Growth of prostate cancer cells is dependent upon androgen stimulation of the androgen receptor (AR). Dihydrotestosterone (DHT), the most potent androgen, is usually synthesized in the prostate from ...testosterone secreted by the testis. Following chemical or surgical castration, prostate cancers usually shrink owing to testosterone deprivation. However, tumors often recur, forming castration-resistant prostate cancer (CRPC). Here, we show that CRPC sometimes expresses a gain-of-stability mutation that leads to a gain-of-function in 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1), which catalyzes the initial rate-limiting step in conversion of the adrenal-derived steroid dehydroepiandrosterone to DHT. The mutation (N367T) does not affect catalytic function, but it renders the enzyme resistant to ubiquitination and degradation, leading to profound accumulation. Whereas dehydroepiandrosterone conversion to DHT is usually very limited, expression of 367T accelerates this conversion and provides the DHT necessary to activate the AR. We suggest that 3βHSD1 is a valid target for the treatment of CRPC.
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•3βHSD1 catalyzes a rate-limiting step for DHT synthesis in CRPC•Selection for N367T mutant 3βHSD1 occurs in human CRPC tumors•The N367T 3βHSD1 mutation confers resistance to ubiquitination and degradation•Mutant 3βHSD1 protein accumulates, increasing DHT synthesis and causing CRPC
Dihydrotestosterone (DHT), a potent androgen secreted by the testis, promotes the development of prostate cancer. Castration limits tumor growth, but castration-resistant tumors often recur. A gain-of-stability mutation in the enzyme 3βHSD1, an upstream regulator of DHT biosynthesis, drives this resistance and may be a valid therapeutic target.
Male lower urinary tract symptoms, benign prostatic hyperplasia, enlargement of the prostate, and bladder outlet obstruction are common among aging men and will increase in socioeconomic and medical ...importance at a time of increased life expectancy and aging of the baby boomer generation. This article reviews the epidemiology, management, and therapeutic options for these conditions. In patients bothered by moderate to severe symptoms, providers can make educated and differential choices between several classes of drugs, alone or in combination, to treat effectively and improve the symptoms in most men. Despite the efficacy of medical therapy, there will be patients who require referral to a urologist either early, to rule out prostate cancer and other conditions, or later, after initial medical therapy and lifestyle management has failed. Perhaps as many as 30% of patients fail to achieve sufficient symptom improvement with medication, lifestyle adjustment, and fluid management, and may require more invasive or surgical treatment options.
To report 4-year outcomes of the randomized controlled trial of water vapor thermal therapy for treatment of moderate to severe lower urinary tract symptoms due to benign prostatic hyperplasia.
Total ...188 subjects; 135 men ≥50years old, International Prostate Symptom Score ≥ 13, maximum flow rate (Qmax) ≤15 mL/s and prostate volume 30 to 80 cc treated with Rezūm System thermal therapy were followed 4 years; subset of 53 men who requalified for crossover from control to active treatment were followed 3years.
Lower urinary tract symptoms were significantly improved within ≤3 months after thermal therapy and remained consistently durable (International Prostate Symptom Score 47%, quality of life 43%, Qmax 50%, Benign Prostatic Hyperplasia Impact Index 52%) throughout 4years (P <.0001); outcomes were similarly sustained in crossover subjects at 3years. Surgical retreatment rate was 4.4% over 4years. No disturbances in sexual function were reported.
The minimally invasive thermal therapy provides effective symptom relief and improved quality of life that remains durable for over 4years. It is applicable to all prostate zones with procedures performed under local anesthesia in an office setting.
Objectives
To provide an update on novel minimally invasive lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) treatments in a non‐systematic review. To define ...potential target populations for the various new minimally invasive treatments.
Methods
Recent literature, meta‐analyses and guideline recommendations for aquablation (AquaBeam®; PROCEPT BioRobotics, Redwood City, CA, USA), water vapour thermal therapy (Rezūm®; Boston Scientific, Natick, MA, USA), prostate artery embolisation (PAE), prostatic urethral lift (UroLift®; NeoTract‐Teleflex, Pleasanton, CA, USA) and the temporary implantable nitinol device i‐TIND® (nitinol butterfly‐like stent ); Medi‐Tate Ltd., Or‐Akiva, Israel were reviewed.
Results
Procedures that can be performed on an outpatient basis (Rezūm, PAE, UroLift and i‐TIND) are not an alternative for the standard patient requiring BPH surgery. Their effect on urinary flow, post‐void residual urine volume or bladder outlet obstruction is less pronounced than that of transurethral resection of the prostate (TURP). Yet, these options appear to be valuable for those patients unfit for surgery, men who want to avoid medical therapy in general, or those who want to avoid sexual side‐effects associated with medical therapy or standard BPH surgery (e.g. TURP). Aquablation is the first successfully operationalised robotic resection system, especially for patients with prostates >50 g. Nevertheless, long‐term data are necessary for all novel, minimally invasive treatments.
Conclusions
Better designed clinical trials, a clearer definition of target populations and a more realistic marketing allow a better characterisation of novel minimally invasive therapies for LUTS/BPH. It is hoped that some of these novel devices will stand the test of time, in contrast to the vast majority of their predecessors.
Benign prostatic hyperplasia (BPH) represents a significant burden in ageing men due to frequently associated lower urinary tract symptoms (LUTS), which may impair quality of life. BPH is also a ...progressive disease, mainly characterized by a deterioration of LUTS over time, and in some patients by the occurrence of serious outcomes such as acute urinary retention (AUR) and need for BPH‐related surgery. The goals of therapy for BPH are not only to improve bothersome LUTS but also to identify those patients at risk of unfavourable outcomes, to optimize their management.
In selected patients, combination of an α1‐blocker and a 5α‐reductase inhibitor is the most effective form of BPH medical therapy to reduce the risk of clinical progression and relieve LUTS. Monotherapy also significantly reduces the risk of BPH clinical progression, mainly through a reduction of LUTS deterioration for α1‐blockers while 5α‐reductase inhibitors also reduce the risk of AUR and need for BPH‐related surgery.
Enlarged prostate and high serum prostate‐specific antigen levels have been consistently found to be good clinical predictors of AUR and BPH‐related surgery in longitudinal population‐based studies and placebo arms of controlled studies. High post‐void residual urine (PVR) is also associated with an increased risk of LUTS deterioration and should thus be reconsidered in practice as a predictor of BPH progression. Conversely, baseline LUTS severity and low peak flow rate, initially identified as predictors of unfavourable outcomes in community setting, behave paradoxically in controlled trials, probably as a consequence of strict inclusion criteria and subsequent regression to the mean and glass ceiling effects. Lastly, there is increasing evidence that dynamic variables, such as LUTS and PVR worsening, and lack of symptomatic improvement with α1‐blockers are important predictors of future LUTS/BPH‐related events, allowing better identification and management of patients at risk of BPH progression.
Male lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) is common in men and can have negative effects on quality of life (QoL). It is the hope that this Guideline ...becomes a reference on the effective evidence-based surgical management of LUTS/BPH.
The evidence team searched Ovid MEDLINE, the Cochrane Library, and the Agency for Healthcare Research and Quality (AHRQ) database to identify studies indexed between January 2007 and September 2017. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions (table 1 in supplementary unabridged guideline, http://jurology.com/).
This Guideline provides updated, evidence-based recommendations regarding management of LUTS/BPH utilizing surgery and minimally invasive surgical therapies; additional statements are made regarding diagnostic and pre-operative tests. Clinical statements are made in comparison to what is generally accepted as the gold standard (i.e. transurethral resection of the prostate TURP–monopolar and/or bipolar). This guideline is designed to be used in conjunction with the associated treatment algorithm.
The prevalence and the severity of LUTS increases as men age and is an important diagnosis in the healthcare of patients and the welfare of society. This document will undergo additional literature reviews and updating as the knowledge regarding current treatments and future surgical options continues to expand.
To report 3-year outcomes of a prospective, multicenter, randomized, blinded control trial after treatment with convective radiofrequency (RF) water vapor thermal therapy for moderate to severe lower ...urinary tract symptoms due to benign prostatic hyperplasia (BPH).
Fifteen centers enrolled and randomized 197 men ≥50 years old with International Prostate Symptom Score (IPSS) ≥13, maximum flow rate (Qmax) ≤15 mL/s, and prostate volume 30 to 80 cc to thermal therapy with Rezūm System or control (2:1). Rigid cystoscopy with simulated active treatment sound effects served as the control procedure. Convective RF thermal energy was delivered into obstructive prostate tissue including the median lobe as needed. After randomized comparison at 3 months, thermal therapy subjects were followed annually for 3 years.
Convective RF thermal therapy yielded IPSS improvement of 160% compared with control subjects at 3 months (P <.0001). Maximal symptom relief of at least 50% improvement in IPSS, quality of life, Qmax, and BPH Impact Index remained durable throughout 3 years (P <.0001). Subjects with a treated median lobe had similar responses. No late-related adverse events occurred, and no de novo erectile dysfunction was reported. The surgical retreatment rate was 4.4% over 3 years.
The minimally invasive convective RF thermal therapy is an office or ambulatory outpatient procedure with minimal transient perioperative side effects. It provides early effective and durable relief of BPH symptoms with preservation of sexual function in subjects followed up for 3 years and is applicable to treatment of the median lobe and hyperplastic central zone tissue.
What's known on the subject? and What does the study add?
Prostate cancer is the most common malignancy in men. Treatment is costly; the majority of men are treated with radiation or surgery, but ...even watchful waiting strategies are expensive. With increasing life expectancy more men are being diagnosed with prostate cancer, effectively increasing the economic burden of this disease.
This study provides estimates of the cost of prostate cancer for different countries. These estimates could be used to populate models that explore economic costs of treating and preventing prostate cancer. Our review found considerable variation in costs across different countries, which may be due to differences in detection and management practices.
In the present review we discuss expenditure on prostate cancer diagnosis, treatment and follow‐up and evaluate the cost of prostate cancer and its management in different countries. Prostate cancer costs were identified from published data and internet sources. To provide up‐to‐date comparisons, costs were inflated to 2010 levels and the most recent exchange rates were applied. A high proportion of the costs are incurred in the first year after diagnosis; in 2006, this amounted to 106.7–179.0 million euros (€) in the European countries where these data were available (UK, Germany, France, Italy, Spain and the Netherlands). In the USA, the total estimated expenditure on prostate cancer was 9.862 billion US dollars ($) in 2006. The mean annual costs per patient in the USA were $10 612 in the initial phase after diagnosis, $2134 for continuing care and $33 691 in the last year of life. In Canada, hospital and drug expenditure on prostate cancer totalled C$103.1 million in 1998. In Australia, annual costs for prostate cancer care in 1993–1994 were 101.1 million Australian dollars. Variations in costs between countries were attributed to differences in incidence and management practices. Per patient costs depend on cancer stage at diagnosis, survival and choice of treatment. Despite declining mortality rates, costs are expected to rise owing to increased diagnosis, diagnosis at an earlier stage and increased survival. Unless new strategies are devised to increase the efficiency of healthcare provision, the economic burden of prostate cancer will continue to rise.
Lower urinary tract symptoms (LUTS) are highly prevalent among older men and have a negative impact on health-related quality of life. Frequent comorbidity with potential prostatic disease adds ...complexity to the management of male LUTS. In this review, we discuss the pathophysiological conditions that underlie male LUTS, and examine the relationship between symptoms and urodynamic findings. The contribution of bladder dysfunction to male LUTS, with a particular emphasis on overactive bladder (OAB) symptoms, is explored. We also consider pharmacotherapeutic options for male LUTS. Pharmacotherapies that target the prostate (α1-receptor antagonists and 5α-reductase inhibitors) often fail to alleviate OAB symptoms, and may not be the most appropriate therapy for men with storage LUTS. Multiple studies have suggested that antimuscarinic therapy alone or in combination with α1-receptor antagonists improve OAB symptoms in men with and without bladder outlet obstruction. Although these agents may represent appropriate first-line therapies for men with OAB symptoms, the therapeutic potential of antimuscarinics alone or in combination with α1-receptor antagonists in this population should be evaluated in large-scale, well-designed clinical trials.
Purpose Phosphodiesterase type 5 inhibitors are widely used to treat erectile dysfunction. Preliminary data have suggested phosphodiesterase type 5 inhibitor efficacy in men with lower urinary tract ...symptoms associated with clinical benign prostatic hyperplasia. Materials and Methods After a 4-week placebo run-in period 1,058 men with benign prostatic hyperplasia lower urinary tract symptoms were randomly allocated to receive 12-week, once daily treatment with placebo or tadalafil (2.5, 5, 10 or 20 mg). Results The International Prostate Symptom Score least squares mean change from baseline to end point was significantly improved for 2.5 (−3.9, p = 0.015), 5 (−4.9, p <0.001), 10 (−5.2, p <0.001) and 20 mg (−5.2, p <0.001) tadalafil compared to placebo (−2.3). International Prostate Symptom Score improvements at 4, 8 and 12 weeks were significant for all tadalafil doses and they demonstrated a dose-response relationship. Tadalafil (2.5 mg) significantly improved the International Prostate Symptom Score obstructive subscore and the International Index of Erectile Function-Erectile Function domain, the latter in sexually active men with a history of erectile dysfunction. Statistically significant improvements were noted for 5, 10 and 20 mg tadalafil compared to placebo, as assessed by the International Prostate Symptom Score irritative and obstructive subscores, International Prostate Symptom Score Quality of Life, Benign Prostatic Hyperplasia Impact Index (nonsignificant for 10 mg), Global Assessment Question and International Index of Erectile Function-Erectile Function domain. No statistically significant effect of treatment compared to placebo was noted for peak flow at any tadalafil dose. Treatment emergent adverse events were infrequent in all tadalafil groups. Conclusions Once daily tadalafil demonstrated clinically meaningful and statistically significant efficacy and it was well tolerated in men with benign prostatic hyperplasia lower urinary tract symptoms. Of the doses studied 5 mg tadalafil appeared to provide a positive risk-benefit profile.
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