Archivio Italiano di Urologia e Andrologia - Vol. 90 - n. 4 - 2018 by Edizioni Scripta Manent

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ISSN 1124-3562

(Citrate in the management of urolithiasis – Pattaras JG, Moore RG – J Endourol. 1999 Nov;13(9):687-92.)

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INIZIO DELLA DISSOLUZIONE DELLA COMPRESSA DEL

STOMACO

GASTROPROTEZIONE: NE: ASSENZA DI EFFETTI SECONDARI ARI

3 INTESTINO TENUE: INTES

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Archivio Italiano di Urologia e Andrologia / Archives of Italian Urology and Andrology - Vol. 90; n. 4 December 2018

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Vol. 90; n. 4, December 2018

ORIGINAL PAPERS 227

Multidisciplinary approach to prostatitis Vittorio Magri, Matteo Boltri, Tommaso Cai, Roberto Colombo, Salvatore Cuzzocrea, Pieter De Visschere, Rosanna Giuberti, Clara Maria Granatieri, Maria Agnese Latino, Gaetano Larganà, Christian Leli, Giorgio Maierna, Valentina Marchese, Elisabetta Massa, Alberto Matteelli, Emanuele Montanari, Giuseppe Morgia, Kurt G. Naber, Vaia Papadouli, Gianpaolo Perletti, NeKtaria ReKleiti, Giorgio I. Russo, Alessandra Sensini, Konstantinos Stamatiou, Alberto Trinchieri, Florian ME Wagenlehner

249

Vesicourethral anastomosis including rhabdosphincter in retropubic radical prostatectomy: Technique and results

254

The aging male: Relationship between male age, sperm quality and sperm DNA damage in an unselected population of 3124 men attending the fertility centre for the first time

̈ nol Ramazan Topaktaş, Ahmet Ürkmez, Musab Ali Kutluhan, ̇Ismail Başıbüyük, ̧Sinasi Yavuz O

Alessandro Colasante, Maria Giulia Minasi, Filomena Scarselli, Valentina Casciani, Vincenzo Zazzaro, Alessandra Ruberti, Pierfrancesco Greco, Maria Teresa Varricchio, Ermanno Greco

260

The role of nutraceutical medications in men with non bacterial chronic prostatitis and chronic pelvic pain syndrome: A prospective non blinded study utilizing flower pollen extracts versus bioflavonoids Angela Maurizi, Francesco De Luca, Antonino Zanghi, Emy Manzi, Costantino Leonardo, Michele Guidotti, F.P. Antonaccio, Valerio Olivieri, Carlo De Dominicis

265

Treatment of retained encrusted ureteral Double-J stent Ibrahim Alnadhari, Mohammed Ahmed Alwan, Morshed Ali Salah, Abdulelah M. Ghilan

270

Lymphocyte-to-monocyte ratio is a valuable marker to predict prostate cancer in patients with prostate specific antigen between 4 and 10 ng/dl Volkan Caglayan, Efe Onen, Sinan Avci, Murat Sambel, Metin Kilic, Sedat Oner, Mustafa Murat Aydos, Halil Emre Yıldız

276

Low-intensity shock wave therapy for erectile dysfunction and the influence of disease duration

283

Penile fracture with urethral injury: Our experience in a tertiary care hospital

́lvaro Nunes, Francisco Martins, Tomé Lopes Pedro Simoes de Oliveira, Tiago Ribeiro de Oliveira, A

Priyatham Kasaraneni, Prasad Mylarappa, Ramesh Desi Gowda, Sandeep Puvvada, Dheeraj Kasaraneni

288

Low systolic blood pressure values, renal resistive index measurement and glomerular filtration rate in a non-dialysis dependent chronic kidney disease population Simone Brardi, Gabriele Cevenini continued on page III

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L’IPOCITRATURIA È LA PRINCIPALE CAUSA DI FORMAZIONE DEI CALCOLI RENALI… … FORTUNATAMENTE ANCHE LA PIÙ FACILMENTE CORREGGIBILE!

ISSN 1124-3562

(Citrate in the management of urolithiasis – Pattaras JG, Moore RG – J Endourol. 1999 Nov;13(9):687-92.)

2 DUODENO

INIZIO DELLA DISSOLUZIONE DELLA COMPRESSA DEL

STOMACO

GASTROPROTEZIONE: NE: ASSENZA DI EFFETTI SECONDARI ARI

3 INTESTINO TENUE: INTES

SITO SIT OD D’ASSORBIMENTO ’A DEL CITRATO

COMPRESSA RETARD

“ULTRADENSE” da 1,5 g di Citrato

L’UNICA L ’UNICA COMPRESSA COMPRESSA A LENTO LENTO RILASCIO CON BREVETTO ON BREVETT O EUROPEO: C

il Citr Citrato ato viene rilasciat rilasciato o nel suo principal principale e sit sito o di as assorbimento. sorbimento.

www.biohealth.it

Poste Italiane S.p.A. - Spedizione in abbonamento postale - D.L. 353/2003 (conv. in L. 27/02/2004 n. 46) Art. 1, comma 1 DCB Milano

Archivio Italiano di Urologia e Andrologia / Archives of Italian Urology and Andrology - Vol. 90; n. 4 December 2018

Il Citrato nella sua forma migliore!

Vol. 90; n. 4, December 2018

ORIGINAL PAPERS 227

249

Vesicourethral anastomosis including rhabdosphincter in retropubic radical prostatectomy: Technique and results

254

The aging male: Relationship between male age, sperm quality and sperm DNA damage in an unselected population of 3124 men attending the fertility centre for the first time

̈ nol Ramazan Topaktaş, Ahmet Ürkmez, Musab Ali Kutluhan, ̇Ismail Başıbüyük, ̧Sinasi Yavuz O

Alessandro Colasante, Maria Giulia Minasi, Filomena Scarselli, Valentina Casciani, Vincenzo Zazzaro, Alessandra Ruberti, Pierfrancesco Greco, Maria Teresa Varricchio, Ermanno Greco

260

265

Treatment of retained encrusted ureteral Double-J stent Ibrahim Alnadhari, Mohammed Ahmed Alwan, Morshed Ali Salah, Abdulelah M. Ghilan

270

276

Low-intensity shock wave therapy for erectile dysfunction and the influence of disease duration

283

Penile fracture with urethral injury: Our experience in a tertiary care hospital

́lvaro Nunes, Francisco Martins, Tomé Lopes Pedro Simoes de Oliveira, Tiago Ribeiro de Oliveira, A

Priyatham Kasaraneni, Prasad Mylarappa, Ramesh Desi Gowda, Sandeep Puvvada, Dheeraj Kasaraneni

288

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Official Journal of SIA, SIEUN, SIUrO and UrOP EDITORS

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EDITORIAL BOARD

P.F. Bassi (Roma), F. Boccafoschi (Novara), A. Bossi (Villejuif - France), P. Caione (Roma), F. Campodonico (Genova), L. Carmignani (Milano), L. Cheng (Indianapolis - USA), L. Cindolo (Avellino), G. Colpi (Milano), G. Corona (Firenze), A. Giannantoni (Perugia), P. Gontero (Torino), S. Joniau (Leuven - Belgio), F. Keeley (Bristol - UK), L. Klotz (Toronto - Canada), M. Lazzeri (Firenze), B. Ljungberg (Umeå - Svezia), A. Minervini (Firenze), N. Mondaini (Firenze), G. Muir (London - UK), G. Muto (Torino), R. Naspro (Bergamo), A. Patel (London - UK), G. Preminger (Durham - USA), D. Ralph (London - UK), A. Rodgers (Cape Town - South Africa), F. Sampaio (Rio de Janeiro - Brazil), K. Sarica (Istanbul - Turkey), R. Schiavina (Bologna), L. Schips (Vasto), H. Schwaibold (Bristol - UK), A. Simonato (Genova), S. Siracusano (Trieste), C. Terrone (Novara), A. Timoney (Bristol - UK), A. Tubaro (Roma), R. Zigeuner (Graz - Austria)

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SIEUN EDITOR

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SIEUN CO-EDITOR P. Martino (Bari)

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M. Barbera (Sciacca), L. Barozzi (Bologna), M. Bertolotto (Trieste), M. Bitelli (Roma), S. Bucci (Trieste) A. D’Amelio (Lecce), M. Del Zingaro (Perugia), L. Dell’Atti (Ferrara), A. Fandella (Monastier di Treviso) R. Gunelli (Forlì), S. Palazzo (Bari), P. Pepe (Catania), V. Scattoni (Milano), C. Trombetta (Trieste)

SIUrO EDITOR

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SIUrO ASSISTANT EDITOR G.N. Conti (Como)

SIUrO EDITORIAL BOARD

V. Altieri (Salerno), B. Avuzzi (Milano), E. Bollito (Torino), M. Borghesi (Bologna), S. Bracarda (Arezzo), O. Caffo (Trento), R. Colombo (Milano), G.F. Da Pozzo (Bergamo), F. Lanzi (Siena), A. Lapini (Firenze), G. Martorana (Bologna), C. Ortega (Alba - CN), G.L. Pappagallo (Mirano - VE), M. Rizzo (Trento), R. Sanseverino (Nocera Inferiore - SA), V. Vavassori (Bergamo)

UrOP EDITOR

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UrOP EDITORIAL BOARD

R. Colombo (Milano), R. Giulianelli (Roma), M. Lazzari (Firenze), A. Porreca (Abano Terme - PD), A. Russo (Milano), M. Scarcia (Acquaviva delle Fonti - BA), N. Suardi (Milano)

ASSOCIAZIONE UROLOGI LOMBARDI EDITOR E. Montanari (Milano)

HONORARY EDITOR E. Pisani (Milano)

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CASE REPORTS 293

Advanced chondrosarcoma of the pelvis: A rare case of urinary obstruction Valerio Olivieri, Valentina Fortunati, Scipio Annoscia, Massimo Massarelli, Luca Bellei, Massimo Ollino, Emy Manzi, Angela Maurizi, Francesco De Luca

295

Isolated corpus spongiosum injury after sexual intercourse Ioannis Anastasiou, Aikaterini Anastasiou, Ioannis Katafigiotis, Dimitrios Tsavdaris, Constantinos Constantinides

297

Undiagnosed paraganglioma; A challenge during laparoscopic retroperitoneal resection Alexander Heinze, Periklis Nikomanis, Ferdinand Petzold, Jens Jochen Rassweiler, Ali Serdar Goezen

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DOI: 10.4081/aiua.2018.4.227

ORIGINAL PAPER

Multidisciplinary approach to prostatitis Vittorio Magri 1, Matteo Boltri 2, Tommaso Cai 3, Roberto Colombo 4, Salvatore Cuzzocrea 5, Pieter De Visschere 6, Rosanna Giuberti 7, Clara Maria Granatieri 1, Maria Agnese Latino 9, Gaetano Larganà 9, Christian Leli 10, Giorgio Maierna 1, Valentina Marchese 11, Elisabetta Massa 1, Alberto Matteelli 11, Emanuele Montanari 12, Giuseppe Morgia 9, Kurt G. Naber 13, Vaia Papadouli 14, Gianpaolo Perletti 15, NeKtaria ReKleiti 14, Giorgio I. Russo 9, Alessandra Sensini 8, Konstantinos Stamatiou 14, Alberto Trinchieri 16, Florian ME Wagenlehner 17 1 ASST

Nord Milano, Italy; Medical School, University of Trieste, Trieste, Italy; 3 Department of Urology, Santa Chiara Regional Hospital, Trento, Italy; 4 Synlab Italia, Castenedolo (BS), Italy; 5 Università degli Studi di Messina, Messina, Italy; 6 Department of Radiology and Nuclear Medicine, Ghent University Hospital, Ghent, Belgium; 7 SICT Società Idrocolonterapia, Milano, Italy; 8 Working Group on Sexually Transmitted Infections, Italian Association of Clinical Microbiologists, GLIST-AMCLI, Italy; 9 Department of Urology, Università degli Studi di Catania, Catania, Italy; 10 Unit of Microbiology, SS Antonio, Biagio and C. Arrigo Hospital, Alessandria, Italy; 11 Department of Infectious and Tropical Diseases, University of Brescia, Brescia, Italy; 12 Department of Urology, IRCCS Ca’ Granda Ospedale Maggiore Policlinico - University of Milan, Milan, Italy; 13 Technical University of Munich, Munich, Germany; 14 Tzaneio Hospital; 15 Department of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, University of Insubria, Varese, Italy; 16 Urology Unit, Manzoni Hospital, Lecco, Italy; 17 Clinic for Urology, Pediatric Urology and Andrology, Justus Liebig University Giessen, Germany. 2 Urology

Report of the meeting Prostatitis: A Multidisciplinary Approach (Issues and Controversies), Milano, Italy, 26-27 Oct 2018

Summary

The modern clinical research on prostatitis started with the work of Stamey and coworkers who developed the basic principles we are still using. They established the segmented culture technique for localizing the infections in the males to the urethra, the bladder, or the prostate and to differentiate the main categories of prostatitis. Such categories with slight modifications are still used according to the NIH classification: acute bacterial prostatitis, chronic bacterial prostatitis, Chronic Pelvic Pain Syndrome (CPPS) and asymptomatic prostatitis. Prostatic inflammation is considered an important factor in influencing both prostatic growth and progression of symptoms of benign prostatic hyperplasia and prostatitis. Chronic inflammation/neuroinflammation is a result of a deregulated acute phase response of the innate immune system affecting surrounding neural tissue at molecular, structural and functional levels. Clinical observations suggest that chronic inflammation correlates with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and benign prostatic hyperplasia (BPH) and an history of clinical chronic prostatitis significantly increases the odds for prostate cancer. The NIHNIDDK classification based on the use of the microbiological 4glasses localization test or simplified 2-glasses test, is currently accepted worldwide. The UPOINT system identifies groups of clinicians with homogeneous clinical presentation and is used to recognize phenotypes to be submitted to specific treatments. The UPOINTS algorithm implemented the original UPOINT adding to the urinary domains (U), psycho-social (P), organspecific (O), infection (I), neurological (N), muscle tension and tenderness (T) a further domain related to sexuality (S). In fact sexual dysfunction (erectile, ejaculatory, libido loss) has been described in 46-92% of cases with a high impact on the quality

of life of patients with CP/CPPS. Prostatic ultrasound represents the most popular imaging test in the work-up of either acute and chronic prostatitis although no specific hypo-hyperechoic pattern has been clearly associated with chronic bacterial prostatitis and CPPS. Use of a digital-processing software to calculate the extension of prostatic calcification area at ultrasound demonstrated a higher percentage of prostatic calcification in patients with chronic bacterial prostatitis. Multiparametric Magnetic Resonance Imaging (mpMRI) is the current state-of-the art imaging modality in the assessment of patients with prostate cancer although a variety of benign conditions, including inflammation, may mimic prostate cancer and act as confounding factors in the discrimination between neoplastic and non-neoplastic lesions. Bacteria can infect prostate gland by: ascending the urethra, reflux of urine into the prostatic ducts, direct inoculation of bacteria through inserted biopsy needles or hematogenous seeding. Enterobacteriaceae are the predominant pathogens in acute and chronic bacterial prostatitis, but an increasing role of Enterococci has been reported. Many strains of these uropathogens exhibit the ability to form biofilm and multidrug-resistance. Sexually Transmitted Infections (STI) agents, in particular Chlamydia trachomatis and Mycoplasma genitalium, have been also considered as causative pathogens of chronic bacterial prostatitis. On the contrary the effective role in genital diseases of other "genital mycoplasmas" is still a much debated issue. Sexually Transmitted Infections agents should be investigated by molecular methods in both patient and sexual partner. “Next generation” investigations, such as cytokine analysis, cytological typing of immune cells could help stratifying the immune response. Epigenetic dysregula-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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tion of inflammatory factors should be investigated according to systemic and compartment-specific signals. The search for biomarkers should also include evaluation of hormonal pathways, as measurement of estrogen levels in semen. Antimicrobials are the first line agents for the treatment of bacterial prostatitis. The success of antimicrobial treatment depends on the antibacterial activity and the pharmacokinetic characteristics of the drug which must reach high concentrations in prostate secretion and prostate tissue. Acute bacterial prostatitis can be a serious infection with a potential risk for urosepsis For iInitial treatment of severely ill patients, intravenous administration of high doses of bactericidal antimicrobials, such as broad-spectrum penicillins, third-generation cephalosporins or fluoroquinolones, is recommended in combination with an aminoglycoside. Use of piperacillin-tazobactam and meropenem is justified in presence of multiresistant gramnegative pathogens. The antibiotic treatment of chronic prostatitis is currently based on the use of fluoroquinolones that, given for 2 to 4 weeks, cured about 70% of men with chronic bacterial prostatitis. For the treatment of Chlamydial prostatitis macrolides were shown to be more effective than fluoroquinolones, whereas no differences were observed in microbiological and clinical efficacy between macrolides and tetracyclines for the treatment of infections caused by intracellular pathogens. Aminoglycosides and fosfomycin could be considered as a therapeutic alternative for the treatment of quinolone resistant prostatitis. Use of alpha-blockers in CP/CPPS patients with urinary symptoms and analgesics +/non steroidal anti-inflammatory drugs (NSAID), in presence of pain demonstrated a reduction of symptoms reduction and an improvement of quality of life, although long term use of NSAID is limited by side effect profile. However, the multimodal therapeutic regimen by contemporary use of alphablockers, antibiotics and anti-inflammatory showed a better

control of prostatitis symptoms than single drug treatment. Novel therapeutic substances for the treatment of pain, such as the cannabinoid anandamide would be highly interesting to test. An alternative for the treatment of chronic prostatitis/chronic pelvic pain syndrome is phytotherapy, as primary therapy or in association with other drugs. Quercetin, pollen extract, extract of Serenoa repens and other mixtures of herbal extracts showed a positive effect on symptoms and quality of life without side effects. The association of CP/CPPS with alterations of intestinal function has been described. Diet has its effects on inflammation by regulation of the composition of intestinal flora and direct action on the intestinal cells (sterile inflammation). Intestinal bacteria (microbiota) interacts with food influencing the metabolic, immune and inflammatory response of the organism. The intestinal microbiota has protective function against pathogenic bacteria, metabolic function by synthesis of vitamins, decomposition of bile acids and production of trophic factors (butyrate), and modulation of the intestinal immune system. The alteration of the microbiota is called “dysbiosis” causing invasive intestinal diseases pathologies (leaky gut syndrome and food intolerances, irritable bowel syndrome or chronic inflammatory bowel diseases) and correlating with numerous systemic diseases including acute and chronic prostatitis. Administration of live probiotics bacteria can be used to regulate the balance if intestinal flora. Sessions of hydrocolontherapy can represent an integration to this therapeutic approach. Finally, microbiological examination of sexual partners can offer supplementary information for treatment.

HISTORICAL

massage were used together with the clinical symptoms to differentiate between the main categories of prostatitis: acute bacterial prostatitis (ABP), chronic bacterial prostatitis (CBP), nonbacterial prostatitis, and prostatodynia. In principle, these categories with slight modifications were also used for the NIH classifications: 1. Acute bacterial prostatitis; 2. Chronic bacterial prostatitis; 3. Chronic Pelvic Pain Syndrom (CPPS); 3a. Inflammatory; 3b. Noninflammatory; and 4. Asymptomatic prostatitis (3). In his review Stamey also presented the principles concerning pharmacokinetics (PK) of antibiotics used for the treatment of acute and chronic bacterial prostatitis and the role of non-ionic diffusion of weak acids and bases across membranes with a pH gradient (1). He and his coworkers found out, that besides protein binding and lipid solubility the pH of the prostatic secretion on one side and the isoelectric point of the compound on the other side were playing a major role for drug penetration into the prostatic secretion which was considered crucial at least for the antibacterial therapy of CBP. At that time most studies were performed in a dog model (1). Thereafter, many PK studies were also performed in humans, especially with fluotoquinolones considered the most appropriate antibiotics to treat CBP because of their broad spectrum, including most of the causative pathogens, and because most fluoroquinolones were neither pure acids nor bases, but amphoteric (zwitterionic) drugs with an isoelectric point between the two pKa values (4). Since CPPS on the

REMARKS

(Kurt G. Naber) The modern clinical research on prostatitis started with the work by Meares EM jr. and Stamey TA and coworkers, which Stamey nicely summarized 27 years ago (1). Now we have to see which of their achievements are still valid and which of them have to be reconsidered or even need to be replaced by new findings. In summary, Stamey (1) stated that “Prostatitis” is a common and frustrating problem for the urologist and the general practitioner. Not only is there no generally accepted definition, but there are no clearly established criteria for making the diagnosis, and no definite pathophysiology. Because very few authors have defined prostatitis and almost no two works use the same criteria for inclusion of patients within a study, few comparisons can be made from the findings of one author to those of another. Except for true bacterial prostatitis, it is fair to comment that little more is known about prostatitis than was reported by Hugh H Young and his associates in 1906 (2). Despite this rather pessimistic view, he and his coworkers developed the basic principles we are still using. Together with Meares they established the segmented culture technique for localizing the infections in the males to the urethra, the bladder, or the prostate. Their four glass test results with first voided urine sample, midstram urine sample, expressed prostatic secretion and first voided urine sample after prostate

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Archivio Italiano di Urologia e Andrologia 2018; 90, 4

KEY WORDS: Chronic bacterial prostatitis; Chronic pelvic pain syndrome; Inflammation; Antibiotic treatment; Phytotherapy; Dysbiosis. Submitted 12 Decembrer 2018; Accepted 18 Decembrer 2018

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Multidisciplinary approach to prostatitis

other side was considered a multifactorial disease with many pathophysiological causes a more symptom related approach was finally recommended. For this reason the NIH-CPSI (5) and the UPOINT concept was developed (6). Many other detailed investigations were performed thereafter, but not many had a great impact on the clinical practice so far. Unfortunately the management of CPPS remains still unsatisfactory for the patients as well as for the urologists. Role of inflammation and infection in the determinism of benign prostatic hyperplasia and prostatitis.

PHYSIOPATHOLOGICAL ASPECTS (Salvatore Cuzzocrea)

In the spectrum of benign prostatic syndrome (PBS), chronic prostatitis (CP/CPPS) and benign prostatic hyperplasia (BPH) represent very important pathologies. Prostatic inflammation is considered an important factor in influencing both prostatic growth and progression of symptoms. The common inflammatory/neuroinfalmmatory aspects in CP/CPPS and BPH are represented by reactive astrocytes and activated microglia and involvement of the adaptive immune system, over expression of immune molecules such as chemokines and cytokines and increased oxygen and nitrogen reactive species concentration (ROS/RNS). Chronic inflammation/neuroinflammation is a result of a deregulated acute phase response of the innate immune system effecting surrounding neural tissue on a molecular, structural and functional levels. Clinical observations suggest that chronic inflammation correlates with CP/CPPS and BPH, as prostate tissues often have infiltrating lymphocytes and macrophages around glandular elements. The principal therapeutics for treatment of an enlarged prostate are α-blockers and 5α-reductase inhibitors (5ARIs). Alpha-blockers are often used as first-line therapy, as they relax muscles in the prostate and around the neck of the bladder and facilitate passage of urine but cannot reduce an enlarged prostate; in addition, these agents have side-effects such as first dose syncope, dizziness, tachycardia, hypotension, headache, asthenia, rhinitis and ejaculatory dysfunction. Moreover, cannabinoids have been demonstrated to exert an important role in the resolution of inflammation via multiple mechanisms. In the light of the above, we designed a study to evaluate the anandamide congener N- palmitoylethanolamide (PEA) and the flavonoid polydatin (PLD), as the formulation m(PEA/PLD), in terms of impact on the inflammatory process and oxidative stress in BPH. Recently, literature data reported that PEA, an endogenous fatty acid amide of the Nacylethanolamine family possess analgesic, antiinflammatory and neuroprotective actions, acting at different cellular targets such as immune cells; PEA is classified as a “Food for Special Medical Purposes” by health authorities of the European Union member states. PEA treatment in animals has demonstrated the efficacy and great promise for its use in the treatment of a lot of different inflammatory disorders. Nevertheless, PEA lacks direct antioxidant action to counteract free radical development as well as DNA, protein and lipid damage which

are important events occurring in BPH. Polydatin (3,4,5trihydroxystilbene-3-β-single-D-glucoside), also known as polygonin, is a polyphenolic phytoalexin with potent anti-oxidative activity that can be isolated from numerous plant species and can be easily synthesized. Our findings led us to assess the therapeutic effects of oral administration of a composite consisting of comicronized PEA + polydatin m(PEA/Pol) in a model of testosterone-induced benign hyperplasia (BPH) in terms of its therapeutic effects and efficacy as an anti-oxidant and antinflammatory drug (7). The results of our study show, for the first time, that m(PEA/Pol) has the ability to decrease prostate weight and DHT production in BPH-induced rats. These effects may be due to the antiinflammatory and apoptotic effects of m(PEA/Pol). Preliminary results suggest that m(PEA/Pol) may exert therapeutic effect event in a model of CP/CPPS. Accordingly, these results support the hypothesis that m(PEA/Pol) should be further explored as a valid candidate for the treatment of BPH. the I2 value. Pooled analysis resulted in a crude odds ratio of 1.83, indicating a significant association between a history of prostatitis and prostate cancer (95% CI: 1.43 to 2.35; P < 0.00001) (5). The 1.83 odds ratio could be converted into a significant risk-ratio estimate of 1.63 (95% CI: 1.23 to 2.17). The set of pooled data showed considerable heterogeneity (I2 = 91%). Sensitivity analysis performed by excluding an extreme outlier decreased heterogeneity (I2 = 81%) and resulted in an odds ratio equal to 1.55 (95% CI: 1.30-1.85,

PROSTATITIS AND PROSTATE CANCER RISK: META-ANALYSIS (Gianpaolo Perletti)

Inflammation is a major risk factor for several types of cancer. Conditions like ulcerative colitis, Barrett’s esophagus, chronic urothelium inflammation and hepatitis can increase the likelihood of developing malignancies. In the last years, several studies investigated whether a history of clinical chronic prostatitis can be a risk factor for prostate cancer. A meta-analysis of such studies, performed on data published up to July 2012 indicates that clinical prostatitis may be moderately associated with prostate cancer, since the odds ratio between a history of prostatitis and prostate cancer was shown to be 1.64 (95% CI: 1.36 to 1.98) (8). After year 2012, new quality studies have been performed on over 7000 patients (911). Thus, we deemed necessary to perform an updated meta-analysis to complement the data so far produced, and to further investigate the relationship between prostate cancer and previous exposure to chronic prostatitis. The main outcome of our systematic review was the association between a history of clinical chronic prostatitis (NIH category II or III) and a histologically confirmed diagnosis of prostate cancer of any grade. Out of 2794 de-duplicated records published between year 2000 and January 31st, 2017, we retrieved sixteen fulltext articles reporting the data of fifteen case-control studies including a total population of 422943 men. Prostate cancer cases were 13942 (with previous history of prostatitis, n = 1806) and controls were 409001 (with Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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previous history of prostatitis, n = 57203). We analyzed binary data by calculating odds ratios and 95% confidence intervals (95% CI). We applied a random-effects model to the analysis of pooled data, and heterogeneity was assessed by calculating the I2 value. Pooled analysis resulted in a crude odds ratio of 1.83, indicating a significant association between a history of prostatitis and prostate cancer (95% CI: 1.43 to 2.35; P < 0.00001) (12). The 1.83 odds ratio could be converted into a significant risk-ratio estimate of 1.63 (95% CI: 1.23 to 2.17). The set of pooled data showed considerable heterogeneity (I2 = 91%). Sensitivity analysis performed by excluding an extreme outlier decreased heterogeneity (I2 = 81%) and resulted in an odds ratio equal to 1.55 (95% CI: 1.30-1.85, P < 0.00001). No significant publication bias was evidenced by the Egger’s and Begg's tests for funnel plot asymmetry. The ‘trim and fill’ method applied to the funnel plot imputed 3 missing studies and the resulting adjusted estimate of the odds ratio was 2.12 (95% CI: 1.38 to 3.22). Detection bias was virtually present in all included studies, mainly due to the increased probability of prostate cancer detection in prostatitis patients repeatedly subjected to thorough clinical assessments. Five among the included studies reported data assessed in 8015 African-American subjects. A subgroup meta-analysis was attempted, resulting in a non-significant crude odds ratio of 1.59 (95% CI: 0.71 to 3.57, P = 0.26). In conclusion, meta-analysis shows that a history of clinical chronic prostatitis can significantly increase the odds for prostate cancer. The odds ratio of 1.83, calculated on a larger patient population, is higher than the one reported by Jiang (OR = 1.6) (8), though association between exposure to prostatitis and cancer could not be demonstrated in African-American individuals. Conversely, a recent meta-analysis showed a clear association in Asian patients (OR = 3.54, 95% CI: 2.60-4.82) (13) Since – compared with Caucasian men – in men of African descent the prostate cancer incidence is 60% higher and the mortality rate is up to 3 times greater, new quality studies performed on larger sample sizes are urgently needed to provide unequivocal evidence in this population.

PROSTATITIS: A CONDITION STILL TO BE EXTENSIVELY INVESTIGATED (Vittorio Magri, Emanuele Montanari) Prostatitis is still an enigmatic disease due to the inconsistency of the epidemiological data, the uncertainty etiology, the inadequacy of the diagnosis and the absence of a standardized pharmacological treatment. The term prostatitis, which literally means "inflammation of the prostate", is currently used to describe a set of clinical conditions of uncertain etiology that are not always associated with a clear demonstration of the presence of an inflammatory process and that include painful pelvic symptoms, low urinary tract symptoms and sexual disorders that require differentiated treatment. The prevalence of these symptoms has been estimated at 8% of the adult male population (14). Patients with prostatitis were initially classified into four groups of acute bacterial prostatitis, chronic bacterial prostatitis, chronic bacterial prostatitis and prostatodynia.

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From this classification derived the NIH-NIDDK (National Institute of Health -National Institutes of Diabetes and Digestive and Kidney Diseases) classification (15), which is currently accepted worldwide (Table 1). These classifications are based on the use of the microbiological 4-glasses localization test of Meares-Stamey or of the simplified 2glases test (16, 17). The success of this examination requires an appropriate collection of the prostatic secretion after adequate prostatic massage. The UPOINT system identifies groups of clinicians with homogeneous clinical presentation and is used to recognize phenotypes to be submitted to specific treatments (Table 2) (18). To improve the clinical approach to prostatitis it is crucial to speak a shared language starting from what is already defined in the guidelines of the European Association of Urology (EAU) (19) and other national guidelines like those of the Prostate Expert Reference Group (PERG) of the National Health Service (NHS) (20). The answers of 266 out 1483 (17.9%) urologists associated to the Società Italiana di Urologia (SIU) who had been sent an e-mail questionnaire to describe the current methods of diagnosis and treatment of chronic prostatitis among Italian urologists showed that a mean of 23 patients with symptoms of prostatitis presented to their clinics in a month. The majority of the respondents still prefers the collection of a narrative clinical history together with the clinical examination whereas the use of validated questionnaires is still not widespread. The NIH-CPSI (National Institute of Health – Chronic Prostatitis Symptom Index) (5) was administered only by 17.29%. The most frequently used laboratory tests are the measurement of PSA and the culture tests of semen and urine. The use of microbiological localization tests is still poorly widespread. The most common instrumental examinations were uroflowmetry and suprapubic ultrasound. Transrectal ultrasound (TRUS) is used only by 10%. An extended protocol, such as that we adopted at our institution, should include: history and physical examination, administration of symptom questionnaires (NIH-CPSI, IPSS, IIEF-15 or -5, PEDT, UPOINT or UPOINTS), microbiological evaluation, prostatic ultrasound and uroflowmetry. In particular we suggest the use of the UPOINTS algorithm that has implemented the original UPOINT proposed by Skoskes (18). To the urinary domains (U), psycho-social (P), organ-specific (O), infection (I), neurological (N), muscle tension and tenderness (T) a further domain related to sexuality (S) was added (21). In fact sexual dysfunction (erectile, ejaculatory, libido loss) has been described in 46-92% of cases with a high impact on the quality of life of patients with CP/CPPS. In our experience we observed erectile dysfunction in 49.9% (although of mild severity in 75% of cases) and ejaculatory dysfunction in 59.9% (predominantly burning or ejaculatory pain and premature ejaculation) (22). According to PERG (20) we also suggest to investigate the presence of irritable bowel syndrome. In fact, in a group of 232 patients we observed the concomitant presence of intestinal disorders (diarrhea or constipation, abdominal pain or bloating) in 69% and 60.5% of patients with chronic bacterial prostatitis or pelvic pain syndrome, respectively. Furthermore, the possibility of a sexually transmitted infection starting from a urethral infection that spreads progressively to the prostate and to the accessory

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Table 1. NIH-NIDDK classification of prostatitis. Category I II III IIIA IIIB IV

Designation Acute bacterial prostatitis Chronic bacterial prostatitis Chronic non-bacterial prostatitis/chronic pelvic pain syndrome (CPPS) Inflammatory Non-inflammatory Asymptomatic inflammatory prostatitis

Status of infection Acute infection of prostate Recurrent infection of prostate No demonstrable infection WBC in semen/EPS/post-prostatic massage urine No WBC in semen/EPS/post-prostatic massage urine Asymptomatic

WBC: white blood cell, EPS: expressed prostatic secretion.

Table 2. UPOINTS classification for phenotypic domains (modified by Shokes et al and Magri et al.). DOMAIN Urinary

Psychosocial

Organ specific

Infection Neurological/systemic

Tenderness (skeletal muscles)

Sexual dysfunction

DIAGNOSIS CPSI urinary score > 4 Urgency, frequency or nocturia Post-void residual urine > 100 Clinical history of depression Ongoing antidepressant therapy Evidence of catastrophizing at interview and visits Specific prostate tenderness Leucocytosis in prostate fluid and/or VB3 Hemospermia Extensive prostate calcification Gram neg or Enterococcus in prostate fluid or 4-glass test Pain beyond abdomen or pelvis Irritable bowel syndrome history Fibromyalgia history Chronic fatigue syndrome history Palpable muscle spasm or trigger points in abdomen and pelvic floor

Erectile dysfunction (IIEF questions 1-5 + 15 < 26 Orgasmic dysfunction evidence (IIEF 9+10 < 9) Sexual desire impairment evidence (IIEF questions 11+12 < 9)

sexual glands has to be considered. Gonococcal infection is infrequent today, but it is still frequent the finding of other sexually transmitted pathogens. In our experience we isolated with the 4-glasses test and/or seminal analysis Chlamydia trachomatis in 26.8-33.6%, Ureaplasma urealyticum in 56.3-59.7%, Mycoplasma hominis in 7.3% and Trichomonas vaginalis in 1.4-1.8%. Finally it is recommended to correctly record the results of treatment on the basis of clinical criteria (NIH-CPSI decrease of at least 4-6 points of the total score or at least 25% decrease of total score) or of microbiological criteria (eradication, persistence, relapse).

SEXUAL

DYSFUNCTION AND CHRONIC PROSTATITIS

(Giuseppe Morgia)

Chronic prostatitis has an important role in men sexual function. Sexual dysfunction is difficulty experienced by an individual or a couple during any stage of a normal sexual activity. It could be sexual desire disorders, sexual arousal disorder, orgasmic disorders, sexual pain disorders. The prevalence of sexual dysfunctions is: 2-40%

TREATMENT Anticholinergic Alpha-blockers Counseling Antidepressant Referral to psychologist 5-ARI Phytotherapy (quercitin, pollen extracts, Serenoa) Prostatic massage Alpha-blockers Antibiotics Gabapentinoids Antidepressants Specific treatments Skeletal muscle miorelaxants Pelvic floor physiotherapy Physical activity PDE5-inhibitors

for erectile dysfunction, 15-25% decreased interest or desire, 8-32% ejaculation dysfunction, 12-19% orgasm, 17% dyspareunia. Prostatitis and sexual dysfunction are 2 common diseases, the prevalence of sexual dysfunction among men with CP/CPPS was 62%. Among chronic bacterial prostatitis symptoms one of the most important symptoms is pain with ejaculation, symptom also present among chronic pelvic pain syndrome symptoms, with erectile dysfunction and premature ejaculation. Ejaculation pain is one of the most important and frequent chronic prostatitis symptoms, in fact in NIH Chronic Prostatitis Symptoms Index there is a question on pain or burning during or after sexual climax. It could be the only manifestation of prostatitis. 24% of patients have regularly ejaculatory pain, 50% intermittently and only 26% of patients with CPPS never experienced ejaculatory pain. There isnâ&#x20AC;&#x2122;t a single cause of post-ejaculatory pain. Seminal infection, ejaculatory duct obstruction (with or without stones), neuromuscular spasm instigated by the muscular constriction of emission, interstitial cystitis could cause pain during ejaculation. Premature ejaculation (PE) is male inability to inhibit ejaculation long enough for the partner to reach orgasm, time before Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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ejaculation varied from 1 to 7 minutes after vaginal intromission. PE is an important sexual dysfunction strongly associated to CP/CPPS, chronic bacterial prostatitis and prostatic inflammation. The prevalence of PE among men with CP/CPPS is 40%. The rates of PE and possible PE assessed with the premature ejaculation diagnostic tool (PEDT) significantly increased with an increase in pelvic pain severity, as assessed by the NIH-CPSI. In the moderate to severe symptom group, 45.0% men demonstrated PE. In an Italian study of 399 men with symptoms suggesting prostatitis (23), 220 patients (55%) had ejaculatory dysfunctions, more frequently in patients with bacterial chronic prostatitis with respect to patients with chronic pelvic pain syndrome. In particular Chlamydia trachomatis infection is related to a major incidence of premature ejaculation in patients with CBP (37.2%), rather than common uropathogen bacteria (11.5%) (24). The incidence of erectile dysfunction is increasing with age, the prevalence of erectile dysfunction among men with CP/CPPS was 29%. Aetiology of ED in patients with CP/CPPS could be vasculogenic arterial insufficiency and veno-occlusive disease, endocrine, neurogenic, psychogenic. In men with chronic prostatitis there is an arterial stiffness associated with nitric oxide-mediated vascular endothelial dysfunction and 50% patients have signs of pelvic floor spasm that decrease arterial penile inflow. Hypogonadism is a common finding in men with ED. It has been postulated that sex hormones may also be an important factor in the development of prostatitis. Differences have been reported in the frequency of 3 alleles near the phosphoglycerate kinase gene between patients with CPPS and controls, a gene associated to familiar prostate cancer, hypospadias and specially androgen insensitivity (25). In patients with CP/CPPS there is a higher serum level of androstenedione and testosterone, with a lower serum level of cortisol. In 10-19% of patients there are abnormalities in the afferent and efferent autonomic nervous systems associated to neuropathic pain, linked to erectile dysfunction. At least, CP/CPPs is strongly linked with stress, anxiety and maladaptive responses to stressful situation, problems associated with erectile dysfunction. What kind of therapy we could use for sexual dysfunction? Unfortunately, there are still few studies in sexual dysfunction treatment. Alfuzosin 10 mg could be used for chronic prostatitis, improving IPPS score and bother score (26), but this alpha-blocker improved sexual function with lower pain/discomfort and better rigidity and increased ejaculate. Also use of doxazosin shows a reduction of NIH-CPSI (27), but demonstrates a not yet clear role of alpha-blockers for sexual dysfunction in CP/CPPS patients. Trigger point release and paradoxical relaxation training of pelvic floor could also have considered in a multimodal therapy for chronic prostatitis. This training shows an improvement in pain, urinary and sexual scores after therapy, as assessed by Pelvic Pain Symptom Survey. Phytotherapy represents an attracting option: treatment with curcumin and Calendula extract improved significantly IIEF-5 and PEDT in patients with CP/CPPS type III (28) and quercetin ameliorated erectile dysfunction in streptozotocin-induced diabetic rats (29).

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UTILITY OF ULTRASOUND IN PATIENTS WITH PROSTATITIS: COMPUTERIZED ANALYSIS (Matteo Boltri)

Prostatic ultrasound represents the main imaging test in the work-up of either acute and chronic prostatitis. TRUS and transperineal (TPUS) approaches are superior to transabdominal ultrasound with TRUS being more accurate (30). Transrectal probes are divided into monoplanar, biplanar and end-fire according to transducer arrangement. The US anatomy of apex is well defined by linear probes, whereas end-fire probes better define the base. Color-Doppler mode, tissue harmonic imaging and contrast-enhanced techniques may provide additional information. Utility of ultrasound in the evaluation of acute prostatitis might be of clinical interest in the differential diagnosis of parenchymal abscess (31) or in the detection of a significant post-voiding volume, which is an indication for temporary bladder catheterization. The role of ultrasound in the work-up of chronic bacterial prostatitis (CBP) and chronic pelvic pain syndrome (CP/CPPS) is still debated. To date, no specific hypohyperechoic pattern has been clearly associated with CBP and CP/CPPS. The detection of hypoechoic periurethral zone volume, posterior prostate lip thickness and bladder neck thickness might be a hallmark of CP/CPPS (32). Hyperechoic areas should be described in the ultrasound report because of their clinical significance. Prostatic calcifications are common in the elderly, although younger people with CBP and CP/CPPS also develop prostatic calcifications of varying size, that could be associated with: presence of a more intense chronic inflammation, positive cultures of the prostatic fluid, longer duration of symptomatology according to NIH/CPSI score (33) and lower efficacy of antibiotic treatment in eradicating the infection of the prostate (34). For a long time the evaluation of the presence of prostate calcification has been based on subjective evaluations, ending in a qualitative dichotomy between patients “with” and “without” calcifications. The development of a standardized method for a quantitative assessment of such calcification has been advocated. Transrectal images of the prostate acquired with a standard protocol can easily been analyzed using a digital-processing software, able to calculate the extension of calcification area. Open-source software like ImageJ by NIH are of great importance in making the access to this technology easier. The relation between the area of prostatic calcification and the prostate area can be expressed as a percentage. In a recent study it has been demonstrated that in a quantitative-based model, a higher percentage of prostatic calcification is more frequently observed in patients with chronic bacterial prostatitis and is related to worse urinary symptoms (35). The utility of an objective method could be of augmented interest either for researchers and clinician. 3D transrectal scanners integrated with a digital-processing software could lead to a better comprehension of the utility of this procedure.

MULTIPARAMETRIC MAGNETIC RESONANCE IMAGING OF NEOPLASTIC AND NON-NEOPLASTIC LESIONS (Pieter J.L. De Visschere)

Multiparametric Magnetic Resonance Imaging (mpMRI) is the current state-of-the art imaging modality in the

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assessment of patients with suspected or confirmed prostate cancer (PC). It consists of morphological T2weighted images (T2-WI) supplemented with functional imaging techniques such as diffusion-weighted (DWI) imaging, dynamic contrast-enhanced imaging (DCE) and/or MR spectroscopic imaging (MRSI). T2-WI exquisitely depicts the prostatic anatomy and pathology. DWI provides information about the amount of random movement of water molecules as determined by tissue density and cell organization. In DCE, the prostate is repetitively scanned before and during intravenous bolus injection of contrast agent. MRSI demonstrates the relative concentrations of the cellular metabolites citrate and choline in the prostate. Poorly differentiated PC can be detected on mpMRI with high accuracy as it typically appears as a low signal intensity (dark) lesion on T2-WI, with restricted DWI, strong contrast enhancement on DCE and high choline/citrate ratio on MRSI (36). Currently, there is a trend to treat only patients with clinically significant PC. In patients with elevated PSA, it is advantageous to perform mpMRI of the prostate before a biopsy. When a suspicious lesion is detected on mpMRI, a targeted biopsy can be performed. When a suspicious lesion is detected on mpMRI, a targeted biopsy can be performed. When mpMRI is normal, it has been shown that a biopsy postponed (provided that the patient is closely followed up), as alternative to systematic biopsies (37), but the debate is still ongoing about which strategy should be recommended (38). Interpretation of mpMRI may however be difficult, because every prostate exists of a mixture of histological conditions, which are highly variable in extent and distribution among patients and some of them may mimic PC. In our own study (36), we compared a series of whole-mount radical prostatectomy specimens with the corresponding mpMRI images. Pure normal prostate glands are iso-intense on T2-WI and the high signal intensity areas represent cystic atrophy (CyA) or largegland variant of simple atrophy (SA). Due to the high water content of CyA it can easily be recognized on mpMRI and PC can be excluded with high certainty. Inflammation, adenosis, post-atrophic hyperplasia (PAH) and high-grade prostatic intra-epithelial neoplasia (HGPIN) may mimic well differentiated PC on mpMRI because they all show indistinct low signal intensity on T2-WI, moderate contrast enhancement on DCE and slightly decreased citrate concentrations on MRSI (39, 40). On DWI, there is a considerable overlap in imaging characteristics between inflammation and well-differentiated PC (41). The restricted diffusion in (peri)glandular inflammation may be explained by the high density of inflammatory cells. Granulomatous prostatitis, a chronic inflammation that may develop after Bacillus Calmette-Guerin therapy for bladder cancer, is a well-known mimicker of PC on mpMRI. A variety of benign conditions may thus mimic PC and act as confounding factors in the discrimination between neoplastic and non-neoplastic lesions at mpMRI. It is the challenging role of the radiologist to distinguish this multitude of benign or indolent conditions from aggressive forms of PC.

CAUSATIVE

PATHOGENS OF BACTERIAL PROSTATITIS

(Alessandra Sensini, Christian Leli) Any microorganism virtually can cause prostatitis. Bacteria infect prostate gland by: ascending the urethra, reflux of urine into the prostatic ducts, direct inoculation of bacteria through inserted biopsy needles or hematogenous seeding. Enterobacteriaceae, especially Escherichia coli, are the predominant pathogens in acute and chronic bacterial prostatitis, but an increasing role of Enterococci has been reported (42, 43). Many strains of these uropathogens exhibit the ability to form biofilm, which can be responsible of the treatment failure. Moreover, the emergence of multidrug-resistant organisms, mostly by means of extended-spectrum beta-lactamases, AmpC beta-lactamases and carbapenemases for Enterobacteriaceae, vanA gene for Enterococci and mecA/mecC genes for Staphylococcus aureus, make antimicrobial therapy very challenging. Fungal etiology is generally limited to patients with impaired immunity. Sexually Transmitted Infections (STI) agents, in particular Chlamydia trachomatis, have been also considered as causative pathogens of chronic bacterial prostatitis (44). Due to the improvement of diagnostic technologies, recent studies supported the etiologic role of Mycoplasma genitalium, a cell wall-deficient small bacterium belonging to the Mycoplasmataceae family, as a true causative pathogen of STI and possibly of prostatitis. Under the designation "Genital Mycoplasmas" are included other species, Mycoplasma hominis, Ureaplasma parvum and Ureaplasma urealyticum. They are considered commensals of the lower female genital tract, indeed are frequently recovered from genital samples in asymtomatic subjects. Their effective role in genital diseases of both women and men is still a much debated issue. Likewise, if chronic prostatitis/chronic pelvic pain syndrome is really an infectious disease is still doubtful (45, 46).

MICROBIOLOGICAL DIAGNOSIS AND MICROBIOLOGICAL PROTOCOL PROPOSALS (Maria Agnese Latino, Alessandra Sensini, Christian Leli) Microbiological diagnosis is imperative to identify the etiologic agent of prostatitis (19, 20, 47-49). The midstream specimen of urine (MSU) is the sample of choice to test in acute bacterial prostatitis. In presence of clinical signs suggestive of a blood-stream infection, a blood culture should be taken. The traditional Meares-Stamey 4glass test is recommended for the diagnosis of chronic bacterial prostatitis. The 2-glass test (also called Nickel test) is an acceptable alternative. The analyses of data collected by a questionnaire sent to italian urologists showed that a higher number of seminal fluid cultures than Meares-Stamey test were performed for diagnosis of chronic bacterial prostatitis. Semen culture is not recommended by the European guidelines because of low specificity due to possible contamination by urethral and skin bacteria. Moreover, a diagnostic cut-off in colony count for symptomatic patients has not been determined. Semen culture can be used for diagnosis in addition to Meares-Stamey test as 5th glass and results compared to the other samples. If used alone, it should be Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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preceded by a first 10-mL void as urethral specimen. All samples should undergo microscopic examination for the presence of leukocytes, culture for isolation of Gramnegative or Gram-positive bacteria and/or fungi and bacterial count, reporting also small numbers of colonies. In case of positive cultures, antimicrobial susceptibility testing should be performed, according to EUCAST rules. Sexually Transmitted Infections agents should be investigated by molecular methods (test of choice) in both patient and sexual partner.

ANALYSIS OF TOTAL EJACULATE IN THE DIAGNOSTIC EVALUATION OF BACTERIAL PROSTATITIS

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together with the 4-glass test and a study showed a positive response after antibiotic treatment of infections diagnosed with semen examination. Finally, the examination of the seminal fluid allows the identification of atypical sexually transmitted pathogens in high percentages (50% of cases with Chlamydia infection and 73% of cases infected with Ureaplama urealyticum and Mycoplasma hominis. In conclusion, the microbiological examination of the seminal fluid may present a useful integration of the results of the Meares-Stamey test.

(Vittorio Magri)

ROLE OF BIOFILMS: PATHOGENESIS AND THERAPEUTIC IMPLICATIONS

The possible diagnostic role of the microbiological examination of the seminal fluid is still controversial, due to the possible contamination of the fluid in the urethral passage and the presence of secretions from accessory glands (seminal vesicles, bulbo-urethral glands of Cowper and urethral of Litrrè). The EAU guidelines (19) exclude the use of semen culture in the diagnosis of chronic prostatitis, although the recommendation strength is weak, and the PERG (20) does not mention this test. On the other hand, in the NIH/NIDKK classification (16), microscopic examination of the seminal fluid in the definition of non-inflammatory CPPS (IIIb) and asymptomatic prostatitis (IV) is envisaged. Furthermore, Stamey himself (1) has argued that semen cultures may be likely reliable for the identification of Gram negative infections and other authors have considered the use of this investigation if associated with a collection of urine VB1 (first voiding) and VB2 (midstream) or when it is not possible to obtain the expressed prostatic secretion (EPS) sample with prostate massage (50, 51). In our experience in 81.7 and 99.9% of patients with chronic bacterial prostatitis and CP/CPPS respectively it was not possible to obtain an EPS sample and that the examination of the seminal fluid in patients with CBP allowed to demonstrate the presence of Gram negative more frequently than in VB3 or EPS (52). In a 565 series of samples with positive microbiological tests of seminal fluid and/or Meares-Stamey test samples 284 patients (52%) had a positive semen test in the presence of negative Meares-Stamey test, 153 (27.1%) negative seminal examination and Meares-Stamey positive test and 118 (20.9%) positive concordance of the two tests. These data agree with a previous study that showed that the semen examination is positive in 78.6% of samples of patients with chronic bacterial prostatitis and in no case of CP/CPPS. This observation confirms what was said by Nickel (53) that observed that the culture of the seminal fluid increased the number of patients classified as category II, even in the absence of precise evidence of the literature and data that demonstrate a clinical improvement after antibiotic treatment of patients with positive culture of seminal fluid. Subsequently, however, some numerically consistent studies (54, 55) have confirmed that the examination of the seminal fluid may be a good indicator of prostatic infection when the semen was analyzed

Chronic bacterial prostatitis (CBP) is diagnosed by clinical symptoms and microbiological analysis by using biological samples from Meares-Stamey test; treatment with appropriate antibiotics is usually prescribed, in line with the European Association of Urology (EAU) guidelines (42). Several times, fluorquinolones are considered drugs of choice to treat patients with CBP, regardless of a bacterial isolation. Antibiotic treatment usually improves the clinical symptoms, although short-term recurrences are reported frequently (56). It is probably due to the incomplete eradication of the causative pathogens, by phenotypical antibiotic resistance at the site of infection and/or lack of antibiotic penetration into prostate tissue. On the other hand, antimicrobial treatment is most effective in acute infection when bacteria are in the ‘planktonic’ state, before they form biofilms. The role of biofilm-producing bacteria in development of acute and chronic prostatitis have been recently discussed. Bacteria living in a biofilm usually have significantly different properties compared with free-floating bacteria (planktonic) of the same species, as the dense and protected environment of the film allows them to interact in various ways (57). They benefit in this environment by an increased resistance to antibiotics, as the dense extracellular matrix and the outer layer of cells protect the interior of the community. Moreover, it is well demonstrated that biofilm persisting bacteria, which are usually adherent to tissue surfaces through their own fimbriae and slime, represent the main limitation of antibiotic efficacy and the potential site of short-term infection recurrences. Recently, Bartoletti and Cai demonstrated that biofilm-producing bacteria were commonly found in CBP patients and had a significant negative impact on the clinical response to antibiotic therapy (58). Moreover, they demonstrated that the relief of symptoms seemed to be much more inversely related to the bacterial biofilm production than to apparent negative microbiological tests after treatment. On the other hand, Cai et al. focused their attention on the role of bacterial biofilms in the genesis of prostate calcifications, suggesting a possible role of bacterial biofilm in the genesis of prostate calcifications and in the development of symptoms in chronic prostatitis (59). In this sense the role of prostate calcifications should be reconsidered. Prostate calcifications are not only a sonographic sign of

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(Tommaso Cai)

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previous prostatitis but should be considered a locus for difficult-to-treat bacteria (organized in a biofilm and having the potential to persist after common antibiotic treatments) within the prostate tissue. The presence of a bacterial biofilm represents a chronic inflammatory stimulus that could lead to the development of symptoms related to the grade of inflammation and the immune response of the patients. In the case of high-grade inflammation, the patient could report urinary or pelvic pain. The fluctuating symptomatology reported by the majority of patients might be explained by variation in the inflammatory response to the development and maturation of the bacterial biofilm (59). The antibiotic treatment is probably effective in mitigating the grade of the infection but is not fully effective in eradicating the bacterial biofilm. Future studies should be designed to explore whether effective eradication of the bacterial biofilm could be associated with a good medium- and long-term clinical outcome of treatment.

RESISTANCE OF GERMS TO ANTIBACTERIAL DRUGS IN PATIENTS WITH CHRONIC BACTERIAL PROSTATITIS (CBP): THE HELLENIC EXPERIENCE

(Konstantinos Stamatiou, Nektaria Rekleiti, Vaia Papadouli)

CBP is a very common and highly bothersome urologic condition. It remains poorly understood (14, 60, 61). Despite progress in its management, many cases are undertreated and a significant number relapse . The reasons are practically unknown and include host, bacterial and treatment-related factors. Inappropriate treatment, incomplete treatment and increased resistance of responsible bacteria to antibiotics have been proposed to contribute most (62-65). While the two first conditions can be easily rule out, the hypothesis of alteration of drug resistance patterns of responsible bacteria remains relatively unclarified. We planned a study to retrospectively investigate the resistance of microbes to antibacterials in patients with chronic bacterial prostatitis that had as secondary objective to determine whether the resistance of pathogens increases in patients with CBP recurrence. We studied bacterial isolates from urine and/or prostatic secretions or sperm cultures obtained from individuals with CBP visiting the prostatitis clinic of our department since its establishment (03/2009). Patients underwent the Meares-Stamey test (a few cases underwent the 2-glass test). Depending on medical history and specific symptoms, urethral smear and sperm cultures were additionally obtained from several patients. Those presenting with febrile prostatitis were investigated by a midstream specimen of urine culture (MUC) only. Samples from patients diagnosed with chronic prostatitis for the first time were compared with those of patients with a history of chronic prostatitis and previous antibiotic treatment. The Meares-Stamey test was considered positive when: 1) bacteria grew in the culture of the EPS and VB3/PoPM (post-prostate massage) urine sample but not in VB1 and VB2/PrPM (pre-prostate massage) sample; 2) bacterial colonies in VB3 were higher than that of VB1 and VB2 samples. Given that no standard cut-off level of

the number of bacteria in both urine and prostate secretion samples exists for the diagnosis of chronic bacterial prostatitis, we defined no lower acceptable level for either one. Bacterial identification was performed using the Vitek 2 Compact system and susceptibility testing was performed by disc diffusion and/or the Vitek 2 system. Interpretation of susceptibility results was based on Clinical and Laboratory Standards Institute (CLSI) Guidelines. Recorded demographical data and medical history of the patients were revised: patients suffering from conditions affecting either bacterial virulence or host response (eg. immunodeficiencies, abnormalities of the urogenital system) and individuals who received antibiotics or immunosuppressive treatment within 4 weeks from the visit were excluded from the study. The statistical analysis was performed using Fisherâ&#x20AC;&#x2122;s exact test of significance. The accepted level of significance in this study was 0.05 (p value < 0.05 is significant). The locally appointed Ethics Committee approved the research protocol. A total of 548 bacterial isolates obtained from the eligible patients in 1324 visits owing to CBP recorded over a 6-year period (03/2009-05/2015) were analyzed. In 114 cases the number of colonies was quite similar in both VB2/pre-PPM and VB3/post-PPM cultures. These cases were excluded from the study. In addition 44 cases with negative cultures (despite presence of bacteria in EPS/VB3/post-PPM) were also excluded from the study as possibly false negative since no previous antibiotic intake was reported. The remaining 390 out of 548 bacterial isolates diagnosed as CBP finally consisted the material of the study. Of them, 253 (44 EPS/sperm and 209 VB3/PPM) were from patients diagnosed with CBP for the first time (group A) and 137 (42 mid-stream urine, 51 EPS/sperm and 44 VB3/PPM) were from patients with a history of CBP and previous antibiotic treatment (group B) (Table 1 in Supplementary Materials). The most frequent pathogen -in both groups was E. coli. Other frequent types were Coagulase negative Staphylococci (hominis & haemolyticus) and Enterococcus spp. The overall frequency of gram (+) was greater than that of gram (-). Of note, bacterial frequencies were similar in both groups (A and B) (Table 2 in Supplementary Materials). Most cases were found with one type of bacteria from each isolate (monomicrobial) however several cases in both groups (49 & 43) were identified with more than one type of bacteria from each isolate (polymicrobial) (Table 3 in Supplementary Materials). Regarding clinical relapses, pathogens most commonly associated were Enterococcus faecalis, Staphylococcus CoN and E coli. The mean time interval between chronic prostatitis relapses was 13.9 months (minimum 2 and maximum 56 months). In sperm cultures, in both groups, the most frequent isolate was Enterococcus faecalis (13 and 8 respectively). A remarkably higher Enterococcus faecalis isolate resistance was noticed in group B (69% vs 25%) (Table 4 in Supplementary Materials). In urethral cell/discharge cultures Staphylococcus CoN and Clamydiae trachomatis were the most common pathogens in both groups (Table 4). Generally, a relatively increased resistance to quinolones was observed and a sufficient degree of susceptibility to the least used antibiotics (TMP-SMX, tetracyclines, aminoglycosides, penicillins, and macrolides) (Table 5 in Supplementary Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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Materials). In some cases cross resistance between ciprofloxacin and newest quinolones was not observed. The nature of this study explain the high rate (41.3%) of positive Meares-Stamey and/or 2-glass tests, however, combined with the fact that no cut-off level of the number of bacteria in both urine and prostate secretion samples was used for the diagnosis of CBP may indicate a relative high underdiagnoses rate. The low number of assessable EPSs in this study may indicate the need of better preparing (e.g. abstain from sexual intercourse for 3 to 5 days before S/M test). In confirmation to the above, the number of assessable EPSs in Group B was greater probably because of the familiarization of patients of Group B with the examination process. The proportion of Gram-positive isolates in the current study is high. The reason explaining the above fact is unknown however it may be associated with the better understanding of the role of Gram-positive bacteria in the development of the disease and the consequent awareness of clinicians and laboratory assistants. The rate of polymicrobial isolates was significantly higher in group B than in group A (31% vs 19%). The interpretation of this finding is twofold: on one hand it is possible that repeated antibiotic treatment reveals participating microbial members of prostate biofilm and in the other hand may suggest a chronic decline of the immune system function. Our finding of increased resistance to quinolones has been previously described. Combined with the finding of sufficient degree of susceptibility to the least used antibiotics this fact can be easily attributed explained by the over-prescription of quinolones in our country . High resistance rates of Enterococci strains may reflect its intrinsic resistance to antibiotics. Of note, differences in susceptibility between Enterococci strains in monomicrobial isolates and polymicrobial isolates may be explained by genomic interactions. Notably, the coexistent urethral infection found in patients of both groups indicates the continuity of the infection of the genitourinary tract system4. In addition, the fact that the findings from sperm cultures were comparable to those of EPS and post PM cultures supports the supplementary role of sperm cultures to the MearesStamey test. Finally, the wide variation in the number of colonies, the presence of different microorganisms in the same culture as well as the presence of CoN Staphylococcus, strengthen the newer appreciation of chronic prostatitis as a biofilm disease. In conclusion, given the regional variation of the distribution of uropathogens and their susceptibility pattern to antibiotics, knowledge of the susceptibility of causative microorganisms to various antibiotics is necessary in order to select the optimal treatment thus providing better eradication rates and make the creation of drug-resistant strains less likely.

MEDICAL TREATMENT OF CHRONIC BACTERIAL PROSTATITIS (Alberto Trinchieri)

Chronic bacterial prostatitis (CBP) is a clinical entity defined by the isolation of bacteria in the prostatic secretion that according to National Institutes of Health -

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National Institute of Diabetes and Digestive and Kidney Diseases (NIH - NIDDKD) criteria is classified as category II. The use of sequential bacteriologic localization cultures represents the most accurate method for diagnosing CBP. The most common organism associated with CBP is Escherichia coli, although infections with Klebsiella, Enterobacter, Proteus, Pseudomonas, and enterococci have also been documented (66). In CBP patients biofilm-producing bacteria were frequently demonstrated as an explanation of the unsatisfactory response to antibiotic therapy (58). Antimicrobials are the first line agents for the treatment of CBP (67). The success of antimicrobial treatment of chronic bacterial prostatitis depends on the antibacterial activity and the pharmacokinetic characteristics of the drug which must reach high concentrations at the site of infection, that is prostate secretion and prostate tissue (68). Diffusion of antibiotics in prostatic secretion/tissue To penetrate the prostatic epithelium, the drug must be lipid soluble, have minimal binding to serum protein and favorable size, shape and degree of ionization in order to diffuse across biological membranes in presence of a pH gradient (considering that ionized molecules do not cross epithelial membranes). The acid molecules reach greater concentrations in the plasma (pH 7.4) and the basic ones in the acidic prostatic fluid. Beta-lactam drugs have a low pKa and poor lipid solubility, and thus penetrate poorly into prostatic fluid; macrolides, tetracyclines and trimethoprim are bases showing excellent penetration into prostatic fluid and tissue. Fluoroquinolones are amphoteric and have a more complex behavior acting either as zwitterions or neutral molecules depending on the medium. Experimental results in the dog confirm this tendency (Table 1 in Supplementary Materials). Experimental animal studies are not easily transferred to the human clinic because the pH of the prostatic secretion in humans is less acidic and it is increased in chronic prostatitis. Evaluation of tissue concentrations of antimicrobials measured on samples coming from endoscopic prostate resections after antibiotic administration confirms the good penetration of fluoroquinolones in prostatic tissues (Table 2 in Supplementary Materials). Clinical results of antibiotic treatment in CBP Before 2000 there are only few randomized studies on the use of non-quinolone drugs in the treatment of CBP, the studies are underpowered so it is difficult to draw conclusions on the effectiveness of these treatments (Table 3 in Supplementary Materials). In patients with CBP treated with trimethoprim/sulfamethoxazole (TMP/SMX) cure rates of 0% to 71% were reported. When treatment was prolonged for over a 12week period the cure rate was about 40%. Tetracyclines, especially doxycycline and minocycline, and macrolides have been extensively used to treat CBP. In a RCT minocycline demonstrated better microbiological (45 vs 21%) and clinical (65 vs 46%) cure rates than cephalexin. In a small series, use of carbenicillin indanyl sodium has been associated with cure clinical and microbiological rates of 93 and 75% respectively and a RCT of CBP treatment demonstrated similar cure rates of carbeni-

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cillin and ofloxacin. Amoxicillin-clavulanic acid or clindamycin were used to treat patients with prostatic infection resistant to empirical treatment with quinolones (50% anaerobic bacteria). In more recent years the antibiotic treatment of CBP was mainly based on the use of fluoroquinolones that, given for 2 to 4 weeks, cured about 70% of men with CBP due to their broad antibacterial spectrum and efficient distribution to the prostate tissue and glandular ducts (Table 4 in Supplementary Materials). Fluoroquinolones are generally well tolerated but In some patients prolonged use of quinolones may be contraindicated due to potential adverse effects in presence of various contraindications (history of tendonitis or long QT syndrome). Randomized clinical trials The meta-analysis of Perletti et al. took into consideration the RCTs published between 1966 and 2012 (69). Authors concluded that for the treatment of traditional pathogens the different fluoroquinolones used in the treatment of CBP have equal microbiological and clinical efficacy. The rate of adverse events of treatment also appeared to be equivalent. On the contrary, for the treatment of Chlamydial prostatitis macrolides were shown to be more effective than fluoroquinolones, both microbiologically and clinically. No differences were observed in microbiological and clinical efficacy and adverse effect between macrolides and tetracyclines for the treatment of patients with CBP caused by intracellular pathogens, both Chlamidial and Mycoplasma (Table 5 in Supplementary Materials). Alternative antibiotic regimens The increased emergence of bacterial resistance and the decline in newly developed antibiotics are limiting the armamentarium for the treatment of CBP. The possible options to counteract this problem are the increase in the dosage of the antibiotics already in use, the combination of antibiotics and the reintroduction of “old” antibiotics that were previously abandoned or not used for the treatment of CBP (Table 6 in Supplementary Materials). Aminoglycosides diffuse in the prostatic tissue and fluids although less than other antibiotics and in previous years, some aminoglycosides, such as kanamycin and streptomycin were successfully used in small series of patients with CBP. A recent larger study of the administration of aminoglycosides alone or in combination with a β-lactam antibiotic showed microbiological eradication and clinical remission in 79% of patients. Genetic testing of patients for mutations predisposing to sensorineural deafness allowed safer administration of aminoglycosides. Orally absorbed fosfomycin trometamol has also been proposed for the treatment of CBP because of its good penetration in prostatic tissue. A recent review found two small series and two case reports of patients with CBP treated with fosfomycin after treatment failure with fluorquinolones and TMP/SMX (70). Fosfomycin was administered orally (3 grams every 48 or 72 hours) for periods of 2 to 6 weeks, although in some critical cases it was administered for longer periods of up to 16 weeks. In the two series, microbiological cure rate > 50% and of clinical cure rate of 50-77% were reported. The

results of these studies suggest that aminoglycosides and fosfomycin could be considered as a therapeutic alternative for the treatment of quinolone resistant CBP although their use should be still validated by randomized-controlled studies. An another option to improve the success rate of antibiotic treatment of CBP is the association of two antibiotics. In particular, macrolides can be associated with quinolones to exploit their ability to reduce biofilms growth. Combination treatment of ciprofloxacin and azithromycin showed a 64.2% microbiological eradication rate after a 6-week cycle of therapy that reached 83.9% after a second 6-week cycle in patients showing persistence of infection or reinfection at the end of the first cycle of treatment. Combination treatment showed high eradication rates of infection by both traditional uropathogens and unusual pathogens. An higher dose of ciprofloxacin (750 mg/daily) in combination with azithromycin (500 mg, thrice-weekly) for 4 weeks showed enhanced eradication rates and lower inflammatory white blood cell counts compared to a 500 mg/daily dose for 6 weeks. Locally injected antimicrobial drugs Local injection of antibiotics into the prostate has been reported to be effective although no RCT validated this modality of treatment The potential advantage of direct injection into the prostate should be to bypass the prostatic capsule to allows use of antimicrobials that are not easily concentrated in the prostatic tissue after oral administration. Small case series showed encouraging results and a small RCT (50 men with prostatic secretions sensitive to amikacin) demonstrated that anal submucosal injection of amikacin for 10 days significantly improved clinical and bacteriological cure rate at 3 months in comparison with intramuscular injection for the same period. Adjuvant treatment with herbal products and probiotics A few RCTs on adjuvant treatment with herbal products (mainly Serenoa repens extract) and probiotics have been published (Table 7 in Supplementary Materials) The combination treatment was able to improve the clinical (and in some studies the microbiological efficacy) of prulifloxacin in patients affected by CBP. In patients with CBP and irritable bowel syndrome a prolonged treatment with rifamixin and probiotics was effective in lowering the progression of prostatitis into more complicated forms of male accessory gland infections. Length of treatment The optimal duration of antibiotic treatment for CBP has not been defined by controlled trials, although a study demonstrated the superiority of a 12 week TMP/SMX treatment with respect to a 10 day course of the same antimicrobial agent. However a minimum duration of antibiotic treatment of 4 weeks should be considered. In a RCT clinical success at the 6-month follow up of levofloxacin 750 mg/day for 2 or 3 weeks was inferior to the standard therapy with levofloxacin 500 mg/day for 4 weeks (71). Chronic oral antibiotic suppression has been proposed to reduce or eliminate bacterial growth in the urine in order to limit the urinary symptoms of the disease. A chronic suppression approach only mandates adequate Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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drug levels in the urine and does not require penetrance of the prostate, thus many antibiotic choices with a safer side effect profile are available, such as nitrofurantoin and cephalosporins. Low-dose trimethoprim (50 or 100 mg once daily), trimethoprim-sulfamethoxazole (40 and 200 mg once daily), and nitrofurantoin (50 or 100 mg once daily) are remarkably effective for this purpose.

BACTERIAL

RESISTANCE: WHICH ANTIBIOTICS TO USE?

(Valentina Marchese, Alberto Matteelli)

Enterobacteriaceae are the most common cause of either acute or chronic prostatitis. Resistance to fluoroquinolones, considered the drug of choice for the management of prostatitis, has been increasing since 2000 (72). The progressive increase in fluoroquinolone resistance is also associated with the spread of extended spectrum Î˛-lactamase (ESBL), which are enzymes that confer resistance to most beta-lactam antibiotics with the exception of carbapenems and, in some selected cases, betalactam/beta-lactamase inhibitors (70). These enzymes are frequently associated with the expression of additional genes harboring resistance to other antimicrobial classes, such as fluoroquinolones and aminoglycosides (73). Treatment of acute and chronic bacterial prostatitis represents always a challenge, as only few antimicrobials reach therapeutic concentrations in the prostate (72). High lipid solubility, a low degree of ionization, a high dissociation constant (pKa, allowing diffusion of the unionized component into the prostate), low protein binding, and small molecular size enhance molecular penetration within prostate (72). Only a limited number of agents adopted for infections due to multi-drug resistant (MDR) gram-negative bacteria (showing resistance to at least three different classes of antimicrobials) have these characteristics (72). In some cases, even if limited pharmacokinetic data available, they have been described to be effective in treating prostatitis (72). For severely ill patients, empirical coverage for MDR bacteria should be provided in presence of risk factors such as hospitalization, recent use of fluoroquinolones and/or beta-lactams, immunosuppression, recent invasive procedures (73). In all other cases, especially in chronic prostatitis, antimicrobial treatment should be guided by drug susceptibility test (DST). Whenever possible outpatient treatment should be preferred, but the majority of antibiotics for MDR bacteria require parenteral administration. Studies on site-specific pharmacokinetic and pharmacodynamic of piperacillin-tazobactam and meropenem justify their administration in susceptible gram-negative prostatitis (74, 75). Prostate tissue penetration of colistin has not been studied and should possibly not be used. Tigecycline undergoes minimal urinary excretion and is usually not considered the first choice for susceptible MDR gram-negative bacteria in urinary tract infections. Nevertheless, few case reports describe the utilization of tigecycline in susceptible strains, with variable clinical and microbiological outcomes (76). So far, Fosfomycin seems the most interesting drug for its susceptibility profile, prostate penetration and availability of oral administration. In patients

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with bacterial prostatitis caused by antimicrobial-resistant E. coli, oral fosfomycin has shown clinical cure rates of 50-77% and microbiological eradication rates above 50% (70). Ceftolozane-tazobactam and ceftazidimeavibactam are two novel drugs which have been introduced for the management of MDR gram-negative infections. At the moment, there are no data on their utilization and penetration in prostate tissues. However, based on previously available data on cephalosporins prostate penetration, both are unlikely to be considered the primary choice in prostate infections, but further studies are needed to assess their possible role in this clinical setting.

ANTIBIOTIC-RESISTANCE,

A PUBLIC HEALTH PROBLEM

(G. Maierna)

The problem of antibiotic resistance poses some questions. 1) When did it become a public health problem? 2) What is the answer of scientific societies to this problem? 3) How civil society deals with antibiotic resistance? In the 40s, shortly after the introduction of the antibiotic into the therapeutic armamentarium of the clinicians, there appeared the first bacterial resistance. From the 60s onwards it has been a progressive and constant increase of antibiotic resistances that has been overcome with the use of new molecules that were periodically synthesized and marketed. In the last decades it is no longer like that. The antibiotic resistance is still increased and many bacterial strains also became multi-resistant to various antibiotics (77-81). This modification of the bacterial ecosystem has been accompanied by progressive abandonment of the research for new anti-infective by most pharmaceutical companies. Meanwhile the ecosystem has further changed and not only for the use and abuse of antibiotic therapy in the human field but also for the spread in the veterinary, zootechnical and aquaculture sectors. All this brought to recent finding of infections related to bacteria that are less sensitive to antibiotics available and always more often multi-resistant, if not even resistant to all the antibiotics tested and available. At this point the diffusion of bacterial resistance has so spread to make the phenomenon no longer a problem limited to some clinical cases to be treated in hospital but a global threat that we have to considered as a public health problem. In this last decade, in particular, it has started a run to find solutions (at least so hopefully). The alternative is a return to the pre-antibiotic era when there were no suitable drugs to treat most infections. Of course, now there are the alarms of the scientific and health world to combat the phenomenon but the reaction of the political authorities and civil society is still ongoing. The G20 of Health, held in Argentina in 2018, like many other international meetings, confirmed the "One Health" plan presented in May 2015 at the 68th World Assembly WHO. Everyone agrees for this global and synergistic action at world and national level promoting a collaborative and inter-sectorial commitment among the various operators of human and veterinary medicine, agriculture and food production and consumers. It is crucial to increase the level of awareness that a prudent and responsible use of antibiotics is necessary in order to counteract antimicrobial resistance that is a growing threat involving

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infections caused by bacteria, fungi, parasites, viruses to determine a progressive a reduction of efficacy of antibacterial, antifungal, antiparasitic and antiviral chemotherapeutic drugs. At this point the treatment of patients with infection becomes difficult, expensive and often impossible. For the most fragile, immunocompromised, and elderly this results in a prolongation of the disease, and in the hospitalization and always more often an increase in mortality. In the "One Health" program of the WHO the objectives to be pursued are: improve awareness of antimicrobial resistance; reinforce knowledge with surveillance and research; reduce the incidence of infections; optimize the use of antimicrobial drugs; develop the necessary investments with adequate financial support. Also in September 2015 the European Parliament approved a resolution for the development of "One Health" in human and animal health to limit multi-resistance to antimicrobials in these areas. At European level, the European Center for Disease Prevention and Control (ECDC), with its own specific prevalence studies conducted among 2011 and 2017 identified as a significant problem of public health related Infections assistance and antimicrobial resistance. Various microorganisms, taken into consideration for their characteristics of pathogenicity, resistance and epidemiology, are considered in these years a real emergency for their ability to resist the action of different antimicrobial agents with various resistance mechanisms. The American Society of Infectious Diseases (IDSA) in 2008 hasgrouped six pathogens in the acronym ESKAPE from the initials of their names: Enterococcus spp, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp. The CDC quantified in 2008-2011 an annual number of infections supported by ESKAPE equal to 130,000 cases with 15,000 related deaths. This evaluation proved to be just outdated for the period 2011-2017 when some microbial species, endowed with complex resistances, have shown an increase in their epidemic impact with resistance phenotypes more difficult to treat while other microbial species, not included in the ESKAPE, have become clinically relevant as Streptococcus pneumoniae, Neisseriae gonorrhoeae, Clostridium difficilis and Candida spp. In hospitals, infections caused by antibiotic-resistant bacteria are now associated with greater morbidity and mortality as well as a longer hospitalization, compared to infections by susceptible bacteria. Every year in the world, the antibiotic resistance determines 700,000 deaths of which 25,000 in Europe with a cost of 1.5 billion euros. If the antibiotic resistance will remain at current levels of growth, the deaths could reach 10 million in 2050. For this, according to WHO, antimicrobial resistance is considered one of the biggest threats to public health due to its epidemiological impact. The WHO underlines how the inappropriate use of antibiotics has led to the phenomenon of antibiotic resistance. By using antibiotics in inappropriate doses and timing, treating non bacterial infections with antibiotics, using an intramuscular route when the oral route is appropriate, not following the guidelines of prescription or for inappropriate self-prescription or use of antibiotics beyond the necessary. Some studies have shown that in hospital 30-50% use of antibiotics used is inappropriate and that improving prescription determines a reduction of antibiotic resistance and related hospital infections

assistance. The final consequence of antibiotic resistance is the reduction of effectiveness of antimicrobial therapies puts at risk the anti-infective medical therapy that currently allows us to treat prosthetic infections, infections in severe oncological-haematological diseases and organ transplants and more. If the current prescribing behaviors and inappropriate use of antibiotics will not be changed, in 2050 the antibiotic resistance will cause more deaths from infection than cancer. Hence the commitment to antibiotic government programs (antimicrobial stewardship) in order to improve: the prescription, with the use of optimal therapy regimens, diagnosis, surveillance and prevention of bacterial infections. All this with strategies of control of infections and their transmission in acute and long-term facilities; antimicrobial stewardship programs for antiinfective drugs; re-evaluation of the therapeutic potential of previous used anti-infective drugs; improvement of microbiological response times to reduce the duration of empirical therapy; development of new antimicrobial molecules. The American Society of Infectious Diseases (IDSA), in its guidelines, highlights how the Antimicrobial stewardship (AS) has a fundamental role in achieving prescriptive and responsible appropriateness, not only for the individual patient but for the whole general context of the ecosystem. Moreover the activity of the Infectious diseases department in the hospital and on the territory can help to sensitize the clinicians to follow the principles for the correct use of antibiotics with appropriate use that requires an adequate microbiological study before the prescription; prescription of the drug in the presence of infection and not colonization; correct administration by dose, time and duration in respect of pharmacokinetics and pharmacodynamics of the molecule (PK/PD); de-escalation of therapy based on microbiological tests and clinical parameters; optimal surgical prophylaxis by choice, time of administration and duration (82).

MANAGEMENT OF CHRONIC PROSTATITIS/CHRONIC PELVIC PAIN SYNDROME (Florian ME Wagenlehner)

CP/CPPS is a not well defined entity. In everyday clinical practice frequently the diagnosis is based upon pain symptoms in the abdomen or pelvis region radiating to adjacent areas and might be accompanied with lower urinary tract symptoms. Painful prostate on palpation is also frequently described without any standardization of the investigation. Usually rudimentary diagnosis is done, if at all including a urinalysis and possibly a urine culture. No further refined diagnosis is made and almost always prolonged and multiple antibiotics courses are prescribed, sometimes alpha blockers, or pain medication is added. The difficulties in the management of CP/CPPS arise from the fact that it is a multifactorial condition, with diverse etiologies. So very different circumstances might lead to the same clinical picture, but possibly warrant different diagnosis and treatment. There is no objective diagnosis, such as a histology, that can proof the condition. There is no biomarker that can be used for diagnosis or follow up of patients, and there is lack of novel treatment strategies taking into account pathophysiological pathways. Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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In terms of diagnosis there is an agreement that infection should be ruled out by localization tests, as described early by Stamey (1). To what extent ejaculate investigations could be beneficial is not entirely clear. Ejaculate testing is frequently performed on routine examinations heading for mere culture, which frequently provides contamination samples, or in other words reflects the microbiome of the external genitalia. However “next generation” investigations, such as cytokine analysis, cytological typing of immune cells etc., that could help stratifying the immune response can nowadays be performed in clinical routine (83). Epigenetic changes are frequently seen in chronic inflammatory diseases and should be investigated according to systemic and compartmentspecific signals for epigenetic dysregulation of inflammatory factors. By doing so a significant association with systemic and local epigenetic inactivation of a mast-cell recruiting molecule CXCR4, the receptor for CXCL12 was identified (83). The search for biomarkers should include various pathways, including hormonal pathways (84). In one study elevated local estrogen levels associated with an epigenetic down-regulation of the estrogen receptors was identified. Investigating estrogen levels in semen could therefore serve as a promising biomarker to select patients for estrogen targeted therapy (84). As pain is the main driver of reduced quality of life in patients suffering from CP/CPPS (85), novel therapeutic substances for the treatment of pain would be therefore be highly interesting to test. Anandamide is a cannabinoid (CB) produced on demand in response to elevated intracellular calcium levels in post-synapse. It is an endogenous agonist of the CB1 receptor which exerts potent inhibitory effects on pre-synaptic glutamate release. The fatty acid amide hydrolase (FAAH) is involved in the enzymatic regulation of anandamide and the inhibition of FAAH elevates levels of anandamide in hyperexcited synapse and potentially could reduce pain perception. In a phase 2 study a peripherally active FAAH inhibitor ASP3652 was investigated in CP/CPPS patients, as inhibition of FAAH is hypothesized to reduce the excitability of urinary tract afferents including nociceptors (86). The results of the study however did not show efficacy of ASP 3652 on pain symptoms in patients with CP/CPPS (86). Most monotherapy studies in general have not been successful, since CP/CPPS is a multifactorial disease with different pathophysiological causes. A phenotyping approach, the UPOINT concept, has therefore been recommended (6). This concept includes a multimodal therapy for CP/CPPS in phenotyped patients, where each identified phenotype according to the enlarged UPOINTS classification is treated separately (87). Using such a treatment concept, 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 (87).

ROLE

OF MULTIMODAL THERAPY FOR TREATMENT OF CHRONIC PROSTATITIS

(Giorgio I. Russo, Gaetano Larganà) Prostatitis is considered the “black sheep” of the prostate

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family of disease, due to difficult to understand its causes and its definitive therapy. It can be considered one of the challenges that urologists have to face. In the last decade, in fact, Google trend showed how the term “prostatitis” has been looking several times more compared to the past, like prostatitis and therapy, like prostatitis + phytotherapy and Serenoa repens. What kind of therapy urologists could use against prostatitis? First of all, in case of diagnosis of prostatitis, antibiotics are the firstline agents for the treatment of CP, for 4-6 weeks. Penicillin, fluoroquinolone, third-generation cephalosporin, macrolides could be used for CP/CPPS. If patient has voiding low urinary tract symptoms (LUTS), alphablockers for 4-6 weeks are also used. The use of alphablockers demonstrates an average NIH-CPSI total score reduction, an average pain e average voiding symptoms reduction with an increase of quality of life (88). If pain is present, simple analgesics +/- non steroidal anti-inflammatory drugs (NSAIDs) can be used. Different studies compare the use of rofecoxib and celecoxib against placebo. They demonstrate a pain reduction and a better quality of life (89). Unfortunately, long-term use of antiinflammatory agents for CP/CPPS is limited by complications due to side effect profile, moderate effect on symptoms (predominantly pain) and lack of data for their use. Improvement of results has instead been reached by the contemporary use of alpha-blockers, antibiotics and anti-inflammatory (90), showing a better control of prostatitis symptoms than use of a single drug. In fact, unfortunately, no efficient monotherapeutic option is available. The best evidence-based management of CP/CPPS is a multimodal therapeutic approach addressing the individual clinical phenotypic profile (91); antibiotics, alpha-blockers and anti-inflammatory, although they have an effect on the disease, cannot be recommended as first-line monotherapy but could be considered in a multimodal therapeutic regimen. A different and new point of view in the treatment of CP/CPPS is to considered phytotherapy. It could be recommended as primary therapy or in association with other drugs to treat CP, because of their few side effects. The use of quercetin (500 mg twice a day), in man with Chronic pelvic pain syndrome, show a better control urinary symptoms, a lower symptoms duration and a better quality of life against placebo (92). Cernilton, a pollen extract, show a better control of pain and a 25% decrease in NIH-CPSI score, with better quality of life against placebo, in CP/CPPS patients (93). Pollen extract was studied against placebo also in association with vitamins (Deprox 500) for pain relief: after only 1 month from start of therapy it was observed a decrease of NIH-CPSI score, although IPSS remain constant. Most important was the comparison between Deprox 500 mg and Ibuprofen 600 mg for early pain relief. Pollen extract demonstrated a better quality of life and a major decrease in NIH-CPSI score, avoiding all the side effect of the continuous use of NSAIDs like ibuprofen. Eviprostat has an identical effect compared to pollen extract in patients with CP/CPPS. IPSS total score, IPSS storage score, IPSS voiding score after 4 and 8 week of treatment with Cernilton or Eviprostat showed no statically difference in results from baseline. Another studied phytotherapy drug is Serenoa repens. Profluss, an associa-

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tion of Serenoa repens plus selenium and lycopene has better results in IPSS score, Qmax score than Serenoa repens alone. In the last years other drug associations were studied for the treatment of patients with chronic prostatitis. An Italian study reported about the association between curcumin and Calendula (Riflog) versus placebo. The results were encouraging, with a reduction of the NIHCPSI score and changes of peak flow, IIEF-5, VAS and PEDT. Moreover, as already mentioned before, multimodal therapy has greater effectiveness than a single therapy. Riflog, in association with alpha-blocker and antibiotics, improves quality of life, Qmax and reduced Santorini ectasia and number of Stamey positive patients. At last Calendula officinalis could be another phytotherapy drug used in prostatitis, exploiting the numerous effect already studied and know, like antiflammatory, antioxidant, antiedematous or analgesic effects.

PROSTATITIS

AND INTESTINAL DISEASES

(Clara Maria Granatieri) The association of CP/CPPS syndrome with intestinal symptoms has been described in the literature. In our experience out of 232 patients suffering from prostatic inflammation, 146 (63.2%) frequently exhibited alterations of intestinal function (alternating constipation and diarrhea, abdominal pain and bloating) and previous urinary infections. The study of functional bowel pathologies (Irritable bowel syndrome - IBS, IDP) has focused the attention on the intestinal microbiota. The interaction of bacterial intestinal flora interaction with food is the basis of many phenomena that influence the state of health or illness. In fact the microbiota, according to its composition and by means of the products of bacterial metabolism, influences the metabolic, immune and inflammatory response of the organism (94). An anti-inflammatory action occurs at the level of Toll-like receptors (TLR); probiotics are able to regulate the balance if intestinal flora, so the TLR can correctly distinguish dangerous antigens from those that must be tolerated. Reduced intake of fiber in the diet alters the intestinal microbiota, with reduced bacterial production of compounds modulating the immune response. To regulate the intestinal flora, proper nutrition is therefore crucial. Numerous studies attest the important role of diet in proper formation and maintenance of the intestinal microbiome. Epidemiological studies have correlated the increase of inflammatory pathologies with "modern" nutrition, the so called "Western diet" that is the intake of large quantities of red meat, simple carbohydrates, fat, refined cereals and poor portions of vegetables, fruit and fish. The damages caused by this diet are due to the inability of the human genome to adapt to rapid changes in the environment, especially diet (95). The "Mediterranean diet” is more similar to that of our ancestors and is considered the standard diet for human health (96). The complex cumulative nutritional effects of the foods rather than the intake of single macronutrients (proteins, carbohydrates, fats) and micronutrients (minerals and vitamins) play an important role in the protective effect of the Mediterranean diet (96). The diet has its effects on inflammation both by direct

action on the cells and regulation of the composition of intestinal flora. Foods directly influence the immune response and therefore inflammation of intestinal and extra-intestinal tissue. Intestinal cells, in particular enterocytes and immunocompetent cells, are equipped with complex systems for “sensing” foods and respond to them (97). In fact, intestinal cells express pattern recognition receptors, such as the TLR, the NOD-like receptors (NLR) and the Leucine rich alpha-2-glycoprotein1 (LRG1). They recognize both pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs). In fact an inflammation in the absence of pathogens can occur in all the tissues, in response to a wide range of stimuli, which cause stress and damage to cells (sterile inflammation) (98). In the sterile inflammation some nutrients are able to cause conditions of cellular stress. Various DAMPs are released from damaged cells and activate immune cell receptors (TLR, NLR, LRG1) which were originally identified as PAMPs sensors. In particular DAMPs lead to the assembly of a cytosol protein complex, called inflammasome, which activates the caspase-1 protease with consequent activation and secretion of IL-1beta. The nutrients can therefore interact with the intestinal epithelium and the cells of the system immune, as do viruses, bacteria and other environmental factors, activating the same pathways of cellular signals that activate or reduce inflammation.

MICROBIOTA-EUBIOSIS-DYSBIOSIS (Roberto Colombo)

The pool of bacteria and other microorganisms (viruses and prokaryotes) that lives in coexistence in the human intestine is called intestinal microbiota (99-107). The Microbiota is made up of 100 trillion bacteria in a balanced composition of several divisions (Phyla), genera and bacterial species, which can act as – "commensals" that do not provide any benefits or harm to the guest – "symbionts" mainly Bifidobacteria and Lattobacilli with probiotic activity – "pathobionts" resident bacteria with potential for pathological induction. The composition and concentration of bacterial genera and species differs in the various segments of the gastrointestinal tract from 102 in the stomach to 1012 in the colon. The intestinal microbiota implements 3 probiotic functions: – protective function against pathogenic bacteria from the outside and pathobiont bacteria: this action is carried out by anti-bacterial activity (bacteriocins) for space and nutrient competition and for slight acidification of the environment to inhibit the growth of pathogenic bacteria – metabolic function by synthesis of vitamins, decomposition of bile acids and above all production of short-chain, butyric, propionic and acetic fatty acids (butyrate is the trophic factor for intestinal mucosal cells) Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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– probiotic bacteria, especially Bifidobacteria and Lattobacilli, that also have the function of modulation of the intestinal immune system (GALT: Gut Associated Lymphoid Tissue, 60% of the entire intestinal system); this occurs because the products of probiotic bacteria (lipopolysaccharides, peptidoglycans) stimulate specific receptors of the dendritic cells of the intestinal mucosa which, for this stimulation, produce Interleukin 10 which stimulates the regulatory T lymphocytes that implement the modulation of the GALT. In addition, the intestinal epithelial cells produce a mucous layer that covers the intestinal surface, consisting of mucin polymers that act as nutrients and sites of adhesion of probiotic bacteria. The balanced microbiota is in a state of “eubiosis” with welfare functions for the whole organism. The qualitative and quantitative alteration of the Microbiota is called “dysbiosis” which, by altering the probiotic functions, causes invasive intestinal diseases and correlates with numerous systemic diseases. The causes of dysbiosis in adults are determined by drugs, stress, wrong diet, bad lifestyle, infections and food intolerances. Dysbiosis can be "deficienct" when caused by drugs or stress or wrong fiber-free diet, or "stagnant" or "putrefactive" when foods such as fats and red meat that stimulate the flora to putrefactive activity prevail in the diet or, on the other side, when fermentable foods (legumes, citrus fruits, etc.) are excessive. A diagnostic innovation regards the evaluation of the dysbiotic action of colina (by excess of eggs) and carnitine (by excess of red meat). The dysbiotic flora induced by excess intake of these substances produces Trimethylamine Oxide (TMAO). This product stimulates the formation of foam cells, inflammatory cells with oxidized LDL, which stimulate the formation of atheromatous plaque. TMAO represents an important new cardiovascular risk marker. The presence of dysbiosis mainly determines low-grade inflammation with hyperstimulation of the immune system and endotoxaemia, because the dysbiotic bacteria produce substances that stimulate the receptors of dendritic cells inducing the production of inflammatory interleukins with increased reactivity of T17 and T1 lymphocytes to pro-inflammatory action. Dysbiosis, as well as other stimuli, such as gluten, determine the secretion by intestinal cells of the zonulin protein, which acts on the "tight junctions" of the intestinal epithelial cells, causing increased intestinal permeability. Dysbiosis, zonulin and consequent low-grade inflammation are the pathophysiological causes of the numerous diseases related to the alteration of the microbiota. The gastrointestinal pathologies are at first local (as leaky gut syndrome) developing food intolerances, subsequently they can worsen when there is a concomitant alteration of the balance of the brain intestinal axis (psychosocial hypersensitivity/excess of catecholamines) with IBS or vice versa when polymorphisms predisposing to inflammation cause the onset of a chronic inflammatory bowel diseases (IBD). Dysbiosis can cause, for the pathophysiological factors mentioned above, systemic diseases such as diabetes mellitus (as the produced inflammatory factors as inter-

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leuchin-6, IL6, and Tumor Necrosis factor, TNF) determine insulin resistance) or cardiopathies (due to production of Trimethylamine Oxidize, TMAO) or allergies in atopic subjects or autoimmune diseases secondary to synovial migration of inflammatory cells or depression due to reduction of serotonin production by intestinal cells or cystitis and vulvovaginitis in the female caused by migration of pathobionts bacteria of the dysbiotic intestinal flora. The alteration of the microbiota is also related to obesity because of the alteration of the relationship between Bacteroidetes and Firmicutes that are the two main bacterial divisions that make up 90% of the intestinal microbiota whose relationship represents a main biodiversity index. This ratio is normally about 0.8, but in obesity it is changed with an increase of Firmicutes that determines an increase in the ability to recover energy from the diet due to increased carbohydrate metabolism. Low-grade inflammation, increased intestinal permeability, presence of pathobionts bacteria and trans-parietal migration may also be involved in the pathogenesis of acute and chronic prostatitis. Repeated antibiotic therapies that often accompany the clinical process of urogenital and prostatic infections represent a factor that repeatedly feeds the dysbiosis related to these diseases highlighting the importance of the therapy with probiotic bacteria to restore the eubiosis and stop the vicious circle of dysbiosis-urogenital infections. Bacterial therapy is based on the use of live probiotic bacteria, with correct taxonomic identity according to Qualified Presumption of Safety (QPS) and International Depository Authority (IDA) status. The timing of administration of bacterial therapy should never be less than 21 days and the amount of live bacteria should never be less than one billion daily.

HYDROCOLONTHERAPY: THERAPEUTIC OPTION IN PATIENTS WITH CHRONIC PROSTATITIS AND DYSBIOSIS? (R. Giuberti)

The investigation on the intestinal microbiota in the CP/CPPS has detected less alpha diversity of the microbiota respect to controls (lower presence of Prevotella genus, to which an anti-inflammatory role is recognized) (108). The microbiota can generate, amplify and maintain a systemic or a local inflammatory condition, causing, as a consequence, a possible painful state, that could have a role in the etiology of the CP/CPPS (109). Dysbiosis with persistence of pathogenic noxae can activate mast cells causing chronic inflammation. Bacteria belonging to the phylum Proteobacteria have an outer membrane composed mainly of lipopolysaccharides (LPS) that stimulate monocyte activity through various steps. LPS are anchored to the external membrane of the bacteria and are released once bacteria die provoking a reaction from the organism with possible increase of the vascular permeability and consequent inflammatory state. They increase intestinal permeability through an intracellular mechanism that involves the up-regulation of TLR-4, which depends on the membrane expression of CD-14 (110). TLRs are receptors expressed on the membrane of sentinel cells such as macrophages, dendritic cells and antigen-presenting cells (APC). In particular,

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TLR-4 is crucial in the recognition of LPS. The activation of TLRs in the intestinal microbiota by the presence of pathogenic microorganisms induces the triggering of the mechanisms of innate immunity and the onset of inflammatory phenomena. The condition of dysbiosis leads to an indirect dysfunction, therefore not primary but secondary, of the intestinal epithelia barrier which creates a way of entry into the organism, through the blood, of bacteria, giving rise to phenomena of bacterial translocation (bacteria in places other than those of origin). The alteration of intestinal permeability, due to lactobacilli and bifidobacteria deficiency, leads to loss of integrity of the mucosal barrier, passage of antigens in the submucosa and immune activation. The activation of the mast cells maintain an up-regulation with acute and chronic pro inflammatory consequences. Recent studies have widely established that mast cells can also respond to non-IgE dependent stimulation. In these cases, mast cells appear to undergo ultrastructural alterations of the granular nucleus, that appears dense with electrons, without the classic evidence of degranulation that is related to an increase of IgE. A condition of chronic mild inflammation is developed that reverberates at the intestinal, prostatic and vaginal level. The best known triggers of this alternative activation path include bacterial toxins, neurotransmitters and stress that may be involved in the pathophysiology of IBS. Patients with IBS have a 150% increase in mast cells compared to a control group. The involvement of mast cells in abdominal pain of patients with IBS has been widely demonstrated, in particular the presence of activated mast cells near the nerve endings, is related to the intensity and frequency of abdominal pain. Mast cells represent the most active sentinels towards the external environment having a high quantity of receptors that can be activated by allergens such as food, drugs, cytokines. The mast cell can acts both by paracrine signaling, especially for the presence of pseudopods which can extend the inflammatory response to blood vessels and nerve endings, and autocrine signaling to itself because it has receptors to the substances that it releases. Consequently, if the causes of its activation are not removed, the inflammatory process can become chronic. Some studies have shown that dysbiosis can cause the release of zonulin which leads to the passage of endoluminal contents through the epithelial barrier with consequent release of pro-inflammatory cytokines. Zonulin is a protein that regulates the junctions of the intestinal walls and ,if in excess, loosens them, favoring a state of intestinal permeability. It was first described in 2000 by Fasano et al. at the Celiac Research Center of the University of Maryland School of Medicine. who focused on the role of zonulin in intestinal tissues during the acute phase of coeliac disease (111). The values of zonulin may represent the reference parameter for the evaluation of the extent of the intestinal mucosa alteration and the consequent state of its permeability. The values found are significant of the progression of the inflammatory condition and correlated with clinical symptoms and can be a guide of the treatment. In 22-31% of patients with chronic bacterial prostatitis

and chronic pelvic pain syndrome a condition of IBS can increase the severity of the pain symptom in the following regions: perineum, supra-pubic region, testes, penis, pelvis, inguinal region, rectum, pain in urination, pain during ejaculation and neuropathic pain (1). Accordingly, the therapeutic approach could aim at restoring the intestinal microbiota through the examination of the stool, the rebalancement of the microbiota, an adequate diet and the application of hydrocolon therapy to eliminate bacterial over-growth and pro-inflammatory toxins generated by lipopolysaccharides (LPS). The application of hydrocolon therapy in chronic prostatitis is based on the ability of a gentle and targeted flow of water entering the intestine during the treatment sessions to regenerate the intestinal environment, through the elimination of inflammatory components that reside in the microbiota. The regularity of the incoming flow through the targeted maneuvers of the operator, which operates on the water flow and pressure parameters in an appropriate manner, allows to create an environment favorable to the regrowth of a microbiota rich in lactobacilli and bifidobacteria that is essential to maintain the intestinal mucosal integrity and to guarantee an effective motor peristalsis. The application of hydrocolon therapy in vulvodinia has achieved a significant improvement of pain with concomitant decrease of inflammatory parameters. It is desirable that the application of the technique on subjects with CP/CPPS can lead to an equally significant benefit, in association with therapies targeted to the restoration of a balanced intestinal microbiota and functional to the elimination of the noxae pathogenic of the inflammatory activation that can support the syndrome. The restoration of intestinal eubiosis, through the targeted integration of probiotics, guided by the examination of stools, a healthy and balanced dietary approach aimed at maintaining a balanced microbiota and hydrocolontherapy sessions can represent a new integrated therapeutic approach, centered on the multi-factorial biological etiology, that support a chronic inflammatory process as the CP/CPPS could be defined.

GYNECOLOGICAL INVESTIGATION OF THE PARTNERS OF CHRONIC BACTERIAL PROSTATITIS PATIENTS (Elisabetta Massa) The human vagina is the location of an ecosystem whom different participants (local microbial populations, local environment and hostâ&#x20AC;&#x2122;s characteristics) always are in a dynamic equilibrium. This ecosystem is open to contaminations both from the external and from the intestinal environment, so it is susceptible to colonization from microorganism that can be symbiotic or pathogenic according to their bacterial counts and to their ability to modify the vaginal homeostatic mechanisms. All the participants to vaginal ecosystem (vaginal epithelium, pH, glycogen and lactobacillary flora) are modified along the different ages of a woman due to different hormonal production. A high oestrogen production, such as during puberty or pregnancy, stimulates the vaginal cells to proliferation and the glycogen storage. Moreover, glycogen facilitates the lactic Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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acid production and the lowering of vaginal pH. Moreover, the lactobacillary flora, divided in five groups following the predominant species (L. crispatus, L. gasseri, L. iners, mixed group e L. Jensenii) (112), has a protective role because it stops the pathogens’ growth and their cohesion (113). All these mechanisms are the first line in vagina’s defences. Furthermore, menstrual cycles , sexual activity, antibiotics or oral contraceptives assumption can modify the vaginal macrobiotic. The vaginal microbiota has an active role in the mechanisms of conception, pregnancy and delivery (time and modality) (114). In presence of disruption of vaginal homeostasis (due to alteration of control mechanisms or to different susceptibility of the host), there are vaginal infections (vaginitis) due to attack from external pathogens or dysbiosis (vaginosis) due to a quantitative redistribution of local flora. For a correct diagnosis, it is important to evaluate the patient’s clinical history, characteristic signs or symptoms, vaginal pH value, the fish’s odor test, the microscopic exam with or without staining and a cultural/molecular test. Partners of 399 patients suffering from Chronic Prostatitis or Chronic Pelvis Pain Syndrome: who underwent to a vaginal, cervical or urethral swab showed the same pathogen isolated in male patients, namely Enterobacteria, Uraplasma uralyticum, Gardnerella vaginalis and Chlamydia. Moreover, clinical characteristics of vaginal infections, their association with sexual transmitted diseases (STD), the gynaecological and reproductive consequences and the obstetric complications have to be analysed (115-117).

ACKNOWLEDGEMENT

To Konpharma Srl for supporting the meeting Prostatitis: A Multidisciplinary Approach (Issues and Controversies), Milano, Italy, 26-27 Oct 2018.

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Correspondence Vittorio Magri, MD vittorio.magri@virgilio.it Urology – ASST Nord Milano, Milan, Italy Matteo Boltri, MD matteo.boltri@gmail.com Urology Medical School, University of Trieste, Trieste, Italy Tommaso Cai, MD ktommy@libero.it Department of Urology,Santa Chiara Regional Hospital, Trento, Italy Roberto Colombo, MD roberto.colombo@synlab.it Synlab Italia Srl Via Beato Lodovico Pavoni 18, 25014 Castenedolo (BS) Salvatore Cuzzocrea, MD salvatore.cuzzocrea@unime.it Università degli Studi di Messina, Messina, Italy Pieter De Visschere, MD, PhD pieter.devisschere@ugent.be Department of Radiology and Nuclear Medicine, Ghent University Hospital, Ghent, Belgium Gaetano Larganà, MD Giuseppe Morgia, MD gmorgia@policlinico.unict.it Departmento of Urology, Università degli Studi di Catania, Catania, Italy Rosanna Giuberti, MD giuroti@gmail.com SICT Società Idrocolonterapia, Milan, Italy Clara Maria Granatieri, MD clara.granatieri@gmail.com Internal Medicine, ASST Nord Milano, Milan, Italy

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Maria Agnese Latino maglatino@gmail.com Alessandra Sensini, MD alessandrasensini@yahoo.it Working Group on Sexually Transmitted Infections - Italian Association of Clinical Microbiologists, GLIST-AMCLI Christian Leli, MD Unit of Microbiology, SS Antonio, Biagio and C. Arrigo Hospital, Alessandria, Italy. Giorgio Maierna, MD giorgio.maierna@asst-nordmilano.it Quality and Risk Management - ASST Nord Milano, Milan, Italy Valentina Marchese, MD v.marchese@unibs.it Alberto Matteelli, MD Department of Infectious and Tropical Diseases, University of Brescia, Piazzale Spedali Civili, 25123, Brescia, Italy Elisabetta Massa, MD empmassa@gmail.com Gynaecology - ASST Nord Milano, Milan, Italy Emanuele Montanari, MD emanuele.montanari@unimi.it Department of Urology, IRCCS Caâ&#x20AC;&#x2122; Granda Ospedale Maggiore Policlinico - University of Milan, Milan, Italy Kurt G, Naber, MD, PhD kurt@nabers.de Assoc. Professor of Urology - Technical University of Munich, Munich, Germany -Karl-Bickleder-Str. 44c, 94315 Straubing, Germany Vaia Papadouli, MD Nektaria Rekleiti, MD nekrek@gmail.com Microbiology Department, Tzaneion Hospital, Piraeus, Greece Gianpaolo Perletti, PhD gianpaolo.perletti@uninsubria.it Department of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences,University of Insubria, Varese, Italy Giorgio I. Russo, MD giorgioivan1987@gmail.com Department of Urology, UniversitĂ degli Studi di Catania Konstantinos Stamatiou, MD stamatiouk@gmail.com Urology Department, Tzaneio Hospital, Piraeus, Greece Alberto Trinchieri, MD (Corresponding Author) alberto.trinchieri@gmail.com Urology Unit, Manzoni Hospital, Lecco, Italy Florian ME Wagenlehner, MD florian.wagenlehner@chiru.med.uni-giessen.de Clinic for Urology, Pediatric Urology and Andrology - Justus Liebig University Giessen, Germany

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DOI: 10.4081/aiua.2018.4.249

ORIGINAL PAPER

Vesicourethral anastomosis including rhabdosphincter in retropubic radical prostatectomy: Technique and results Ramazan Topaktaş 1, Ahmet Ürkmez 1, Musab Ali Kutluhan 1, "smail Başıbüyük 2, Şinasi Yavuz Önol 3 1 Haydarpaşa

Numune Training and Research Hospital, Department of Urology, Istanbul, Turkey; Kolan Hospital, Department of Urology, Istanbul, Turkey; 3 Onol Urology Center, Department of Urology, Istanbul, Turkey. 2 Beylikdüzü

Summary

Objective: Retropubic radical prostatectomy (RRP) is still widely used in clinical practice in localized prostate cancer because of its high oncological success. The aim of this study was to define the continence status in patients where rhabdosphincter was included in the vesicourethral anastomosis. Materials and methods: Between November 2004 and September 2010, 90 cases who underwent RRP by the same surgeon in our clinic were taken into the study. In all cases vesicourethral anastomosis was performed include the rhabdosphincter. The anastomosis was performed with mean 2.9 (0-7) interrupted no 2-0 vicryl sutures, depending on the angulation of symphysis pubis and pelvic cavity. Pad test was performed to all patients at 1, 3, 6 and 12 months postoperatively. We defined patients as ‘continent’ when they no need pad, as ‘mild incontinence’ when they use only one pad daily, as ‘moderate incontinence’ when they use two or three pads daily and as ‘severe incontinence’ when they use more than three pads daily. Results: Preoperative total PSA value was 12.2 ng/ml (range: 2.7-84 ng/ml). Preoperative prostate biopsy results were found that Gleason scores were 5, 6, 7 and 8 in 7, 53, 21, 9 patients, respectively. Mean operation and urethral catheter removal time was 103 minutes (60-200) and 14,6 days (9-28), respectively. Mean hospital stay was 4.6 days (2-20). According to results of postoperative pad tests, 38 (42.2%), 48 (53.3%), 55 (61.1%) and 75 (83.3%) patients were defined as continent in first, third, sixth and twelfth months, respectively. Conclusions: We think that, our novel technique of vesicourethral anastomosis in standard RRP provides more optimal urethral position during fixation of pelvic floor and urethra, protect caudal retraction, preserve functional urethral length. Also strong full thickness stitch on urethra provides better urinary continence by hanging urethra in our patients. Although our early continence rate is better, our long term continence rate is similar to literature.

KEY WORDS: Retropubic radical prostatectomy; Vesicourethral anastomosis; Incontinence; Rhabdosphincter. Submitted 3 June 2018; Accepted 19 July 2018

INTRODUCTION

Prostate cancer is common in man and is the second most common cause of death after lung cancer. Incidence of prostate cancer incline after 50 years old and change in different countries according to diet, ethnicity, life style and screening protocols (1).

Prostate cancer is organ defined in almost 40% of cases and gold standard treatment is radical prostatectomy (RP) if patient has ten-year life expectancy (2). After 1970s this procedure has been standard treatment especially after Walsh’s contributions (3). Although this surgical procedure has important efficiencies it has also morbidities that should be considered. To get rid of morbidities and increase efficiency some modified techniques have been tried over years. Although in recent decades, laparoscopic and robot-assisted laparoscopic RP have been utilized as alternatives to traditional open surgery, RRP is still widely used in clinical practice (4). In all surgical techniques main aim is to get oncologic control and at the same time to maintain erectile function and continence which otherwise affected can decrease patient quality of life. Perioperative and post-operative early complications of radical prostatectomy are bleeding, rectal injury, deep venous thrombosis, pulmonary emboli and lymphocele. Late complications are urinary incontinence, erectile dysfunction and anastomotic stricture. Most important complication that affect quality of life is urinary incontinence. According to studies incidence is between 5%30% (5, 6). Although older studies indicate higher incidence of urinary incontinence in recent years with better knowledge about pelvic anatomy this incidence has decreased. Vesicoureteral anastomosis is one of the most important step in radical prostatectomy and if it is not done properly it leads urinary leak, urine accumulation in surgical field and prolonged drainage (7). On the other hand, it leads periurethral fibrosis, bladder neck stricture and urinary incontinence (8). Recently improvements in techniques of vesicoureteral anastomosis provides decrease in incidence of stricture and incontinence. Urinary continence recovery is a fundamental goal for patients RRP and several surgical techniques, mainly based on musculofascial posterior and/or anterior ligaments reconstructions, have been proposed with the aim of improving urinary continence recovery. Aim of our study is to evaluate post-operative urinary incontinence in patients who underwent RRP and had vesicoureteral anastomosis that includes rhabdosphincter.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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R. Topaktaş, A. Ürkmez, M. Ali Kutluhan, ". Başıbüyük, Ş. Yavuz Önol

Figure 1. Suture that involves the rhabdospinchter.

Table 1. Preoperative clinical features, operative and early postoperative results of patient.

40 30 20 10 0 Sutureless

PATIENTS

1-3 suture

4-6 suture

7 suture

Mean ± Standard deviation (distribution) or number 90 64.3 ± 6.01 (51-78) 49.2 ± 24.18 (20-160) 12.2 ± 9.54 (2.7-84) 6.3 ± 0.42 (5-8) 103 ± 52 (60-200) 780 ± 723.25 (150-3500) 4.3 ± 2.82 (2-19) 14.6 ± 4.39 (9-28) 4.6 ± 7.89 (2-29) 15.3 ± 2.25 (14-25)

AND METHODS

Ninety patient who underwent RRP because of clinically localized prostate cancer between November 2004 and September 2010 in Bezmialem Vakıf University Medicine faculty hospital urology clinic was included in our study. Local ethics committee approval was taken for study and written consent for each patient was also taken. Preoperative and postoperative information of all patient was recorded prospectively. Exclusion criteria were: previous urethral or prostatic endoscopic procedures, preoperative urinary incontinence and concomitant neurological diseases (e.g. Parkinson disease). Bone scan was performed for intermediate and high-risk prostate cancer group and also patients who were symptomatic. In some patients MRI was used for confirmation of bone scan lesion. One experienced surgeon performed all surgeries and bladder neck preserved as much as possible. When indicated lymph node dissection was performed and in proper patients nerve sparing technique was used 2-0 vicryl suture was used in vesicourethral anastomosis. Sutures placed on urethra including rhabdospinchter from out to in and in to out for bladder (Figure 1). 22 F Foley catheter was placed. A watertight test was performed at the end of the procedure. Age, psa levels, prostate volumes and prostate biopsy results of all patients were recorded preoperatively. Operation time, urethral catheterization time, retrivel of drenage time, hospital stay, suture number for vesicoureteral anastomosis and perioperative bleeding was recorded for all patient. Also, post-operative follow up period, pathological parameters and complications were recorded. For all patients postoperative third-generation cephalosporin, low-molecular-weight heparin, and elasto-compressive stockings were used for prophylaxis of infections and thromboembolic events, respectively. In postoperative period patients were followed up regularly for urinary incontinence. After retrieval of urethral catheter pad test were used for evaluation of urinary incontinence in 1, 3 and 12 months. Patients who didn’t use pad in a day described as continent, patients who used one pad a day described as mild incontinent, patients who used 2-3 pad a day described as moderate incontinent and patients who used 4 pad and more described as severe incontinent.

250

Total number of patients Age (year) Prostate volume (ml) Preoperative serum PSA level (ng/ml) Preoperative Gleason score Operation time (minute) "ntraoperative bleeding (ml) Drainage time (day) Urethral catheterization time (day) Hospital stay (day) Mean follow up (month)

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RESULTS

Patient number, age, prostate volume, preop PSA values, prostate biopsy results, surgical parameters, hospitality and follow up period were summarized in Table 1. 48.8% (44) of patient had history of cigarette smoking. Mean operative bleeding was 780 ml (150-3500 ml) and 32,2% (29) of patient had blood transfusion. In one patient myocardial infarction occurred in postoperative second day and transferred to coronary intensive care unit. In this patient urethral catheter was taken off at postoperative 28th day. Average suture number for vesicourethral anastomosis was 2.9 (0-7) and in two patient there was no suture (Figure 2). In three patients (3.3%) acute urinary retention occurred after urinary catheter retrieval and these patients were catheterized with 12F catheter for three more day. In four patients (4.4%) rectal damage occurred in operation and primer reconstruction with two layers without colostomy was performed. In one patient omental flap with pedicul was used for strengthening rectal repair. In one patient during bladder neck dissection ureteral damage occurred and repaired intraoperatively with ureteroneocystostomy. Figure 2. Suture numbers for vesicourethral anastomosis. 80 70 Number of patients

Number of patients

Continent

60 50

Mild incontinence

Moderate incontinence

30 20

Severe incontinence

10 0 1. ay

3. ay

6. ay

12. ay

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Vesicourethral anastomosis including rhabdosphincter in retropubic radical prostatectomy: Technique and results

Figure 3. Pad test classification according to months after catheter removal.

After catheter retrivel bladder neck stenosis developed in 10 patients (11,1%) after a mean of 4.3 months (range 27 months) and treated with endoscopic incision. According to pathologic reports 13 (14.4%) patient had pT2a, 15 (16.6%) had pT2b, 28 (31.1%) had pT2c, 27 (30%) had pT3a and 7 (7.7%) patient had pT3b. On the other hand, 6 (6.6%) patient had positive surgical margin and 84 (93.3%) patient had negative surgical margin. In 6 patients with surgical margin positivity, 4 positivity was in prostatic apex while 2 positivity was in other regions of the prostate At first year of follow up 75 (83.3%) patient was continent, 7 (7.7%) patient had mild urinary incontinence, 5 (5.5%) patient had moderate urinary incontinence and 3 (3.3%) patient had severe urinary incontinence. The continence status of the patients according to the postoperative month was summarized in Figure 3. Seven patients with moderate incontinence and three patients with severe incontinence were found to have endoscopic procedures due to bladder neck stenosis after RRP at the first year of follow-up

DISCUSSION

The most important factor that affect patient’s quality of life after RRP is urinary continence status and early recovery of continence increases patient satisfaction (9). Although there was high rate of urinary incontinence in first years of radical prostatectomy prevalence has decreased over years with better understanding of pelvic anatomy, increase in experience, technology and surgical techniques. Although there are many studies that try to explain which factors like nerve sparing surgery, tabularization of bladder neck, anastomosis suture number and laparoscopic continuous suturing effect post prostatectomy incontinence, we still can’t estimate which patient has urinary incontinence after radical prostatectomy (1012). One of the most important step in radical prostatectomy is vesicourethral anastomosis. General principles for good anastomosis are watertight, non-stretch, anastomoses that provide the best urethral length and mucosa to mucosa anastomosis

Several surgical techniques have been proposed in the recent years, with the aim of reducing the urinary continence recovery time and/or improving long-term urinary continence rates. Some authors indicated that nerve sparing surgery had positive affect on recovery of urinary continence (12). On the other hand, few studies indicated that nerve sparing surgery had no effect on urinary continence (13). In summary nerve sparing surgery has positive contribution on urinary continence. In our study we did not evaluate the nerve-sparing technique variable in our study this deficiency can cause misconceptions. Rhabdospinchter is major structure that influence continence anatomically. It extends like Ω-shaped from membranous urethra to prostatic apex anterolaterally. In normal conditions, the urethral sphincter is supported anteriorly by puboprostatic and pubourethral suspensory components, laterally by the medial portion of the levatori ani muscle forming a hammock around the urethra, and by the ischioprostatic ligaments. In our study we placed anastomotic sutures deeply unlike the traditional RRP described by Walsh especially in anterior urethra where intense rabdosphincter that surrounds urethra exist (3). We suppose that anastomotic suture that includes rhabdosphincter provides almost original urethral length, prevent caudal retraction of urethra and provide better anatomic positioning of urethra and bladder on pelvic floor. In patients with our technique early functional results are better than literature but long-term outcomes are same. Proper and well done apical dissection leads to a better appearance of rhabdosphincter by protecting it. In 2005 Montorsi et al. demonstrated that well done apical dissection in nerve sparing surgery protects rhabdosphincter and after catheter retrieval 44% of patient was continent (14). In our study apical surgical margin positivity was seen only in four (4.4%) patient. Prevalance of apical surgical margin positivity in literature is between 6.5%-38% (15). We think that well done apical dissection for protecting rhabdospincter provides better continence status. Rocco et al. stated that restoration of rhabdosphincter posteriorly or in other word placing Rocco sutures provides retraction of rhabdospinchter caudally and prevents separation at posterior median raphe (16). In this study 250 patient who underwent posterior rhabdospinchter repair were compared to 50 patient who didn’t. At the third month of follow up incontinence rate was 85.2% in first group who underwent rhabdospincter repair while it was 46% in control group (16). Long term incontinence rate was same in both groups (94% vs 90%) and rhabdospinchter repair didn’t cause additional complication. There are conflicts in studies which evaluate the relationship between incontinence and intraoperative hemorrhage. In some studies, there was no relationship between intraoperative hemorrhage and post prostatectomy incontinence. On the other hand, some studies reported that there was significant relationship between intraoperative hemorrhage and post prostatectomy incontinence (13, 17). Intraoperative hemorrhage alone is not a predictive factor for post prostatectomy incontinence without evaluation of other surgical factors. In our Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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study at first year of follow up only 2 patients out of 15 patient who had mild, moderate and severe incontinence had more than 1000 cc intraoperative bleeding. Some studies stated that urethral length should be kept as long as possible for the recovery of continence after RRP and too many sutures for anastomosis shortens urethral length (18). Additionally, some studies indicated that less suture number for vesicourethral anastomosis had positive effects on urinary continence and bladder neck stenosis (19). In our study mean suture number was 2.9 (0-7). We think that too many sutures for anastomosis has negative effects on urethral length. Another topic related to continence is preservation of bladder neck in radical prostatectomy. Many authors investigated relationship between urinary continence and preservation of bladder neck. Licht et al. reported in their study which includes 206 patients that preservation of bladder neck didn’t have positive affect on urinary continence, but it was related to less bladder neck stenosis (20). Another study indicated that 24 patient who had bladder preserving radical prostatectomy had early recovery of urinary incontinence (21). When we look at these studies, the continence effect of preservation of internal sphincter is to passively keep urine above in the storage phase. In our study we didn’t perform bladder neck preserving RRP and widely resected bladder neck with preservation of ureteral orifices. Preservation of puboprostatic ligaments is another topic which can be related to urinary incontinence. Some authors indicated positive effects of preservation of puboprostatic ligaments on post prostatectomy incontinence. Poore et al. preserved puboprostatic ligaments in 18 patients and compared them to control group which includes 25 patients (22). As a conclusion he founded early continence recovery in patients who underwent puboprostatic ligament preservation. In another study patients were divided into three groups. In first group bladder neck preserving surgery was done in second group puboprostatic ligament preserving surgery was done and to last group both bladder neck and puboprostatic preserving surgery was performed (23). There was no significant difference between three groups in long term urinary incontinence. But bladder neck preserving group had earlier urinary continence than ligament preserving group. In another study sling technique was performed by suturing bladder neck to pubic bone and significant earlier continence rates were indicated according to control group (24). In our study we didn’t perform puboprostatic ligament preserving surgery. But we think that wide suturing in anterior urethra provides normal anatomic position of urethra and by this way it can help external sphincter functions by preventing urethral hypermobility. Lack of control group, randomization and the small number of patients included in this preliminary analysis could be considered as the main limitations of the present study.

CONCLUSIONS

Urinary incontinence after radical prostatectomy affects patients’ quality of life and need to be treated early. Recovery of urinary continence depends on patient selection, surgical techniques and definition of conti-

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nence. We think that by modifications in our vesicourethral anastomosis technique; urethra is placed more anatomically on pelvic floor; caudal retraction of urethra is prevented and by this way functional urethral length stays long and especially wide suturing on anterior urethra sling the urethra anteriorly. According to our experience placing vesicourethral anastomotic suture along with rhabdospinchter is easy to perform. We also think that It is safe and shortens operation time and on the same time offers promising functional results. Multicentered, randomized controlled wide series is needed for these topics.

REFERENCES

1. Jemal A, Tiwari RC, Murray T, et al. Canser statistics. Canser J Clin. 2004; 54:8-29. 2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013; 63:11-30. 3. Walsh PC, Lepor H, Eggleston JC. Radical prostatectomy with preservation of sexual function: anatomical and pathological considerations. Prostate. 1983; 4:473-85. 4. Gandaglia G, Sammon JD, Chang SL, et al. Comparative effectiveness of robot-assisted and open radical prostatectomy in the postdissemination era. J Clin Oncol. 2014; 32:1419-26. 5. Kundu SD, Roehl KA, Eggener SE, et al. Potency, continence and complications in 3,477 consecutive radical retropubic prostatectomies. J Urol. 2004; 172:2227-31. 6. Walsh PC, Marschke P, Ricker D, Burnett AL. Patient-reported urinary continence and sexual function after anatomic radical prostatectomy. Urology. 2000; 55:58-61. 7. Arslan M, Tuncel A, Aslan Y, Kozacioglu Z, et al. Comparison of the urethrovesical anastomoses with polyglecaprone (Monocryl®) and bidirectional barbed (V-Loc 180®) running sutures in laparoscopic radical prostatectomy. Arch Ital Urol Androl. 2014; 86:90-4. 8. Kylmala T, Kaipia A, Matikainen M. Management of prolonged urinary leakage at the urethra-vesical anastomosis. Urol Int. 2005; 74:298-300. 9. Castle EP, Andrews PE, Itano N, et al. Male sling postprostatectomy incontinence: Mean follow up 18 months. J Urology. 2005; 173:1657-60. 10. Sacco E, Prayer-Galetti T, Pinto F, et al. Urinary incontinence after radical prostatectomy: incidence by definition, risk factors and temporal trend in a large series with a long-term follow-up. BJU Int. 2006; 97:1234-41. 11. Lee SE, Byun SS, Lee HJ, et al. Impact of variations in prostatic apex shape on early recovery of urinary continence after radical retropubic prostatectomy. Urology. 2006; 68:137-41. 12. Burkhard FC, Kessler TM, Fleischmann A, et al. Nerve sparing open radical retropubic prostatectomy--does it have an impact on urinary continence? J Urol. 2006; 176:189-95. 13. Lepor H, Kaci L. The impact of open radical prostatectomy on continence and lower urinary tract symptoms: a prospective assessment using validated self-administered outcome instruments. J Urol. 2004; 171:1216-9. 14. Montorsi F, Salonia A, Suardi N, et al. Improving the preservation of the urethral sphincter and neurovascular bundles during open radical retropubic prostatectomy. Eur Urol. 2005; 48:938-45.

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Vesicourethral anastomosis including rhabdosphincter in retropubic radical prostatectomy: Technique and results

15. Kim A, Kim M, Jeong SU, et al. Level of invasion into fibromuscular band is an independent factor for positive surgical marginand biochemical recurrence in men with organ confined prostate cancer. BMC Urol. 2018; 18:7. 16. Rocco F, Carmignani L, Acquati P, et al. Early continence recovery after open radical prostatectomy with restoration of the posterior aspect of the rhabdosphincter. Eur Urol. 2007; 52:376-83. 17. Eastham JA, Kattan MW, Rogers E, et al. Risk factors for urinary incontinence after radical prostatectomy. J Urol. 1996; 156:1707-13. 18. Myers RP. Male urethral sphincteric anatomy and radical prostatectomy. Urol Clin North Am. 1991; 18:211-27. 19. Mazaris EM, Chatzidarellis E, Varkarakis IM, et al. Reducing the number of sutures for vesicourethral anastomosis in radical retropubic prostatectomy. Int Braz J Urol. 2009; 35:158-63.

20. Licht MR, Klein EA, Tuason L, Levin H. Impact of bladder neck preservation during radical prostatectomy on continence and cancer control. Urology. 1994; 44:883-7. 21. Gaker DL, Gaker LB, Stewart JF, Gillenwater JY. Radical prostatectomy with preservation of urinary continence. J Urol. 1996; 156:445-9. 22. Poore RE, McCullough DL, Jarow JP. Puboprostatic ligament sparing improves urinary continence after radical retropubic prostatectomy. Urology. 1998; 51:67-72. 23. Deliveliotis C, Protogerou V, Alargof E, Varkarakis J. Radical prostatectomy: bladder neck preservation and puboprostatic ligament sparing-effects on continence and positive margins. Urology. 2002; 60:855-8. 24. Kojima Y, Hamakawa T, Kubota Y, et al. Bladder neck sling suspension during robot-assisted radical prostatectomy to improve early return of urinary continence: a comparative analysis. Urology. 2014; 83:632-9.

Correspondence Ramazan Topaktaş, MD (Corresponding Author) ramazantopaktas@yahoo.com Ahmet Ürkmez, MD ahmeturkmez@hotmail.com Musab Ali Kutluhan, MD dr.musab151@hotmail.com Haydarpaşa Numune Training and Research Hospital, Clinic of Urology, "stanbul, Turkey Tıbbiye street No:23 - 34668 Uskudar/Istanbul "smail Başıbüyük, MD dr.ismailbb@gmail.com Beylikdüzü Kolan Hospital, Department of Urology, Istanbul, Turkey Şinasi Yavuz Önol, MD

onolurology@yahoo.com Onol Urology Center, Department of Urology, Istanbul, Turkey

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ORIGINAL PAPER

DOI: 10.4081/aiua.2018.4.254

The aging male: Relationship between male age, sperm quality and sperm DNA damage in an unselected population of 3124 men attending the fertility centre for the first time Alessandro Colasante, Maria Giulia Minasi, Filomena Scarselli, Valentina Casciani, Vincenzo Zazzaro, Alessandra Ruberti, Pierfrancesco Greco, Maria Teresa Varricchio, Ermanno Greco Centre for Reproductive Medicine, European Hospital, Rome, Italy.

Summary

Objective: the aim of our study was to put forward insights to treat any possible correlation among sperm quality, sperm DNA damage and male age as they may have fertility implications for men who choose to delay fatherhood. Materials and methods: Our study is a non-interventional retrospective analysis of 3124 semen samples from patients that were investigated for the conventional semen parameters. Tunel test assay was set up for the evaluation of the sperm DNA fragmentation index (DFI). We applied the Kappa index to compare both the 1999 and the 2010 World Health Organization (WHO) reference criteria to evaluate the competence of such semen parameters categorization during the standard routine of our laboratory. Results: With regards to our findings, it is possible to underline a significant relationship between aging and semen volume (p = 0.001), motility (p = 0.009), semen viscosity (p < 0.003) and sperm DNA damage (p < 0.009). We found a trend when focusing on the semen concentration (p = 0.05). The analysis of sperm morphology did not show any influence with advancing age (p = 0.606). When comparing both the 1999 and the 2010 WHO scales we found no accordance in the appraisal of sperm morphology but a very good one in the evaluation of the other parameters. Conclusions: Conventional semen analysis represents the opportunity to draw up a proxy insight on the male fertility status even if semen quality can only indirectly assess the probability of pregnancy. Several studies have verified a decay in the male reproductive system, sperm quality and fertility with advancing age although the reported results are not yet conclusive. Our results substantially agree with those findings outlined in the literature. Moreover we find that the discrepancy between the two WHO reference scales would eventually lead to an improper diagnosis of infertility.

KEY WORDS: Aging; Male; Semen; Analysis; WHO; Infertility. Submitted 25 june 2018; Accepted 31 July 2018

INTRODUCTION

Infertility has a wide impact on public health. In developed countries, where expectancy of a prolonged life is well established, modern trends have enforced the delay of first parenthood (1). It partly reflects the complica-

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tions of an overwhelming course marked by the achievement of individual goals such as education and economic solidity prior to attempting conception (2). Aging is explained by biological and demographic topics characterized by the impairment of several physiological functions and to what concern human reproduction, age related decrease of couples fertility potential is usually associated to female aging (1, 3). Female germ cells are lessened during life span and do not replace (4). Therefore, as ovary grow older, the total number of oocytes and their quality decrease, lowering female fecundity (5). Female age has been explained as a predictor of poor reproductive success resulting in decreased fertilization and implantation rates as well as in increased abortion rates (5). Efficient reproduction and early embryonic development mostly rely on oocyte quality with those from older women being more prone to nondisjunction caused by meiotic errors and therefore impaired by an increased occurrence of aneuploid abnormalities (4, 5). Male reproductive functions do not suddenly come to an end as spermatogenesis continues into advanced ages. Consequently men can conceive children at later ages (6). Anyway a large number of studies have marked a linkage between advanced male age and the decrease in fertility potential status (1, 3, 7). The effect of advanced paternal age on embryo quality, miscarriage rate or pregnancy rate has been assessed for the general population and for infertile patients outlining an increased time-to-pregnancy disorder (2, 8). Older fathers are reported to imply higher rates of miscarriages and several diseases in the new generations: altered designs of genetic expression in aged male are related to a wide range of genetic disorders through descendants as the rate of denovo inheritable mutations is strictly linked to the male age (8). Substantial interest exists in studying effects of aging on semen quality and sperm DNA damage (1, 3, 7, 9). Conventional semen analysis represents the opportunity to draw up an insight on the male fertility status even if semen quality is an indirect measure of the probability of pregnancy (7). Advanced paternal age is related to a decline in sperm quality and to an increased sperm DNA damage referring to a combination No conflict of interest declared.

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of genetic and environmental factors which can lead to a condition of oxidative stress impairing the integrity of sperm DNA (1, 10). Several studies tried to fix an age effect on semen quality indicating a broad trend in age ranges (1) but the effect of advanced paternal age on semen parameters is not yet conclusive and its impact on fertility is still debated (1, 2). Our study is then meant to put forward stronger insights to help clarify any possible correlation among sperm quality, sperm DNA damage and male age as they may have fertility implications for men who choose to delay fatherhood.

MATERIALS

AND METHODS

Patients enrolled in this study were recruited from January 2009 to December 2012. Semen samples were obtained from unselected males attending, for the first time in their life, the andrology laboratory both for infertility problems as well as for a spontaneous screening provided for free, during the so-called “Fertility Days” arranged at our Centre. Each patient produced a semen sample by masturbation into a sterile plastic container. As the number of days of abstinence may have influence on semen parameters, patients included in this study were previously taught to observe 2 up to a maximum of 5 days of abstinence from intercourse before their planned analysis. Semen samples were collected in a room next to the laboratory. All the samples were allowed to liquefy for at least 20 minutes at 37°C, prior to be processed. Analysis of semen samples, liquefaction, viscosity and volume were recorded. A 10 µL drop was examined using phase contrast microscopy to assess sperm concentration, motility and morphology according to WHO guidelines for the examination and processing of human semen (11). We both used the 2010 and the 1999 reference cutoff values to evaluate the competence of such semen categorization during the standard routine of our laboratory (12). A raw portion of the semen sample was then taken out at the time of the semen evaluation. It was immediately processed for the subsequent assessment of the DFI (DNA fragmentation index) setting up the Tunel test assay. Visualization of fragmented sperm nuclear DNA was performed with the use of Cell Death Detection Kit with tetramethylrhodamine-labelled dUTP (Roche, Monza, Italy), according to the manufacturer’s instructions. Ejaculated sperm samples were washed from seminal plasma by low-speed centrifugation, smeared on microscope slides, air-dried, fixed with 4% paraformaldehyde in phosphate-buffered saline at 4°C for 25 minutes, and permeabilized with 0.1% Triton X-100 in 0.1% sodium citrate. Spermatozoa with fragmented DNA were detected in an epifluorescence microscope with a X100 oil immersion objective and the percentage of TUNELpositive spermatozoa was determined (13).

Statistical analysis Shapiro-Wilk test was used to test normality assumption. Chi square test (or Fisher exact test when appropriate), was used to compare categorical variable. To set up the evaluations, records were ranked by age brackets to create three consecutive age groups each containing suitable observations to be analysed as described in previous studies. Bonferroni correction was used to adjust multiple comparisons. Non parametric Mann-Withney test was used for continuous variables. To compare classification of same subjects with two different scale, Mc Nemar test was used. Kappa index was then calculated to evaluate accordance between the two scale using the Landis-Koch reference model (14). Such model ranges from 0 to 1 to point out respectively “no-accordance” (value = 0) and “overlapping conformity” (value = 1) between the used examiners (Table 1). A p value < 0.05 was considered statistically significant.

RESULTS Population characteristics Our study is a non-interventional retrospective analysis of 3124 semen samples from patients that were investigated for the conventional semen parameters and the DFI. None of the men included in the study revealed having or having suffered cryptorchidism, hypospadias or testicular cancer. All the patients enrolled in the study were investigated for smoking habits and none of them has disclosed a heavy consumption of cigarettes. When considering the whole sample, a share of around 65% of the men investigated were found to be pathological for at least one of the features investigated: concentration, motility or morphology as well. The remaining 35% was normozoospermic. The age of the patients ranged from 21 to 65 with a mean of 40 years (SD 5, 9). The results of our study were allocated to three age groups: younger than 35 years (n = 775, 25%); 36-40 years (n = 1110, 35%); 41 years and older (n = 1239, 40%). Semen volume The median semen volume was 3 ml (Table 2). Patients with normal volume values were 87% of the entire samTable 1. Landis-Koch model. <0 0-20 0.2-0.40 0.41-0.60 0.61-0.80 0.81-1.00

Poor Slight Fair Moderate Substantial Almost perfect

Table 2. Median and interquartile range (IQR, 25th-75th percentile) of semen parameters. N 3124

Volume (ml) 3 (2,4)

Sperm concentration 106/ml 24 (12, 38)

Sperm motility % (a+b+c) 60 (50, 70)

Sperm morphology % 4 (3, 7)

Sperm DNA damage 5 (2, 10)

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Table 3. Median and interquartile range (IQR, 25th-75th percentile) of semen parameters. N N Volume Concentration Motility Morphology Viscosity (augmented)

< 35 years N 775 77 281 138 397 195

36-40 years % 9.9 36.3 17.8 51.2 25.2

N 1110 130 396 202 546 287

ple. Those with abnormal ones were 13%. When referring to the whole sample we found a weak relationship between the two variables investigated (r = 0,1). On the contrary, when we focused attention only on the subjects who were estimated having abnormal volume values, we found a significant trend toward age groups (p = 0,001) and the number of patients with abnormal semen volume raising up as age increased. Sperm concentration and total sperm count The median sperm concentration was 24*106/ml (Table 2). Patients with normal sperm concentration were 66% of the entire sample, those with abnormal ones were 34%. We found a trend when focusing on the whole population (r = 0.04, p = 0.05) and a trend (p = 0.037) across the three groups but no clear post-hoc analysis confirmation emerged. Total sperm count analysis failed to point out any relationship with age (p = 0.769) among groups. Motility The median motility was 60% (Table 2). Patients with normal motility values were 80% of the entire sample, those with abnormal ones were 20%. No clear trend was revealed for the whole sample analysis (r = -0.01). Quite the opposite emerged when we analyzed only the subjects who were estimated having abnormal values. We found a significant trend toward age groups (p = 0,009) and the number of subjects with abnormal assessments raised up as age increased. Morphology The analysis of sperm morphology, with the sample equally divided in normal and abnormal estimations,

>= 41 years % 11.7 35.7 18.2 49.2 25.9

N 1239 189 390 279 631 398

% 15.3 31.5 22.5 50.9 32.1

p value 0.001 0.037 0.009 0.606 < 0.001

(median value = 4, r = 0.01) did not show any influence by advancing age (p = 0.606). Semen viscosity Twenty-eight percent of our sample reported an increased semen viscosity estimation. It was possible to point out a clear deviation within age groups (p < 0.001) toward the older one (p < 0.003). Sperm DNA damage The analysis for the three age groups point out a clear trend toward older subjects (p < 0.009). When we have analysed the relationship between sperm morphology linked to sperm DNA fragmentation, we found a negative correlation between the variables investigated both for the whole sample (r = -0.16, p < 0.001) and for all the three age groups respectively: r = -0.17; r = -0.16; r = -0.18 (p < 0.001). Comparison between WHO 2010 and WHO 1999 Once the primary data analysis was concluded (Table 3), we have reloaded the data of the whole population. To this, we have applied the older WHO reference values scale (12) for semen analysis (Table 4). In this subsequent investigation we found again that the third group, that including men at older ages, still issued a significant difference regarding semen values if referred to the other two groups and mainly, when evaluating concentration and motility, toward the first group of younger subjects. Considering the amount of difference between the scale currently in use and the 1999 replaced one, we have decided to match them up, so to evaluate any possible divergence which could reveal a clinical weight in the IVF treatment of couples. To this purpose, McNemar test

Table 4. Number of subjects with abnormal values (WHO, 1999). N N Volume Concentration Motility Morphology Viscosity (Augmented)

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< 35 years N 775 170 376 216 758 195

36-40 years % 21.9 48.5 27.9 97.8 25.2

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N 1110 260 524 332 1072 287

>= 41 years % 23.4 47.2 29.9 96.6 25.9

N 1239 359 531 416 1203 398

% 29.0 42.9 33.6 97.1 32.1

p value 0.001 0.023 0.018 0.295 < 0.001

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Table 5. Two scale comparison (WHO, 1999 vs. WHO, 2010). WHO (1999)

WHO (2010)

Total

p value*

Kappa

Volume Concentration Motility Morphology

3124 3124 3124 3124

789 1431 964 3033

25.3 45.8 30.9 97.1

396 1067 619 1574

12.7 34.2 19.8 50.4

< 0.001 < 0.001 < 0.001 < 0.001

0.601 0.761 0.713 0.059

Volume Concentration Motility Morphology

775 775 775 775

170 376 216 758

21.9 48.5 27.9 97.8

77 281 138 397

9.9 36.3 17.8 51.2

< 0.001 < 0.001 < 0.001 < 0.001

0.564 0.753 0.719 0.046

Volume Concentration Motility Morphology

1110 1110 1110 1110

260 524 332 1072

23.4 47.2 29.9 96.6

130 396 202 546

11.7 35.7 18.2 49.2

< 0.001 < 0.001 < 0.001 < 0.001

0.605 0.766 0.685 0.066

Volume Concentration Motility Morphology

1239 1239 1239 1239

359 531 416 1203

29.0 42.9 33.6 97.1

189 390 279 631

15.3 31.5 22.5 50.9

< 0.001 < 0.001 < 0.001 < 0.001

0.612 0.760 0.730 0.060

Whole sample

< 35 years

36-40 years

> =41 years

*Mc Nemar test.

was applied to the entire sample and then to the three different groups (Table 5). Kappa index was then used to evaluate the accordance between the two different WHO reference values scales (Table 5). It is possible to highlight greater percentages of subjects with pathological semen evaluations when the 1999 WHO scale is applied due to its stringent criteria of estimation. Moreover, Kappa index exhibits a valuable accordance between the two guidelines if referred to the estimation of volume, concentration and motility. On the contrary, such correspondence failed when we analyzed the morphology parameters determining the misidentification of a remarkable infertility male factor (Table 5).

DISCUSSION

Several studies have demonstrated a decline in the male reproductive system, sperm quality and fertility with advancing age but many of the biological mechanisms of such processes are poorly understood and the reported results are not conclusive (2). In the present analysis, methods, personnel, and instrumentation were consistent throughout the study period because study settings represent a topic of wide importance: earlier attempts to draw conclusions from pooled data from different publications or from the same investigators at different locations have been troubled by differences in methods, personnel, and instrumentation. The lack of standardization in analytic techniques weakened statistical analysis of pooled data by compounding the existent inherent variability in measured semen characteristics. Moreover, in our study we enrolled subjects at older ages preventing the loss of statistical power as occurred in some of the past clinical studies, where older patients (e.g. > 50 years) were under-represented (3, 15). In this way a lim-

ited age range may have improved the possibility to ignore the threshold age at which the biological consequences of aging are disclosed. With regards to our current findings, it is possible to underline a significant relationship between advancing age and semen volume, viscosity, motility and sperm DNA damage and a trend for sperm concentration. Despite other previous findings we could underline no significant relationship emerging when age and sperm morphology were linked (3). Quite a lot of mechanisms have been suggested to explain how advancing age may influence semen quality (3). For instance abnormal semen volume alterations could be caused by seminal vesicle deficiency as vesicle fluid itself largely provides most of the ejaculate volume (16). Variations in the prostate arise with aging and the related decay in protein and water contents can clarify the negative impact on semen volume, motility and viscosity (16). Once more, the epididyms have a valuable importance: considering sperm acquiring its straight motility only during the transition through the epididymal tract, any alteration may negatively restrict this parameter (3). Aging may regulate tubular lumen suffering a condition of sclerosis determining a decline in the spermatogenic activity, loss of germ cells proliferation and a deficiency of Leydig cells functions (7). Testes compromised responsiveness to the endocrinological stimuli can possibly explain the alterations of sperm concentration and the increase in sperm count with age may be also explained by urogenital infections (9). Spermatozoa are constantly produced by the testes as germ cells and go through enduring replication, meiosis and spermiogenesis. Cell selection is a major process during early years. It has been speculated that when DNA damage is induced in cells of young men equally levels of apoptosis also increase to eliminate cells with Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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irreversible DNA damage (17). On the contrary, when DNA damage is induced in cells from older men, apoptosis do not increase, implying that the ability to remove damaged cells decrease (17). In such a way it can be assumed the existence of age-induced anomalies in the apoptotic pathway leading to an age-linked increase in sperm cells with higher DNA damage (17). Confirming the contradiction of the literature published results and in spite of what other authors reported (2, 3, 16, 17), we found no decline in sperm concentration levels with advancing age. Sperm DNA damage has been associated to both male aging and infertility and it has been linked to several factors such as oxidative stress, abortive apoptosis and deviations in the process of recombination and protamine replacement during spermatogenesis (8). Oxidative stress occurs when the generation of free radicals and the scavenging ability of antioxidants become unbalanced. The performance of antioxidant enzymes from older men may be reduced if compared to those of younger ones leading spermatozoa to be more suitable for mutational changes due to the endogenous activity of ROS (8). High DNA fragmentation is linked to diminished sperm concentration, motility and morphology. Decreased fertilization rates and implantation rates are associated to DNA fragmentation (8). Higher levels of sperm DNA damage are associated to decreased embryo quality and pregnancy rates (10). Several studies dealt with the relationship between sperm damaged DNA and the impairment of embryonic developmental stages and it has been marked a strong evidence of lowered quality in embryo development at later stages (4). As a final point, it has been long recognized that the female aging increases the odds for meiotic errors in oogenesis resulting in offspring with chromosome affected by aneuploid abnormalities (4, 5, 18). Therefore, there seems to be a lesser impact for paternal than maternal age on the couple fertility potential (4, 18). Nevertheless, various authors have pointed out that the oocytes are able to mend up DNA damages of paternal origin thus saving the aging spermatozoa (19). Consequently, repairing mechanisms of oocytes from older women may be less competent and may give rise to a condition of infertility or to a prolonged time to pregnancy (19). In conclusion there are lots of difficulties in using semen parameters to screen and clear male health condition when considering the wide impact of the physiological variations of spermatogenesis combined with the distinct lifestyle habits and the growing effects of a lifelong exposure to those factors usually considered as exogenous pollutants (20).

CONCLUSIONS

The semen analysis stands for one of the first essential steps in the assessment of the male fertility condition (3). Starting from 2010 renewed semen standard thresholds has been defined for the WHO reference manual (11). This resulted in the statement of lower cutoffs than the previously practiced to handle semen analysis. Comparing both the 1999 and the 2010 reference values in the evaluation of broad semen parameters, we found no accordance in the appraisal of sperm morphology but a very good one in the evaluation of the other parame-

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ters. We can therefore speculate that, based on such innovation, a large number of couples previously detected with male factor infertility would now be ranked as having normozoospermia. In such a way, we find that the discrepancy between the two WHO reference scales would eventually lead to an improper diagnosis of infertility. As the new reference values are almost similar to the previous ones, it has become quite difficult to clearly set apart fertile from infertile male patients and it therefore seems of pressing utility to manage a more comprehensive clinical approach when couples with problems of infertility come up to a fertility center.

REFERENCES

1. Winkle T, Rosenbusch B, et al. The correlation between male age, sperm quality and sperm DNA fragmentation in 320 men attending a fertility center. J Assist Reprod Genet. 2009; 26:41-46. 2. Bellver J, Garrido N, et al. Influence of paternal age on assisted reproduction outcome. Reprod Biomed Online. 2008; 17:595-604. 3. Kidd SA, Eskenazi B, Wryobek AJ. Effects of male age on semen quality and fertility: a review of the literature. Fertil Steril. 2001;75:237-48. 4. Munne S, Alikani M, et al. Embryo morphology, developmental rates and maternal age are correlated with chromosome abnormalities. Fertil Steril. 1995; 64:382-391. 5. Gindoff PR, Jewelewicz R. Reproductive potential in the older women. Fertil Steril. 1986; 46:989-1001. 6. Pasqualotto FF, Borges Junior E, Pasqualotto EB. The male biological clock is ticking: a review of the literature. Sao Paulo Med J. 2008; 126:197-201. 7. Stone BA, Alex A, et al. Age thresholds for changes in semen parameters in men. Fertil Steril. 2013; 100:952-958. 8. Robinson L, Gallos ID, Conner SJ, et al. The effect of sperm DNA fragmentation on miscarriage rates: a systematic review and metaanalysis. Hum Reprod. 2012; 27:2908-17. 9. Ford WC, North K, Taylor H, et al. Increasing paternal age is associated with delayed conception in a large population of fertile couples: evidence for declining fecundity in older men. Hum Reprod. 2000; 15:1703-8. 10. Bungum M, Humaidan P, Axmon A, et al. Sperm DNA integrity assessment in prediction of assisted reproduction technology outcome. Hum Reprod. 2007; 22:174-9. 11. World Health Organization. Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction. 2010; World Health Organization, Cambridge, UK. 12. World Health Organization. Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction. 1999; World Health Organization, Cambridge, UK. 13. Greco E, Romano S, Iacobelli M, et al. ICSI in cases of sperm DNA damage: beneficial effect of oral antioxidant treatment. Hum Reprod. 2005; 20:2590-4. 14. Landis J, Koch G. The measurement of observer agreement for categorical data. Biometrics. 1977; 33:159-174. 15. Stewart TM, Liu D, Garrett C, et al. Recruitment bias in studies of semen and other factors affecting pregnancy rates in fertile men. Human Reprod. 2009; 24:2401-2408. 16. Ausmees K, Korrovits P, et al. Decline of seminal parameters in

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middle.aged males is associated with lower urinary tract symptoms, prostate enlargement and bladder outlet obstruction. Int Braz J Urol. 2013; 39:727-40. 17. Brahem S, Mehdi M, et al. The effects of male aging on semen quality, sperm DNA fragmentation and chromosomal abnormalities in an infertile population. J Assist Reprod Genet. 2011; 28:425-432. 18. Angell RR. Aneuploidy in older women. Higher rates of aneu-

ploidy in oocytes from older women. Human Reprod. 1994; 9:11992000. 19. Ashwood-Smith MJ, Edwards RG. DNA repair by oocytes. Mol Hum Reprod. 1996; 2:46-51. 20. De Rosa M, Zarrilli S, et al. Traffic pollutants affect fertility in men. Hum Reprod. 2003; 18:1055-1061.

Correspondence Alessandro Colasante, PhD, MSc (Corresponding Author) a.colasante@tiscali.it Maria Giulia Minasi, MSc mg.minasi@gmail.com Filomena Scarselli, MSc filomenascarselli@virgilio.it Valentina Casciani, PhD valcasciani@gmail.com Vincenzo Zazzaro, PhD enzozazzaro@yahoo.it Alessandra Ruberti, BSc alessandra.ruberti@virgilio.it Pierfrancesco Greco, MD piergreco@hotmail.it Maria Teresa Varricchio, MD mtvarricchio@gmail.com Ermanno Greco, MD ergreco1@virgilio.it Centre for Reproductive Medicine, European Hospital, Rome, Italy

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DOI: 10.4081/aiua.2018.4.260

ORIGINAL PAPER

The role of nutraceutical medications in men with non bacterial chronic prostatitis and chronic pelvic pain syndrome: A prospective non blinded study utilizing flower pollen extracts versus bioflavonoids Angela Maurizi 1, Francesco De Luca 1, Antonino Zanghi 2, Emy Manzi 3, Costantino Leonardo 1, Michele Guidotti 1, F.P. Antonaccio 1, Valerio Olivieri 4, Carlo De Dominicis 1 1 Department

of Gynaecological and Urological Sciences, Sapienza University of Rome, Rome, Italy; di Medical and Surgical Sciences and Advanced Technologies G.F. Ingrassia, University of Catania, Catania, Italy; 3 Department of General Surgery, Santa Scolastica Hospital, Cassino (FR), Italy; 4 Division of Urology, Ivrea Hospital - ASL TO4, Ivrea, Turin, Italy. 2 Dipartimento

Summary

Introduction: Chronic prostatitis (CP)/chronic pelvic pain syndrome (CPPS) represents a challenge for the urologist, since the therapeutic efficacy does not always result in a satisfactory quality of life for the patients. Often the side effects of the medications used (antiinflammatories, antibiotics, alpha blockers) far outweighs the benefits gained with their admission. The choice of nutraceutical medications is preferred for their effectiveness, that has been accepted and proven by the scientific community, and for the low incidence of side effects. The objective of this study to compare the therapeutic efficacy of the flower pollen extracts (Deprox®) versus Bioflavonoids in terms of reduction of symptoms, and in the average waiting time of the variation of the National Institute of Health Chronic Prostatitis Symptom Index (NIH-CPSI), and to evaluate the quality of life improvement of the patients affected by CP/CPPS. Methods: Among the 68 patients presented with prostatic symptoms to the Hospital “Umberto I” in Rome, Italy between March 2016 and June 2016, 54 patients met the clinical diagnosis of CP/CPPS (class IIIa or IIIb according to the NIH classification). The patients were assigned to either treatment with Deprox® or quercetin based on a randomization scheme previously determined.The NIH- CPSI, IPSS, QoL questionnaires were administered. Every patient underwent bacterial cultures and trans-rectal ultrasound. Results: There was a statistically significant improvement of the NIH-CPSI score and QoL in the Deprox® group (p = < 0.0001 and p = 0.003 respectively). The average waiting time of the variation of the National Institute of Health Chronic Prostatitis Symptom Index (NIH-CPSI) was statistically significant (p = 0.0019). In the absence of efficacy of the “conventional” medications, which also carries significant side effects, the dietary supplements may represent a valid alternative. Conclusions: DEPROX® has demonstrated a significant improvement of the symptoms and quality of life of patients diagnosed with by CP/CPPS. Furthermore, there was a statistical difference in the average waiting time of the variation of the NIH-CPSI) score without side effects as compared to the bioflavonoids complex with quercetin.

KEY WORDS: Chronic prostatitis; Chronic pelvic pain syndrome; Prostatic benign diseases; Inflammation; Pollen extracts.. Submitted 3 July 2018; Accepted 19 August 2018

260

INTRODUCTION

In 1995 the National Institute of Health (NIH) proposed a classification of the prostatitis now internationally accepted (1). The overall incidence of prostatitis in Italy results to be about 13.8% (2). Based on the literature available data, 5% of the prostatitis belongs the categories I and II. The antibiotics treatment, in general, results in a good response with resolution of symptoms. The majority of the prostatitis, however, is represented by the category III type. This is a therapeutic challenge for the practitioners. Following a first episode of prostatitis, the likelihood of subsequent episodes is very high, ranging from 20% to 50% in proportion to the age of the subject. Prior to establish a possible treatment protocol an accurate medical history and physical examination should be carried out. This obviously includes an accurate digital rectal examination. It is also mandatory to administer the NIH-CPSI and the International Prostate Symptom Score (I-PSS) questionnaires and to perform the Meares and Stamey test (3), uroflowmetry, urethral swap test, semen culture, total PSA and a transrectal ultrasonography. In spite of the fact that type III prostatitis is by definition non-bacterial, in many cases the antibiotics administration has resulted in a significant improvement of the symptoms. In fact, the literature supports the use of antibiotics in these cases (4, 5). In both cases bacterial and non-bacterial prostatitis alfa blockers can be added to the antibiotics. Modern naturopathic doctors however believe that the prescription of antibiotics for chronic pelvic pain syndrome (CPPS) can do more harm than good when bacteria has not been identified. However, CPPS is linked to a high rate of treatment failure and patient’s frustration due to their unclear etiology and complexity of symptoms. The primary objectives, addressing this condition, are the mitigation of the symptoms, the improvement of the quality of life, minimizing the side effects of the medical treatment. No conflict of interest declared.

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Efficacy of flower pollen extracts versus bioflavonoids

Phytotherapeutic agents remains then a suitable choice, who qualified for the study were randomized to either especially for their low or absent side effects. However, receive flower pollen extract (DEPROX 500® mg 2 capthere are few prospective and controlled studies to supsules once a day), or quercetin (500 mg twice a day) for port their use (6, 7). Several studies demonstrated that 4 weeks. a complex of flower pollen extract is able to produce a The use of bioflavonoids was selected based on the persistent improvement in symptoms of CPPS with a results of Shoskes et al. (15). The patients enrolled were significant reduction of the NIH-CPSI index (8, 9). blinded to the type of treatment. A telephone follow up A phase II study by Cai et al. demonstrated that the was then conducted 10 days after the treatment to ensure flower pollen extract, in association with vitamins, the correct compliance, whilst an outpatients follow up improved significantly the symptoms, the pain, and the was carried out 30 days after the treatment consisting in QoL score of patients with non-inflammatory Chronic a new set of questionnaires plus a urological examinaProstatitis (CP)/CPPS, without severe side effects (10). tion and repeat microbiology cultures. Additional studies have demonstrated that several other extract might be able to treat CP/CPPS. Inclusion/exclusion criteria Bioflavonoids are a family of polyphenolic molecules, of Inclusion criteria for the enrolment were defined as folwhich the quercetin is a representative. Quercetin has a lows: the presence of persistent pelvic pain for at least 3 theoretical benefits for patients with an ongoing inflammonths, in the 6 months preceding the study according matory or ischemic process of the prostate, mechanisms, to the EAU guidelines; NIH-CPSI pain score greater than which are recognized to be the basis of CPPS. 7 and a negative Meares-Stamey test (14). Furthermore, the usually suggested diet poor in bioflavonoids (green tea, caffeine, red wine), quercetin in particular, could Figure 1. Flowchart of the study. worsen the symptoms of CP/CPPS (11). The administration of bioflavonoids is then indicated in order to improve the Diagnosis of CP/CPPS quality of life of CP/CPPS patients. Also, n = 68 the bioflavonoids have been shown to play a key role in the inhibition of prostatic cancer cells in vitro (19). The objective of this study is to assess the efficacy and tolerability of the pollen extract compared to the quercetin in Esclusion criteria patients with CP/CPPS. The evaluation of – N = 0. Age less than 18 years and more than 65 years the quality of life and the safety of the – N = 0 Preexisting serious diseasesDiagnosis of CP/CPPS active principle represent the secondary n = 68 – N = 2 Known adverse reaction to the active substance endpoints of the study.

MATERIALS

– N = 0 Positivity to Chlamydia trachomatis test, Ureaplasma urealyticum, Neisseria gonorrhoeae, herpes virus (HSV 1/2) and Human Papillomavirus (HPV) – N = 5 Current antibiotic therapy

AND METHODS

We performed a non-sponsored phase I-II study in a single urological institution. The study was conducted according to Good Clinical Practice guidelines and the ethical principles of the Declaration of Helsinki. Before the beginning of the study, all participants signed a written informed consent. Between March 2016 to June 2016, all consecutive patients presenting with clinical diagnosis of CP/CPPS (classes IIIa or IIIb) were recruited in a single urological institution. The study was designed in accordance with the CP/CPPS clinical trial guidelines described by Chronic Prostatitis Collaborative Research Network NIH (12). All the eligible patients completed and returned also the base questionnaires (IPSS, QoL, NIH-CPSI). Following the guidelines of the European Association of Urology (EAU) every patient underwent an thorough urological examination and Meares-Stamey test (13). All the patients

Inclusion criteria – Presence of persistent pelvic pain – Pain score (NIH-CPSI) > 7 – Negative Meares-Stamey test

Patients enrolled n = 54

Control group n = 27

Study group n = 27

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A. Maurizi, F. De Luca, A. Zanghi, E. Manzi, C. Leonardo, M. Guidotti, F.P. Antonaccio, V. Olivieri, C. De Dominicis

Exclusion criteria were defined as follows: age less than 18 years old and more than 65 years old; anatomical abnormalities of the urinary tract system; additional urologic diseases; post-void residual urine volume (PVR) > 50 cc; known allergy to the active substance; patients who had recently undergone (< 4 weeks) oral or parenteral antibiotics treatment or who were using prophylactic antibiotic treatment (< 4 weeks); positivity to Chlamydia Trachomatis test, Ureaplasma Urealyticum, Neisseria Gonorrhoeae, Herpes Virus (HSV 1/2) and Human Papillomavirus (HPV). Patients were randomized into two arms: one had flower pollen extract, two tablets in a single daily dose for four weeks in line with the previous study of Cai et al. (10). Each dose contained 1 g of pollen extract and B1, B6, B2, B 9, B12, and PP vitamins. The remnant patients received quercetin (500 mg) complex twice daily for four weeks, in line with the study conducted by Shoskes et al. (15). Validated Italian versions of NIH-CPSI questionnaires (16) and the International Prostate Symptom (IPSS) scores were administered to each patient. The quality of life was evaluated via a translated version of the QoL (17). The NIH-CPSI was used to determine the effectiveness of clinical therapy (18). In particular, the expected mean difference for NIH-CPSI was chosen as the primary endpoint. All the specimen were collected during the urological examination and brought to the laboratory under refrigerated conditions, for cultures, DNA extraction and polymerase chain reaction for Chlamydia Trachomatis, Neisseria Gonorrhoeae, HSV 1/2, and HPV detection. In addition all the subjects included in the study underwent rectal examination, transrectal ultrasonography, urine and semen cultures, colonies count, and antibiogram if needed (Figure 1). Statistical analysis The main statistical analysis was performed on the patient population “Intent-To-Treat”, corresponding to all the ranTable 1. Calculation of the sample size. Alpha level

0.05

Power

90%

Observed average score

Expected average delta

Standard deviation N

2.2 54 (27 per arm)

Table 2. Patients enrolled in the study. Number of patients Age

262

54 33 ± 5.25

Condition duration

18.85 ± 4.17

NIH-CPSI T0

25.81 ± 1.61

IPSS T0

8.39 ± 1.74

QoL T0

0.55 ± 0.1

Archivio Italiano di Urologia e Andrologia 2018; 90, 4

domized patients described in the CONSORT diagram (Figure 1), a flowchart including the patients evaluated, randomized, analysed and excluded (for any reason). The baseline patient characteristics are reported as mean, standard deviation (SD), median, interquartile range (IQR), frequency, or relative percentage, depending on the type of variable distribution. For the baseline comparison (T0) in the two arms of the study we utilized the T-test for the independent variables and the comparisons of mean values. The chi-square was instead used for the comparison of proportions. The comparison of the mean values of the NIH-CPSI index between baseline (T0) and at 30 days (T1) was done using paired T-test. All the tests were two-tailed and the statistical significant value was determined to be 0.05. The sample size was calculated from a starting average waiting time of the variation of the National Institute of Health Chronic Prostatitis Symptom Index (NIH-CPSI) of 13 and a mean observed difference of 11 (SD ± 2.2) (Table 1).

RESULTS

Of the 68 patients presented at our institution with prostatic like symptoms during the study time, 54 were enrolled and randomized. Of the 14 patients excluded, 7 refused the enrolment, 5 were on antibiotic treatment, and 2 reported known allergy to the active substance. The pre-intervention questionnaires had the following scores: NIH-CPSI 25.81 ± 1.61; IPSS 8.39 ± 1.74; QoL 0.55 ± 0.1 (Table 2). Table 3 summarizes the clinical characteristics and the enrolment data of the samples taken by arm. There was a statistically significant difference in the duration of the symptoms pre-treatment, and a positive trend in the QoL. There were no other statistically significant differences. At one month follow up the observed results between patients that had taken the flower pollen extract were as follows: NIH-CPSI 12.22 ± 1.84, IPSS 7.3 ± 1.54, QoL 0.66 ± 0.1. Whereas the results for patients that had taken quercetin at the same interval were: NIH-CPSI 14.85 ± 1.85, IPSS 7.67 ± 1.27, QoL 0.59 ± 0.1 (Table 4). The improvement of the symptoms after taking flower pollen extract was statistically significant as compared to them taking quercetin (p = < 0.0001). The QoL score was also statistically superior in those taking flower pollen extract (p = 0.003). On the other hand, the IPSS score was similar among the two groups (p = 0.39). At the follow up all patients had a negative Meares-Stamey test, and showed similar laboratory values, as compared to the initial parameters. No adverse reactions have been reported from the treatment in either arms. The expected value (∆ NIH-CPSI), depicted in Chart I and II, obtained by evaluating the expected mean difference for the two arms of the NIH-CPSI pre and post treatment, was of 13.4444 ± 2.55 for the flower pollen extract , and of 11.11 ± 2.69 for the quercetin, being statistically significant (p = 0.0019) (Figure 1).

DISCUSSION

The main result of this study is the efficacy of the flower pollen extract in improving the quality of life and

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Efficacy of flower pollen extracts versus bioflavonoids

Table 3. Clinical characteristics and enrollment data of the samples taken by arm. DEPROX 500® group

Quercitina group

p value

34 ± 5.9

33.7 ± 4.62

0.81

63%

48%

0.27

Condition duration

17.56 ± 3.88

20.15 ± 4.11

0.02

NIH-CPSI T0

25.67 ± 1.62

25.96 ± 1.63

0.5

Number of patients Age Smokers (%)

IPSS T0

8.3 ± 2.13

8.5 ± 1.3

0.7

QoL T0

0.53 ± 0.1

0.58 ± 0.1

0.07

Dysuria Urgency Dysuria+frequency Burning sensation

11 (40.8%) 6 (22.2%) 4 (14.8%) 6 (22.2%)

12 (44.5%) 5 (18.5%) 3 (11%) 7 (26%)

0.95

Perineal pain Scrotal pain Soprapubic pain Lower abdominal pain No pain

12 (44..5) 5 (18.5) 5 (18.5) 5 (18.5)

7 (26%) 8 (30%) 6 (22%) 5 (18%) 1 (4%)

0.54

Erectile dysfunction (ED) Pramture ejaculation PE) DE+PE No sexual symptoms

12 (44%) 3 (11%) 4 (15%) 8 (30%)

10 (37%) 3(11%) 4 (15%) 10 (37%)

0.94

Type IIIa Type IIIb

13 (48%) 14 (52%)

11 (41%) 16 (29%)

0.58

CONCLUSIONS

Considering the above mentioned limitations, the flower pollen extract determined a significant improvement of the symptoms (pain, and quality of life) in the patients with CP/CPPS. A statistically significant difference was also noted in the expected value of the National Institute of Health Chronic Prostatitis Symptom Index (∆ NIH-CPSI) in the flower pollen extract group as compared to the Bioflavonoids complex with quercetin, without side effects.

REFERENCES

Table 4. 1 month follow up.

1. Krieger JN, et al. NIH consensus definition and classification of prostatitis. JAMA. 1999; 282:236-7

Variables DEPROX 500® (after 30 days of therapy) group NIH-CPSI T1

pain associated with diabetic polyneuropathy (24). In contrast to previous studies, our results show that there was no difference in either treatment arms between patient with non-inflammatory CP/CPPS and inflammatory CP/CPPS. Both the flower pollen extract and the quercetin were well tolerated for the entire duration of the protocol. The limitations of this study are the small number of patients enrolled, a short follow up period, and the selected nature of the patients enrolled. Furthermore, this was not set up as a double blind study. In the absence of a therapeutic efficacy of the “conventional” medications, the therapeutic options with nutritional supplements are a valid alternative. In deciding the therapeutic intervention it is necessary to choose the active principle that determines an improvement of the QoL, the reduction of pain, with high safety levels.

Quercitina group

p value < 0.0001

12.22 ± 1.84

14.85 ± 1.85

IPSS T1

7.3 ± 1.54

7.67 ± 1.27

0.39

QoL T1

0.66 ± 0.1

0.59 ± 0.1

0.003

reduce pain in patients with CP/CPPS in a statistically significant way compared to the bioflavonoids complex with quercetin. This therapeutic improvement holds true for both the type IIIa and IIIb CP/CPPS patients. Those results are in line with the current literature showing the reduction of pain after 30 days of use of flower pollen extract compared to quercetin (10). This effect is probably secondary to the association between the pollen extract and the vitamins B6 and B12, which enhances the protective effects of the pollen extract on the nerves. In fact, as demonstrated in animal experiments, the vitamin B complex (including B1, B6, and B12) has analgesic effects in acute and chronic pain secondary to electrical and thermal stimulation, primary and post diabetic neuronal damage (20, 21). Several studies have demonstrated that certain vitamin B, B6 and B12 in particular, are capable of protecting the neurons from specific lesions (22, 23). Vitamin B1, B6, and B12 are effective in the treatment of painful syndromes such has lumbago, sciatic nerve neuralgia, trigeminal neuralgia, and the chronic

2. Bartoletti R, et al. Italian prostatis study group. Prevalence, incidence estimation, risk factors and characterization of chronic prostatitis/ chronic pelvic pain syndrome in urological hospital outpatients in Italy: results of a multicenter case-control observational study. J Urol. 2007; 178:2411-5 3. Stamey TA. Prostatitis. J R Soc Med. 1981; 74:22-40. 4. Wagenlehner FM, Weidner W, Naber KG. Therapy for prostatitis, with emphasis on bacterial prostatitis. Expert Pin Pharmacother. 2007; 8:1667-74. 5. Nickel JC. Treatment of chronic prostatitis/chronic pelvic pain syndrome. Int J Antimicrob Agents. 2008; 31 (Suppl 1):S112-6. 6. Herati AS, Moldwin RM. Alternative therapies in the management of chronic prostatitis/chronic pelvic pain syndrome. World J Urol. 2013; 31:761-766. 7. Shoskes DA, Zeitlin SI, Shahed A, Rajfer J. Quercetin in men with category III chronic prostatitis: a preliminary prospective, doubleblind, placebo-controlled trial. Urology. 1999; 54:960-963. 8. Rugendorff EW, Weidner W, Ebeling L, Buck AC. Results of treatment with pollen extract (Cernilton N) in chronic prostatitis and prostatodynia. Br J Urol. 1993; 71:433-438. 9. Kamijo T, Sato S, Kitamura T. Effect of cernitin pollen-extract on experimental nonbacterial prostatitis in rats. Prostate. 2001; 49:122-131. 10. Cai T, Luciani LG, Caola I, et al. Effects of pollen extract in association with vitamins (DEPROX 500®) for pain relief in patients affected by chronic prostatitis/chronic pelvic pain syndrome: results from a pilot study. Urologia. 2013; 80(Suppl 22):5-10. Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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11. Shoskes DA, Nickel JC. Quercetin for chronic prostatitis/chronic pelvic pain syndrome. Urol Clin North Am. 2011; 38:279-84.

Institutes of Health chronic prostatitis symptom index. J Urol. 2001; 165:842-845.

12. Propert KJ, Alexander RB, Nickel JC, et al. Chronic Prostatitis Collaborative Research Network. Design of a multicenter randomized clinical trial for chronic prostatitis/chronic pelvic pain syndrome. Urology. 2002; 59:870-876.

19. Sharma V, et al. Sensitization of androgen refractory prostate cancer cells to anti-androgens through re- expression of epigenetically repressed androgen receptor - Synergistic action of quercetin and curcumin. Mol Cell Endocrinol. 2016; 431:12-2.

13. Grabe M, Bjerklund-Johansen TE, Botto H, et al. Guidelines on Urological Infections. European Association of Urology; Arnhem, The Netherlands: 2012. p. 66.

20. Jolivalt CG, Mizisin LM, Nelson A, et al. B vitamins alleviate indices of neuropathic pain in diabetic rats. Eur J Pharmacol. 2009; 612:41-47.

14. Wagenlehner FM, Schneider H, Ludwig M, et al. A pollen extract (Cernilton) in patients with inflammatory chronic prostatitis-chronic pelvic pain syndrome: a multicentre, randomised, prospective, double-blind, placebo-controlled phase 3 study. Eur Urol. 2009; 56:544-551.

21. Yu CZ, Liu YP, Liu S, et al. Systematic administration of B vitamins attenuates neuropathic hyperalgesia and reduces spinal neuron injury following temporary spinal cord ischaemia in rats. Eur J Pain. 2014; 18:76-85.

15. Shoskes DA. Quercetin in men with category III chronic prostatitis: a preliminary prospective, double-blind, placebo- controlled trial. Urology. 1999; 54:960-963. 16. Giubilei G, Mondaini N, Crisci A, et al. The Italian version of the National Institutes of Health Chronic Prostatitis Symptom Index. Eur Urol. 2005; 47:805-811. 17. Kaplan RM, Bush JW, Berry CC. Health status: types of validity and the index of well-being. Health Serv Res. 1976; 11:478-507. 18. Nickel JC, Downey J, Hunter D, Clark J. Prevalence of prostatitis-like symptoms in a population based study using the National

Correspondence Angela Maurizi, MD (Corresponding Author) angmau81@hotmail.com Francesco De Luca, MD francescodeluca10@gmail.com Costantino Leonardo, MD Michele Guidotti, MD F.P. Antonaccio, MD Carlo De Dominicis, MD, Professor Dipartimento di Scienze Ginecologico-ostetriche e Scienze Urologiche, Università Sapienza Viale dell'Università, 31/33, 00161, Roma, Italy Antonino Zanghì, MD Dipartimento di Scienze Mediche, Chirurgiche e Tecnologie Avanzate G.F. Ingrassia, Università di Catania, Catania, Italy Emy Manzi, MD emymanzi@gmail.com Via San Pasquale, 03043 Cassino (FR), Italy Valerio Olivieri, MD valerio.olivieri@uniroma1.it Piazza Credenza 2, 10015 Ivrea (TO), Italy

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22. Wang ZB, Gan Q, Rupert RL, et al. Thiamine, pyridoxine, cyanocobalamin and their combination inhibit thermal, but not mechanical hyperalgesia in rats with primary sensory neuron injury. Pain. 2005; 114:266-277. 23. Hung KL, Wang CC, Huang CY, Wang SJ. Cyanocobalamin, vitamin B12, depresses glutamate release through inhibition of voltage-dependent Ca2+ influx in rat cerebrocortical nerve terminals (synaptosomes) Eur J Pharmacol. 2009; 602:230-237. 24. Mäder R, Deutsch H, Siebert GK, et al. Vitamin status of inpatients with chronic cephalgia and dysfunction pain syndrome and effects of a vitamin supplementation. Int J Vitam Nutr Res. 1988; 58:436-441.

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DOI: 10.4081/aiua.2018.4.265

ORIGINAL PAPER

Treatment of retained encrusted ureteral Double-J stent Ibrahim Alnadhari 1, 2, Mohammed Ahmed Alwan 1, Morshed Ali Salah 1, 2, Abdulelah M. Ghilan 1 1 Urology

and Nephrology Center, at Al-Thawra Modern General and Teaching Hospital, Sanaâ&#x20AC;&#x2122;a, Yemen; of Urology, Al Wakra Hospital, Hamad Medical Corporation, Al Wakra, Qatar.

2 Department

Summary

Objectives: We conducted this study to evaluate patients with retained encrusted ureteral stents, identify the predisposing factors and present our experience in the management of such challenging problem. Materials and Methods: This prospective study was carried out in the period from May 2007 to February 2011 at the Urology and Nephrology Center, Al-Thawra General Hospital, Sanaâ&#x20AC;&#x2122;a, Yemen. 40 patients with retained encrusted ureteric stents were treated at our center. All patients were initially evaluated with a radiographic imaging for assessment of stent encrustation and stone burden. Treatment decisions were based on the site and severity of encrustations in the renal pelvis, ureter and bladder and on our technical situation and availability of instrumentations. Multi-modal approaches ranging from extracorporeal shock wave lithotripsy (ESWL) to endourological and open urologic procedures were used to achieve stent removal. Results: A total of 90 urological procedures were performed to render all 40 patients stent and stone free. The average duration of stent remained indwelling was 24.2 months (range 4 months -16 years). All patients were managed either by minimally or more invasive multi-modal endourological approaches. For upper coil encrustation percutaneous nephrolithotripsy was performed in eight patients, pyelolithotomy in two patients and ESWL in three patients. Encrustation of the body was treated initially by ESWL, followed by retrograde ureteroscopic manipulation in 12 patients. Lower coil encrustation was successfully managed by cystolitholapaxy in seven patients and one patient required cystolithotomy. Cystolithotomy, pyelolithotomy and ureterolithotomy were carried out in two patients. Two patients who had large burden bladder and kidney stones with loss of kidney function underwent nephrectomy and cystolithotomy. Conclusions: The retrieval of severely encrusted retained ureteral stent and its associated stone burden poses a real management challenge for urologists due to the need for multimodal procedures and the lack of standardized treatment plan.

KEY WORDS: Ureteral stent; Double-J stent; Encrustation. Submitted 25 July 2018; Accepted 13 August 2018

INTRODUCTION

The use of indwelling ureteral stents has become an integral part of many urological procedures. They provide free drainage from upper urinary tract to the bladder in cases of renal and ureteral obstruction secondary to a variety of intrinsic or extrinsic factors such as calculi, strictures, congenital anomalies, pelvic malignancies, retro-peritoneal tumors, and fibrosis (1-4). Common indications for stent placement include the prevention or

relief of obstruction prior to Extracorporal Shock Wave Lithotripsy (ESWL) and after ureteroscopy (URS) (5, 6). They are also placed after iatrogenic injuries of the ureter and for the purpose of easy identification and protection of the ureter during complex abdominal procedure (7). Since Zimskind et al. first described the original use of endoscopically inserted indwelling ureteral stent in 1967 (8),various modifications on stent design have been made allowing for easier manipulation (1, 6). Modern ureteral stents are generally designed in a double-pigtail or double-J (JJ) configuration (3, 9). The ideal stents are those which are easy to insert and remove, radiologically-opaque, having good flow characteristics, biologically inert and chemically stable in urinary tract, and the stent biomaterial should resist encrustation, prevent infection and be widely avail-able at a reasonable cost (3). Unfortunately, no stent biomaterial is currently available that meets all of these criteria. A variety of materials including synthetic polymeric compounds (polyurethane/polyethylene) and silicon are available with various biocompatibility and biodurability (3, 6). Despite advances in stent deigns and materials, problems related to indwelling ureteral stent use, such as infection, encrustation, stone formation, occlusion, migration and breakage continue to occur (1, 5, 10, 11). Retained ureteral stents especially those that are encrusted can be a challenging problem that may lead to serious complications of obstruction, infection and renal impairment if not managed properly (1, 2, 6, 12). The problem of retained stents occurs due to variety of causes. Illiteracy and non-compliance of the patient together with poor communication between patients and physicians are the main contributing causes for delay in timely removal of stents (2, 13). We conducted this study to evaluate patients with retained encrusted indwelling ureteral stents, identify the predisposing factors and present our experience in the management of such challenging problem.

MATERIALS

AND METHODS

A prospective, observational and cohort study was carried out in the period from May 2007 to February 2011 at the Urology and Nephrology Center, Al-Thawra General and Teaching Hospital, the main referral hospital in the country, Sanaâ&#x20AC;&#x2122;a, Yemen. 40 patients (30 males and 10 females) who were presented with retained encrusted

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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I. Alnadhari, M. Ahmed Alwan, M. Salah, A.M. Ghilan

ureteric stents and managed at our hospital during this period. All patients with a retained stent which was defined as “one which could not be removed cystoscopically at the first attempt and required other auxiliary measures or surgical procedure for removal”, were included in the study. Patients with no visible encrustation on their stents, in whom the stents were easily removed cystoscopically at first attempt, were excluded from the study, no matter how long was the duration of missing. The indications of initial stent placement, the duration of stent in the urinary system, and the reasons for delayed removal were all reviewed in the history. All patients were initially evaluated with a plain radiography (KUB), abdominal ultrasonography and intravenous urography (IVU) for assessment of stent encrustation and associated stone burden. Intravenous urography and in some cases, renal isotope scan were also obtained to document the degree of renal function loss. Laboratory tests such as complete blood count, urea and creatinine measurements and urine culture and sensitivity tests were routinely performed. Treatment decisions were based on the site and severity of encrustations in the renal pelvis, ureter and bladder and on our technical situation and availability of instrumentations. Patients were counseled about the benefits, risks and possible complications including sepsis, loss of renal function, injury to surrounding organs and the possible need for further interventions. Cystolithotripsy and cystolithotomy were required to treat the distal components of stent. ESWL, ureterorenoscopic (URS) manipulations, and ureterolithotomy were used to treat the ureteric part of the stent. ESWL, percutaneous nephrolithotripsy (PCNL), and pyelolithotomy were performed to treat the upper coil of the stent, and nephrectomy for removal of non-functioning kidney. All of these procedures were carried out under general anesthesia, except ESWL sessions which were performed under parenteral analgesia. Post-treatment control KUB films and/or ab-domino-pelvic ultrasonography were routinely performed for our patients.

RESULTS

Forty patients with retained ureteral stents were managed in our center during the period of the study. Patients’ ages ranged from 4 to 70 years (mean 30 years), 30 patients were males and 10 were females. The average duration of stent remained indwelling was 24.2 months (range 4 months- 16 years). All stents (except two) were placed in the capital Sana’a. One of the remaining two was placed in Saudi Arabia and the other in Ibb city. In 22 patients (55%), the stent side was the right while in the remainder 18 (45%), the side was the left. The most common reasons for stent missing, as shown in Table 1, were poor compliance of the patients (patients ignored or forgot physicians’ advice regarding its timely removal) and seen in 47.5% of cases, followed by inability to return back to hospital due to financial reasons (30%), and delayed referral after ESWL to endourology department for stent replacement or removal in the optimal time (12.5%). In 10% of patients, the reason was poor communication between patients and physicians

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Table 1. Baseline characteristic and clinical features of the study population. Number of patients n° Sex (male/female) Age Residency

no (%) 40 (Male/female) 30/10 (75/25%) Mean (range) 30 (4-70) years Sana’a 13 (32.5%) Others 27(67.5%) Cause of missing stents Poor compliance 19 (47.5%) Inability to return back 12 (30%) Delay in referral 5 (12.5%) Poor communication 4 (10%) Indication for initial stent Relieve of obstruction 16 (40%) placement Intra-operative 15 (37.5%) Before ESWLa 9 (22.5%) Site of maximum encrustation Kidney (upper coil) 6 (15%) Kidney & ureter 4 (10%) Ureter (body) 15 (37.5%) Bladder (lower coil) 6 (15%) Kidney & bladder 4 (10%) Totally encrusted 2 (5%) Not visible 3 (7.5%) Executed therapy ESWL 50 (55.5%) URSb 12 (13.3%) Cystolitholapaxy 7 (7.7%) PCNLc 8 (8.8%) Cystolithotomy 5 (5.5%) Pyelolithotomy 4 (4.4%) Ureterolithotomy 2 (2.2%) Nephrectomy 2 (2.2%) a ESWL = extracorporeal shock wave lithotripsy; b URS=ureterorenoscopy; c PCNL = percutaneous nephrolithotomy.

(the patients did not know about the presence of stent and/or the need for its timely removal). The main initial indications of ureteral stenting and the sites of maximum encrustation are shown in Table 1. Combinations of ESWL, endourologic and open urologic procedures were required to facilitate removal of retained stent and associated stones. A total of 90 urologic procedures were performed to render all 40 patients stent free. Averages of 2.25 urologic procedures per patients (range 1-10) were performed during either single or multiple anesthetic sessions as shown in Table 1. In 25 out of 40 patients, it was possible to have patients cleared from their retained stents and stone burden in a single anesthetic session. We began by careful evaluation of plain KUB for the presence of encrustation on the proximal coil, body and distal coil of the stent. In cases of no visible encrustation, cystoscopy and trial of stent extraction by gentle traction under fluoroscopic control was applied. If it was removed easily, then we did not include the case in our study despite the duration of missing. If we found difficulties in stent extraction, no force was applied to avoid damaging the ureter and the case was considered as a retained stent. ESWL was our first choice for cases of retained stent without visible encrustation or with minor encrustation especially on the proximal coil and body. We had three patients with retained stent without clear calcifications in whom ESWL to the proximal coil was carried out and then the stent was removed easily. In cases of visible encrustations

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Retained encrusted Double-J stent treatment

on plain KUB, no attempts at direct removal were done, but we proceeded according to the site and severity of encrustations. If there were linear encrustations on the proximal coil or body, we performed ESWL to the site of encrustation and then trial of removal of stent by gentle traction without force. For linear or minor encrustation on the distal coil, we crushed them with forceps or lithotripter to fragment them and remove the fragments. Pneumatic lithotripter was used whenever needed. When these less invasive measures failed or if the encrustations were severe, then we manage our patients in retrograde fashion, starting with the bladder component, then the ureter and kidney. Cystolithotripsy was our first option for bladder component of encrustations. In children, we did cystolithotomy in two patients to remove bladder encrustations because of large stone burden and to avoid repeated urethral instrumentation and the risk of urethral injury in children, especially males. Cystolithotomy was also performed for three adults who had large bulky bladder stone around the distal coil. For ureteral components, we mostly started by preliminary ESWL to fragment the encrustations around the stent and then we passed a small (7F) semi-rigid ureteroscope alongside a safety guide-wire under vision and we performed fragmentation of encrustation and removed the fragments. We had one patient with heavy encrustations in the ureteric component and associated cardiac disease that made him unfit for anesthesia, he needed ten sessions of ESWL to render him stone- and stent-free. Encrustations with large stone burden on the kidney component of the stent were solved by percutaneous nephrolithotripsy (PCNL). Solving the bladder and ureteric components, always preceded PCNL. Pyelolithotomy was carried out for managing the proximal components in children because we have no pediatric PCNL set in our center and in one adult due to accidental technical problem in our endoscopy unit at that time. We resorted to nephrectomy in two patients who had large bladder and kidney stones burden with loss of kidney function which was demonstrated by radioisotope scanning. Cystolithotomy for the bladder component was done during the same session. All procedures were done without intra-operative complications, and there were no significant postoperative complications. Two cases with totally encrusted ureteric stent and large stone burden over the entire length of the stent worth detailed reporting as they were managed by cystolithotomy, ureterolithotomy and pyelolithotomy in a single anesthetic session. One of them had a solitary ectopic pelvic kidney. Case 1 A five year old boy who had a congenital right solitary ectopic pelvic kidney and presented with a ureteral stent retained for about three years which was inserted as an emergency procedure to relieve upper urinary obstruction. Poor compliance was the reason for long indwelling time. His renal functions were normal. KUB and IVU radiographs are shown in (Figures 1, 2). Through a single small oblique incision in the right lower abdomen and in a single anesthetic session, cystolithotomy, then ureterolithotomy and pyelolithotomy were performed

Figure 1. KUB X ray film shows severe encrustations around ureteral stent, renal pelvis and in the bladder.

Figure 2. Intravenous Urography shows solitary pelvic kidney with significant hydronephrosis.

Figure 3. Oblique lower abdominal incision and removal of the renal pelvic stone through pyelotomy.

Figure 4. Demonstration of the stones with the extracted retained ureteral stent after their reconfiguration.

for removal of the stent and stone burden. (Figures 3, 4). Control urinary tract ultrasound showed clearance of stones and the double j stent removed two weeks later. Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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Figure 5. KUB X ray film shows severe encrustations and large stone burden around retained ureteric stent.

Figure 6. Shows demonstration of the stones with the extracted retained ureteric stent after their reconfiguration.

Case 2 This was a 25-year-old man who had a forgotten encrusted ureteral stent placed as an emergency procedure to relieve a ureteric obstruction two years prior to his presentation to our department. Poor compliance was the reason for long indwelling time. His KUB radiograph is shown in (Figure 5). The vesical and lower ureteric calcifications were managed by cystolithotomy and ureterolithotomy through a lower abdominal incision. The patient was then shifted to flank position where pyelolithotomy and ureterolithotomy for removal of the kidney and upper ureteric encrustations. All of these procedures were performed during a single anesthetic session (Figure 6).

DISCUSSION

Severely encrusted forgotten ureteral stent is one of the difficult problems in urological practice. Major complications associated with retained stents include infection, migration, fragmentation, stone formation, and ureteral obstruction (6, 7, 14-17). These complications, in addition to the potential need for multiple surgical interventions and the lack of defined therapeutic guidelines for treatment represent a real challenge for urologist (3, 15, 16, 18). Although the exact etiology of encrustation is unclear, the incidence of encrustation increases with indwelling stent duration. In one study, overall 47.0% of

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stents were encrusted and the encrustation rate was 26.8% at less than 6 weeks, 56.9% at 6 to 12 weeks and 75.9% at more than 12 weeks (17). Risk factors for stent encrustation are poor patient compliance to follow-up, long indwelling time, sepsis, pyelonephritis, recurrent or residual stone formation, lithogenic history, chronic renal failure, pregnancy metabolic and congenital abnormalities (2, 10, 11, 18). The stent indwelling duration in the current series ranged between 4 months to 16 years, with average of 24.2 months, which is comparable with the mean duration time of 22.7 months reported by Monga et al. (19). Still two other series reported longer average indwelling time of 4.4 years and 4.9 years, with a range of 1-8 years and 1-12 years respectively (4, 7). Many times, stents are forgotten either because of illiteracy, non-compliance of the patients who ignore or forget physician advice regarding its timely removal. Poor compliance of the patients was the commonest reason for forgotten stents in our study and this can be explained to some extent by the educational level of patients, as many of our patients were either of low educational level or illiterates. All of the retained stents, except two, were inserted in one city (the capital Sanaâ&#x20AC;&#x2122;a) due lack of endourologic units in the other cities till the near time. As most of patients lived in areas far from the capital Sanaâ&#x20AC;&#x2122;a, they found it difficult to come back for follow-up or removal of their stents. This constitutes another contributing factor for poor compliance and therefore stent missing. The inability of the patient to attend again to hospitals due to financial reasons (poverty) is another considerable cause for retained stent problems in our patients. Delayed referral from ESWL department to the endoscopy department for removal of the stent within the optimum time is a third reason for stent retention. The last important contributing factor for retained stents in our study was the presence of communication gaps between patient and physician, with failure of the physician to adequately council the patient about the presence of stent, and/or the need for its timely removal. Similar to our series, some other series reported poor compliance as the most common reason for retention of these stents (1, 4) while delayed referral by lithotripsy department for stent replacement within the optimal time was reported as the commonest reason by another series (2). Multimodal approach is often required for the management of forgotten ureteral stents to achieve successful retrieval of the retained stent and removal of associated stone burden. Although there are no standard and specific guidelines for the management of encrusted ureteral stents, many authors have reported their series and proposed their own management algorithms (1, 3, 7, 11). These include multiple urological modalities which may require single or multiple endourological sessions. Our treatment options were based upon our technical situations and resources. We utilized an average of 2.25 urologic procedures per patient to render our patients stent and stone free, an average that is comparable with the results of other series which reported average of 2.7 and 2.38 procedures for clearing their patients from retained stents and the associated stones (1, 2). Bostanci et al. reported the use of various combinations of endourological techniques in 19 patients with encrusted

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Retained encrusted Double-J stent treatment

ureteral stents and they were able to render all patients stent and stone free after a single anesthetic session with minimal morbidity and short hospital stay (14). Other reports of fewer patients undergoing one-stage removal of encrusted ureteral stents were also published by other authors (2, 15, 20). In 25 out of 40 of our patients, we were able to remove the retained stents and associated stone burden in a single anesthetic session. We were obligated to perform open pyelolithotomy in children due to unavailability of pediatric PCNL set in our center and in one adult due to accidental technical trouble in our endoscopy unit at that time. The advent of modern endourologic technology has enabled the removal of all the retained stents utilizing complete endourologic approach. However, in some cases of sever encrustations, endoscopic manipulations may fail and the options of open or laparoscopic surgery are considered (1, 2 ,7).

CONCLUSIONS

The widespread use of indwelling ureteral stent has been translated into documentation of increased number of forgotten stents with their potential complications. Stent encrustation and stone formation are among the serious complications of retained ureteral stents. Noncompliance of some patients together with poor communication between patients and attending urologists constitute important contributing factors to the missing of ureteral stents. The retrieval of severely encrusted retained ureteral stent and its associated stone burden poses a real management dilemma for urologists due to the need for multimodal procedures and the lack of standardized treatment plan. Ideally, the best treatment of these difficult problems is prevention through patients’ education and proper patient-physician communication to conduct clear information to the patient about the presence of the indwelling stent, the risks associated with prolonged indwelling times and the need for its timely removal or replacement.

REFERENCES

7. Murthy KV, Reddy SJ, Prasad DV. Endourological management of forgotten encrusted ureteral stents. Int Braz J Urol. 2010; 36:420-9. 8. Zimskind PD, Fetter TR, Wilkerson JL. Clinical use of long-term indwelling silicone rubber ureteral splints inserted cystoscopically. J Urol. 1967; 97:840-4. 9. Ather MH, Talati J, Biyabani R. Physician responsibility for removal of implants: the case for a computerized program for tracking overdue double-J stents. Tech Urol. 2000; 6:189-92. 10. Borboroglu PG, Kane CJ. Current management of severely encrusted ureteral stents with a large associated stone burden. J Urol. 2000; 164:648-50. 11. Singh I, Gupta NP, Hemal AK, et al. Severely encrusted polyurethane ureteral stents: management and analysis of potential risk factors. Urology. 2001; 58:526-31. 12. Adanur S1, Ozkaya F. Challenges in treatment and diagnosis of forgotten/encrusted double-J ureteral stents: the largest single-center experience. Ren Fail. 2016; 38:920-6. 13. Singh V, Srinivastava A, Kapoor R, Kumar A. Can the complicated forgotten indwelling ureteric stents be lethal? Int Urol Nephrol. 2005; 37:541-6. 14. Bostanci Y, Ozden E, Atac F, et al. Single session removal of forgotten encrusted ureteral stents: combined endourological approach. Urol Res. 2012; 40:523-9. 15. Singh D, Goel A, Ahmed N, Singh BP. Forgotten stent leading to complex panurinary stone: single-sitting endourologic management. BMJ Case Rep. 2011; 2011:bcr0620103079 16. Ecke TH, Hallmann S, Ruttloff J. Multimodal stone therapy for two forgotten and encrusted ureteral stents: a case report. Cases J. 2009; 2:106. 17. Kawahara T, Ito H, Terao H, et al. Ureteral stent encrustation, incrustation, and coloring: morbidity related to indwelling times. J Endourol. 2012; 26:178-82. 18. Abdelaziz AY, Fouda WB, Mosharafa AA, et al. Forgotten ureteral stents: Risk factors, complications and management. AFJU 2018; 24:28-33. 19. Monga M, Klein E, Castañeda-Zúñiga WR, Thomas R. The forgotten indwelling ureteral stent: a urological dilemma. J Urol. 1995; 153:1817-9. 20. Bukkapatnam R, Seigne J, Helal M. 1-step removal of encrusted retained ureteral stents. J Urol. 2003; 170:1111-4.

1. Lam JS, Gupta M. Tips and tricks for the management of retained ureteral stents. J Endourol. 2002; 16:733-41. 2. Rana AM, Sabooh A. Management strategies and results for severely encrusted retained ureteral stents. J Endourol. 2007; 2:62832. 3. Acosta-Miranda AM, Milner J, Turk TM. The FECal Double-J: a simplified approach in the management of encrusted and retained ureteral stents. J Endourol. 2009; 23:409-15. 4. Rabani SM. Combined percutaneous and transurethral lithotripsy for forgotten ureteral stents with giant encrustation. Nephrourol Mon. 2012; 4:633-5. 5. Keane PF, Bonner MC, Johnston SR, et al. Characterization of biofilm and encrustation on ureteric stents in vivo. Br J Urol. 1994; 73:687-91. 6. Mohan-Pillai K, Keeley FX Jr, Moussa SA, et al. Endourological management of severely encrusted ureteral stents. J Endourol. 1999; 13:377-9.

Correspondence Ibrahim Ahmed Alnadhari, MD (Corresponding Author) ibrahimah1978@yahoo.com Morshed Ali Salah, MD morshed.salah@gmail.com Urology and Nephrology Center, at Al-Thawra Modern General and Teaching Hospital, Sana’a, Yemen Department of Urology, Al Wakra Hospital, Hamad Medical Corporation, Al Wakra, Qatar Mohammed Ahmed Alwan, MD MAlwan197200@gmail.com Abdulelah M Ghilan, MD dr_ghilan1@yahoo.com Urology and Nephrology Center, at Al-Thawra Modern General and Teaching Hospital, Sana’a, Yemen, AlKhamseen Street, Sana’a, Yemen

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DOI: 10.4081/aiua.2018.4.270

ORIGINAL PAPER

Summary

Objective:To evaluate the diagnostic value of serum inflammation markers derived from complete blood count in diagnosis of prostate cancer (PCa). Methods: We retrospectively analyzed the data of 621 patients who underwent prostate biopsy between March 2013 and April 2018. Age, prostate specific antigen (PSA), free PSA, platelet count, neutrophil count, lymphocyte count, monocyte count, prostate volume (PV) and pathology result of the patients were recorded. Patients were grouped as benign prostatic hyperplasia (BPH), prostatitis and PCa. Patients were also grouped according to PSA values, as PSA < 4 , PSA 4-10 and PSA > 10 ng/dl. Results: The mean lymphocyte-to-monocyte ratio (LMR) value of the patients with PCa was significantly lower in the entire cohort (p = 0.047). In the PSA 4-10 ng/dl range, LMR value wassignificantly lower in patients with PCa than those with BPH or prostatitis ( p = 0.012). In this PSA range, free/total PSA ratio and LMR were significant factors to predict PCa. The cut-off values of LMR, free/total PSA were 3.05 and 0.15 respectively. The sensitivities, spesificities, positive predictive values (PPV) and negative predictive values using LMR cut-off, free/total PSA cut-off and their combination were assessed. Specificity and PPV of the combination group were higher (97.2%, 83.3% respectively) compared to free/total PSA cut-off group (91.6%, 76.6%) and LMR cut-off group (67.8%, 43.7%). Conclusions: LMR is a useful tool at detecting PCa especially in patients with PSA value between 4 and 10 ng/dl. The combination of free/total PSA ratio and LMR improves the diagnostic accuracy more than the use of free/total PSA ratio alone.

KEY WORDS: Lymphocyte-to-monocyte ratio; Prostate cancer. Aubmitted 19 August 2018; Accepted 19 August 2018

INTRODUCTION

Prostate cancer (PCa) is the second most frequently diagnosed cancer and the fifth most common cause of cancer-associated death in men worldwide (1). Despite the recent advances in diagnostic and therapeutic approaches, it is still a major health concern especially in developed countries and especially in elderly men (2). Serum prostate-specific antigen (PSA) is widely used as a biomarker for this cancer, and its widespread introduction has undoubtedly enhanced the early detection of

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PCa and reduced the associated mortality. However, the low specificity of PSA can lead to unnecessary biopsies, overdiagnosis and overtreatment (3). PSA is organ but not cancer-specific, therefore it may be elevated in benign conditions such as benign prostate hyperplasia (BPH), prostatitis, urinary tract infections and trauma. After detection of elevated PSA, it is recommended to perform prostate biopsy (PBx) which is still the gold standard method for diagnosis of PCa. However PBx is associated with several complications, including pain, hematospermia, haematuria, hematochezia, and potentially severe infectious complications, ranging from urinary tract infections (UTIs) and prostatitis to sepsis (4). Although PSA is a useful tool at detecting PCa, concern about performing unnecessary PBx considering overdiagnosis and complications is the crucial problem for urologists. Some PSA-related testing parameters (e.g., PSA density, free/total PSA ratio, PSA doubling time, and prostate health index test) have been used to improve the accuracy of PCa prediction (5). Thus, new biomarkers may be needed to improve decision-making regarding initial management, including whether to biopsy. Over the last decade, it has become clear that systemic inflammation plays an important role in the development and progression of cancer. The markers of the systemic inflammatory response are usually based around composite ratios or cumulative scores of different circulating white blood cells representing the systemic responses of lymphoid/myeloid tissue. The main approach is to take the ratio of different white blood cells and then apply a prognostic threshold to the ratio such that outcome is effectively stratified. The most repeatedly validated examples of this approach are the neutrophil-lymphocyte ratio (NLR) based on the ratio of circulating neutrophil and lymphocyte counts, the platelet-lymphocyte ratio (PLR) based on the ratio of circulating platelet and lymphocyte counts and the lymphocyte-monocyte ratio (LMR) based on the ratio of circulating lymphocyte and monocyte counts. In this study, we aimed to investigate the role of the systemic inflammatory response markers prior to PBx at predicting histologic≠al outcomes. No conflict of interest declared.

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Lymphocyte-to-monocyte ratio is a valuable marker to predict prostate cancer in patients with prostate specific antigen between 4 and 10 ng/dl.

METHODS

30 patients, presence of metastasis in the imaging reports We retrospectively analyzed the data of 621 patients who in 47 patients and presence of PSA higher than 100 ng/dl underwent 12-core PBx between March 2013 and April in 25 patients). Finally the data of 621 patients were inves2018. PBx was performed within 4 weeks after blood tigated. The mean age was 64.97 ± 6.36 years. The mean tests. Age, total PSA level, free PSA level, hemoglobin prostate volume was 71.64 ± 39.9 cc. level, platelet count, neutrophil count, lymphocyte The mean PSA and free/total PSA value were 9.86±7.43 count, monocyte count, prostate volume and pathology ng/dl and 0.23 ± 0.10, respectively. The mean NLR, PLR result of the patients were recorded. and LMR values were 2.50 ± 1.17, 124.94 ± 51.81 and Patients with symptomatic prostatitis or urinary tract 3.84 ± 1.44, respectively. Additionally, patients were infection or systemic inflammatory disease or any histogrouped with regard to histology of the biopsy. Among all ry of anti-inflammatory drug use within 2 weeks before PBx were excluded. Also patients with high grade intraep- Table 1. Comparison of the study parameters of 3 histology groups in entire cohort. ithelial neoplasia (H-PIN) and atypical small acinar proliferation (ASAP) were BPH (n = 357) Prostatitis (n = 24) PCa (n = 240) p value excluded due to the low number of Age, years (mean ± SD) 64,45 ± 6,08 64 ± 5,87 65,85 ± 6,74 0,004 cases. Finally the patients whose PSA Total PSA, ng/dl (mean ± SD) 8,82 ± 6,61 6,27 ± 2,46 11,79 ± 8,68 0,001 was less than 100 ng/ml and those had Free/total PSA (mean ± SD) 0,25 ± 0,10 0,29 ± 0,06 0,18 ± 0,10 0.000 no evidence of metastasis in imaging Prostate volume, cc (mean ± SD) 82,82 ± 43,49 72,75 ± 51,14 54,90 ± 24,30 0.000 reports were included. Comparison of the study parameters of 3 histology groups in PSA 4-10 range The patients were laid down in left latBPH (n = 252) Prostatitis (n = 18) PCa (n = 150) eral decubitus position and in the flexAge, years (mean ± SD) 64.58 ± 5.89 63.17 ± 6.5 66.64 ± 6.04 0.000 ion of knees and hips. General Electric LOGIQ 100 PRO Series ultrasound Total PSA, ng/dl (mean ± SD) 6.6 ± 1.63 6.13 ± 1.72 6.86 ± 1.72 0.106 device was used with 6.5 MHz rectal Free/total PSA (mean ± SD) 0.25 ± 0.09 0.30 ± 0.06 0.19 ± 0.11 0.000 probe, the widest diameter of which Prostate volume, cc (mean ± SD) 80.3 ± 39.6 80.17 ± 54.75 50.78 ± 19.08 0.000 was 23 mm. Biopsy samples were PCa: Prostate cancer; BPH: Benign prostate hyperplasia; SD: Standart deviation; PSA: Prostate spesific antigen. taken as 12 cores with the use of 30 cm 18 Gauge full automatic biopsy Table 2. needle. Data analysis Biopsy results, Gleason scores, PSA, free/total PSA ratio, prostate volume, age, NLR results, PLR results, LMR results were assessed using the Chisquare test or Mann-Whitney U-test to determine statistically significant differences. After adjusting for confounding factors, univariate and multivariate logistic regression analyses were performed to determine the factors effecting PCa diagnosis. The predictive accuracy of the multivariate model was assessed using receiver operating characteristic (ROC)-derived area under the curve (AUC) analysis. The IBM SPSS software package version 21.0 (Statistical Package for Social Sciences™, Chicago, IL, USA) weas used for statistical analysis. A two-tailed P < 0.05 was considered as significant for all analyses.

RESULTS

A total of 800 patients who underwent transrectal ultrasound guided PBx were recorded. Of these, 179 did not meet inclusion criterias and were excluded (lack of data regarding CBC in 77 patients, presence of HPIN or ASAP in

Mean ± SD values of the inflammation markers and p values for comparison of the histological groups in the entire cohort. NLR value (mean ± SD) PLR value (mean ± SD) LMR value (mean ± SD)

BPH = 2,50 ± 1,22 Prostatitis = 2,34 ± 0,96 PCa = 2,51 ± 1,10 BPH = 124,02 ± 49,25 Prostatitis = 108,93 ± 39,05 PCa = 127,89 ± 56,30 BPH = 3,92 ± 1,45 Prostatitis = 4,11 ± 1,19 PCa = 3,67 ± 1,44

BPH (n = 357) 1 0,529 0,543 1 0,480 0,669 1 0,485 0,047

Prostatitis (n = 24) PCa (n = 240) 0,529 0,543 1 0,207 0,207 1 0,480 0,669 1 0,512 0,512 1 0,485 0,047 1 0,098 0,098 1

PCa: Prostate cancer; BPH: Benign prostate hyperplasia; SD: Standart deviation; PSA: Prostate spesific antigen; NLR: Neutrophile to lymphocyte ratio; PLR: Platelet to lymphocyte ratio; LMR: Lymphocyte to monocyte ratio.

Table 3. Mean ± SD values of the inflammation markers and p values for comparison of the histological groups in the cohort PSA 4-10 ng/dl range. NLR value (mean ± SD) PLR value (mean ± SD) LMR value (mean ± SD)

BPH = 2.52 ± 1.31 Prostatitis = 2.64 ± 0.94 PCa = 2.55 ± 1.10 BPH = 123.64 ± 49.58 Prostatitis = 114.06 ± 28.13 PCa = 124.13 ± 48.79 BPH = 3.95 ± 1.54 Prostatitis = 3.80 ± 1.19 PCa = 3.56 ± 1.33

BPH (n = 252) 1 0.439 0.295 1 0.910 0.743 1 0.536 0.012

Prostatitis (n = 18) PCa (n = 150) 0.439 0.295 1 0.982 0.982 1 0.910 0.743 1 0.782 0.782 1 0.536 0.012 1 0.533 0.533 1

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Table 4. Mean ± SD values of the inflammation markers and p values for comparsion of the histological groups in the patients with PSA higher than 10 ng/dl.

Any statistically significant difference was not observed for NLR and PLR values. Mean LMR value of the patients with PCa was significantly lower than BPH (n = 78) PCa (n = 72) patients with BPH and prostatitis (p = NLR (mean ± SD) BPH = 2.63 ± 1.0 1 0.839 0.047) (Table 2). PCa = 2.66 ± 1.1 0.839 1 The patients were divided into 3 PLR (mean ± SD) BPH = 133.3 ± 51.1 1 0.965 groups as; with PSA lower than 4 ng/dl, PCa = 143±71 0.965 1 with PSA between 4 and 10 ng/dl and LMR (mean ± SD) BPH = 3.76 ± 1.1 1 0.892 with PSA higher than 10 ng/dl. In the PCa = 3.69 ± 1.3 0.892 1 patients with PSA between 4 and 10 PCa: Prostate cancer; BPH: Benign prostate hyperplasia; SD: Standart deviation; PSA: Prostate spesific antigen; ng/dl, LMR value was significantly NLR: Neutrophile to lymphocyte ratio; PLR: Platelet to lymphocyte ratio; LMR: Lymphocyte to monocyte ratio. lower in patients with PCa than those with BPH or prostatitis (p = 0.012) (Table 3). Any statistically significant Table 5. Mean ± SD values of the inflammation markers and p values for comparsion difference between the groups was not of the Gleason score groups in the entire cohort. observed in NLR and PLR in the PSA 410 ng/dl range. In the group of the Gleason 6 (n = 173) Gleason > 7 (n = 67) patients with PSA higher than 10 ng/dl, NLR (mean ± SD) GS 6 = 2.5 ± 1.05 1 0.454 there was not any statistically signifiGS > 7 = 2.57 ± 1.23 0,454 1 cant variation for NLR, PLR and LMR PLR (mean ± SD) GS 6 = 122.1 ± 46.8 1 0.082 (Table 4). In this group, the presence of GS > 7 = 142.8 ± 73.8 0,082 1 prostatitis could not be compared due LMR (mean ± SD) GS 6 = 3.7 ± 1.15 1 0.177 to the low number of patients. GS > 7 = 3.6 ± 2.02 0,177 1 The patients with PCa were seperated SD: Standart deviation; NLR: Neutrophile to lymphocyte ratio; PLR: Platelet to lymphocyte ratio; into 2 groups as patients with Gleason LMR: Lymphocyte to monocyte ratio; GS: Gleason score. score 6 and patients with Gleason score 7 and above. There was no statistically significant difference between the Table 6. groups in NLR, PLR and LMR value Univariate and multivariate analyses for predicting prostate cancer. (Table 5). In the patients with PSA between 4 and n Univariate analysis Multivariate analysis HR 95% CI p HR %95 CI p 10 ng/dl, age, free/total PSA ratio and Age (year) LMR were significant factors to predict < 65.5 186 1 1.14-1.86 0.01 1 1.68-4.56 < 0.001 PCa. Based on the AUROC curve, the > 65.5 216 1.45 2.77 cut-off points of LMR, free/total PSA LMR value and age were 3.05, 0.15 and 65.5 > 3.05 258 1 0.99-1.37 0.04 1 1.02-2.6 0.037 respectively (Figure 1). Multivariate < 3.05 144 1.17 1.65 analysis showed that LMR (HR = 1.65), Free/total PSA value age (HR = 2.77) and free/total PSA ratio > 0.15 1 1.45-1.97 < 0.001 1 6.80-22.22 < 0.001 (HR = 12.3) were independent risk fac< 0.15 1.69 12.3 tors to predict PCa (Table 6). The senPSA: Prostate spesific antigen; LMR: Lymphocyte to monocyte ratio; HR: Hazard ratio; CI: confidence interval. sitivities, spesificities, positive predictive values and negative predictive valthe individuals, BPH was detected in 357 patients, proues using LMR cut-off, free/total PSA cut-off and their statitis was detected in 24 and PCa was detected in 240. combination were showed in Table 7. Specificity and The mean age and the mean PSA value of the PCa group positive predictive value of the combination group were were significantly higher when compared to the other higher (97.2%, 83.3% respectively) compared to the groups. Also the mean prostate volume and free/total PSA free/total PSA cut-off group (91.6%, 76.6% respectively) ratio were significantly lower (Table 1). NLR, PLR and and LMR cut-off group (67.8%, 43.7% respectively) LMR values of the histological groups were compared. (Table 7). Table 7. Mean ± SD values of the inflammation markers and p values for comparison of the histological groups in the cohort PSA 4-10 ng/dl range. Free/total PSA < 0.15 LMR < 3.050 Free/total PSA < 0.15 & LMR < 3.050

Sensitivity 46% (69 of 150) %42 (63 of 150) %16.6 (25 of 150)

Specificity %91.6 (231of 252) %67.8 (171 of 252) %97.2 (247 of 252)

PPV %76.6 (69 of 90) %43.7 (63 of 144) %83.3 (25 of 30)

PPV: Positive predictive value; NPV: Negative predictive value; PSA: Prostate spesific antigen; LMR: Lymphocyte to monocyte ratio.

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NPV %71.7 (231 of 322) %73 (171 of 234) %66.4 (247 of 372)

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Lymphocyte-to-monocyte ratio is a valuable marker to predict prostate cancer in patients with prostate specific antigen between 4 and 10 ng/dl.

Figure 1. AUROC for variables to predict prostate cancer.

DISCUSSION

The immune system plays an important role in cancer pathogenesis. Serum biomarkers which can be easily derived from complete blood count (CBC) are useful tools to estimate the prognosis and survival in many solid cancers. The presence of low LMR, high PLR and high NLR values were associated with poor overall survival (OS) in the published systemic reviews (6-8). In the study performed by Gu et al., elevated NLR was closely associated with poor OS in PCa (9). Also a similar study in Japan, revealed that elevated NLR was correlated with both poor cancer-spesific survival (p = 0.018) and OS (p = 0.008) in patients with metastatic PCa.10 Besides, nonsteroidal anti-inflammatory drug medications have been suggested to reduce the development risk of PCa (11, 12). Additionally to the prognostic value of serum inflammation markers, there are also many studies assessing the diagnostic value of those prior to the PBx with controversial results in the literature. In the study performed by Kamali et al., 500 patients who underwent PBx were evaluated but statistically significant difference was obtained between the NLR of the patients with positive biopsy and those with negative biopsy p = 0.112): NLR was not described as a predictive factor for positive PCa biopsy (13).

In another study, 3913 men who underwent PBx were analyzed retrospectively. The NLR value was higher in the biopsy-positive group than in the biopsy-negative group (p < 0.001). Also the NLR value was significantly higher in high-grade Gleason PCa group than the biopsy-negative group and low-grade PCa group (p < 0.001). On multivariate analyses, a higher NLR was associated with PCa detection (OR = 1.37, 95% CI: 1.017-1.850, p = 0.038) (14). Kawahara et al. investigated the data of 810 men with PSA value between 4 and 10 ng/ml who underwent PBx. NLR value was significantly higher in men with positive biopsy than in those with negative biopsy (p < 0.001). Using NLR cut-off point of 2.40 determined by the AUROC curve, positive/negative predictive values of NLR alone and NLR combined with free/total PSA ratio (cut-off: 0.15) were 56.6%/60.8% and 80.7%/60.1%, respectively (15). Huang et al. analyzed a total of 662 patients who underwent transperineal template guided PBx. In the entire cohort, any significant difference was not found in NLR when patients were grouped with regard to histology of the biopsy (cancer and no cancer) (p = 0.424). However, they observed additional significant difference in NLR Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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value (p = 0.002) when analyses were restricted to patients with PSA ranged from 4 to 10 ng/ml (cut-off value was set at 2.44). Accordingly the patients were classified into high-NLR and low-NLR group. The highNLR showed significantly high PCa detection rate in the entire cohort and in the cohort with PSA ranged from 4 to 10 ng/ml (175/338, 142/324, p = 0.041 and 36/77, 14/87, p < 0.001 respectively) (16). Gokce et al. investigated the data of 1836 patients. Patients were divided as follows: the group with BPH, the group with prostatitis and the group with PCa. Pre-biopsy mean NLR value of the prostatitis group was significantly higher compared to the PCa and BPH groups (p = 0.0001). The mean NLR of PCa group was significantly higher compared to the BPH group (p = 0.002). Also, the PCa patients with high Gleason score (GS) (GS 8 and above) had a significantly higher mean NLR compared to the PCa patients with GS 5-6 and GS 7 (p = 0.0001) (17). In the present study; when evaluating the NLR, any statistically significant difference was not observed based on the biopsy results. Also, cohort were seperated into 3 groups as men with PSA value of < 4, PSA between 4 and 10 and PSA of > 10 ng/dl. No statistically significant NLR difference was observed based on the biopsy results in any PSA range. We divided the PCa patients into 2 groups as the group with GS 6 and GS 7 and above. There was not a statistically significant difference between the GS groups. Additionally, controversial to the study performed by Gokce et al., we did not observe a significant highness in the prostatitis group compared to the PCa and BPH group. Our data showed that chronic prostatitis does not effect the inflammation markers derived from CBC considerably. Kaynar et al. retrospectively reviewed the data of 201 patients. Pathological sample results were categorized as chronic prostatitis, BPH and PCa. PSA levels were also categorized as 0-4 ng/ml, 4-10 ng/ml, and 10 ng/ml and above.Any statistically significant difference was not observed between benign or malign groups in terms of age, NLR and mean prostate volume. Statistically significant differences were present only in the PSA 10 ng/ml and above group related to mean PLR values (p: 0.044) (18). In another study, PLR value was statistically higher in PCa group than in BPH group while NLR value was not (19). In our study, pre-biopsy PLR value was not associated with higher PCa detection rate in any PSA range or in any Gleason score range. To our knowledge, there is not any study assessing the predictive value of LMR for PCa risk. In the present study, LMR was the only inflammation marker associated with PCa diagnosis (p = 0.047 ). Interestingly, in the 4-10 ng/dl PSA range LMR value was extremely lower in patients with positive biopsy than those with negative biopsy (p = 0,012). In this group free/total PSA ratio lower 0.15 and age higher than 65.5 were also risk factors to predict PCa. Additionally our data showed that, when LMR and free/total PSA cut-off values were combined, the specificity and positive predictive value were higher compared to the use of LMR or free/total PSA ratio alone. There are many limitations in our study. Firstly, our data derived from retrospective cohort. The next, we could

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not evaluate the factors, such as body mass index, smoking, metabolic syndrome which may be associated with the inflammatory response. Also the number of patients was relatively low. Especially, the low number of the patients with prostatitis inhibited some analysis. However we think that, regarding our limited data, asymptomatic prostatitis does not effect CBC parameters. Furthermore, the initial PBx may miss cancer in some men and 20% of men may be diagnosed as PCa in repeated biopsy (20).

CONCLUSIONS

Regarding our data LMR value is a useful tool at detecting PCa especially in patients with PSA value between 4 and 10 ng/dl. The combination of free/total PSA ratio and LMR improves the diagnostic accuracy more than the use of free/total PSA ratio alone. This model can assist urologists in deciding whether prostate biopsy is advisable.

REFERENCES

1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015; 136:E359-86. 2. Arnold M, Karim-Kos HE, Coebergh JW, et al. Recent trends in incidence of five common cancers in 26 European countries since 1988: Analysis of the European Cancer Observatory. Eur J Cancer. 2015; 51:116487. 3. Salman JW, Schoots IG, Carlsson SV, et al. Prostate Specific Antigen as a Tumor Marker in Prostate Cancer: Biochemical and Clinical Aspects.Adv Exp Med Biol. 2015; 867:93-114. 4. Ganeswaran D, Sweeney C, Yousif F, et al. Population-based linkage of health records to detect urological complications and hospitalisation following transrectal ultrasound-guided biopsies in men suspected of prostate cancer. World J Urol. 2012; 32:309-15. 5. Heidenreich A, Bolla M, Joniau S, et al. Guidelines on Prostate Cancer. Update. 2011; 53:31-45. 6. Nishijima TF, Muss HB, Shachar SS, et al. Prognostic value of lymphocyte-to-monocyte ratio in patients with solid tumors: A systematic review and meta-analysis. Cancer Treat Rev. 2015; 41:971-8. 7. Templeton AJ, Ace O, McNamara MG, et al. Prognostic role of platelet to lymphocyte ratio in solid tumors: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2014; 23:1204-12. 8. Templeton AJ, McNamara MG, Šeruga B, et al. Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst. 2014; 106:dju124. 9. Gu X, Gao X, Li X, et al. Prognostic significance of neutrophil-tolymphocyte ratio in prostate cancer: evidence from 16,266 patients. Sci Rep. 2016; 6:22089. 10. Kawahara T, Yokomizo Y, Ito Y, et al. Pretreatment neutrophillymphocyte ratio predicts the prognosis in patients with metastatic prostate cancer. BMC Cancer. 2016; 16:111. 11. Kawahara T, Ishiguro H, Hoshino K, et al. Analysis of NSAID activated gene 1 expression in prostate cancer. Urologia internationalis. 2010; 84:198-202.

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Lymphocyte-to-monocyte ratio is a valuable marker to predict prostate cancer in patients with prostate specific antigen between 4 and 10 ng/dl.

12. Ishiguro H, Kawahara T. Nonsteroidal anti-inflammatory drugs and prostatic diseases. BioMed research international. 2014; 2014:436123.

value of neutrophil-to-lymphocyte ratio in diagnosis of prostate cancer among menwho underwent template-guided prostate biopsy. Medicine 2016; 95:44(e5307).

13. Koosha Kamali, Mojtaba Ashrafi, Pejman Shadpour, et al. The role of blood neutrophil count and the neutrophil-to-lymphocyte ratio as a predictive factor for prostate biopsy results. Urologia. 2018 Apr 1:391560318766822.

17. Gokce MI, Hamidi N, Suer E, et al. Evaluation of neutrophil-tolymphocyte ratio prior to prostate biopsy to predict biopsy histology: results of 1836 patients. Can Urol Assoc J. 2015; 9:E761-E765.

14. Jong Jin Oh, Ohsung Kwon, Jung Keun Lee, et al. Association of the neutrophil-to-lymphocyte ratio and prostate cancer detection rates in patients via contemporary multi-core prostate biopsy. HongAsian J Androl. 2016; 18:937-941. 15. Takashi Kawahara, Sachi Fukui1, Kentaro Sakamaki, et al. Neutrophil-to-lymphocyte ratio predicts prostatic carcinoma in men undergoing needle biopsy. Oncotarget 2015; 6:32169-76. 16. Tian-bao Huang, Shi-yu Mao, Sheng-ming Lu,et al. Predictive

18. Kaynar M, Yıldırım ME, Gul M, et al. Benign Prostatic Hyperplasia and prostate cancer differentiation via platelet to lymphocyte ratio. Cancer Biomark. 2015; 13:317-23. 19. Ozgur Haki Yuksel, Ahmet Urkmez, Serkan Akan,et al. Predictive Value of the Platelet-To-Lymphocyte Ratio in Diagnosis of Prostate Cancer. Asian Pac J Cancer Prev. 2015; 16:6407-6412. 20. Ploussard G, Nicolaiew N, Marchand C, et al. Risk of repeat biopsy and prostate cancer detection after an initial extended negative biopsy: longitudinal follow-up from a prospective trial. BJU Int. 2013; 111:988-996.

Correspondence Volkan Caglayan volkantuysuz@hotmail.com Efe Onen efe17@yahoo.com Sinan Avci sinavci@yahoo.com Murat Sambel muratsambel@hotmail.com Metin Kilic kilicmetin@yahoo.com Sedat Oner sedatoner@yahoo.com Mustafa Murat Aydos mudos16@hotmail.com Halil Emre Yıldız halilemreyldz@gmail.com University of Health Sciences, Bursa Yuksek Ihtisas Training and Research Hospital, Bursa, Turkey

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DOI: 10.4081/aiua.2018.4.276

ORIGINAL PAPER

Low-intensity shock wave therapy for erectile dysfunction and the influence of disease duration Pedro Simoes de Oliveira, Tiago Ribeiro de Oliveira, Álvaro Nunes, Francisco Martins, Tomé Lopes SCI-Centro de Urologia, Lisbon, Portugal.

Summary

Objective: Low-intensity shock-wave treatment (LiSWT) is a therapy for erectile dysfunction (ED) with good results reported in the literature. The aim of this study was to evaluate the results of LiSWT on patients treated for ED and the influence of ED duration in treatment outcomes. Material and methods: We performed an open-label single-arm prospective study of patients treated with LiSWT for ED. Patients were assessed with the IIEF-5 at baseline and at six weeks and three months after LiSWT, and with penile dynamic Doppler ultrasound before treatment and six weeks after. Patients were divided into two groups accordingly to ED evolution time: ≤ 24 months and > 24 months. Results: Twenty-five patients were enrolled, 13 had ED ≤ 24 months and 12 > 24 months. Median baseline IIEF-5 was 14, at 6 weeks post LiSWT was 16 (p < 0.001) and at 3 months post LiSWT was 18 (p < 0.001). Mean baseline peak systolic velocity (PSV) was 29.3 ± 13.0 cm/s, after LiSWT was 35.9 ± 15.2 cm/s (p 0.001). Mean baseline end-diastolic velocity (EDV) was 2.6 ± 4.8 cm/s and after LiSWT was 1.3 ± 4.3 cm/s (p 0.015). No statistical significative difference was identified between the two groups. Conclusions: LiSWT is a safe, harmless and repeatable treatment tool for ED with good outcomes reported. Our results suggest that length of disease duration doesn´t negatively influences treatment results.

KEY WORDS: Erectile dysfunction; Penis; Shock wave therapy; Time-to-treatment; Treatment outcome. Submitted 4 October 2018; Accepted 15 November 2018

INTRODUCTION

Erectile dysfunction (ED) is a common condition affecting more than 50% of men aged 40-70 years (1). Available treatments include phosphodiesterase type 5 inhibitors (PDE5i), vacuum devices, topical, intraurethral or intracavernosal, administration of vasoactive agents or, in the most severe cases, penile prosthesis. Although many patients are satisfied with these treatments, others are not, due to poor response or impossibility of using them. Low-intensity shock wave therapy (LiSWT) is another available first line therapy for ED. Since Vardi et al. (2) first described its use on ED, several reports have been published with encouraging results. Although the mechanism of action is poorly understood, it is suggested that LiSWT can induce neovascularization, anti-inflammation and tissue regeneration leading to structural changes

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and, therefore improvement in erectile function (3). Published studies have different samples, different protocols and different inclusion criteria. There is still no evidence of which patient is the best candidate for LiSWT. The aim of our study was to evaluate the results of LiSWT on patients treated for ED and looking for cofounding factors that could influence treatment outcomes, specially duration of ED.

MATERIALS

AND METHODS

We performed an open-label single-arm prospective study of all patients who underwent LiSWT for ED, at a single center from June 2016 to March 2018. Patients were assessed with the simplified International Index of Erectile Function (IIEF-5) before starting the treatment and at six weeks and three months after. Assessment included also penile dynamic Doppler ultrasound (PDDU) before treatment and six weeks after. Inclusion criteria included, age over 18 years-old, a total IIFE-5 score < 22, no psychiatric disturbance and no active skin lesion at the treatment site. Treatment was performed using the PiezoWave2 (Richard Wolf GmbH, Knittlingen, Germany) device with a linear probe. Treatment protocol included a weekly session for six weeks. Each session delivered 2000 shocks on the perineum plus 2000 shocks on dorsum penis with an energy flux density (EFD) of 0.160 mJ/mm2. During treatment every patient had tadalafil 5 mg daily. Patients were divided into two groups accordingly to ED evolution time, defined by time-to-treatment since the beginning of symptoms: ≤ 24 months (group 1) and > 24 months (group 2). Other analyzed variables included, age, type of ED (arteriogenic, arteriogenic + venous leak, post radical prostatectomy and, venous leak), ED risk factors and PDE5i treatment necessity and response. An increase in the IIEF-5 after LiSWT was considered “improvement”. Regarding PDDU, an increase in peak systolic velocity (PSV) and/or decrease in end-diastolic velocity (EDV) after LiSWT was considered “improvement”. Regarding PDE5i treatment, “improvement” was defined when a patient previously on PDE5i, was able to leave medication. “Improvement” in PDEi5 response was considered whenever a patient subjectively improved the response to medication after LiSWT considering three categories: “good”, “moderate” and “bad”. No conflict of interest declared.

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Low-intensity shock wave therapy

The primary endpoint was any observed change in IIEF-5 and PDDU associated with LiSWT and comparing results between groups 1 and 2 regarding the influence of disease duration in treatment response. The secondary endpoint was to evaluate the response to treatment with PDE5i associated with LiSWT and comparing results between groups 1 and 2. Also, LiSWT results were evaluated accordingly with ED type and risk factors. Adverse events, patient satisfaction and recommendation were also assessed. Clinical data was analyzed using IBM SPSS Statistics, version 24.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics were reported as frequencies for categorical variables and, mean, median (first quartile - third quartile) and standard deviation for continuous variables. Comparison between pre-treatment and posttreatment and between groups 1 and 2 results was performed using the Wilcoxon Signed-Rank test. χ2-test (two-sided Pearson χ2-test with two degrees of freedom) was used between IIEF-5, PDDU, PDE5i, ED type and ED risk factors. Fisher's exact test was used when the expected frequency was of five or less. Statistical significance was considered for p values < 0.05.

Table 1. Patient demographics. Total number 25 patients total 13 patients ED ≤ 24 months 12 patients ED > 24 months Age at LiSWT (years) Median (range) Total 61 (27-73) ED ≤ 24 months 56 (42-73) ED > 24 months 62.5 (27-73) ED type n (%) n (%) Total ED ≤ 24 months Arteriogenic 15 (60) 9 (69) Arteriogenic + venous leak 4 (16) 1 (8) Post-radical prostatectomy 3 (12) 2 (15) Venous leak 3 (12) 1 (8) ED risk factors n (%) n (%) Total ED ≤ 24 months Hypertension 16 (64) 8 (62) Dyslipidemia 15 (60) 8 (62) Diabetes 7 (28) 5 (39) Tobacco 5 (20) 4 (31) Obesity 8 (32) 5 (39) ED evolution time Median (months) Range (months) Total 24 5 - 192 ED ≤ 24 months 18 5 - 24 ED > 24 months 66 30 -192

n (%) ED > 24 months 6 (50) 3 (25) 1 (8) 2 (17) n (%) ED > 24 months 8 (67) 7 (58) 2 (17) 1 (8) 3 (25)

LiSWT: Low-intensity shock wave therapy; ED: Erectile dysfunction.

RESULTS

Twenty-five patients were enrolled, 13 had ED ≤ 24 months (group 1) and 12 > 24 months (group 2). Fifteen patients had arteriogenic ED, four arteriogenic and venous leak ED, three post-radical prostatectomy ED and, three venous leak. Median age was 61 years-old (range: 27-73). Patient demographics are described in Table 1. Table 2 shows the results of the total study sample. Median baseline IIEF-5 was 14, at 6 weeks post LiSWT was 16 (p < 0.001) and at 3 months post LiSWT was 18 (p < 0.001), with an improvement of 68% and 72% respectively. Mean baseline PSV was 29.3 ± 13.0 cm/s, after LiSWT was 35.9 ± 15.2 cm/s (p 0.001) representing an 84% improvement. Mean baseline EDV was 2.6 ± 4.8 cm/s, after LiSWT was 1.3 ± 4.3 cm/s (p 0.015) representing an 68% improvement. There was no significative result in PDE5i treatment, nevertheless, PDE5i response had an improvement of 36% (p 0.004). Tables 2a and 2b show the specific results of group 1 and group 2 respectively and separately.

Table 2. Results. IIEF-5 Summary statistics Pre-LiSWT 6 weeks Post-LiSWT p value 3 months Post-LiSWT p value Min-max 5-21 5-24 5-25 Median (IQR) 14 (10.0-16.5) 16 (11.0-20.5) *< 0.001 18 (11.5-22) *< 0.001 Mean ± SD 13.3 ± 4.9 15.6 ± 5.9 16.6 ± 6.3 Improvement % (n) 68.0 (17) 72.0 (18) Penile dynamic duplex ultrasound Summary statistics PSV PSV p value EDV EDV p value Pre-LiSWT Post-LiSWT Pre-LiSWT Post-LiSWT Min-max 4,7-59.2 8.0-70.0 -6.0-13.8 -7.3-8.0 Median (IQR) 27.4 31.6 *0.001 2.1 2.6 *0.015 (21.0-32.4) (27.2-42.1) (-0.9 -6.3) (-2.2 -4.9) Mean ± SD 29.3 ± 13.0 35.9 ± 15.2 2.6 ±4.8 1.3 ± 4.3 Improvement % (n) 84.0 (21) 68.0 (17) PDE5i treatment Pre-LiSWT % (n) Post-LiSWT % (n) p value Yes 72.0 (18) 52.0 (13) 0.063 No 28.0 (7) 48.0 (12) Improvement % (n) 20.0 (5) PDE5i response Pre-LiSWT % (n) Post-LiSWT % (n) p value Good 16.0 (4) 20.0 (5) Moderate 32.0 (8) 20.0 (5) *0.004 Bad 24.0 (6) 12.0 (3) Improvement % (n)

36.0 (9)

IIEF-5: international index of erectile function (5 questions); LiSWT: Low-intensity shock wave therapy; IQR: Interquartile range; SD: Standard deviation; PSV: Peak systolic velocity; EDV: End-diastolic velocity; PDE5i: Phosphodiesterase type 5 inhibitors. * Statistical significance with p < 0.05

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Table 2a. Results ED ≤ 24 months. IIEF-5 Summary statistics Pre-LiSWT 6 weeks Post-LiSWT p value 3 months Post-LiSWT p value Min-max 5-21 5-24 5-25 Median (IQR) 15.0 (10.5-16.5) 17 (11.5-22) *0.008 17 (11.5-22.5) *0.012 Mean ± SD 13.8 ± 4.6 16.4 ± 5.9 16.9 ± 6.2 Improvement % (n) 69.2 (9) 61.5 (8) Penile dynamic duplex ultrasound Summary statistics PSV PSV p value EDV EDV p value Pre-LiSWT Post-LiSWT Pre-LiSWT Post-LiSWT Min-Max 4,7 - 59.2 8.0-70.0 -6.0 – 10.1 -7.3-8.0 Median (IQR) 27.0 30.1 *0.017 1.5 2.6 *0.630 (21.0-36.9) (25.2-40.6) (-2.2 -4.2) (-0.1 -4.2) Mean ± SD 29.6 ± 14.5 34.6 ± 15.5 1.6 ±4.0 2.2 ± 4.0 Improvement % (n) 84.6 (11) 61.5 (8) PDE5i treatment Pre-LiSWT % (n) Post-LiSWT % (n) p value Yes 46.2 (6) 38.5 (5) 1.000 No 53.8 (7) 61.5 (8) Improvement % (n) 7.7 (1)) PDE5i response Pre-LiSWT % (n) Post-LiSWT % (n) p value Good 15.4 (2) 7.7 (1) Moderate 7.7 (1) 15.4 (2) 0.500 Bad 23.1 (3) 15.4 (2) Improvement % (n) 15.4 (2) IIEF-5: international index of erectile function (5 questions); LiSWT: Low-intensity shock wave therapy; IQR: Interquartile range; SD: Standard deviation; PSV: Peak systolic velocity; EDV: End-diastolic velocity; PDE5i: Phosphodiesterase type 5 inhibitors. * Statistical significance with p < 0.05

Table 2b. Results ED > 24 months. IIEF-5 Summary statistics Pre-LiSWT 6 weeks Post-LiSWT p value 3 months Post-LiSWT p value Min-max 5-21 5-22 5-24 Median (IQR) 12.5 (9.3-17.3) 15 (10.3-20.8) *0.008 18 (10.5-22.0) *0.018 Mean ± SD 12.8 ± 5.4 14.8 ± 6.1 16.2 ± 6.6 Improvement % (n) 66.7 (8) 83.3 (10) Penile dynamic duplex ultrasound Summary statistics PSV PSV p value EDV EDV p value Pre-LiSWT Post-LiSWT Pre-LiSWT Post-LiSWT Min-max 13.2-58.8 14.7-68.2 -5.1-13.8 -7.3-6.9 Median (IQR) 28.5 32.7 *0.016 5.6 1.7 *0.005 (20.5-29.6) (28.5-47.5) (-1.3 -7.2) (-5.1 -5.5) Mean ± SD 29.0 ± 11.7 37.3 ± 15.5 3.8 ± 5.4 0.3 ± 5.4 Improvement % (n) 83.3 (10) 75.0 (9) PDE5i treatment Pre-LiSWT % (n) Post-LiSWT % (n) p value Yes 100 (12) 66.7 (8) 0.125 No 0.0 (0) 33.3 (4) Improvement % (n) 33.3 (4) PDE5i response Pre-LiSWT % (n) Post-LiSWT % (n) p value Good 16.7 (2) 33.3 (4) Moderate 58.3 (7) 25.0 (3) *0.016 Bad 58.3 (7) 25.0 (3) Improvement % (n) 58.3 (7) IIEF-5: international index of erectile function (5 questions); LiSWT: Low-intensity shock wave therapy; IQR: Interquartile range; SD: Standard deviation; PSV: Peak systolic velocity; EDV: End-diastolic velocity; PDE5i: Phosphodiesterase type 5 inhibitors. * Statistical significance with p < 0.05

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Table 3 shows the results of the total study sample accordingly with type of ED. Statistical significance was seen only in the IIEF-5 at 6 weeks after LiSWT, presenting the best response patients with arteriogenic and/or venous leak ED (p 0.021). Table 4 shows the results of the total study sample accordingly with ED risk factors. Statistical significance was seen in the PDE5i response improvement, where diabetic patients presented the worse response (p 0.027). Table 5 compares the results and treatment improvement between the two groups. No statistical significative difference was identified beside a better PDE5i response in patients with ED > 24 months. At the end of the study, overall patient satisfaction with LiSWT was 76% and, 80% of patients would recommend it (Table 6). No adverse effect was reported.

DISCUSSION

ED is a common medical condition and epidemiological data have shown a high incidence and prevalence worldwide (1). This greatly disseminated and progressive condition has great impact in patient´s quality of life and it´s no wonder efforts have been made in order to find a successful treatment. Although the true mechanism of action is not well understood, according to basic science evidences it can be hypothesized that LiSWT may act by several pathways leading to cell proliferation, angiogenesis, nerve regeneration and anti-inflammation (3). It is theorized that energy carried by LiSWT compresses the tissue and the following negative pressure originates tensile forces leading to shear stress on cell membranes. This phenomenon is called “cavitation” and triggers a chain of events that cause the release of angiogenic factors such as endothelial NO synthase, vascular endothelial growth factor and proliferating cell nuclear antigen (3). Following this rationale, Vardi et al pioneered the first study using LiSWT for ED. Twenty men with vasculogenic ED were included in their study: at one-month post-

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Table 3. Results by ED type. IIEF-5 improvement

6 weeks Post-LiSWT Arteriogenic 80.0 (12) Arteriogenic + venous leak 50.0 (2) Post-RP 0.0 (0) Venous leak 100 (3) Penile dynamic duplex ultrasound improvement PSV Post-LiSWT % (n) Arteriogenic 86.7 (13) Arteriogenic + venous leak 75.0 (3) Post-RP 66.7 (2) Venous leak 100 (3) PDE5i treatment improvement % Arteriogenic 20.0 Arteriogenic + venous leak 25.0 Post-RP 0 Venous leak 33.3 PDE5i response improvement % Arteriogenic 20.0 Arteriogenic + venous leak 75.0 Post-RP 33.3 Venous leak 66.7

p value *0.021

p value 0.532

3 months Post-LiSWT 73.3 (11) 75.0 (3) 33.3 (1) 100 (3)

p value

EDV Post-LiSWT % (n) 60.0 (9) 100 (4) 33.3 (1) 100 (3)

p value

n 3 1 0 1

p value

n 3 3 1 2

p value

0.459

0.133

1.000

0.119

ED: Erectile dysfunction; IIEF-5: international index of erectile function (5 questions); LiSWT: Low-intensity shock wave therapy; Post-RP: Post radical prostatectomy; PSV: Peak systolic velocity; EDV: End-diastolic velocity; PDE5i: Phosphodiesterase type 5 inhibitors. * Statistical significance with p < 0.05

Table 4. Results by ED risk factor. IIEF-5 improvement

6 weeks Post-LiSWT HTA 58.8 (10) Diabetes 29.4 (5) Tobacco 17.6 (3) Dyslipidemia 58.8 (10) Obesity 35.3 (6) Penile dynamic duplex ultrasound improvement PSV Post-LiSWT % (n) HTA 57.1 (12) Diabetes 23.8 (5) Tobacco 23.8 (5) Dyslipidemia 61.9 (13) Obesity 38.1 (8) PDE5i treatment improvement % HTA 40.0 Diabetes 0.0 Tobacco 20.0 Dyslipidemia 60.0 Obesity 20.0 PDE5i response improvement % HTA 44.4 Diabetes 0.0 Tobacco 22.2 Dyslipidemia 55.6 Obesity 22.2

p value 0.661 1.000 1.000 1.000 0.680

3 months Post-LiSWT 55.6 (10) 22.2 (4) 16.7 (3) 55.6 (10) 38.9 (7)

p value 0.208 0.355 0.597 0.659 0.362

p value 0.260 0.548 0.549 1.000 0.269

EDV Post-LiSWT % (n) 64.7 (11) 23.5 (4) 29.4 (5) 70.6 (12) 35.3 (6)

p value 1.000 0.640 0.140 0.194 0.680

n 2 0 1 3 1

p value 0.312 0.274 1.000 1.000 0.642

n 4 0 2 5 2

p value 0.200 *0.027 1.000 1.000 0.661

treatment, mean IIEF-ED (erectile function domain) significantly improved from 13.5 ± 4.1 to 20.9 ± 5.8 (p < 0.001) (2). Later, this group conducted a randomized, double-blind, sham controlled study with 67 men. At one-month post-treatment, the mean IIEF-ED increased by 6.7 points in the treated group while in the sham group increased by 3.0 points (p 0.0322) (4). Another randomized, doubleblind, placebo-controlled study by Yee et al, with 58 men, concluded that LiSWT presented significant improvement at 4 weeks post-treatment only in patients with severe ED (IIEF-ED improvement in LiSWT group was 10.1 ± 4.1, in placebo group was 3.2 ± 3.3 (p 0.003)) (5). Ruffo et al reported a study with 31 patients with mild to moderate ED.that achieved significant improvement in IIEF-ED: baseline mean IIEF-ED was 16.54 ± 6.35, at one-month post-treatment was 21.13 ± 6.31 (p 0.0075) and, at three-month was 21.03 ± 6.38 (p 0.0096) (6). A meta-analysis conducted by Lu et al., comprising 14 studies including 833 patients revealed that LiSWT could significantly improve IIEF (mean difference 2.00; p < 0.0001) (7). Another meta-analysis conducted by Clavijo et al., comprising seven randomized controlled trials involving 602 patients, also reported a statistically significant improvement in pooled change in IIEF-ED score from baseline to follow-up in men treated with LiSWT compared with those receiving sham therapy (6.40 points; 95% CI 1.78-11.02; p < 0.001 vs 1.65 points; 95 CI 0.92-2.39; p < 0.0001; between-group difference p 0.047) (8). Our results are in line with previous reported studies. Overall baseline median IIEF-5 was 14, at six weeks post-treatment was 16 (p < 0.001) and, at 3 months 18 (p < 0.001), corresponding to an improvement of 68% and 72% respectively. At 3 months, median IIEF-5 actually changed category from mild-to-moderate to mild. Lu et al. (7) in his metaanalysis also reported a good therapeutic effect by 3 months, suggesting that changes induced by LiSWT may not be immediate but

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Table 5. Results comparison.

ence between the two groups (PSV improvement in group 1 was vs 83.3% in group 2; p 84.6% IIEF-5 improvement 1.000 and EDV improvement in 6 weeks 6 weeks p value 3 months 3 months p value group 1 was 61.5% vs 75.0% in Post-LiSWT % (n) Post-LiSWT % (n) Post-LiSWT % (n) Post-LiSWT % (n) group 2; p 0.673).The majority of ED > 24 months ED ≤ 24 months ED > 24 months ED > 24 months 69.2 (9) 66.7 (8) 1.000 61.5 (8) 83.3 (10) 0.378 published studies addressed treatment outcomes with sexual funcPenile dynamic duplex ultrasound improvement PSV PSV p value EDV EDV p value tion and quality of live questionPost-LiSWT % (n) Post-LiSWT % (n) Post-LiSWT % (n) Post-LiSWT % (n) naires but not many have assessed ED > 24 months ED ≤ 24 months ED > 24 months ED > 24 months penile hemodynamics in patients 84.6 (11) 83.3 (10) 1.000 61.5 (8) 75.0 (9) 0.673 treated with LiSWT for ED. Kalyvianakis et al., in a doublePDE5i treatment improvement Post-LiSWT % (n) Post-LiSWT % (n) p value blinded, randomized, sham conED ≤ 24 months ED > 24 months trolled trial with 46 patients, like in our study, used PDDU to evalu7.7 (1) 33.3 (4) 0.160 ate patients at 3 months post-treatPDE5i response improvement Post-LiSWT % (n) Post-LiSWT % (n) p value ment and reported a mean change in PSV of 4.5 cm/s and 0.6 cm/s for ED ≤ 24 months ED > 24 months the treatment and sham-control 15.4 (2) 58.3 (7) *0.041 groups, respectively (p < 0.001) IIEF-5: international index of erectile function (5 questions); LiSWT: Low-intensity shock wave therapy; IQR: Interquartile range; (12). Other studies, namely Vardi SD: Standard deviation; PSV: Peak systolic velocity; EDV: End-diastolic velocity; PDE5i: Phosphodiesterase type 5 inhibitors. * Statistical significance with p < 0.05 et al (4) and Kitrey et al. (13) also assessed penile hemodynamics with another technique using the flow mediated dilation. Both groups reported significant Table 6. Patient questionnaire. improvement (p < 0.0001). These results show that LiSWT indeed produces changes in penile vascularizaSatisfaction Recommendation Adverse effects tion associated with improved hemodynamics. Another % (n) % (n) % (n) endpoint of our study was to evaluate the influence of Total 76.0 (19) 80.0 (20) 0.0 (0) LiSWT in PDE5i response and if patients were able to ED ≤ 24 months 76.9 (10) 84.6 (11) 0.0 (0) leave this medication after treatment. Significant results ED > 24 months 75.0 (9) 75.0 (9) 0.0 (0) were seen in patients who still needed PDE5i after treatment, because their response to medication improved (overall improvement of 36.0%; p 0.004). Significant difrather delayed in time. Our subgroups analysis by length ference was present between groups (p 0.041), being of disease duration showed no significant difference group 2 the major responsible for this improvement, improvement in IIEF-5 between groups at 6 weeks or at showing that patients with longer ED responded better 3 months follow-up post-treatment (p 1.00 and p 0.378 to PDE5i after LiSWT. It is a fact that these patients were respectively), suggesting that time of ED do not alter all on PDE5i previously, thus, more used to it and more treatment outcomes. Pelayo-Nieto et al, in a study with aware, and this might have influenced the results. At the 15 patients reported an overall improvement in IIEF-ED end of the study 5 patients (20%) were able to leave perof 80% (14.23 vs 19.69; p < 0.0013) and no influence of manently PDEi5 and achieve spontaneous erections, ED duration was found using a cut-off of 3 years (p < nevertheless this was not statistically significative (p 0.20) (9). In a multicenter open-label prospective study 0.063). Others have evaluated the effect of LiSWT on with 58 patients, Reisman et al. reported an overall PDE5i response. Grueenwald et al., in a study with 29 improvement of 81.03% in IIEF-ED (IIEF-ED average men with severe ED and poor response to PDEi5, increase 7.5 ± 4.7; p < 0.001). Furthermore, a only modshowed that one month post-treatment, 34% of patients erate negative Pearson correlation coefficient of -0.62 returned to sexual activity without the necessity for was found between the duration of ED and success of pharmacotherapy (14). treatment, showing satisfactory success rates in cases of Our protocol included having tadalafil 5 mg daily. ED up to 10 years of duration (10). Also, Bechara et al, in Although it could induce a bias in the results, following a study with 50 patients, concluded that time of ED did the concept of angiogenesis and neovascularization assonot influenced the results (11). Our study evaluation ciated with LiSWT, concomitant PDE5i produces a conrelied not only in subjective patient questionnaire like tinuous local stimulus that might contribute to a synerIIEF-5, but also assessed penile hemodynamics with a gic effect with LiSWT and potentiate global response in tangible tool like penile Doppler ultrasound. Our overall the best interest for the patient. Kitrey et al., in a prospecresults showed a significant improvement both in mean tive randomized, double-blind sham-controlled study PSV (29.3 cm/s vs 35.9 cm/s; p 0.001) and mean EDV with 55 patients, also used PDEi5 during LiSWT and (2.6 cm/s vs 1.3 cm/s; p 0.015) with both post-treatment showed that 54% of these patients achieved erections values within normal ranges. Also, subgroups analysis by hard enough for penetration, in comparison of 0% of the length of disease duration showed no significant differsham group (PDE5i only) (13). The meta-analysis per-

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formed by Lu et al. showed that the IIEF increased more significantly in the group with LiSWT combined with PDE5i use (mean difference: 4.20; 95% CI, 0.16-8.24; p 0.04), supporting the use of combination therapy (7). When stratified by type of ED, our results showed that patients with vasculogenic ED, whether arteriogenic and/or venous leak, presented the best results, regarding IIEF-5 at 6 weeks post-treatment and, patients with ED post radical prostatectomy, the worse results (p 0.021). There is a consensus in the literature that the major suggested mechanism of action of LiSWT is by angiogenesis and neovascularization, and that explains why patients with vasculogenic ED are expected to be the best candidates to this treatment. Nevertheless, assuming mechanisms of action like nerve regeneration, other patients may be candidates. Frey et al., in a study with 16 patients who underwent nerve-sparring robotic radical prostatectomy, reported significant changes in IIEF-5 post-LiSWT, with a median increase of +3.5 at one-month (p 0.0049) and, +1 at one-year post-treatment (p 0.046), nevertheless, the majority of patients achieved only marginal improvements in ED category (15). ED postprostatectomy is usually a severe and complex side-effect, caused by direct trauma, stretching, heating, ischemia and local inflammation of the cavernous nerves (16). Nerve damage results in impaired erections and inadequate penile oxygenation, leading to smooth muscle apoptosis and fibrosis (17). In this setting, it may be too ambitious expecting evident results with LiSWT, but it may have a role as adjunctive therapy in penile rehabilitation. When looking for the influence of ED risk factors on LiSWT outcomes, our study showed that diabetic patients presented the worse results. In fact, statistical significance was found in PDEi5 response, where diabetic patients didn´t show any improvement (p 0.027). Reisman et al., comparing diabetic and non-diabetic patients, had a success rate 25% higher in the latter group (70.83% vs 88.24% respectively) (10). Hisasue et al, in subgroup analysis by comorbidities, found worse results in diabetic patients with only 3/10 achieving a score of 3 in Erection Hardness Score (18). These results all together suggest a negative impact of diabetes on the efficacy of LiSWT. Contemporary LiSWT machines can be divided into 3 main types based on the mechanism of shock waves namely electrohydraulic, electromagnetic and piezoelectric. The majority of studies have used the first two types. The piezoelectric device differs from the others in that it offers full organ coverage and higher treatment parameters. Motil et al., like in our study, used a piezoelectric machine and reported an average IIEF-5 score improvement from 14.4 baseline to18.6 at 1-month post-treatment. A total of 75 patients were treated and they had PDE5i during treatment (19). Fojecki et al., in a randomized, double-blinded, sham-controlled study with 126 patients, also used a piezoelectric device, and reported success rates based on the IIEF-EF score of 38.3% in the sham group and 37.9% in the active group (OR = 95, 95% CI = 0.45-2.02, p 0.902), showing no clinical relevant effect of LiSWT (20). Although using the same device, Fojecki et al., delivered less energy to the penis, using an EFD of 0.09 mJ/mm2, in contrast Motil et al., like

in our study an EFD of 0.160 mJ/mm2 was used. Also, in the Fojecki study, patients had a 4-weeks wash-out period of PDEi5 and medication was not allowed during treatment. This protocol differences may be responsible for different outcomes between these studies, reinforcing the benefit of using adjuvant PDEi5 with LiSWT. Limitations of our study are the absence of a sham-control arm, a small number of patients and the short follow-up period. Also, the concomitant use of PDE5i could induce a bias. Nevertheless, the strengths include being prospective, having evaluated penile hemodynamics in all patients with a tangible and reliable tool as PDDU, no limitation in inclusion criteria regarding type of ED and looking for cofounding factors that could influence treatment outcomes, specially duration of ED. LiSWT is a safe, harmless, repeatable treatment modality for ED with good functional outcomes reported. Our results suggest that length of disease duration doesn´t negatively influences treatment results. Also, concomitant use of PDE5i should be considered.

REFERENCES

1. Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol. 1994; 151:154. 2. Vardi Y, Appel B, Jacob G, et al. Can low intensity extracorporeal shockwave therapy improve erectile function? A 6-month followup pilot study in patients with organic erectile dysfunction. Eur Urol. 2010; 58:243-248. 3. Wang HJ, Cheng JH, Chuang YC. Potential applications of lowenergy shock waves in functional urology. Int J Urol. 2017; 24:573581. 4. Vardi Y, Appel B, Kilchevsky A, Gruenwald I. Does low intensity extracorporeal shockwave therapy have a physiological effect on erectile function? Short-term results of a randomized, double-blind, sham controlled study. J Urol. 2012; 187:1769-1775. 5. Yee CH, Chan ES, Hou SS, Ng CF. Extracorporeal shockwave therapy in the treatment of erectile dysfunction: a prospective, randomized, double-blinded, placebo controlled study. Int J Urol. 2014; 21:1041-1045. 6. Ruffo A, Capece M, Prezioso D, et al. Safety and efficacy of low intensity shockwave (LISW) treatment in patients with erectile dysfunction. Int Braz J Urol. 2015; 41:967-974. 7. Lu Z, Lin G, Reed-Maldonado A, et al. Low-intensity extracorporeal shock wave treatment improves erectile function: a systematic review and meta-analysis. Eur Urol. 2017; 71:223-233. 8. Clavijo RI, Kohn TP, Kohn JR, Ramasamy R. Effects of low-intensity extracorporeal shockwave therapy on erectile dysfunction: a systematic review and meta-Analysis. J Sex Med. 2017; 14:27-35. 9. Pelayo-Nieto M, Linden-Castro E, Alias-Melgar A, et al. Linear shock wave therapy in the treatment of erectile dysfunction. Actas Urol Esp. 2015; 39:456-459. 10. Reisman Y, Hind A, Varaneckas A, Motil I. Initial experience with linear focused shockwave treatment for erectile dysfunction: a 6-month follow-up pilot study. Int J Impot Res. 2015; 27:108-112. 11. Bechara A, Casabé A, De Bonis W, Gomez Ciciclia P. Twelvemonth efficacy and safety of low-intensity shockwave therapy for erectile dysfunction in patients who do not respond to phosphodiesterase type 5 inhibitors. Sex Med. 2016; 4:e225-e232. Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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12. Kalyvianakis D, Hatzichristou D. Low-intensity shockwave therapy improves hemodynamic parameters in patients with vasculogenic erectile dysfunction: a triplex ultrasonography-based shamcontrolled trial. J Sex Med. 2017; 14:891-897. 13. Kitrey ND, Gruenwald I, Appel B, et al. Penile low intensity shock wave treatment is able to shift PDE5i nonresponders to responders: a double-blind, sham controlled study. J Urol. 2016; 195:1550-1555. 14. Gruenwald I, Appel B, Vardi Y. Low-intensity extracorporeal shock wave therapy–a novel effective treatment for erectile dysfunction in severe ED patients who respond poorly to PDE5 inhibitor therapy. J Sex Med. 2012; 9:259-264. 15. Frey A, Sonksen J, Fode M. Low-intensity extracorporeal shockwave therapy in the treatment of postprostatectomy erectile dysfunction: a pilot study. Scand J Urol 2016; 50:123-127. 16. Burnett AL. Rationale for cavernous nerve restorative therapy to

Correspondence Pedro Simoes de Oliveira, MD (Corresponding Author) pedrosimoesdeoliveira@gmail.com Tiago Ribeiro de Oliveira,MD tiagoribeirooliveira@sapo.pt Álvaro Nunes, MD alvaronunes@portugalmail.pt Francisco Martins, MD faemartins@gmail.com Tomé Lopes, MD tomematoslopes@gmail.com SCI-Centro de Urologia Av. Defensores de Chaves, 83, 1º, 1000-115, Lisbon, Portugal

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preserve erectile function after radical prostatectomy. Urology 2003; 6:491-497. 17. Iacono F, Gianella R, Somma P, et al. Histological alterations in cavernous tissue after radical prostatectomy. J Urol. 2005; 173:1673-1676. 18. Hisasue S, China T, Horiuchi A, et al. Impact of aging and comorbidity on the efficacy of low- intensity shock wave therapy for erectile dysfunction. Int J Urol. 2016; 23:80-84. 19. Motil I, Kubis I, Sramkova, T. Treatment of vasculogenic erectile dysfunction with Piezowave2 device. Application of low intensity shockwaves using novel linear shockwave tissue coverage (LSTCED®) technique. A prospective, multicentric, placebo-controlled study. Adv Sex Med. 2016; 6:15-18. 20. Fojecki GL, Tiessen S, Osther PJS. Effect of low-energy linear shockwave therapy on erectile dysfunction – a double-blinded, shamcontrolled, randomized clinical trial. J Sex Med 2017; 14:106-1.

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DOI: 10.4081/aiua.2018.4.283

ORIGINAL PAPER

Penile fracture with urethral injury: Our experience in a tertiary care hospital Priyatham Kasaraneni, Prasad Mylarappa, Ramesh Desi Gowda, Sandeep Puvvada, Dheeraj Kasaraneni Department of Urology MS Ramaiah Medical College, Bengaluru, India.

Summary

Penile fracture is a rare urological emergency that always requires immediate attention. It may be associated with urethral trauma in 9% to 20% of cases. We present our experience in treating 12 such cases. This is a prospective observational study extending from January 2000 to December 2016. Each patient with penile fracture underwent a thorough clinical evaluation and received proper treatment. Seventy-five patients with penile fracture, aged 25 to 36 years (mean, 31.5 years) were evaluated in this study. Sexual intercourse was the common mechanism of injury in most of the patients. 12 of the patients had associated urethral injury. All the patients were diagnosed on taking proper history and after clinical examination. All patients were subjected emergency surgical exploration. All the patients underwent minimum of 1 year of follow-up, and were evaluated with local examination, uroflowmetry and Colour Doppler ultrasonography. Penile fracture is associated with urethral injury especially in the presence of suggestive history and physical examination like acute urinary retention, bleeding per urethra. Immediate primary surgical management of both the penile fracture and urethral injury is a safe and effective option with minimal complications.

KEY WORDS: Penile fracture; Urethral injury; Corpora; Tunica; Detumescence. Submitted 4 October 2018; Accepted 15 November 2018

INTRODUCTION

Penile fracture is defined as the rupture of the tunica albuginea of the corpus cavernosum caused by blunt trauma to the erect penis (1). There might be associated injuries which include partial or complete transection of urethral or spongiosal tissue (2). The tunica albuginea layer is a tough fibroelastic sheath, which envelops the ventral corpus spongiosum and dorsally paired corpora cavernosa (3). Buck’s fascia and the deep perineal tissue plane that surrounds both the cavernosa and penile vessels, merges proximally with the deep urogenital region. The characteristic injury patterns associated with penile fractures depend on the integrity of this tissue plane. Upon tunical disruption, cavernosal bleeding can leak into surrounding tissues and remains in the penis by an intact Buck’s fascia (4). Penile fracture is mostly associated with sexual intercourse and occurs when the rigid penis slips from the vagina striking the partner’s perineum or pubic bone. In Middle East countries, a com-

mon cause of penile fracture is self-inflicted injury. The other cause, Taqaandan has been described as an intentional, forceful bending of the erect penile shaft as cultural habit to provide relaxation and release tension (5). With an annual incidence of 0.29-1.36 cases per 100,000 people, some additional etiologies were mentioned in the literature which include impaling a penis in a mattress, slamming the penis in a door, placing an erect penis into tight pants, striking a toilet seat, hitting a bedpost, falling from a tree, and masturbating into a cocktail shaker (6-12). Most likely, the laceration is unilateral though bilateral rupture accounts for 2% to 10% of cases. Associated urethral injury is rare, with reported frequencies in 10% to 38% (13). Urethral injury may be suspected if there is hematuria and inability to void. The presenting features are relatively consistent and typically straightforward. The simple clinical diagnosis usually renders adjunct imaging unnecessary. Historically, penile fracture management included mostly conservative, nonsurgical measures. In the 1980s, operative intervention became favorable after several studies demonstrated a decrease in long-term morbidity (14-15). Nowadays, immediate surgical exploration is the standard of care because of its advantages like lesser complications, decreased hospital stays, improved outcomes, and better patient satisfaction. Not many studies were present on case series of penile fracture with urethral injury apart from case reports. This study is based on our experience with 8 cases of penile fracture associated with urethral injury that were treated at a tertiary care hospital.

MATERIALS

AND METHODS

We did a prospective observational study. Seventy-five cases of penile fracture were presented to the emergency ward from January 2000 to December 2016. Out of them, only 12 had associated urethral injury. Informed written consent was taken from all the patients. Diagnosis was made on patient’s history and clinical examination alone. We didn’t subject the patients to any radiological investigation. When clinical diagnosis was in doubt in cases of no urethral injury, we had done ultrasonography of penis to look for tunical tears. We subjected all cases to emergency surgical exploration (Figures 1-4). Circumferential sub coronal incision was

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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Figure 1. Penile fracture with blood at meatus and developing hematoma.

Figure 2. Hematoma in the Buck’s fascia at the proximal part.

Figure 3. Intraoperative photo demonstrating bilateral transverse rupture of the corpora and complete urethral transection.

if present, mobilization of urethra done to get length for tension free anastomosis. Urethra was anastomosed after cutting the margins with absorbable suture (4-0 vicryl) for water tight anastomosis. A 16 Fr Foley catheter was used for urinary catheterization. All patients were discharged on the 2nd postoperative day. To prevent painful erections, estradiol 0.05 mg was given for 3 weeks. The urethral catheter was removed after 3 weeks. All the patients were followed up at 3 months and 1 year with clinical examination, uroflowmetry and color Doppler.

RESULTS

Twelve patients out of 75 patients with penile fracture had associated urethral injury. The following Table 1 shows the demographical values of the study. We suspected urethral injury clinically on the basis of history in all patients as they had either difficulty voiding, retention of urine or bleeding per urethra and rest of typical features like Aubergine sign, crackling sound were also looked for (Table 2). Retrograde urethrogram was not used in our study. History of sexual intercourse with woman on top position was present in 7 patients whereas 1 patient had history of blunt injury and 2 patients had history of rolling over in the bed. Seven patients heard crackling sound at the time of injury. Eleven patients had bleeding per urethra. Three patients Table 1. Demographics of the study. Parameter Incidence of urethral injury Mean time from the time of injury to the time of presentation to the hospital Mean age Age range No of urban population affected No of rural population affected

Value 12 out of 75 cases (16%) 4.62 hours 31.5 years 25-36 years 10 (83.33%) 2 (16.66%)

Table 2. Clinical findings. Figure 4. Photo showing primary reanastomosis of urethra.

Clinical findings History of sexual intercourse with woman on top position History of rolling over in the bed History of blunt injury History of crackling sound Bleeding per urethra Aubergine sign/egg-plant deformity Acute retention of urine

Incidence 9 (75%) 2 (16.66%) 1 (12.5%) 7 (58.33%) 11 (91.66%) 12 (100%) 3 (25%)

Table 3. Intraoperative findings.

given to deglove the penis for complete evaluation of injuries. Corporal tears were closed with non-absorbable suture (vicryl 3-0). Urethral injuries were looked for and

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Intra operative findings Partial urethral disruption Complete urethral disruption Location of injury – Proximal shaft of penis Location of injury – Mid shaft of penis Location of injury – Distal shaft of penis

Number of cases 11 (91.66%) 1 (8.33%) 6 (50%) 2 (16.66%) 4 (33.33%)

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weren’t able to void from the time of injury. Aubergine sign was present in all the cases. On examination, diagnosis of penile fracture was straight forward in 11 patients with typical findings. One patient didn’t have bleeding per urethra and was voiding, we found urethral injury intraoperatively. The intraoperative findings are given in the following flow chart (Figure 5) and Table 3. The postoperative course for all the six patients was uneventful. All the patients were discharged by postoperative day 2. The mean follow-up of patients was 24 months from the day of surgery. All patients voided well and were documented by uroflowmetry. All patients had no problems with erection. One patient developed penile curvature which did not affect his sexual health. Another patient developed stricture urethra. Two patients developed urinary tract infections (Table 4). Figure 5. Flow chart of intraoperative findingsrupture of the corpora and complete urethral transection.

Table 4. Complications. Complications Penile curvature Stricture urethra Urinary tract infections

DISCUSSION

Number of cases 1 (8.33%) 1 (8.33%) 2 (16.66%)

The literature shows an incidence of 10% to 38% of urethral injury overall (13). We observed 14.03% incidence in our case series of 75 patients. The frequency of urethral involvement was between 0 and 3 per cent in the Middle Eastern studies (10). The most common cause of penile fracture with urethral injury in our patients was vaginal intercourse with women on top position in 9 out of 12 patients (75%). During intercourse with woman on top position, the angulation of erect penis makes its ventral surface vulnerable to collision with inferior margin of the pubic arch & symphysis pubis of the woman. In a phase of excitement or during a stage when they are unable to keep rhythm, the penis instead of penetrating deep into vagina, becomes entangled at the introitus and collides on its ventral surface with pubic arch of female partner. This phenomenon is exaggerated due to down-

ward thrust of the woman or the upward stroke of man. Therefore, the urethra gets sandwiched between erect corpora of the man and pubic arch of the woman causing mucosal tear & bleeding per urethra (16). In our series of 75 patients, patients with urethral injury presented earlier compared to patients with only penile fracture, most likely because they were unable to void. Diagnosis of urethral injury associated with penile fracture is based on history in patients if they had either difficulty voiding, retention of urine or bleeding per urethra. Urinalysis is not a mandatory component in the diagnosis of suspected urethral injuries, as it can confuse sometimes. In our study, 11 patients had macroscopic hematuria, whereas Gedik et al. reported the presence of microscopic hematuria in 6 out of 107 patients, but none of them had a urethral injury on exploration (17). So, presence of microscopic hematuria might not be an indication of urethral injury, so urinalysis test can be omitted. When in doubt retrograde urethrogram(RGU) is helpful in confirming the presence of a urethral injury but, it’s not without false negative results. Mydlo and colleagues reported a false negative rate of 28.5% (2/7 patients) in their small series (18), which might be due to overlying hematoma at the site of injury, which masks the defect. Hence the test is not recommended in routine practice. We did not perform any retrograde urethrogram in any of our patients, but we did adequate exposure of penis by circumferential sub coronal incision to prevent missing out urethral injury. Eleven patients presented with classical features with penile fracture with urethral injury, apart from one patient without bleeding per urethra, we were able to identify urethral injury intraoperatively which signifies the importance of proper degloving of penile skin for complete examination of injuries. All patients were subjected to emergency surgical exploration to prevent complications like urethral stricture, urethra-cavernous fistula and erectile dysfunction (14, 19-21). Complete rupture of urethra has been reported in literature (22), we got only one case (8.33%) with complete rupture of urethra. Bilateral corporal injury occurs in 4-10% of cases (23-24), we reported one case with an incidence of 8.33%. Isolated urethral injury is very rare and might occur with absence of a snapping sound, sharp pain and detumescence (16). Most of our patients had partial urethral tears which account to 11 (91.66%). All patients had the site of the urethral trauma near the site of the corporal tear, which made it easy to identify the site of urethral injury. In one patient we weren’t able to identify the location of urethral injury, so we took the help of saline mixed with methylene blue dye and introduction of a guide wire helped in the identification of urethral injury with more ease. Shaeer investigated the value of methylene blue in locating urethral tears in fracture penis and found it reliable and safe (25). Primary urethral anastomosis and corporal repair can be done after evacuation of hematoma and removing any devitalized tissue under cover of antibiotics. The outcomes of penile fracture with associated urethral injury repair are dependent on the timing of surgical exploration, the need for urethral catheterization, the type of incision and fashion of suture material utilized, and the requirement Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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P. Kasaraneni, P. Mylarappa, R. Desi Gowda, S. Puvvada, Dheeraj Kasaraneni

CONCLUSIONS

Table 5. Comparison of different studies. Parameter No of patients Mean age Age range Median time from the time of injury to the time of presentation to the hospital Crackling sound Acute retention of urine Bleeding per urethra Aubergine sign/egg-plant deformity Bladder palpable Urethrogram Bilateral corporal involvement Unilateral corporal involvement Right corporal involvement Left corporal involvement Proximal corpora Mid corpora Distal corpora Median length of laceration Partial urethral disruption Complete urethral disruption Supra-pubic cystostomy tube Penrose drain Medication to prevent erection Median duration of transurethral catheterization Median hospital stay Follow up mean

Our study 12 31.5 years 25-36 years 6 hours

Derouiche et al. (28) 10 30 years 19-46 years 10 hours

7 (58.33%) 3 (25%) 11 (91.66%) 12 (100%) 3 (25%) Not done 1 (8.33%) 11 (91.66%) 5 (41.66%) 6 (50%) 6 (50%) 2 (16.66%) 4 (33.33%) 28 mm 11 (91.66%) 1 (8.33%) Not used Not used Estradiol 21 days

10 (100%) 2 (20%) 10 (100%) 10 (100%) 2 (20%) Not done 10 (100%) 6 (60%) 4 (40%) 5 (50%) 4 (40%) 1 (10%) 24 mm 10 (100%) Used Used Diazepam 13 days

Attam et al. (27) 8 30.4 years 23-51 years Mean duration was 2.7 days, median not assessed 6 (75%) Not mentioned 6 (75%) 6 (75%) Not mentioned Not done 1 (12.5%) 7 (87.5%) 5 (62.5%) 2 (25%) 6 (75%) Not mentioned Not mentioned Not mentioned 7 (87.5%) 1 (12.5%) Not used Not Used Estradiol 21 days

2 days 24 months

14 days 18 months

2 days 34.3 months

for prophylactic antibiotics (18). With early repair, adequate exposure, complete hematoma evacuation, adequate rest to urethra for healing by catheterization can lead to favorable outcomes in the management of penile fracture associated with urethral injury. We used estradiol to prevent erections whereas Jallu et al. preferred using diazepam along with oxyphenbutzone (26). We advised the patients to refrain from sexual activity for 6 weeks post-surgery but some studies showed sexual intercourse can be resumed 2 weeks after surgery (27-29). Different follow-up protocols and strategies have been reported in different published series (28). In this study, the first follow-up was in the third week after the operation, and all patients underwent clinical evaluation. Later the patients were followed up at 3 months and 1 year with clinical examination, uroflowmetry and colour Doppler. We noted penile curvature in one patient which didn’t affect their sexual activity. One patient developed short segment stricture of the urethra which was managed with endoscopic dilatation. Two patients developed urinary tract infections which were treated conservatively with antibiotics based on urine culture and sensitivity. The limitation of our study is limited sample size. The Table 5 shows comparison between 2 similar studies.

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Penile fracture is associated with urethral injury especially in the presence of suggestive history and physical examination like acute urinary retention or bleeding per urethra. Immediate primary surgical management of both the penile fracture and urethral injury is a safe and effective option with minimal complications.

Compliance with ethical standards The approval of ethical committee of our institution was taken before starting the study. Funding This study was not funded by anyone.

REFERENCES

1. McAninch JW, Santucci RA. Genitourinary trauma. In: Walsh P, Retik A, Vaughan E, Wein A, 2. editors. Campbell’s urology. 8th ed. Philadelphia: Saunders. 2002; p. 3707-44. 2. Maharaj D, Naraynsingh V. Fracture of the penis with urethral rupture. Injury. 1998; 29:483. 3. Hsu GL, Hsieh CH, Wen HS, et al. Penile venous anatomy: an additional description and its clinical implication. J Androl. 2003; 24:921-7.

4. Sawh SL, O’Leary MP, Ferreira MD, et al. Fractured penis: a review. Int J Impot Res. 2008; 20:366-9. 5. Zargooshi J. Sexual function and tunica albuginea wound healing following penile fracture: an 18 year follow-up study of 352 patients from Kermanshah. Iran J Sex Med. 2009; 6:1141-50. 6. Kalash SS, Young Jr JD. Fracture of penis: controversy of surgical versus conservative treatment. Urology. 1984; 24:21-4. 7. Eke N. Fracture of the penis. Br J Surg. 2002; 89:555-65. 8. Khinev A. Penile fracture. Khirurgiia (Sofiia) 2004; 60:32-41. 9. Chung CH, Szeto YK, Lai KK. ‘Fracture’ of the penis: a case series. Hong Kong Med J. 2006; 12:197-200. 10. Zargooshi J. Penile fracture in Kermanshah, Iran: the long-term results of surgical treatment. BJU Int. 2002; 89:890-4. 11. Klein FA, Smith MJ, Miller N. Penile fracture: diagnosis and management. J Trauma. 1985; 25:1090-2. 12. El-Taher AM, Aboul-Ella HA, Sayed MA, Gaafar AA. Management of penile fracture. J Trauma. 2004; 56:1138-40. 13. Sant GR. Rupture of the corpus cavernosum of the penis. Arch Surg. 1981; 116:1176-8. 14. Wespes E, Libert M, Simon J, Schulman CC. Fracture of the penis: conservative versus surgical treatment. Eur Urol. 1987; 13:166-8. 15. Seaman E, Santarosa R, Walton G. Immediate repair; key to managing the fractured penis. Contemp Urol. 1993; 5:13.

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16. Mohapatra TP. Kumar S. reverse coitus. Mechanism of urethral injury in male partner. J Urol. 1990; 144:1467-83.

23. Mydlo JH Surgeon experience with penile fracture. J Urol. 2001; 166:526-528.

17. Gedik A, Kayan D, Yamis S, et al. The diagnosis and treatment of penile fracture: our 19-year experience. Ulus Travma Acil Cerrahi Derg. 2011; 17:57-60.

24. Koifman L, et al. Penile fracture experience in 56 cases. Int Braz J Urol. 2003; 29:35-39.

18. Mydlo JH, Hayyeri M, Macchia RJ. Urethrography and cavernosography imaging in a small series of penile fractures: a comparison with surgical finding. Urology. 1998; 51:616-9. 19. Touiti D, Ameur A, Beddouch A, Oukheira H. La rupture de lâ&#x20AC;&#x2122;urethre au cours des fractures de la verge. A propos de 2 observations. Prog Urol. 2000; 10:465-468. 20. Biserte J, Nivet J. Traumatisme de lâ&#x20AC;&#x2122;urethre anterieur: diagnosticet traitement. Ann Urol. 2006; 40:220-232. 21. Paparel P, Ruffion A. Rupture des corps caverneux: aspects techniques de la prise en charge. Ann Urol. 2006; 40:267-272. 22. Heng CT, Brooks AJ. Penile fracture with complete urethral rupture. Asian J Surg. 2003; 26:126-7.

25. Shaeer O. Methylene blue-guided repair of fractured penis. J Sex Med. 2006; 3:349-54. http://dx.doi.org/10.1111/j.1743-6109. 2005.00155.x 26. Jallu A, Wani NA, Rashid PA. Fracture of the penis. J Urol. 1980; 123:285-286. 27. Masarani M, Dinneen M. Penile fracture: diagnosis and management. Trends in Urology Gynaecology & Sexual Health. 2007; 12:20-24. 28. Derouiche A, Belhaj K, Hentati H, et al. Management of penile fractures complicated by urethral rupture. Int J Impot Res. 2008; 20:111-114. 29. Amit A, Arun K, Bharat B, et al. Penile fracture and associated urethral injury: experience at a tertiary care hospital. Can Urol Assoc J. 2013; 7:E168-E170.

Correspondence Priyatham Kasaraneni, MD kasaraneni.priyatham@gmail.com; kpriyatham@yahoo.co.in Prasad Mylarappa, MD prasadmyluro2@gmail.com Ramesh Desi Gowda, MD arunacr1@gmail.com Sandeep Puvvada, MD dr.sandeep001@gmail.com Dheeraj Kasaraneni, MD dheerajkasaraneni@gmail.com Department of Urology MS Ramaiah Medical College, Bengaluru, India Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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DOI: 10.4081/aiua.2018.4.288

ORIGINAL PAPER

Unit, S. Donato Hospital, Arezzo, Italy; of Medical Biotechnologies, University of Siena, Italy.

Summary

Objective: A longitudinal prospective case control study was organized to explore the relationships between glomerular filtration rate (GFR), renal resistive index (RRI) and blood pressure values in a non-dialysis dependent adult population affected by chronic kidney disease and exposed to low systolic blood pressure (SBP) values. Material and methods: The study sample (54 patients: 31 males and 23 females with an average age of 61.7 ± 19.2 years) was randomly selected from a population of adult non-dialysis dependent patients that scored a SBP < 100 mmHg at the medical examination. The patients were equally divided in two groups defined by the presence and absence of chronic kidney disease, (i.e. a GFR less or greater than 60 ml/min/1.73 m2, respectively). Patients were submitted to a full therapeutic and dietetic intervention to correct the hypotension until reaching a steady SBP > 100 mmHg. Results: In the group with chronic renal disease, the comparison between the data recorded with SBP < 100 mmHg (t0) and those detected with SBP ≥ 100 mmHg (t1) showed a statistically significant decrease of serum creatinine as well as an increase of GFR (mean serum creatinine t0 – serum creatinine t1: 0.194 ± 0.35, p < 0.01; mean GFR t0 – GFR t1: -4.615 ± 8.8, p < 0.013). There was also a statistically significant reduction of the RRI (mean right kidney RRI t0 – mean right kidney RRI t1: + 0.082 ± 0.03, p < 0; mean left kidney RRI t0 – mean left kidney RRI t1: 0.076 ± 0.03, p < 0). Conclusion: We concluded that, in CKD, when aorta is stiffed, a decrease of SBP can limit the renal perfusion that, in this condition, is mostly dependent by stroke volume, causing an increase of RRI and a decrease of GFR that we suppose as reversible with the restoration of SBP.

KEY WORDS: Longitudinal prospective case control study; Chronic kidney disease; Renal Doppler ultrasonography; Renal resistive index; Low systolic blood pressure. Submitted 1 November 2018; Accepted 15 December 2018

INTRODUCTION

Recently it has emerged that in a non-dialysis dependent population suffering from chronic kidney disease (CKD) and subjected to conventional therapeutic and dietary treatment there is a statistically significant correlation between reduction of renal resistive index (RRI) (which if high, i.e. ≥ 0.7, represent an unfavorable prognostic

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index of renal disease progression) and reduction of systolic blood pressure (SBP) (1). While it is known what should be the normal range for resistance indices (0.47-0.70) (2), the same cannot be said about the ideal thresholds for arterial pressure. In this regard, although there is consensus in setting a target for blood pressure lower than 140/90 mmHg for most individuals, according to some Authors the achievement of blood pressure values lower than 130/80 mmHg could guarantee an improvement of the clinical outcome compared to the 140/90 mmHg threshold in adults with chronic kidney disease (3, 4). However, there is no consensus on what may be a minimum threshold for the same blood pressure and this despite it being well known how damage can occur if intensive blood pressure treatment is implemented in patients with chronic renal failure (3). In particular, in a cohort of over 650.000 American veterans suffering from chronic kidney disease, patients who had an "ideal" blood pressure (< 130/80 mmHg) showed an increase in mortality due to the inclusion in this group of individuals with low systolic and/or diastolic arterial values. This association was confirmed both in diabetics and in non diabetics, or in those who had microalbuminuria or not (5). We organized a longitudinal prospective case control study with the intent to explore the relationships between renal function, renal resistive index (RRI) (used as a monitoring tool) and blood pressure values in a nondialysis dependent adult population affected by chronic kidney disease and exposed to reduced systolic blood pressure values (SBP < 100 mmHg).

MATERIALS

AND METHODS

A longitudinal prospective case control type study was planned. The study sample (54 patients: 31 males and 23 females with an average age of 61.7 ± 19.2 years) was randomly selected from a population of adult non-dialysis dependent patients attending the outpatient nephrology clinic of San Donato Hospital in Arezzo that scored a systolic blood pressure < 100 mmHg at medical examination. The study population was initially affected by hypertenNo conflict of interest declared.

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Low systolic blood pressure values, renal resistive index measurement and glomerular filtration rate in a non-dialysis dependent chronic..

sion and/or diabetes mellitus and/or chronic glomerulonephritis with or without chronic kidney disease or albuminuria. Patients with obstructive uropathy, acute glomerulonephritis, tubulointerstitial renal diseases, Table 1. Baseline characteristics of the population enrolled. GFR group (ml/min/1.73 m2) Age t0 (years) < 60 > 60 Height (cm) < 60 > 60 Weight t0 (kg) < 60 > 60 Body mass index t0 (kg/m2) < 60 > 60 creatinine t0 (mg/dl) < 60 > 60 GFR t0 (ml/min/1.73 m2) < 60 > 60 proteinuria t0 (gr/24h) < 60 > 60 Hba1c t0 (%) < 60 > 60 SBP t0 (mmHg) < 60 > 60 DBP t0 (mmHg) < 60 > 60 right kidney RRI t0 < 60 > 60 left kidney RRI t0 < 60 > 60 right kidney diameter t0 (mm) < 60 > 60 left kidney diameter t0 (mm) < 60 > 60 age t1 (years) < 60 > 60 Weight t1 (kg) < 60 > 60 Body mass index t1 (kg/m2) < 60 > 60 creatinine t1 (mg/dl) < 60 > 60 GFR t1 (ml/min/1.73 m2) < 60 > 60 proteinuria t1 (gr/24h) < 60 > 60 Hba1c t1(%) < 60 > 60 SBP t1 (mmHg) < 60 > 60 DBP t1 (mmHg) < 60 > 60 right kidney RRI t1 < 60 > 60 left kidney RRI t1 < 60 > 60 right kidney diameter t1 (mm) < 60 > 60 left kidney diameter t1 (mm) < 60 > 60

N°

Mean

26 25 26 24 26 24 26 24 26 25 26 25 25 20 6 4 26 25 26 25 25 23 24 20 26 23 24 22 26 25 25 23 25 23 26 25 26 25 22 18 5 2 26 25 26 25 24 23 24 22 26 24 24 23

69.35 54.36 164.038 167.5 73.146 76.817 27.1753 27.25421 1.7892 0.9456 38.615 82.96 0.2256 0.31645 6.75 5.975 90.115 91.6 58.192 66.72 0.746 0.6265 0.7413 0.63 99.538 109.478 103.958 116.045 68.46 53.04 74.44 78.448 27.62463 27.65597 1.5946 0.978 43.231 81.4 0.323682 0.342389 6.34 6.05 114.654 109.44 74.154 76.84 0.6638 0.6348 0.665 0.6355 101 110.417 104.458 116.13

Standard deviation 18.974 16.671 10.5356 8.3406 12.2153 15.1616 3.6804 4.3580 0.6175 0.1712 12.9648 17.3505 0.3884 0.5184 0.5089 0.5123 5.2484 4.7697 9.9881 6.9072 0.06212 0.05407 0.06306 0.07138 12.7349 13.5139 12.2065 12.0217 19.59 16.352 13.4028 15.3239 4.0364 4.3396 0.43552 0.17769 13.5685 21 0.5561 0.5020 0.5727 0.2121 10.2526 7.6381 13.5135 8.0658 0.06309 0.07391 0.06164 0.07645 13.1088 14.7852 12.7381 11.8372

renal artery stenosis and malignant disease were excluded. Pregnant women and children were also excluded. The total number of patients was selected to be equally divided in two groups defined by the presence (case) and absence (control) of chronic renal disease, defined by a glomerular filtration rate (GFR) less or greater than 60 ml/min/1.73 m2, respectively. Mean The average GFR (calculated by the CKD standard error EPI equation) (6), was 38.5 ± 12.7 3.721 ml/min/1.73 m2 for case group and 82.3 3.334 ± 17 ml/min/1.73 m2 for control group 2.0662 (Table 1). A prevalence of male gender 1.7025 was observed in both study and control 2.3956 groups. The anthropometric parameters 3.0948 (weight, height, age, sex and body mass 0.721794187 index) did not differ statistically (at a sig0.88958826 nificance level of 95%) in the two groups 0.12112 (Table 1). At the time of enrollment a 0.03424 written informed consent was obtained 2.5426 by all the patients. 3.4701 After the enrollment the patients were sub0.0776993 mitted to a complete medical examination, 0.1159197 comprehensive of the recording of weight 0.2078 0.2562 and height. A measure of blood pressure was taken with a mercury sphygmo1.0293 0.9539 manometer applied around each patient’s 1.9588 non-dominant arm after the patient had 1.3814 rested for 15 minutes in a sitting position 0.01242 and with his/her arm placed at the level of 0.01127 the heart. Two consecutives blood pres0.01287 sure recordings, taken at 5 minute interval, 0.01596 were averaged to provide clinic systolic 2.4975 and diastolic blood pressure values. 2.8178 Blood and urine samples were obtained 2.4916 for measurement of serum creatinine, gly2.563 cated hemoglobin and 24-hour urinary 3.842 albumin excretion. Finally, renal Doppler 3.27 ultrasonography examination was carried 2.6806 out by the same nephrologist experienced 3.1952 in ultrasound examination using the same 0.807297865 ultrasound device that was a Logiq S7 0.904875025 (GE Medical Systems Italy S.P.A. Milan, 0.08541 Italy) sonographic system equipped with 0.03554 3 to 5 Mhz transducers. Doppler signals 2.661 4.2 were obtained from the interlobar arteries from the upper, middle and lower third 0.118575 0.1183385 of both kidneys and resistive index was 0.2561 calculated as the average of 6 measure0.15 ments (3 from each of the 2 kidneys) 2.0107 taken for each patient. The Doppler angle 1.5276 was chosen as close to 0°as possible and 2.6502 special care was taken not to compress 1.6132 the kidney and not to have the patient 0.01288 performing Valsalva maneuver because 0.01541 both of them can increase the renal resis0.01258 tive index value. We recorded also the 0.0163 diameters in the longitudinal axis of each 2.5708 kidney and the cortical thickness of each 3.018 kidney, measured in the portion closer to 2.6002 the upper pole and the lower pole of the 2.4682 same kidney. Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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We recorded any data about the therapeutic and dietary treatment of the patients with special regard to the use of drugs that may interfere with the RRI determinations such as angiotensin II receptor blockers (ARBs) or angiotensin converting enzyme (ACE) inhibitors and beta blockers and the use or not of an hyposodic, hypoproteic, hypoglicemic as well as hypocaloric diet. Then the patients were submitted to a full therapeutic and dietetic intervention to correct the hypotension by a reduction of dosage or removal of hypotensive drugs. After a variable interval period, depending from the time necessary to recovery a steady systolic blood pressure > 100 mmHg for on average one year, patients were submitted again to a new medical examination comprehensive of the recording of weight and clinic blood pressure values with the same modalities above mentioned. Values of serum creatinine, glycated hemoglobin and 24hour urinary albumin excretion were collected again and a new renal Doppler ultrasonography was carried out by the above mentioned nephrologist experienced in ultrasound investigation by using the same ultrasound device. All data relating to the therapeutic and dietary treatment used by the patients were recorded again. Statistical analysis Descriptive statistics included mean and standard deviation for quantitative data, and frequency count and percentage for qualitative data. For quantitative variables, groups were compared with the Student t test for unpaired data or the Mann-Whitney rank test, respectively depending on the normal or non-normal distribution of population data. The normality was assessed by applying the Kolmogorov-Smirnov test to sample data. Comparisons between t0 and t1 were made using the Student t test for paired data or the Wilcoxon rank test for normal or non-normal data respectively. For dichotomous qualitative variables, frequency counts between groups were compared using the Fisher exact test applied to 2 x 2 contingency data. A statistical significance level of 95% was chosen for all statistical analyses (p < 0.05) that were performed using SPSS software, version 10.

RESULTS

Considering the two groups with GFR < 60 and GFR ≥ 60 ml/min/1.73 m2 separately, within the group with GFR < 60 ml/min/1.73 m2, the comparison between the data recorded with systolic blood pressure (SBP) < 100 mmHg (t0) and those detected with SBP ≥ 100 mmHg (t1) showed that, passing from time 0 to time 1, there was a statistically significant increase of body weight (BW) (mean BWt0 - BWt1: -1.428 ± 3.2; p < 0. 04), although the clinical significance of this observation was not very relevant as it was about 2%. A statistically and clinically significant decrease of serum creatinine as well as a statistically and clinically significant increase of the glomerular filtrate rate was observed (mean creatinine t0 - creatinine t1: 0.194 ± 0.35; p < 0.01; equal to a reduction of approximately 11%; mean GFR t0 - GFR t1: 4.615 ± 8.8, p < 0.013, equal to an increase of over 12%). A statistically and clinically significant decrease of

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the renal resistive index (RRI) was also observed (mean right kidney RRI t0 – mean right kidney RRI t1: + 0.082 ± 0.03, p < 0, equal to a 10.8% reduction. Mean left kidney RRI t0 – mean left kidney RRI t1: 0.076 ± 0.03, p < 0, equal to a reduction of 10.2%). Comparison for paired data also identified a statistically significant reduction of the glycated hemoglobin data, to which, however, given the small number of diabetics on the total (6 out of 27 equal to about 22% of the total), it was not possible to attribute a clinical relevance. Within the control group (GFR ≥ 60 ml/min /1.73 m2) there was no statistically significant variation between times t0 and t1 except, of course, the increase in the arterial pressure values (systolic and diastolic), a finding that was also found in the cases (GFR < 60 ml/min /1.73 m2) confirming the respect of the working hypothesis. Finally considering the two groups together, the comparison for all the variables between time zero and time 1 confirmed a statistically significant increase of body weight as well as a statistically significant decrease in serum creatinine levels and a statistically significant reduction of the intrarenal arterial resistance indices of the right kidney and of the left kidney. In the comparison for paired data a statistically significant reduction of glycated hemoglobin was found for the entire population such as , both for the two groups separately. The comparison of data from the two groups for all the variables, confirmed the quality of the above exposed observations by detecting a significant difference between groups for creatinine at both time intervals, GFR at both time intervals, right kidney RRI and left kidney RRI at time 0 as well as right kidney diameter and left kidney diameter at both time intervals.

DISCUSSION

A unique feature of the kidney is that it is continually and passively perfused at high volume flow throughout systole and diastole. Its vascular resistance is very low so that in comparison to other vascular beds resistance is closer to input and characteristic impedance (7). It is therefore susceptible to upstream influences that may increase fluctuations of pressure and flow, whereas small vessels in other organs are protected by relatively intense vasoconstriction upstream (7). In patients with chronic kidney disease (CKD) and endstage renal disease (ESRD) all epidemiological studies have clearly shown that an accelerated arterial and cardiac aging by atherosclerosis is characteristic of these populations. Atherosclerosis is a generalized arterial disease of the arterial intima characterized by the presence of plaque and occlusive arterial lesions. The functional consequence of these structural alterations is hardening/sclerosis of vessel walls (arteriosclerosis) and loss of compliance, that is increased stiffness. When the arterial premature aging involves the aorta it stands out for an aortic stiffening and for the disappearance of stiffness/impedance gradients between the central and peripheral arteries. These changes have a double impact: on the heart, upstream, with high systolic and pulse pressures and decreasing diastolic pressure, increased cardiac afterload and arterial circumferential

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Low systolic blood pressure values, renal resistive index measurement and glomerular filtration rate in a non-dialysis dependent chronic..

stress. All these factors promote left ventricular hypertrophy (LVH) which may evolve toward heart failure. Downstream, on renal and brain microcirculation, with decrease in glomerular filtration and cognitive functions (8). Proof of all this is the fact that strong associations between aortic stiffness and indicators of renal dysfunction (glomerular filtration rate and microalbuminuria) have been described such as with cognitive impairment and dementia besides (as previously mentioned), left ventricular hypertrophy and left ventricular dysfunction (8). Physiologically, the higher compliance of the aorta coupled with a progressively lower compliance in peripheral vessels creates a “stiffness gradient” that works as a “hydraulic filter” and acts to buffer pressure pulsations and their transmission to microcirculation and capillary network (principally in the main parenchymal organs such as the kidney and the brain). The more distensible the arterial wall (that is, the lower the stiffness) the smoother the provision of proper flow to peripheral tissues. When the aorta is rigid and cannot be stretched, the entire stroke volume flows through the arterial system and peripheral tissues only during systole with two consequences: intermittent flow and short capillary transit time with reduced metabolic exchanges (9). Therefore we believe that, in such a condition, a reduce of the systolic arterial blood pressure, such as a SBP < 100 mmHg, can further and definitely limit the renal perfusion that is already damaged by lacking of a proper aortic buffer. About the Doppler renal Resistive index (RRI) described by Pourcelot (10) ((peak sistolic velocity-end diastolic velocity)/peak sistolic velocity) we observe that RRI is a traditional index used as a measure of vascular resistance. A value of 0.60 is considered as a normal value for renal RRI, whereas 0.70 is usually considered the upper threshold of normal RRI in adults. Several factors have been described to influence Doppler renal arterial waveform and therefore the RRI as renal vascular compliance, central hemodynamics (especially arterial stiffness, blood pressure and heart rate), and other factors including age, underlying acute or chronic renal disease and drugs too (11). In this regard it is known that RRI decreases with use of renin angiotensin system (RAS) inhibitors, due to hemodynamic changes induced by these antihypertensive agents (12) while RRI, significantly and independently, increased with use of beta-blockers (13). In the setting of an acute kidney injury the first clinical application of RRI was the detection of renal obstruction because renal vasoconstriction is believed to be a key factor in the pathophysiology of acute kidney obstruction. Platt et al had proposed that an RRI ≥ 0.7 was in favor of an acute renal obstruction and may precede pyelocalicectasis (14). Afterwards in 91 patients with acute kidney injury (AKI), Platt et al. demonstrated that mean RRI was significantly higher in patients with persistent AKI than in patients with transient AKI (15). Lastly in a small number of patients with septic shock, Deruddre et al. have shown a significant decrease in renal RRI when increasing mean arterial pressure (MAP) with norepinephrine from 65 to 75 mmHg. This study suggests that Doppler renal ultrasound may help to determine in each patient the optimal MAP for renal tissue perfusion and

may be a relevant end point to titrate the hemodynamic treatment in septic shock (16). Accordingly, we believe that RRI may be used as a noninvasive and repeatable tool to assess changes in renal perfusion and it may be useful to determine the optimal therapeutic/preventive modalities for kidney perfusion at the bedside (11).

CONCLUSIONS

On the basis of all the above mentioned, we therefore believe that, when in CKD the aorta is stiffed and cannot be stretched, a decrease of the systolic arterial blood pressure, even temporary, can limit the renal perfusion that, in this condition, it is mostly (or entirely) a function of the stroke volume, causing an increase of the RRI and a reduction of the glomerular filtration rate as proven by this paper. This scientific work shows that reduced systolic arterial pressure values (i.e. SBP < 100 mmHg) have an effect of worsening of renal function only when there is already a pre-existent significant impairment of the GFR (such as a GFR < 60 ml/min/1.73 m ^ 2) and not when a similar kidney damage is not present. However we believe that, since this decrease in renal function is a function of reduced systolic arterial pressure values, the restoration of the systolic pressure may recover the decrease of renal function that therefore can be considered reversible. These observations appear congruent with what has already been reported by Judd et al. and Kovesdy et al. (3, 5) who, inspired by the association of low arterial pressure values with an increase in mortality, warns that "lowering SBP to the strict limits recommended by current guidelines (i.e. SBP < 130 mmHg or even lower) in patients with CKD (at the expense of lowering DBP below approximately 70 mmHg) may be deleterious". Above all, the data of this study are fully supported by the results of the SPRINT trial (17) which showed as an intensive blood pressure control (i.e. SBP < 120 mmHg) produces a significant cardiovascular benefit in high-risk patients with hypertension at the price of an higher risk of hypotension, syncope, and accelerated reductions in GFR. In fact in the SPRINT trial, acute kidney injury or acute renal failure occurred more frequently in the intensively treated group than in the standard-treated group and the Authors of this trial believe that the differences in adverse renal outcomes may be related to a reversible intrarenal hemodynamic effect of the greater reduction in blood pressure. Furthermore the Authors of the SPRINT trial, as the Authors of the present paper, believe that with the currently available data, there is no evidence of substantial permanent kidney injury associated with a treatment with the goal of lower systolic blood-pressure although the possibility of a long-term adverse renal outcome cannot be excluded (17).

REFERENCES

1. Brardi S, Cevenini G, Giovannelli V, Romano G. Longitudinal prospective observational type study about determinants of renal resistive index variations in chronic renal failure patients treated Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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with conventional medical and dietetic therapy. Arch Ital Urol Androl. 2017; 89, 4.

Paris. Seminare Institut National de la Santè et de la Recherche Medicale. 1975; pp 213-40.

2. Lubas A, Kade G, Niemczyk S. Renal resistive index as a marker of vascular damage in cardiovascular diseases. Int Urol Nephrol. 2014; 46:395-402.

11. Le Dorze M., Bouglè A, Deruddre S, et al. Renal Doppler ultrasound: a new tool to assess renal perfusion in critical illness. Shock 2012; 37:360-365

3. Judd E, Calhoun DA. Management of hypertension in CKD: beyond the guidelines. ADV Chronic Kidney Dis. 2015; 22:116-122.

12. Leoncini G, Martinoli C, Viazzi F, et al. Change in renal resistive index and urinary albumin excretion in hypertensive patients under long-term treatment with lisinopril and nifedipine GITS. Nephron. 2002; 90:169-173.

4. Taler SJ, Agarwal R, Bakris GL et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for management of blood pressure in CKD. Am J Kidney Dis. 2013; 62:201-213. 5. Kovesdy CP, Bleyer AJ, Molnar MZ, et al. Blood Pressure and Mortality in US Veterans with Chronic Kidney Disease. Ann Intern Med. 2013; 159:233-242. 6. Levey AS, Stevens LA, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009; 150:604-612. 7. O’Rourke MF, Safar ME. Relationship between aortic stiffening and microvascular disease in brain and kidney cause and logic of therapy. Hypertension. 2005; 46:200-204. 8. London G, Covic A. Goldsmith D, et al. Arterial aging and arterial disease: interplay between central hemodynamics, cardiac work, and organ flow-implications for CKD and cardiovascular disease. Kidney Int Sup. 2011; 1:10-12. 9. Briet M, Boutouyrie P, Laurent S, et al. Arterial stiffness and pulse pressure in CKD and ESRD. Kidney Int. 2012; 82:388-400. 10. Pourcelot L. Applications cliniques de l’examen Doppler transcutanè. In Peronneau P (ed). Velocimetrie ultrasonore Doppler.

Correspondence Simone Brardi, MD (Corresponding Author) Hemodialysis Unit, S. Donato Hospital, Arezzo, Italy Gabriele Cevenini, MD Department of Medical Biotechnologies, University of Siena, Italy

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13. Kuznetsova T, Cauwenberghs N, Knez J, et al. Doppler indexes of left ventricular systolic and diastolic flow and central pulse pressure in relation to renal resistive index. Am J Hypertens. 2015; 28:535-45. 14. Platt JF, Rubin JM, Ellis JH. Acute renal obstruction: evaluation with intrarenal duplex Doppler and conventional US. Radiology. 1993; 186:685. 15. Platt JF, Rubin JM, Ellis JH. Acute renal failure: possible role of duplex Doppler US in distinction between acute prerenal failure and acute tubular necrosis. Radiology. 1991; 179:419. 16. Deruddre S, Cheisson G, Mazoit JX et al. Renal arterial resistance in septic shock: effects of increasing mean arterial pressure with norepinephrine on the renal resistive index assessed with Doppler ultrasonography. Intensive Care Med. 2007; 33:1557. 17. The SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015; 373:2103-2116.

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CASE REPORT

Advanced chondrosarcoma of the pelvis: A rare case of urinary obstruction Valerio Olivieri 1, Valentina Fortunati 1, Scipio Annoscia 1, Massimo Massarelli 1, Luca Bellei 1, Massimo Ollino 1, Emy Manzi 2, Angela Maurizi 3, Francesco De Luca 3 1 Urology

Department, Ivrea Hospital - ASL TO4, Ivrea, Turin, Italy; of General Surgery, Santa Scolastica Hospital Manzi, Cassino (FR), Italy; 3 Department of Gynaecological and Urological Sciences, Sapienza University of Rome, Rome, Italy. 2 Department

Summary

Chondrosarcoma is the second most common malignant tumor of the bone with an incidence of 1 in 200.000 per year. Axial skeleton is frequently involved showing poorer oncological outcomes than appendicular one: human pelvis is a site predilection (1). It is rarely associated to urinary obstruction but according to its localization, it can be frequently linked to compression of pelvic organs as bladder, prostate or bowel. We describe the case of a 52 years old caucasian male with history of advanced pelvic chondrosarcoma and severe hydronephrosis due to total bladder dislocation.

KEY WORDS: Urology; Urinary obstruction; Hydronephrosis; Bladder dislocation; Pelvic chondrosarcoma. Submitted 13 August 2018; Accepted 19 August 2018

CASE

REPORT

A 52 years old feeble-minded male presented to our facility for bilateral flank pain poorly responsive to nonsteroidal anti-inflammatory therapy. The patient was previously diagnosed with pelvic chondrosarcoma but due to his general conditions, the advanced state of the tumor and its localization, no further therapies were offered to him just suggesting best supportive care. He has suffered for several months but pain intensified during last weeks: the pain was described as severe, originating in the flank bilaterally, irradiating anteriorly and associated to nausea and vomiting. Anyway he did not give history of urolithiasis, haematuria or previous flank pain episodes: no bowel diseases were mentioned. He solely referred a contraction of the diuresis which occurred during the last four weeks without any lower urinary tract symptoms. On physical examination he was alert and afebrile. The abdomen was soft with Giordanoâ&#x20AC;&#x2122;s test fully positive on bilateral flank: no signs of acute urinary retention was found neither evoked pain in hypogastric region. Blood examination revealed severe renal failure with creatinine on the high values; anyway white blood cells and haemoglobin were both normal. Abdominal ultrasound showed a voluminous bilateral renal pelvis with short residual parenchyma, highly suggestive for chronic distal obstruction. Moreover bladder

ultrasound was inconclusive being unable to visualize the pelvic organ due to skeleton artifacts due to his bone pathology. Due to the discovery of bilateral hydronephrosis, the inability of bladder visualizing and the presence of a pelvic bone tumor, the patient underwent to no-contrast computerized tomography (CT) in order to exclude ureteric compression by the tumor: no iodinated contrast material was given due to renal failure. The exam confirmed a voluminous bilateral hydronephrosis and hydroureter highly suggestive for chronic distal obstruction (Figure 1). No signs of urinary stones in both ureters were described. The scan also revealed a total bladder dislocation due to the pelvic chondrosarcoma (Figure 2) originating from left ischiopubic ramus and occupying almost the entire pelvis (Figure 3). As compared with a previous computerized tomography, it resulted highly increased in size and the bladder, which was previously orthotopic, was now entirely located and compressed in the upper part of the right pelvis. No visceral metastases were detected on tomography. Patient urgently underwent bilateral nephrostomy tubes placing in order to drain hydronephrosis, improve renal failure and alleviate the flank pain. Figure 1. Bilateral hydronephrosis due to urinary obstruction.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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Figure 2. Total bladder dislocation due to pelvic chondrosarcoma.

extension, the patient was considered as unfit for any major surgical approach simply receiving palliative nephrostomy.

CONCLUSIONS

Pelvic chondrosarcoma have been rarely shown to cause total bladder dislocation and bilateral hydronephrosis but according to the risk of obstructive renal failure, the work-up of patient affected by this tumor should include a regular monitoring of renal function and mass growth.

REFERENCES Figure 3. Pelvic chondrosarcoma originating from left ischiopubic ramus.

1. Mavrogenis AF, Angelini A, Drago G, et al. Survival analysis of patients with chondrosarcomas of the pelvis. J Surg Oncol. 2013; 108:19-27. 2. Guder WK, Hardes J, Gosheger M, et al. Osteosarcoma and chondrosarcoma of the pelvis and lower extremities. Chirurg. 2015; 86:993-1003. 3. Salunke AA, Shah J, Warikoo V, et al. Surgical management of pelvic bone sarcoma with internal hemipelvectomy: oncologic and functional outcomes. J Clin Orthop Trauma. 2017; 8:249-253.

Correspondence

DISCUSSION

Chondrosarcoma is a malignant tumor of the bone originating from axial or appendicular skeleton. Femur and proximal humerus are frequently involved as site of predilection: pelvis localization is also much common and this represent a major risk factor for pelvic organs compression. Bladder, bowel or major vessels may be easily involved but to our knowledge this is the first case in literature associated with severe bilateral hydronephrosis and total bladder dislocation. Many authors have shown how a wide tumor resection is essential in the therapy of primary bone neoplasms in order to ensure long-term survival particularly in chondrosarcoma but tumor localization and pelvic organs involving may result as a challenging surgical case (2). Anyway proper selection of patient, preoperative planning and reconstruction provides good functional outcome also in patients affected by pelvic chondrosarcoma following internal hemipelvectomy (3). In our case, due to general conditions and tumor

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Valerio Olivieri, MD valerio.olivieri@uniroma1.it Valentina Fortunati, MD valentina.fortunati@email.it Scipio Annoscia, MD sannoscia@aslto4.piemonte.it Massarelli Massimo, MD mmassarelli@gmail.com Luca Bellei, MD lbellei@aslto4.piemonte.it Massimo Ollino, MD mollino@aslto4.piemonte.it Sandro Guglielmetti, MD gugls76@yahoo.it Urology Dpt, Ivrea Hospital - ASL TO4, Piazza Credenza 2, 10015 Ivrea, Turin, Italy Emy Manzi, MD emymanzi@gmail.com Department of General Surgery, Santa Scolastica Hospital Manzi, Via San Pasquale, 03043 Cassino (FR), Italy Angela Maurizi, MD angmau81@hotmail.com Francesco De Luca, MD (Corresponding Author) francescodeluca.md@gmail.com Department of Gynaecological and Urological Sciences, Sapienza University Viale dell'UniversitĂ , 31/33, 00161 Roma, Italy

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DOI: 10.4081/aiua.2018.4.295

CASE REPORT

Isolated corpus spongiosum injury after sexual intercourse Ioannis Anastasiou, Aikaterini Anastasiou, Ioannis Katafigiotis, Dimitrios Tsavdaris, Constantinos Constantinides 1st Urology Department, Laiko Hospital, University of Athens, Athens, Greece.

Summary

Penile fractures are generally rare and underreported. The mechanism of injury is due to a rupture of the corpora cavernosa following blunt or sexual trauma to the penis when fully erect. Penile fractures usually present with a ‘popping’ sound with concomitant sudden swelling and ecchymosis of the penis followed by rapid detumescence. Urethral involvement occurs only in a small part of the cases. Isolated spongiosal injury after sexual intercourse is also extremely rare. The cardinal sign of urethral injury is blood at the meatus. A small laceration can be repaired by simple closure with absorbable sutures, while a complete rupture requires a more complex anastomotic repair. We report a case of a typically presenting penile fracture that was eventually proven to be an isolated corpus spongiosum injury, with no corpora cavernosa involvement.

KEY WORDS: Penile fracture, Urethral injury, Urological trauma, Urethroplasty. Aubmitted 6 March 2018; Accepted 7 May 2018

INTRODUCTION

Penile fractures are generally rare and underreported. The mechanism of injury is due to a rupture of the corpora cavernosa following blunt or sexual trauma to the penis when fully erect (1). Penile fractures usually present with a ‘popping’ sound with concomitant sudden swelling and ecchymosis of the penis followed by rapid detumescence. Urethral involvement happens only at a small percentage of the cases (1). Symptoms from the urinary tract include blood at the meatus and subsequently a positive urinalysis for blood and/or acute urinary retention (2). We report a case of a typically presenting penile fracture that was eventually proven to be an isolated corpus spongiosum injury, with no corpora cavernosa involvement.

CASE

Subsequently, he presented at the emergency department 6 hours after the accident. During physical examination he presented with a flaccid edematous penis with ecchymosis and blood at the meatus. There was marked tenderness on palpation of the ventral surface of the penis but no palpable abnormalities were noted (Figure 1). The patient was able to void. A complete blood count, serum electrolytes revealed no abnormalities and urine analysis revealed haematuria. Our patient was scheduled for surgery in order to repair what obviously appeared as a penile fracture using a degloving incision. During surgical exploration no recognizable trauma of the corpora cavernosa was demonstrated so we decided to create an artificial erection, which confirmed our findings. A hematoma was discovered at the abdominal surface of the shaft that was lying over a tear in the corpus spongiosum at the level of the penile urethra approximately 4cm from the glans. The urethra appeared to be torn with the Foley catheter easily shown underneath. (Figure 1). The defect was closed primarily with 3-0 absorbable sutures, with the Foley catheter in place. The urethral catheter remained for 2 weeks. The patient returned six weeks later fully recovered and able to achieve micturition with no problems whatsoever.

Figure 1. Isolated corpus spongiosum injury.

REPORT

A 47-year-old man visited the emergency department of our hospital complaining of severe pain and a swollen penis shortly after sexual intercourse the previous night. His medical and surgical history was unremarkable. He mentioned a sudden pain on his penis followed by prompt detumescence after failing to enter his partner’s vagina and hitting with his partially loose penis on her buttocks. He passed blood-stained urine mainly at the beginning of the stream, but was otherwise able to void. No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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DISCUSSION

Our patient showed typical clinical characteristics of blunt cavernosal trauma with concomitant urethral involvement. However, it was eventually discovered surgically that he suffered an isolated injury to the corpus spongiosum. In our patient, the diagnosis of penile fracture was made due to the typical clinical features he presented with. No further imaging was performed because surgical exploration was already indicated and surgical repair was probably required. The typical mechanism of injury is during sexual intercourse when the penis fails to enter the vagina and strikes against the pubic symphisis or perineum of the partner involved. At the time of injury a rupture of the cavernosal tunica albuginea occurs with subsequent subcutaneous hematoma of the shaft and involvement of the corpus spongiosum or urethra in approximately 10-22% of cases (1). Isolated spongiosal injury after sexual intercourse is extremely rare. Blood at the meatus is the cardinal sign of urethral injury and signifies the necessity for further evaluation. In the case of a complete urethral rupture acute urinary retention is the rule with evidence of a palpable distended bladder (2). Other signs and symptoms of urethral trauma include hematuria, pain while urinating, and scrotal, penile or perineal edema and ecchymosis due to urinary extravasation and bleeding which can present spontaneously or with a several hour delay (2). Penile fractures require immediate exploration because delayed treatment results in higher rates of erectile dysfunction (3). The surgical technique consists of closing the tear in the cavernosal tunica albuginea as well as the concomitant tear in the urethra (3). A small laceration can be repaired

Correspondence Ioannis Anastasiou, MD ekati2@otenet.gr Aikaterini Anastasiou, MD (Corresponding Author) aikatianast@gmail.com Ioannis Katafigiotis, MD katafigiotis.giannis@gmail.com Dimitrios Tsavdaris, MD dimtsavdaris@gmail.com Constantinos Constantinides, MD ckonstan@med.uoa.gr Laiko Hospital, Agiou Thoma 17, Athens 11527, Greece

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by simple closure with absorbable sutures, while a complete rupture requires a more complex anastomotic repair (3). If a concomitant urethral injury is suspected, the gold standard approach for diagnostic evaluation is a retrograde urethrogram (RUG). An alternative and more frequently used examination is the flexible cystoscopy under anesthesia during exploration/ repair.

CONCLUSIONS

The common presentation of sexual trauma is penile fracture. The majority of the cases have a typical etiology of a penis collision against the perineum or the symphysis pubis. The urologist that encounters a patient with a sexual trauma usually manages the sexual trauma as a common penile fracture and an isolated spongiosal injury could be easily missed. It is important for the urologist that deals with this emergency situation to be aware of the possibility of urethral injury even though the penis is integral, especially when there is blood at the meatus (cardinal sign) or inability to void.

REFERENCES

1. Nicolaisen GS, et al. Rupture of the corpus cavernosum: surgical management. J Urol. 1983; 130:917. 2. Mundy AR, et al. Urethral trauma. Part I: introduction, history, anatomy, pathology, assessment and emergency management. BJU Int. 2011; 108:310. 3. Derouiche A, et al. Management of penile fractures complicated by urethral rupture. Int J Impot Res. 2008; 20:111.

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DOI: 10.4081/aiua.2018.4.297

CASE REPORT

Undiagnosed paraganglioma; A challenge during laparoscopic retroperitoneal resection Alexander Heinze 1, 3, Periklis Nikomanis 2, Ferdinand Petzold 2, Jens Jochen Rassweiler 1, Ali Serdar Goezen 1 1 SLK

Kliniken Heilbronn, Department of Urology, University of Heidelberg, Germany; Kliniken Heilbronn, Department of Anaesthesiology, University of Heidelberg Germany; 3 School of Medicine, Universidad Nacional Autónoma de México, México City. 2 SLK

Summary

Objective: Report our experience of the management of a patient with undiagnosed retroperitoneal paraganglioma and the intraoperative complications that the theatre team faced. Case report: We present a case of a 36-year-old patient who during oncological follow-up for a previous diagnosis of parotid acinar cell carcinoma was incidentally identified as having an interaortocaval tumour. Following routine preoperative assessment the patient was arranged to undergo a laparoscopic retroperitoneal tumour resection. After minimal tumour manipulation the patient developed cardiac rhythm abnormalities and became hypertensive. The tumour was successfully removed laparoscopically after a cautious interaortocaval dissection. Abruptly, prior to extraction of the tumour containing endobag, the patient developed cardiac arrest. Following 35 minutes of life support measures there was a return of spontaneous circulation. The endobag was laparoscopically removed from the abdominal cavity 24 hours later using the initial operative port sites. The patient´s progression was satisfactory and he could be discharged six days postoperatively. Conclusions: Asymptomatic undiagnosed paragangliomas represent a real challenge during laparoscopic operations. Haemodynamic changes and life-threatening events can arise acutely intraoperatively, where an immediate and coordinated response of the whole theatre team may be required to avoid fatal outcomes.

KEY WORDS: Paraganglioma; Laparoscopic approach; Intraoperative complications. Aubmitted 25 March 2018; Accepted 7 May 2018

INTRODUCTION

Paragangliomas are defined as neuroendocrine tumors (NET) which may or may not produce catecholamines. These tumors emerged out of chromaffin cells from the neural crest. These type of tumors are distributed along the sympathetic and parasympathetic chains. The most common location is retroperitoneal accounting for up to 77% often pictured as a mass around the corpora paraaortica (1). Surgical resection represents the only available curative treatment for these tumors. The laparoscopic approach has proved to be a safe and effective technique for retroperitoneal tumor resection in experienced hands (2, 3). But serious challenges and complications can arise during these operations both for

urology and anesthesia teams when the correct diagnosis is not suspected preoperatively.

CLINICAL

CASE

We present the case of a 36-year-old man who attended our urological service. The patient received a diagnosis of parotid acinar cell carcinoma nine months prior, and during oncological follow-up was incidentally identified through the use of computed tomography (CT) imaging which revealed a 4.8 cm lesion with heterogeneous softtissue density in an interaortocaval localization without any sign of vascular infiltration, hence his referral to our urology service. The patient was asymptomatic with a background history of hypothyroidism, gastrooesophageal reflux disease, parotidectomy and neck dissection. Physical examination and vital sign parameters were unremarkable and routine laboratory blood tests were within normal ranges. The patient was arranged to undergo laparoscopic retroperitoneal tumor resection following preoperative assessment. After positioning the patient in supine position, we favored a transperitoneal 4-trocars approach, and establishment of a pneumoperitoneum up to 14 mm/hg of pressure. The access to the retroperitoneum was achieved by incision the white line of Toldt and by displacing medially the ascendant colon. The interaortocaval localized tumor was then visualized and a careful dissection of the surrounding big vessels and tissue was undertaken. The dissection was carried out with a minimal blood loss. After a minimal tumor manipulation the patient developed cardiac rhythm abnormalities – possibly atrioventricular block – and rapidly became hypertensive with a systolic blood pressure of 250 mmHg and a tachycardia of 160 bpm. The patient was initially administered β-blockers and an attempt to deepen the anesthesia using opiates was undertaken, unfortunately with poor response. The patient subsequently developed respiratory failure with hypoxia and clinically was found to have pulmonary edema. Meanwhile surgery was accomplished successfully and the resected specimen was placed into an endobag. Abruptly prior to extraction of the endobag through the paraumblical optic trocar incision the patient developed cardiac arrest, indicating pulseless

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2018; 90, 4

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electrical activity on electrocardiography. Therefore, resuscitation maneuvers’ were employed immediately following standardized life support protocols. The port incisions were closed rapidly while operating team begun manual chest compressions – initially by hand and subsequently aided with the mechanical chest compression device ‘“LUCAS’™ (physio Control Inc. Redmond WA)”. Following 35 minutes of resuscitation measures there was a return of spontaneous circulation (ROSC) with sinus rhythm, and the patient was transferred to the Operative Intensive Care Unit (OPI) where respiratory and cardiovascular support was offered through ventilation and catecholamine perfusions. Cardiac rhythm and function was assessed with electrocardiography and echocardiography, which initially showed findings consistent with post-resuscitation reduced left ventricular function. Follow-up echocardiography indicated a possible early stage hypertensive cardiomyopathy. Coronary angiography excluded any coronary artery disease. Chest CT of the patient’s identified mild pulmonary edema and postresuscitation atelectasis. A control CT of the patient’s abdomen showed the endobag containing the resected tumor and no other acute pathology. Further laparoscopic intervention using the same port places was carried out 24 hours after the initial surgery in order to remove of the endobag with resected tumor. The endobag has been visualized easily in the abdominal cavity and could be removed after minimal manipulation safely through the paraumblical optic trocar incision, Tumor pathology and histology results reported a 4.5 cm x 4.5 cm x 2 cm tissue of yellow brownish color surrounded by a thin capsule. Inmunohistology was performed being positive for chromogranin A and synaptophysin and negative for pancytoqueratine, protein S-100 and melanina A. This findings were compatible with characteristics of paraganglioma tumors.

Correspondence Alexander Heinze, MD Periklis Nikomanis, MD Ferdinand Petzold, MD Jens Jochen Rassweiler, MD Ali Serdar Goezen, MD FEBU (Corresponding Author) ali.goezen@slk-kliniken.de SLK-Kliniken Heilbronn, Department of Urology Am Gesundbrunnen 20-26, D-74078 Heilbronn, Germany

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The patient remained on the OPI for a further 72 hours. During this period, the patient showed clinical stabilization and improvement with no lasting neurological or end-organ damage evident. Therefore, the patient was transferred to the urological ward from which he was formally discharged six days post-operatively. Further followup will be carried out by urology department and further genetic analysis will be performed by genetic department.

CONCLUSIONS Asymptomatic undiagnosed paragangliomas represents a real perioperative challenge. Ideally, patients with suspected diagnoses of paraganglioma or pheochromocytoma should receive adequate preoperative management for optimal surgical conditions. Laparoscopic approach should be considered in experienced hands due to its well known advantages. Nevertheless risk of acute hemodynamic changes and life-threatening events can arise in these subgroups of patients; for this reason the entire operating team should be prepared in order to avoid fatal outcomes.

REFERENCES

1. Purnell S, Sidana A, Maruf M, et al. Genitourinary paraganglioma: Demographic, pathologic, and clinical characteristics in the surveillance, epidemiology, and end results database (2000-2012). Urol Oncol. 2017; 35:457.e9-457.e14. 2. Abe T, Sazawa A, Harabayashi T, et al. Laparoscopic resection of paraaortic/paracaval neurogenic tumors: surgical outcomes and technical tips. Surg Endosc. 2016; 30:4640-4645. 3. Ping W, Hong Zhou M, Jie Q, et al. Laparoscopic Resection of Retroperitoneal Paragangliomas: A Comparison with Conventional Open Surgical Procedures. J Endourol. 2016; 30:69-74.

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INSTRUCTIONS OPEN ACCESS

Open access publishing does have its costs. Information regarding authors’ payment are not made available to editors and reviewers ensuring that they cannot be influenced in their selection of papers for publication by payment conditions or limitations. The Article Processing Charge for publication in this journal is EUR 200,00 (plus VAT, if applicable). Our fees cover the costs of peer review, copyediting, publication, different format of publication (HTML, PDF), inclusion in many Open Access databases. All bank charges shall be borne by the payer. Please note that our fees do not include taxes (VAT): - Private or public ITALIAN customers (individuals, universities, hospitals, other organizations) must ALWAYS add VAT (IVA) at standard rate (4%); - European Union PRIVATE customers must add the standard rate of their own country VAT tax; - European Union private/public ORGANIZATIONS (universities, hospitals, others with regular VAT number) should not add any taxes at standard rate, provided that they indicate their VAT number; - Outside the European Union, individuals and organizations should not add any taxes at standard rate. Important: Authors are NOT required to pay at the moment of submission. If the paper is accepted, the Managing Editor of Open Access Edition will guide the Authors through the payment procedure. No article will be published before waiver or payment. According to the United Nations list of Least Developed Countries (LCDs) available from: http://www.un.org/en/development/desa/policy/cdp/ldc2/ldc_countries.shtml Authors coming from those countries are entitled to ask for a discount. A “Formal Request for discount” has to be forwarded to the Managing Editor of Open Access Edition, after receiving the acceptance letter. The Editorial Committee will then evaluate the merits of each individual case. Any other informal request (such as comments at the moment of submission, or made in the covering letter of the revised version) will not be taken into consideration.

FAST-TRACK PEER REVIEW

We offer fast-track peer review and publication of controlled trials that we judge of importance to practice or research. If you wish to discuss your proposed submission, please write (scriman@tin.it) or call our editorial office in Milan (+39 02 70608060). With the payment of a supplementary fee of 488 Euros (VAT included), the review, editorial decision, and author notification on this manuscript is guaranteed to take place within 4 weeks.

TRANSLATION

Manuscripts in Italian language can be published after translation (a supplementary fee for printed page will be charged to the Authors).

METHODS OF PAYMENT Authors can pay their fees by: PayPal PayPal is the most recommended and secure payment system. It enables you to pay getting your payment receipt immediately and without sharing your financial information. Other methods of payment are: Bank transfer BANK NAME: Banca Popolare di Sondrio, Branch #1, Strada Nuova 75, I-27100 Pavia, Italy ACCOUNT HOLDER: PAGEPress Srl BIC/SWIFT: POSOIT22 IBAN: IT85Y0569611301000005086X83 Credit Card The credit card form to be filled and returned either via e-mail or via fax is available for download here. http://www.pagepress.org/journals/public/credit_card.pdf Check sent by surface mail Checks must be made payable to PAGEPress Srl and must be sent to our full postal address: PAGEPress Publications, via A. Cavagna Sangiuliani 5, 27100 Pavia, Italy. Note: In any method of payment you choose, kindly specify: 1. journal name; 2. paper ID number; 3. first author. Important: All papers published in Archivio Italiano di Urologia e Andrologia (AIUA) are peer reviewed. At present, Edizioni Scripta Manent Edizioni let everyone to read and download papers from its website. However, Edizioni Scripta Manent will retain copyright and will be granted publishing and distribution rights.

AUTHORS’ RESPONSIBILITIES

Manuscripts are accepted with the understanding that they have not been published or submitted for publication in any other journal. Authors must submit the results of clinical and experimental studies conducted according to the Helsinki Declaration on clinical research and to the Ethical Code on animal research set forth by WHO (WHO Chronicle 1985; 39:51). The Authors must obtain permission to reproduce figures, tables and text from previously published material. Written permission must be obtained from the original copyright holder (generally the Publisher).

MANUSCRIPT PRESENTATION

Authors must submit their manuscripts (MAC and WINDOWS Microsoft Word are accepted) after registration and login to the link: http://www.aiua.it. Surface or e-mail submission are not accepted. Manuscripts must be written in English language in accordance with the “Uniform Requirements for Manuscripts submitted to biomedical journals” defined by The International Committee of Medical Journal Editors (http://www.ICMJE.org). Manuscripts in Italian language can be published after translation (expenses will be charged to the Authors). Manuscripts should be typed double spaced with wide margins. They must be subdivided into the following sections:

AUTHORS TITLE PAGE

It must contain: a) title; b) a short (no more than 40 characters) running head title; c) first, middle and last name of each Author without abbreviations; d) University or Hospital, and Department of each Author; e) last name, address and e-mail of all the Authors; f) corresponding Author; g) phone and/or fax number to facilitate communication; h) acknowledgement of financial support; i) list of abbreviations.

SUMMARY

The Authors must submit a long English summary (300 words, 2000 characters). Subheadings are needed as follows: Objective(s), Material and method(s), Result(s), Conclusion(s). After the summary, three to ten key words must appear, taken from the standard Index Medicus terminology.

TEXT

For original articles concerning experimental or clinical studies, the following standard scheme must be followed: Summary - Key Words - Introduction - Material and Methods - Results - Discussion - Conclusions - References - Tables - Legends - Figures. Case Report should be divided into: Summary - Introduction (optional) - Case report(s) - Conclusions - References (Discussion and Supplementary Figures, Tables and References can be submitted for publication in Supplementary Materials).

SIZE OF MANUSCRIPTS

Literature reviews, Editorials and Original articles concerning experimental or clinical studies should not exceed 3500 words with 3-5 figures or tables, and no more than 30 references. Case reports, Notes on surgical technique, and Letters to the editors should not exceed 1000 words (summary included) with only one table or figure, and no more than three references. No more than five authors are permitted. As an accompaniment to Case reports manuscripts for the print version of Archivio Italiano di Urologia e Andrologia (AIUA), authors may submit supplementary materials for posting on www.aiua.it. The material is subject to the same editorial standards and peer-review procedures as the print publication.

REFERENCES

References must be sorted in order of quotation and numbered with arabic digits between parentheses. Only the references quoted in the text can be listed. Journal titles must be abbreviated as in the Index Medicus. Only studies published on easily retrieved sources can be quoted. Unpublished studies cannot be quoted, however articles “in press” can be listed with the proper indication of the journal title, year and possibly volume. References must be listed as follows:

JOURNAL ARTICLES

All Authors if there are six or fewer, otherwise the first three, followed by “et al.”. Complete names for Work Groups or Committees. Complete title in the original language. Title of the journal following Index Medicus rules. Year of publication; Volume number: First page. Example: Starzl T, Iwatsuki S, Shaw BW, et al. Left hepatic trisegmentectomy Surg Gynecol Obstet. 1982; 155:21.

BOOKS

Authors - Complete title in the original language. Edition number (if later than the first). City of publication: Publisher, Year of publication. Example: Bergel DIA. Cardiovascular dynamics. 2nd ed. London: Academic Press Inc., 1974.

BOOK CHAPTERS

Authors of the chapters - Complete chapter title. In: Book Editor, complete Book Title, Edition number. City of publication: Publisher, Publication year: first page of chapter in the book. Example: Sagawa K. The use of central theory and system analysis. In: Bergel DH (Ed), Cardiovascular dynamics. 2nd ed. London: Academic Press Inc., 1964; 115.

TABLES

Tables must be aimed to make comprehension of the written text easier. They must be numbered in Arabic digits and referred to in the text by progressive numbers. Every table must be accompanied by a brief title. The meaning of any abbreviations must be explained at the bottom of the table itself. (If sent by surface mail tables must be clearly printed with every table typed on a separate sheet).

FIGURES

(Graphics, algorithms, photographs, drawings). Figures must be numbered and quoted in the text by number. The meaning of all symbols, abbreviations or letters must be indicated. Histology photograph legends must include the enlargement ratio and the staining method. Legends must be collected in one or more separate pages. Please follow these instructions when preparing files: • Do not include any illustrations as part of your text file. • Do not prepare any figures in Word as they are not workable. • Line illustrations must be submitted at 600 DPI. • Halftones and color photos should be submitted at a minimum of 300 DPI. • Power Point files cannot be uploaded. • If at all possible please avoid transmitting electronic files in JPEG format. If this is unavoidable please be sure to save the JPEG at the highest quality available and at the correct resolution for the type of artwork it is. • PDF files for individual figures may be uploaded.

MANUSCRIPT REVIEW Only manuscript written according to the above mentioned

rules will be considered. All submitted manuscripts are evaluated by the Editorial Board and/or by two referees designated by the Editors. The Authors are informed in a time as short as possible on whether the paper has been accepted, rejected or if a revision is deemed necessary. The Editors reserve the right to make editorial and literary corrections with the goal of making the article clearer or more concise, without altering its contents. Submission of a manuscript implies acceptation of all above rules.

PROOFS Authors are responsible for ensuring that all manuscripts are accurately typed before final submission. Galley proofs will be sent to the first Author. Proofs should be returned within seven days from receipt.

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GENERAL INFORMATION

BUSINESS INFORMATION

AIMS

SUBSCRIPTION

AND

SCOPE

â&#x20AC;&#x153;Archivio Italiano di Urologia e Andrologiaâ&#x20AC;? publishes

DETAILS

Annual subscription rate (4 issues) is Euro 52 for Italy and US $130 for all other Countries. Price for single issue: Euro 13 for Italy US $32,5 for all other Countries. Issues will be sent by surface mail; single issues can also be sent by air mail at an extra charge of US $12.

papers dealing with the urological, nephrological and andrological sciences. Original articles on both clinical and research fields, reviews, editorials, case reports, abstracts from papers published elsewhere, book rewiews, congress proceedings can be published. Papers submitted for publication and all other editorial correspondence should be addressed to:

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Via Melchiorre Gioia 41/A - 20124 Milano, Italy Tel. +39 0270608060 e-mail: scriman@tin.it

COPYRIGHT Papers are accepted for publication with the understanding that no substantial part has been, or will be published elsewhere. By submitting a manuscript, the authors agree that the copyright is transferred to the publisher if and when the article is accepted for publication. The copyright covers the exclusive rights to reproduce and distribute the article, including reprints, photographic reproduction and translation. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior written permission of the Publisher.

Claim for missing issues should be made within 3 months from publication for domestic addresses, otherwise they cannot be honoured free of charge. Changes of address should be notified Edizioni Scripta Manent s.n.c. at least 6-8 weeks in advance, including both old and new addresses. The handling of personal data concerning subscribers is managed by our electronic data base. It is in accordance with the law 675/96 regarding the tutorship of personal data. The use of data, for which we guarantee full confidentiality, is to keep our readers up to date with new initiatives, offers and publications concerning Edizioni Scripta Manent s.n.c. Data will not be released or disseminated to others and the subscriber will be able to request, at any time, variation or cancellation of data.

ADVERTISING

For details on media opportunities within this journal please contact Mrs. Donatella Tedeschi, MD at +39 0270608060

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ll ruolo della SIEUN La SIEUN (Società Italiana di Diagnostica Integrata in Urologia, Andrologia, Nefrologia) riunisce diversi medici specialisti e non che si occupano di tutte quelle metodiche in cui gli ultrasuoni vengono utilizzati a scopo diagnostico ed interventistico in ambito uro-nefro-andrologico. La SIEUN organizza un Congresso Nazionale con cadenza biennale e diverse altre iniziative in genere con cadenza annuale (corsi monotematici, sessioni scientifiche in occasione dei congressi nazionali delle più importanti società scientifiche in ambito Uro-Nefro-Andrologico). Dal 2001 la SIEUN è affiliata all’ESUI (European Society of Urological Imaging); pertanto tutti i soci possono partecipare alla iniziative della Società Europea. L’Archivio Italiano di Urologia e Andrologia è l’organo ufficiale della SIEUN. Questa pagina permette una informazione puntuale sulla attività della nostra Società e consente al Consiglio Direttivo della SIEUN di comunicare non solo ai soci, ma ad una platea più ampia, ogni nuova iniziativa.

Società Italiana di Diagnostica Integrata in Urologia, Andrologia, Nefrologia

I PROSSIMI APPUNTAMENTI SIEUN La SIEUN nel 2019 sarà presente con relazioni, moderazioni e letture nei congressi delle più prestigiose Società scientifiche di Urologia, Andrologia ed Ecografia. Per informazioni ed iscrizioni: www.sieun.eu

NUOVO SITO WEB La SIEUN, con il suo nuovo sito www.sieun.eu, volge lo sguardo all’Europa.

QUOTE ASSOCIATIVE 2019 Socio ordinario - Euro 100,00 Socio Junior - Euro 50,00 Per la modalità di pagamento della quota sociale collegarsi al sito della Società www.sieun.eu. La segreteria della Società

I PUNTI SIEUN

(una possibilità di incontro tra Soci SIEUN e di contatto con altri specialisti) Presso i punti SIEUN i nostri soci potranno essere continuamente informati su tutte le attività e le iniziative della Società e rinnovare il pagamento della quota associativa.

ELLERRE

CENTRE

è a disposizione per ulteriori informazioni.

Via Orfeo Mazzitelli 47/G - 70124 BARI Tel. 080.5045353 - Fax 080.5045362 E-mail: ellerre@ellerrecentre.com www.ellerrecentre.com

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CONGRESSO NAZIONALE 6 6-8 -8 GIUGNO 2019

Grand Hotel La Chiusa di Chietri Alberobello (BA) Presidente del Congresso: Giuseppe Mario Ludovico Presidente UrOP:Angelo Porreca

Giovedì, 6 Giugno 2019 Apertura del Congresso TUMORE DELLA PROSTATA Best papers 2018/2019 sul tumore della prostata Risonanza magnetica e target biopsy: nuovo gold standard? Prostatectomia radicale nel 2019 Terapia del primitivo nel paziente oligometastatico La terapia di prima linea nel tumore prostatico metastatico TUMORE DELLA VESCICA NON MUSCOLO INVASIVO Best papers 2018 Instillazione endovescicali: c’è qualcosa di nuovo? Moderne tecniche di resezione endoscopica e di view enhancement TUMORE DEL RENE Best papers 2018 Nefrectomia parziale oggi Nefrectomia citoriduttiva: quando e perché? Il moderno trattamento dell’UTUC TUMORE DELL’APPARATO RIPRODUTTIVO MASCHILE Best papers del tumore del testicolo 2018 Best papers del tumore del pene 2018 TEAM MULTIDISCIPLINARE TMD Inaugurazione del Congresso

Venerdì, 7 Giugno 2019

CISTECTOMIA Best paper cistectomia robotica: lo studio RAZOR La cistectomia in Italia oggi: registro italiano delle cistectomie La cistectomia open rimane il gold standard La cistectomia robotica nuovo gold standard Discussione sui temi trattati Dibattito su: La gestione delle complicanze MEDICINA LEGALE Legge Gelli LIVE SURGERY

Sabato, 8 Giugno 2019 PRESENTAZIONE E PREMIAZIONE 3 ABSTRACTS E 3 VIDEO CALCOLOSI APPARATO URINARIO Best papers 2018 Calcolosi urinaria: opzioni terapeutiche a confronto - Perché ESWL ? - Perché chirurgia endourologica? - Discussione sui temi trattati New trends in PCNL Prevenzione e terapia medica della calcolosi: cosa c’è di nuovo? ANDROLOGIA Best papers 2018 mortality: any link? Riabilitazione andrologica post chirurgia radicale pelvica: cosa c’è di nuovo? Gestione pratica della terapia medica dell’IPP

IPERTROFIA PROSTATICA Best papers 2018 - I nuovi parametri diagnostici e funzionali dell’ostruzione cervico uretrale - Terapia medica dei LUTS: oltre gli alfalitici - Il futuro della terapia mininvasiva dell’ostruzione prostatica - Disfunzioni sessuali post trattamento dell’IPB

Società Italiana

CHI PUÒ F FARNE ARNE PARTE PARTE Ordinario

gli

Specialisti

Urologia

oper operanti anti

strutture

di Socio Sost Sostenitore, enitore, gli Urologi non ffacenti acenti parte parte dell'ospedalità a gestione priv privata ata e gli specializz specializzandi. andi. QUOTA SO QUOTA SOCIALE CIALE La quota sociale, per il Socio Ordinario, per l'anno 2019 è stabilita in € 100,00 e dà diritto diritto alla ric ricezione ezione della rivista "Archivio Italiano di Il Socio sostenitore sostenitore paga il 50% della quota Sociale pari a € 50,00.

ISCRIZIONE Iscriversi Iscriv ersi è semplic semplice, e, basta c compilare ompilare il fform orm al sit sito o www www.urop.it .urop.it INFORMAZIONI Per richiedere inf informazioni nfforma ormazioni contattare contattare la segret segreteria eria dell'Associazione. dell'Associazione. SEGRETERIA UROP Elena Rapisarda Tel. T el. 380 3626311 segreteria@urop.it segret eria@urop.it

SEGRETERIA ORGANIZZATIVA ORGANIZZA ATIV TIIV VA DEL C ONGRESSO CONGRESSO

Mec C Congress ongress s.r.l. Tel. T el. 371 3376532 Fax 0294755038 www.meccongress.it www .meccongress.it

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CONGRESSO NAZIONALE 6 6-8 -8 GIUGNO 2019

Grand Hotel La Chiusa di Chietri Alberobello (BA) Presidente del Congresso: Giuseppe Mario Ludovico Presidente UrOP:Angelo Porreca

Venerdì, 7 Giugno 2019

Società Italiana

CHI PUÒ F FARNE ARNE PARTE PARTE Ordinario

gli

Specialisti

Urologia

oper operanti anti

strutture

SEGRETERIA ORGANIZZATIVA ORGANIZZA ATIV TIIV VA DEL C ONGRESSO CONGRESSO

Mec C Congress ongress s.r.l. Tel. T el. 371 3376532 Fax 0294755038 www.meccongress.it www .meccongress.it