A systematic review of cytoreductive prostatectomy outcomes and complications in oligometastatic disease

Objective: To analyze outcomes and complications of cytoreductive prostatectomy (CRP) for oligometastatic prostate cancer (PCa) in order to elucidate its role in this space.Methods: We performed a systematic literature search using three databases (Medline, Scopus, and Web of Science). The primary endpoints were oncologic outcomes. The secondary endpoints were complication rates and functional results.Results: In all studies, overall survival was better or at least comparable variable in the groups with CRP compared to no local treatment. The greatest benefit from CRP in 5-year overall survival in one study was 67.4% for CRP versus 22.5% for no local treatment. Cancer-specific survival (CSS) showed the same trend. Several authors found significant benefits from CSS in the CRP group: from 79% vs. 46% to 100% vs. 61%. CRP was a predictor of better CSS (hazard ratio 0.264, p=0.004). Positive surgical margin rates differed widely from 28.6% to 100.0%. Urinary continence in CRP versus RP for localized PCa was significantly lower (57.4% vs. 90.8%, p<0.0001). Severe incontinence occurred seldom (2.5%-18.6%). Total complication rates after CRP differed widely, from 7.0% to 43.6%. Rates of grades 1 and 2 events prevailed. Patients on ADT alone also showed a considerable number of complications varying from 5.9% to 57.7%.Conclusion: CRP improves medium-term cancer control in patients with oligometastatic PCa. The morbidity and complication rates of this surgery are comparable with other approaches, but postoperative incontinence rate is higher compared with RP for localized disease.

NADPH oxidase： recent evidence for its role in erectile dysfunction

Important roles for reactive oxygen species （ROS） in physiology and pathophysiology have been increasingly recognized. Under normal conditions, ROS serve as signaling molecules in the regulation of cellular functions. However, enhanced ROS production as a result of the activation of nicotinamide adenine dinucleotide phosphate （NADPH） oxidase contributes significantly to the pathogeneses of vascular diseases. Although it has become evident that increased ROS is associated with erectile dysfunction （ED）, the sources of ROS in the penis remain largely unknown. In recent years, emergent evidence suggests the possible role of NADPH oxidase in inducing ED. In this review, we examine the relationship between ROS and ED in different disease models and discuss the current evidence basis for NADPH oxidase-derive＇d ROS in ED.

Medical management of ischemic stuttering priapism： a ：ontemporary review of the literature

Priapism is defined as a prolonged and persistent erection of the penis without sexual stimulation. This is a poorly understood disease process with little information on the pathophysiology of this erectile disorder. Complications from this disorder are devastating due to the irreversible erectile damage and resultant erectile dysfunction （ED）. Stuttering priapism, though relatively rare, affects a high prevalence of men with sickle-cell disease （SCD） and presents a challenging problem with guidelines for treatment lacking or resulting in permanent ED. The mechanisms involved in the development of priapism in this cohort are poorly characterized; therefore, medical management of priapism represents a therapeutic challenge to urologists. Additional research is warranted, so we can effectively target treatments for these patients with prevention as the goal. This review gives an introduction to stuttering priapism and its clinical significance, specifically with regards to the patient with SCD. Additionally, the proposed mechanisms behind its pathophysiology and a summary of the current and future targets for medical management are discussed.

Cyr61 is a potential prognostic marker for prostate cancer

Cysteine-rich angiogenic inducer 61 （Cyr61） is an extracellular matrix protein involved in the transduction of growth factor and hormone signaling that is frequently altered in expression in several types of cancers. In prostate cancer （PCa）, Cyr61 is highly expressed in organ-confined disease. Further, Cyr61 expression levels are associated with a lower risk of disease recurrence, and can be quantitatively measured in the serum. Considered together, these results indicate that Cyr61 is a potential and clinically useful tissue, as well as serum-based biomarker for differentiating lethal and non-lethal PCa.

Cancer/testis antigens： novel tools for discerning aggressive and non-aggressive prostate cancer

The introduction of serum prostate-specific antigen （PSA） in the 1980s has dramatically altered and benefited the initial diagnosis of prostate cancer. However, the widespread use of PSA testing has resulted in overdetection and overtreatment of potentially indolent disease. Thus, a clinical dilemma today in the management of prostate cancer is to discern men with aggressive disease who need definitive treatment from men whose disease are not lethal. Although several serum and tissue biomarkers have been evaluated during the past decade, improved markers are still needed to enhance the accuracy, with which patients at risk can be discerned and treated more aggressively. The cancer/testis antigens （CTAs） are a group of proteins that are restricted to the testis in the normal adult, but are aberrantly expressed in several types of cancers. Because of their restricted expression pattern, the CTAs represent attractive biomarker candidates for cancer diagnosis/prognosis. Furthermore, several studies to date have reported the differential expression of CTAs in prostate cancer. Here, we review recent developments that demonstrate the potential of the CTAs as biomarkers to discern the a^ressive Dhenotvoe of orostate cancer.

RhoA/ROCK activation in major pelvic ganglion mediates caspase-3 dependent nitrergic neuronal apoptosis following cavernous nerve injury

Severe erectile dysfunction （ED） remains a significant side effect among men following surgical intervention for treatment of clinically localized prostate cancer, despite development of nerve-sparing techniques （Weyne et al., 2015a; Sopko and Burnett, 2016）. The type of axonal injury due to prostatectomy is a classic peripheral neuropathy with an acute inflammatory phase that leads to Wallerian degeneration of the canvernous nerve （CN）, which can be followed by a regenerative phase characterized by enhanced neu- rotrophic factor activation and reduction in neuroinflam- mation （Weyne et al., 2015b）.

Non-invasive actionable biomarkers for metastatic prostate cancer

In the current clinical setting,many disease management options are available for men diagnosed with prostate cancer.For metastatic prostate cancer,first-line therapies almost always involve agents designed to inhibit androgen receptor(AR)signaling.Castration-resistant prostate cancers(CRPCs)that arise following first-line androgen deprivation therapies(ADT)may continue to respond to additional lines of AR-targeting therapies(abiraterone and enzalutamide),chemotherapies(docetaxel and cabazitaxel),bonetargeting Radium-223 therapy,and immunotherapy sipuleucel-T.The rapidly expanding therapies for CRPC is expected to transform this lethal disease into one that can be managed for prolonged period of time.In the past 3 years,a number of promising biomarkers that may help to guide treatment decisions have been proposed and evaluated,including androgen receptor splice variant-7(AR-V7),a truncated AR lacking the ligand-binding domain(LBD)and mediate constitutively-active AR signaling.Putative treatment selection markers such as ARV7 may further improve survival benefit of existing therapies and help to accelerate development of new agents for metastatic prostate cancer.In the metastatic setting,it is important to consider compatibility between the putative biomarker with non-invasive sampling.In this review,biomarkers relevant to the setting of metastatic prostate cancer are discussed with respect to a number of key attributes critical for clinical development of non-invasive,actionable markers.It is envisioned that biomarkers for metastatic prostate cancer will continue to be discovered,developed,and refined to meet the unmet needs in both standard-of-care and clinical trial settings.

Regulation of androgen receptor variants in prostate cancer

Aberrant activation of androgen receptor(AR)signaling occurs in patients treated with AR-targeted therapies,contributing to the development of castration-resistant prostate cancer(CRPC)and therapeutic resistance.Over the past decade,many AR variants(AR-Vs)have been identified in prostate cancer cell lines and clinical CRPC specimens.These AR-Vs lack the COOH-terminal ligand-binding domain(LBD),and may mediate constitutively active AR signaling acquired following AR-targeting therapies.AR splice variant-7(AR-V7),one of the most well characterized AR-Vs,can be reliably measured in tissue and liquid biopsy specimens,and blood-based detection of AR-V7 is a reliable indicator of poor outcome to relatively novel hormonal therapies(NHT)such as abiraterone and enzalutamide in men with metastatic CRPC(mCRPC).Given the important clinical implication of AR-Vs,this short review will focus on studies addressing how AR-Vs are regulated in prostate cancer.With regard to the molecular origin of AR-Vs,it is established that expression of AR-Vs is highly correlated with androgen deprivation and suppression of AR signaling.Therapeutic targeting of the AR axis may result in active transcription of the AR gene,elevated activities of certain components of the mRNA splicing machinery,as well as AR genomic alterations,all of which may explain the molecular origin of AR-Vs.Although a unified hypothesis is currently lacking,existing data suggest that elevated expression of AR-Vs,which in general occurs quite specifically in a cellular environment where the canonical AR signaling is suppressed,is driven by both genomic and epigenomic features acquired in the development of CRPC.

Novel approaches for the molecular classification of prostate cancer

Among the urologic cancers, prostate cancer is by far the most common, and it appears to have the potential to affect almost all men throughout the world as they age. A number of studies have shown that many men with prostate cancer will not die from their disease, but rather with the disease but from other causes. These men have a form of prostate cancer that is described as ＂very low risk＂ and has often been called indolent.

Alternative polyadenylation:An untapped source for prostate cancer biomarkers and therapeutic targets?

Objective:To review alternative polyadenylation(APA)as a mechanism of gene regulation and consider potential roles for APA in prostate cancer(PCa)biology and treatment.Methods:An extensive review of mRNA polyadenylation,APA,and PCa literature was performed.This review article introduces APA and its association with human disease,outlines the mechanisms and components of APA,reviews APA in cancer biology,and considers whether APA may contribute to PCa progression and/or produce novel biomarkers and therapeutic targets for PCa.Results:Eukaryotic mRNA 30-end cleavage and polyadenylation play a critical role in gene expression.Most human genes encode more than one polyadenylation signal,and produce more than one transcript isoform,through APA.Polyadenylation can occur throughout the gene body to generate transcripts with differing 30-termini and coding sequence.Differences in 30-untranslated regions length can modify post-transcriptional gene regulation by microRNAs and RNA binding proteins,and alter mRNA stability,translation efficiency,and subcellular localization.Distinctive APA patterns are associated with human diseases,tissue origins,and changes in cellular proliferation rate and differentiation state.APA events may therefore generate unique mRNA biomarkers or therapeutic targets in certain cancer types or phenotypic states.Conclusions:The full extent of cancer-associated and tissue-specific APA events have yet to be defined,and the mechanisms and functional consequences of APA in cancer remain incompletely understood.There is evidence that APA is active in PCa,and that it may be an untapped resource for PCa biomarkers or therapeutic targets.

TRPM8 and prostate cancer:to overexpress or repress,that is the question-comment on“Effects of TRPM8 on proliferation and motility of prostate cancer PC-3 cells”by Yang ZH et al.in Asian Journal of Andrology

The progression of cells from a normal differentiated state in which the rates of proliferation and apoptosis are in check,to a tumorigenic and metastatic state where these rates are imbalanced,likely involves the accumulation of mutations in multiple genes,and the evolution and clonal selection of more aggressive phenotypes.These events are associated with changes in the expression of numerous gene products including the transient receptor potential(TRP)proteins.

Obituary for Donald S.Coffey:Remembering a pioneer in the field of prostate cancer research.(1932-2017)

It is with the deepest sadness that we publish the following obituary for Donald S.Coffey,an Asian Journal of Urology(AJU)respected author.Dr.Coffey was invited to write a paper for the inaugural issue of AJU in 2014.Despite he was 82 years old,he accepted our invitation and contributed a thoughtful perspective article.

A Single Therapeutic miRNA Rescues the Oncolysis of Androgen Activated Prostate Specific Virus in Androgen Independent Cell Model

Prostate specific conditionally replicating adenoviruses (CRAd) are made by placing a tissue specific promoter upstream of one or more of the viral genes required for replication (e.g., E1A, E1B). However, one major problem associated with these vectors is their dependency for androgen receptor (AR), to transactivate the immediate early gene of the virus. This absolute necessity of androgens for prostate specific promoters renders them less useful in patients that have undergone or are currently on total androgen ablation therapy. Therefore, an alternative approach is needed for the existing vectors to be useful in clinical settings. To overcome this problem, we have generated a prostate specific CRAd by introducing a single therapeutic miRNA (miR-34c) that was identified in our library screen to synergize with viral oncolysis. Overexpression of miR-34c from the backbone of virus not only helped in suppressing the proliferation of AR positive cells but also rescued the oncolysis of androgen activated prostate specific virus in androgen independent cell model. To our knowledge this is the first report describing the utility of a single therapeutic miRNA construct to rescue viral oncolysis in advanced androgen resistant AR negative prostate cancer cell line model.

Helping to address the over treatment of prostate cancer： tools to differentiate lethal and non-lethal phenotype in prostate cancer

2011 was a noteworthy year for those interested in the care of patients with prostate cancer. First, the US Preventive Services Task Force （USPSTF） released an update on prostate cancer screening, and recommended against the use of the prostate-specific antigen （PSA） test for all men, regardless of family history or race. While this surprised many in the field, the conclusion that there is more harm than benefit is inescapable on a population level--the focus of the USPSTF. Most men with newly diagnosed prostate cancer have favorable risk disease and are at an age when treatment is unlikely to extend life---a conclusion that is supported by randomized trials. Second, the National Institutes of Health convened a ＇State of the Science＇ conference on active surveillance for prostate cancer, and concluded that the rates of overtreatment of prostate cancer are high and surveillance is greatly underutilized. Both the USPSTF and the National Institutes of Health conference were prompted in large part by the recognition that widespread PSA testing leads to prostate biopsies that often uncover indolent disease. In the majority of cases,

The impact of subcentimeter cysts on chronic scrotal pain

Subcentimeter cysts can be the cause of severe chronic scrotal pain(CSP),a condition that significantly impacts patients and is often difficult to manage.This article aims to investigate the impact of subcentimeter cysts on CSP and compare the effectiveness of surgical removal for cysts of different sizes.The primary outcome was the comparison of the average pain reduction pre-and postoperatively.After a median postoperative time of 27.80(range:0.59–36.30)months,the average pain reduction was 6.00(standard deviation[s.d.]:2.27)for subcentimeter cysts and 2.72(s.d.:1.43)for larger cysts(P=0.0031).In total,81.0%of all patients were pain-free after cyst removal and 100.0%reported some improvement in pain.The postoperative pain reduction was significantly greater for subcentimeter cysts.

Development of AR-V7 as a putative treatment selection marker for metastatic castration-resistant prostate cancer

Prostate cancer cells demonstrate a remarkable ＂addiction＂ to androgen receptor （AR） signaling in all stages of disease progression. As such, suppression of AR signaling remains the therapeutic goal in systemic treatment of prostate cancer. A number of molecular alterations arise in patients treated with AR-directed therapies. These molecular alterations may indicate the emergence of treatment resistance and may be targeted for the development of novel agents for prostate cancer. The presence of functional androgen receptor splice variants may represent a potential explanation for resistance to abiraterone and enzalutamide, newer AR-directed agents developed to treat metastatic castration-resistant prostate cancer （mCRPC）. In the last 8 years, many androgen receptor splice variants have been identified and characterized. Among these, androgen receptor splice variant-7 （AR-V7） has been investigated extensively. In AR-V7, the entire COOH-terminal ligand-binding domain of the canonical AR is truncated and replaced with a variant-specific peptide of 16 amino acids. Functionally, AR-V7 is capable of mediating constitutive nuclear localization and androgen receptor signaling in the absence of androgens, or in the presence of enzalutamide. In this review, we will focus on clinical translational studies involving detection/measurement of AR-V7. Methods have been developed to detect AR-V7 in clinical mCRPC specimens. AR-V7 can be reliably measured in both tissue and circulating tumor cells derived from mCRPC patients, making it possible to conduct both cross-sectional and longitudinal clinical correlative studies. Current evidence derived from studies focusing on detection of AR-V7 in mCRPC support its potential clinical utility as a treatment selection marker.

MicroRNA expression and function in prostate cancer： a review of current knowledge and opportunities for discovery

MicroRNAs （miRNAs） are well-conserved noncoding RNAs that broadly regulate gene expression through posttranscriptional silencing of coding genes. Dysregulated miRNA expression in prostate and other cancers implicates their role in cancer biology. Moreover, functional studies provide support for the contribution of miRNAs to several key pathways in cancer initiation and progression. Comparative analyses of miRNA gene expression between malignant and nonmalignant prostate tissues, healthy controls and prostate cancer （PCa） patients, as well as less aggressive versus more aggressive disease indicate that miRNAs may be future diagnostic or prognostic biomarkers in tumor tissue, blood, or urine. Further, miRNAs may be future therapeutics or therapeutic targets. In this review, we examine the miRNAs most commonly observed to be de-regulated in PCa gene expression analyses and review the potential contribution of these miRNAs to important pathways in PCa initiation and progression.

Resident involvement in the prostatic urethral lift:implementing innovative technology in an academic setting

Adoption of the prostatic urethral lift(PUL)as a treatment for benign prostatic hyperplasia highlights the importance of training residents with novel technology without compromising patient care.This study examines the effect of resident involvement during PUL on patient and procedural outcomes.Retrospective chart review was conducted on all consecutive PUL cases performed by a single academic urologist between October 2017 and November 2019.Trainees in post-graduate year(PGY)1–3 are considered junior residents,while those in PGY 4–6 are senior residents.The International Prostate Symptom Score(IPSS)and quality of life(QOL)scores were used to measure outcomes.Simple and mixed-effects linear regression models were used to compare differences.There were 110 patients with a median age of 66.4 years.Residents were involved in 73 cases(66.4%),and senior residents were involved in 31 of those cases.Resident involvement was not associated with adverse perioperative outcomes with respect to the number of implants fired,the percentage of implants successfully placed,or the postoperative catheterization rate.After adjustment for confounding factors,junior residents were associated with significantly longer case length compared to the attending alone(+12.6 min,P=0.003)but senior residents were not(+2.4 min,P=0.59).IPSS and QOL scores were not significantly affected by resident involvement(P=0.12 and P=0.21,respectively).The presence of surgeons-in-training,particularly those in the early stages,prolongs PUL case length but does not appear to have an adverse impact on patient outcomes.

Associations of preorchiectomy hormone levels to testicular germ cell tumor pathology,clinical stage,and size

Dear Editor,Despite the substantial body of evidence describing the alternations in and impact of hormones after treatment of unilateral testicular germ cell tumors(GCTs),only a few studies have examined hormone levels before radical orchiectomy.1 This letter details our investigation of the relationship between preorchiectomy hormone levels and surgical pathology,clinical stage,and tumor size among patients with GCTs.Differences in GCT presentation were expected based on varying preorchiectomy hormone levels.

Postphalloplasty urinary function test:an observational study of novel outcome instrument to capture urinary dysfunction and quality of life after phalloplasty

Due to growing social acceptance,there has been an increasing number of gender-affirmation surgeries performed in North America.Most research in this patient population focuses on surgical outcomes and advancing techniques.However,little work has been done to study functional outcomes.To better evaluate urinary dysfunction in the postphalloplasty trans men patient population,our group developed a novel patient-reported outcome instrument-the postphalloplasty urinary function test(PP UFT)and protocol to measure postvoid urethral volume(PVUR),and we present our preliminary results.We conducted a cross-sectional pilot study in a cohort of 15 adult trans men who had undergone phalloplasty with urethral lengthening surgery between 2018 and 2021.Patients had stable urinary function via the neophallus at the time of survey.Patients filled out the PP UFT and were asked to record their PVUR as per our protocol.The average PP UFT score was 8.9 out of 40 and the average quality-of-life(QOL)score was 2.6.Postvoid dribbling constituted the major complaint and on average comprised 63.2%of the reported PP UFT score.The average PVUR was 2.2 ml(range:0.5-5.6 ml).There was a positive correlation between higher PP UFT and worse-reported quality of life(P<0.01;R?=0.4).Current questionnaires accepted in cis-male urology have limitations for accurately capturing urinary dysfunction in this specific patient group.The combination of PP UFT and PVUR measurement offers potential for quantifying urinary function and quality of life in patients who undergo phalloplasty.Future studies will validate these instruments.