Targeted prostate biopsy： value of multiparametric magnetic resonance imaging in detection of localized cancer

Prostate cancer is the second most common cancer in men, with 1.1 million new cases worldwide reported by the World Health Organization in one recent year. Transrectal ultrasound （TRUS）-guided biopsy has been used for the diagnosis of prostate cancer for over 2 decades, but the technique is usually blind to cancer location. Moreover, the false negative rate of TRUS biopsy has been reported to be as high as 47%. Multiparametric magnetic resonance imaging （mp-MRI） includes T1- and T2-weighted imaging as well as dynamic contrast-enhanced （DCE） and diffusion-weighted imaging （DWI）. mp-MRI is a major advance in the imaging of prostate cancer, enabling targeted biopsy of suspicious lesions. Evolving targeted biopsy techniquesmincluding direct in-bore biopsy, cognitive fusion and software-based MRI-ultrasound （MRI-US） fusion--have led to a several-fold improvement in cancer detection compared to the earlier method. Importantly, the detection of clinically significant cancers has been greatly facilitated by targeting, compared to systematic biopsy alone. Targeted biopsy via MRI-US fusion may dramatically alter the way prostate cancer is diagnosed and managed.

Emerging neuromodulatory molecules for the treatment of neurogenic erectile dysfunction caused by cavernous nerve injury

Advances in the neurobiology of growth factors, neural development, and prevention of cell death have resulted in a heightened clinical interest for the development of protective and regenerative neuromodulatory strategies for the cavernous nerves （CNs）, as therapies for prostate cancer and other pelvic malignancies often result in neuronal damage and debilitating loss of sexual function. Nitric oxide released from the axonal end plates of these nerves within the corpora cavernosa causes relaxation of smooth muscle, initiating the haemodynamic changes of penile erection as well as contributing to maintained tumescence; the loss of CN function is primarily responsible for the development of erectile dysfunction （ED） after pelvic surgery and serves as the primary target for potential neuroprotective or regenerative strategies. Evidence from pre-clinical studies for select neuromodulatory approaches is reviewed, including neurotrophins, glial cell line-derived neurotrophic factors （GDNF）, bone morphogenic proteins, immunophilin ligands, erythropoetin （EPO）, and stem cells.

Kavalactone yangonin induces autophagy and sensitizes bladder cancer cells to flavokawain A and docetaxel via inhibition of the mTOR pathway

Consumption of kava(Piper methysticum Forst) has been linked to reduced cancer risk in the South Pacific Islands.Kavalactones are major bioactive components in kava root extracts, which have recently demonstrated anti-cancer activities. However, molecular mechanisms of kavalactones' anti-cancer action remain largely unknown. We have identified two kavalactones, yangonin and 5' 6'-dehydrokawain, as potent inducers of autophagic cell death in bladder cancer cells. The effect of yangonin inducing autophagy is associated with increased expression of beclin and ATG5.In addition, yangonin increases the expression of LKB1 and decreases the phosphorylation of Akt, PRAS40, rpS6,p70S6 K and 4E-BP1, leading to increased binding of 4E-BP1 to m7 GTP. The growth inhibitory effects of yangonin were attenuated in TSC1 or LKB1 knockout mouse embryonic fibroblasts, suggesting that TSC1 and LKB1 expression may contribute to optimal growth inhibition by yangonin. Furthermore, yangonin reduces the viability of bladder cancer cell lines derived from different stages of human bladder cancer, and acts synergistically with apoptosis-inducing agents such as docetaxel and flavokawain A. Our results support a novel anti-bladder cancer mechanism by yangonin and further studies are needed to assess the potential use of yangonin for bladder cancer prevention and treatment

Current strategies for targeting the activity of androgen receptor variants

Current therapies for advanced prostate cancer,such as enzalutamide and abiraterone,focus on inhibiting androgen receptor(AR)activity and reducing downstream signaling pathways to inhibit tumor growth.Unfortunately,cancer cells are very adaptable and,over time,these cells develop mechanisms by which they can circumvent therapeutics.One of the many mechanisms that have been discovered is the generation of AR variants.These variants are generated through alternative splicing of the full length AR and often lack the ligand binding domain.This leads to forms of the AR that are constitutively active that continue to promote prostate cancer cell growth even in the absence of ligand.The high prevalence of AR variants and their role in disease progression have prompted a number of studies investigating ways to inhibited AR variant expression and activity.Among these are the antihelminthic drug,niclosamide,which selectively promotes degradation of AR variants over full length AR and re-sensitizes anti-androgen resistant prostate cancer cells to treatment with enzalutamide and abiraterone.Other AR variant targeting mechanisms include interfering with AR variant co-activators and the development of drugs that bind to the DNA or N-terminal AR domains,which are retained in most AR variants.The clinical efficacy of treating prostate cancer by targeting AR variants is under investigation in several clinical trials.In this review,we provide an overview of the most relevant AR variants and discuss current AR variant targeting strategies.

Specific bone region localization of osteolytic versus osteoblastic lesions in a patient-derived xenograft model of bone metastatic prostate cancer

Objective:Bone metastasis occurs in up to 90%of men with advanced prostate cancer and leads to fractures,severe pain and therapy-resistance.Bone metastases induce a spectrum of types of bone lesions which can respond differently to therapy even within individual prostate cancer patients.Thus,the special environment of the bone makes the disease more complicated and incurable.A model in which bone lesions are reproducibly induced that mirrors the complexity seen in patients would be invaluable for pre-clinical testing of novel treatments.The microstructural changes in the femurs of mice implanted with PCSD1,a new patient-derived xenograft from a surgical prostate cancer bone metastasis specimen,were determined.Methods:Quantitative micro-computed tomography(micro-CT)and histological analyses were performed to evaluate the effects of direct injection of PCSD1 cells or media alone(Control)into the right femurs of Rag2
/
gc
/
male mice.Results:Bone lesions formed only in femurs of mice injected with PCSD1 cells.Bone volume(BV)was significantly decreased at the proximal and distal ends of the femurs(p<0.01)whereas BV(p<0.05)and bone shaft diameter(p<0.01)were significantly increased along the femur shaft.Conclusion:PCSD1 cells reproducibly induced bone loss leading to osteolytic lesions at the ends of the femur,and,in contrast,induced aberrant bone formation leading to osteoblastic lesions along the femur shaft.Therefore,the interaction of PCSD1 cells with different bone region-specific microenvironments specified the type of bone lesion.Our approach can be used to determine if different bone regions support more therapy resistant tumor growth,thus,requiring novel treatments.

Comment on the discovery of prostate specific antigen

The discovery of prostate specific antigen(PSA)and the clinical application of the PSA blood test as a diagnostic tool for prostate cancer is an important chapter in the history of urology.Innumerable men have been cured of prostate cancer as a direct result of early detection by the PSA test.

In honor of Dr. Donald S. Coffey-Prostate cancer biology and therapy

This special issue of the Asian Journal of Urology(AJU)is dedicated to Donald S.Coffey,Ph.D.who passed away on Nov.9,2017.Dr.Coffey,professor at Johns Hopkins University,made monumental impacts on the advancement of urological research and the lives of people around him in and out of the urological research community.Dr.Coffey played an essential role in the Society for Basic Urologic Research(SBUR)as a devoted member and former president.We have collected 11 articles written by former students,trainees,fellows and colleagues of Dr.Coffey that cover a wide range of topics considered to be of prime interest to Dr.Coffey,which include the genetics,diagnosis,and treatment of advanced prostate cancer(PCa).

A systematic review of robot-assisted partial nephrectomy outcomes for advanced indications:Large tumors(cT2-T3),solitary kidney,completely endophytic,hilar,recurrent,and multiple renal tumors

Objective:Robot-assisted partial nephrectomy(RAPN)has become widely used for treatment of renal cell carcinoma and it is expanding in the field of complex renal masses.The aim of this systematic review was to analyze outcomes of RAPN for completely endophytic renal masses,large tumors(cT2-T3),renal cell carcinoma in solitary kidney,recurrent tumors,completely endophytic and hilar masses,and simultaneous and multiple tumors.Methods:A comprehensive search in the PubMed,Scopus,Web of Science,and Cochrane Central Register of Controlled Trials databases was performed in December 2022 for English language papers.The primary endpoint was to evaluate the role of RAPN in the setting of each category of complex renal masses considered.The secondary endpoint was to evaluate the surgical and functional outcomes.Results:After screening 1250 records,43 full-text manuscripts were selected,comprising over 8500 patients.Twelve and thirteen studies reported data for endophytic and hilar renal masses,respectively.Five and three studies reported outcomes for cT2-T3 and solitary kidney patients,respectively.Four studies focused on redo-RAPN for recurrent tumors.Two studies investigated simultaneous bilateral renal masses and five reports focused on multiple tumor excision in ipsilateral kidney.Conclusion:Over the past decade,evidence supporting the use of RAPN for the most challenging nephron-sparing surgery indications has continuously grown.Although limitations remain including study design and lack of detailed long-term functional and oncological outcomes,the adoption of RAPN for the included advanced indications is associated with favorable surgical outcomes with good preservation of renal function without compromising the oncological result.Certainly,a higher likelihood of complication might be expected when facing extremely challenging cases.However,none of these indications should be considered per se an exclusion criterion for performing RAPN.Ultimately,a risk-adapted approach should be employed.

Practice patterns and outcomes of equivocal bone scans for patients with castration-resistant prostate cancer: Results from SEARCH

Objective:To review follow-up imaging after equivocal bone scans in men with castration resistant prostate cancer(CRPC)and examine the characteristics of equivocal bone scans that are associated with positive follow-up imaging.Methods:We identified 639 men from five Veterans Affairs Hospitals with a technetium-99m bone scan after CRPC diagnosis,of whom 99(15%)had equivocal scans.Men with equivocal scans were segregated into“high-risk”and“low-risk”subcategories based upon wording in the bone scan report.All follow-up imaging(bone scans,computed tomography[CT],magnetic resonance imaging[MRI],and X-rays)in the 3 months after the equivocal scan were reviewed.Variables were compared between patients with a positive vs.negative follow-up imaging after an equivocal bone scan.Results:Of 99 men with an equivocal bone scan,43(43%)received at least one follow-up imaging test,including 32/82(39%)with low-risk scans and 11/17(65%)with high-risk scans(p=0.052).Of follow-up tests,67%were negative,14%were equivocal,and 19%were positive.Among those who underwent follow-up imaging,3/32(9%)low-risk men had metastases vs.5/11(45%)high-risk men(p=0.015).Conclusion:While 19%of all men who received follow-up imaging had positive follow-up imaging,only 9%of those with a low-risk equivocal bone scan had metastases versus 45%of those with high-risk.These preliminary findings,if confirmed in larger studies,suggest follow-up imaging tests for low-risk equivocal scans can be delayed while high-risk equivocal scans should receive follow-up imaging.

UroPrecision(UP):Turn UPthevolume of precision medicine in urology

More than 100 years ago,urology was recognized as an independent specialty.It is a dynamic and rapidly evolving field that plays a critical role in the diagnosis,treatment,and management of a wide range of urologic disorders.Over the past few decades,a splendid range of diagnostic options and therapeutic strategies in urooncology,endourology,female urology,and andrology has emerged.In particular,the explosion in precision medicine in the field of urology has revolutionized the way urologic malignancies are treated,and has led research and discovery on a new journey.

Percutaneous nephrolithotomy for staghorn calculi: Troubleshooting and managing complications

Staghorn calculi comprise a unique subset of complex kidney stone disease. Percutaneousnephrolithotomy (PCNL) is the gold standard treatment for staghorn stones. Despitecontinuous refinements to the technique and instrumentation of PCNL, these stones remaina troublesome challenge for endourologists and are associated with a higher rate of perioperativecomplications than that for non-staghorn stones. Common and notable intraoperativecomplications include bleeding, renal collecting system injury, injury of visceral organs, pulmonarycomplications, thromboembolic complications, extrarenal stone migration, andmisplacement of the nephrostomy tube. Postoperative complications include infection and urosepsis,bleeding, persistent nephrocutaneous urine leakage, infundibular stenosis, and death.In this review, we report recommendations regarding troubleshooting measures that can beused to identify and characterize these complications. Additionally, we include informationregarding management strategies for complications associated with PCNL for staghorn calculi.

阴茎勃起神经再生模型和机制的研究

探明神经性勃起功能障碍(NED)的分子生物学机制以期对该类疾病进行神经调控干预,是男科学研究的当务之急。本文回顾了急性神经损伤、前列腺癌、糖尿病和帕金森病所致的NED的研究进展。通过利用大鼠阴茎勃起神经的盆腔大神经节(MPG),在体外构建一个三维培养体系来研究各种生长因子和细胞信号通路对神经再生的影响。体外结果表明脑源性神经生长因子(BDNF)通过JAK/STAT信号通路可显著促进NED的恢复,并在体内证实了该效应。因此,通过调控JAK/STAT信号通路来达到神经调控干预措施预防治疗神经性勃起功能障碍成为可能。

脊髓损伤与男性不育(英文)

脊髓损伤 (SCI)通常会对育龄男性造成一定的影响。脊髓受损后的男性大多会在以下方面发生问题 :如勃起和射精功能障碍 ,精子发生受损 ,精子存活力、活率及形态异常 ,泌尿生殖系统感染以及内分泌异常。本文将从病理生理、评价和治疗等方面对脊髓损伤引起的男性不育症进行论述。脊髓损伤可对精浆产生影响并加速精液氧化 ,从而使得SCI男性的精液质量下降。本文还将对用于SCI男性的精子复苏技术和辅助生育技术所取得的进展进行讨论。

Penile prosthesis implantation in Chinese patients wit severe erectile dysfunction： 10-year experience

We retrospectively evaluated the clinical outcome of penile prosthesis implantation （PPI） in Chinese patients with severe erectile dysfunction （SED）. From July 2000 to December 2011, 224 patients （mean age： 35.9±11.8 years, range： 20-75 years） with SED underwent PPI by experienced surgeon according to standard PPI procedure at our centre. A malleable prosthesis （AMS 650） was implanted in 45 cases （20.1%）, and a three-piece inflatable prosthesis （AMS 700 CXM or AMS 700 CXR） was implanted in 179 cases （79.9%）. Surgical outcomes, including postoperative complications, clinical efficacy and couple satisfaction, were evaluated over than 6 months postoperatively using medical record abstraction, IIEF-5, quality of life （QoL） scores, and the patient/partner sexual satisfaction score proposed by Bhojwani etaL Of the 224 patients eligible for the study, 201 subjects （89.7%） completed follow-up. All of patients could perform sexual intercourse post PPI with the mean postoperative IIEF-5 and QoL scores were 20.02±2.32 and 5.28±0.76, respectively, which were significantly improved compared with the preoperative scores （6.29±1.5 and 2.13±0.84, P〈0.01）. Of the 201 men, mechanical malfunction occurred in four cases （2.0%） and three cases were re-implanted new device, and two cases （1.0%） developed a mild curvature of the penis. Scrotal erosion with infection occurred in one case with diabetes mellitus （0.5%） and required complete removal of the implanted AMS 700 CXM. Satisfactory sexual intercourse at least twice per month was reported by 178 men （88.6%）, and overall satisfaction with the PPI surgery was reported by 89.0% of men and 82.5% of partners. Patient satisfaction in the three-piece inflatable prosthesis group was higher than in the malleable prosthesis group （P〈0.05）. Satisfaction, however, between the types of prostheses, did not differ in the partner survey. PPI is a safe and effective treatment option for Chinese patients with SED and experienced surgeon perform PPI according to standard PPI procedure could reduce the postoperative complications of PPI and could improve patient satisfaction ratio and QoL.

Pentoxifylline treatment and penile calcifications in men Nith Peyronie＇s disease

This retrospective cohort study from a single clinical practice enrolled patients with evidence of calcified Peyronie＇s disease （PD） plaques detected on penile ultrasound at the time of initial presentation. The primary objective was to describe the effect of pentoxifylline （PTX） treatment on subtunical calcifications in men with PD. A PD-specific questionnaire was administered and sonographic evaluations were performed at baseline and follow-up visits. Descriptive statistics and X2 analysis were used to characterize the effect of PTX on calcified tunical plaques. In all, 71 men （mean age： 51.9 years） with PD and sonographic evidence of calcification were identified. Of them, 62 of these men were treated with PTX for a mean duration of I year, and nine with vitamin E or no treatment. Improvement or stabilization in calcium burden at follow-up was noted in 57 （91.9%） of men treated with PTX versus four （44,4%） of those not treated with PTX （P〈0.001）. PTX users were much less likely to have a subjective worsening of their clinical condition （25.0% versus 78.3%, P=0.002）. Treatment with PTX appeared to stabilize or reduce calcium content in PD plaques. A randomized controlled trial is warranted to further explore this effect.

Adaptive pathways and emerging strategies overcoming treatment resistance in castration resistant prostate cancer

The therapies available for prostate cancer patients whom progress from hormonesensitive to castration resistant prostate cancer include both systemic drugs,including docetaxel and cabazitaxel,and drugs that inhibit androgen signaling such as enzalutamide and abiraterone.Unfortunately,it is estimated that up to 30%of patients have primary resistance to these treatments and over time even those who initially respond to therapy will eventually develop resistance and their disease will continue to progress regardless of the presence of the drug.Determining the mechanisms involved in the development of resistance to these therapies has been the area of intense study and several adaptive pathways have been uncovered.Androgen receptor(AR)mutations,expression of AR-V7(or other constitutively active androgen receptor variants),intracrine androgen production and overexpression of androgen synthesis enzymes such as Aldo-Keto Reductase Family 1,Member C3(AKR1C3)are among the many mechanisms associated with resistance to anti-androgens.In regards to the taxanes,one of the key contributors to drug resistance is increased drug efflux through ATP Binding Cassette Subfamily B Member 1(ABCB1).Targeting these resistance mechanisms using different strategies has led to various levels of success in overcoming resistance to current therapies.For instance,targeting AR-V7 with niclosamide or AKR1C3 with indomethacin can improve enzalutamide and abiraterone treatment.ABCB1 transport activity can be inhibited by the dietary constituent apigenin and antiandrogens such as bicalutamide which in turn improves response to docetaxel.A more thorough understanding of how drug resistance develops will lead to improved treatment strategies.This review will cover the current knowledge of resistance mechanisms to castration resistant prostate cancer therapies and methods that have been identified which may improve treatment response.

All about Peyronie’s disease

Peyronie’s disease(PD)is an acquired connective tissue disorder of the tunica albuginea of the corpus cavernosum,characterized by excessive fibrosis and plaque formation.PD can result in significant physical and psychological morbidity;as it may prevent intercourse and cause adverse impacts on partner relationships.The exact etiology and pathophysiology remain unclear,and many misconceptions about the disease associations,course and treatment exist.The disease has two distinct stages.The acute stage is characterized by pain,and disease may progress during this stage.Non-surgical managements at this stage aim to alleviate pain and stabilize the disease.Results for non-surgical treatment are often conflicting.The chronic stage occurs 6e12 months later,where pain disappears and the deformity stabilizes.Surgical treatment is reserved for significant deformity or with inability to penetrative intercourse.The choice of the surgical technique depends on the length of the penis,degree of deformity,erectile function,patients’expectations and surgeon’s preference.

Downregulation of serum CXCL4L1 predicts progression and poor prognosis in prostate cancer patients treated by radical prostatectomy

Our previous study found that plate factor-4 variant (CXCL4L1) was downregulated in the serum of patients with prostate cancer (PCa). The aim of the present study was to investigate the prognostic value of CXCL4L1 in PCa. In total, 213 PCa patients treated with radical prostatectomy were enrolled and peripheral blood samples of all patients were collected. Expression of serum CXCL4L1 in patients with different tumor stages and grades were measured by enzyme-linked immunosorbent assay (ELISA). The Kaplan-Meier method was applied to estimate the progression to castration-resistant prostate cancer (CRPC), metastasis, biochemical recurrenee (BCR)-free survival, and overall survival (OS). Prog no stic factors for BCR-free survival and OS were determi ned by univariate and multivariate analyses using the Cox proportional hazards regression model. The expression of CXCL4L1 was significantly lower in PCa patie nts with adva need pathological tumor stage, high-grade Gleason score, and metastasis. Moreover, down regulation of CXCL4L1 not only strongly correlated with aggressive clinicopathological features, but also predicted tumor progress!on and unfavorable outcomes. Finally, multivariate Cox regression analyses identified CXCL4L1 as an independent prognostic factor for both BCR-free survival (hazard ratio [HR]: 2.03, 95% confidence interval [Cl]: 1.26-3.27;P = 0.004) and OS (HR: 2.26, 95% Cl: 1.07-4.79;P= 0.033). In con elusion, our results in dicate that CXCL4L1 might serve as a no vel and promising prog no stic biomarker for patients with PCa and potential therapeutic target in the future.

Risk of complications and urinary incontinence following cytoreductive prostatectomy： a multi-institutional study

Emerging evidence has suggested that cytoreductive prostatectomy （CRP） allows superior oncologic control when compared to current standard of care androgen deprivation therapy alone. However, the safety and benefit of cytoreduction in metastatic prostate cancer （mPCa） has not been proven. Therefore, we evaluated the incidence of complications following CRP in men newly diagnosed with mPCa. A total of 68 patients who underwent CRP from 2006 to 2014 at four tertiary surgical centers were compared to 598 men who underwent radical prostatectomy for clinically localized prostate cancer （PCa）. Urinary incontinence was defined as the use of any pad. CRP had longer operative times （200 min vs 140 min, P 〈 0.0001） and higher estimated blood loss （250 ml vs 125 ml, P 〈 0.0001） compared to the control group. However, both overall （8.82% vs 5.85%） and major complication rates （4.41% vs 2.17%） were comparable between the two groups. Importantly, urinary incontinence rate at 1-year after surgery was significantly higher in the CRP group （57.4% vs 90.8%, P 〈 0.0001）. Univariate logistic analysis showed that the estimated blood loss was the only independent predictor of perioperative complications both in the unadjusted model （OR： 1.18; 95% Ch 1.02-1.37; P= 0.025） and surgery type-adjusted model （OR： 1.17; 95% Ch 1.01-1.36; P= 0.034）. In conclusion, CRP is more challenging than radical prostatectomy and associated with a notably higher incidence of urinary incontinence. Nevertheless, CRP is a technically feasible and safe surgery for selecting PCa patients who present with node-positive or bony metastasis when performed by experienced surgeons. A prospective, multi-institutional clinical trial is currently underway to verify this concept.

A pathophysiology-based approach to the management ot early priapism

Priapism is a rare condition that involves persistent penile erection for greater than 4 h. Distinct variants exist, each with unique characteristics. Ischemic priapism is a painful medical emergency that may occur as a result of veno-occlusion leading to hypoxia and tissue death. Recurrent bouts of ischemic priapism, or stuttering priapism, require treatment for individual attacks as well as long-term prevention. Non-ischemic priapism is associated with trauma and may be managed conservatively. Recent advances into the pathophysiology of priapism have allowed the development of treatment algorithms that specifically target the mechanisms involved. In this review, we outline the basics of smooth muscle contraction and describe how derangement of these pathways results in priapism. A pathophysiological approach to the treatment of priapism is proposed with duration-based algorithms presented to assist in management.