Extensive Alteration of Androgen Precursor Levels After Castration in Prostate Cancer Patients and Their Association With Active Androgen Level.

PURPOSE: Dihydrotestosterone and testosterone are thought to be major contributors of prostate cancer progression and resistance. We studied the modulation of 15 circulating steroids by castration and their association with dihydrotestosterone and testosterone levels. MATERIALS METHODS: A total of 116 serum samples were collected from 99 prostate cancer patients and categorized as eugonadal, castration-sensitive prostate cancer, castration-resistant prostate cancer, or castration-resistant prostate cancer under abiraterone acetate. Serum levels of 15 steroids were measured using mass spectrometry and compared between groups using analysis of variance. Intrapatient association of steroid levels and the androgens testosterone and dihydrotestosterone were assessed using Pearson correlation and linear regression. RESULTS: Testosterone, dihydrotestosterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androsterone, androstenediol, estrone, estrone-sulfate, estradiol, and androsterone/3α-diol-3/3α-diol-17-glucuronide levels were significantly decreased in castration-sensitive prostate cancer (castrated) compared to eugonadal patients. Testosterone levels were strongly associated with multiple steroids under eugonadal conditions, whereas they were weakly affected by precursor steroids in castrated patients. By contrast, dihydrotestosterone levels under androgen deprivation therapy were associated with testosterone and the backdoor pathway metabolite androsterone. In castration-resistant prostate cancer patients, levels of androstenedione were significantly associated with testosterone level, while testosterone was the only steroid associated with dihydrotestosterone levels. CONCLUSIONS: Androgen deprivation therapy significantly reduces the levels of 13 circulating steroids. Upon androgen deprivation therapy initiation, the backdoor pathway metabolite androsterone are strongly associated with dihydrotestosterone levels. Under castration-resistant prostate cancer conditions, androstenedione was significantly associated with testosterone levels, suggesting the presence of tumor-related circulating androgens in these patients. These results provide further rationale to intensify treatments with androgen receptor axis signaling pathway inhibitors in patients with prostate cancer.

Extragonadal Steroids Contribute Significantly to Androgen Receptor Activity and Development of Castration Resistance in Recurrent Prostate Cancer after Primary Therapy.

PURPOSE: Beyond testosterone, several steroids contribute to the activation of the androgen receptor pathway, but their relative contributions to the activation of the androgen receptor signaling axis in patients with castrated prostate cancer remain unknown. MATERIALS AND METHODS: Serum levels of 9 steroids were measured by mass spectrometry from continuously castrated patients of the PR.7 study (219) and from the PCA24 cohort (116). For each steroid standard curves for dose dependent prostate specific antigen promoter activation were built in castration sensitive (LAPC4) and resistant (VCaP) prostate cancer models. Standard curves were used to determine the androgen receptor activation potency for each steroid measurement from patients in these trials. RESULTS: In LAPC4 and VCaP cells testosterone, dihydrotestosterone and androstenedione induced androgen receptor transcriptional activity, while dehydroepiandrosterone, 5alpha-androstan-3beta,17beta-diol, androstenediol and androsterone stimulated androgen receptor only in VCaP cells. Extragonadal steroids were responsible for 34% (LAPC4) and 88% (VCaP) of the serum total androgen receptor transcriptional activity found in castrated cases. The total androgen receptor transcriptional activity secondary to testosterone, dihydrotestosterone and androstenedione was associated with time to castration resistance in patients from the PR.7 study (HR 2.17, 95% CI 1.12-4.23, p=0.02) in multivariate analysis using the castration sensitive model (LAPC4). Androgen receptor transcriptional activity of extragonadal androstenedione was the only steroid statistically associated with time to castration resistance in univariate analysis (HR 1.89, 95% CI 1.04-3.44, p=0.036). CONCLUSIONS: Extragonadal steroids contribute significantly to the androgen receptor axis activation at castration levels of testosterone in recurrent nonmetastatic prostate cancer and these sustain the development of castration resistance after primary local treatment.

Safety and efficacy of Tamsulosin as medical expulsive therapy in pregnancy.

PURPOSE: Use of medical expulsive therapy (MET) is common practice in urology for the treatment of symptomatic urolithiasis, despite this its efficacy is debated. Its use in pregnancy is controversial. Our objective was to evaluate the safety and efficacy of Tamsulosin as a MET in pregnant women. MATERIAL AND METHODS: We retrospectively identified pregnant patients who presented with renal colic at the CHU de Québec from 2000 to 2015. We compared patients who received Tamsulosin as MET to a control group without MET. We evaluated efficacy as passage rate of lithiasis and necessity of intervention. We evaluated safety of the treatment according to fetal outcomes (birth weight, APGAR, gestational age). RESULTS: We evaluated 207 pregnant patients presenting renal colic, 69 patients in the MET group were compared to 138 patients in the control group. Of these, 48 (70%) in the Tamsulosin therapy group and 76 (56%) in the control group had proven urolithiasis. No significant difference was found for mean gestational age at birth, birth weight and APGAR. No sudden infant death syndrome was encountered in Tamsulosin group. There was no significant difference for length of hospital stay and need for surgical intervention. The spontaneous passage rate was 58% (25/48) in the MET group compared to 43% (29/76), but this difference was not statistically significant (p = 0.18). CONCLUSIONS: Short-term utilisation of Tamsulosin as MET in second and third trimester of pregnancy is not associated with adverse maternal or infant outcomes. Moreover, there was no significant adjunct for the rate of stone passage.

Plasma extracellular vesicles as phenotypic biomarkers in prostate cancer patients.

BACKGROUND: The development of phenotypic biomarkers to aid the selection of treatment for patients with castrate-resistant prostate cancer (CRPC) is an important priority. Plasma exosomes have excellent potential as real-time biomarkers to characterize the tumor because they are easily accessible in the blood and contain DNA, RNA, and protein from the parent cell. This study aims to investigate the characteristics of putative prostate-specific plasma extracellular vesicle (EV) markers and their relationship with clinical outcomes. METHODS AND PATIENTS: We investigated plasma EVs in a total of 89 patients with prostate cancer (PCa) at different stages of disease progression. EVs were isolated using both precipitation and ultracentrifugation methods; physical characterization was performed using dynamic light scattering, acetylcholinesterase (AChE) activity, and velocity gradients. An immunocapture method was developed for the evaluation of prostate-specific membrane antigen (PSMA)-positive exosomes. Exosomal messenger RNA (mRNA) was quantified using droplet digital polymerase chain reaction for the expression of KLK3 and androgen receptor splice variant 7 (AR-V7) genes, which code prostate-specific antigen (PSA) and AR-V7, respectively. Serum sex steroids were measured using liquid chromatography-tandem mass spectroscopy. RESULTS: Isolated exosomes from patients with CRPC had a smaller hydrodynamic size than those isolated from localized patients with PCa, while AChE activity showed no difference. Moreover, no differences were observed after initiation of androgen deprivation therapy in serial patient samples. Velocity gradients identified that PSMA-positive exosomes occupied a specific fraction of isolated EVs. A total of 35 patients with CRPC had mRNA analyzed from isolated plasma exosomes. Detectable exosomal KLK3 corresponded with higher concomitant serum PSA measurements, as expected (mean, 112.6 vs 26.61 ng/mL; P = .065). Furthermore, detectable levels of AR-V7 mRNA were associated with a shorter time to progression (median, 16.0 vs 28.0 months; P = .0499). Furthermore, detectable exosomal AR-V7 was significantly associated with testosterone levels below the lower limit of quantification (<0.1 nM). CONCLUSIONS: Our results suggest that exosomal AR-V7 is correlated with lower sex steroid levels in CRPC patients with a poorer prognosis. PSMA immunocapture does not appear sufficient to isolate PCa-specific exosomes.

Dual Therapy for Refractory Overactive Bladder in Children: A Prospective Open-Label Study.

PURPOSE: Mirabegron (ß3 adrenoreceptor agonist) is a new molecule with a mechanism of action distinct from antimuscarinics. Combination therapy with solifenacin was recently studied in an adult population. We evaluated the efficacy and safety of mirabegron as add-on therapy to treat urinary incontinence in children with idiopathic overactive bladder refractory/intolerant to antimuscarinics. MATERIALS AND METHODS: A prospective off-label study using add-on regimens of mirabegron was conducted in pediatric patients presenting with no symptom improvement while undergoing intensive behavioral and medical therapies and/or significant side effects while undergoing antimuscarinic dose escalation. Our primary outcome was better reported efficacy than with the use of prior antimuscarinic monotherapy. Secondary end points were tolerability, safety and satisfaction. Efficacy and tolerability were assessed based on voiding diaries, post-void residuals, urine cultures, electrocardiograms and vital signs. Families were questioned regarding continence, side effects and compliance. Wilcoxon signed-rank test was used for statistical analysis. RESULTS: A total of 35 patients were recruited at a median age of 10.3 years and were administered add-on mirabegron for a median of 16.4 months. Median bladder capacity improved from 50% to 74% expected bladder capacity (p <0.001). Continence improved in all patients, with 12 being completely dry. Post-void residual was increased in 2 patients and 1 urinary tract infection was reported. Seven patients reported mild or moderate side effects, with 2 withdrawals because of side effects (1 patient) and post-void residual (1). CONCLUSIONS: Add-on mirabegron appears to be a safe alternative for children with refractory overactive bladder. Dual therapy is well tolerated and adjusted dose regimen appears safe in this first pediatric study.

Polyacrylamide Hydrogel as a Bulking Agent for the Endoscopic Treatment of Vesicoureteral Reflux: Long-Term Results and Safety.

PURPOSE: Polyacrylamide hydrogel has been shown to offer good short-term success for the endoscopic treatment of vesicoureteral reflux. Our objective was to provide long-term results of its efficacy and safety. MATERIALS AND METHODS: We performed a prospective study using polyacrylamide hydrogel to treat all grades of vesicoureteral reflux. Every patient underwent endoscopic injection of polyacrylamide hydrogel followed by 3-month postoperative renal ultrasound and voiding cystourethrogram. Renal ultrasound was repeated at 12 and 36 months. Treatment success was defined as the absence of de novo or worsening hydronephrosis and the absence of reflux. Safety elements included new or worsening hydronephrosis, calcifications of the injected material and urinary tract infections. RESULTS: A total of 76 patients (123 refluxing renal units) were assessed. Median age at surgery was 45 months and median followup was 36 months. Median injected volume of hydrogel per refluxing renal unit was 1.0 ml. The overall success rate 3 months after a single injection was 71%. During long-term followup 68 of 70 eligible patients underwent 12-month ultrasound and 40 of 46 underwent 36-month ultrasound. No upper tract deterioration or bulking agent calcifications were reported. Nine (12%) and 2 patients (3%) presented with nonfebrile and febrile urinary tract infections, respectively. CONCLUSIONS: The success rate of polyacrylamide hydrogel for endoscopic treatment of vesicoureteral reflux is comparable to published results of dextranomer hyaluronic acid. The long-term safety data and potential lower cost of polyacrylamide hydrogel provide further support for the use of this nonparticulate bulking agent to treat reflux.

Perception and satisfaction of patients after telemedicine urology consultations: A matched analysis with physicians' perspective.

INTRODUCTION: During the first regional COVID-19 lockdown in March 2020, we conducted a study aimed at evaluating completeness of telemedicine consultation in urology. Of 1679 consultations, 67% were considered completely managed by phone. The aim of the present study was to assess patients' experience and satisfaction with telemedicine and to compare them with urologists' perceptions about quality and completeness of the telemedicine consultation. METHODS: We contacted a randomly selected sample of patients (n=356) from our previous study to enquire about their experience. We used a home patient experience questionnaire, inspired by the Patient Experiences Questionnaire for Out-of-Hours Care (PEQOHC) and the Consumer Assessment Health Profile Survey (CAHPS). RESULTS: Of 356 patients contacted, 315 agreed to complete the questionnaire. Urological consultations were for non-oncological (104), oncological (121), cancer suspicion (41), and pediatric (49) indications. Mean patient satisfaction score after telemedicine consultation was 8.8/10 (median 9/10) and 86.3% of patients rated the quality of the consultation as either excellent (54.6%) or very good (31.7%). Consultations regarding cancer suspicion had the lowest score (8.3/10). Overall, 46.7% of all patients would have preferred an in-person visit outside of the pandemic situation. Among patients whose consultations were rated suboptimal by urologists, almost a third more (31.2%) would have preferred an in-person visit (p=0.03). CONCLUSIONS: Despite high reported patient satisfaction rates with telemedicine, it is noteworthy that nearly half of the patients would have preferred an in-person visit. Post-pandemic, it will be important to incorporate telemedicine as an alternative, while retaining and offering in-person visits.

A prospective, multisite study analyzing the percentage of urological cases that can be completely managed by telemedicine.

INTRODUCTION: The COVID-19 pandemic has accelerated the development of telemedicine due to confinement measures. However, the percentage of outpatient urological cases that could be managed completely by telemedicine outside of the COVID-19 pandemic remains to be determined. We conducted a prospective, multisite study involving all urologists working in the region of Quebec City. METHODS: During the first four weeks of the regional confinement, 18 pediatric and adult urologists were asked to determine, after each telemedicine appointment, if it translated into a complete (CCM), incomplete (ICM), or suboptimal case management (SCM, adequate only in the context of the pandemic). RESULTS: A total of 1679 appointments representing all urological areas were registered. Overall, 67.6% (95% confidence interval [CI] 65.3; 69.8), 27.1% (25.0; 29.3), and 4.3% (3.5; 5.4) were reported as CCM, SCM, and ICM, respectively. The CCM ratio varied according to the reason for consultation, with cancer suspicion (52.9% [42.9; 62.8]) and pediatric reasons (38.0% [30.0; 46.6]) showing the lowest CCM percentages. CCM percentages also varied significantly based on the setting where it was performed, ranging from 61.1% (private clinic) to 86.8% (endourology and general hospital). CONCLUSIONS: We show that two-thirds of all urological outpatient cases could be completely managed by telemedicine outside of the pandemic. After the pandemic, it will be important to incorporate telemedicine as an alternative for a patient's first or followup visit, especially those with geographical, pathological, and socioeconomic considerations.

Metabolic Imaging of Prostate Cancer Reveals Intrapatient Intermetastasis Response Heterogeneity to Systemic Therapy.

Although intrapatient heterogeneity of prostate cancer (PCa) has recently been characterized via genomic and transcriptomic studies, the heterogeneity of systemic treatment responses has yet to be reported or imaged. Our objective was to evaluate the intrapatient intermetastasis response to systemic treatment among patients with metastatic PCa. We evaluated the metabolic response for each individual metastatic lesion (n=165) in 15 patients with metastatic PCa who underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography before and at least 3 mo after initiation of a systemic therapy that did not change in that period. Intermetastasis heterogeneity was defined as opposite metabolic responses for at least two metastases from the same compartment (bone or soft tissue) between the two time points. We found intrapatient intermetastasis response heterogeneity in 40% of the cases in our retrospective series. Our results suggest that systemic therapies can induce heterogeneous responses among individual metastases in patients with PCa, supporting the polyclonal evolution of PCa in advanced disease. Molecular imaging may thus be useful in identifying clinical resistance early after therapy initiation and could also allow targeted biopsy of resistant clones for molecular analysis. PATIENT SUMMARY: Systemic therapies can lead to heterogeneous responses in individual metastases of prostate cancer in a patient. Molecular imaging may be useful for identifying heterogeneity and could allow targeted biopsy for molecular analysis or therapy.

Efficacy of dextranomer hyaluronic acid and polyacrylamide hydrogel in endoscopic treatment of vesicoureteral reflux: A comparative study.

INTRODUCTION: Various bulking agents are available for vesicoureteral reflux (VUR) endoscopic treatment, but their inconsistent success rates and costs are concerns for urologists. Recently, polyacrylamide hydrogel (PAHG) has been shown to have a good overall success rate, which seems comparable to dextranomer hyaluronic acid (Dx/HA), currently the most popular bulking agent. Our objective was to compare the short-term success rate of PAHG and Dx/HA for VUR endoscopic treatment in children. METHODS: We performed a prospective non-randomized study using PAHG and Dx/HA to treat VUR grades I to IV in pediatric patients. All patients underwent endoscopic sub-ureteric injection of PAHG or Dx/HA, using the double-HIT technique, followed by a 3-month postoperative renal ultrasound and voiding cystourethrogram. Treatment success was defined as the absence of de novo or worsening hydronephrosis and absence of VUR. RESULTS: A total of 90 pediatric patients underwent an endoscopic injection: 45 patients (78 ureters) with PAHG and 45 patients (71 ureters) with Dx/HA. The mean injected volume of PAHG and Dx/HA was 1.1 mL and 1.0 mL, respectively. The overall success rate 3 months after a single treatment was 73.1% for PAHG and 77.5% for Dx/HA. Postoperatively, 1 patient in each group presented with acute pyelonephritis and 2 patients in the Dx/HA group developed symptomatic ureteral obstruction. CONCLUSION: Success rates of PAGH and Dx/HA in endoscopic injections for VUR treatment were comparable. The rate of resolution obtained with Dx/HA was equivalent to those previously published. The lower cost of PAHG makes it an interesting option.