Prospective Longitudinal Health-related Quality of Life Analysis of the Finnish Arm of the PRIAS Active Surveillance Cohort: 11 Years of Follow-up.

BACKGROUND: Living with an untreated cancer may alter quality of life (QoL) in the long term. OBJECTIVE: To prospectively study long-term changes in general, mental, and physical QoL in a contemporary active surveillance (AS) patient cohort with low-risk prostate cancer (PCa). DESIGN, SETTING, AND PARTICIPANTS: The study population consisted of patients enrolled in the PRIAS trial in Helsinki University Hospital (n = 348). The RAND-36 questionnaire was used to assess general QoL at the start of AS and at 1, 3, 5, 7, 9, and 11 years during follow-up. Patients who had undergone robot-assisted laparoscopic prostatectomy (RALP; n = 88) also received the questionnaire after treatment. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Changes over time were analysed using multilevel mixed-effects regression models, and reported as the mean and95% confidence interval. A rule of 0.5 × standard deviation was used to estimate changes of clinical importance. RESULTS AND LIMITATIONS: Median follow-up until the end of AS or last follow-up was 7.2 (range 0.3-12.7) yr. A decrease was observed in six of eight QoL subdomains at 7 yr. However, all scores were above age-stratified reference values. There was no difference between the group who continued AS throughout the study period and the group who discontinued AS and underwent RALP. More than half of the study cohort discontinued AS (n = 198; 57%), 135 men (68%) because of events specified in the protocol and only seven (3.5%) because of anxiety. Metastatic disease developed in six patients (1.7%), and two cases (0.6%) of PCa-related death were recorded among 348 patients in more than 12 yr of overall follow-up. The lack of a randomised control population is a limitation of the study. CONCLUSIONS: Contemporary protocolised AS does not impair general QoL. Men undergoing a treatment change (RALP) did not experience a decrease in QoL before or after their treatment change. PATIENT SUMMARY: Active surveillance is a safe treatment option for men with low-risk prostate cancer. We show that this follow-up strategy does not cause a decline in patients' general quality of life.

PTEN and ERG expression in MRI-ultrasound guided fusion biopsy correlated with radical prostatectomy findings in men with prostate cancer.

BACKGROUND: Conventional systematic prostate biopsies (SBx) have multiple limitations, and magnetic resonance imaging (MRI)-ultrasound fusion targeting is increasingly applied (fusion biopsies [FBx]). In our previous studies, we have shown that loss of the tumor suppressor gene phosphatase and tensin homolog (PTEN) in radical prostatectomy (RP) specimens predicts poor disease-specific survival, and in active surveillance (AS), PTEN loss in SBx predicts an adverse AS outcome, although SBx PTEN status does not correlate well with the corresponding RP status. Here, we have hypothesized that PTEN and erythroblast transformation-specific related gene (ERG) status in FBx correlate better with RP than they would in SBx. METHODS: A total of 106 men, who had undergone FBx and subsequent RP in a single center between June 2015 and May 2017 were included. Fifty-three of the men had concomitant or previous SBx's. All biopsy and RP specimens were collected, and tissue microarrays (TMA) were constructed from RP specimens. Immunohistochemical stainings for PTEN and ERG expression were conducted on biopsies and RP TMAs and results were compared by using Fisher's exact test. RESULTS: The immunohistochemical predictive power of FBx, determined by the concordance of biopsy PTEN and ERG status with RP, is superior to SBx (77.6% vs 66.7% in PTEN, 92.4% vs 66.6% in ERG). FBx was superior to SBx in correlation with RP Gleason Grade Groups and MRI prostate imaging reporting and data system scores. CONCLUSION: FBx grading correlates with RP histology and MRI findings and predicts the biomarker status in the RP specimens more accurately than SBx. A longer follow-up is needed to evaluate if this translates to better prediction of disease outcomes, especially in AS and radiation therapy where prostatectomy specimens are not available for prognostication.

Evaluation of combined therapeutic effects of hydrogen sulfide donor sodium hydrogen sulfide and phosphodiesterase type-5 inhibitor tadalafil on erectile dysfunction in a partially bladder outlet obstructed rat model.

AIMS: To evaluate the impacts of hydrogen sulfide (H2 S) donor, sodium hydrogen sulfide (NaHS), and phosphodiesterase type-5 inhibitor (PDE5i), tadalafil per se and their combination treatment on partial bladder outlet obstruction (PBOO)-induced erectile dysfunction (ED). METHODS: Sprague-Dawley rats were equally divided into five groups: (a) sham-operated control; (b) PBOO; (c) PBOO-treated with NaHS (5.6 mg/kg/day, ip); (d) PBOO-treated with tadalafil (2 mg/kg/day, oral); and (e) PBOO-treated with combination of NaHS and tadalafil. The obstruction was created by urethral ligation for 6 weeks. In vivo erectile responses, in vitro relaxant and contractile responses in penile tissue as well as protein expression of nitric oxide synthases (NOS), H2 S synthesis enzymes, oxidative stress, hypoxia, fibrosis markers, and the smooth muscle/collagen ratio and apoptosis were analyzed. RESULTS: Combined treatment entirely returned increased bladder mass, reduced erectile responses, relaxation responses to acetylcholine, and electrical field stimulation in obstructed rats, while partial amelioration was observed after mono-treatment. Decreased neuronal NOS and 3-mercaptopiruvate transferase enzyme expressions in penile tissue from obstructed rats were also entirely restored by the combined treatment. Mono-treatment partially improved increased hypoxia, oxidative stress, fibrosis markers, decreased smooth muscle mass, and H2 S levels, while combined therapy completely recovered. CONCLUSIONS: The combination therapy with H2 S donor and PDE5i had positive effects on erectile responses through the improvement of ischemia-induced morphological and functional penile alterations in obstruction. H2 S and NO may likely play a synergistic role in the regulation of erectile function and have constructive effects on clinical outcomes in male patients with ED and benign prostatic hyperplasia/lower urinary tract symptoms.

Comparison of the treatment efficacies of paroxetine, fluoxetine and dapoxetine in low socioeconomic status patients with lifelong premature ejaculation.

INTRODUCTION: To assess the treatment efficacies of paroxetine, fluoxetine and dapoxetine in patients with lifelong premature ejaculation (PE). MATERIAL AND METHODS: One hundred and seventy male patients with lifelong PE were included in our study. Premature ejaculation profile (PEP) and Intravaginal ejaculation latency times (IELT) were recorded. Paroxetine 20 mg/d was given in Group 1 (n = 64), fluoxetine 20 mg/d was given in Group 2 (n = 47) and dapoxetine 30 mg on demand (at least two times/week) was given in Group 3 (n = 59) patients. After 1 month of treatment, the patients' IELT, PEP and patient reported clinical global impression of change (CGIC) were completed. RESULTS: The mean age was 36 ±9.2 years. There was no difference between the groups' age, PEP and IELT before treatment (p >0.05). PEP and IELT improved in all three groups (p <0.001). The changes in the 1st and 3rd questions of PEP was significantly higher in group 1 than in the other groups (pPEP-1 = 0.042, pPEP-3 = 0.001). The changes in the 2nd and 4th questions of PEP were similar between groups (pPEP-2 = 0.444, pPEP-4 = 0.442). In group 1 and 3 IELT changes were better than group 2 (pIIEL1-3 = 0.297, pIIEL1-2 = 0.017, pIIEL2-3 = 0.100). There was no difference between CGIC scores (p = 0.087). The treatment was terminated by 8 patients in Group 1 and 9 patients in Group 2 because of side effects. CONCLUSIONS: While paroxetine treatment seemed to be better than the other medications, dapoxetine 30 mg treatment has less side effects than the two others and its' on demand usage makes it more prominent than the others.

Evaluation of Erectile Dysfunction and Left Ventricular Diastolic Parameters in Lead Exposed Workers.

BACKGROUND: Lead exposure causes a wide range of vascular diseases through oxidative stress, sympathetic hyperactivity and impairment in nitric oxide bioavailability. In this study, the association between the effects of lead exposure on left ventricular diastolic indices and erectile function were assessed. METHODS: A total of 94 lead-exposed workers without known cardiovascular diseases or risk factors and 30 healthy subjects were enrolled. Systolic and diastolic functions were measured using transthoracic echocardiography. All participants were non-smokers. The International Index of Erectile Function Questionnaire (IIEF-5) was used to diagnose and grade erectile dysfunction (ED). Echocardiographic parameters, IIEF-5 score and blood lead level (BLL) were analyzed. RESULTS: The mean age and median BLL were 32.3 ± 6.4 years and 19 µg/dL in the workers, respectively. Sixty-five (69.1%) workers and 9 control subjects (30%) had ED. The IIEF-5 score was lower in the workers (17.0 ± 6.1) than in the controls (22.7 ± 2.1). In the workers, E and e' waves and E/A ratio were lower, and A wave, E/e' ratio, and left atrial volume index (LAVI) were higher than in the controls. Additionally, BLL was correlated with IIEF-5 score, e' wave, and E/e' ratio. IIEF-5 score was correlated with e' wave, E/e' ratio and LAVI. BLL was an independent risk factor for a decreased e' wave and IIEF-5 score and increased E/e' ratio in the lead-exposed workers. CONCLUSIONS: Impairment of diastolic and erectile functions, despite a younger age and in the absence of accompanying risk factors, was correlated with increased BLL.

Effects of varying degrees of partial bladder outlet obstruction on urinary bladder function of rats: A novel link to inflammation, oxidative stress and hypoxia.

OBJECTIVES: The aim of the present study was to investigate the effects of different degrees of obstruction, and the roles of inflammation, oxidative stress, and hypoxia parameters on bladder function. METHODS: Thirty male Sprague-Dawley rats were divided into 3 groups (n = 10 in each group): (i) sham-operated control; (ii) severe partial bladder outlet obstruction (PBOO); and (iii) moderate PBOO. Severe and moderate PBOO were induced by urethral ligation using 3-Fr and 4-Fr catheters, respectively, for 6 weeks. After 6 weeks, the in vitro contractile responses to carbachol, electrical field stimulation, ATP and KCl were measured in bladder strips. In addition, mRNA and protein expression of nuclear factor kappa B (NF-κB) hypoxia-inducible factor (HIF) and nuclear factor, erythroid 2-like 2 (Nrf2) in bladder were determined by real-time polymerase chain reaction and western blotting. Malondialdehyde (MDA) levels in bladder tissues were also determined. RESULTS: Rats in the severe PBOO group had the highest bladder weight. Detrusor strips from rats in the severe PBOO group exhibited 61%-82% smaller contractile responses to all four stimuli than those from the sham-operated group. Activity of NF-κB as an inflammatory marker was increased in the severe PBOO group, whereas HIF-1α and HIF-2ß protein levels were increased significantly in the moderate PBOO group. A master regulator of oxidative stress, Nrf2 expression was increased in all obstructed rats. MDA levels were higher in the severe PBOO group than in sham-operated group. CONCLUSION: The results of the present study reveal the importance of oxidative stress-induced NF-κB signaling in bladder dysfunction with severe obstruction. Altered HIF signaling may contribute to the functional impairment after PBOO. Novel and evolving therapies targeting oxidative and/or inflammatory pathways may be a reasonable strategy for the management of lower urinary tract symptoms or benign prostatic hyperplasia.

[Bladder stone secondary to prolene suture after gynecologic surgery].

Bladder stones are usually seen among patients with bladder outlet obstruction, especially in men over the age of 50 years. There are several risk factors for bladder stones, including urinary tract infections, abnormal urinary tract system anatomy, and presence of foreign bodies. In addition, migrating intrauterine contraceptive devices through the wall of the urinary bladder and foreign bodies such as surgical sutures may act as a nidus for developing stone formation. Here in, we report a case of bladder stone associated with surgical non-absorbable suture, used for gynecologic surgery 4 years ago, and treated endoscopically. The aim of this paper was to know gynecological association and the management of bladder stones. The patients who had a history of pelvic surgery previously and present with lower urinary tract symptoms such as dysuria, voiding difficulties, weak micturition and hematuria should be evaluated for the foreign body-associated disorders.

Hydrocalyx: Uncommon Complication of Percutaneous Nephrolithotomy.

The success rate of percutaneous nephrolithotomy (PNL) is about 90%, but overall complications of this surgery have been reported in up to 83% cases. The complications are graded using Clavien classification system from grade 1 to 5. Grade 1 needs simple treatments without surgical, endoscopic, and radiologic interventions like antiemetics, antipyretics, and analgesics. Grade 5 denotes death of the patient. Calyx neck stricture is grade 3b complication with an incidence of 0.1%. In this study, a case of hydrocalyx, which is very rare complication after PNL, is presented. To the best of the authors' knowledge, there is no hydrocalyx case reported after PNL in the literature.

Urethral calculi: A rare cause of acute urinary retention in women.

Urinary retention is defined as the inability to void; frequently the patient is able to void partially, thus can not completely empty the bladder and diagnosed by increased post-void residual urine (PVR) volumes. It is usually seen in men, but a rare condition in women. The etiological factors may be neurological, anatomical, infectious or pharmacological. It can be encountered after gynecological or incontinence surgery. Urethral calculi associated with acute urinary retention in women is a very rare condition, because of the anatomic structure of female urethra. In this study, a case of acute urinary retention due to the urethral calculus in a middle-aged woman was presented.

PTEN Loss but Not ERG Expression in Diagnostic Biopsies Is Associated with Increased Risk of Progression and Adverse Surgical Findings in Men with Prostate Cancer on Active Surveillance.

BACKGROUND: Active surveillance (AS) is an option for men with low-risk prostate cancer (PCa). PTEN and ERG have been considered as potential biomarkers of PCa progression and survival. OBJECTIVE: To study the role of ERG and PTEN status in the Prostate Cancer Research International: Active Surveillance (PRIAS) trial diagnostic biopsies (DBxs) in predicting surveillance discontinuation and adverse surgical findings in subsequent radical prostatectomy (RP). DESIGN, SETTING, AND PARTICIPANTS: A total of 231 patients were recruited to the PRIAS between 2007 and 2013 in Helsinki. DBx tissue for immunohistochemistry (IHC) was available from 190 patients. Tissue microarrays (TMAs) were constructed from 57 specimens of subsequent RPs. DBxs containing grade group (GG) 1 PCa and RP TMA sections were stained with ERG and PTEN antibodies, and scored as either negative or positive. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Outcomes were followed up by biopsy GG upgrade (GG ≥ 2) and protocol-based treatment change, as well as adverse findings in RP (GG ≥ 3 or pathological stage≥3). Clinical variables and biomarker status in DBx were correlated in Cox regression analysis and cumulative survival in Kaplan-Meier analysis, and finally, Gray's competing risk analysis was performed and nonprotocol-based discontinuation was considered as a competing event. RESULTS AND LIMITATIONS: In both uni- and multivariate Cox regression analyses, only the number of positive cores in the DBx, the number of rebiopsy sessions, and PTEN status at diagnosis were significantly associated with rebiopsy GG upgrade, treatment change, and adverse histopathology in RP. In Kaplan-Meier analysis, PTEN loss was associated with a shorter time to GG upgrade and treatment change. Patients with PTEN loss had a higher probability for protocol-based discontinuation but not for competing risk factors compared with patients with intact PTEN. Biopsy ERG status was concordant with RP TMA ERG status, while PTEN was not. Limitations include a retrospective analysis of prospective cohort data. CONCLUSIONS: PTEN status at diagnosis is a potential biomarker for identifying patients with PCa on AS with a high risk for progression or adverse findings on subsequent RP. PATIENT SUMMARY: A simple diagnostic biopsy-based analysis of PTEN status may help identify patients with high risk for prostate cancer progression.

Comparison of Monopolar and Bipolar Transurethral Resection of Non-Muscle Invasive Bladder Cancer.

OBJECTIVE: We aimed to compare the safety and efficacy of monopolar and bipolar transurethral resection (TUR) of bladder tumors (TURBTs). MATERIAL AND METHODS: A total of 240 patients who underwent TURBT were prospectively included in the study from May 2011 to May 2014. All patients with suspected bladder tumors were eligible for study inclusion. Those who refused consent and those undergoing routine restaging TURBT were excluded from analysis. Patients were divided on the basis of the monopolar arm and the bipolar arm. Study outcomes included the incidence of bladder perforation and obturator jerk, decrease in hemoglobin and sodium levels, rates of re-coagulation and blood transfusion, TUR syndrome, and operation time. RESULTS: The mean age of the patients was 62 ± 13.7 years. The incidence of obturator jerk and bladder perforation was greater in the bipolar arm. However, with a decrease in the hemoglobin and sodium levels, rates of re-coagulation and blood transfusion were greater in the monopolar arm. Statistical analysis did not show significant differences with regard to study outcomes between the groups. There was no case of TUR syndrome in the 2 arms. The residual tumors' rate was similar between the 2 groups. CONCLUSIONS: Our results showed that efficacy and safety of the monopolar and bipolar methods seems to be comparable in patients with bladder tumors.

Update on drug interactions with phosphodiesterase-5 inhibitors prescribed as first-line therapy for patients with erectile dysfunction or pulmonary hypertension.

Phosphodiesterase-5 inhibitors (PDE5i, sildenafil, vardenafil, tadalafil and avanafil) are a first-line medical therapy for erectile dysfunction (ED). In all likelihood, PDE5i usage will increase because sildenafil (Viagra® and Revatio®) and tadalafil (Cialis® and Adcirca®) have recently been recommended as first-line therapy for patients with pulmonary hypertension (PH). PDE5i exhibit higher plasma concentrations when co-administered with cytochrome P (CYP) 3A inhibitors, which influences their side-effect profile. The higher PDE5i plasma concentrations, caused by CYP3A inhibitors, influence the severity and timing of PDE5i drug interactions and require dose adjustment. PDE5i are safe when used with most antihypertensive agents, but co-administration with nitrates or α-blockers can cause severe hypotension and syncope. Dose adjustment is also necessary when PDE5i are co-administered with CYP3A inducers. The combination of oral tadalafil and bosentan (endothelin receptor antagonist) reduces tadalafil levels and requires dose adjustment. Current literature reports a number of interactions between PDE5i and other agents and further studies are needed to expand our knowledge base of these interactions. This review discusses relevant PDE5i drug interactions, including those with CYP 450 inhibitors and inducers which are frequently used during the treatment of ED and PH.

Incomplete recovery of erectile function in rat after discontinuation of dual 5-alpha reductase inhibitor therapy.

AIM: The association of 5-alpha reductase inhibitor (5ARI) therapy and sexual dysfunction has been reported. Some patients claim persistent erectile dysfunction despite long-term discontinuation of 5ARI treatment. The aim of this study was to assess erectile function after cessation of 5ARI therapy using a rat model. METHODS: Twenty-six adult male Sprague-Dawley rats were randomized into three groups: (i) control (N = 10); (ii) 8-week dutasteride treatment (0.5 mg/rat/day, in drinking water, N = 8); and (iii) 6-week dutasteride treatment followed by a 2-week washout period (N = 8). The experiments were performed after 8 weeks from the initiation of treatment in all groups. In vivo erectile activity and in vitro contractile and relaxant responses of cavernosal smooth muscle were investigated. RESULTS: In vivo erectile activity (intracavernosal pressure [ICP]/mean arterial pressure [MAP] and total ICP) in treatment groups were significantly decreased compared with controls (ICP/MAP: P < 0.001 for 2.5 v, 5 v, and 7.5 v; total ICP: P < 0.001 for 5 v and P < 0.01 for 7.5 v). Acetylcholine-induced relaxations were diminished in treatment groups (P < 0.05). Relaxant responses to electrical field stimulation (EFS) were decreased in the 8-week treatment group (P < 0.05) but were similar to controls in the washout group. Sodium nitroprusside (SNP)-induced endothelium-independent relaxations were reduced in the 8-week dutasteride treatment group (P < 0.01), while these responses were restored in the washout group. The contractile responses to the alpha1-adrenergic agonist phenylephrine were decreased in treatment groups compared with controls (P < 0.01). Direct neurogenic contractile responses in the dutasteride groups were significantly lower than controls between 1 and 15 Hz frequencies (but not at 20 Hz) and washout partially restored the responses at 10 and 15 Hz. CONCLUSION: Discontinuation of dutasteride improved the relaxant responses to EFS and SNP, while cholinergic and adrenergic responses remained depressed. Our findings suggest a time-dependent detriment of dutasteride on erectile function. The withdrawal/washout effect of 5ARIs on parameters of human sexual function warrants further investigation.

Prostate cancer active surveillance and health-related quality of life: results of the Finnish arm of the prospective trial.

UNLABELLED: Study Type - Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Active surveillance is a management option in patients with localized prostate cancer. One concern is the possible psychological burden and quality-of-life effects caused by consciousness of living with untreated cancer. Previous studies have reported controversial results about the impact of active surveillance on patient's health-related quality of life. The data of the present study support the idea that patients with low-risk prostate cancer manage well on active surveillance and do not develop short-term mental or physical quality-of-life sequelae. OBJECTIVE: To analyse longitudinal changes in general, mental and physical health-related quality of life (HRQL) and urinary and erectile function in patients with low-risk prostate cancer (PC) on active surveillance (AS). PATIENTS AND METHODS: Patients comprised those (n= 124) enrolled in the Finnish arm of the Prostate Cancer Research International: Active Surveillance (PRIAS) study who were followed for at least 1 year (n= 80). All patients with PC received validated questionnaires at the start of surveillance and after 1 year of follow-up. General HRQL was assessed with the RAND 36-Item Health Survey (RAND-36), erectile function with the International Index of Erectile Function-5 (IIEF-5), and urinary symptoms with the International Prostate Symptom Score (IPSS) questionnaires. Results were also compared with an age-stratified general Finnish male population. A paired t-test served to compare results over time and a non-paired t-test or a corresponding non-parametric test, when applicable, served to compare the study group with the general population. Pearson and Spearman correlations were analysed between possible HRQL-affecting factors (demographic and clinical data) and HRQL data, followed by linear regression analysis to further evaluate any possible associations. RESULTS: Of the 124 patients, 105 (85%) returned the baseline RAND-36 questionnaire, and 75 (94%) of the 80 patients answered both the baseline and follow-up questionnaires; 15 patients (12%) had discontinued AS, all for protocol-based reasons, none due to anxiety or distress. No differences existed in the HRQL main categories at the 1-year follow-up (mental and physical: P= 0.142 and P= 0.154, respectively). When all the eight dimensions were analysed separately, the physical role showed statistically significant improvement from a mean of 81 to a mean of 89 (P= 0.010). No clinically significant correlations appeared between HRQL and age, diagnostic prostate-specific antigen (PSA), free PSA or PSA change during follow-up at any of the time points; in regression analysis, HRQL was not predictable by any of the variables available at diagnosis or during follow-up. No statistically significant changes occurred in urinary function as analysed by the IPSS (P= 0.121) or in erectile function by the IIEF-5 questionnaire (P= 0.583). Compared with an age-stratified Finnish general male population, patients with PC on AS had a significantly better general mental and physical HRQL at diagnosis and after 1 year of follow-up (P < 0.05). CONCLUSIONS: Active surveillance does not provoke short-term quality-of-life disturbances as assessed by standardized RAND-36, IIEF-5 and IPSS questionnaires. None of the patients changed treatment due to anxiety. Unexpectedly, PC patients on AS had significantly better general mental and physical HRQL than did a general age-stratified Finnish male population.