reach international consensus on definitions of terms related to this management option. An iterative three-round sequence of online questionnaires designed to address 61 individual items was completed by each panel member. Consensus was considered to be reached if ≥70% of the experts agreed on a definition. To facilitate a common understanding among all experts involved and resolve potential ambiguities, a face-to-face consensus meeting was held between Delphi survey rounds two and three. Convenience sampling was used to construct the panel of experts. In total, 12 experts from Australia, France, Finland, Italy, the Netherlands, Japan, the UK, Canada and the USA participated. By the end of the Delphi process, formal consensus was achieved for 100% (n = 61) of the terms and a glossary was then developed. Agreement between international experts has been reached on relevant terms and subsequent definitions regarding AS for patients with localized prostate cancer. This standard terminology could support multidisciplinary communication, reduce the extent of variations in clinical practice and optimize clinical decision making.

Contemporary management of patients with penile cancer and lymph node metastasis.

Abstract: Penile cancer is a rare disease that causes considerable physical and psychological patient morbidity, especially at advanced stages. Patients with low-stage nodal metastasis can achieve durable survival with surgery alone, but those with extensive locoregional metastasis have overall low survival. Contemporary management strategies for lymph node involvement in penile cancer aim to minimize the morbidity associated with traditional radical inguinal lymphadenectomy through appropriate risk stratification while optimizing oncological outcomes. Modified (or superficial) inguinal lymph node dissection and dynamic sentinel lymph node biopsy are diagnostic modalities that have been recommended in patients with high-risk primary penile tumours and nonpalpable inguinal lymph nodes. In addition, advances in minimally invasive and robot-assisted lymphadenectomy techniques are being investigated in patients with penile cancer and might further decrease lymphadenectomy-related adverse effects. The management of patients with advanced disease has evolved to include multimodal treatment with systemic chemotherapy before surgical intervention and can include adjuvant chemotherapy after pelvic lymphadenectomy. The role of radiotherapy in the neoadjuvant or adjuvant setting remains largely unclear, owing to a lack of high-level evidence of possible benefits. New targeted therapies have shown efficacy in squamous cell carcinomas of other sites and might also prove effective in patients with penile cancer.

Prevalence and treatment of LUTS in patients with Parkinson disease or multiple system atrophy

Abstract: The lower urinary tract is controlled by complex neural mechanisms not only in the periphery, but also in the central nervous systems (CNS). Thus, patients with a wide variety of neurological diseases often also have lower urinary tract symptoms (LUTS), including those with Parkinson disease (PD) or multiple system atrophy (MSA). LUTS are common comorbidities associated with both of these neurodegenerative diseases and are likely to impair patients' quality of life. The motor symptoms of PD and MSA often seem similar; however, the pathophysiology, and thus the treatment of LUTS differs considerably. Antimuscarinics are the first-line treatment of storage LUTS in patients with PD or MSA; however, care should be taken in the management of these patients, especially in those with MSA owing to the high risk of inefficient voiding, and thus an increased post-void residual volume. Other treatments of PD-related LUTS include α-adrenoceptor antagonists, which improve voiding dysfunction, transurethral resection of the prostate for bladder outlet obstruction owing to prostate enlargement, and neuromodulation and intradetrusor botulinum toxin injections for storage LUTS. However, more conservative treatments, including intermittent catheterization, are required for LUTS in patients with MSA, owing to the high incidence of impaired detrusor contractility and detrusor-sphincter dyssynergia.

Low-intensity shockwave therapy for erectile dysfunction: is the evidence strong enough?

Abstract: Low-intensity extracorporeal shockwave therapy (Li-ESWT) has gained popularity as a noninvasive treatment for erectile dysfunction (ED), with the potential to cure, rather than simply provide symptomatic relief. However, the quality of data regarding this treatment option is variable, and drawing conclusions is a challenge. In this Review, a team of expert authors describe the rationale and potential mechanisms of Li-ESWT for ED and discuss the available evidence for its clinical use.