Vittorio Magri

Use of the UPOINT Chronic Prostatitis/Chronic Pelvic Pain Syndrome Classification in European Patient Cohorts: Sexual Function Domain Improves Correlations

PURPOSE Patients with chronic prostatitis-chronic pelvic pain syndrome are difficult to treat due to the unknown etiology and complex clinical presentation. Clinical phenotyping may better correlate with multimodal treatment concepts than a current diagnosis. We evaluated a novel clinical phenotyping system in a database of patients with chronic prostatitis-chronic pelvic pain syndrome at 2 European institutions and correlated it with patient symptoms. We also investigated the addition of a sexual dysfunction domain in regard to symptom correlation and system internal consistency. MATERIALS AND METHODS We retrospectively classified 937 patients from Milan, Italy, and 290 from Giessen, Germany, with chronic prostatitis-chronic pelvic pain syndrome into a 6-domain phenotyping system, consisting of urinary, psychosocial, organ specific, infection, neurological and muscle tenderness domains, termed UPOINT. Symptom severity was assessed by the National Institutes of Health Chronic Prostatitis Symptom Index and the International Prostate Symptom Score. RESULTS There was significant correlation between the number of positive UPOINT domains and Chronic Prostatitis Symptom Index/International Prostate Symptom Score symptoms in the total and Italian cohorts but not in the German cohort. After adding a sexual dysfunction domain to create the modified UPOINTS system phenotypic domains also correlated significantly with Chronic Prostatitis Symptom Index symptoms in the German cohort. CONCLUSIONS Consistency of the UPOINT chronic prostatitis-chronic pelvic pain syndrome clinical phenotyping system was generally confirmed by our study and further refined by adding a sexual dysfunction domain. The treatment effect of clinical phenotyping with UPOINT(S) must be extensively evaluated in prospective treatment studies.

National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) Symptom Evaluation in Multinational Cohorts of Patients with Chronic Prostatitis/Chronic Pelvic Pain Syndrome

BACKGROUND The assessment of patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) in everyday practice and clinical studies relies on National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) scores for symptom appraisal, inclusion criteria for clinical trials, follow-up, and response evaluation. OBJECTIVE We investigated multiple databases of CP/CPPS patients to determine the prevalence and impact of pain locations and types to improve our strategy of individualized phenotypically guided treatment. DESIGN, SETTING, AND PARTICIPANTS Four major databases with CPSI scores for nonselected CP/CPPS clinic patients from Canada, Germany, Italy, and the United States. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Individual question scores and subtotal and total scores of CPSI were described and correlated with each other. Ordinal regression analysis was performed to define pain severity categories. RESULTS AND LIMITATIONS A total of 1563 CP/CPPS patients were included. Perineal pain/discomfort was the most prevalent pain symptom (63%) followed by testicular pain (58%), pain in the pubic area (42%) and penis (32%); reports of pain during ejaculation and voiding were 45% and 43%, respectively. European patients had a significantly higher number of pain localizations and symptoms compared with North American patients (p<0.001). Severity of pain correlated well with frequency of pain (r = 0.645). No specific pain localization/type was associated with more severe pain. Correlation of pain domain with quality of life (QoL) (r = 0.678) was higher than the urinary domain (r = 0.320). Individually, pain severity (r = 0.627) and pain frequency (r = 0.594) correlated better with QoL than pain localization (r = 0.354). Pain severity categories results for NIH-CPSI item 4 (0-10 numerical rating scale for average pain) were mild, 0-3; moderate, 4-6; severe, 7-10; CPSI pain domain (0-21): mild, 0-7; moderate, 8-13; and severe, 14-21. CONCLUSIONS Pain has more impact on QoL than urinary symptoms. Pain severity and frequency are more important than pain localization/type. Cut-off levels for disease severity categories have been identified that will prove valuable in symptom assessment and the development of therapeutic strategies.

Fluoroquinolone–macrolide combination therapy for chronic bacterial prostatitis: retrospective analysis of pathogen eradication rates, inflammatory findings and sexual dysfunction

We previously demonstrated the safety and efficacy of fluoroquinolone-macrolide combination therapy in category II chronic bacterial prostatitis (CBP). The aim of this study is to retrospectively compare the microbiological and clinical findings of two treatment schemes for CBP based on the combination of azithromycin (500 mg, thrice-weekly) with a once-daily 500- or 750-mg dose of ciprofloxacin (Cipro-500 or Cipro-750 cohort, respectively). Combined administration of azithromycin (1500 mg week(-1)) with ciprofloxacin at the rate of 750 mg day(-1) for 4 weeks rather than at 500 mg day(-1) for 6 weeks increased the eradication rates from 62.35% to 77.32% and the total bacteriological success from 71.76% to 85.57%. A significant decrease in pain and voiding signs/symptoms and a significant reduction in inflammatory leukocyte counts and serum prostate-specific antigen (PSA) were sustained throughout an 18-month follow-up period in both groups. Ejaculatory pain, haemospermia and premature ejaculation were significantly attenuated on microbiological eradication in both groups, but the latter subsided more promptly in the Cipro-750 cohort. In total, 59 Cipro-750 patients showed mild-to-severe erectile dysfunction (ED) at baseline, while 22 patients had no ED on microbiological eradication and throughout the follow-up period. In conclusion fluoroquinolone-macrolide therapy resulted in pathogen eradication and CBP symptom attenuation, including pain, voiding disturbances and sexual dysfunction. A once-daily 750-mg dose of ciprofloxacin for 4 weeks showed enhanced eradication rates and lower inflammatory white blood cell counts compared to the 500-mg dose for 6 weeks. Our results are open to further prospective validation.

Multimodal therapy for category III chronic prostatitis/chronic pelvic pain syndrome in UPOINTS phenotyped patients.

The complex network of etiological factors, signals and tissue responses involved in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) cannot be successfully targeted by a single therapeutic agent. Multimodal approaches to the therapy of CP/CPPS have been and are currently being tested, as in the frame of complex diagnostic-therapeutic phenotypic approaches such as the urinary, psychosocial, organ-specific, infection, neurological and muscle tenderness (UPOINTS) system. In this study, the effect of combination therapy on 914 patients diagnosed, phenotyped and treated in a single specialized prostatitis clinic was analyzed. Patients received α-blockers, Serenoa repens (S. repens) extracts combined or not with supplements (lycopene and selenium) and, in the presence of documented or highly suspected infection, antibacterial agents. Combination treatment induced marked and significant improvements of National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) prostatitis symptom scores, International Index of Erectile Function (IIEF) sexual dysfunction scores, urinary peak flow rates and bladder voiding efficiency. These improvements, assessed after a 6-month course of therapy, were sustained throughout a follow-up period of 18 months. A clinically appreciable reduction of ≥6 points of the total NIH-CPSI score was achieved in 77.5% of patients subjected to combination therapy for a period of 6 months. When the patients were divided in two cohorts, depending on the diagnosis of CP/CPPS [inflammatory (IIIa) vs. non-inflammatory (IIIb) subtypes], significant improvements of all signs and symptoms of the syndrome were observed in both cohorts at the end of therapy. Intergroup comparison showed that patients affected by the IIIa sub-category of CP/CPPS showed more severe signs and symptoms (NIH-CPSI total, pain and quality of life impact scores, and Qmax) at baseline when compared with IIIb patients. However, the improvement of symptoms after therapy was significantly more pronounced in IIIa patients when compared with IIIb patients. In contrast to current opinion, the evidence emerging from the present investigation suggests that the inflammatory and non-inflammatory sub-categories of CP/CPPS may represent two distinct pathological conditions or, alternatively, two different stages of the same condition. In conclusion, a simple protocol based on α-blockers, S. repens extracts and supplements and antibacterial agents, targeting the urinary, organ specific and infection domains of UPOINTS, may induce a clinically appreciable improvement of the signs and symptoms of CP/CPPS in a considerable percentage of patients. In patients not responding sufficiently to such therapy, second-line agents (antidepressants, anxiolytics, muscle relaxants, 5-phosphodiesterase inhibitors and others) may be administered in order to achieve a satisfactory therapeutic response.

Enhanced distribution of fourth-generation fluoroquinolones in prostatic tissue

A recently published pharmacokinetic trial showed that the fluoroquinolone moxifloxacin administered to healthy volunteers at the single oral dose of 400mg accumulates in prostatic secretions (PS) up to a median concentration of 3.99 mg/L and reaches a PS/plasma concentration ratio of 1.57, far higher than values shown by other fluoroquinolones such as norfloxacin (ratio 0.1) or ciprofloxacin (ratio 0.2). Ion trapping mechanisms were hypothesised to be among the determinants of this effect. However, whether ion trapping would solely account for the observed differences in fluoroquinolone pharmacokinetics was left to further research and discussion. In this hypothesis paper, we review various published evidence on the tissue distribution of moxifloxacin and other quinolones, suggesting that increased lipophilicity, binding to cellular matrices and fast cellular uptake/release kinetics may be mechanisms compatible with enhanced prostatic accumulation and secretion of fourth-generation fluoroquinolones.

Macrolides for the treatment of chronic bacterial prostatitis: An effective application of their unique pharmacokinetic and pharmacodynamic profile (Review)

Chronic bacterial prostatitis (CBP) is a persistent infection of the prostate characterized by poor quality of life mainly due to frequent relapse episodes caused by incomplete eradication of causative pathogens. Aggressive antibacterial therapy is required to attenuate the severe symptoms of CBP and to achieve a permanent cure. Although fluoroquinolones are currently recommended as first-choice agents, macrolide antibiotics are emerging as a noteworthy option for the treatment of CBP. Macrolide antibiotics are characterized by an impressive array of distinct pharmacokinetic (PK) and pharmacodynamic (PD) properties. These properties include high intracellular accumulation in phagocytes and at sites of infection, including the prostate; broad antibiotic but also biofilm-inhibiting properties; immunomodulating and inflammation-resolving activities. These features offer particular advantages for the treatment of chronic infections of the prostate gland, which are not easily amenable to drug therapy. Macrolides may be exploited to counteract the unsatisfactory rates of clinical symptom improvement and pathogen eradication. The results of a number of clinical trials support this proposal.

Multiparametric magnetic resonance imaging characteristics of normal, benign and malignant conditions in the prostate

AbstractObjectivesTo identify the multiparametric magnetic resonance imaging (mpMRI) characteristics of normal, benign and malignant conditions in the prostate.MethodsFifty-six histopathological whole-mount radical prostatectomy specimens from ten randomly selected patients with prostate cancer (PC) were matched with corresponding transverse mpMRI slices. The mpMRI was performed prior to biopsy and consisted of T2-weighted imaging (T2-WI), diffusion-weighted imaging (DWI), dynamic contrast-enhanced imaging (DCE) and magnetic resonance spectroscopic imaging (MRSI).ResultsIn each prostate specimen, a wide range of histopathological conditions were observed. They showed consistent but overlapping characteristics on mpMRI. Normal glands in the transition zone showed lower signal intensity (SI) on T2-WI, lower ADC values and lower citrate peaks on MRSI as compared to the peripheral zone (PZ) due to sparser glandular elements and more prominent collagenous fibres. In the PZ, normal glands were iso-intense on T2-WI, while high SI areas represented cystic atrophy. Mimickers of well-differentiated PC on mpMRI were inflammation, adenosis, HG-PIN and post-atrophic hyperplasia.ConclusionEach prostate is a unique mix of normal, benign and/or malignant areas that vary in extent and distribution resulting in very heterogeneous characteristics on mpMRI. Understanding the main concepts of this mpMRI-histopathological correlation may increase the diagnostic confidence in reporting mpMRI.Keypoints• In each prostate specimen a wide range of histopathological conditions was observed. • Interpretation of mpMRI may be difficult because benign conditions may mimic PC. • High signal intensity areas in the PZ on T2-WI represented cystic atrophy. • The TZ showed sparser glands and more collagenous fibres than the PZ.

Chlamydia trachomatis infection is related to premature ejaculation in chronic prostatitis patients: results from a cross-sectional study

INTRODUCTION Chronic bacterial prostatitis (CBP) is reported to be a common finding in men with acquired premature ejaculation (PE). The impact of different pathogens on PE development in chronic prostatitis patients is, however, unknown. AIM To assess a possible link between CBP caused by Chlamydia trachomatis (Ct) and PE. METHODS A consecutive series of 317 patients with clinical and instrumental diagnosis of CBP due to Ct was enrolled (group A) and compared with data obtained from a control group of 639 patients with CBP caused by common uropathogen bacteria (group B). Prostatitis symptoms were investigated with the National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI), while the ejaculatory status of patients was assessed using the PE Diagnostic Tool (PEDT). MAIN OUTCOME MEASURES All participants were asked to complete the NIH-CPSI, the International Index of Erectile Function-15 erectile function domain (IIEF-15-EFD), the PEDT, and the Short Form (SF)-36 questionnaires. RESULTS Patient groups A and B had comparable scores of NIH-CPSI (P = 0.07), IPSS (P = 0.32), and IIEF-15-EFD (P = 0.33) tests. PE was assessed in 118 patients in group A (37.2%) and in 73 subjects in group B (11.5%). The two groups are different in terms of PE prevalence (P < 0.0002). Compared with group B, group A showed significantly higher scores of the PEDT test (11.3 [±2.6] vs. 4.5 [±2.9], P < 0.0001) and lower scores of the SF-36 tool (96.5 [±1.1] vs. 99.7 [±1.3], P < 0.0001). In our multivariate model assessment, being positive for a Ct infection marker was independently associated with the PEDT score even after adjusting for age, smoking habit, body mass index, and education level (adjusted odds ratio = 3.21; 95% confidence interval: 2.02-4.27; P < 0.003). CONCLUSIONS Patients affected by CBP due to Ct infection reported higher prevalence of PE and lower quality of life when compared with patients affected by CBP caused by traditional uropathogenic bacteria.

A severely symptomatic case of anaerobic chronic bacterial prostatitis successfully resolved with moxifloxacin therapy.

It has been demonstrated that patients showing symptoms of chronic bacterial prostatitis but culture-negative prostate-specific specimens can benefit from administration of antibacterial agents. This suggests that organisms that are not isolated in the routine practice may be responsible for prostate infection in an undefined fraction of subjects. Anaerobic bacteria have been proposed to play a pathogenic role in CBP, on the basis of studies describing clinical remission after eradication of pathogens like Peptostreptococcus spp or Bacterioides spp from prostatic secretions of symptomatic patients, or the significant association between prostatic infection by anaerobes and the presence of inflammation markers in prostatic secretions. In this paper, we report in detail a case of severely symptomatic chronic prostatitis in a patient with evidence of infection by Peptostreptococcus. We also report for the first time that treatment with the 3rd generation fluoroquinolone moxifloxacin was successful in eradicating the pathogen and in causing dramatic resolution of signs and symptoms of chronic bacterial prostatitis. The strict association between eradication of Peptostreptococcus and the rapid disappearance of clinical signs/symptoms points to a causative role of this anaerobe in the chronic bacterial prostatitis case described in this report.

Herbal medicines for urinary stone treatment. A systematic review

OBJECTIVE To analyze the clinical evidence on the efficacy of phytotherapy in the treatment of calculi in the urinary tract. METHODS To be eligible, full-length articles should include the results of randomized controlled trials enrolling patients affected by urolithiasis, reporting any comparison between an experimental herbal agent versus placebo or any active comparator, aimed at preventing the formation or facilitating the dissolution of calculi in any portion of the urinary tract. Fifteen databases were searched for relevant references. The primary outcomes investigated were (i) the reduction of stone size and/or number and (ii) the urinary excretion rates of calcium, urate, or oxalate. The secondary outcome of the review was the adverse effects (AE) of treatment. Risk of bias (ROB) and quality of the evidence were assessed according to Cochrane and GRADE guidelines. We performed a random-effect meta-analysis. RESULTS 541 articles were retrieved and 16 studies were finally confirmed as eligible. Multiple Cochrane ROB tool items were rated as having high risk of bias in each analyzed trial report. Pooled analysis of continuous data could be performed for three different comparisons: (i) phytotherapy versus citrate as single agent (ii) phytotherapy versus placebo, (iii) preparation of Didymocarpus pedicellata (DP)--combined with other herbal agents--versus placebo. Results showed that citrate is superior to phytotherapy in significantly decreasing both the size of urinary stones (mean difference: phytotherapy, 0.42 mm higher; 95% CI: 0.23 to 0.6; Z = 4.42, P < 0.0001; I2 = 30%) and the urinary excretion rate of urate (mean difference: 42.32 mg/24h higher, 95% CI: 19.44 to 65.19; Z = 3.63, P = 0.0003; I2 = 96%), assessed after 3 months on-therapy. No significant differences in the excretion rates of urinary calcium or oxalate were found. The DP preparation was superior to placebo in inducing total clearance (risk ratio: 6.19, 95% CI: 2.60 to 14.74; Z = 4.12, P < 0.0001; I2 = 0%) and size reduction (mean difference: DP preparation, 4.93 mm lower; 95% CI: -9.18 to -0.67; Z = 2.27, P = 0.02; I2 = 99%) of renal and ureteral stones after 3 months of therapy. No significant differences in the inter-arm variation of excretion rates of urinary calcium or urate were found as result of the pooled phytotherapy-placebo comparison. Herbal remedies were in general devoid of side effects and in few cases citrate appeared to induce GI disturbances in a higher fraction of patients. Most reports did not provide inferential data concerning AE, and meta-analysis was not feasible. CONCLUSIONS Citrate is more effective than phytotherapy in decreasing the size of existing calculi in the urinary tract and in decreasing the urinary excretion rate of uric acid. A preparation containing Didymocarpus pedicellata combined with other herbal agents induces stone size reduction and clearance significantly better than placebo. Mayor limitations in the applicability of these results are the low quality of the evidence and the multiple sources of bias assessed in the studies included in the present review.