The role of autophagy in prostate cancer and prostatic diseases: a new therapeutic strategy.

BACKGROUND: Autophagy is a well-conserved catabolic process that plays a key role in cell homeostasis. In the prostate, defective autophagy has been implicated in the genesis and progression of several pathological conditions. AIM: The present review explored the autophagy pathway in prostate-related dysfunctions, focusing on prostate cancer (PCa), benign prostatic hyperplasia (BPH) and prostatitis. RESULTS: Impaired autophagy activity has been shown in animal models of BPH and prostatitis. Moreover, autophagy activation by specific and non-specific drugs improved both conditions in pre-clinical studies. Conversely, the efficacy of autophagy inducers in PCa remains controversial, depending on intrinsic PCa characteristics and stage of progression. Intriguingly, autophagy inhibitors have shown beneficial effects in PCa suppression or even to overcome chemotherapy resistance. However, there are still open questions regarding the upstream mechanisms by which autophagy is deregulated in the prostate and the exact role of autophagy in PCa. The lack of specificity and increased toxicity associated with the currently autophagy inhibitors limits its use clinically, reflecting in reduced number of clinical data. CONCLUSION: New therapeutic strategies to treat prostatic diseases involving new autophagy modulators, combination therapy and new drug formulations should be explored. Understanding the autophagy signaling in each prostatic disease is crucial to determine the best pharmacological approach.

A Clinical Trial Evaluating the Usefulness of Tailored Antimicrobial Prophylaxis Using Rectal-culture Screening Media Prior to Transrectal Prostate Biopsy: A Multicenter, Randomized Controlled Trial.

The aim of this report is to introduce an on-going, multicenter, randomized controlled trial to evaluate whether tailored antimicrobial prophylaxis guided by rectal culture screening prevents acute bacterial prostatitis following transrectal prostate biopsy (TRPB). Patients will be randomized into an intervention or non-intervention group; tazobactam-piperacillin or levofloxacin will be prophylactically administered according to the results of rectal culture prior to TRPB in the intervention group whereas levofloxacin will be routinely given in the non-intervention group. The primary endpoint is the occurrence rate of acute bacterial prostatitis after TRPB. Recruitment begins in April, 2021 and the target total sample size is 5,100 participants.

Prostatic abscess: clinical features, management, and outcomes of a "Stealth" infection: retrospective case series and review of the literature.

Prostatic abscess (PA) is uncommon and may be difficult to distinguish from acute prostatitis which often leads to delayed or missed diagnoses. Although gram-negative bacilli are the traditional etiology of PA, Staphylococcus aureus is an emerging cause. The goals of this study were to characterize the current clinical features, microbiology, management, and outcomes of PA at a US academic center. A retrospective review of adult patients hospitalized with an ICD-9/10 diagnosis of PA between January 2013 and July 2018 was conducted. Inclusion criteria included age ≥18 years, a compatible genitourinary (GU) infection syndrome, and imaging consistent with PA. Relevant data were extracted and analyzed by univariate analysis as appropriate. Twenty-two patients with PA were identified with median age 57 years. Five patients (23%) were immunosuppressed and 11 (50%) had diabetes. No patient had prior PA but 3 had past prostatitis. Only 1 patient had recent GU instrumentation and none had indwelling urinary catheters. The most common presenting symptoms were fever (59%), dysuria (45%), and urinary retention (32%). Only 7 out of 18 (39%) patients had prostate tenderness on exam and none had fluctuance. As demonstrated by computed tomography, PAs were multifocal in 8 (36%) patients and 16 (73%) had PAs >2 cm in diameter. The median abscess size was 3.2 cm. S. aureus was isolated in 60% of positive urine cultures and 78% of positive blood cultures; 46% were methicillin-resistant. Nine patients (41%) received antibiotics alone whereas 13 (59%) required antibiotics plus drainage. The median duration of antimicrobial therapy was 34.5 days. Four week mortality was 9%. When comparing S. aureus PA to other causes, S. aureus patients tended to have higher fevers, more often had diabetes, and received longer durations of antibiotic therapy (median 35 days vs 31 days, P = 0.04) but age, abscess size, and mortality did not differ. PA is relatively uncommon and often clinically unsuspected. Imaging may be critical to accurate diagnosis. Optimal management usually requires antibiotics and sometimes drainage depending on abscess size. We found a significant proportion of cases due to S. aureus which might be relevant when deciding empiric antimicrobial therapy.

[Nitrofurantoin for urinary tract infections in men: it is possible]. / Nitrofurantoïne voor urineweginfecties bij mannen?

Most uropathogens are sensitive to nitrofurantoin. Urinary tract infections with systemic symptoms cannot be treated with nitrofurantoin. Unfortunately, the frequency of prostate involvement in (suspected) cystitis without anamnestic and physical features of tissue invasion is unknown. Clinical studies are limited to retrospective observational studies in which approximately one third of men received a second course of antibiotics within 60-90 days. Exact interpretation of the retreatment is difficult, but it is certainly not only explained by a failure of nitrofurantoin. In addition, the number of men who come to the emergency room with urosepsis during treatment with nitrofurantoin is probably outweighed by the large number of nitrofurantoin prescriptions. The oral alternative to nitrofurantoin is ciprofloxacin. However, this is undesirable because of side effects, more microbiome disturbance and resistance development. Therefore, nitrofurantoin is a valuable treatment option for a urinary tract infection in men, provided that systemic symptoms are absent.

[Development of a large intraprostatic cyst following the use of a GnRH agonist-implant in a male dog with benign prostatic hyperplasia]. / Entwicklung einer großen intraprostatischen Zyste nach Einsatz eines GnRH-Agonist-Implantats bei einem Rüden mit benigner Prostatahyperplasie.

A male dog with benign prostatic hyperplasia and several small intraprostatic cysts was treated with a GnRH-agonist implant containing 4,7 mg deslorelin (Suprelorin®). Within 2 weeks after the implantation, the prior urethral bleeding worsened. A large intraprostatic cyst was detected sonographically. The patient was subsequently treated with osaterone acetate (0.4 mg/kg p. o. once a day for 7 days) and enrofloxacin (5 mg/kg p. o. once a day for 21 days). The clinical symptoms receded within 10 days. Within one month, the cyst regressed completely. The mechanisms of cyst enlargement are discussed.

[Nitrofurantoin for uncomplicated urinary tract infections in men: should it be the first choice?] / Nitrofurantoïne voor urineweginfecties bij mannen.

Nitrofurantoin is a commonly prescribed antibiotic for uncomplicated urinary tract infections. The Dutch College of General Practitioners guideline recommends the use of this drug for the treatment of uncomplicated urinary tract infections in both male and female patients. Treatment with nitrofurantoin has several advantages. Resistance to this antibiotic is low and does not increase in the hospitalized patient population. Treatment with nitrofurantoin is generally well-tolerated. However, two independent studies estimated that approximately 27% of male patients are undertreated with nitrofurantoin. The main downside of nitrofurantoin is the low blood concentration that leads to insufficient tissue penetration. There is little evidence on how often prostatic tissues are involved in male urinary tract infections. Unrecognized tissue involvement can lead to breakthrough urinary tract infections despite nitrofurantoin treatment. Because of this, the safety of nitrofurantoin for male patients is unknown and treatment with this antibiotic should be administered with caution.

The Polyphenols as Potential Agents in Prevention and Therapy of Prostate Diseases.

In recent years, the progress of science and medicine greatly has influenced human life span and health. However, lifestyle habits, like physical activity, smoking cessation, moderate alcohol consumption, diet, and maintaining a normal body weight represent measures that greatly reduce the risk of various diseases. The type of diet is very important for disease development. Numerous epidemiological clinical data confirm that longevity is linked to predominantly plant-based diets and it is related to a long life; whereas the western diet, rich in red meat and fats, increases the risk of oxidative stress and thus the risk of developing various diseases and pre-aging. This review is focused on the bioavailability of polyphenols and the use of polyphenols for the prevention of prostate diseases. Special focus in this paper is placed on the isoflavonoids and flavan-3-ols, subgroups of polyphenols, and their protective effects against the development of prostate diseases.

Anti-androgenic therapy with finasteride in patients with chronic heart failure - a retrospective propensity score based analysis.

Sex hormones influence the prevalence and the outcome of heart diseases. The conversion of testosterone to its more active metabolite dihydrotestosterone drives cardiac growth and dysfunction, while inhibition of this step by the anti-androgenic drug finasteride counteracts these pathological processes in preclinical models. In this retrospective, observational study, we aim to investigate whether finasteride, which is in clinical use mainly for prostate disease, might ameliorate cardiac hypertrophy and heart failure in patients. Retrospective chart review of 1041 medical cases with heart failure between 1995 and 2015 was conducted. Stratification was performed by concomitant prostate treatment status (tamsulosin versus finasteride). A propensity score analysis yielded a total of 328 matched medical cases without residual differences in the baseline patient characteristics. In this propensity score matched samples, anti-androgenic therapy with finasteride was associated with significantly reduced left ventricular hypertrophy (interventricular septal thickness 13.3 ± 2.4 mm control vs. 12.6 ± 2.1 mm finasteride group (p = 0.029); estimated average treatment effects on the treated: -0.7 mm, 95% CI mean difference -1.3 to -0.1). In this retrospective analysis anti-androgenic therapy with finasteride for prostate disease was associated with attenuated cardiac hypertrophy in patients with heart failure. Therefore, our data encourage further analysis of this approach in larger heart failure patient cohorts.

Repetitive urinary tract infections and two prostatic masses: Prostatic soft tissue infection with Actinomyces neuii.

Actinomyces infection is a tissue destructive, low-grade infection that often resembles malignancy. We report the case of a 70-year-old male with repeated, culture-negative urinary tract infections while intermittently catheterized. At presentation, the patient reported a new episode of urinary tract infection with white discharge in his urine. Transrectal ultrasonography showed two lesions in the prostate, suspect for prostate cancer. However, biopsy did not show cancer, and anaerobic culture grew Actinomyces neuii. A 3-month antibiotic course of amoxicillin eventually cured the infection. This is a case of prostatic soft tissue infection with A. neuii. It is important to consider Actinomyces infection in patients with a non-malignant prostatic mass. Although ß-lactam antibiotics do not penetrate the prostate well, the Actinomyces infection was cured by prolonged amoxicillin treatment in this case. It is possible that the tissue damage enhanced the amoxicillin concentration in the infected prostate.

Chronic nonbacterial prostate inflammation in a rat model is associated with changes of gut microbiota that can be modified with a galactoglucomannan-rich hemicellulose extract in the diet.

OBJECTIVES: To investigate dietary effects on the gut microbiota composition in a rat model of nonbacterial chronic prostate inflammation (CPI). MATERIALS AND METHODS: Nonbacterial CPI was induced in the Wistar rat strain with subcutaneous testosterone and 17ß-oestradiol (E2 ) hormone pellets for 18 weeks. Rats with placebo pellets served as healthy controls. Rats with CPI were stratified into two groups, which drank either plain tap water (control group) or tap water supplemented with 2% galactoglucomannan-rich hemicellulose extract (GGM group) from Norway spruce (Picea abies) for 5 weeks. Faecal samples were collected at the end of the study, total DNA was extracted, and the bacterial composition was analysed by 16S rRNA gene sequencing. In addition, faecal samples were assayed for short-chain fatty acid (SCFA) concentrations using gas chromatography. Lipopolysaccharide-binding protein (LBP) was measured in serum samples, as an indirect indicator for bacterial lipopolysaccharide (LPS) load in blood. RESULTS: The microbial biodiversity was significantly different between the treatment groups. In the rats with CPI, there was a significant increase in gut microbial populations Rikenellaceae, Odoribacter, Clostridiaceae, Allobaculum and Peptococcaceae compared with healthy rats. Conversely, levels of Bacteroides uniformis, Lactobacillus and Lachnospiraceae were decreased in rats with CPI. SCFA butyric-, valeric- and caproic-acid concentrations were also decreased in the faecal samples of the rats with CPI. In contrast, acetic acid concentrations and serum LBP were significantly elevated in CPI rats compared with healthy ones. Amongst rats with CPI, treatment with the GGM extract significantly reduced the abundance of Odoribacter and Clostridiaceae levels, and increased the B. uniformis levels compared with CPI rats drinking tap water only. In addition, GGM significantly increased the levels of butyric acid and caproic acid, and reduced the levels of LBP in serum. CONCLUSIONS: Hormone-induced nonbacterial CPI in rats is associated with specific changes in gut microbiota and secondary changes in SCFAs and LPS due to gut microbiota alteration. Our results further suggest that fermentable compounds may have a beneficial effect on CPI.

A pilot study in intraparenchymal therapy delivery in the prostate: a comparison of delivery with a porous needle vs standard needle.

BACKGROUND: New biologic therapies directly injected into the prostate are in clinical trials for prostatic diseases. There is a need to understand distribution of injected therapies as a function of prostatic anatomy, physiology, and device design. METHODS: A needle with a porous length of customizable-length was tested and its performance compared with a standard needle. Injections of magnetic resonance contrast reagent were placed into ex-vivo human prostates after surgical excision in standard of care therapy for invasive bladder cancer patients. Magnetic resonance images were acquired using sequences to quantify volume delivered, distributed, and backflow. RESULTS: Magnetic resonance images analysis revealed heterogeneity distribution with injection into the specimens. There was low resistance to flow along ductal pathways and high resistance to flow into glandular nodules and smooth muscle/fibrous parenchyma. Data confirm previous studies showing injection loss via urethra backflow, urethra, and prostatic ducts. Tissue fraction of dose was significantly higher with porous needle compared with standard needle (p = .03). We found that a greater volume of distribution divided by the amount infused (Vd/Vi) increased by 80% with the porous needle, though no statistically significant association due to small sample size. CONCLUSIONS: This study demonstrated that prostatic tissue is anatomically heterogenic and limits distribution of needle injection. There is greater distribution in the ex-vivo prostate using a porous needle. The complexity of intra prostatic flow pathways suggests preoperative imaging and pre-treatment planning will enhance therapy.

Effect on prostatic specific antigen by a short time treatment with a Curcuma extract: A real life experience and implications for prostate biopsy.

INTRODUCTION AND OBJECTIVES: PSA elevation is associated with prostate cancer and it is used in screening programs for its diagnosis. It is one of the most common indications for referral to an urologist. There's no consensus about what to do in PSA elevation management. Antibiotics, nutraceuticals or anti-inflammatories are commonly prescribed in daily practice. Our objective was to verify the effect on the PSA value of a short 30-day trial of a curcuma extract, than to discuss the implications in terms of reducing the number of prostate biopsies performed. PATIENTS AND METHODS: We enrolled 50 consecutive patients admitted at our attention for a first PSA over the level of 4 ng/ml or for a suspected PSA rising defined as PSA velocity (PSAv) > 0.75 ng/ml/years. They received treatment with curcuma extract, 2 tablets per day for 30 day. All patients received a second PSA measurement and TRUS within 6 days from the end of the therapy. In case of PSA reduction below 4 ng/ml, patients were reassured and invited to repeat a PSA control over the time. When PSA level were persistently high over 4 ng/ml or in case of any rising, patients underwent a transrectal ultrasound guided 12-core prostatic biopsy (TRUSbx). RESULTS: Mean age of the patients was 64.56 ± 8.88 (range, 42- 81 years). Prostate volume was 48.34 ± 15,77 ml (range, 18-80 ml). At visit 1, PSA value was in mean 6,84 ± 3.79 ng/ml (range 2.93-21ng/ml). Consequently, mean PSA density value was 0.16 ± 0.16 (range 0.05-1.11). PSA free and PSA total ratio at baseline was 16.85 ± 3.9% (range 8-26%). At visit 2, the prostate volume did not change. Total PSA was 4.65 ± 2,67 ng/ml (range 1-16.82 ng/ml). PSA free and PSA total ratio (PSAF/T) after treatment was 19.68 ± 5.35 % (range 7.8-29%). The differences of total PSA and PSAF/T between visit 1 and visit 2 were < 0.0001 and p < 0.0036, respectively. We performed 26 TRUSbx. Prostate cancer was diagnosed in 6 cases, PIN HG in 2 cases and non neoplastic findings in the remnants 18 patients. CONCLUSIONS: Use of the Curcuma extract is able to lower the PSA value after a 30-day intake period. We are not able to state that the reduction of PSA after intake of this Curcuma extract may exclude a prostate cancer. We need further studies to evaluate that.

Metformin: an antiproliferative agent and methylation regulator in treating prostatic disease?

Existing drugs that have been used in clinical practice for other purposes can prove useful for reutilization, since much of the safety profile and pharmacokinetics have been completed. Therefore, the drugs can enter clinical practice for a variety of causes with less regulatory burden. Metformin may prove to be such a drug; it may have a role in other diseases, besides the management of diabetes. In this perspective, we provide our findings and understanding of metformin as an alternative way to treat urological abnormal proliferation. We propose the potential mechanisms into two hallmarks: direct antiproliferative function via insulin-like growth factor (IGF) signaling pathway and epigenetic modulating via adjusting DNA methylation. These specific hallmarks may ultimately contribute to a better understanding of metformin in treating prostatic diseases.

Resveratrol improves prostate fibrosis during progression of urinary dysfunction in chronic prostatitis by mast cell suppression.

Voiding dysfunction is the primary clinical manifestation of chronic prostatitis (CP), which is a common urological disease. The present study investigated whether prostate fibrosis was associated with urinary dysfunction in CP and if resveratrol improved urinary dysfunction, and the underlying molecular mechanism. A rat model of CP was established via subcutaneous injections of the pertussis­diphtheria­tetanus vaccine, which was followed by treatment with resveratrol. Bladder pressure and volume tests were performed to investigate the effect of resveratrol on urinary dysfunction in CP rats. Western blotting and immunohistochemical staining examined the expression levels of tryptase, chymase, transforming growth factor (TGF)­ß, Wnt and α­smooth muscle actin (α­SMA). The results demonstrated that the maximum capacity of the bladder, residual urine volume and maximum voiding pressure were increased significantly in the CP group compared with the control group. Mast cell (MC) activation, the activity of TGF­ß/Wnt/ß­catenin pathways, and the expression levels of tryptase and α­SMA in the CP group were increased significantly compared with the control group. Resveratrol treatment significantly reversed these factors. Therefore, the results indicate that MC infiltration may induce prostate fibrosis, which exhibits a close association with urinary dysfunction in CP. Resveratrol may improve fibrosis via the suppression of MC activation and TGF­ß/Wnt/ß­catenin pathway activities.