Archivio Italiano di Urologia e Andrologia Vol. 90; n. 1, March 2018 by Edizioni Scripta Manent

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s w ces i t o N Ac u a. i en w.a p O ww

ISSN 1124-3562

Vol. 90; n. 1, March 2018

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. 1 March 2018

ORIGINAL PAPERS 1

The impact of a structured intensive modular training in the learning curve of robot assisted radical prostatectomy Riccardo Schiavina, Marco Borghesi, Hussam Dababneh, Martina Sofia Rossi, Cristian Vincenzo Pultrone, Valerio Vagnoni, Francesco Chessa, Lorenzo Bianchi, Angelo Porreca, Alexandre Mottrie, Eugenio Brunocilla

Pathology outcomes in patients with transurethral bladder tumour resection in a Turkish population: A retrospective analysis Salih Budak, Cem Yücel, Mehmet Zeynel Keskin, Mehmet Yoldas, Erdem Kısa, Ertan Can, Ulku Kucuk, Zafer Kozacıoğlu

Intravesical administration of combined hyaluronic acid and chondroitin sulfate can improve symptoms in patients with refractory bacillus Calmette-Guerin-induced chemical cystitis: Preliminary experience with one-year follow-up Vittorio Imperatore, Massimiliano Creta, Sergio Di Meo, Roberto Buonopane, Nicola Longo, Ferdinando Fusco, Lorenzo Spirito, Ciro Imbimbo, Vincenzo Mirone

The impact of ureteral Double-J stent insertion following ureterorenoscopy in patients with ureteral stones accompanied by perirenal fat stranding Ercan Ogreden, Ural Oğuz, Erhan Demirelli, Erdal Benli, Özkan Özen

Semirigid ureteroscopy prior retrograde intrarenal surgery (RIRS) helps to select the right ureteral access sheath Ioannis Boulalas, Mauro De Dominicis, Lorenzo Defidio

Comparison of three most frequently used alpha blocker agents in medical expulsive therapy for distal ureteral calculi, result of a retrospective observational study Aykut Buğra Sentürk, Cemil Aydin, Musa Ekici, Muhammet Yaytokgil, Ali Akkoc, Mehmet Murat Baykam

A new technique of ultrasound guided percutaneous renal biopsy by perforated probe and perpendicular needle trajectory Simone Brardi, Gabriele Cevenini, Angelo Giovanni Bonadio

Injection therapy for chronic prostatitis: A retrospective analysis of 77 cases Attila Toth, Frederico Maria Guercini, Dawn Marta Feldthouse, Jun Chao Zhang

The impact of prostate artery embolization (PAE) on the the physical history and pathophysiology of benign prostatic hyperplasia (BPH) Konstantinos Stamatiou

Erectile dysfunction in patients taking psychotropic drugs and treated with phosphodiesterase-5 inhibitors Rossella Mazzilli, Gloria Angeletti, Soraya Olana, Michele Delfino, Virginia Zamponi, Chiara Rapinesi, Antonio Del Casale, Georgios D. Kotzalidis, Jlenia Elia, Gemma Callovini, Paolo Girardi, Fernando Mazzilli continued on page III

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School 2018

Società Italiana

Chi intende iscriversi alla SIUrO trova le istruzioni sul sito internet www.siuro.it. È possibile pagare direttamente online. Quota Associativa SIUrO per il 2018: la quota associativa è pari a 100 € per i medici over 40 anni e 40 € per i medici under 40 anni. Nel corso del XXVIII Congresso Nazionale SIUrO si terranno le elezioni per il rinnovo delle cariche sociali. Potranno votare solo i soci in regola con la quota associativa 2019. Per ulteriori informazioni sul regolamento elettorale visita il sito www.siuro.it o contatta la segreteria. Via Dante 17 - 40126 Bologna Tel/Fax +39 051 349224 - Cell +39 345 4669048 E-mail: segreteria@siuro.it - www.siuro.it

Ed _Cop+Ed+fisse 2006 27/03/18 09:13 Pagina I

Official Journal of SIA, SIEUN, SIUrO and UrOP EDITORS

M. Maffezzini (Genova), G. Perletti (Busto A.), A. Trinchieri (Lecco)

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)

SIA EDITOR

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SIA ASSOCIATE-EDITORS

T. Cai (Trento), V. Favilla (Misterbianco - CT), P. Verze (Napoli)

SIA EDITORIAL BOARD

P. Capogrosso (Milano), M. Colucci (Bari), E. Conti (La Spezia), M. Paradiso (Asti), G. Paulis (Albano Laziale), N. Pavan (Trieste), M. Polito (Ancona), V. Randone (Catania), G. Romano (Arezzo), G. Sidoti (Catania), A. Vavallo (Altamura)

SIEUN EDITOR

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SIEUN CO-EDITOR P. Martino (Bari)

SIEUN EDITORIAL BOARD

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

R. Valdagni (Milano)

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), G. Sica (Roma), V. Vavassori (Bergamo)

UrOP EDITOR

C. Boccafoschi (Alessandria)

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)

Ed _Cop+Ed+fisse 2006 27/03/18 09:13 Pagina II

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.

I PROSSIMI APPUNTAMENTI SIEUN La SIEUN nel 2018 sarà presente con relazioni, moderazioni e letture nei congressi delle più prestigiose Società scientifiche di Urologia, Andrologia ed Ecografia.

21° Congresso SIEUN 2018 Il 21° Congresso SIEUN si terrà a Trieste. Maggiori informazioni verranno inserite periodicamente sul sito SIEUN (www.sieun.eu). I Presidenti del Congresso saranno Stefano Bucci, Michele Bertolotto, Giuliano Boscutti. Per informazioni e iscrizioni contattare la Segreteria Organizzativa: The Office Referente: Paola - Tel.: 040.368343 int. 32 E-mail: sieun2018@theoffice.it

Società Italiana di Diagnostica Integrata in Urologia, Andrologia, Nefrologia

Topics

•Ecografia Andrologica •Ecografia Diagnostica Urologica •Ecografia Interventistica mininvasiva •Ecografia nefrologica Magnetica (RM) Prostatica e Biopsia •Risonanza imaging guidata •HIFU •Biopsia Prostatica Transperineale/Transrettale •Crioablazione •Nefrolitiasi •Cancro della Prostata •Urological Imaging •Ipertrofia Prostatica Benigna •CEUS •Embolizzazione Prostatica Per la prima volta il Congresso SIEUN sarà diretto da 3 Presidenti (un urologo, un radiologo, un nefrologo), le tre anime della Società, nell’ambito della massima integrazione e collaborazione che la Società esprime. Il Congresso si articolerà in tre giornate. Nella prima giornata si svolgeranno 4 corsi pre-congressuali di cui 3 Hands on dove verranno affrontate tutte le applicazioni che l’ecografia offre a supporto della pratica clinica quotidiana e dove sarà possibile partecipare ad una sezione pratica di ecografia interventistica. La seconda giornata si aprirà con una sessione live dalla sala operatoria robotica e dalle stazioni di radiologia interventistica per poi proseguire con tavole rotonde, letture e comunicazioni. Il terzo giorno si svolgerà una sessione internazionale (SIEUN-ESUI-ESUR) dove sarà possibile confrontarsi con i maggiori esperti europei su argomenti che attualmente rivestono importante interesse clinico: fusion biopsy, focal therapy, cryoablation.

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

QUOTE ASSOCIATIVE 2018 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.

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.

La segreteria della Società

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CENTRE

è a disposizione per ulteriori informazioni.

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ORIGINAL PAPERS 49

Seminal transferrin in the seminal quality evaluation of hemodialytic patients Gilmar Pereira Silva, Fabiana Pirani Carneiro,Vitor Pereira Xavier Grangeiro

How do vegetable oils (hazelnut and canola) affect the reproductive system in male rats? Bülent Kati, Fatih Oguz, Ismet Yilmaz, Ender Akdemir, Ramazan Altintas, Nusret Akpolat, Mehmet Cagatay Taskapan

The role of diallyl thiosulfinate associated with nuciferine and diosgenin in the treatment of premature ejaculation: A pilot study Tommaso Cai, Andrea Cocci, Giamartino Cito, Bruno Giammusso, Alessandro Zucchi, Francesco Chiancone, Maurizio Carrino, Francesco Mastroeni, Francesco Comerci, Giorgio Franco, Alessandro Palmieri

CASE REPORTS 65

Robotic perineal radical prostatectomy with high prostate volume

Bilateral synchronous testicular seminoma: A rare presentation of a rare disease

Volkan Tugcu, Abdulmuttalip Simsek, I·smail Yigitbasi, Mustafa Gürkan Yenice, Selcuk Sahin, Ali I·shsan Tasci Pedro Simões de Oliveira, Tiago Ribeiro de Oliveira, Sérgio Pereira, David Martinho, Tomé Lopes

Conservative management of a bladder leiomyosarcoma in a 43-year-old patient Aikaterini Anastasiou, Ioannis Katafigiotis, Spyridon Skoufias, Ioannis Anastasiou, Constantinos Constantinides

Metastasis of the epididymis and spermatic cord from pancreatic adenocarcinoma: A rare entity. Description of a case and revision of literature Carmelo Agostino Di Franco, Bruno Rovereto, Daniele Porru, Valeria Zoccarato, Cesare Regina, Tiziano Cebrelli, Nicolò Fiorello, Alessandra Viglio, Lavinia Galvagno, Carlo Marchetti, Andrea Ringressi, Davide Barletta, Giovanni Giliberto

Pulmonary recurrence from prostate cancer and biochemical remission after metastasis directed therapy. A case report Riccardo Boschian, Michele Rizzo, Lorenzo Zandonà, Carlo Trombetta, Giovanni Liguori

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Archivio Italiano di Urologia e Andrologia 2018, 90, 1

III

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Chessa_Stesura Seveso 27/03/18 09:15 Pagina 1

DOI: 10.4081/aiua.2018.1.1

ORIGINAL PAPER

The impact of a structured intensive modular training in the learning curve of robot assisted radical prostatectomy Riccardo Schiavina 1, 2, Marco Borghesi 1, 2, Hussam Dababneh 1, Martina Sofia Rossi 1, Cristian Vincenzo Pultrone 1, 2, Valerio Vagnoni 1, Francesco Chessa 1, Lorenzo Bianchi 1, Angelo Porreca 3, Alexandre Mottrie 4, Eugenio Brunocilla 1, 2 1 University

of Bologna, S. Orsola-Malpighi Hospital, Dept. of Urology, Bologna, Italy; of Experimental, Diagnostic and Specialty Medicine (DIMES), Cardio-Nephro-Thoracic Sciences Doctorate, University of Bologna, Bologna, Italy; 3 Policlinico Di Abano, Dept. of Urology, Abano Terme, Italy; 4 OLV Robotic Surgery Institute, Aalst, Belgium. 2 Department

Summary

Aim: The success of Robot Assisted Laparoscopic Prostatectomy (RALP) is mainly due to his relatively short learning curve. Twenty cases are needed to reach a “4 hours-proficiency”. However, to achieve optimal functional outcomes such as urinary continence and potency recovery may require more experience. We aim to report the perioperative and early functional outcomes of patients undergoing RALP, after a structured modular training program. Methods: A surgeon with no previous laparoscopic or robotic experience attained a 3 month modular training including: a) e-learning; b) assistance and training to the operating table; c) dry console training; d) step by step in vivo modular training performing 40 surgical steps in increasing difficulty, under the supervision of an experienced mentor. Demographics, intraoperative and postoperative functional outcomes were recorded after his first 120 procedures, considering four groups of 30 cases. Results: All procedures were completed successfully without conversion to open approach. Overall 19 (15%) post operative complications were observed and 84% were graded as minor (Clavien I-II). Overall operative time and console time gradually decreased during the learning curve, with statistical significance in favour of Group 4. The overall continence rate at 1 and 3 months was 74% and 87% respectively with a significant improvement in continence rate throughout the four groups (p = 0.04). Considering those patients submitted to nerve-sparing procedure we found a significant increase in potency recovery over the four groups (p = 0.04) with the higher potency recovery rate up to 80% in the last 30 cases. Conclusions: Optimal perioperative and functional outcomes have been attained since early phase of the learning curve after an intensive structured modular training and less than 100 consecutive procedures seem needed in order to achieve optimal urinary continence and erectile function recovery.

KEY WORDS: Training; Robot assisted radical prostatectomy. Submitted 18 September 2017; Accepted 23 September 2017

INTRODUCTION

Prostate cancer is the second most common cancer among men, and represents the fifth cause of cancer

death in men worldwide (1). Radical prostatectomy (RP) represents the standard surgical treatment for clinically localized prostate cancer (2). Traditionally this procedure was performed with a retropubic open approach retropubic radical prostatectomy (RRP) (3), with the cost of long hospitalization, the need of additional pain medication and significant blood loss. With the aim to reduce morbidity, hospitalization and to improve functional outcomes, minimally invasive approaches including laparoscopic radical prostatectomy (LRP) and robot assisted laparoscopic prostatectomy (RALP) have been increasingly adopted as alternative to open surgery. In the last two decades RALP has gained more popularity and now is a mainstay of treatment for prostate cancer, with functional and oncological outcomes comparable or even better than RRP and LRP (4-6). One of the main reason for the great diffusion of RALP is the short learning curve: contrarily to LRP, where the learning curve is very steep, those surgeons approaching to RALP were able to perform minimally invasive prostatectomy with optimal results even in the early phase of their learning curve, even with limited laparoscopic skills (7). Several studies estimated that few cases (25-40) are needed to shorten operative time, reduce the intraoperative blood loss and complications, thus rapidly achieving proficiency in RALP (8, 9). However, to reach adequate functional outcomes and optimal oncological results in terms of negative surgical margins, more and more cases are needed and the learning curve is more steep for these outcomes (10). As previous described by other authors (11,12), RALP can count two different pattern of learning curves. The “basic learning curve” is centered on operative outcomes, in which 25-50 cases are needed to reach an operative time plateau of 200-240 minutes with low complication rate, even in more challenging patients (11). The “advanced learning curve” is centered on patients outcomes, in which 100, 200 and 300 cases are needed to achieve satisfactory outcomes for the surgeon in terms of continence, potency recovery and positive surgical margins rates, respectively (11).

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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R. Schiavina, M. Borghesi, H. Dababneh, M.S. Rossi, C.V. Pultrone Cristian, V. Vagnoni, F. Chessa, L. Bianchi, A. Porreca, A. Mottrie, E. Brunocilla

Several parameters can influence the learning curve, such as the type of training program attended, the surgeon-related skills and personal experience in other procedures. A multitude of training programs exists in robotic surgery. Recently, some structured modular training programs were developed with the aim to simplify the learning curve in robotic surgery (13, 14): these trainings allowed surgeons with no robotic experience to perform RARP independently, safely, and effectively with subsequent improvement over time but the “advanced” end-points were not evaluable (15). The aim of the present study is to report the early perioperative and functional outcomes after the first 120 cases with a structured intensive modular training program applied to single surgeon with no previous laparoscopic or robotic experience.

PATIENTS

AND METHODS

Between January 2015 and May 2016, 120 consecutive patients underwent RALP for prostate cancer performed by a single surgeon with some experience in RRP (about 50 cases performed as first surgeon) but no laparoscopic skills (no cases of LRP). All the procedures were performed after attending a structured modular training. RALP was performed transperitoneally using the Da Vinci Xi surgical system (Intuitive Surgical, Inc., Sunnyvale, CA, USA) as previously described in details (16). Routine pelvic lymph node dissection (PLND) at time of RALP was performed in presence of high risk PCa and intermediate risk PCa with estimated risk for positive lymph nodes > 5% (2). Nerve sparing procedure was performed according to the D’Amico risk group classification and preoperative multi-parametric magnetic resonance imaging (mpMRI) results in patients with preoperative International Index of Erectile Function score (IIEF) > 21. Clinical, perioperative and pathological data were recorded. Sexual functional evaluation with IIEF2 and continence rate was assessed before and after surgery (13 months). Postoperative complications were graded according to the Clavien Dindo Classification (17) and grouped as minor (grade 1-2) or major (grade 3-5) complication. Postoperative follow-up and data collection The clinical and radiological assessment during follow-up included cystogram before catheter removal when deemed necessary, physical examination and abdominal ultrasound 1 month after surgery in those submitted to PLND. At 1 and 3 months after surgery we evaluated continence recovery, defined as the need for no pad or one safety-pad per day and potency, defined as erection adequate for penetration or postoperative IIEF score > 21. The study was in line with the local institutional ethical committees (approval code STUD-OF by the S. OrsolaMalpighi Hospital, IRB September 11, 2012). All patients provided informed consent for anonymous publication of data. Modular training Before performing the first RALP of the study, the surgeon attained a 3 month modular training which includ-

Archivio Italiano di Urologia e Andrologia 2018; 90, 1

ing: a) e-learning consisting of theoretical lessons and video sessions concerning the different steps of the procedure; b) dry lab performing procedures on ex-vivo models and wet lab c) assistance at the operating table; d) console training with simulator; e) step-by step in vivo modular training in which the main surgeon, supervised by an expert mentor (A.P.), performing 40 surgical steps in increasing difficulty (14). The training was performed at a training Center in Belgium (ORSI training center) and at a robotic center in the North of Italy (Abano terme Hospital, Padua). Statistical analysis Means and standard deviation, medians and interquartile ranges were reported for continuous variables. Frequencies and proportions were reported for categorical variables. The Mann-Whitney U Test and chi-square tests were used to compare the statistical significance of differences in medians and proportions, respectively. Primary outcomes where the overall operative time (OT) and console time, positive surgical margins (PSM), complication rates, urinary continence recovery and potency recovery during the learning curve. To assess the learning curve, patients were divided into 4 groups of 30 consecutive RALP: Group 1 from case 1 to case 30; Group 2 from case 31 to case 60; Group 3 from case 61 to case 90; and Group 4 from case 91 to case 120. Kaplan-Meier analyses were used to predict early urinary continence and erectile function recovery after surgery. Statistical analyses were conducted using SPSS version 17.0 (IBM Corp, Armonk, NY). Two-tailed P values less than 0.05 were considered statistically significant.

RESULTS

Patient’s demographics and preoperative clinical characteristics are summarized in Table 1. All procedures were completed successfully without conversion to open approach. Overall, 84 (70%) patients were potent (IIEF score > 21) at time of surgery and median baseline IIEF-5 score was 21. All patients were continent before surgery. No statistical differences were found between the four groups. Table 2 depicts intraoperative and postoperative outcomes stratified according to the four groups: median OT and console time was 275 and 220 min and gradually decreased during the learning curve, with statistical significance in favour of Group 4. Median estimated blood loss (EBL) was 470 mL, median hospital stay was 3 day; grade 1-2 postoperative complications were 16 (12%) and grade 3-4 postoperative complications were 3 (2%); the four groups were comparable in terms of estimated blood loss, intraoperative complications, PSM and days of hospitalization. A detailed report of intraoperative and postoperative complications stratified according to the study groups is reported in Table 3. Management of intraoperative complications included intra operative repair of bladder injury (2 cases), bowel injury (1 case) and iliac vein injury (1 case). No intraoperative complications occurred in group 4. Overall 19 (15%) post operative complications were reported in 19 patients. Most of the adverse events (84%) were graded as minor (Clavien

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The impact of a structured intensive modular training in the learning curve of robot assisted radical prostatectomy

Table 1. Demographic and clinical characteristics in overall population and after stratifying patients according to four consecutive groups. Variables Age Mean ± SD Median (IQR) BMI Mean ± SD Median (IQR) Baseline PSA value ng/ml Mean ± SD Median (IQR) Charlson Index n (%) 0 ≥1 Clinical Stage n (%) T1 T2 T3 Gleason Score at biopsy n (%) 6 7 8-10 D’Amico Risk group n (%) Low Intermediate High Baseline IIEF-5 score Mean ± SD Median (IQR)

Overall (n = 120)

Group 1 (n = 30)

Group 2 (n = 30)

Group 3 (n = 30)

Group 4 (n = 30)

64.5 ± 6.5 65 (60-69)

65.2 ± 7.2 67 (60-73)

63 ± 5.8 65 (57-68)

66 ± 5.7 67 (63-71)

62.3 ± 6.8 63 (59-68)

0.3

26.3 ± 4.4 25.8 (23.6-29.4)

25.3 ± 5.8 25.7 (22.5-29.4)

26 ± 3.2 26.3 (23.9-28.9)

27 ± 4.4 27.4 (24.8-30)

26 ± 3.8 24.7 (23.1-29.1)

0.4

7.8 ± 5 6.3 (5.0-8.7)

8.2 ± 5.5 6.0 (4.9-9.5)

13 ± 5.7 6.6 (5-8.4)

7.16 ± 4.8 6.2 (4.9-9.6)

7.8 ± 4.1 6.2 (5-8.9)

0.3

103 (85.8) 17 (14.2)

27 (90) 3 (10)

25 (83.3) 5 (16.7)

24 (80) 6 (20)

0.6

45 (37.5) 73 (60.8) 2 (1.7)

9 (30) 20 (66.7) 1 (3.3)

12 (40) 18 (60) 0

7 (23.3) 22 (73.3) 1 (3.3)

17 (56.7) 13 (43.3) 0

0.1

18 (15.0) 75 (62.5) 27 (22.5)

5 (16.7) 19 (63.3) 6 (20)

4 (13.3) 20 (66.7) 6 (20)

5 (16.7) 16 (53.3) 9 (30)

4 (13.3) 20 (66.7) 6 (20)

0.9

20 (16) 67 (56) 33 (28)

6 (20) 16 (53) 8 (27)

6 (20) 17 (57) 7 (23)

5 (17) 13 (45) 12 (38)

3 (10) 21 (70) 6 (20)

0.3

19 ± 6 21 (15-23)

19 ± 5.4 217 (14-23)

17 ± 7.1 21 (10-22)

19 ± 5.2 22 (18-23)

19 ± 6 22 (21-23)

0.4

Table 2. Intraoperative and postoperative outcomes in overall population and after stratifying patients according to four consecutive groups. Variables Operative time (min) Mean ± SD Median (IQR) Console time (min) Mean ± SD Median (IQR) Estimated Blood loss (mL) Mean ± SD Median (IQR) Nerve sparing procedure, n (%) Not performed Monolateral Bilateral Lymphadenectomy, n (%) Performed Intraoperative complications, n (%) Pathologic stage, n (%) T2 T3a T3b Pathologic Gleason Score, n (%) 6 7 8-10 Positive surgical margins (PSM), n (%) PSM according to pathologic stage, n (%) pT2 (n=83) pT3a (n=32) pT3b (n=5) Hospital stay (days) Median (IQR) Post-operative complications n (%) Clavien 1-2 Clavien 3-4 Post operative IIEF-5 Score** Mean ± SD Median (IQR) Post operative continence recovery Continent , n (%) Not continent***, n (%)

Overall (n = 120)

Group 1 (n = 30)

Group 2 (n = 30)

Group 3 (n = 30)

Group 4 (n = 30)

280 ± 99 275 (245-315)

353 ± 167 330 (294-352)

300 ± 52 304 (253-336)

243 ± 33 245 (225-270)

221 ± 28.6 215 (200-250)

220 ± 47 220 (185-270)

260 ± 46 270 (220-300)

237 ± 52 237 (253-336)

200 ± 33 197 (179-225)

177 ± 28.4 180 (155-200)

460 (160) 470 (350-600)

443 (178) 485 (300-600)

362 (108) 350 (300-410)

450 (146) 430 (365-525)

534 (160) 500 (437-600)

38 (32.5) 22 (18.3) 60 (49.2)

14 (47) 5 (16) 11 (37)

8 (26) 8 (26) 14 (48)

10 (33) 5 (16) 15 (50)

6 (21) 4 (13) 20 (66)

70 (58) 5 (5)

17 (56) 2 (7)

16 (53) 2 (7)

19 (63) 1 (3)

14 (46) 0/

83 (68) 32 (27) 5 (5)

18 (60) 12 (40) -

20 (66) 8 (27) 2 (7)

21 (73) 7 (20) 2 (7)

23 (77) 6 (20) 1 (3)

14 (11) 76 (63) 30 (26) 24 (20)

3 (10) 19 (63) 8 (27) 8 (26)

2 (7) 23 (78) 5 (15) 10 (33)

7 (22) 14 (48) 9 (30) 4 (13)

2 (7) 20 (66) 8 (27) 2 (6)

8 (10) 13 (40) 3 (60)

3 (16) 5 (41) -

3 (15) 6 (75) 1 (50)

1 (5) 1 (14) 2 (100)

1 (4) 1 (16) 0

3.5 (3-4)

3 (3-4)

4 (3-4)

3 (3-4.5)

3 (3-4)

16 (12) 3 (2)

9 (30) -

2 (3) 2 (10)

2 (6) 0

3 (10) 1 (3)

13 (8) 18 (6-21)

12 (7) 14 (6-18)

11 (8) 14 (4-19)

12 (9) 18 (0-20)

18 (8) 21 (18-25)

103 (86) 17 (14)

23 (76) 7 (24)

21 (70) 9 (30)

29 (99) 1 (1)

30 (100) 0

P < 0.001 0.01 0.2 0.3

0.393 0.4 0.5

0.4

0.3 0.5

0.3 0.6 0.04 < 0.001

* p value is obtained comparing the four groups. ** 3 months after surgery considering patients referred to nerve sparing approach. *** 3 months after surgery, not continent (>1 safety pad per day).

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R. Schiavina, M. Borghesi, H. Dababneh, M.S. Rossi, C.V. Pultrone Cristian, V. Vagnoni, F. Chessa, L. Bianchi, A. Porreca, A. Mottrie, E. Brunocilla

Table 3. Incidence and type of intraoperative and post-operative complications according to Dindo-Clavien classification in overall population and after stratifying patients according to four consecutive groups. Type Ureteral injury Bladder injury Bowel injury Iliac vein injury

Type Adductor muscle deficit Fever Lymphocele with fever Anemia Pulmonary embolism Myocardial infarction Ureteral injury

Overall, n 5 (%)

Group 1

1 (0.8) 2 (1.6) 1 (1.6) 1 (1.6)

1 (3) 1 (3) -

Overall, n 19 (%) 1 (1) 5 (4) 4 (3) 6 (5) 1 (1) 1 (1) 1 (1)

Group 1 1 (3) 4 (13) 1 (3) 3 (10) -

Intraoperative complications Group 2 Group 3 Group 4 1 (3) 1 (3)

1 (3) -

Post-operative complications Group 2 Group 3 Group 4 1 (3) 1 (3) 1 (3) 1 (3) 1 (3) 2 (6) 1 (3) 1 (3) 1 (3) -

Treatment

Dindo-Clavien grade

Intraoperative ureteral stent placement Intraoperative surgical reparation Intraoperative surgical reparation Intraoperative surgical reparation

n.v. n.v. n.v. n.v.

Treatment Medical therapy Medical therapy Medical therapy Medical therapy Medical therapy Medical therapy Ureteral reimplantation

Dindo-Clavien grade 1 2 2 2 4 4 3

I-II) such as anaemia (31%), fever (26%) and lymphocele (21%). No statistical differences were found in terms of complications between the four groups. The overall continence rate at 1 and 3 months was 74% and 87% respectively (Table 2). Figure 1 depicts the urinary continence recovery rates after stratifying according to the four groups, 1 month and 3 months after surgery. We found a significant improvement in continence rate throughout the four groups (p = 0.04). All patients in the fourth group were continent 3 months after surgery. Considering those patients submitted to nerve-sparing procedure, the median IIEF-5 was 18 and we found a significant increase in potency recovery over the four groups (p = 0.04). Figure 2 shows the potency recovery rate after stratifying according to the four groups. The sexual function recovery rate rises gradually during the first three groups, however the last 30 procedures revealed significantly higher potency recovery rate up to 80%, 3 months after surgery as compared to previous cases.

Figure 1. Time to potency recovery according to the four groups.

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The impact of a structured intensive modular training in the learning curve of robot assisted radical prostatectomy

Figure 2. Time to continence recovery according to the four groups.

DISCUSSION

The success of RALP is mainly due to the evidence that even inexperienced robotic surgeons could achieve high standards of surgery, with limited operative time, even in the early phase of the learning curve. Instead, complete urinary continence and erectile function recovery may require more surgical experience (18). To date, the number of RALP needed to achieve optimal functional outcomes such urinary continence and erectile function recovery is a hotly debated topic. Only limited studies show the functional outcomes during the learning curve (9, 12, 19). Hence, the present study aimed to evaluate early functional and perioperative outcomes of an inexperienced robotic surgeon, after attending a structured modular training. Notably, in our report of the first 120 consecutive RALP, the intraoperative, post-operative and functional results were comparable to those previously reported in literature (10, 20). The overall operative time, the console time, and the PSM gradually decreased during the learning curve. After the first 30 cases the mean console time was comparable to those reported in hands of more experienced surgeons (237 min ± 52) (21). Ahlering et al showed only 10-20 cases were required to achieve 4-h proficiency (7). However, Doumerc et al. demonstrated that at least 50 patients were needed to achieve a plateau of 200 minutes for an experienced “open-surgeon” who starts with robotic program, without attending a specific modular training (22). Another surrogate of proficiency in RALP is PSM rate, which mainly related to pathological stage and it's invariably higher in non-organ confined disease (≥ pT3a) (23). However, the incidence of PSM in organ confined (OC) prostate cancer is directly related to the quality of surgery (24). Indeed, in an initial report of 45 RALP, Ahlering et al. reported 14% of PSM in organ confined disease (7). Accordingly,

in a recent meta-analysis, Novara et al. shows that PSM rate ranges from 0% to 20 % and from 0 to 60% in OC and nonorgan confined disease, respectively (19). With regard of PSM rate, our findings underlines that a high quality of surgery was achieved even during the early phase of the learning curve. Indeed, overall PSM rate was 10% and 40% in OC and non-organ confined disease, respectively. Moreover, the PSM rate of OC disease decreased from 16% among the initial 30 cases, to 4% in the latter 30 cases. Furthermore, we found no statistical difference with respect of the pathological stage between our groups, underlining that the decrease of PSM rate is mostly due to the improvement in robotic surgical skills. Alike surveillance protocols (25), minimally invasive surgery is aimed to reduce the potential sequelae, morbidity and post-operative complications. In this contest, mean post-operative complication rate for RALP is roughly 9% (21). However, complication rates reported during learning curve could be much higher, ranging from 1% to 40 % (19). In the present series overall post-operative complication rate is 16%, most of them (84%) graded as minor complications (Clavien 1-2). In our experience the most severe complication was a ureteral injury which required a ureteral reimplantation. Notably, complication rates decreased from 30% in the first group to 13% in the last 30 procedures. This data are consistent with previous reported in literature, underlining that 20-30 cases may be need for a surgeon to overcome the “basic” learning curve. Lavery et al. identified an “advanced learning curve” in RALP, concerning urinary continence, erectile function recovery and PSM rate. They concluded that 100-300 cases are needed to overcome this steeper learning curve (11). This is related to the relatively high level of difficulty in performing the anastomosis and the optimal compromise between neurovascular bundle preservation and the achievement of negative surgical margins. Some results of our study are noteworthy. First, despite our limited experience in robotic surgery and the short follow-up (3 months), we report optimal functional outcomes even in the early phase of the learning curve. Second, potency recovery raises exponentially throughout the four groups. In the latter group, 80% of patients undergoing nerve sparing procedures, recovered the preoperative erectile function 3 months after surgery. A wide variability of 3-months potency recovery is reported in literature, ranging from 32% to 68% (18, 26). This could be explained by the several clinical predictors of potency recovery such as age, BMI, baseline IIEF score, nerve sparing technique and CCI (26). Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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R. Schiavina, M. Borghesi, H. Dababneh, M.S. Rossi, C.V. Pultrone Cristian, V. Vagnoni, F. Chessa, L. Bianchi, A. Porreca, A. Mottrie, E. Brunocilla

Third, in our series early (3 months) continence recovery rate, increases during the learning curve, particularly after the first 60 cases, reaching 99% and 100% in Group 3 and Group 4, respectively. Similarly to erectile function recovery, also urinary continence recovery, according to the definition of no-pad, is strongly influenced by age at surgery, prostate volume, BMI, and surgical technique (10, 27). As consequence, more controversial is the impact of surgeon experience and learning curve on the prevalence of urinary incontinence after RALP (10). Samadi et al. reported a significant increase of the continence rate after 500 cases (28); conversely excellent results were also reported in several clinical series including 100-200 cases (5, 22, 28). Notably, no differences were found in terms of age at surgery, baseline IIEF score, CCI, and nerve sparing technique, between the four groups. This underlines that urinary continence and potency recovery are mostly due to improvement in robotic skills and almost 90 cases are needed to master anastomosis and nerve sparing procedure. Despite several strengths, our study has several limitations. First, this study only address perioperative outcomes at short term follow up. Second, the number of enrolled patients is limited, and could underestimate the main outcomes. Third, the great part of patients enrolled revealed low to intermediate risk PCa, since represent a learning curve cohort: it could influence our analysis and it could be not representative of learning curve in different population with higher proportion of high risk disease. Fourth, the main surgeon is a robotic naive surgeon experienced in open surgery but with limited skills in laparoscopic surgery. Indeed, the learning curve could be affected by previous surgical background and our data are not exportable to robot naive surgeons with pure laparoscopic experience.

CONCLUSIONS

In the present series, optimal perioperative and functional outcomes have been attained since early phase of the learning curve after an intensive structured modular training and only 90 consecutive procedures seem needed in order to achieve optimal urinary continence and erectile function recovery. Our data suggest that an intensive structured modular training within RALP allows robotic naive surgeons to achieve optimal perioperative and functional outcomes since the early phase of the learning curve Indeed, after attending a structured modular training, 20-30 cases are sufficient to shorten operative time and lowering the complication rate.

REFERENCES

1. Ferlay J, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015; 136:E359. 2. Heidenreich A, Bellmunt J, Bolla M, et al. EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and treatment of clinically localised disease. Eur Urol. 2011; 59:61-71. 3. Walsh PC, Partin AW, Epstein JI. Cancer control and quality of

Archivio Italiano di Urologia e Andrologia 2018; 90, 1

life following anatomical radical retropubic prostatectomy: results at 10 years. J Urol. 1994; 152:1831-6. 4. Badani KK, Kaul S, Menon M. Evolution of robotic radical prostatectomy: assessment after 2766 procedures. Cancer. 2007; 110:1951-8 5. Ficarra V, Novara G, Rosen R, et al. Systematic review and metaanalysis of studies reporting urinary continence recovery after robot-assisted radical prostatectomy. Eur Urol. 2012; 62:405-17. 6. Ficarra V, Novara G, Ahlering T, et al. Systematic review and meta-analysis of studies reporting potency rates after robot-assisted radical prostatectomy. Eur Urol. 2012; 62:418-30. 7. Ahlering TE, Skarecky D, Lee D, Clayman RV. Successful transfer of open surgical skills to a laparoscopic environment using a robotic interface: initial experience with laparoscopic radical prostatectomy. J Urol. 2003; 170:1738-41. 8. Smith Jr JA. Robotically assisted laparoscopic prostatectomy: an assessment of its contemporary role in the surgical management of localized prostate cancer. Am J Surg. 2004; 188:63S-67S. 9. Patel VR, Tully AS, Holmes R, Lindsay J. Robotic radical prostatectomy in the community settingâ&#x20AC;&#x201D;the learning curve and beyond: initial 200 cases. J Urol. 2005; 174:269-72. 10. Young Hwii Ko, Jeong Hyeon Ban, Seok Ho Kang. Does robotassisted laparoscopic radical prostatectomy enable to obtain adequate oncological and functional outcomes during the learning curve? From the Korean experience. AJA. 2009; 167-175. 11. Hugh J. Lavery, David B. Samadi, Rahul Thaly. The advanced learning curve in robotic prostatectomy: a multi-institutional survey. J Robotic Surg. 2009; 3:165-169. 12. Hashimoto T, Yoshioka K, Gondo T, et al. Learning curve and perioperative outcomes of robot-assisted radical prostatectomy in 200 initial Japanese cases by a single surgeon. J Endourol. 2013; 27:1218-23. 13. Volpe A, Ahmed K, Dasgupta P, et al. Pilot validation study of the European Association of Urology robotic training curriculum. Eur Urol. 2015; 68:292-9. 14. Lovegrove C, Novara G, Mottrie A, et al. Structured and modular training pathway for robot-assisted radical prostatectomy (RARP): validation of the RARP assessment core and learning curve assessment. Eur Urol. 2016; 69:526-35. 15. Sood A, Jeong W, Ahlawat R, et al. Robotic surgical skill acquisition: What one needs to know? J Minim Access Surg. 2015; 11:10-5. 16. Mottrie A, Van Migem P, De Naeyer G, et al. Robot-assisted laparoscopic radical prostatectomy: oncologic and functional results of 184 cases. Eur Urol. 2007; 52:746-50 17. Clavien PA, Barkun J, de Oliveira ML, et al. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg. 2009; 250:187-96. 18. Schiavina R, Borghesi M, Dababneh H, et al. Survival, Continence and Potency (SCP) recovery after radical retropubic prostatectomy: a long-term combined evaluation of surgical outcomes. Eur J Surg Oncol. 2014; 40:1716-23. 19. Artibani W, Fracalanza S, Cavalleri S. Learning curve and preliminary experience with da Vinci-assisted laparoscopic radical prostatectomy Urol Int. 2008; 80:237-44. 20. Novara G, Ficarra V, Mocellin S. Systematic review and metaanalysis of studies reporting oncologic outcome after robot-assisted radical prostatectomy. Eur Urol. 2012; 62:382-404.

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The impact of a structured intensive modular training in the learning curve of robot assisted radical prostatectomy

21. Novara G, Ficarra V, Rosen RC. Systematic review and metaanalysis of perioperative outcomes and complications after robotassisted radical prostatectomy. Eur Urol. 2012; 62:431-52. 22. Doumerc N, Yuen C, Savdie R, et al. Should experienced open prostatic surgeons convert to robotic surgery? The real learning curve for one surgeon over 3 years. BJU Int. 2010; 106:378-84. 23. Schiavina R, Borghesi M, Fiorentino M, et al. Identification of prostate cancer risk categories according to surgical margins status, pathological stage and Gleason score. Int J Urol. 2013; 20:1097-103. 24. Heidenreich A. Quality control in radical (laparoscopic) prostatectomy. Eur Urol. 2006; 49:767-768. 25. Brunocilla E, Borghesi M, Schiavina R, et al. Small renal masses initially managed using active surveillance: results from a retro-

spective study with long-term follow-up. Clin Genitourin Cancer. 2014; 12:178-81. 26. Eastham JA. Robotic-assisted prostatectomy: Is there truth in advertising? Eur Urol. 2008; 54:720-2. 27. Brunocilla E, Schiavina R, Pultrone CV, et al. Preservation of the smooth muscular internal (vesical) sphincter and of the proximal urethra for the early recovery of urinary continence after retropubic radical prostatectomy: a prospective case-control study. Int J Urol. 2014; 21:157-62. 28. Samadi DB, Muntner P, Nabizada-Pace F. Improvements in robot-assisted prostatectomy: the effect of surgeon experience and technical changes on oncologic and functional outcomes. J Endourol. 2010; 24:1105-10.

Correspondence Schiavina Riccardo, MD rschiavina@yahoo.it Borghesi Marc, MD mark.borghesi1@gmail.com Dababneh Hussam, MD drdababneh@gmail.com Rossi Martina Sofia, MD martinasofia.rossi@gmail.com Pultrone Cristian Vincenzo, MD cristian.pultrone@gmail.com Vagnoni Valerio, MD vagno07@libero.it Chessa Francesco, MD (Corresponding Author) francesco.chessa2@studio.unibo.it Bianchi Lorenzo, MD lorenzo.bianchi3@studio.unibo.it Brunocilla Eugenio, MD eugenio.brunocilla@unibo.itUniversity of Bologna, S. Orsola-Malpighi Hospital, Dept. of Urology, Bologna via Palagi 9 40134, Bologna, Italy Porreca Angelo, MD angeloporreca@gmail.com Policlinico Di Abano, Dept. of Urology, Abano Terme, Italy Mottrie Alexandre, MD a.mottrie@telenet.be OLV Robotic Surgery Institute, Aalst, Belgium

Archivio Italiano di Urologia e Andrologia 2018; 90, 1

Budak_Stesura Seveso 27/03/18 09:15 Pagina 8

DOI: 10.4081/aiua.2018.1.8

ORIGINAL PAPER

Pathology outcomes in patients with transurethral bladder tumour resection in a Turkish population: A retrospective analysis Salih Budak 1, Cem Yücel 1, Mehmet Zeynel Keskin 1, Mehmet Yoldas 1, Erdem Kısa 1, Ertan Can 1, Ulku Kucuk 2, Zafer Kozacıoğlu 1 1 Tepecik 2 Tepecik

Training and Research Hospital, Urology Clinic, Izmir, Turkey; Training and Research Hospital, Pathology Department, Izmir, Turkey.

Summary

Objectives: Transurethral bladder tumour resection (TURBT) is the common surgical method used in the diagnosis, staging and treatment of patients with bladder tumour. Most of the rare tumours other than the urothelial carcinomas of the bladder are in advanced stage on diagnosis and necessitate aggressive treatment. In our study, we aimed to the histologic types of bladder cancer and to determine the regional incidence of rare bladder cancer types in our region. Materials and methods: We retrospectively evaluated 815 patients who underwent TURBT surgery between January 2010 and March 2016 in our clinic with a diagnosis of bladder cancer and at least 1 year follow-up. Patients with tumour histopathological examination including histological tumour type, grade and were reported. Thirty-nine patients with an unclear pathology report (neighboring organ invasion, cautery artifact, etc) and 17 patients whose data could not be accessed were excluded from the study. The patients who had received chemotherapy or radiotherapy due to any type of malignancy (23) were also excluded from the study. Results: The outcomes of 736 patients operated in our clinics due to bladder tumour were evaluated. The mean age was 65.2 ± 8.4; 135 were female and 601 were male. Among them 711 patients with urothelial carcinoma were reported (94.2%). According to TNM classification, stage Ta was observed in 270 patients (37.9%), stage T1 in 297 (41.7%), and stage T2 in 144 (20.3%). Non-urothelial cancers were reported in 25 cases (3.3%). Conclusion: The incidence of bladder carcinoma varies between regions. The results of our study are similar to those of the western countries. Increased smoking and exposure to environmental carcinogenetic agents may lead to altered incidences and histological types of bladder tumours. Revision of regional tumour records may be useful to develop and evaluate future treatment strategies.

KEY WORDS: Bladder cancer; Transurethral resection; Pathology; Squamous cell; Adenocarcinoma. Submitted 14 July 2017; Accepted 19 July 2017

INTRODUCTION

Bladder cancer is the second most common tumour of the genitourinary system (1). Global cancer burden continues to increase due to increased age of population, smoking, western diet and exposure to environmental carcinogene-

sis (2, 3). Transurethral bladder tumour resection (TURBT) is the basic surgical method used in the diagnosis, staging and treatment of bladder cancer (4). Prognosis of urinary bladder tumors is directly connected to histological type and stage of the tumour (5). Urothelial carcinomas (UC) constitute 90-95% of bladder cancers (4). The second most common subtype is the squamous cell carcinoma (SCC) that has an incidence of less than 5% in western countries (6). Adenocarcinomas constitute less than 2% of all bladder cancers (7). Most of these rare histologic subtypes are in advanced stage when they are diagnosed and they require more aggressive treatment options (8). In our study, we aimed to the histologic types of bladder cancer and to determine the regional incidence of rare bladder cancer types in our region.

MATERIALS

AND METHODS

We retrospectively evaluated 815 patients who underwent TURBT surgery between January 2010 and March 2016 in our clinic with at least 1 year follow-up. All operations were performed under spinal or general anesthesia. TURBT was performed with bipolar energy system using saline irrigation. All obtained materials were placed in containers with 10% formaldehyde and sent to the pathology laboratory. The materials were buried in paraffin blocks after tissue follow-up procedures. Sections with 5 micron thickness were prepared from paraffin blocks and stained with hematoxylon-eosin. The cases in which tumours were determined in the histopathological examination were reported by specifying tumour histological subtype, grade and pathological tumour stage. Second transurethral resection was performed in cases which had recurrence from clinical and radiologic follow-up, and the highest tumour stage and grade was recorded. Thirty-nine cases with unclear pathology (adjacent organ invasion, cautery artifact etc.), 17 cases the data of which could not be accessed, and 23 cases with chemotherapy/radiotherapy due to any malignancy were excluded from the study.

RESULTS

One hundred and eighty five of the 736 patients (25.1%) included in the study were diagnosed as primary bladder No conflict of interest declared.

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Pathology outcomes in bladder tumor resection

cancer and 551 (74.9%) as recurrent after surgery due to bladder tumour. One hundred and thirty five of the patients were female, 601 were male and the mean age was 65.2 ± 8.4. It was determined that incidence of bladder carcinoma is 4.5 times more common in males than females. According to our results of pathological examination, UC was reported at a rate of (94.2%). According to TNM classification, it was determined that 270 patients were in Ta stage (38%), 297 patients were in T1 stage (41.8%), and 144 patients were in T2 stage (20.3%) (Table 1). Twenty five (3.3%) cases were reported as non-urothelial carcinoma. In the pathological evaluation result of these tumours, it was seen that 10 cases were squamous cell carcinoma (1.3%), 9 cases were adenocarcinomas (1.2%), 1 case was neuroendocrine (0.1%), 1 case was small cell carcinoma (0.1%), 2 cases were sarcomatoid carcinoma (0.3%), and 2 cases were bladder leiomyoma (0.3%) (Table 2).. Table 1. Clinical stages of UC cases with TNM classification. Stage and grade TAG1 TAG2 TAG3 T1G1 T1G2 T1G3 T2 Total

Number of patients 167 87 16 92 79 126 144 711

(% ) (23.5%) (12.2%) (2.3%) (12.9%) (11.1%) (17.7%) (20.3%) (100%)

Table 2. Distribution of TURBT pathologic diagnosis (n = 736). Histopathological diagnosis Urothelial carcinomas Squamous cell carcinoma Adenocarcinoma Neuroendocrine Leiomyoma Small cell carcinoma Sarcomatoid carcinoma Total

DISCUSSION

Number of patients 711 10 9 1 2 1 2 736

(% ) (94.2) (1.3%) (1.2%) (0.1%) (0.3%) (0.1%) (0.3%) (100%)

Currently, the most important prognostic factors in bladder tumours are the pathological stage and the grade of tumour as determined by histopathological examination (5). Presence of muscle invasion in bladder carcinomas is very important in terms of foreseeing the prognosis and determining the treatment approach. In the study conducted by Horstmann et al., in which 1269 bladder tumours were evaluated, incidence of muscle invasion was reported to be 35.8% (9). In our study, incidence of muscle invasion was determined as 21.9% (161). In western countries, primary SCC of bladder is 1.2-

4.5% of all bladder tumours and it is often seen in the seventh decade (10, 11). Radical cystectomy is still the most suitable treatment for bladder SCC. The 5-year survival rate after cystectomy was reported to be 50% and mean period of survival was 5.4 years (12). Almost all squamous cell cancers are already advanced and muscle infiltrative at the time of diagnosis (13). In our study we determined the incidence of SCC as 1.3%. Adenocarcinomas constitute less than 2% of all bladder cancers (14). Adenocarcinoma diagnosis may be considered as originating primarily from the bladder after excluding metastasis or invasion from neighboring organs. Due to poor prognosis, standard treatment for adenocarcinomas is radical cystectomy and dissection of the pelvic lymph nodes (15). Therefore, early diagnosis is important. In our study we determined the incidence of adenocarcinoma as 1.2%. The benign tumours that are seen in the bladder are myoma, leiomyoma, rhabdomyoma, fibroma, angioma, osteoma and myxoma. The most common benign mesenchymal bladder tumour is leiomyoma (16).The available evidence about most of these rare tumours originate from small retrospective case series (17). In our study, 2 (0.3%) cases of bladder leiomyoma were detected.

CONCLUSIONS

There are differences in incidence of bladder carcinoma between regions. The results of our study are similar to those of the western countries. The diagnosis of nonurothelial cancers is usually made in the advanced stage and the most applied treatment is radical surgery. Increased smoking and exposure to environmental carcinogenesis may lead to a change in the frequency of histological type of bladder tumours. It may be useful to update regional tumour records to develop and evaluate future treatment strategies.

REFERENCES

1. Grossfeld GD, Carroll PR. Evaluation of asymptomatic microscopic hematuria. Urol Clin North Am. 1998; 25:661-76. 2. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011; 61:69-90. 3. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012; 62:10-29. 4. Richterstetter M, Wullich B, Amann K, et al. The value of extended transurethral resection of bladder tumour (TURBT) in the treatment of bladder cancer. BJU Int. 2012; 110:76-79. 5. Arslan B, Bozkurt IH, Yonguc T, et al. Clinical features and outcomes of nontransitional cell carcinomas of the urinary bladder: analysis of 125 cases. Urol Ann 2015;7:177-82. 6. Shokeir AA. Squamous cell carcinoma of the bladder: pathology, diagnosis and treatment. BJU international. 2004; 93:216-20. 7. Dahm P, Gschwend JE. Malignant non-urothelial neoplasms of the urinary bladder: a review. Eur Urol. 2003: 44:672-81. 8. Manunta A, Vincendeau S, Kırıkakou G, et al. Non-transitional cell bladder carcinomas. BJU Int. 2005; 95:497-502. 9. Horstmann M, Witthuhn R, Falk M, Stenzl A. Gender-specific difArchivio Italiano di Urologia e Andrologia 2018; 90, 1

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S. Budak, C. Yücel, Mehmet Z. Keskin, M. Yoldas, E. Kısa, E. Can, U. Kucuk, Z. Kozacıoğlu

ferences in bladder cancer: a retrospective analysis. Gen Med. 2008; 5:385-94.

with Non-metastatic Squamous Cell Carcinoma of the Urinary Bladder. Middle East J Cancer. 2011; 2: 59.

10. Lopez JI, Angulo CJ, Flores CN, Toledo JD. Squamous cell carcinoma of the urinary bladder. Clinico-pathologic study of 7 cases. Arch Esp Urol. 1994; 47:756-60.

14. Dahm P, Gschwend JE. Malignant non-urothelial neoplasms of the urinary bladder: a review. Eur Urol. 2003; 44:672-81.

11. Serretta V, Pomara G, Piazzo F, Gange E. Pure squamous cell carcinoma of the bladder in western countries. Eur Urol. 2000; 37:85-9. 12. Ghoneim MA, El Mekresh MH, El Baz MA, et al. Radical cystectomy for carcinoma of the bladder: Critical evaluation of the results in 1026 cases. J Urol. 1997; 158:393-9. 13. El-Sayed MI, Abdel-Rahim AM. Survival Analysis in Patients

Correspondence Salih Budak, MD (Corresponding Author) salihbudak1977@gmail.com Tepecik Training and Research Hospital, Urology Clinic 206/26 sok. no:16 D:24 yıldız mah. Buca/Izmir, Turkey Cem Yücel, MD meclecuy@hotmail.com Mehmet Zeynel Keskin, MD zeynel_akd@hotmail.com Mehmet Yoldas, MD yoldas_2297@hotmail.com Erdem Kısa, MD drerdemkisa@hotmail.com Ertan Can, MD drertancan@yahoo.com Ulku Kucuk, MD Associate Professor kucukulku@hotmail.com Zafer Kozacıoğlu, MD Associate Professor zaferkozacioglu@gmail.com Tepecik Training and Research Hospital, Urology Clinic Tepecik EAH, Üroloji Kliniği, Yenişehir, Izmir, Turkey

Archivio Italiano di Urologia e Andrologia 2018; 90, 1

15. Wilson TG, Pritchett TR, Lieskovsky G, et al. Primary adenocarcinoma of bladder. Urology. 1991; 38:223-6. 16. Goktug GH, Ozturk U, Sener NC, et al. Transurethral resection of a bladder leiomyoma: A case report. Can Urol Ass J. 2014; 8:111. 17. Park JW, Jeong BC, Seo SI, et al. Leiomyoma of the urinary bladder: A series of nine cases and review of the literature. Urology. 2010; 76:1425-9.

Imperatore.e$S_Stesura Seveso 27/03/18 09:16 Pagina 11

DOI: 10.4081/aiua.2018.1.11

ORIGINAL PAPER

Intravesical administration of combined hyaluronic acid and chondroitin sulfate can improve symptoms in patients with refractory bacillus Calmette-Guerin-induced chemical cystitis: Preliminary experience with one-year follow-up Vittorio Imperatore 1, Massimiliano Creta 2, Sergio Di Meo 1, Roberto Buonopane 1, Nicola Longo 2, Ferdinando Fusco 2, Lorenzo Spirito 2, Ciro Imbimbo 2, Vincenzo Mirone 2 1 Unità

Operativa di Urologia, Ospedale Buon Consiglio - Fatebenefratelli, Napoli, Italy; Urologica, Università Federico II di Napoli, Napoli, Italy.

2 Clinica

Summary

Objective: We investigated the efficacy of intravesical instillations of combined hyaluronic acid (HA) and chondroitin sulphate (CS) in patients with bacillus Calmette-Guérin (BCG)-induced chemical cystitis unresponsive to first-line therapies. Patients and methods: We retrospectively reviewed the clinical records of patients with grade 2 BCG-induced chemical cystitis unresponsive to first line therapeutic options performed according to the International Bladder Cancer Group guidelines who underwent intravesical instillations of HA/CS. Bladder pain, urinary urgency, voiding volume and number of voids/24 hours recorded prior to treatment, at the end of the treatment, at six months and at one-year follow-up were recorded and analyzed. Results: The records of 20 patients were identified. All patients underwent eight weekly instillations of HA/CS. Mean baseline visual analogue scale (VAS) scores ± Standard Deviation (SD) for urinary urgency and bladder pain were 7.8 ± 0.5 and 7.2 ± 1.0, respectively. Mean number of voids/24 hours ± SD was 15.4 ± 2.3 and mean urine volume per void ± SD was 85.8 ± 21.0 mL. At the end of the treatment, mean VAS scores ± SD for urgency and pain significantly decreased to 4.7 ± 1.1 and 4.2 ± 0.9, respectively (p < 0.05 in both cases). Mean number of voids/24 hours ± SD decreased to 9.6 ± 1.4 (p < 0.05) and mean urine volume per void ± SD significantly increased to 194.1 ± 59.5 mL (p < 0.05). At six months and one-year followup, all outcome measures remained stable. Conclusions: Bladder instillations of HA/CS provide significant and durable improvement of bladder pain, urinary urgency, urinary volume per void and urinary frequency in patients with refractory BCG-induced chemical cystitis.

KEY WORDS: Bacillus Calmette-Guérin; Bladder cancer; Chondroitin sulphate; Cystitis; Hyaluronic acid. Submitted 25 August 2017; Accepted 23 October 2017

INTRODUCTION

Intravesical immunotherapy with bacillus CalmetteGuérin (BCG) is the most effective prophylactic treatment for patients with non-muscle invasive bladder cancer (BCa) at intermediate and high risk of recurrence and/or progression after complete tumor removal (1). BCG-related toxicity is a great concern for these patients and it can occur locally and/or systemically (1). Chemical cystitis is the most common local side effect

and has been reported in in up to 80% of patients (2-4). Histologically, BCG-induced chemical cystitis is characterized by an intense inflammatory reaction involving the lamina propria associated with nonspecific reactive atypia of the overlying urothelium that may be partially or entirely denuded (5). Clinically, it is characterized by storage lower urinary tract symptoms and hematuria with negative urine cultures. Reduced functional bladder capacity has been also reported. Most patients experience self-limiting symptoms that usually begin 2 to 4 hours after instillation and resolve rapidly over the next 24 to 48 hours (5). However, symptoms may persist or worsen and can become a troubling problem for some patients during BCG therapy and in the post-BCG observation period (5). The management of BCG-related side effects should reflect their type and grade and involves a stepwise approach according to the recommendations provided by the International Bladder Cancer Group (IBCG) (1, 6). First-line therapeutic options for patients with BCG-related cystitis include phenazopyridine, propantheline bromide or non-steroidal anti-inflammatory drugs (1, 6). If symptoms persist or worsen, guidelines recommend postponing therapy, perform a urine culture, and start empirical antibiotic therapy with subsequent adjustments in case of positive culture (1, 6). In cases of negative culture, quinolones and potentially analgesic anti-inflammatory instillations are recommended (1, 6-8). A defective glycosaminoglycan (GAG) barrier has recently emerged as the key factor in the pathogenesis of many pathophysiological processes that involve multiple biological systems including the bladder (i.e. biofilm formation, chemical and radiation damage) (9, 10). The GAGs best represented within the urothelial coating are hyaluronic acid (HA) and chondroitin sulfate (CS). The balanced association of HA and CS is indicated to treat chronic inflammatory diseases of the bladder originated from damage of the GAG layer of the bladder epithelium. Studies on bladder instillations of HA/CS as GAG replenishment therapy suggest that this formulation is efficacious in a wide range of clinical conditions characterized by chronic bladder inflammation including interstitial cystitis/painful bladder syndrome,

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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V. Imperatore, M. Creta, S. Di Meo, R. Buonopane, N. Longo, F. Fusco, L. Spirito, C. Imbimbo, V. Mirone

recurrent urinary tract infections, radiation cystitis (11, 12). To date, only few studies evaluated the benefits of bladder instillations with HA/CS in patients with chemical cystitis induced by BCG (8, 13). We aimed to investigate the efficacy of intravesical instillations of combined HA/CS in patients with BCG-induced chemical cystitis unresponsive to first-line treatments.

PATIENTS

AND METHODS

The clinical records of patients with diagnosis of BCGinduced grade 2 chemical cystitis unresponsive to first line therapeutic options performed according to IBCG recommendations who underwent intravesical instillations of combined HA/CS between January 2010 to January 2015 were retrospectively reviewed (6). Grade 2 chemical cystitis was defined as severe and/or > 48 hours cystitis according to the World Health Organization grading scale (14). Patients with systemic side effects related to BCG, active genitourinary tract infections, actinic bladder, follow-up < 1 year, or incomplete data were excluded. The followings were considered outcome measures: urinary urgency, bladder pain, urinary volume per void, number of voids/24 hours. Urinary urgency and bladder pain were investigated through a 0-10 visual analogue scale (VAS) score. Urinary volume per void and number of voids/24 hours were investigated through frequency/volume charts. Demographic and clinical data were collected including ethnicity, age, gender, tumor characteristics, previous therapies, symptoms onset, oncologic follow-up. For all outcome measures, values recorded at baseline, at the end of the treatment, at six months and one-year follow-up were collected and compared. Moreover, treatment related adverse event were also collected. Continuous variables were reported as mean, standard deviations (SD) and ranges. Categorical variables were reported as absolute values and percentages. Data were analyzed using the Student’s t test, the MannWhitney and the Wilcoxon test, as appropriate. P values < 0.05 were considered statistically significant. Analyses were performed with SPSS version 17.0 (SPSS Inc, Chicago, IL, USA). The study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

RESULTS

A total of 20 Caucasian patients were identified who met the study criteria. Mean age was 61.8 years (range 4877), 9 patients were males (45%) and 11 (55%) were females. BCa risk stratification revealed high- and intermediate-risk tumors in 14 and 6 patients, respectively. BCG-induced grade 2 chemical cystitis occurred after a mean of 3.5 instillations (range: 2-6). Symptoms persisted in all patients despite therapy with non-steroid antiinflammatory drugs and quinolones. The treating physician decided to definitively stop BCG instillations in all cases. Patients were counseled about early cystectomy and refused. All patients received intravesical instillations of combined HA and CS (HA 1.6% 800 mg/50 mL and CS 2% 1000 mg/50 mL) weekly for eight weeks. All patients underwent follow-up investigations for BCa

Figure 1. Mean Visual Analogue Scale (VAS) scores for symptoms of urinary urgency and bladder pain at baseline, at the end of the treatment 8 weeks), at six-months and at one-year follow-up. (*: p < 0.05 with respect to baseline).

Archivio Italiano di Urologia e Andrologia 2018; 90, 1

according to recommendations provided by European Urology Guidelines. At baseline, mean VAS scores ± SD for bladder pain and urinary urgency were 7.2 ± 1.0 and 7.8 ± 0.5, respectively. while mean number of voids/24 hours ± SD, and mean urinary volume per void ± SD were 15.4 ± 2.3 and 85.8 ± 21.0 mL, respectively. At the end of the treatment (8 weeks), symptoms improved in all but one patient. Mean VAS scores ± SD for bladder pain and urinary urgency significantly decreased to 4.2 ± 0.9 and to 4.7 ± 1.1, respectively (Figure 1). Mean number of voids/24 hours ± SD, and mean urinary volume per void ± SD significantly improved to 9.6 ± 1.4 and 194.1 ± 59.5 mL, respectively (Figures 2 and 3). At six months follow up, mean VAS scores ± SD for bladder pain and urinary urgency were 4.4 ± 1.1 and 4.5 ± 1.0, respectively. Mean number of voids/24 hours ± SD, and mean urinary volume per void ± SD were 9.1 ± 1.6 and 210.8 ± 58.3 mL, respectively. At one year follow up, mean VAS scores ± SD for bladder pain and urinary urgency were 4.2 ± 0.8 and 4.3 ± 0.9, Figure 2. Mean number of voids/24 hours at baseline, at the end of the treatment (8 weeks), at six-months and at one-year follow-up. (*: p < 0.05 with respect to baseline).

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BCG-induced cystitis

Figure 3. Mean urine volume per void at baseline, at the end of the treatment (8 weeks), at six-months and at one-year followup. (*: p < 0.05 with respect to baseline).

respectively. Mean number of voids/24 hours ± SD, and mean urinary volume per void ± SD were 9.0 ± 0.9 and 220.7 ± 55.3 mL, respectively (Figures 2 and 3). Not statistically significant differences were evident when comparing values recorded at eight weeks, six months and one-year follow-up for all outcome measures. We did not observe any side effect due to the treatment. At one-year follow-up none of the patients had BCa recurrence.

DISCUSSION

BCa is the most common malignancy of the urinary tract, the seventh most common cancer in men and the 17th in women (1, 15-17). Transurethral resection of bladder tumors is the gold standard for removal of BCa, to allow diagnosis and, in many cases, definitive treatment (1, 1517). However, tumor may recur or progress to muscle invasive disease and further adjuvant intravesical therapies are often needed (1). BCG intravesical immunotherapy is the most effective prophylactic management for BCa in situ as well as for Ta and T1 BCa at intermediate and high risk of recurrence and progression after complete transurethral resection (1). Morbidity secondary to intravesical BCG represents a great clinical concern. Toxicities requiring treatment discontinuation or interruption are frequently seen during the first year of therapy and chemical cystitis represents the most common local side effect (18, 19). Chemical cystitis is characterized by negative urine cultures and symptoms resemble to those of the urgency/frequency and painful bladder syndromes (8, 18). Symptoms are generally self-limited. However, they can persist or worsen in some cases (18). The IBCG published recommendations for the treatment of intravesical therapy-associated adverse events (6). The management of BCG-related side-effects should reflect their type and grade and involves a stepwise approach (1). Analgesic and anti-inflammatory intravesical instillations are recommended as an adjunctive option for patients with symptoms of cystitis that persist despite first-line antiinflammatory therapies (1, 6). To date, however, evidences about the efficacy of intravesical instillations in this clinical scenario are limited. Palou et al. treated 16 patients with severe BCG cystitis unresponsive to systemic medical treat-

ments with an anaesthetic anti-inflammatory solution administered by intravesical instillations (19). Authors obtained good results in 94% of the cases with immediate clinical improvement in terms of pain and urinary symptoms, and no side effects (19). Chuang et al. investigated, in a retrospective review, the potential utility of botulinum toxin A bladder injections in two patients with BCGinduced chemical cystitis who had failed conventional therapies (20). The Authors reported significant symptomatic improvements in both patients. The bladder capacity increased from 110 to 230 mL, urinary frequency decreased from 16 to 12 episodes per day, and using a 10point visual analogue pain scoring system, the perceived pain score decreased from 8 to 2 (20). However, theoretical risks of the injection procedure of botulinum toxin A exist, including hematuria, perforation, urinary tract infections, and injection-site pain (20). The role of GAG replenishment therapy in patients with chemical cystitis was investigated by Sommariva et al. (8). Authors evaluated the efficacy of intravesical instillations with sodium hyaluronate in 55 male patients with acute iatrogenic cystitis secondary to bladder chemo-immunoinstillation or pelvic radiotherapy. Of these, 17 patients received BCG. After 16 weeks VAS for pain improved in every case of chemical cystitis from an initial mean value of 8.6 to a final mean value of 1. Bladder capacity increased in all cases of chemical cystitis from a mean value of 56 mL to 276 mL. However, the study population was highly heterogeneous as 12 patients were treated with contemporary bladder hyperthermia. Moreover, patients also received dexamethasone intravesical (8). Results from the present study showed statistically significant improvements of bladder pain, urinary urgency, number of voids/24 hours and voided volume in patients with chemical cystitis secondary to intravesical immunotherapy with BCG and unresponsive to anti-inflammatory and quinolone therapies who received intravesical instillations of HA/CS. These results are in line with those reported by Sommaviva et al. (8) Moreover, for the first time, we observed a persistence of benefits after treatment discontinuation up to one year. The rationale behind the clinical benefits of intravesical instillations of HA/CS in patients with diagnosis of chemical cystitis secondary to intravesical immunotherapy with BCG is unknown. However, some potential mechanisms can be hypothesized. Evidences exist suggesting that a defective urothelial barrier is involved in the pathogenesis of several chronic bladder conditions, such as interstitial cystitis/painful bladder syndrome, recurrent urinary tract infections, chemical and radiation cystitis (20). The surface of the urothelial cells carries a thick layer of glycoproteins and proteoglycans, together forming a GAG layer, which constitutes a hydrophilic mucosal coating and a barrier against solutes or noxious substances in the urine. A defect in this layer may be the first step in the development of urothelial dysfunction (9). Bladders lacking the apical layer of cells become more permeable, but impermeability can be restored with exogenous GAGs (21). Moreover, HA/CS may act in the context of chemical cystitis secondary to BCG by interfering with the inflammatory process. Indeed, studies have demonstrated that CS and HA may inhibit leukocyte migration, adherence of immune complexes, and binding to specific receptors (22). Moreover, reduction Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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V. Imperatore, M. Creta, S. Di Meo, R. Buonopane, N. Longo, F. Fusco, L. Spirito, C. Imbimbo, V. Mirone

of local production of proinflammatory cytokines has been also described (9). However, further studies are needed to specifically address these issues. Other Authors have investigated the benefits of GAG replenishment therapy in patients receiving BCG in a preventive setting. In their pilot study, Topazio et al. evaluated the role of the sequential administration of HA and BCG (22). Authors found significantly lower VAS scores for pain, number of daily micturitions, and International Prostate Symptom Scores in patients receiving HA and BCG with respect to patients receiving BCG alone (22). However, cost/benefits issues and potential interaction between BCG and HA deserve careful evaluations (22). Interestingly, none of the subjects in the present study had BCa recurrence at one-year follow-up despite BCG interruption. To date, little is known about the optimal treatment in patients with high-risk tumors who could not complete BCG instillations because of intolerance (1). Although GAG replenishment therapy may potentiate the protective barrier of the urothelium to prevent implantation of BCa tumor cells, the role of intravesical HA/CS in terms of BCa recurrence and progression is poorly understood and this issue deserves well designed pre-clinical and clinical studies (9). We acknowledge potential limitations of the present study. First, it was a retrospective study thus selection bias cannot be avoided. Moreover, the number of patients was low and there was not a control group. Therefore, formal randomized controlled trials and wider series are required to confirm these preliminary data and to draw definitive conclusions.

8. Sommariva ML, Sandri SD, Ceriani V. Efficacy of sodium hyaluronate in the management of chemical and radiation cystitis. Minerva Urol Nefrol. 2010; 62:145-50.

CONCLUSIONS

17. Creta M, Mirone V, Di Meo S, et al. Endoscopic spatulation of the intramural ureter: a technique to prevent stenosis of the ureterovesical junction in patients undergoing resection of the ureteral orifice. J Endourol. 2016; 30:913-7.

Intravesical instillations of HA/CS combination can improve urinary urgency, bladder pain, urinary frequency, and voided volume in patients with refractory BCGinduced chemical cystitis. Clinical benefits can persist up to one year after the suspension of the treatment.

10. Cennamo P, Caputo P, Giorgio A, et al. Biofilms on tuff stones at historical sites: identification and removal by nonthermal effects of radiofrequencies. Microb Ecol. 2013; 66:659-68. 11. Damiano R, Cicione A. The role of sodium hyaluronate and sodium chondroitin sulphate in the management of bladder disease. Ther Adv Urol. 2011; 3:223-32. 12. Nordling J, van Ophoven A. Intravesical glycosaminoglycan replenishment with chondroitin sulphate in chronic forms of cystitis. A multi-national, multi-centre, prospective observational clinical trial. Arzneimittelforschung. 2008; 58:328-35. 13. Finazzi Agro E, Bove P, Perugia C, et al. Could hyaluronic acid reduce bacillus calmette guerin (bcg) local side effects? a preliminary report. J Urol. 2012; 187(4 Supplement:S):230-230. 14. Saint F, Irani J, Patard JJ, et al. Tolerability of bacille CalmetteGuerin maintenance therapy for superficial bladder cancer. Urology. 2001; 57:883-8. 15. Longo N, Imbimbo C, Fusco F, et al. Complications and quality of life in elderly patients with several comorbidities undergoing cutaneous ureterostomy with single stoma or ileal conduit after radical cystectomy. BJU Int. 2016; 118:521-6. 16. Imbimbo C, Mirone V, Siracusano S, et al. Quality of life assessment with orthotopic ileal neobladder reconstruction after radical cystectomy: results from a prospective Italian multicenter observational study. Urology. 2015; 86:974-9.

18. Anastasiadis A, de Reijke TM. Best practice in the treatment of nonmuscle invasive bladder cancer. Ther Adv Urol. 2012; 4:13-32.

REFERENCES

19. Palou J, Rodríguez-Villamil L, Andreu-Crespo A, et al. Intravesical treatment of severe bacillus Calmette-Guerin cystitis. Int Urol Nephrol. 2001; 33:485-9.

1. Babjuk M, Böhle A, Burger M, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. Eur Urol. 2017; 71:447-461.

20. Chuang YC, Kim DK, Chiang PH, Chancellor MB. Bladder botulinum toxin A injection can benefit patients with radiation and chemical cystitis. BJU Int. 2008; 102:704-6.

2. Shang PF, Kwong J, Wang ZP, et al. Intravesical Bacillus Calmette-Guérin versus epirubicin for Ta and T1 bladder cancer. Cochrane Database Syst Rev. 2011; (5):CD006885.

21. Hauser PJ, Buethe DA, Califano J, et al. Restoring barrier function to acid damaged bladder by intravesical chondroitin sulfate. J Urol. 2009; 182:2477-82.

3. Bohle A, Balck F, von Wietersheim J, Jocham D. The quality of life during intravesical bacillus Calmette-Guerin therapy. J Urol. 1996; 155:1221-6.

22. Topazio L, Miano R, Maurelli V, et al. Could hyaluronic acid (HA) reduce Bacillus Calmette-Guérin (BCG) local side effects? Results of a pilot study. BMC Urol. 2014; 14:64.

4. Braasch MR, Bohle A, O’Donnell MA. Intravesical Instillation Treatment of Non-muscle-invasive Bladder Cancer Eur Urol Suppl. 2009; S8:549-555. 5. Vogelzang NJ, Scardino PT, Shipley WU, et al. (eds). Comprehensive textbook of genitourinary oncology Third edition. Philadelphia, Lippincott Williams & Wilkins. 2006; ISBN: 0-7817-4984-0. 6. Witjes JA, Palou J, Soloway M, et al. Clinical practice recommendations for the prevention and management of intravesical therapyassociated adverse events. Eur Urol Suppl. 2008; 7:667-674. 7. Rischmann P, Desgrandchamps F, Malavaud B, Chopin DK. BCG intravesical instillations: recommendations for side-effects management. Eur Urol Suppl. 2000; 37:33-6.

9. Bassi PF, Costantini E, Foley S, Palea S. Glycosaminoglycan Therapy for Bladder Diseases: Emerging New Treatments. Eur Urol Suppl. 2011; 10: 451-459.

Archivio Italiano di Urologia e Andrologia 2018; 90, 1

Correspondence Vittorio Imperatore, MD (Corresponding Author) v.imperatore@alice.it Sergio Di Meo, MD - s.dimeo72@gmail.com Roberto Buonopane, MD - robertobuonopane@libero.it Unità Operativa di Urologia, Buon Consiglio Fatebenefratelli Hospital, Via A. Manzoni, 220, 80123, Napoli, Italy Massimiliano Creta, MD - max.creta@gmail.com Nicola Longo, MD - Ferdinando Fusco, MD - Lorenzo Spirito, MD Ciro Imbimbo, MD - Vincenzo Mirone, MD Clinica Urologica, Università Federico II di Napoli Via S.Pansini, 5, 80131 Napoli, Italy

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DOI: 10.4081/aiua.2018.1.15

ORIGINAL PAPER

The impact of ureteral Double-J stent insertion following ureterorenoscopy in patients with ureteral stones accompanied by perirenal fat stranding Ercan Ogreden 1, Ural Oğuz 1, Erhan Demirelli 1, Erdal Benli 2, Özkan Özen 3 1 Giresun

University, Faculty of Medicine, Department of Urology, Giresun, Turkey; University, Faculty of Medicine, Department of Urology, Ordu, Turkey; 3 Giresun University, Faculty of Medicine, Department of Radiology, Giresun, Turkey. 2 Ordu

Summary

Objective: To evaluate the impact of ureteral stent insertion following semirigid ureterorenoscopy (URS) in patients with perirenal fat stranding (PFS) due to ureteral stones. Material and methods: Data of 600 patients who underwent URS were analyzed retrospectively. Seventy-two patients detected to have PFS accompanying ureteral stone were included. Patients who did not undergo double J (DJ) stent insertion following semirigid URS were classified as Group I (n: 52), while those who underwent stent insertion were classified as Group II (n: 20). Side distribution; localization of the stones, stone size, presence of fever, urinary tract infection (UTIs) and urosepsis rates were compared in the two groups. Results: The average age of the patients was 44.4 (20-71) years. Male/female ratio and side of the stone location showed similar distribution in both groups (p > 0.05). Fever occurred in 23 cases (44.2%) in Group I and in 15 cases (75%) in Group II (p = 0.038). UTIs occurred in 15 cases (28.9%) in Group I and in 12 cases (60%) in Group II (p = 0.03). Urosepsis presented in 3 (5.8%) and 5 (25%) of the patients in Group I and II, respectively (p = 0.033). Conclusions: According to our results, ureteral DJ stent insertion following URS in patients with PFS due to ureteral stone caused an increase on postoperative infection related complications.

KEY WORDS: Perirenal fat stranding; Ureteral stents; Ureteral stones; Ureterorenoscopy. Submitted 15 October 2017; 10 December 2017

INTRODUCTION

Ureteral stones can lead to partial or complete obstruction of ureteral lumen (1). Computerized tomography (CT) is the ideal method for detecting obstructing stones. There are primary and secondary findings of ureteral obstruction due to stones on CT. The primary finding is the detection of stone. Secondary findings are hydronephrosis, enlarged ureter, perirenal fat stranding (PFS), pararenal facial thickening, perirenal fluid collection (2). PFS is a CT imaging of the perirenal fat tissue. Asymmetric or unilateral PFS is an important indicator of renal inflammation or acute obstruction. It is detected especially in the presence of inflammation such as acute pyelonephritis and acute obstruction secondary to

ureteric stones (3). Extracorporeal Shock Wave Lithotripsy (ESWL), ureterorenoscopy (URS) and endoscopic lithotripsy are the most common treatment modalities currently used in ureteral stones. The ureteral DJ stent insertion indications are the complications that develop secondary to the presence of the stones and the complications that arise during the surgical procedure (4). However, the use of stents can lead to side effects such as pain, urinary infection, and irritable voiding symptoms (5, 6). Thus, we aimed to evaluate the correlation between ureteral DJ stent and infective complications such as fever, UTIs and urosepsis in patients with PFS who develop secondary to ureteral stones.

MATERIAL

AND METHODS

Data of 600 patients who underwent URS in two tertiary centers between May 2010 and May 2017 were analyzed retrospectively. Routine laboratory, complete urinalysis, urine cultures, blood cultures and CT scan results were obtained by a comprehensive review of medical records. Vital signs were also reviewed and presence of any UTIs, fever and urosepsis were noted. Urine cultures were obtained from patients with asymptomatic bacteriuria and appropriate empirical treatment was started. Symptomatic urinary infection criteria included fever, costovertebral angle sensitivity, pyuria (≥ 10 white blood cells per high-power field), and positive urine culture (≥ 105 colony-forming units of uropathogen/mL). Urosepsis criteria included at least 2 findings of Systemic Inflammatory Response Syndrome (SIRs) in the presence of infection. SIRs criteria included fever > 38 C° or < 36 C°, heart rate > 90 beats/min, respiratory rate > 20/min or PaCO2 < 32 mmHg, leucocytes > 12.000/mm3 or < 4.000/mm3. Patients diagnosed with urosepsis was treated empirically considering antibiotic susceptibility results. Of 600 patients, 72 with PFS and hydronephrosis due to ureteral stones were included in the study. PFS defines the appearance of edema of the fat of the perirenal space at CT. Presence of PFS, stone size, side distribution and localization of the stones were documented by reviewing the CT scans (Figure 1). Patients who did not undergo stent insertion following semirigid URS were classified as

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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E. Ogreden, U. Oğuz, E. Demirelli, E. Benli, Ö. Özen

Figure 1. Unenhanced tomography of a 53-year-old male patient with left lateral and left testicular pain. [1a - perirenal fat stranding (shown by the white arrow) image, 1b - perirenal lines (shown by the white arrow) and two stones in the lower calyx of left kidney (indicated by a white arrowhead). 1c - perirenal streaks (shown by the white arrow) and dilatation of the left ureter (indicated by a white arrowhead), 1d - the left distally ureteral stone (shown by the white arrow)].

Statistical analysis Results are presented as frequency and percentage (%). The abnormal distribution of data from each group was confirmed with the Kolmogorov-Smirnov test, thus statistical comparisons were performed using Mann Whitney-U Test. Chi-square test was used to examine the dependency between the groups. SPSS 22.0 software for Windows (SPSS Inc., Chicago, IL) was used for analysis of data. A P value less than 0.05 was considered statistically significant.

RESULTS

Group I (n:52), while those who underwent stent insertion were classified as Group II (n:20). Side distribution; localization of the stones, stone size, presence of fever, UTI and urosepsis rates were compared in the two groups.

The mean age of the patients was 44 (2370) years in Group I and 45.3 (20-71) years in Group II (p = 0.811) (Table 2). Female patients were 14 (26.9%) and 2 (10%) in Group I and II, respectively. Male patients were 38 (73.1%) and 18 (90%) in Group I and II, respectively (p = 0.205) (Table 1). Stones were detected in the right ureter in 27(51.9%) patients in Group I and 10(50%) patients in Group II. Left ureteric stones were detected in 25 (48.1%) patients and 10 (50%) patients in Group I and II, respectively (p = 1.00) (Table 1). Lower ureteric stones were found in 46 (88.5%) patients in Group I and 9 (45%) patients in Group II. Mid ureteric stones were found in 9 (11.5%) patients and 6 (30%) patients in Group I and Group II, respectively. Upper ureteral stones were observed in only 5 (25%)

Table 1. Demographic distribution of infective complications, gender, stone side and localization according to groups. Group I Gender

Side

Localization

Fever

UTIs

Urosepsis

Female Male Total Left ureter Right ureter Total Lower ureter Middle ureter Upper ureter Total Absent Present Total Absent Present Total Absent Present Total

n 14 38 52 25 27 52 46 6 0 52 29 23 52 37 15 52 49 3 52

% 26.9 73.1 100 48.1 51.9 100 88.5 11.5 0 100 55.7 44.2 100 71.2 28.9 100 94.2 5.8 100

UTIs: Urinary tract infections.

Archivio Italiano di Urologia e Andrologia 2018; 90, 1

Chi Square Test Group II n % 2 10 18 90 20 100 10 50 10 50 20 100 9 45 6 30 5 25 20 100 5 25 15 75 20 100 8 40 12 60 20 100 15 75 5 25 20 100

Total n 16 56 72 35 37 72 55 12 5 72 34 38 72 45 27 72 64 8 72

% 22.2 77.8 100 48.6 51.4 100 76.4 16.7 6.9 100 47.2 52.8 100 62.5 37.5 100 88.9 11.1 100

Chi Square Fisher's exact

p 0,205

1,00

0,001

4,322

0,038

4,726

0,03

Fisher's exact

0,033

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Double-J stent and perirenal fat stranding

Table 2. The differences between groups in terms of age and stone size.

Age

Size/mm

Group I Group II Total Group I Group II Total

n 52 20 72 52 20 72

Mean 44.0 45.3 44.4 7.2 11.4 8.3

Median 42 43 43 7 10 8

Min 23 20 20 4 4 4

Max 70 71 71 13 20 20

ss 11.9 15.1 12.8 2.1 4.2 3.4

Mann Whitney U Test Rank Avg. z p 36.13 -0.239 0.811 37.45 29.87 53.75

-4.381

0.001

DJ stent: Double J stent.

patients in Group II (p = 0.001) (Table 1). Fever was detected in 23 (44.2%) patients and 15 (75%) patients in Group I and Group II, respectively (p = 0.038). In 25 of the 38 patients with fever, at least one species of a microorganism was isolated in their urine and/or blood cultures. The most isolated microorganism was E. coli (95%). UTI was detected in 15 patients (28.9%) in Group I and 12 patients (60%) in Group II (p = 0.03). In 10 of the 27 patients, urine culture was positive. The most frequently isolated bacteria was E. coli (98%). Urosepsis was seen in 3 (5.8%) patients in Group I and in 5 (25%) patients in Group II (p = 0.033). All of these patients were found to have microorganisms in both urine and blood cultures (Table 1). Mean size of the stones was 7.2 mm (4-13 mm) in Group I and 11.4 mm (4-20 mm) in Group II. Mean size of the stones did significantly differ between the groups (p = 0.001) (Table 2). Preoperative hydronephrosis was seen in all patients in both groups, whereas postoperative hydronephrosis was not seen in any patient. Success was defined as the stone free and success rates of the treatment was 100% in both groups. Catastrophic ureteral injuries such as avulsion or perforation did not occur in any patient.

DISCUSSION

Perirenal fat stranding (PFS) indicates the appearance of edema in the fat of the perirenal space in CT. Asymmetric or unilateral PFS is an important indicator of renal inflammation or acute obstruction. CT is the ideal method for detecting obstructing stones. There are primary and secondary findings of ureteral stones that have acute ureteral obstruction in CT. Primary findings are the appearance of stone. Secondary findings include hydronephrosis, enlarged ureter, PFS, pararenal fascia thickening, perirenal fluid collection. Secondary findings have a high positive and negative predictive value for ureteral stone presence or absence (2, 3, 7). Semirigid ureterorenoscopy is a rather effective and minimally invasive method of treatment for ureteral stones. Until recently, DJ stent insertion was performed in all patients who underwent URS in order to decrease the risk of postoperative ureteral edema and obstruction, to avoid the development of ureteral stenosis, to facilitate the spontaneous passage of small stone fragments and to diminish the postoperative risk of pain. However, rou-

tine insertion of DJ stent has been questioned because redesigned endoscopic equipments cause less URS complications, intracorporeal lithotripsy devices are quite improved and irritative voiding symptoms secondary to DJ stent along with side effects such as hematuria, catheter migration, fever and urinary infection may be seen (8). While ureteral DJ stent insertion is not recommended in patients who do not have complications, it is still recommended in patients with complications such as mucosal edema, mucosal damage, hemorrhage, ureteral laceration and stone migration, and in patients with solitary kidney (9, 10). Boridy et al. (11) found that there was a significant relationship between the degree of PFS and obstruction in the study of patients with acute ureteral obstruction and the degree of obstruction was high in this study when PFS was excessive. In our study, complications related to infection in the postoperative period were found to be high in patients with PFS. PFS, urine leakage due to small tears in the calyx fornixes is seen as a linear increase in perinephric fat tissue density. However, PFS is not a specific finding. PFS is also seen in acute pyelonephritis, pyelonephrosis and renal vein thrombosis (12). It is recommended to perform contrastenhanced CT scan to exclude other possible causes in patients without stone in CT (13). Both obstruction and stasis in ureteral lumen caused by ureteral stones and DJ catheter insertion following treatment increase the risk of urinary infection. Risk of hydronephrosis, risk of PFS, level of thickening in the pararenal fascias and level of unilateral parenchymal thickening are proportional to severity of ureteral obstruction. PFS is more common in ureteral stones complicated by infection (14, 15). Stent insertion is an effective method to provide acute drainage of the hydronephrotic or pyonephrotic kidney (16). But in contrast, it may be the source of the infection in the long term period. Several studies reported bacterial colonization rates from 44% to 69% on ureteral stents and bacteriuria rates from 21% to 29.9%. Mild fever, urinary tract infection, even sepsis can be seen due to bacterial colonization of DJ stents (17). In a study conducted with 87 patients who underwent DJ stent insertion following emergency intervention (n:34) or elective intervention (n:53), postoperative fever was seen in 22 (25%) patients who did not have preoperative fever. Fever was seen in 56% of the patients who underwent stent insertion following emergency intervention, while it was present in only 6% of the patients underwent stent Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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E. Ogreden, U. Oğuz, E. Demirelli, E. Benli, Ö. Özen

insertion following elective intervention. Hence it was reported that stent insertion following emergency intervention significantly increased risk of fever (18). In another study, DJ stent was inserted in 26 of the 48 patients who underwent URS because of distal ureteral stone and 22 patients were followed up without a stent. Urosepsis was found in only 1 patient who underwent DJ stent insertion and the difference was not significant (19). A similar study reported that presence of fever was not associated with stent insertion (20). Ibrahim at al. (21) analyzed 110 patients with stent and 110 without stent in their large series, prospectively. Fever developed in 8 (7.3%) patients and UTIs developed in 5 (4.5%) patients in the stent group, while fever was present in 10 (9.1%) cases and UTIs were present in 7 (6.4%) cases in not stented group. Although there was no significant difference between the groups, presence of fever and infection were slightly higher in not stented group. They did not evaluate the radiological findings such as PFS. At the end of the URS procedures, stent insertion is not recommended in patients with hydronephrosis and PFS caused by ureteral stones. And the effects of the PFS on postoperative complications is still unclear. To the best of our knowledge, this is the first study focus on this topic in the literature. Compared with the literature, we found higher rates of infection related complications of URS in our study. Thus PFS due to ureteral obstruction can be a predisposing factor for the postoperative complications associated with infection. In addition, stent insertion did not reduce the risk for fever, UTIs and sepsis. Eventually, they were higher in stented patients without a significant difference. Prior studies reported that the necessity of DJ stent insertion increases in patients with higher stone burden and in male patients (22, 23). In the population of this study, female/male ratio, side and mean operative times did not significantly differ between the groups (p > 0.05). In contrast, mean stone burden and the localization of the stone were significantly higher in stenting patients. The surgeons' decision for inserting ureteral DJ stent seems to be affected mainly by the stone burden and the localization of the stone just like in the literature. We acknowledge that there were several limitations of this study. The most important limitation was that the study was designed in a retrospective nature. Thus patients were not randomized, and the surgeons might not be aware of the PFS, especially when the radiologist did not report it. In addition real incidences of significant or insignificant mucosal injuries in the study groups are not clear. Therefore, we cannot present the real indications for the ureteral DJ stent insertion. Hence, we believe that our findings need to be confirmed by further randomized prospective studies. Despite the shortcomings mentioned above, this is an important study since there is no previous data in the literature about this topic.

CONCLUSIONS

Compared with the literature, we found higher rates of infection related complications of URS in this study. Ureteral DJ stent insertion following URS due to ureteral

Archivio Italiano di Urologia e Andrologia 2018; 90, 1

stones did have a significant effect on postoperative infection related complications such as fever, UTIs and sepsis in patients with PFS.

REFERENCES

1. Straub M, Strohmaier WL, Berg W, et al. Diagnosis and metaphylaxis of stone disease. Consensus concept of the National Working Committee on Stone Disease for the Upcoming German Urolithiasis Guideline. World J Urol. 2005; 23:309-23. 2. Takahashi N, Kawashima A, Ernst RD, et al. Ureterolithiasis: can clinical outcome be predicted with unenhanced helical CT? Radiology. 1998; 208:97-102. 3. Stunell H, Buckley O, Feeney J, et al. Imaging of acute pyelonephritis in the adult. Eur Radiol. 2007; 17:1820-8. 4. Nabi G, Cook J, N'Dow J, McClinton S. Outcomes of stenting after uncomplicated ureteroscopy: systematic review and meta-analysis. BMJ. 2007; 334:572. 5. Joshi HB, Newns N, Stainthorpe A, et al. Ureteral stent symptom questionnaire: development and validation of a multidimensional quality of life measure. J Urol. 2003; 169:1060-64. 6. Keeley Jr FX, Timoney AG. Routine stenting after ureteroscopy: think again. Eur Urol. 2007; 52:642-44. 7. Fielding JR, Steele G, Fox LA, et al. Spiral computerized tomography in the evaluation of acute flank pain: a replacement for excretory urography. J Urol. 1997; 157:2071-73. 8. Hiller N1, Berkovitz N, Lubashevsky N, et al. The relationship between ureteral stone characteristics and secondary signs in renal colic. Clinical Imaging. 2012; 36:768-72. 9. Kara C, Bayındır M, Çiçekbilek I, et al. Comparison between ureteroscopy and extracorporeal shock wave lithotripsy in the treatment of distal ureteral stones. Turkish Journal of Urology. 2009; 35:28-33. 10. Cevik I, Dillioglugil O, Akdas A, Siegel Y. Is stent placement necessary after uncomplicated ureteroscopy for removal of impacted ureteral stones? J Endourol. 2010; 24:1263-67. 11. Boridy IC, Kawashima A, Goldman SM, Sandler CM. Acute ureterolithiasis: nonenhanced helical CT findings of perinephric edema for prediction of degree of ureteral obstruction. Radiology. 1999; 213:663-7. 12. Heneghan JP, Dalrymple NC, Verga M, et al. Soft-tissue "rim" sign in the diagnosis of ureteral calculi with use of unenhanced helical CT. Radiology. 1997; 202:709-11. 13. Chong WK, Wysoki M, Heller LG, Zegel HG. Renal carcinoma presenting with flank pain: a potential drawback of unenhanced CT. AJR Am J Roentgenol. 2000; 174:667-9. 14. Smith RC, Levine J, Rosenfeld AT. Helical CT of urinary tract stones. Radiol Clin N Am. 1999; 37:911-52. 15. Tenke P, Jackel M, Nagy E. Prevention and treatment of catheterassociated infections: Myth or reality? Eur Urol. 2004; 106-15. 16. Goldsmith ZG, Oredein-McCoy O, Gerber L, et al. Emergent ureteric stent vs percutaneous nephrostomy for obstructive urolithiasis with sepsis: patterns of use and outcomes from a 15-year experience. BJU Int. 2013; 112:122-8. 17. Paick SH, Park HK, Oh SJ, Kim HH. Characteristics of bacterial colonization and urinary tract infection after indwelling of double-j ureteral stent. Urology. 2003; 62:214-17. 18. Paz A, Amiel GE, Pick N, et al. Febrile complications follow-

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Double-J stent and perirenal fat stranding

ing insertion of 100 double-J ureteral stents. J Endourol. 2005; 19:147-50. 19. Srivastava A, Gupta R, Kumar A, Kapoor R, Mandhani A. Routine stenting after ureteroscopy for distal ureteral calculi is unnecessary: results of a randomized controlled trial. J Endourol. 2003; 17:871-74. 20. Cevik I, Dillioglugil O, Akdas A, Siegel Y. Is stent placement necessary after uncomplicated ureteroscopy for removal of impacted ureteral stones? J Endourol. 2010; 24:1263-67.

21. Ibrahim HM, Al-Kandari AM, Shaaban HS, et al. Role of ureteral stenting after uncomplicated ureteroscopy for distal ureteral stones: a randomized, controlled trial. J Urol. 2008; 180:961-65. 22. Matani YS, Al-Ghazo MA, Al-azab RS, et al. Emergency double-J stent insertion following uncomplicated Ureteroscopy: risk-factor analysis and recommendations. Int Braz J Urol. 2013; 39:203-8. 23. Tanriverdi O, Yencilek F, Koyuncu H, et al. Emergent stenting after uncomplicated ureteroscopy: evaluation of 23 patients. Urology. 2011; 77:305-08.

Correspondence Ercan Ogreden, MD (Corresponding Author) ercanogreden@gmail.com Ural Oğuz, MD uraloguz@yahoo.com Erhan Demirelli, MD erhandemirelli@yahoo.com Giresun University, Faculty of Medicine, Department of Urology Giresun, Turkey Erdal Benli, MD drerdalbenli@gmail.com Ordu University, Faculty of Medicine, Department of Urology Ordu, Turkey Özkan Özen, MD ozen@doctor.com Giresun University, Faculty of Medicine, Department of Radiology Giresun, Turkey Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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DOI: 10.4081/aiua.2018.1.20

ORIGINAL PAPER

Semirigid ureteroscopy prior retrograde intrarenal surgery (RIRS) helps to select the right ureteral access sheath Ioannis Boulalas, Mauro De Dominicis, Lorenzo Defidio Department of Urology, Cristo Re Hospital, Rome; Italy.

Summary

Objective: To evaluate ureteral compliance through semirigid ureteroscopy (sURS) in order to select the proper ureteral access sheath (UAS) size for retrograde intrarenal surgery (RIRS). Patients and methods: In a prospective study, 100 consecutive patients selected for elective sURS or RIRS were recruited. Each patient, initially underwent 9.5 Fr sURS with a safety guidewire 3Fr, in order to estimate ureteral compliance. If the ureter was compliant, a gently passage of a 12/14Fr UAS was attempted. If the ureter was not deemed compliant, passage of either a smaller UAS or a smaller semirigid 7Fr or a flexible 7.5Fr or a digital 8.5Fr scope with and without safety guidewire, was attempted. Age, gender, disease location, prestenting, previous RIRS and/or stone elimination, hydronephrosis, ureteral strictures, unsuccessful procedures, and complications, were analyzed as possible correlated factors of ureteral compliance. Results: In 77 patients the ureter was deemed compliant ≥ 14Fr. Of the preoperative factors that were examined, stent placement before RIRS (P < 0.002), previous RIRS (P = 0.000) and previous stone elimination (P = 0.004), correlated with ureter ≥ 14Fr. Ureteral lithiasis (P < 0.001), ureteral strictures (P < 0.05), unsuccessful procedures (P < 0.005) and complications (P = 0.01) correlated with ureter < 14Fr. The complication rate was 10% (10 patients) with ureteral injuries grade I in 9 patients and grade III in 1 patient according to the endoscopic grading system. Age, gender, hydronephrosis and urothelial carcinoma (UC) had no influence. Conclusions: sURS performed before RIRS allows selection of the right ureteral access sheath (UAS) and avoidance of major complications. Pre-stenting, previous RIRS and stone elimination history are all factors correlating with a compliant ureter.

KEY WORDS: Semirigid ureteroscopy; Retrograde intrarenal surgery (RIRS); Ureteral compliance; Ureteral access sheath (UAS). Submitted 8 November 2017; 19 November 2017

INTRODUCTION

The management of intra-renal collecting system pathology has changed radically over the recent decades mainly due to increasing use of flexible uretero-renoscopy (fURS), constituting one of the most dynamic fields of endourology. Thanks to technologic improvements in the endoscopic armamentarium, flexible uretero-renoscopic approaches to the kidney have evolved from a mere diagnostic tool, to a complex diagnostic and therapeutic procedure in the entire upper tract collecting system (1).

Nowadays, retrograde intrarenal surgery (RIRS) (2, 3) is used in the treatment of urinary lithiasis (4), upper tract urinary tumors (5, 6), as well as in special circumstances such as pregnancy, anatomic malformations, coagulopathy or solitary kidney (7, 8). Urinary stones disease poses a significant health care burden in a working-age population. A recent analysis of National Health and Nutrition Examination Survey (NHANES) data in the United States from 2007 to 2010 reported that the prevalence had increased to 8.8% (10.6% among men vs 7.1% among women), compared with 5.5% in NHANES III (1988-1994) (9). Upper tract urothelial carcinoma (UTUC) constitutes approximately 5-6% of all urothelial malignancies. Ureteral tumors represent approximately 25% of UTUCs (10). In 2013, the European Association of Urology (EAU) for the first time included RIRS as a viable treatment option for renal stones, even larger than 2 cm in diameter (11). Moreover, the UTUC EAU Guidelines support renalsparing surgery in imperative cases and low-risk patients (12). The ureteral access sheath (UAS) was introduced as a means of passing a flexible uretero-renoscope into the distal ureter. Its use also facilitates multiple re-entries into the kidney, improves fluid outflow, thereby reducing the intrarenal pressure, decreases operative time, increases stone clearance, and protects the endoscope from damage (13, 14). However the routine use of a UAS is matter of debate (11). Limited data is available to predict which patients selected for RIRS may have a difficult ureter and in which cases success is most probable. The hypothesis that endoscopic evaluation of ureteral size may help urologists to select the proper UAS size for RIRS, was prospectively tested and possible correlating factors for success or failure were analyzed.

PATIENTS

AND METHODS

This study was carried out at ‘Cristo Re’ Hospital in Rome, after institutional review board approval was obtained, by two experienced urologists, who treated a similar number of patients. Both surgeons were present during the procedures, thus avoiding any difference in the assessment accuracy. A total of 100 consecutive patients (72 males and 28 females) between March 2016 and September 2016, with urinary lithiasis, upper urinary tract tumors, No conflict of interest declared.

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Semirigid ureteroscopy prior RIRS

hematuria and ureteral stenosis planned for elective semirigid ureterorenoscopy or RIRS were included in the study. All patients had a clinical evaluation, urine dipstix analysis with additional culture and sensitivity if a urinary tract infection (UTI) was suspected, a measurement of serum creatinine level, abdominal ultrasonography (US) and a plain abdominal X- ray. Additional computed tomography (CT) was used, according to the level of serum creatinine and stone radiolucency. Patients were placed in the lithotomy position and received prophylactic parenteral antibiotics before the procedure, which was performed under spinal or general anesthesia. The standard technique was initiated with rigid cystoscopy, followed by ureteral catheterization of the renal unit in question with an end-hole 5Fr catheter (Pollack Cook Urological, Spencer, IN). A retrograde pyelogram was performed to define the anatomy and visualize any filling defect. A hydrophilic tipped guidewire 0.035/150 cm (Sensor®, Boston Scientific, Marlborough, MA, USA) was passed via the ureteral catheter, just to the renal pelvis under fluoroscopic guidance, and set aside as a safety wire, and then the cystoscope and the retrograde catheter were removed. A second hydrophilic tipped guidewire was introduced into the ureteral orifice through the 9.5Fr Storz semirigid ureteroscope’s (27002L Karl Storz, Rietheim-Weilheim, Germany) working channel that allowed retrograde ureteral access with relative ease. A gentle attempt was made for ureteroscopic access between these two guidewires. This maneuver allowed the optical ureteral dilation, permitting an easier upper tract access as well as inspection for the presence of pathology such as stones, strictures, or tumors, offering the possibility of treatment along all the ureter and, often, also in the kidney. At the same time, ureteral compliance and caliber were assessed in order to select the proper UAS size, avoiding ureteral injuries. The ureteroscope was withdraw and the UAS 12\14 Fr 35 cm (Flexor, Cook Urological, Spencer, IN) was introduced gently into the ureter under fluoroscopic control, by gliding over the working guidewire. In patients with ureteral stent, a PTFE guidewire 0.035/145 cm (Cook Urological, Spencer, IN) was inserted and advanced to the kidney through the distal end of the stent which had been brought to the urethral meatus. Finally the inner UAS obturator with the guidewire was removed and the 7Fr\43 cm Storz semirigid, or flexible or digital ureteroscope (27000L, Flex-X2 or, Flex- XC Karl Storz, Rietheim-Weilheim, Germany) was inserted to complete the operation with a Holmium or Thulium Iaser device (15). We selected 12\14Fr as the best UAS size because it can accept all the flexible and some semirigid ureteroscopes, while maintaining a good drainage in order to keep low intrarenal pressures. In difficult cases, when the ureter didn’t accept the larger UAS, first we tried to remove the safety guide wire with the purpose to get more room. If still the passage of the larger UAS was not easy, we used a smaller UAS (11\13Fr Flexor, Cook Urological, Spencer, IN). If this attempt was also without success, we then tried to introduce the flexible or digital scope, with or without the safety guidewire, under visual or fluoroscopic control. If again this attempt was encountered with resistance, we stopped the procedure, put a DJ stent and tried the week after. If the patient was not planned for RIRS, but presented

with an impacted ureteral stone with hydronephrosis, we still inserted an access sheath just below the stone and we performed a lasertripsy of the stone with a semirigid scope (7Fr or smaller) inside the access sheath, in order to have a continuous flow with gravity irrigation and still low retro-pulsion pressures and expulsion of fragments retrieval through the sheath. The primary outcome was the assessment of the ureteral compliance to identify a potential difficult ureter. A compliant ureter was defined as a ureter ≥ 14Fr if accepted easily the passage of a semirigid scope 9.5Fr with a safety guidewire 3Fr aside. Patient’s data collected, included age, gender, side, hydronephrosis, stone location (renal, ureteral, renal & ureteral), UTUC, presence of ureteral strictures, an indwelling ureteral stent, previous RIRS, and previous stone elimination history. Statistical analyses The significance of possible factors affecting ureteral compliance was analyzed. Statistical analysis was performed with SPSS 20 adopting the chi-square test for nominal variables and the Mann-Whitney U test for continuous variables. Statistical significance was considered at p < 0.05.

RESULTS

The study group included 100 consecutive patients that were treated at ‘Cristo Re’ Hospital in Rome. Patient’s data are presented in Table 1. 82% and 18% of the patients were submitted to RIRS and sURS respectively, with or without use of UAS. Hydronephrosis was present in 56% of the patients while in 29% a DJ stent was inserted before (24 patients) and during surgery (5 patients) due to acute obstruction, insistent pain, fever, pus, ureteral injury, ureteral stricture and non compliant ureter. A compliant ureter with a diameter ≥ 14Fr was present in 77 patients because a 12/14Fr UAS was inserted gently with or without a safety guidewire, either a 9.5Fr semirigid ureteroscope with a safety guidewire was used (objective evaluation). In 23 patients, the ureter was non Table 1. Patient demographics. Patient, n Mean age years (range) Men Women Ureteral stone Renal stone Ureteral & Renal Stone UTUC, hematuria Ureteral stricture Side right/left Hydronephrosis (%) Indwelling Double-J stent, n(%) Previous RIRS, n(%) Previous stone elimination, n(%)

100 54 (16-89) 72 28 18 45 12 22 23 51/49 56 29 29 42

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I. Boulalas, M. De Dominicis, L. Defidio

DISCUSSION

Table 2. Results of ureteral calibration. Patients Ureter diameter 77 ≥ 14fr Gently passage of a 12/14Fr UAS with or without a safety guidewire Gently passage of a 9.5 Semirigid Ureteroscope with a safety guidewire

≥ 14fr

4 ≥ 14fr Patients Ureter diameter 23 < 14fr

Gently passage of a 11/13F UAS after removal of the safety guidewire Gently passage of a 7Fr Semirigid, flexible or or digital Uretero-renoscope with or without a safety guidewire

< 14fr

Table 3. Complications. Guidewire UAS

Patient 10 8 2

Patients, grade 8 Grade I 1 Grade I 1 Grade III

compliant with a diameter < 14Fr due to insertion of either a 11/13Fr UAS after removal of the safety guidewire, or of a 7Fr semirigid or flexible or digital ureteroscope with or without safety guidewire (Table 2). In 7 patients, we had to stop the procedure and a DJ stent or nephrostomy tube was introduced. Complications were noted in 10 patients. Guidewire-induced ureteral damage occurred in 8 patients with grade I lesions, while UAS- induced ureteral injuries occurred in 2 patients with grade I lesion in one case and grade III in the other according to the endoscopic grading system (16) (Table 3). Different factors that may influence the ureteral compliance were examined. The following parameters correlated statistically with a ureter ≤ 14F: ureteral lithiasis, ureteral stricture, unsuccessful procedures and complications (Table 4). Table 4. Parameters of compliant ureter.

Age Sex (males) Ureteral lithiasis Pre-stenting Hydronephrosis First time RIRS Previous RIRS Number of patients with renal stones ≤ 1.5 cm (%) Number of patients with ureteral stones ≤ 1 cm (%) UTUC Ureteral stricture Previous stone elimination Unsuccessful procedures Complications

Compliant ≥ 14Fr 77 pts 57.6 53 (69%) 13 (17%) 28 (36%) 39 (51%) 47 (61%) 26 (34%) 22 (28%)

Non compliant < 14Fr 23 pts 52 19 (83%) 14 (61%) 1 (4%) 17 (74%) 15 (65&) 3 (13%) 4 (17%)

(2.6%)

(8.6%)

18 1 29 0 5

(23%) (1.3%) (38%)

4 22 11 7 5

(17%) (95%) (49%) (30%) (21%)

(6.5%)

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Over the last decade the advancements in technology and digital optics have led to an increasing role of fURS in the treatment of upper urinary tract pathology. A ureteral access sheath is an important tool during RIRS, because it lowers intra-renal pressure, facilitates ureteral re-entry, decreases costs, reduces operative time, and improves flexible uretero-renoscope longevity (17). There are different UAS’s in the market with different characteristics, sizes and lengths. Factors that are important in clinical application include a lubricated outer coating to facilitate entry, a lower friction inner coating for easy uretero-renoscope insertion, and a reinforced wall to decrease sheath kinking and bulking (18). The standard UAS has an external diameter of 14Fr, which is larger than the median 9Fr to 10Fr diameter of non stented ureters, as evaluated on imaging studies (19). Insertion of a UAS depends on the ureter status and on its anatomic variants. Failure rates of primary access due to difficult impassable ureter range from 8%-10% (20, 21). Lallas et al. in animal models showed that the over distention created by the UAS caused a transient decrease in ureteral blood flow which restored at a basal level by the compensatory mechanisms of the ureteral wall and the integrity of the ureter was preserved. However, care must be taken for selecting an appropriate-size sheath and the duration of surgery should not be long because the risk of stricture development has not been clearly put forward (22). Viers et al. examined the association between clinic-radiographic features and need for pre-stenting due to inability of the ureter to accommodate the ureteroscope or the UAS, and found 17% incidence of primary upper tract access failure. Prior ipsilateral ureteral surgery and stenting were protective whereas < 50% ureteral opacification was associated with an increased risk of access failure (23). Some authors position the UAS under fluoroscopic guidance with the application of reasonable strength on the working guidewire without the performance of semi-rigid ureteroscopy (23) whereas others calibrate the ureter with an 8F/10F coaxial dilator (Boston Scientific) (24). Additional strategies, that are used to go into the ureter, include p-value routine stent placement before RIRS which entails two-stage procedure, sequential 0.1 ureteral dilators or balloon dilation with sig0.4 nificant risk of ureteral injury (25). < 0.001 In a prospective study in 248 patients < 0.002 undergoing sURS and fURS Mogilevkin et al. 0.1 found that in 22% of patients the UAS was 1 not easily passed. Factors of successful 0.000 insertion were: older age, presenting and 0.6 previous same-side ureteroscopy (25). Traxer and Thomas, in a two center 1 prospective review, collected data on 359 patients who received a 12/14Fr UAS 0.5 before a RIRS for renal stones. The authors < 0.05 identified and classified any ureteral 0.004 injuries. UAS-induced ureteral lesions < 0.005 occurred in 46.5% of patients, with com< 0.01 plete wall perforation in 13.4%.

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The authors conclude that is imperative to visualize the ureter at the end of the procedure and that pre-stenting can reduce the risk of severe injury to the ureter. Risk factors for high grade lesions included age, male gender, and lack of preoperative stent (26). However, in another work on 2239 patients treated with fURS from the Clinical Research Office of the Endourological Society (CROES), Traxer et al. reported that UAS usage did not increase the risk of ureteral wall damage (27). Guzelburc et al. in a prospective study investigated ureteral injuries by placing two different UAS (9.5/11.5Fr-12/14Fr) during retrograde intrarenal surgery (RIRS) for renal stones. The researchers identified 41,6% ureteral lesions, with deep tear of the mucosal and submucosal layer in 2.97% (PULS grade 2) of patients and no injuries of grade 3+. PULS grade 2 patients were all males and a DJ stent was placed preoperatively in all cases (28, 29). Yet, there have been few studies demonstrating significant long-term ureteral damage following the use of a UAS. In the past, one ureteropelvic junction stricture (1.4%) was noted to occur during a mean follow-up of 11 months after UAS use (30). In our study 77% of the patients had a compliant ureter ≥ 14Fr, and 23 a not compliant ureter < 14Fr. Age, sex, stone size, hydronephrosis, or UTUC had no influence on ureteral compliance in this analysis. Patients with an indwelling DJ stent, previous RIRS history and previous stone elimination accommodated easily a 12/14Fr UAS. The presence of ureteral stone adversely affected compliance due to acute or chronic inflammation. The ureteral stricture caused by impacted stones, recurrences, or conservative treatment of UTUC’s were also consistent with a non compliant ureter < 14Fr. Finally the unsuccessful procedures and the complications were correlated with a not compliant ureter. The overall low incidence of unsuccessful procedures (7%) is due to the adoption of some tricks before interrupting the procedure, such as the removal of safety guidewire or the use of a smaller UAS or ureteroscope. Only in 8 patients complications were caused by the guidewire and only in 2 by the UAS, of which only one had a grade 3 lesion. The low complications rate (10%), most of them of grade I, is probably due to the respect of the two fundamental endourological rules: the first one is to adapt the instrument\device to the ureter and not the ureter to the instrument, and the second one is to never force in the introduction or extraction of instrument or device. In the current study the importance of our technique to perform sURS prior to UAS insertion during RIRS is demonstrated, as it permits ureteral inspection and allows assessment of ureteral compliance. Those with a low likelihood for effective 12/14Fr UAS include patients with ureteral stricture and ureteral stone. However, this study presents some limitations due to the small number of patients. Probably the data can be different in a larger cohort of patients. Also, we didn’t have a follow-up of patients to report possible postoperative complications.

CONCLUSIONS

Semirigid ureteroscopy performed prior retrograde intrarenal surgery (RIRS) is an outstanding tool for evaluation of ureteral compliance, allowing selection of the correct UAS size. A compliant ureter ≥ 14Fr was found in 3/4 of the patients. Parameters of successful insertion of a 12/14Fr UAS were an indwelling DJ stent, and a history of previous RIRS or stone elimination while the presence of a ureteral stone or stricture, unsuccessful procedures and complications significantly predicted a non compliant ureter < 14Fr.

REFERENCES

1. Oberlin DT, Flum AS, Bachrach L, et al. Contemporary surgical trends in the management of upper tract calculi. J Urol. 2015; 193:880. 2. Patel A, Fuchs GJ. Expanding the horizons of SWL through adjunctive use of retrograde intrarenal surgery: New techniques and indications. J Endourol. 1997; 11:33. 3. Shin R, Lipkin M, Preminger G. Disposable devices for RIRS: Where do we stand in 2013? What do we need in the future? World J Urol. 2015; 33:241. 4. Ordon M, Urbach D, Mamdani M, et al. The surgical management of kidney stone disease: a population based time series analysis. J Urol. 2014; 192:1450. 5. Cornu JN, Rouprêt M, Carpentier X, et al. Oncological control obtained after exclusive flexible ureteroscopic management of upper urinary tract urothelial carcinoma. World J Urol. 2010; 28:151. 6. Cutress ML, Stewart GD, Wells-Cole S, et al. Long-term endoscopic management of upper tract uothelial carcinoma (UTUC): 20years single-centre experience. BJU Int. 2012; 110:1608. 7. Giusti G, Proietti S, Cindolo L, et al. Sky is not the limit for ureteroscopy: extending the indications and special circumstances World J Urol. 2015; 33:257. 8. Giusti G, Proietti S, Cindolo L, et al. Is retrograde intrarenal surgery a viable treatment option for renal stones in patients with solitary kidney? World J Urol. 2015; 33:309. 9. Shoag J, Tasian GE, Goldfarb DS, et al. The new epidemiology of nephrolithiasis. Adv Chronic Kid Dis. 2015; 22:273. 10. Bader MJ, Sroka R, Gratzke C, et al. Laser therapy for upper urinary tract transitional cell carcinoma: indications and management. Eur Urol. 2009; 56:65. 11. Türk C, Petrik A, Sarica K, et al. EAU Guidelines on Interventional Treatment for Urolithiasis. Eur Urol. 2016; 69:475. 12. Rouprêt M, Babjuk M, Compérat E, et al. European Association of Urology Guidelines on Upper Urinary Tract Urothelial Cell Carcinoma. Update Eur Urol. 2015; 68:868. 13. Stern JM, Yiee J, Park S. Safety and efficacy of ureteral access sheaths. J Endourol. 2007; 21:119. 14. Bach C, Nesar S, Kumar P, et al. The new digital flexible ureteroscopes: ‘size does matter’- increased ureteric access sheath use. Urol Int. 2012; 89:408. 15. Defidio L, De Dominicis M, Gianfrancesco D, et al. First collaborative experience with thulium Laser ablation of localized upper urinary tract urothelial tumors using retrograde intra-renal surgery Arch Ital Urol Androl. 2011; 83:147. 16. Karakan T, Kilinc MF, Demirbas A, et al. Evaluating Ureteral Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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I. Boulalas, M. De Dominicis, L. Defidio

Wall Injuries with Endoscopic Grading System and Analysis of the Predisposing Factors. J Endourol. 2016; 30:375. 17. Defidio L, De Dominicis M, Di Gianfrancesco L, et al. Improving Flexible Ureterorenoscope Durability Up to 100 Procedures. J Endourol. 2012; 26:1329. 18. Khanna R and Monga M. Instrumentation in endourology. Ther Adv Urol. 2011; 3:119. 19. Zelenko N, Coll D, Rosenfeld AT, et al. Normal ureter size on unenhanced helical. CT AJR. 2004; 182:1039. 20. Cetti RJ, Biers S, Kcoghane SR. The difficult ureter: what is the incidence of presenting? Ann R Coll Surg Engl. 2011; 93:31. 21. Bourdoumis A, Tanabalan C, Goyal A, et al. Stent and come back or balloon dilate and proceed with ureteroscopy? What does the evidence say? Urology. 2014; 83:1. 22. Lallas C, Auge B, Raj G, et al. Laser Doppler flowmetric determination of ureteral blood flow after ureteral access sheath placement J Endourol. 2002; 16:583. 23. Viers B, Viers L, Hull N, et al. The difficult ureter: Clinical and radiographic characteristics associated with upper urinary tract access at the time of ureteroscopic stone treatment. Urology. 2015; 86:878. 24. Goldberg H, Holland R, Tal R, et al. The impact of retrograde

Correspondence Boulalas Ioannis, MD, PhD (Corresponding Author) iboulalas@yahoo.gr De Dominicis Mauro, MD dedominicism@alice.it Defidio Lorenzo, MD defidio@tin.it Department of Urology - Cristo Re Hospital Via delle Calasanziane 25, 00167 Rome, Italy

Archivio Italiano di Urologia e Andrologia 2018; 90, 1

intrarenal surgery for asymptomatic renal stones in patients undergoing ureteroscopy for a symptomatic ureteral stone J Endourol 2013; 27: 970. 25. Mogilevkin Y, Sofer M, Margel D, et al. Predicting an effective ureteral access sheath insertion: A bicenter prospective study. J Endourol. 2014; 28:1414. 26. Traxer O. and Thomas A.Prospective evaluation and classification of Ureteral wall injuries resulting from insertion of a ureteral access sheath during retrograde intrarenal surgery. J Urol. 2013; 189:580. 27. Traxer O, Wendt-Nordahl G, Sodha H, et al. Differences in renal stone treatment and outcomes for patients treated either with or without the support of a ureteral access sheath: The Clinical Research Office of the Endourological Society Ureteroscopy Global Study. World J Urol. 2015; 33:2137. 28. Guzelburc V, Guven S, Boz MY, et al.Intraoperative Evaluation of Ureteral Access Sheath-Related Injuries Using Post-Ureteroscopic Lesion Scale J Laparoendosc Adv Surg Tech A. 2016; 26:23. 29. Schoenthaler M, Buchholz N, Farin E, et al. The PostUreteroscopic Lesion Scale (PULS): a multicenter video-based evaluation of inter-rater reliability. World J Urol. 2014; 32:1033. 30. Delvecchio FC, Auge BK, Brizuela RM, et al. Assessment of stricture formation with the ureteral access sheath. Urology. 2003; 61:518.

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ORIGINAL PAPER

DOI: 10.4081/aiua.2018.1.25

Comparison of three most frequently used alpha blocker agents in medical expulsive therapy for distal ureteral calculi, result of a retrospective observational study Aykut Buğra Sentürk 1, Cemil Aydin 1, Musa Ekici 1, Muhammet Yaytokgil 2, Ali Akkoc 3, Mehmet Murat Baykam 1 1 Hitit

University Corum Training and Research Hospital, Turkey; State Hospital, Turkey; 3 Alanya Alattin Keykubat University, Turkey. 2 Rize

Summary

Purpose: In this study, we compared the effects of three agents frequently used in daily life for medical expulsive therapy. Materials and methods: A total of 143 patients meeting the criteria were included in the study. Patients were divided into three homogeneous drug groups which were tamsulosin group (n:48), alfuzosin group (n:47) and silodosin group (n:48). The time of stone expulsion, analgesic needs, side effects of the medicine and endoscopic intervention needs of the patients were recorded. Results: The rate of stone expulsion was 70.8% (n:34) in tamsulosin group, 70.2% (n:33) in alfuzosin group, and 75% (n:36) in silodosin group. No significant difference was observed among the rates of stone expulsion in three groups, and the rates of stone expulsion were similar (p = 0.778). The duration of stone expulsion was significantly different in the groups (p = 0.012): the time of stone expulsion for tamsulosin was 2.33 ± 0.78 days longer than for Silodosin, indicating a significant difference. There was no significant difference between tamsulosin-alfuzosin and silodosin-alfuzosin (respectively p = 0.147, p = 0.925). Conclusions: The results of this study showed that medical expulsive therapy by using alpha blocker agents is safe and efficacious. This option must be kept in mind for patients who do not ask for surgery as the first-step treatment for eligible patients.

KEY WORDS: Urology; Ureter; Stone. Submitted 13 February 2018; 24 February 2018

INTRODUCTION

Urolithiasis is one of the most common disorders of urinary tract affecting about 5%-10% of the population. Renal stones are most prevalent between the ages of 20 and 40 years and are three times greater in men than women (1). Women typically excrete more citrate and less calcium than men, which may explain the higher incidence of stone diseases in men. Twenty-two percent of all urinary tract stones are found in ureter, of which 68% are seen in the distal ureter (2). The treatment of urinary stones basically varies depending on the anatomic location of the stone, the size of the stone and the factors related with the patient. The treatments of the ureteral calculi are observation, medical

expulsive therapy, extracorporeal shock wave and lithotripsy (ESWL), retrograde ureterorenoscopy, antegrade percutaneous ureterorenoscopy, and laparoscopic and open ureterolithotomy (3). The location and the size of the stone, the availability of the technology, the treatment cost, the experience of the surgeon, and the preference of the patients are considered when a treatment is chosen among the other alternatives (4). The probability of spontaneous expulsion of the ureteral calculi has two factors: the size of the calculi and the anatomic location of the calculi. According to a metaanalysis, the rate of spontaneous expulsion of the stones smaller than 5 mm is 68% while it is 47% for the stones bigger than 5 mm and smaller than 10 mm (5). When anatomic location is considered, it is seen that 71% of the distal ureteral calculi and 22% of the proximal ureteral calculi expulse spontaneously (6). Therefore, spontaneous expulsion of the stone protects the patient from surgical intervention, anesthesia risk and additional costs, who does not have infection history and who has pain control and small size of calculi. By this way, with the understanding of the ureter physiology in detail, the concept of medical expulsive therapy has been developed in order to make the spontaneous expulsion of the stone easier. The purpose of the medical expulsive therapy is to increase the spontaneous probability of the stone expulsion by enabling relaxation in the ureter smooth muscle structure and eventually it reduces the pain level and frequency felt by the patient, shorten the time of stone expulsion, reduces the need of operation, prevents the risk and complications related with the operation and reduces the cost of the treatment. Some main points need attention during the medical expulsive treatment. The most important two factors of them are the location of the calculi in the ureter and the size of the calculi. The maximum upper limit recommended for the treatment of the medical expulsive is 10 mm (7). Many treatment alternatives are available for medical expulsive treatment. Calcium channel blockers, alpha blockers, phosphodiesterase type 5 inhibitors and corticosteroids are the most frequently used drugs. In the guide of European Society of Urology, it is mentioned that

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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A. Buğra Sentürk, C. Aydin, M. Ekici, M. Yaytokgil, A. Akkoc, M. Murat Baykam

alpha blockers are more successful for medical expulsive treatment and calcium channel blockers are successful only when nifedipine is used for medical expulsive treatment. Also corticosteroids are recommended to be used not alone but with other drugs for medical expulsive treatment purpose (8). In the various studies, it was shown that phosphodiesterase type 5 inhibitors increase the spontaneous stone expulsion by causing the relaxation of ureter smooth muscles; however, there is no sufficient data for its clinical use (9). Although alpha adrenergic receptors are available in all ureter segments, these receptors are usually located at distal ureter (10). Density order in distal ureter is alpha1d> alpha-1a>alpha-1b (11). In this retrospective study, we investigated the effects of three agents frequently used in daily life for medical expulsive therapy on each other.

MATERIALS

AND METHODS

22.0, SPSS Inc., Chicago, IL, USA). Descriptive statistics were presented as mean ± standard deviation (SD) values. Shapiro-Wilk test was used to check for normality of distribution. Patient characteristics in the three age groups were compared using Pearson's chi-squared test in case of discrete variables. The significance of the difference between three groups were assessed by using one-way analysis of variance (ANOVA) in case of normal data distribution, or KruskalWallis test (non-parametric analysis of variance) in case of non-normal distribution for continuous variables. Bonferroni post hoc test was applied to determine the differences between the pairwise groups. P values < 0.05 were considered to be statistically significant.

RESULTS

In each group, the sizes of the stones were similar (p = 0.224) (Table 1). The sizes of the stones were 7.10 ± 1.80 mm in tamsulosin group, 6.55 ± 1.58 mm in alfuzosin group, and 6.65 ± 1.57 mm in silodosin group. The rate of stone expulsion was 70.8% (n:34) in tamsulosin group, 70.2% (n:33) in alfuzosin group, and 75% (n:36) in silodosin group. No significant difference was observed among the rates of stone expulsion in the three groups, and the rates of stone expulsion were similar (p = 0.778). Despite the medical expulsive treatment lasting for four weeks, the rates of ureterorenoscopy operations due to non-expulsing stone was 29.2% (n:14) in tamsulosin group, 10.6% (n:14) in alfuzosin group and 25% (n:12) in silodosin group. The duration of stone expulsion was 10.41 ± 3.61 days in tamsulosin group, 8.87 ± 3.54 days in alfuzosin group, and 8.09 ± 3.66 days in silodosin group. The duration of stone expulsion was significantly different in the groups (p = 0.012). According to post hoc test results, the difference between silodosin and tamsulosin groups was (p = 0.010). So, the time of stone expulsion in tamsulosin was 2.33 ± 0.78 days longer than the one in silodosin, indicating a significant difference. There was no significant difference between tamsulosinalfuzosin and silodosin-alfuzosin (respectively p = 0.147, p = 0.925). No statistical difference was found between 3 drug groups in terms of frequency of colic attack and analgesic usage (respectively p = 0.25, p = 0.45). Hypotension which is a major adverse effect of the drug was 8.5% in tamsulosin group, 4.5% in silodosin group, and 6.4% in alfuzosin group. Although retrograde ejaculation was seen more frequently in silodosin group than the other groups, there was no statistical difference (p = 0.35).

The study was undertaken retrospectively in accordance with the principles of the Declaration of Helsinki. Between January 2013 and October 2017, the data of 365 patients who were admitted to a polyclinic with distal ureter calculi size between 4-10 mm were investigated retrospectively. They were grouped homogeneously in terms of calculi size, patient age and gender. Those patients who had bilateral ureter calculi, severe urinary tract infection, severe colic attack, fever, severe hydronephrosis, renal impairment, history of endoscopic surgery due to ureter calculi, and history of drug which interact with alpha blockers were excluded from the study. Urine analysis, blood urea and creatinine values and complete blood count of all the patients were recorded before the treatment. Those patients who had calculi with the size of 410 mm which were located under the common iliac arteries and confirmed by computarized tomography, and those responding to the analgesic treatment were included in the study. A total of 143 patients meeting the criteria were included in the study. Patients were divided into three homogeneous drug groups which were tamsulosin group (n:48), alfuzosin group (n:47) and silodosin group (n:48). The patients in tamsulosin group received one dose of 0.4 mg/day tamsulosin orally, the patients in alfuzosin group received one dose of 10 mg/day alfuzosin orally, and those in silodosin group received one dose of 8 mg/day silodosin orally. In each group, the medical treatment was maintained until the patients expulsed the stone or for four weeks. When the patients had pain, they were administered analgesic. The time of stone expulsion, analgesic needs, side effects of the drug and endoscopic intervention needs of the patients Table 1. Demographic values of groups. were recorded. The expulsion of the non-transparent stones was confirmed Tamsulosin by ultrasonography and transparent Mean age ± SD (year) 40.37 ± 12.43 stones were confirmed by unenhanced tomography. Mean stone diameter ± SD (mm) 7.10 ± 1.80 All statistical analysis were performed Male/female (n) 24/24 with SPSS statistical software (Version

Archivio Italiano di Urologia e Andrologia 2018; 90, 1

Alfuzosin

Silodosin

P value

41.15 ± 12.15

41.46 ± 15.04

p = 0.919

6.55 ± 1.58

6.65 ± 1.57

p = 0.224

27/20

26/22

p = 0.778

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Alpha blockers in medical expulsive therapy

Figure 1. Stone expulsion duration in the groups.

DISCUSSION

Due to risk of complications for ureteral stones less than 10 mm in size during minimal invasive treatments and their high costs, nowadays the treatment of ureteral stones vary in the direction of conservative treatment. Management of ureteral stones depends on the size, location, number, structure of the stone and presence of the symptoms. Ureteral spasm, ureteral anatomy and mucosal edema by inflammation affect the rate of stone expulsion. Watchful waiting for distal ureteral stones is a good option in patients with no infection, tolerable colic attacks and small stone size. The aim of medical expulsive therapy is to facilitate spontaneous stone expulsion by relaxing ureteral smooth muscle without any disruption of ureteral peristalsis and to reduce the severity of pain of the patient. This idea depends on good spontaneous expulsion rates of small ureteral stones. Natural spontaneous expulsion rate of distal ureteric calculi is 68% for stones less than 5 mm in size. And this rate is about 47% for stones with sizes between 5 and 10 mm (5). Besides of the size, the localization of the calculi is also an important factor for spontaneous expulsion. The spontaneous expulsion rate of proximal ureter stone is 21%, of middle ureter stone 46%, and of distal ureteral stone 71% (6). Alpha-1 receptors have been classified into three subtypes, which are alpha-1A, alpha-1B and alpha-1D. Alpha-1D and alpha-1A are the most common adrenoceptors found in the ureter (12) and the distributions of these receptors are alpha-1D > alpha-1A > alpha-1B (11). Alpha-1D receptors are found predominantly in the intramural ureter and detrusor muscle and they are the target of medical expulsive therapy as they are found generally in the distal ureter (13). Itoh et al. reported that the distal part of the ureter expresses the higher amount of alpha-1 adrenoceptor than the other parts. Also it was demonstrated that alpha-1D adrenoceptor mRNA is much more common than alpha-1A adrenoceptor mRNA in each part of the ureter. Therefore, alpha-1D adrenoceptor blocker can be more useful than alpha 1A adrenoceptor blocker to facilitate expulsion of ureteral calculi according to their study (11). But in contrast, Tatemichi et al. reported that ureteral motility is medicated more commonly by alpha 1A adrenoceptors (14).

A study comparing the efficacy of silodosin to tamsulosin including 136 patients with proximal ureter stone which are in diameter of 4-10 mm showed that the patients treated with silodosin demonstrated a significant increase in expulsion rate and a decrease in expulsion duration of lower ureteral stones (61.2 versus 80.3%) (19). A meta-analysis involving eight publications from Huang W et al. indicated that silodosin was superior to placebo or tamsulosin in the efficacy for distal ureteral calculi treatment with better control of pain (18). Also, a multi-institutional, randomized, double-blinded, placebo-controlled trial from Sur RL et al. reported that silodosin was found to be well tolerated and beneficial in facilitating the expulsion of distal ureteral stones (17). In our study, we found a similar effect between silodosin and tamsulosin groups in terms of stone expulsion (p = 0.010). Stone expulsion duration was 10.41 + 3.61 days in tamsulosin group and 8.09 + 3.66 days in silodosin group. The stone expulsion duration of tamsulosin was significantly longer than the duration with silodosin (2.33 Âą 0.78 days). As mentioned in similar studies, we consider that this finding is associated with the selective alpha 1-A adenoceptor antagonist effect of silodosin rather than the alpha-1 adrenoceptor antagonist effect of tamsulosin. We also did not found any statistical difference between tamsulosin-alfuzosin and silodosin-alfuzosin in terms stone expulsion duration (p = 0.147, p = 0.925 respectively). In the study of Imperatore V et al., it was reported that both tamsulosin and silodosin are equally effective as medical expulsive treatment (MET) for distal ureteral calculi sized < 10 mm. Stone-expulsion rate was 88% in silodosin group and 82% in tamsulosin group (20). Similarly, while stone expulsion rate was 70.8% in tamsulosin group, 70.2% in alfuzosin group and 75% in silodosin group in our study, we found no statistical difference between three groups in terms of stone expulsion rates (p = 0.778). Increase in intraureteral pressure due to obstruction causes colic pain attacks. Alpha blockers which are used predominantly for stone expulsion may also decrease analgesic drug usage by expulsion of ureteral calculi (16). Kumar et al. reported that stone expulsion by an alpha 1 adrenoceptor on the obstructed ureter is facilitated by increasing the intaureteral pressure gradient around the stone and decreasing peristalsis below the ureter (13) and alpha blockade may decrease ureteric colic attacks by blocking C fibers which are responsible for pain (15). Although we could not find any statistical difference between three groups in terms of the frequency of colic attack in our study (p = 0.45). The medical expulsive treatment should be discontinued in case of severe urinary infection and hydronephrosis, and endoscopic surgery should be considered. In our study, the rate of patients who needed endoscopic procedure due to nonexpulsing stones was 29.2% (n:14) in tamsulosin group, 10.6% (n:14) in alfuzosin group, and 25% (n:12) in silodosin group. Medical expulsive therapy is a cost-effective non-surgical treatment for ureteral calculi less than 10 Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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A. Buğra Sentürk, C. Aydin, M. Ekici, M. Yaytokgil, A. Akkoc, M. Murat Baykam

mm in size. Several studies showed that alpha-1 adrenoceptor blockers can facilitate spontaneous passage of distal ureteral calculi with minimal side effects. A study from Bensalah K et al. reported that medical expulsive therapy using tamsulosin resulted in a cost advantage for 1,132 USD over observation in USA. Since the cost of tamsulosin is only 2.08 USD per day whereas the estimated cost of ureteroscopy is 4973 USD in USA (4). According to a systematic review and meta-analysis based on 21 studies, of which the main topic was to understand the effect of medical expulsive treatment (MET) of ureter stone, by Picozzi SC et al., it was reported that medical expulsive therapy should be offered to patients who are complaining about distal ureteral calculi (21). Our study have some limitations. One of them is that we do not have a control group since the main objective of the study was to compare the effects of these three different type of alpha blockers. Other limitation was the small number of the samples. However, the results of the power analysis during the design of the study showed that current numbers were not statistically problematic.

and Conservative Management of Urolithiasis. Eur Urol. 2016; 69:468-74.

CONCLUSION

15. Kinnman E, Nygards EB, Hansson P. Peripheral alpha-adrenoceptors are involved in the development of capsaicin induced ongoing and stimulus evoked pain in humans. Pain. 1997; 69:79-85.

No significant difference was found between the three groups in terms of the rate of stone expulsion (p = 0.778). However, the duration of stone expulsion had a significant difference among the groups (p = 0.012). Stone expulsion duration for tamsulosin was 2.33 ± 0.78 days longer than for silodosin, which is a considerable difference (p = 0.010). There was no significant difference between tamsulusin-alfuzosin and silodosin-alfuzosin (p = 0.147 and p = 0.925, respectively). The results of this study showed that medical expulsive therapy by using alpha blocker agents are safe and efficacious. This option must be kept in mind who do not ask for surgery as the first-step treatment for eligible patients.

REFERENCES

1. Manglaviti G, Tresoldi S, Guerrer CS, et al. In vivo evaluation of the chemical composition of urinary stones using dual-energy CT. AJR Am J Roentgenol. 2011; 197:W76-83. 2. Hollingsworth JM, Rogers MA, Kaufman SR, et al. Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet. 2006; 368:1171-1179. 3. Ergun O, Gonen M. Üriner sistem tas hastalıgında medikal ekspulsif tedavi: Kime, nasil, ne kadar? Endoüroloji bülteni 2014; 7:74-76.

9. Gratzke C, Uckert S, Kedia G, et al. In vitro effects of PDE5 inhibitors sildenafil, vardenafil and tadalafil on isolated human ureteral smooth muscle: a basic research approach. Urol Res. 2007; 35:49-54. 10. Atan A. Medikal Ekspulsif Tedavi: Yeni Olan Nedir? Endoüroloji Bülteni. 2015; 8:78-80. 11. Itoh Y, Kojima Y, Yasui T, Tet al. Examination of alpha 1 adrenoceptor subtypes in the human ureter. Int J Urol. 2007; 14:749-53. 12.Sigala S, Dellabela M, Milanese G, et al. Evidence for the presence of alpha 1adrenoceptor subtypes in the human ureter. Neurourol Urodyn. 2005; 24:142-148. 13. Kumar S, Kurdia KC, Ganesamoni R, et al. Randomized controlled trial to compare the safety and efficacy of naftopidil and tamsulosin as medical expulsive therapy in combination with prednisolone for distal ureteral stones. Korean J Urol. 2013; 54:311-5. 14. Tatemichi S, Tomiyama Y, Maruyama I, et al. Uroselectivity in male dogs of silodosin (KMD-3213), a novel drug for the obstructive component of benign prostatic hyperplasia. Neurourol Urodyn. 2006; 25:792-9; discussion 800-1.

16. Kumar S, Jayant K, Agrawal MM, et al. Role of tamsulosin, tadalafil, and silodosin as the medical expulsive therapy in lower ureteric stone: a randomized trial (a pilot study). Urology. 2015; 85:59-63. 17. Sur RL, Shore N, L'Esperance J, et al. Silodosin to facilitate passage of ureteral stones: a multi-institutional, randomized, doubleblinded, placebo-controlled trial. Eur Urol. 2015; 67:959-64. 18. Huang W, Xue P, Zong H, Zhang Y. Efficacy and safety of silodosin in the medical expulsion therapy for distal ureteral calculi: a systematic review and meta-analysis. Br J Clin Pharmacol. 2016; 81:13-22. 19. Dell'Atti L. Silodosin versus tamsulosin as medical expulsive therapy for distal ureteral stones: a prospective randomized study. Urologia. 2015; 82:54-7. 20. Imperatore V, Fusco F, Creta M, et al. Medical expulsive therapy for distal ureteric stones: tamsulosin versus silodosin. Arch Ital Urol Androl. 2014; 86:103-7. 21. Picozzi SC, Marenghi C, Casellato S, et al. Management of ureteral calculi and medical expulsive therapy in emergency departments. J Emerg Trauma Shock. 2011; 4:70-6.

4. Bensalah K, Pearle M, Lotan Y. Cost-effectiveness of medical expulsive therapy using alpha-blockers for the treatment of distal ureteral stones. Eur Urol. 2008; 53:411-8. 5. Preminger GM, Tiselius HG, Assimos DG, et al. EAU/AUA Nephrolithiasis Guideline Panel. 2007 guideline for the management of ureteral calculi. J Urol. 2007; 178:2418-34. 6. Morse RM, Resnick MI. Ureteral calculi: natural history and treatment in an era of advanced technology. J Urol. 1991; 145:263-5. 7. Singh A, Alter HJ, Littlepage A. A systematic review of medical therapy to facilitate passage of ureteral calculi. Ann Emerg Med. 2007; 50:552-63. 8. Türk C, Petrík A, Sarica K, et al. EAU Guidelines on Diagnosis

Archivio Italiano di Urologia e Andrologia 2018; 90, 1

Correspondence Aykut Buğra Sentürk, MD (Corresponding Author) aykutbugra@gmail.com Cemil Aydin, MD cemilaydin78@yahoo.com.tr Musa Ekici, MD musaekici40@gmail.com Hitit University Corum Training and Research Hospital, Turkey

Brardi2_Stesura Seveso 27/03/18 09:20 Pagina 29

ORIGINAL PAPER

DOI: 10.4081/aiua.2018.1.29

A new technique of ultrasound guided percutaneous renal biopsy by perforated probe and perpendicular needle trajectory Simone Brardi 1, Gabriele Cevenini 2, A.G. Bonadio 3 1 Hemodialysis

Unit, S. Donato Hospital, Arezzo, Italy; of Medical Biotechnologies, University of Siena, Italy; 3 Pathological Anatomy 1, University of Pisa, Italy. 2 Department

Summary

The percutaneous biopsy of native kidneys according to the classical methodology is performed under real time ultrasound guidance with the needle introduction along a trajectory of about 30°, aimed to the lower pole of the kidney. Recently, a variant of the classical technique has been introduced by which a perforated ultrasound probe is used to guide the needle along a perpendicular trajectory to the terminal section of the lower kidney pole where the front and back margins of the cortical kidney tissue join each other without renal sinus interposition so to offer to the needle a 3-4 cm thick cortical tissue front which allows to obtain a cortical tissue sample suitable for histological examination even with a single needle pass, while at the same time limiting the possibility of damaging the smaller kidney calices of the lower group whose lesion causes hematuria. In this paper, we present a large survey (50 patients) to compare to data from the literature obtained by using similar needle gauge and with a similar follow-up period after biopsy. The result of this comparison confirms the efficacy of this variant of the classical technique because in front of a statistically lower number of needle passes, it allowed to obtain 100% of samples suitable for histological analysis, in absence of major complications and with a statistically lower post-biopsy hemoglobin drop in comparison to that observed in a group of 44 patients biopsied with a greater number of needle passes, in the only study of the literature which is directly comparable to our study in relation to needle gauge and duration of monitoring.

KEY WORDS: Percutaneous renal biopsy; Perforated ultrasound probe; Perpendicular needle trajectory; Number of needle passes.

the guidelines, with the patient in the prone position, the biopsy needle is driven according to a sagittal ultrasound scan, with an angle of about 30 degrees towards the lower kidney pole. Usually two needle passes are carried in order to obtain a sufficient amount of renal parenchyma tissue for optic microscopy, immunofluorescence and electron microscopy analysis when necessary (1). Recently, in a limited series (4), a variant of the classical technique has been proposed according which placing the patient in the prone position the biopsy needle is driven by a perforated ultrasound probe with a perpendicular trajectory in order to reach the more lower portion of the lower kidney pole, where the front and back margins of the renal cortical join each other without renal sinus interposition (Figure 1). By the use of the perforated probe, the needle advances perpendicularly toward a 3-4 cm thick cortical tissue front, without the renal sinus interposition, allowing to collect a suitable sample of cortical kidney tissue with a single needle pass and, at the same time, limiting the possibility of damage to the smaller kidney calices of the lower group whose lesion causes hematuria (5). The first purpose of this technique is therefore to obtain with only one needle pass (compared to the two or more required according to the classical method) (1) and thus with less kidney parenchyma trauma, a quantity of material sufficient to put an histological diagnosis and at the same time to limit the possibility of damaging the calices

Submitted 30 October 2017; Accepted 15 November 2017

INTRODUCTION

Percutaneous kidney biopsy is an important and often irreplaceable instrument for the diagnosis and treatment of kidney disease although it may be associated with multiple complications, most commonly with bleeding which in rare cases can lead to sometimes fatal retroperitoneal bleeding (1-3). For this reason, the renal biopsy technique has evolved over the years to increase its safety until the introduction of spring-loaded needle biopsy device and of real-time ultrasound guidance which are currently considered the “gold standard” procedure for the percutaneous renal biopsy as they allow to minimize the incidence of associated complications (3). According to the classical methodology, as proposed by

Figure 1. The path of the needle according to the technique of percutaneous renal biopsy with perforated probe and perpendicular needle trajectory.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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present in the renal sinus and therefore the possibility of bleeding because the biopsy is performed where the front and back margins of the cortical kidney tissue join each other without the renal sinus interposition. In the following paper we present therefore a survey carried out in a large population with this technique in order to confirm or not the supposed advantages offered by this technique.

SUBJECTS

AND METHODS

Compared to the previously published pilot survey that counted only 26 cases (4), for this paper. We retrospectively evaluated 50 consecutive patients submitted to percutaneous renal biopsy by the technique of the perforated ultrasound probe with perpendicular needle trajectory at the Nephrology ward of the San Donato Hospital of Arezzo from November 2012 to October 2017. The mean age of the 50 patients (32 males and 18 females) was 52.7 ± 16.7 (mean ± SD, range 18-83) years, with average creatinine values (before the biopsy) of 1.7 ± 1.7 mg/dl. (Table 1). The bleeding time, prothrombin time, and platelet counts were within the normal range across all patients. Each patient, before the procedure, was subjected to renal ultrasound in order to exclude the presence of any of the known contraindications for the execution of renal biopsy (5) and any platelet anti-aggregant and/or anticoagulant was stopped 7 days before the procedure (6). In the case of arterial hypertension, a sufficient control of arterial pressure values was assured, eventually with the addition to the therapy of a calcium channel blocker. Finally an informed consent was obtained from each patient (7). Percutaneous kidney biopsies were always performed on native kidneys and always at the lower left kidney pole with the exception of two cases (with solitary kidneys) where the biopsy was performed at the lower right kidney pole. For real-time ultrasound guidance, a Hitachi convex 3.5hhz perforated ultrasound probe coupled to a Hitachi Astro 256 ultrasonograph was used. In all cases, the Bard monopty needles (Bard biopsy systems, Tempe, Arizona, USA) were used with needle gauge size and length of 16 Gauge x 16 mm. Renal biopsy was performed with the patient in the prone position while a pillow was placed under the abdomen of the patient (5). After disinfection of the skin with povidone iodine and local anesthesia (lidocaine 20 mg/ml) under real-time ultrasound guidance, according to longitudinal scan planes on the rear axillary line and tilting the probe towards the spine, the needle was directed to the more Table 1. Characteristics of the patients enrolled. Patients, n. Age (years)* Range (years) Male/female, n. Pre-biopsy creatinine (mg/dl)*

50 52.72 ± 16.70 18-83 32/18 1.66 ± 1.68

* mean ± SD

Figure 2. The moment of needle drive operation with perpendicular needle trajectory; to note the absence of renal sinus interposed.

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lower portion of the kidney lower pole where the front and back margins of the cortical kidney tissue join each other without the renal sinus interposition, along a bound path perpendicular to the lower pole by the needle passage of a special adapter for the zero degrees angle previously inserted on the ultrasound perforated probe (Figure 2). Only one needle pass was carried out; the needle pass was repeated only when the sample was not suitable to a first optical analysis. In particular insufficient sampling happened only in those patients who, at the moment of the firing of the needle mechanism for the core sampling, moved for fear or inability to keep the position set (4). All the patients were then subjected to ultrasound imaging immediately after the biopsy, at a distance of about 6 hours and ultimately after the first 24 hours (1, 4). Besides, all the patient, after the biopsy, remained in bed for the first 24 hours as recommended by the Italian national guidelines (1, 4). Before the procedure a blood sample was drawn for blood count that was repeated six hours after the biopsy, while subsequent blood count collections were dictated by the possible presence of hematomas or by major reductions of the hemoglobin at the six-hour control after the biopsy (1, 4). Urination was monitored to exclude macrohaematuria and the blood pressure was measured intensively for the first two hours and then at regular intervals of eight hours (1, 4).

RESULTS

Even in the larger survey that we present here, as in the preliminary data (4), the biopsy sampling (examined for the most at the Pathological Anatomy 1 of the University of Pisa) was successful (more than 5 glomeruli per biopsy specimen and/or a validation by the anatomopathologist about the presence of sufficient material to diagnose) (5, 8) in the 100% of the cases. The sample then was obtained at the first and only needle pass in 90% of cases (with a slight increase compared to the 88.5% rate found in the first published survey) (4).

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A new technique of ultrasound guided percutaneous renal biopsy by perforated probe and perpendicular needle trajectory

As in the pilot casuistry, no major complications of renal biopsy were observed and in particular transient macrohaematuria was found only in a patient and no patient was subjected to blood transfusion or death (Table 2). However, we must point out that a female patient was transfused far beyond 24 hours of observation due to the failure to observe the expected period of bed rest, so it was necessary a further bed forced rest period but no embolization was required. However subcapsular hematomas was found in 40% of the patients (with a slight reduction versus the 42% found in the pilot survey) but all hematomas were of a non-significant type (i.e. with a maximum thickness of ≤ 2 cm as by definition of Italian guidelines) (1) (Table 2). Finally, the mean hemoglobin value was reduced from the pre-biopsy value of 12.4 ± 2.1 g/dl to the post-biopsy value of 12.0 ± 2.03 g/dl. However, a decrease in hemoglobin values ≥ 2 g/dl (considered significant or associated with increased risk of complications) (9) was reported only in 4.25% of patients (Table 2). Table 2. Results. Patients, n. Needle passes, n.* Sample adequacy for the histological analysis Small non-significant hematomas, n. Large hematomas, n. Macrohematuria, n. Embolizations, n. Blood transfusions, n. Death, n. Hemoglobin decrease (g/dl) to 6 hours after biopsy* Hemoglobin fall ≥ 2 gr/dl after biopsy as percent of the total patients

50 1.10 ± 0.30 100% 20 (40%) 0 1 0 0 0 -0.44 ± 0.89 4.25%

* mean ± SD

DISCUSSION

Since the present series did not include controls, as our preliminary study previously published, in order to assess effectiveness and safety of this variant of the classical biopsy technique we had to make a comparison with literature data homogeneous for needle gauge and length of post-bioptic monitoring period (4). For this comparison homogeneity with regard to needle gauge is important as 18 Gauge needles were found to have a greater number of complications (10) (probably due to the greater number of needle passes necessary to obtain adequate material for diagnosis) (11) and fewer biopsy specimens in comparison to the use of 14 or 16 Gauge needles (10). Furthermore in the meta-analysis of Corapi et al. (12) there was an increase in the number of blood transfusions in studies with 14 Gauge needles compared to 16 or 18 Gauge needles. Equally important for comparison is the homogeneity of the patient's monitoring period after kidney biopsy, which must be at least 12 hours and better over 24 hours (1), since 33% of the complications occur after the first eight hours and 91% within 24 hours (1, 13). So we have selected within the largest meta-analysis at the

time available in literature, that is Corapi et al. (12), the studies comparable to our study for needle gauge and duration of the monitoring with sufficient data to calculate the confidence interval for the number of needle passes per patient and the variations of hemoglobin between the pre and post-biopsy value at a distance of about six hours. We identified three papers from which, for completeness of data, we have been able to extrapolate the 95% confidence interval for the number of needle passes carried out, namely Maya and Allon's study of 2009 (6), for which it is necessary underline that both needles 16 and 18 Gauge were used, Lin et al. study of 2006 (14), where 16 Gauge needles were used for adult patients and 18 Gauge needles for pediatric patients (which number is not specified) and, finally, Ori et al. study of 2002 (15) where only 16 Gauge needles were used. In all three studies selected for comparison, a histological sample sufficient for diagnosis was obtained for almost all patients, though with a number of needle passes greater than in our study. In Maya and Allon's paper (6) with a 100% validity of the sample for the histological analysis, 1.6 ± 0.8 needle passages (IC 95%: 1.44-1.76) were performed in the 100 patients enrolled. In the paper of Lin et al. (14) with a 100% validity of the sample for the histological analysis, 2.2 ± 0.6 passages were performed in 183 outpatients (IC 95%: 2.11-2.29) and 2.3 ± 0.7 passages were performed in 147 inpatients (IC 95%: 2.19-2.41). In the paper of Ori et al. (15) in 44 biopsied patients with an older model of ultrasonograph with a 98% of sample adequacy for histological analysis, 4.7 ± 0.3 passages (IC 95%: 4.61-4.79) were performed, while in 41 biopsied patients with a newer ultrasonograph, with a 95% of sample adequacy for histological analysis, 4 ± 0.1 passages (IC 95%: 3.97-4.03) were performed, that is a statistically significant smaller number of needle passes when compared to the other group of 44 patients (Table 3). By comparing these data with those of our larger survey in which with a 100% of sample adequacy for the histological analysis, 1.1 ± 0.30 needle passes (IC 95%: 1.021.18) were performed, it clearly emerges a statistically significant difference already found in our preliminary series (4) (Table 3). Regarding the complications related to renal biopsy and specifically the hemoglobin variations between the prebiopsy value and the one found after an average interval of 6 hours from the biopsy, we could only compare Maya and Allon's paper (6 ) and the paper of Ori et al. (15) since in the work of Lin et al. (14) blood count was not routinely collected in all patients after renal biopsy. Then comparing 95% confidence intervals for the pre and post-biopsy variation of hemoglobin, we observed that there was no statistically significant difference with Maya and Allon work data (as in the pilot survey already published) (6), while there was a statistically significant difference with the subgroup of 44 patients undergoing biopsy with the aid of an older ultrasonograph in the work of Ori et al. (15) where the hemoglobin reduction was significantly greater than in our patients. Indeed there was no statistically significant difference between our data and those of the second group of 41 Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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S. Brardi, G. Cevenini, A.G. Bonadio

Table 3. 95% confidence interval (CI) for the needle passes. Author (years of publication) Maya and Allon (2009) Lin et al. (2006)

Ori et al. (2002)

Brardi S et al. (2017)

Patients, n.

Needle gauge

100

16 e 18 Gauge (but the 16 Gauge was used more frequently) 16 and 18 Gauge (but the 16 Gauge was used more frequently)

183 (outpatients) 147 (inpatients) 44 (subject to biopsy by an older ultrasonograph) 41 (subjected to biopsy by a newer ultrasonograph) 50

Number of needle passes (mean ± SD) 1.6 ± 0.8 2.2 ± 0.6

2.3 ± 0.7 4.7 ± 0.3

4 ± 0.1

1.10 ± 0.30

patients in the same work by Ori et al. (15) that were biopsied with the aid of a newer ultrasonography that, as already mentioned, were subjected to a statistically minor number of needle passes than the other group in the same study (Table 4). However, to properly evaluate the outcome of this comparison it is necessary to keep in mind that while in the work of Ori et al. (15), as in ours, 16 Gauge needles were used and the patient remained in bed for the first 24 hours, 18-Gauge needles were used in Maya's and Allon's work (6), and the observation time was limited to only eight hours. Since, as well explained in Whittier et al. (13), the clinical recognition of major complications increases proportionally to observation time, it is legitimately possible to assume that an observation time of only eight hours (as in the Maya and Allon's work) (6) may have lost up to 33% of later post-biopsy complications and this is the reason why the only work that can be compared with ours (for the needle gauge and for the duration of the monitoring period) is that of Ori et al. (15). Likewise, and for the same reasons, regarding to the major complications of renal biopsy (macrohematuria, blood transfusions or deaths) and the formation of post-biopsy hematomas, the only work comparable with ours remains that of Ori et al. (15) where in front of only one patient with gross hematuria, two patients (4.5% of the total) in Table 4. 95% confidence interval (CI) for the hemoglobin variations after biopsy. Author

Patients, n.

(years of publication) Maya and Allon (2009) 100 Ori et al. (2002) 44 (subjected to biopsy by an older ultrasonograph) 41 (subjected to biopsy by a newer ultrasonograph) Brardi S et al. (2017) 50

Hemoglobin variations (g/dl)* -0.54 ± 0.29 -0.86 ± 0.16

95% CI for the hemoglobin variations (g/dl)* -0.48-0.6 -0.91-0.81

-0.47 ± 0.10

-0.5-0.44

-0.44 ± 0.89

-0.18-0.69

*mean ± SD

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the group of 44 patients subjected to biopsy with an older ultrasonograph and two 95% CI Duration of patients (4, 9% of the total) of post-biopsy monitoring the group of 41 biopsied (hours) patients with a newer ultra1.44-1.76 8 sonograph were transfused, while in our present larger sur2.11-2.29 6 vey in front of only one patient with gross hematuria no major complication was reported and 2.19-2.41 no patient was transfused 4.61-4.79 24 except one female that did not comply with post-biopsy bed 3.97-4.03 resting and had to be transfused after 24 hours. In the same work by Ori et al. 1.02-1.18 24 (15) significant hematomas were also reported in 5 patients (equal to 11.4% of the total) of the group of 44 patients subject to biopsy with an older ultrasonograph and in 2 patients (equal to 4.9% of the total) of the group of 41 patients subjected to biopsy with a newer ultrasonograph, while in our larger survey, as well as in the preliminary study (4), only non-significant (i.e. with a maximum thickness of ≤ 2 cm) (1, 2) hematomas were found in 20 patients equal to 40% of the total (Table 2). This high number of non-significant hematomas, however, may be related to the fact that while in the work of Ori et al. (15) after ultrasound examination performed at the time of biopsy, no further ultrasound tests were performed except in the case of complications, in our protocol, renal ultrasound was repeated at 6 and 24 hours after the biopsy in all patients regardless of any symptomatology.

CONCLUSIONS

The data provided by the present larger survey confirm the findings of our preliminary series (4) though the lack of a control group is still a limitation of the strength of our conclusions. On this basis we believe that the percutaneous renal biopsy with perforated ultrasound probe and perpendicular needle trajectory, performed in that portion of kidney lower pole where the front and back margins of the cortical kidney tissue join each other without the renal sinus interposition, allows to obtain (in native adult kidneys) samples suitable for histological analysis comparable to those provided by repeated needle passes performed according to the classical technique. The statistically lower number of passages is explained by the abundance of cortical tissue that the needle crosses. Performing the needle pass in that portion of the lower pole of the kidney where there is no renal sinus interposition and so avoiding to damage the smaller kidney calices of the lower group whose lesion causes hematuria (5) achieved in this larger survey as in the preliminary smaller sample (4), a post-biopsy reduction of the hemoglobin statistically lower than that observed in a subgroup of 44 biopsied patients with an older ultrasonograph and therefore subjected to a statistically significant greater number of needle passes Ori et al. (15).

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A new technique of ultrasound guided percutaneous renal biopsy by perforated probe and perpendicular needle trajectory

As already pointed out in the study of Eiro et al. (7) and also reported by Zhu et al. (16) in a recent review of factors that can minimize post-biopsy bleeding, although the frequency of needle passes does not differ significantly between cases with moderate complications and cases with no or only mild complications, the frequency of needle passes however represents an independent risk factor, as evidenced by the multivariate logistics analysis conducted in the work of Eiro et al. (7). Besides the frequency of the needle passes is amongst all (age > 60 years, marked hypertension with PAS > 140 or PAD > 90 mmHg and amyloidosis) the only risk factor for bleeding, as highlighted in the work of Eiro et al. (7), that can be addressed using a technique such as described here, oriented to minimize the number of the needle passes. To confirm this we can also remember the already mentioned fact that with the use of 18 Gauge needles, despite a lower caliber, a greater number of complications were found, probably due to the greater number of needle passes required to obtain valid samples for the histological analysis (10, 11).

REFERENCES

guided renal biopsy: report of 650 consecutive cases. Nephron. 1994; 67:425-430. 6. Maya ID, Allon M. Percutaneous renal biopsy: outpatient observation without hospitalization is safe. Seminars in Dialysis. 2009; 22:458-461. 7. Eiro M, Katoh T, Watanabe T. Risk factors for bleeding complications in percutaneous renal biopsy. Clin Exp Nephrol. 2005; 9:40-45. 8. Geldenhuys L, Nicholson P, Sinha N, et al. Percutaneous native renale biopsy adequacy: a successful interdepartmental quality improvement activity. Canadian Journal of Kidney Health and Disease 2015; 2:8. 9. Visconti L, Cernaro V, Ricciardi CA, et al. Renal biopsy: still a Landmark for the nephrologist. World J Nephrol. 2016; 5:321-327. 10. Tøndel C, Vikse BE, Bostad L, Svarstad E. Safety and complications of percutaneous kidney biopsies in 715 children and 8573 adults in Norway 1988-2010. Clin J Am Soc Nephrol. 2012; 7:1591. 11. Cagnoli L, Fuiano G, Imbasciati E, et al. Linee Guida sulle indicazioni ed esecuzione della biopsia renale percutanea e sulla terapia delle nefropatie glomerulari. Linee Guida SIN Revisione 2003. Giornale Italiano di Nefrologia. 2003; 20:S3-S47. 12. Corapi KM, Chen JL, Balk EM, Gordon CE. Bleeding complications of native kidney biopsy: a systematic review and meta-analysis. Am J Kidney Dis. 2012; 60:62.

1. Commissione SIN-SIAPEC. Requisiti per la biopsia renale: diagnostica nefropatologica ed esecuzione clinica. Release 1. In: Best practice; www.nephromeet.com. 12 Novembre 2015.

13. Whittier W L, Korbet S M. Timing of complications in percutaneous renal biopsy. J Am Soc Nephrol. 2004; 15:142-147.

2. Parrish AE. Complications of percutaneous renale biopsy: a review of 37 years'experience. Clin Nephrol. 1992; 38:135-41.

14. Lin WC, Yang Y, Wen YK, Chang CC. Outpatient versus inpatient renal biopsy: a retrospective study. Clinical Nephrology. 2006; 66:17-24.

3. Brachemi S, Bollèe G. Renal biopsy practice: what is the gold standard? World J Nephrol. 2014; 3:287-294. 4. Brardi S, et al. Una variante della tecnica classica eco guidata della biopsia renale percutanea: l’approccio perpendicolare in scansione longitudinale con sonda forata. GIN. 2017; 34:146-156. 5. Meola M, Barsotti G, Cupisti A, et al. Free-Hand ultrasound-

15. Ori Y, Neuman H, Chagnac A, et al. Using the automated biopsy gun with real-time ultrasound for native renale biopsy. IMAJ. 222; 4:698-701. 16. Zhu MS, Chen JZ, Xu AP. Factors that can minimize bleeding complications after renale biopsy. Int Urol Nephrol. 2014; 46:19691975.

Correspondence Simone Brardi, MD sibrardi@gmail.com Hemodialysis Unit, S. Donato Hospital, Arezzo, Italy Gabriele Cevenini, MD Department of Medical Biotechnologies, University of Siena, Italy A.G. Bonadio, MD Pathological Anatomy 1, University of Pisa, Pisa, Italy

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DOI: 10.4081/aiua.2018.1.34

ORIGINAL PAPER

Injection therapy for chronic prostatitis: A retrospective analysis of 77 cases Attila Toth, Frederico Maria Guercini, Dawn Marta Feldthouse, Jun Chao Zhang The MacLeod Laboratory, Weill-Cornell Medical College, New York Presbyterian Hospital, New York, US.

Summary

Objective: To compare pre- and post-therapy symptom scores reported on the National Institute of Health Chronic Prostatitis Symptom Index (NIHCPSI) after trans-rectal antibiotic injections therapy for men suffering from chronic prostatitis. Materials and methods: Retrospective analysis of NIHCPSI symptom scores obtained from chart reviews of 77 treated males suffering from chronic prostatitis before and after trans rectal injections for the treatment of chronic prostatitis. Results: Most patients reported a 40% to 60% improvement in symptom scores. In subgroups comparing scores in patients with less than 5 injections, the improvement was less than in patients who received 10 or more injections. Patients’ responses after a shorter (3 months) follow up showed better pain scores than patient’s scores after longer, over one-year or more, follow-up periods. Conclusion: Our findings show that direct antibiotic injection for chronic prostatitis is a viable addition to standard therapies. Improvements in symptom scores are long lasting. Discomfort is minimal and side effects are rare and avoidable.

KEY WORDS: Chronic prostatitis; Bacterial prostatitis; Injection therapy of prostatitis. Submitted 14 October 2017; 17 December 2017

INTRODUCTION

Prostatitis accounts for approximately 2 million outpatient visits per year in the United States, including 8% of all visits to urologists and 1% of those to primary care physicians. The direct costs of care approach $4,000 per patient per year (1). The clinical syndrome encompasses a wide range of male pelvic conditions from the well-defined bacterial prostatitis to the ill-defined chronic pelvic pain syndrome (CPPS). Only in about 5% of all cases is there a documented bacterial origin. Still, a very high percentage of patients receive antibiotic therapy at the first visit (2). About half of all patients presenting with prostatitis are in the reproductive age (3) and they have worse scores on questions related to mental and physical health-related quality of life issues than patients with congestive heart failure, diabetes mellitus or Crohn’s disease (4, 5). It has been known for a long time that chronic prostatitis affects sperm quality, fertility and pregnancy rates (6). Symptomatic prostatitis and asymptomatic leucospermia make the treatment of infertility more challenging (7).

In response to failure of oral antibiotics to eradicate pathogens from the genital secretions of male patients being treated for infertility, we adopted direct antibiotic injections to the prostate and offered this treatment to patients for the last 17 years. Histology showing scarring, calcification, and sealed off bacteria in the prostate supported this approach. For the last 10 years, injection therapy has been also offered to patients suffering from symptoms of chronic prostatitis without infertility issues. This work aims to compare National Institute of Health Chronic Prostatitis Symptom Index (NIHCPSI) scores of patients suffering from prostatitis before and after injection therapy.

MATERIALS

AND

METHODS

Eligible candidates for this retrospective study were 77 patients who presented to us for the treatment of prostatitis symptoms during a five-year period, between July 1st, 2008 and July 1st, 2013. The mean duration of prostatitis in the study group was 83.91 and the range was 2-360 (in months). The mean age at first visit was 40.51 and ranged from 20-to 67 (in years). The study was conducted with the approval of the Institutional Review Board at Weill Cornell Medical College - New York Presbyterian Hospital on 07/16/2014 (IRB Protocol Number: 130814262). All patients had been given the diagnosis of chronic prostatitis by a urologist prior to our consultation. Except for a few patients presenting with previous cultures showing mostly enteric bacteria, all others’ cultures were negative or not done, yet all had received courses of oral antibiotics prior. The patients signed a written informed consent for the injection therapy and were asked to fill out an NIHCPSI questionnaire and undergo physical and microbiological examinations prior to the start of the injection therapy. The patients were free to interrupt the injection therapy if they did not feel improvement of symptoms after the first two injections or anytime during the therapy course if there was no further improvement with subsequent injections. Subgroups: Follow up NIHCPSI questionnaires were completed by 9 of the 77 patients within three months after the last injection, 29 subjects completed the questionnaire not more than 12 months and not less than three months following the completion of the therapy and for 38 patients the time for filling out the follow up questionnaire was longer than one year. No conflict of interest declared.

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Injection therapy for prostatitis

Office evaluation: The physical examination included manual and ultrasound evaluations of the prostate and seminal vesicles and taking of a urethral swab specimen for Chlamydia Direct Fluorescent Antibody (DFA) testing. Expressed Prostatic Secretion (EPS) or seminal fluid samples were used for microscopic examination and for bacteria cultures. Microbiological examination of genital secretions: Chlamydia trachomatis was tested using the Pathfinder Direct Antigen Detection System from Bio Rad Laboratories. A7 differential agar was used to identify Mycoplasma, and Application Program Interface (API) systems were used for aerobic bacteria identification. Remel Rapid Ana (Anaerobic) II system was used to identify anaerobic bacteria. The API 20c AUX system (brand name from Biomerieux for yeast identification system) was used to identify yeast. The Rapid NH (Neisseria Hemophilus) System identified Neisseria and Hemophilus. Trichomonas vaginalis was identified by directly observing the fresh secretion for moving parasites with flagella. The result of the culture studies did not influence the recommendation for injection therapy. Antibiotics selected for the injected cocktail: Based on a literature search we compiled a list of bacteria implicated in prostatitis and selected antibiotics with ample coverage for all that were listed. Six compatible antibiotics were mixed in a cocktail to be delivered in one injection. Each 10-ml volume of the cocktail contained the following antibiotics: gentamicin, 80 mg, clindamycin, 150 mg, metronidazole, 10 mg, moxifloxacin, 3.2 mg, fluconazole, 2 mg and azithromycin, 50 mg. Methylprednisolone, 50 mg was added to this mixture to activate intracellular dormant reticulate bodies of Chlamydia trachomatis. The azithromycin and methylprednisolone were reconstituted in 10 ml of 1% lydocaine each. A standard endo-cavitary probe was equipped with a needle guide and a 22-gauge spinal needle was used to deliver 12 ml of the cocktail per injections; 3 ml each to the right and left seminal vesicles and to the right and left lobes of the prostate. One tablet of hydrocodone 5 mg/acetaminophen 300 mg with 800 mg of ibuprofen were sufficient for both sedation and pain management. Statistical analysis Analysis compared pre-and post-therapy NIHCPSI scores and examined whether the magnitude of change in symptom scores after injection therapy related to any of the following: a) Duration of prostatitis in months, b) Age at first visit c) Chlamydia status at first visit d) Number of injections received; less than 5 injections, 5-10 injections, more than 10 injections, e) The difference in reported symptom changes in post-therapy intervals: Follow-up within 3 months, 3-12 months, 12 months or more. SPSS v. 20 (8) was used for all descriptive and inferential analyses. A 95% level of significance was set for all inferential tests. Inferential tests included paired t-tests, within groups analysis of covariance tests (ANCOVA) and mixed between-within groups analysis of variance tests (ANOVA). Chance of benefiting from injection therapy were calculated comparing pre- and post-therapy dependent vari-

ables (outcomes) for the inferential tests. The NIHCPSI scores were defined as the assessment measures for “benefiting from the injection therapy (or the extent of benefit)”, and were classified into four outcomes of: Pain (scale of 0-22), Urinary (scale of 0-10), Quality of Life (scale of 012), and Total Score (scale of 0-44). Higher numbers in the scores indicated more pain, more urinary problems and less quality of life, resulting in higher Total Scores. Questions to be answered were: Does the magnitude of change in symptom scores after injection therapy relate to any of the following categorical variables (Table 1): 1. Duration of prostatitis (in months), 2. Age at first visit (in years), 3. Chlamydia status at first visit, 4. Number of injections received; less than 5 injections, 5-10 injections, more than 10 injections, 5. The difference in reported symptom changes in post-therapy intervals: Follow-up within 3 months, 3-12 months, 12 months or more.

RESULTS

Although, most study patients had been previously classified as suffering from “non-bacterial prostatitis”, we recovered a variety of both aerobic and anaerobic bacteria from genital secretions of those who underwent testing. 80% of those tested were positive for Chlamydia trachomatis from the urethral swab specimens (Table 2). Table 3 calculates the measures of central tendency for variables of the study and ranges of the categorical variables before and after intervention. Preliminary tests performed a series of paired-sample ttests to compare the pre-and post-intervention NIHCPSI scores (N = 77). One ANCOVA was performed for each of the four NIHCPSI variables. For all four NIH symptom scores the t-test analysis showed significant pre-and post-therapy differences (Table 4). The duration of prostatitis (in months) and influence of age at first visit were included as covariates for each of the four ANCOVA tests. There was no significant interaction effect found between the duration of prostatitis or the co-variates of age at first visit and any of the symptom scores or total NIHCPSI scores. However, there was a significant main effect for time. The post-therapy NIHCPSI scores were significantly lower than the pre-treatment NIHCPSI scores for all variables (p < .05), and mirrored the findings of the paired t-test in Table 3. Although there were significant decreases in all four NIHCPSI variable outcomes over time there was no significant effect of age at first visit or the duration of prostatitis.

Chlamydia status at first visit A series of four two-way (2 X 2) mixed between-within groups analysis of variance (ANOVA) tests were performed to answer question number three. Each of the four analyses included one repeated measures (withingroup) independent variable of time with 2 levels (preintervention and post-intervention), and one betweengroup independent variable of chlamydia status at first visit, with two categories (positive vs. negative). Again, time was statistically significant for all four NIH variable outcomes. All four NIHCPSI scores significantly Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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A. Toth, F. Maria Guercini, D. Marta Feldthouse, J. Chao Zhang

NIHCPSI urinary scores: There was no significant interaction effects or main effects found for the number of injections received on the urinary scores. There was a significant effect for the within-groups variable of time. This Categorical variables Frequency Percent finding mirrors the findings of the paired t-test for NIH Chlamydia status at first visit Urinary from Table 4. Positive 56 72.7 NIHCPSI Quality of Life scores: There was a significant Negative 14 18.2 Missing 7 9.1 interaction of the between-groups variable categories of Number of injections received the number of injections variable and the pre-and postLess than 5 12 15.6 intervention Quality of Life score. The Quality of Life 5-10 33 42.9 score decreased more from pre-to post-intervention for More than 10 32 41.6 those who received 5-10 injections or more than 10 Post therapy follow-up intervals injections, than for those who received less than 5 injecWithin 3 months 9 11.7 3-12 months 29 37.7 tions (F (2.74) = 4.19, p = .019). 12 months or more 38 49.4 Figure 1 is a graphical representation of the interaction Missing 1 1.3 effect. Tests of simple effects were performed to investiAge at enrolment in the study (in years) Mean = 40.51, Range 20-67. gate the significant interaction effect. A series of three Duration of prostatitis (in months) Mean = 83.91, Range 2-360. paired-samples t-tests were conducted to look at the difference between Quality of Life score pre-and post-therapy. Table 2. Shows the microbiological findings prior to initiating the injection therapy. A variety of One t-test was performed for aerobic and anaerobic bacteria were isolated and 80% of those tested showed each of the individual between Chlamydia trachomatis elementary bodies in the urethral swab specimen (N=77). group levels of (a) less than 5 injections (Group 1), (b) 5-10 Variable Number % of N Number % of % of Number % of % of tested (n) positive tested N negative tested N injections (Group 2). and (c) Chlamydia 70 91% 56 80% 73% 14 20% 18% more than 10 injections (Group Mycoplasma 60 78% 4 7% 5% 56 93% 73% 3). In Group 1 (less than 5 Aerobes 61 79% 41 67% 53% 20 33% 26% injections), there was no statistiAnaerobes 61 79% 52 85% 68% 9 15% 12% cally significant difference in the Quality of Life score from preto post-therapy [t (11) = 1.915, decreased (p < .05) from pre-to post-intervention. p = .082]. For Group 2 (5-10 injections) the pre-therapy However, there was no significant interaction or main Quality of Life Score (M = 9.79, SD = 2.233) was signifieffect of chlamydia status at first visit. cantly higher compared to the post-therapy score [M = 5.18, SD = 3.21; t 32) = 8.22, p < 0.005]. Number of injections received For Group 3 (more than 10 injections) the pre-therapy A series of four two-way (3 X 2) mixed between-within Quality of Life score was significantly higher (M = 9.94, groups analysis of variance (ANOVA) tests were perSD = 1.90) than the post-therapy Quality of Life score [M formed to address this question. Each of the four analy= 5.47, SD = 2.95; t (31) = 6.901, p < 0.005]. ses included one repeated measures (within-group) independent variable of time with 2 levels (pre-intervenFigure 1. tion and post-intervention), and one between-group Graph shows significant difference between the number of injections and the pre- and post-therapy NIHCPSI Quality independent variable of number of injections received, of Life scores. In Groups 2 and 3 the NIHCPSI Quality of with three categories of: (a) less than 5 (N = 12), (b) 5Life scores significantly decreased from pre- to post10 (N = 33), and (c) more than 10 (N = 32). therapy. Though Group 1 also decreased in scores, the The dependent variables (outcomes) of interest were (a) decrease however was not significant. pain, (b) urinary, (c) Quality of Life, and (d) total score. NIHCPSI Pain scores: In group 1 (less than 5 injections) there was no significant interaction effect found between Pain and the number of injections received, However, in patients who received between 5 and 10 injections, there was a significant main effect of number of injections received [F (2.74) = 4.351, p = 0.016, partial eta squared = .105]. A post hoc analysis via Tukeyâ&#x20AC;&#x2122;s Honestly Significant Difference test (HSD) indicated Group 2 (5-10 injections) showed a significantly lower Pain score (M = 2.667, SE = 1.076) compared to Group 1 (less than 5 injections; M = 8.99, SE =.649; p = .012). Group 3 (more than 10 injections) did not differ significantly from group 2. There was also a significant main effect for the within-groups variable of time. This finding mirrors the findings of the paired t-test for Pain from Table 4. Table 1. Frequencies and percentages of the categorical variables of the study (N = 77).

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number of injections received [F (2,74) = 6.902, p = 0.002, partial eta squared = .157]. A post hoc analysis via Tukeyâ&#x20AC;&#x2122;s HSD indicated that the NIHCPSI Total scores for Group 1 (less than 5 injections; M = 27.708, SE = 1.711) were significantly greater than Group 2 (5-10 injections; M = 20.424, SE = 1.032; p = .001) and Group 3 (more than 10 injections; M = 21.391, SE = 1.048; p = .007). There was also a significant main effect for the withingroups variable of time. The NIHCPSI Total Scores at post-intervention (M = 15.83, SD = 8.979) were significantly lower than the total pre-intervention NIHCPSI Total Scores [M = 28.09, SD = 6.775; F (1.74) = 87.544, p < 0.0005, partial eta squared = 0.542]. This finding mirrors the findings of the paired t-test for NIHCPSI Total Score from Table 4. In conclusion, there were significant decreases in all four NIHCPSI variable outcomes from pre- to post-intervention. Additionally, the mean value of Total Score was significantly higher for Group 1 than for Groups 2 or 3.

Figure 2. Graph shows significant between-groups differences as to the length of time to follow up. NIHCPSI improvement in Pain Score diminished after longer follow up.

Time to follow up A series of four two-way (3 X 2) mixed between-within groups analysis of variance (ANOVA) tests were performed to the lapse of time until follow up. Each of the four analyses included one repeated measures (withingroup) independent variable of time with 2 levels (pre-

Figure 3. Histogram showing the distribution of the percent improvemnet in NIHCPSI Total Scores. 60% of the treated patients reported at least 50% improvement.

Table 3. Measures of central tendency for the four NIHCPSI variables of the study (N = 77). Variable NIH pain Pre-test Post-test NIH urinary Pre-test Post-test NIH Quality of Life Pre-test Post-test NIH total Pre-test Post-test

Mdn

Range

12.66 7.03

4.35 4.944

13 7

0-21 0-19

5.47 2.91

2.950 2.586

6 2

1-10 1-10

9.96 5.90

2.029 3.267

10 6

2-12 0-12

28.09 15.83

6.775 8.979

28 15

14-43 0-38

M = Mean; SD = Standard Deviation; Mdn = Median.

In summary, Group 2 (5-10 injections) and Group 3 (more than 10 injections) showed a significant improvement in the NIHCPSI Quality of Life scores from pre-to post-intervention. However, Group 1 (less than 5 injections) did not. NIHCPSI Total score: A mixedmodel ANOVA was conducted to test the pre-and post-intervention scores for Total score, with the between-subjects variable of number of injections received and the within-subjects variable of time. There was a significant main effect for the between-subjects variable,

Table 4. Descriptive Statistics and Results of Paired Samples T-Tests for Study Outcomes (performed for the four NIHCPSI scores with highly significant p values for the difference between pre-intervention to post-intervention scores (N = 77). Variable/time NIH Pain Pre-test Post-test NIH Urinary Pre Post NIH Quality of life Pre Post NIH Total Pre Post

Mdn

Range

12.66 7.03

4.35 4.94

13 7

0-21 0-19

5.47 2.91

2.95 2.59

6 2

1-10 1-10

9.96 5.90

2.03 3.26

10 6

2-12 0-12

28.09 15.83

6.78 8.98

28 15

14-43 0-38

Mean Diff. 5.63

SE Mean Diff. 0.59

t 9.63

p < .0005

Îˇ2 0.38

2.56

0.31

8.19

< .0005

0.31

7.05

0.35

20.02 < .0005

0.73

12.26

1.09

11.29 < .0005

0.46

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intervention and post-intervention), and one betweengroup independent variable of number of injections received, with three categories of: (a) less than 3 months (N = 9), (b) 3-11 months (N = 29), and (c) 12 or more months (N = 38). The dependent variables (outcomes) of interest were (a) pain, (b) urinary, (c) Quality of Life, and (d) total. NIHCPS Pain scores: There was a significant interaction of the between-groups variable categories of the time to follow up variable and the pre- and post-intervention Pain score. Pain score decreased more for those whose follow up was at the less than 3 months level, than for the other two follow up groups (F (2.73) = 3.43, p = .038) (Figure 2). Tests of simple effects were performed to investigate the significant interaction effect. A series of three paired-samples t-tests were conducted to look at the difference between Pain score pre-and post- therapy intervention. One t-test was performed for each of the individual between group levels of (a) less than 3 months (Group 1), (b) 3-11 months (Group 2), and (c) 12 or more months (Group 3). Group 1 (less than 3 months): There was a statistically significant mean difference from the pre-intervention score (M = 13.33, SD = 6.403) to the post-intervention score [M = 3.78, SD = 4.236; t (28) = 7.373, p < 0.0005]. Group 2 (3-11 months): There was a statistically significant mean difference from the preintervention score (M = 13.07, SD = 2.963) to the postintervention score [M = 7.31, SD = 4.401, t (37) =5 .415, p < 0.0005]. Group 3 (12 or more months): There was a statistically significant mean difference from the preintervention score (M = 11.97, SD = 4.571) to the postintervention scores [M = 4.26, SD = 5.012, t (37) = 5.415, p < 0.005]. All three times to follow-up groups had significant decreases in the mean Pain scores, but Group 1 indicated a larger decrease from pre-to postintervention. NIHCP. SI urinary scores: There was no significant interaction effect found between NIH Urinary from pre- to postintervention and time to follow up or for the main effect of time to follow-up (p > .05). There was a significant effect for the within-groups variable of time. The total post-test Urinary scores were significantly lower than the pre-test NIH Urinary scores (p < .05). This finding mirrors the findings of the paired t-test from Table 4. NIHCPSI Quality of Life: A mixed-model ANOVA was conducted to test the pre- and post-intervention scores for NIH Quality of Life with the between-subjects variable of time to follow up and the within-subjects variable of time. There was a significant effect for the withingroups variable of time. The total post-therapy NIH Quality of Life scores (p < .05). This finding mirrors the findings of the paired t-test for NIH Quality of Life scores from Table 4. NIHCPSI Total scores; A mixed-model ANOVA was conducted to test the pre-and post-intervention scores for Total score with the between-subjects variable of time to follow up and the within-subjects variable of time. There was a significant effect for the within-groups variable of time. The mean post-therapy Total scores were significantly lower than the mean pre-therapy scores (p < .05). This finding mirrors the findings of the paired t-test in Table 4.

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DISCUSSION

Until very recently it was a commonly accepted paradigm that chronic bacterial prostatitis is a rare condition, representing 3% to 10% of all cases of chronic prostatitis (9, 10). Long term antibiotics therapies are still widely administered, and patients report moderate to marked improvement (11). The use of the polymerase chain reaction (PCR) to diagnose bacterial infections in men with prostatitis (49% for Chlamydia) moved a significant % of patient from nonbacterial to bacterial prostatitis (12). In our series of 77 patients, among those tested, finding of Chlamydia trachomatis elementary bodies was 80%. This higher isolation rate suggests that in chronic infections the yield for extracellular Chlamydia forms diminishes in commonly tested genital fluid samples (urine, semen or EPS) and epithelial tissue samples (urethral swab, prostate biopsy) will help identify slow growing intracellular forms more readily (13). In addition to Chlamydia we found a variety of aerobic and anaerobic bacteria in semen or EPS samples suspected of contributing to both local immune responses and to tissue damage associated with Chlamydia infection (14). Though a subgroup analysis did not show influence of the Chlamydia isolation rate and the chance of benefiting from the injection therapy, it is tempting to speculate that the frequently noted exacerbation of symptoms during prostatitis is best understood by following the intra and extra-cellular phases of the Chlamydia life cycle. The frustration with repeatedly failed single antibiotic courses could best be explained by the development of resistant Chlamydia strains to the single antibiotic. We propose that the frequently seen hyaline containing scarred, and later calcified nodules, often seen in chronic prostatitis, represent local tissue reaction to Chlamydia antigens with simultaneous entrapment of Chlamydia and other bacteria. A reduced blood supply to these areas makes it difficult to achieve therapeutic concentration of antibiotics in such areas (15). Even if some antibiotics penetrate the cell wall they will have little effect on the viral, reticulate form of Chlamydia. The rationale behind adding steroids to the antibiotic cocktail is the ability of steroids to enter the cell and activate dormant, altered forms (spore forms) of Chlamydia. By keeping antibiotics in the extracellular space long enough, a gradual depletion of the Chlamydia bacterium can be accomplished. This could explain, at least in part, the inferior response in Quality of Life scores of patients with five or less injections compared to the other two groups, between 5 and 10, or more than 10 injections groups. Histology of the chronically infected prostate showing scarring, calcification, and sealed off bacteria supports injection therapy (16). In some cases, as late as six months to a year following injection therapy we have seen a recurrence of symptoms and offered booster injections that were successful in such cases. Residual, recurring, or re-infection could be the explanation for reduced symptom improvement that was reported after the longer follow ups. Orally given multi-drug regimens are poorly tolerated. By mixing six compatible antibiotics in one cocktail and injecting them trans rectally, one can safely reach thousand-fold the tissue concentration than the one reached

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by a single orally administered antibiotic. In our experience, injection therapy is safe, well tolerated and all complications are minor including the physical discomfort, pain on injection, minimal bleeding in the semen, urine or stool. No local infection, abscess formation or trauma complicated any of several hundreds of injections administered by our clinic. This study is retrospective, and we recognize the limitations. We believe however that the information contained in this study is significant enough to encourage the urology community to adopt injection therapy as a viable therapy for chronic prostatitis.

ACKNOWLEDGEMENTS

The Authors wish to thank Ms. Elaine Eisenbeisz (Statistician, Omega Statistics, 40960 California Oaks Road, Suite 215, Murrieta, CA 92562 http://www.omegastatistics.com) for review and analysis of data and Dr. Yu-Xin Liu (Microbiologist, for the microbiological testing of genital secretions. 40-35 Ithaca Street Apt 5E, Elmhurst, NY 11373, yuxinliu89@hotmail.com).

REFERENCES

1. Schaeffer AJ. Chronic Prostatitis and the Chronic Pelvic Pain Syndrome. N Engl J Med. 2006; 355:1690.

5. McNaughton Collins M, Pontari MA, Oâ&#x20AC;&#x2122;Leary MP, et al. Quality of life is impaired in men with chronic prostatitis: Chronic Prostatitis Collaborative Research Network. J Gen Inter Med. 2001; 16:656. 6. Weidner W, Krause W, Ludwig M. Relevance of male accessory gland infection for subsequent fertility with special focus on prostatitis. Human Reprod Update. 1999; 5:421. 7. Giamarellou H, Tympanidis K, Bitos NA, et al. Infertility and chronic prostatitis. Andrologia 1984; 16:417. 8. Cohen J. Statistical Power Analysis in Directions of Psychological Science, Sage Publications, Inc. 1992; Vol. 1, No. 3, p.98-101. 9. Lipsky, Benjamin A, Byren I, Byren H, Christopher T. Treatment of bacterial prostatitis. Reviews of Anti-Infective Agents. 2010; 50:1641. 10. Orland SM, Hanno PM, Wein AJ. Prostatitis, prostatosis and prostatodynia. Urology. 1985; 25:439. 11. Nickel JC, Downey J, Johnston B, Clark J. Predictors of patient response to antibiotic therapy for the chronic prostatitis/chronic pelvic pain syndrome: a prospective multicenter clinical trial. J Urol. 2001; 165:1544. 12. Choi YS, Kim KS, Choi SW, et al. Microbiological etiology of bacterial prostatitis in general hospital and primary care clinic in Korea. Prostate Int. 2013; 1:133. 13. Stephens RS. The cellular paradigm of chlamydial pathogenesis. Trends Microbiol. 2003; 11:44.

2. Collins M, Fowler F, Elliott D, et al. Diagnosis and treating chronic prostatitis: Do urologist use the four-glass test? Urology. 2000; 55:403.

14. Hu VH, Weiss HA, Ramadhani AM, et al. Innate immune responses and modified extracellular matrix regulation characterize bacterial infection and cellular/connective tissue changes in scarring trachoma. Infect Immune. 2012; 80:121.

3. Collins M, Stafford R, Oâ&#x20AC;&#x2122;Leary M, Barry M. How common is prostatitis? A national survey of physician visits. J Urol. 1998; 159:1224.

15. Darville T, Hiltke TJ. Pathogenesis of genital tract disease due to Chlamydia trachomatis. J Infect Dis. 2010; 201(Suppl. 2): S114.

4. Wenninger K, Heiman J, Rothman I, et al. Sickness, impact of chronic nonbacterial prostatitis and its correlates. J Urol. 1996; 155:965.

16. Madsen PO, Baumueller A, Hoyme U. Experimental models for determination of antimicrobials in prostatic tissue, interstitial fluid and secretion. Scand J Infect Dis Supl. 1978; 14:145.

Correspondence Attila Toth, MD (Corresponding Author) TothMD@gmail.com Director, MacLeod Laboratory, Associate Clinical Professor, New York Presbyterian Medical Center New York Office: 65 East 79th Street, New York, NY. 10075 Florida Office: 3893 Military Trail, Suite 1. Jupiter, FL 33458 (surface correspondence) http://www.fertilitysolution.com Frederico Maria Guercini, MD Professor of Urology Via della Camilluccia 600, 00135 Rome, Italy guercini@mclink.il Dawn Marta Feldthouse dawn.feldthouse@gmail.com Staff Nurse, The MacLeod Laboratory Jun Chao Zhang juneczhang17@gmail.com Pre-Med Student, Syracuse University, US Archivio Italiano di Urologia e Andrologia 2018; 90, 1

DOI: 10.4081/aiua.2018.1.40

ORIGINAL PAPER

The impact of prostate artery embolization (PAE) on the the physical history and pathophysiology of benign prostatic hyperplasia (BPH) Konstantinos Stamatiou Urology Department, Tzaneio Hospital, Piraeus, Greece.

Summary

Aim: Prostate artery embolization (PAE) is a non invasive modality for the treatment of benign prostate hypertrophy (BPH) related lower urinary tract symptoms (LUTS). As a relatively new procedure, data determining the clinical success is somehow scarce. In the present article we examine the current clinical outcome measures in order to identify the most accurate. Results: Current imaging outcome measures are consistent with clinical ones only in the group of patients with adenomatous-dominant BPH while are inconsistent in patients with small sized adenomas. Conclusions: Additional studies and/or evaluation tools are needed in order to provide accurate evaluation of clinical success in the subgroup of patients with non- adenomatous-dominant BPH while they may inspire new options and novel techniques for both BPH treatment and treatment-follow up.

KEY WORDS: Benign prostatic hyperplasia; Lower urinary tract symptoms; Prostate artery embolization. Submitted 12 September 2017; Accepted 8 October 2017

INTRODUCTION

BPH is a histologic diagnosis characterized by proliferation of the cellular elements of the prostate. This involves both stromal and epithelial cells, resulting in the formation of large, fairly discrete nodules in the transition zone of the prostate (1). Almost 50% of BPH patients with enlarged prostate have LUTS (2). The last are the result of either mechanical obstruction due to glandular enlargement, or dynamic obstruction secondary to contraction of the smooth muscles of the prostate, urethra and bladder neck (3). Mild symptoms usually do not require treatment however moderate and severe symptoms could be treated with either medical therapy or surgery. Currently prostatic arterial embolization (PAE) was emerged as a feasible procedure to treat lower urinary tract symptoms associated with BPH. PAE is the less invasive non pharmaceutical treatment. It is performed under local anaesthesia, usually by a right groin approach through the right femoral artery. It consists of selective embolization of prostatic arteries with small-diameter hydrophilic microcatheters and polyvinyl alcohol (PVA) in order to cause interruption of arterial flow. Initial studies showed that PAE led to reduction of the prostatic volume, symptom remission and improvements in quality of life However, as

a relatively new procedure, data determining the accurate evaluation of clinical success of PAE is somehow scarce. In the present article we aim to investigate the potential role of elastography on the evaluation of clinical success of PAE on the treatment of benign prostatic hyperplasia (BPH).

MATERIALS

AND METHODS

A search was performed in MEDLINE, NCBI, Pubmed, Cochrane Library and other electronic libraries using the terms: â&#x20AC;&#x153;prostate artery embolization AND benign prostatic hyperplasiaâ&#x20AC;?. The articles selected were checked for the relevancy of their content to the discussed subject. The bibliographic information in the selected articles was checked for relevant publications that had not been included in the original search.

RESULTS

Since 2008 when embolization of prostatic arteries for the treatment of LUTS associated with BPH has been held for the first time, a total of 104 articles on PAE were published. After being checked for the relevancy of their content to the discussed subject, 22 papers were discarded after lecture of summary and 61 after lecture of the full paper. Finally, 21 peer-reviewed studies providing data on one or more clinical outcomes were retrieved. A recent meta-analysis of 6 large studies showed improvement in Qmax, PVR, IPSS, and QoL endpoints at 12 months, with a low incidence of serious adverse effects (0.3%). Another recent meta-analysis of three studies comparing PAE with other treatments found greater maximum urine flow restoration and reduction in prostate volume in PAE group in relation to controls (4). Current experience shows also promising results in symptom remission and improvements in quality of life. However the overall number of PAE patients and studies meeting reliability criteria is small. Moreover, no generally accepted definition for clinical success exists (Table 1). In fact, principal outcome assessment varies among studies and could be either objective or subjective, laboratory, clinical or both. For example, regaining the ability to urinate after PAE is a measurable size whereas questionnaire-based self-reported improvement of both urination and QoL are not. Furthermore, as long as the exact mechanism by which No conflict of interest declared.

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The impact of prostate artery embolization (PAE) on the the physical history and pathophysiology of benign prostatic hyperplasia (BPH)

lation between PSA level elevation 24 hours after PAE and IPSS decrease at 3 months of follow-up was reported (31). It Authors N. patients Main outcome criteria should be mentioned that other condiLi P et al, 2017 (18) 24 IPSS, PVR, Qmax, PSA tions that can increase PSA levels such as Hwang JH et al, 2017 (19) 9 IPSS, PV, QoL, Qmax pre-existing inflammation, pre-treatment Little MW et al, 2017 (13) 12 MP-MRI, IPSS, EQ-5D-5S prostate manipulations (e.g. catheterization) and prostate size may bias this assoRampoldi A et al, 2017 (20) 43 discontinuation of IBC, IPSS, PV, QoL, Clavien II ciation. Moreover IPSS has inadequate Bilhim T et al, 2016 (21) 183 24-hour post-PAE PSA, MRI sensitivity and specificity to be used as a Isaacson AJ et al, 2016 (22) 12 IPSS-QoL stand-alone tool in the evaluation of cliniPisco J et al, 2016 (23) 152 IPSS, QoL, need for additional treatment cal success of a new method such as PAE. Wang MQ et al, 2016 (14) 157 IPSS, QoL, Qmax, PV, PVR, and PSA Although, a study proposed PSA elevation after PAE to be a prognostic factor for preAmouyal G et al, 2016 (24) 32 Mean IPSS, mean QoL, mean Qmax, mean PV dicting patient response to PAE (31), more de Assis AM et al, 2015 (10) 35 MRI, uroflowmetry, IPSS research is needed in order to confirm this Bagla S et al, 2015 (11) 78 AUA symptom index, QoL, or IIEF suggestion. Russo GI et al, 2015 (25) 287 IPSS, IIEF-5, PF, PVR, IPSS-QoL In fact, uncertainty regarding the role of IPSS: International Prostate Symptom Score, PVR: post void residual volume, PSA: prostate-specific antigen, pre-treatment prostatic volume in the sucIIEF-5: International Index of Erectile Function 5, QoL: quality of life score, TPV transitional zone prostate volume, cessfulness of PAE exists. Bagla et al perPV: prostatic volume (total volume and transition zone), EQ-5D-5S: quality of life assessment 5D-5S, IBC indwelling bladder catheterization. formed an analysis on 78 consecutive patients undergoing PAE, comparing prostate volume groups (group 1 < 50 PAE affects BPH induced LUTS remains unclear, reduccm3; group 2, 50-80 cm3; group 3 > 80 cm3) at baseline tion in prostate volume and serum PSA value may not be and follow-up to assess for differences in outcomes of the most adequate outcome measures. In fact, clinical American Urological Association (AUA) symptom index, success â&#x20AC;&#x201C; in terms of IPSS and Qmax â&#x20AC;&#x201C; is not always analquality of life (QOL)-related symptoms, and International ogous to prostate volume reduction. Moreover, the Index of Erectile Function (IIEF). According to their result reduction on prostate volume occurs progressively and no statistically significant differences in the above paramstabilized within six months of the procedure. Yet, up to eters was found between groups (11). Other authors sug20% of patients undergoing PAE show no prostate volgest that patients with a smaller prostate (i.e., volume < ume reduction 3 months after the procedure (5). 30 cm3) should excluded because PAE is believed to A small MRI study showed that reduction of the prostate work based on prostate volume reduction, which will be volume after embolization was significant only in more limited in patients with almost normal sized patients with infarcts (6). In this study infarcts were seen prostates (12). in only 70.6% of the subjects, exclusively in the central In accordance to the above, Little et al., found a statistigland. However, a retrospective study showed that procally significant reduction in prostate volume following static volume decrease occurs in both central and periphembolization with a median reduction of 34% (30-55) in eral zones (7), a fact suggesting disproportion between the group of patients with adenomatous-dominant BPH infarcts and reduction of the prostate volume. Although, (AdBPH), compared to a mean volume reduction of 22% a small MRI study proposed infarcts to be a good predicin the non-AdBPH group. IPSS and QoL score signifitor of clinical success after PAE in patients with AUR seccantly improved in the AdBPH group while there was no ondary to BPH (8), it seems that it is not the case. deterioration in sexual function in either group post-PAE A significantly high PSA elevation occurs in the 24 hours (13). Similarly, Wang et al., found the clinical and imagafter PAE. During follow-up, mean PSA decreases to a ing outcomes of PAE to be better in patients with larger level significantly lower than at baseline. This is suspectprostate glands than medium-sized ones (14). ed to result from prostate inflammation and ischemia due to embolization and suggests prostate cellular apoptosis after PAE (9). However, no statistically significant correlaDISCUSSION tion was detected between PSA level 24 hours after PAE The abovementioned findings may indicate a greater and prostate volume reduction at 3 months of follow-up impact of PAE induced ischaemia in the adenomatous (10). In contrast, a statistically significant negative correthan in the stromal element of the prostate gland. However, clinical effect occurs progressively and stabilized within six months, Table 2. therefore it is possible that PAE resolves Histological and anatomical findings after PAE and their clinical dynamic obstruction also but at a slower significance (15). rate. The exact mechanism by which PAE resolves dynamic obstruction is the Histological and anatomical findings Clinical significance shrinkage of the enlarged prostate gland Fibroblast accumulation Reparative process as a result of PAE induced ischemic Squamous metaplasia of the surrounding epithelium Transitional process infarction. In contrast, the exact mechaRibbons of neuthrophils, lymphocytes Inflammatory process nism(s) by which PAE resolves dynamic Table 1. Variability of Main outcome criteria among studies.

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K. Stamatiou

obstruction remains practically unknown (15). Currently used imaging techniques are not providing relative information while knowledge on the histology of prostate tissue following PAE is extremely limited. Camara-Lopes et al., described early prostate tissue histology changes after PAE. Along with embolic material (bright eosin-red spheroids filling the vessel lumens) they observed also areas of ischemic necrosis. The transition zone between necrotic and normal prostate tissue was characterized by inflammatory reactions containing ribbons of neuthrophils, lymphocytes and proliferated fibroblasts. Nodular fibrosis with hyalinization as a consequence of the healing process was present in some areas associated with squamous metaplasia of the epithelium lining the surrounding glands (9). Yet there are no studies examining long term prostate tissue histology changes after PAE. However, given that PSA values decreases to a level significantly lower than at baseline but no ejaculation disorders occur it could be assumed that prostate gland return in fully functional state after PAE. As a matter of fact, metaplasia that occurs in response to necrosis and inflammation may represent an adaptive substitution of cells that are sensitive to stress by cell types better able to withstand the adverse environment and is reversible. On the other hand, the regained ability to urinate after PAE may be associated with changes in stromal elements. Because fibroblasts are typically activated following injury and are the main producers of extracellular matrix proteins, their role as reparative cells is widely recognized (16). Fibroblasts may play a critical role in remodeling of the prostate following PAE and thus, clinical success might be also related to the regained elasticity. The stiffness of a tissue, or its ability to resist deformation when subjected to an applied force, is indicative of the regenerative state in most organs in the body. Tissue stiffness is largely defined by chemistry and associated micro-macro structure of the extracellular matrix (ECM). Therefore, the ability to estimate ECM stiffness may assist in monitoring healing after PAE and allow estimation of clinical success. Currently, elastic properties, of biomaterials including stiffness or shear modulus, can be investigated by elastography. The last is the only specialized imaging-based method available to spatially map strain fields, it is costeffective and safe (17). Studies comparing elastographic findings with the conventional outcome measures are needed in order to investigate the role for the elastography on the evaluation of the efficacy of PAE on the treatment of BPH.

CONCLUSION

PAE is a safe and efficient method for the treatment of both mechanical and dynamic component of bladder outlet obstruction in patients with BPH. Current imaging outcome measures are consistent with clinical ones in the group of patients with adenomatous-dominant BPH while are inconsistent in patients with small sized adenomas. Elastography may be useful for the evaluation of PAE outcome in these patients while may shed light on the pathophysiology of BPH and inspire new

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options and novel techniques for both treatment and follow up.

REFERENCES

1. Auffenberg GB, Helfand BT, McVary KT. Established medical therapy for benign prostatic hyperplasia. Urol Clin North Am. 2009; 36:443-59. 2. Roehrborn CG. Pathology of benign prostatic hyperplasia. Int J Impot Res. 2008; 20:S11-S18. 3. Lawrentschuk N, Perera M. Benign Prostate Disorders. In: De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000. 4. Shim SR, Kanhai KJ, KoYM, Kim JH. Efficacy and Safety of Prostatic Arterial Embolization: Systematic Review with Meta-Analysis and Meta-Regression. J Urol. 2016: S0022-5347(16)31197-1. 5. Yoshinaga EM, Galvao O, da Motta-Leal-Filho JM, et al. Magnetic resonance analysis of prostatic volume after prostatic artery embolization (PAE) for treatment of benign prostatic hyperplasia (BPH). J Urol. 2013; 189(4S/Supplement): e820 6. Frenk NE, Baroni RH, Carnevale FC, et al. MRI findings after prostatic artery embolization for treatment of benign hyperplasia. AJR Am J Roentgenol. 2014; 203(4):813-21. 7. Lin YT, Amouyal G, Correas JM, et al.Can prostatic arterial embolisation (PAE) reduce the volume of the peripheral zone? MRI evaluation of zonal anatomy and infarction after PAE. Eur Radiol. 2016; 26:3466-73. 8. Kisilevzky N, Faintuch S. MRI assessment of prostatic ischaemia: best predictor of clinical success after prostatic artery embolisation for benign prostatic hyperplasia. Clin Radiol. 2016; 71:876-82. 9. Camara-Lopes G, Mattedi R, Antunes AA, et al. The histology of prostate tissue following prostatic artery embolization for the treatment of benign prostatic hyperplasia. Int Braz J Urol. 2013; 39:222-7. 10. Assis AM, Rodrigues VCP, Yoshinaga EM, et al. Prostatic artery embolization (PAE) for treatment of benign prostatic hyperplasia in patients with prostates exceeding 90g: a prospective single center study. J Vasc Interv Radiol. 2015; 26:87-93. 11. Bagla S, Smirniotopoulos JB, Orlando JC, et al. Comparative Analysis of Prostate Volume as a Predictor of Outcome in Prostate Artery Embolization. Vasc Interv Radiol. 2015; 26:1832-8. 12. Pereira K, Halpern JA, McClure TD, et al. Role of prostate artery embolization in the management of refractory haematuria of prostatic origin. BJU Int. 2016; 118:359-65. 13. Little MW, Boardman P, Macdonald AC, et al. AdenomatousDominant Benign Prostatic Hyperplasia (AdBPH) as a Predictor for Clinical Success Following Prostate Artery Embolization: An AgeMatched Case-Control Study. Cardiovasc Intervent Radiol. 2017; 40:682-689. 14. Wang MQ, Wang Y, Yan JY, Yuan K, et al. Prostatic artery embolization for the treatment of symptomatic benign prostatic hyperplasia in men ≥ 75 years: a prospective single-center study. World J Urol. 2016; 34:1275-83. 15. Sun F, Crisóstomo V, Báez-Díaz C, Sánchez FM. Prostatic Artery Embolization (PAE) for Symptomatic Benign Prostatic Hyperplasia (BPH): Part 2, Insights into the Technical Rationale. Cardiovasc Intervent Radiol. 2016; 39:161-9. 16. Willems IE, Havenith MG, De Mey JG, Daemen MJ. The alphasmooth muscle actin-positive cells in healing human myocardial scars. Am J Pathol. 1994; 145:868-875.

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The impact of prostate artery embolization (PAE) on the the physical history and pathophysiology of benign prostatic hyperplasia (BPH)

17. Kim W, Ferguson VL. Application of Elastography for the Noninvasive Assessment of Biomechanics in Engineered Biomaterials and Tissues. Ann Biomed Eng. 2016; 44:705-724. 18. Li P, Wang C, Cao Q, Zhang J, et al. Prostatic Arterial Embolization Followed by Holmium Laser Enucleation of the Prostate as a Planned Combined Approach for Extremely Enlarged Benign Prostate Hyperplasia. Urol Int. 2017 Aug 3, [Epub ahead of print]. 19. Hwang JH, Park SW, Chang IS, et al. Comparison of Nonspherical Polyvinyl Alcohol Particles and Microspheres for Prostatic Arterial Embolization in Patients with Benign Prostatic Hyperplasia. Biomed Res Int. 2017; 2017:8732351. (Epub 2017 Jun 22). 20. Rampoldi A, Barbosa F, Secco S, Migliorisi C, et al. Prostatic Artery Embolization as an Alternative to Indwelling Bladder Catheterization to Manage Benign Prostatic Hyperplasia in Poor Surgical Candidates. Cardiovasc Intervent Radiol. 2017; 40:530-536. 21. Bilhim T, Pisco J, Pereira JA, Costa NV, et al. Predictors of Clinical Outcome after Prostate Artery Embolization with Spherical

and Nonspherical Polyvinyl Alcohol Particles in Patients with Benign Prostatic Hyperplasia. Radiology. 2016; 281:289-300. 22. Isaacson AJ, Raynor MC, Yu H, et al. Prostatic Artery Embolization Using Embosphere Microspheres for Prostates Measuring 80-150 cm(3): Early Results from a US Trial. J Vasc Interv Radiol. 2016; 27:709-14. 23. Pisco J, Bilhim T, Pinheiro LC, et al. Prostate Embolization as an Alternative to Open Surgery in Patients with Large Prostate and Moderate to Severe Lower Urinary Tract Symptoms. J Vasc Interv Radiol. 2016; 27:700-8. 24. Amouyal G, Thiounn N, Pellerin O, Yen-Ting L. Clinical Results After Prostatic Artery Embolization Using the PErFecTED Technique: A Single-Center Study. Cardiovasc Intervent Radiol. 2016; 39:367-75. 25. Russo GI, Kurbatov D, Sansalone S, et al. Prostatic Arterial Embolization vs Open Prostatectomy: A 1-Year Matched-pair Analysis of Functional Outcomes and Morbidities. Urology. 2015; 86:343-8.

Correspondence Stamatiou Konstantinos, MD (Corresponding Author) stamatiouk@gmail.com Urology Department, Tzaneio Hospital, 2 Salepoula str. 18536 Piraeus, Greece

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ORIGINAL PAPER

DOI: 10.4081/aiua.2018.1.44

Erectile dysfunction in patients taking psychotropic drugs and treated with phosphodiesterase-5 inhibitors Rossella Mazzilli 1, Gloria Angeletti 2, Soraya Olana 1, Michele Delfino 1, Virginia Zamponi 1, Chiara Rapinesi 2, Antonio Del Casale 2, Georgios D. Kotzalidis 2, Jlenia Elia 1, Gemma Callovini 2, Paolo Girardi 2, Fernando Mazzilli 1 1 Andrology

Unit, Sant’Andrea Hospital, Sapienza University of Rome, School of Medicine and Psychology, Rome, Italy; (Neurosciences, Mental Health, and Sensory Organs) Department, Sant’Andrea Hospital, Sapienza University of Rome, School of Medicine and Psychology, Rome, Italy.

2 NESMOS

Summary

Objectives: The aim of this study was to assess the prevalence of patients with Erectile Dysfunction (ED) receiving psychotropic drugs, the impact of these drugs on hormonal profile, and the efficacy of PDE5-i in these patients. Materials and methods: We recruited 1872 patients referring for ED to our Andrology Unit. Assessment included serum testosterone, gonadotropins, TSH, prolactin, and PSA, and the IIEF-5 questionnaire for ED diagnosis. Inclusion criteria were age 21-75 years and IIEF-5 total score ≤ 21; exclusion criteria included hypogonadism, diabetes mellitus, previous prostatectomy, other medication intake, and ED diagnosis prior to psychotropic drug treatment. Efficacy was rated with the IIEF-5 (remission: total score ≥ 22). Results: The prevalence of ED patients treated with psychotropic drugs since ≥ 3 months was 9.5% (178/1872), subdivided according to the drugs used into: Group A, 16 patients treated with atypical antipsychotics (9.0%); Group B, 55 patients with benzodiazepines (30.9%); Group C, 33 patients with antidepressant drugs (18.5%); and Group D, 74 patients with multiple psychotropic drugs (41.6%). Patients in Group A were significantly younger than other groups (p < 0.05). The hormonal profile presented only higher prolactin level in patients treated with antipsychotics, alone or in combination (p < 0.05). Overall, 146 patients received PDE5-i. Remission rate, after three months of treatment, was significantly higher in Group B compared to C and D groups (p < 0.05). Conclusions: A substantial portion of patients receiving psychotropic drugs show ED. Sexual performance in these patients benefits from PDE5-i. Age, effects of psychiatric disorders, psychotropic drugs, and PDE5-i treatment modality accounted for variability of response in this sample.

KEY WORDS: Erectile dysfunction; Psychotropic drugs; Phosphodiesterase 5-inhibitors; Antipsychotic drugs; Antidepressant drugs; Benzodiazepines. Submitted:14 December 2017; Accepted 20 February 2018

INTRODUCTION

Erectile Dysfunction (ED) is defined as the persistent inability to achieve or maintain penile erection that is sufficient for satisfactory sexual performance. Organic (neurological, endocrine-metabolic disorders, diabetes, vascular, and mechanic), psychological and pharmacological (e.g., drug interference) factors may lead to ED (1). The drug classes most frequently associated with ED are antihypertensive,

alpha-blockers, proton pump inhibitors and psychotropic drugs, especially antidepressants and antipsychotics. There are many ways by which drugs can interfere with the neuro-vascular and sensory mechanisms of sexual function (2). In particular, antipsychotics and serotonin reuptake inhibitors (SSRIs), in addition to anorgasmia and decreased libido, may induce ED, mainly through dopamine inhibition and the consequent increase in prolactin levels. However, antipsychotics differ in their hyperprolactinemic effect; risperidone, olanzapine, ziprasidone, and amisulpride have all been associated with hyperprolactinemia, quetiapine, clozapine and aripiprazole with both hyperprolactinemia and its reversal, and lurasidone has shown no hyperprolactinemizing potential. Furthermore, combining antidepressants with antipsychotics was associated with increased prolactin level (3). There are several reports and studies dealing with the treatment of ED with PDE5-i in patients receiving psychotropic medication, mainly in patients who developed ED secondary to antidepressant or antipsychotic intake. Antidepressants are long known to be associated with sexual side effects (2) and more than half of the patients who receive antidepressants (Ads) develop sexual side effects. The main mechanisms by which antidepressants affect sexual function are monoaminergic, i.e., serotonergic, noradrenergic, and dopaminergic. Almost all currently used antidepressants acutely increase the concentration of biogenic amines in the synaptic cleft and in the longer term down-regulate serotonergic and noradrenergic receptors in the synapses. In man, cavernosal serotonin mediates contraction, hence reduced penile blood influx, with 5-HT1A, 5-HT2A, and 5-HT4 serotonin receptor stimulation inducing detumescence that may be blocked by antagonists of these receptors. To further add to this complexity, dopamine D1 and D2like receptor agonists strain-dependently induce penile erection (4). Antipsychotic drugs, both classical and atypical, are able to block dopaminergic function by inhibiting all types of dopamine receptors, so their ability to cause ED is not surprising (5). Increased intracellular cGMP is crucial for erection; various phosphodiesterases (PDEs) hydrolyze cGMP (PDE5, 6 and 9 specifically) to 5’-GMP thereby decreasing its intracellular concentration and consequently, erection, thus providing an adequate rationale for PDE inhibitors in the treatment of ED. The effects of No conflict of interest declared.

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Erectile dysfunction and psychotropic drugs

sildenafil have been evaluated and found satisfactory in patients treated with antipsychotics who had developed ED, including atypical antipsychotics, such as olanzapine and risperidone or antidepressant drugs; in all studies, sildenafil was effective and well-tolerated (6-9). Tadalafil was also found to be effective in patients treated with antidepressants, like serotonin reuptake inhibitors (SSRIs) (10). However, no studies to date focused conjointly on how many patients with ED were treated with psychotropics and on their endocrine derangement. We aimed to retrospectively investigate: a) the prevalence of patients who are treated with psychotropic drugs among men with ED; b) the impact of these drugs on their hormonal profile; and c) the efficacy of PDE5-i in relieving ED in patients with psychotropic-associated ED who continue on their psychotropic medication.

MATERIALS

AND METHODS

Patients We recruited 1872 patients with ED between 21 and 75 years of age who referred to our Andrology Unit (Sant'Andrea Hospital-Sapienza University, Rome, Italy) between January 2006 and July 2017. Patients were explained the purpose of the study and signed free, informed consent. Assessment comprised medical history collection, physical examination, in particular andrological, and the completion of a sociodemographic data collection sheet. All patients completed the International Index of Erectile Function (IIEF-5) questionnaire (11). Those scoring ≤ 21 were eligible for the study. Exclusion criteria comprised previous radical prostatectomy, hypogonadism in treatment with testosterone, diagnosis of diabetes mellitus (DM), based on fasting plasma glucose and glycosylated hemoglobin-HbA1c levels, a previous PDE5-i treatment, a concomitant treatment with other, non -psychotropic medications. At baseline we obtained blood to evaluate luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone, thyroid stimulating hormone (TSH), prolactin, and prostate specific antigen (PSA). Hormonal assays. Between h 08:00 and 11:00 we withdrew from each patient 5 mL of blood in 5 mL vials. The vials were centrifuged at 3,000 r.p.m. for 10 min and kept at 20°C until the day of the assay. Assays were carried-out using enzyme-linked fluorescence assay (ELFA); we investigated serum testosterone, FT4, TSH, and prolactin. Psychometric assessment. The patients completed the validated Italian version of the abridged IIEF-5 questionnaire, consisting of five items each rated on a 5-point Likert scale ranging from 1 (low on sexuality) to 5 (normal sexual performance) (11). A score of ≤ 21 is considered as showing the existence of ED, while scores of ≥ 22 are considered as remission. Treatment. In the absence of contraindications, included ED patients had the option to choose between an “on demand” schedule of a PDE5-i, i.e., 50-100 mg oral sildenafil, 10-20 mg vardenafil, 10-20 mg tadalafil, and (since 2013) 100-200 mg avanafil, or a 5 mg/day oral tadalafil “once a day” schedule. In particular, the “on demand” drug was chosen with the patient, according to time of onset, duration of action, and interactions with food and alcohol,

which are specific for each PDE5-i. The study adhered to the Hospital’s Ethics Committee guidelines and to the Ethical Principles for Medical Research Involving Human Subjects as adopted at the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the 55th WMA General Assembly, Tokyo, Japan, October 2004 and subsequent modifications when enforced (last, Fortaleza, Brazil, October 2013). Statistics Given the large sample size, we used parametric statistics to analyze our data. We used the paired t-test and Fisher's exact test for continuous and categorical data, respectively. Continuous data were described as absolute values, mean ± Standard Deviation (SD), and range. Categorical data were described as absolute, percentage frequency, and 95% Confidence Intervals (CIs). We set statistical significance at p < 0.05. Analyses were carriedout with the Statistical Package for the Social Sciences (SPSS), version 24 (International Business Machines Corporation [IBM], Armonk, New York, US).

RESULTS

Of the 1872 evaluated patients, 1642 were not receiving any psychotropic medication, while 230 patients (12.3%) were receiving psychotropic drugs; of them, 52 were excluded, 9 because they were previously prostatectomized, 8 were hypogonadic in treatment with testosterone, 14 had DM, and 47 were taking also non-psychotropic medications, thus leaving a final sample of 178 (9.5%). The sample’s sociodemographic characteristics are shown in Table 1. The 178 patients were distributed into 4 groups, according to the psychotropic drugs they used (Table 2): • Group A: 16/178 patients (9.0%) were treated with atypical antipsychotics (olanzapine, aripiprazole, risperidone and quetiapine); Table 1. Sociodemographic characteristics of the included men (N = 178). SD, standard deviation. Age Marital status Single Married Divorced Widowed Educational level Primary school High School Superior high school College/University Specialization/Master/Ph.D. Occupational status Unemployed Blue collar worker Employee Entrepreneur Free-lance professional Executive

Mean (range) 51.6 (21-75) N

SD 13.1 (%)

43 97 25 13

24.2 54.5 14.0 7.3

3 15 83 54 23

1.7 8.4 46.7 30.3 12.9

21 28 44 28 42 15

11.8 15.7 24.8 15.7 23.6 8.4

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R. Mazzilli, G. Angeletti, S. Olana, M. Delfino, V. Zamponi, C. Rapinesi, A. Del Casale, G.D. Kotzalidis, J. Elia, G. Callovini, P. Girardi, F. Mazzilli

N = 178 Group A

Group B

Group C

Group D

Age (years) (range) 42.5 ± 14.1* (25-59) 54.0 ± 13.5 (24-75) 55.3 ± 11.7 (0.6-2.9) 50.2 ± 12.4 (21-75)

LH (mlU/ml) 5.2 ± 2.8 (2.7-9.2) 4.9 ± 2.3 (2.3-8.7) 5.8 ± 2.7 (36-75) 6.0 ± 4.3 (1.4-12.6)

FSH (mlU/ml) 5.1 ± 2.6 (3.1-8.0) 4.4 ± 1.5 (1.8-7.4) 6.6 ± 2.6 (2.0-11.2) 7.3 ± 3.9 (2.5-12.1)

Testosterone (ng/ml) 5.3 ± 2.0 (3.1-8.0) 5.9 ± 2.3 (2.7-8.8) 5.9 ± 1.5 (3.4-12.6) 4.1 ± 2.3 (1.6-8.9)

TSH (mlU/ml) 1.6 ± 0.5 (0.92-2.3) 1.6 ± 0.8 (1.1-3.4) 1.0 ± 0.8 (4.6-7.9) 2.0 ± 0.9 (0.9-3.1)

Prolactin PSA (ng/ml) (ng/ml) 16.9 ± 2.8* 1.4 ± 1.1 (14.0-21.3) (0.58-2.15) 6.8 ± 3.2 1.7 ± 1.2 (4.0-11.2) (0.3-3.3) 7.2 ± 3.7 1.6 ± 1.1 (0.3-1.9) (4.9-13.3) 15.8 ± 5.5* 1.8 ± 1.0 (6.8-25.4) (0.7-1.9)

Table 2. Age and hormonal profile in the different groups considered [mean values ± SD (min.-max)].

*p < 0.01 vs Group B, C e D; **p < 0.01 vs Groups B and C. Legend for groups: A, receiving only atypical antipsychotics; B, receiving only benzodiazepines; C, receiving only antidepressants; D, receiving any combination of the above. Luteinizing hormone (LH), follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), prostate specific antigene (PSA).

Total Group A Group B Group C Group D

N 178 16 55 33 74

Treated patients 146/178 (82.0%; 75.7 to 87.0) 9/16 (56.3%; 33.2 to 76.9) 47/55 (85.5%; 73.6 to 92.7)* 27/33 (81.8%; 65.2 to 91.8) 62/74 (83.8%; 73.6 to 90.6)

Responders (%) 67/146 (45.9%; 38.0 to 54.0) 5/9 (55.6%; 26.6 to 81.2) 31/47 (66.0%; 51.6 to 77.9)** 11/27 (40.7%; 24.5 to 59.3) 20/62 (32.3%; 21.9 to 44.7)

Table 3. Therapeutic efficacy of PDE5-i in the various psychotropic treatment groups (IIEF-5: total score ≥ 22) [N (%, 95%CI)].

* p< 0.05 vs A; ** p<0.05 vs Groups C and D. Legend for groups: A, receiving only atypical antipsychotics; B, receiving only benzodiazepines; C, receiving only antidepressants; D, receiving any combination of the above.

Total Group A Group B Group C Group D

N 113 7/10 42/47 16/27 48/62

On demand Responders (%) 54/113 (47.8%; 38.8-56.9) 3/7 (42.9%; 15.8 to 75.0) 29/42 (69.1%; 53.9 to 81.0)* 6/16 (37.5%; 18.4 to 61.5) 16/48 (33.3%; 21.6 to 47.5)

N 33 3/10 5/47 11/27 14/62

Once a day Responders (%) 14/33 (41.2%; 26.3-57.8) 2/3 (66.7%; 20.2 to 94.4) 3/5 (60.0%; 22.9 to 88.4) 4/11 (36.4%; 15.0 to 64.8) 5/14 (35.7%; 16.2 to 61.4)

Table 4. PDE5-i “on demand” or “once a day” treatment and efficacy (IIEF-5: total score ≥ 22) per psychotropic treatment [N (%, 95%CI)].

*p < 0.05 vs Groups C and D. Legend for groups: A, receiving only atypical antipsychotics; B, receiving only benzodiazepines; C, receiving only antidepressants; D, receiving any combination of the above.

• Group B: 55/178 patients (30.9%) treated with benzodiazepines (alprazolam, lorazepam, clonazepam, bromazepam); • Group C: 33/178 patients (18.5%) treated with antidepressant drugs in monotherapy (SSRIs, i.e., fluoxetine, sertraline, citalopram, escitalopram, or paroxetine; serotonin-norepinephrine reuptake inhibitors (SNRIs), i.e., duloxetine and venlafaxine; and tricyclic antidepressants (TCAs), i.e., amitriptyline and clomipramine); • Group D: 74/178 patients (41.6%) in polytherapy with antidepressant drugs (citalopram, paroxetine, and clomipramine) and/or atypical antipsychotics (olanzapine, aripiprazole, and risperidone) and/or benzodiazepines (alprazolam, lorazepam, and clonazepam) and/or mood stabilizers (lithium carbonate, carbamazepine, and valproic acid). No patient was on monotherapy with monoamine oxidase inhibitors (MAOIs) or mood stabilizers. Age. Patients in Group A were significantly younger compared to the other groups (p < 0.05) (Table 2). Hormonal profile. The four groups did not differ in hormone levels, except for prolactin, that was higher in patients treated with antipsychotics alone or those in polytherapy with respect to the groups treated with benzodiazepines or antidepressants alone (p < 0.05) (Table 2).

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ED Treatment. Of the 178 patients, 146 (82.0%) accepted PDE5-i treatment; patients in group A adhered to treatment significantly more than patients in group B (p < 0.05). The remaining 32 (18.0%) patients refused PDE5-i treatment for various reasons. Response/remission of ED, as assessed after three months of treatment through the IIEF-5 questionnaire (i.e., a total score of ≥ 22), was significantly higher in group B compared to groups C and D (p < 0.05) (Tables 3-4). Regarding PDE5-i treatment modality, 113/146 (77.4%) patients chose “on demand” while 33/146 (22.6%) chose “once a day” administration. “On demand” and “once a day” groups showed no significant differences in positive response rates (47.8% vs. 41.2%; p = n.s.). However, considering individual groups, response/remission in patients who chose an “on demand” modality was significantly higher in Group B, compared to Groups C and D (p < 0.05). Regarding the “once a day” modality, no between-groups differences were shown. Of the 146 patients who adhered to PDE5-i treatment, 67 (45.9%) responded positively to treatment (final IIEF-522). The IIEF-5 total score varied from 12.5 ± 3.8 (range 621) at baseline to 19.8 ± 3.8 (range 8-25) at the threemonth follow-up. The difference was statistically significant (p < 0.01).

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Erectile dysfunction and psychotropic drugs

DISCUSSION

In this study we focused on identifying the prevalence of psychotropic drug use in ED patients, on observing psychotropic drug impact on ED patient’s hormonal profile, and on the efficacy of PDE5-i in such patients. About 12.3 % of patients with ED in our sample were receiving psychotropic medication and about 9.5% met criteria for inclusion; of them, about half achieved remission in response to PDE5-i treatment added on their psychotropic drug(s). In this cross-sectional study, we found the group receiving only benzodiazepines to fare better than groups receiving other drugs or combinations, even after splitting the sample into “on demand” or “once a day” modalities. We also found higher serum prolactin only in patients receiving antipsychotics, alone or in combination, as well as age differences among the four groups. A possible pathogenic factor of ED is represented by drug interference. Among drugs, psychotropics have an important role, even if, in the presence of ED, the line between effect of drug therapy and psychopathology is undefined. In fact, in patients with depressive symptoms, symptoms like apathy or anhedonia, and in those with schizophrenia, specifically anhedonia, could negatively shape sexual life (5-9). We are aware of no studies investigating the prevalence of psychotropic drug use in an ED population. Here we found a 9.5% prevalence involving patients developing ED after at least 3-month psychotropic drug use. Studies investigating psychotropic drug prescription/use in the general population worldwide have produced different results depending on the period of investigation and on the country where the search was conducted (Supplementary Table). Comparing our data with the last European data on general populations (12.3%), our proportion of patients with ED who are on psychotropics is similar. However, given that in most studies significantly more women than men use psychotropics, and considering that our sample was composed of men only, we might suppose that psychotropic drug use in ED populations may be higher than in the general population. We divided our sample into 4 groups according to the type of drugs they used, i.e., atypical antipsychotics, benzodiazepines, and antidepressant drugs in monotherapy and those who were on polytherapy. These subsamples differed for age, in that patients receiving antipsychotics were significantly younger than those in the other groups, probably because the psychoses have an earlier onset and an earlier treatment initiation than other psychiatric disorders. In fact, schizophrenia has an onset around adolescence and early adulthood, while anxiety disorders and depression have a later onset and a later initiation of treatment (12). The hormonal profile (gonadotropins, testosterone and TSH levels) was similar in the different groups; on the other hand, prolactin levels, a hormone related to sexual dysfunction, was significantly higher in the groups treated with atypical antipsychotics, alone or in combination, in line with literature (3, 13). There are few reports on the use of sildenafil and tadalafil in patients treated with atypical antipsychotic or antidepressant drugs in monotherapy, and they showed variable efficacy (6, 14-15). Our study included also people treat-

ed with benzodiazepines and polytherapy, and, among PDE5-i, also vardenafil and avanafil. There are few, sporadic reports on the use of these two PDE5-is in psychotropic-associated ED. The only controlled study regarded vardenafil vs. placebo and found effectiveness for both ED and mild depression in patients receiving no psychotropic drugs, that could mean either intrinsic antidepressant properties for PDE5-is or that improved sexual performance acted on depression to decrease it (16). Acceptance to be treated was higher in patients treated with benzodiazepines, compared to the other groups. In particular, people on benzodiazepines were significantly more likely to endorse PDE5-i treatment than patients on antipsychotics and responders among the former were significantly more likely to have endorsed PDE5-i treatment than those who received either antidepressants or polytherapy. While we are not able to demonstrate why should this occur, we could speculate that people with anxiety, who usually receive benzodiazepines (although antidepressant treatment is the standard for most anxiety disorders), experience less side effects (other than dependence) than those who receive other classes of psychotropics, thus they are more open to further drug treatment to improve their ED. Help-seeking was found to be the most important factor in benzodiazepine and antidepressant use in Europe (17), but factors prompting to further drug use were not examined. We did not investigate help-seeking specifically, but most of our patients were motivated for resolving their ED. Furthermore, people with psychosis tend to be suspicious about drug treatment and doctors and show poor adherence (18). Furthermore, we found significantly more improvement in the group receiving benzodiazepines, indicating their ED was due to an underlying anxiety disorder rather than to their medication. Although benzodiazepines may differ in their ED-inducing potential, results from large cohorts show benzodiazepines to be associated with ED, even after adjusting for comorbidities and health behaviors or addressing possible confounders (19). Benzodiazepine increase GABAA receptor function and GABAA receptor stimulation has been shown to reduce penile erection in rats through central mechanisms, so we could expect that people on benzodiazepines could show similar rates of ED to people taking other ED-associated psychotropic drugs (20). It is possible that in conditions of extreme anxiety, in which GABAergic activity is low, its normalization through benzodiazepines could alleviate impaired erection caused by anxiety itself. Better response in the benzodiazepine group was present also when subdividing the sample according to “on demand” or “once a day” modalities, with better response in the former, while in the latter no significance could be shown, probably due to reduced sample size. On the other hand, the unsatisfactory response of the other groups (antidepressants, antipsychotics and polytherapy) could be possibly due to both the psychopathological condition and to persistent drug interference with erectile function. The limitations of this study is that it included only patients without prior ED who underwent psychotropic drug treatment. Thus, we cannot investigate the extent to which PDE5-i treatment may benefit patients with ED Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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R. Mazzilli, G. Angeletti, S. Olana, M. Delfino, V. Zamponi, C. Rapinesi, A. Del Casale, G.D. Kotzalidis, J. Elia, G. Callovini, P. Girardi, F. Mazzilli

who need psychotropic treatment for their psychological condition. Furthermore, the design was cross-sectional and retrospective. Obviously, a prospective cohort study would be more accurate and specific.

CONCLUSIONS

This study underlines the significant prevalence of patients with ED treated with psychotropic drugs, and confirms, in line with the literature, the possibility of PDE5-i to improve the sexual performances of these patients. The variability of the therapeutic efficacy appears to depend on age, on the effects of psychiatric disorders, on the psychotropic drugs used, and on the choice of PDE5-i treatment modality.

ACKNOWLEDGMENTS

The Authors wish to thank Ms Mimma Ariano, Ms Ales Casciaro, Ms Teresa Prioreschi, and Ms Susanna Rospo, Librarians of the Sant’Andrea Hospital, School of Medicine and Psychology, Sapienza University, Rome, for rendering precious bibliographical material accessible.

REFERENCES

1. Foresta C, Caretta N, Corona G, et al. Clinical and metabolic evaluation of subjects with erectile dysfunction: a review with a proposal flowchart. Int J Androl. 2009; 32:198-211. 2. Waldinger MD. Psychiatric disorders and sexual dysfunction. Handb Clin Neurol. 2015; 130:469-489. 3. Pacchiarotti I, Murru A, Kotzalidis GD, et al. Hyperprolactinemia and medications for bipolar disorder: systematic review of a neglected issue in clinical practice. Eur Neuropsychopharmacol. 2015; 25:10451059. 4. Melis MR, Argiolas A, Gessa GL. Apomorphine-induced penile erection and yawning: site of action in brain. Brain Res. 1987; 415:98-104. 5. Liu-Seifert H, Kinon BJ, Tennant CJ, et al. Sexual dysfunction in patients with schizophrenia treated with conventional antipsychotics or risperidone. Neuropsychiatr Dis Treat. 2009; 5:47-54. 6. Gopalakrishnan R, Jacob KS, Kuruvilla A, et al. Sildenafil in the treatment of antipsychotic-induced erectile dysfunction: a randomized, double-blind, placebo-controlled, flexible-dose, two-way crossover trial. Am J Psychiatry. 2006; 163:494-499. 7. Atmaca M, Kuloglu M, Tezcan E. Sildenafil use in patients with olanzapine-induced erectile dysfunction. Int J Impot Res. 2002; 14:547-549. 8. Aviv A, Shelef A, Weizman A. An open-label trial of sildenafil addition in risperidone-treated male schizophrenia patients with erectile dysfunction. J Clin Psychiatry. 2004; 65:97-103. 9. Nurnberg HG, Hensley PL, Gelenberg A, et al. Treatment of antidepressant-associated sexual dysfunction with sildenafil: a randomized controlled trial. JAMA. 2003; 289:56-64. 10. Segraves RT, Lee J, Stevenson R, et al. Tadalafil for treatment of erectile dysfunction in men on antidepressants. J Clin Psychopharmacol. 2007; 27:62-66. 11. Rosen RC, Cappelleri JC, Smith MD, et al. Development and evaluation of an abriged, 5-item version of the International Index

Archivio Italiano di Urologia e Andrologia 2018; 90, 1

of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res. 1999; 11:319-326. 12. Kessler RC, Amminger GP, Aguilar-Gaxiola S, et al. Age of onset of mental disorders: a review of recent literature. Curr Opin Psychiatry. 2007; 20:359-364. 13. Park YM, Lee SH, Lee BH, et al. Prolactin and macroprolactin levels in psychiatric patients receiving atypical antipsychotics: A preliminary study. Psychiatry Res. 2016; 239:184-189. 14. Fava M, Nurnberg HG, Seidman SN, et al. Efficacy and safety of sildenafil in men with serotonergic antidepressant-associated erectile dysfunction: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2006; 67:240-246. 15. de Boer MK, Oolders JM, van den Heuvel ER, et al. Efficacy of tadalafil on erectile dysfunction in male patients using antipsychotics: a double-blind, placebo-controlled, crossover pilot study. J Clin Psychopharmacol. 2014; 34:380-382. 16. Rosen R, Shabsigh R, Berber M, et al. Vardenafil Study Site Investigators. Efficacy and tolerability of vardenafil in men with mild depression and erectile dysfunction: the depression-related improvement with vardenafil for erectile response study. Am J Psychiatry. 2006; 163:79-87. 17. Demyttenaere K, Bonnewyn A, Bruffaerts R, et al. Clinical factors influencing the prescription of antidepressants and benzodiazepines: results from the European study of the epidemiology of mental disorders (ESEMeD). J Affect Disord. 2008; 110:84-93. 18. García S, Martínez-Cengotitabengoa M, López-Zurbano S, et al. Adherence to antipsychotic medication in bipolar disorder and schizophrenic patients: a systematic review. J Clin Psychopharmacol. 2016; 36:355-371. 19. Kupelian V, Hall SA, McKinlay JB. Common prescription medication use and erectile dysfunction: results from the Boston Area Community Health (BACH) survey. BJU Int. 2013; 112:1178-1187. 20. Melis MR, Argiolas A. Reduction of drug-induced yawning and penile erection and of noncontact erections in male rats by the activation of GABAA receptors in the paraventricular nucleus: involvement of nitric oxide. Eur J Neurosci. 2002; 15:852-860.

Correspondence Rossella Mazzilli, MD rossella.mazzilli@uniroma1.it Sant’Andrea Hospital, Sapienza University of Rome, School of Medicine and Psychology Via di Grottarossa 1035-1039, 00189 Rome, Italy Soraya Olana, MD Michele Delfino, MD, PhD Virginia Zamponi, MD Jlenia Elia, MD Fernando Mazzilli, MD Andrology Unit, Sant’Andrea Hospital, Sapienza University of Rome, School of Medicine and Psychology, Rome, Italy Gloria Angeletti, MD Chiara Rapinesi, MD Antonio Del Casale, MD, PhD Georgios D. Kotzalidis, MD, PhD Gemma Callovini, MD Paolo Girardi, MD NESMOS (Neurosciences, Mental Health, and Sensory Organs) Department, Sant’Andrea Hospital, Sapienza University of Rome, School of Medicine and Psychology, Rome, Italy

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DOI: 10.4081/aiua.2018.1.49

ORIGINAL PAPER

Seminal transferrin in the seminal quality evaluation of hemodialytic patients Gilmar Pereira Silva 1, Fabiana Pirani Carneiro 1,Vitor Pereira Xavier Grangeiro 2 1 University 2 Faculty

of Brasilia, Brasilia, Federal District, Brazil; of Medical Sciences, João Pessoa, Paraiba, Brazil.

Summary

Objective: to verify the association between seminal quality and seminal transferrin (ST) level and fertility index in patients undergoing chronic hemodialysis (CH). Material and methods: This is a cross-sectional study in a group of 60 men (case) undergoing CH for more than 6 months, and a group of 30 healthy men (control), aged 18-60 years, without clinical or laboratory signs of infection/inflammation. Spermiogram was performed, fertility index (FI) was calculated and ST and sex hormones (SH) levels were measured, including follicle-stimulating hormone, luteinizing hormone, total testosterone, and prolactin. Results: All individuals were eugonadal. No differences for age (49.47 ± 5.56, 47.90 ± 6.2, p = 0.22) were observed between cases and controls, whereas there were significant differences between the individuals in the case and control groups with respect to the mean FI (p = 0.000), seminal parameters (SP) (p = 0.000), and ST levels (40.12 ± 08.25 vs 73.32 ± 06.8, p = 0.000). ST levels were correlated with FI (r = 0.787, p = 0.00) and SP (motility: r = 0.857, p = 0.000; vitality: r = 0.551, p = 0.000; density: r = 0.850, p = 0.000; normal morphology: r = 0.386, p = 0.000). Linear regression model showed relationship of ST levels with total sperm motility (R2 = 0.701; p = 0.000) and and FI (R2 = 0.569; p = 0.000). Conclusions: Our results suggest that seminal quality is associated with ST levels and FI and that it can be used the initial investigation of subfertility/infertility of patients undergoing chronic hemodialysis..

KEY WORDS: Chronic kidney disease; Hemodialysis; Male infertility; Seminal transferrin; Seminal quality; Seminal parameters. Submitted 8 January 2018; 20 February 2018

MATERIALS

AND METHODS

Recruitment, inclusion and exclusion A cross-sectional study was realized in the Hemodialysis Sector of the University Hospital of the University of Brasília, between July 2016 and December 2016, after approval by the Research Ethics Committee of the Faculty of Health Sciences of the University of Brasília under number 53172316.9.0000.0030. Inclusion criteria were: age between 18 to 60 years, has been in hemodialysis (HD) for more than 6 months (cases) and absence of acute or chronic liver disease. Exclusion criteria were the presence of hemochromatosis or diseases of iron metabolism.

Patients with hypogonadism and clinical conditions that could alter ST levels such as recent history of genitourinary tract infection, clinical signs of acute or chronic infection/inflammation, positive serology for hepatitis B, C and human immunodeficiency virus (HIV), vascular access infection, leukocytosis, fever, hypoproteinemia were not included in the study. Sample consisted of 60 men (cases) in high flow HD by vascular fistula access, 3x week with duration of 4 hours/HD session and 30 healthy men (control) from the health promotion outpatient clinic of the same hospital without injury of renal function (glomerular filtration rate ≥ than 90 ml/min per 1.73 m2) and sperm without changes. Routine collection of blood and semen The blood sample for analysis was collected from the arteriovenous fistula immediately before the first weekly hemodialysis session in the case group and on a previously scheduled day for the control group, always between 8:00 and 10:00 a.m. in the clinical laboratory of the same hospital to assay ST, follicle stimulating hormone (FSH); luteinizing hormone (LH) and total testosterone (TT). On the same day of blood collection, the semen was collected by voluntary masturbation in an appropriate environment to perform spermiogram by manual method according to the guidelines of the World Health Organization (WHO) laboratory manual for the examination and processing of human semen 5th ed (1). The seminal plasma was prepared by centrifuging at 3500 × g for 20 min after 30 minutes liquefaction. The supernatant was collected into a new tube and held at -20 ° C for the measurement of ST levels. ST and hormones were measured by enzyme immunochemiluminescence using the Immulite 2000/Siemens automatic analyzer. Specific kits were used for quantification, as well as calibrators and controls recommended by the manufacturer. Fertility Index (FI) FI was calculated according to Harvey (2) as follows: FI = sperm concentration (x 106/ml) x sperm motility x percentage of spermatozoa with normal morphology. Statistical analysis After the normal distribution curve of the sample was verified by normality tests (Shapiro-Wilk), for differences

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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G. Pereira Silva, F. Pirani Carneiro, V. Pereira Xavier Grangeiro

Table 1. Comparative evaluation of age, semen and hormone parameters, fertility index and transferrin seminal levels among case and control groups (x ± sd). Observed parameters Age (y) Semen volume (ml) Total motility (PR + NP %) Sperm vitability (%) Sperm density (x 106/ ml) Morphology sperm (%) FSH (mIU/ml) LH (mIU/ml) Testosterone (ng/ml) Prolactin (ng/ml) Fertility index Seminal transferrin(ng/ml)

Case n (60) 49,47 ± 5,56 01,33 ± 00,36 34,00 ± 06,24 47,49 ± 07,31 14,95 ± 06,18 25,40 ± 07,87 06,30 ± 01,21 15,91 ± 02,62 04,11 ± 00,58 16,38 ± 02,92 0, 85 (0,57) 40,12 ± 08,25

Control n (30) 47,90 ± 6,22 02,77 ± 0,44 71,31 ± 7,86 64,41 ± 2,89 50,21 ± 8,57 59,76 ± 10,58 03,40 ± 00,48 02,84 ± 00,54 05,10 ± 00,92 05,86 ± 01,93 5,54 (1,3) 73,32 ± 06,81

PR - Progressive motility; NP - non-progressive motility; FSH - follicle-stimulating hormone; LH - luteinizing hormone; a- t tests.

Table 2. Correlational evaluation Pearson’ between seminal transferrin and fertility index and seminal parameters in case group. Observed parameters

Seminal transferrin versus

Fertility index Sperm motility Sperm viability Sperm density Sperm morphology

Case n (60) r p 0,787 0,000 0,857 0,000 0,551 0,000 0,850 0,000 0,386 0,002

between two independent quantitative variables was used t-test and Pearson correlation analysis. Statistical significance was set at p < 0.05 to reject the null hypothesis. SPSS® for Windows, version 24.0 was used.

RESULTS

All sample of patients were eugonadics (normal LH, FSH, TT). No difference for afe was observed between cases and controls (49.47 ± 5.56, 47.90 ± 6.2, p = 0.229), whereas significant differences between case and control means were observed for FI (p = 0.000), seminal parameters (SPs) (P = 0.000) and ST levels (40.12 ± 08.25 vs 73.32 ± 06.8, p = 0.000). ST maintained correlation (Table 2) with FI (r = 0.787 , p = 0.00) and SPs (motility r = 0.857 and p = 0.000; vitality r = 0.551 and p = 0.000; density r = 0.850 and p = 0.000 and normal morphology r = 0.386 and p = 0.000) and without hormones corrections (p > 0,05). The positive relationships between ST and sperm concentration and fertility index in group case can be explained by the linear regression model in up to 72.2% and 56.9%, respectively.

DISCUSSION

This study is of great importance because it is the first to verify the association between ST levels and SP and FI in patients undergoing HD. The practicality and low cost of

Archivio Italiano di Urologia e Andrologia 2018; 90, 1

the ST measurement can be attractive for the initial evaluation of semen quality in patients undergoing HD with suspected subfertility/infertility. P values ST is an isoform of the human transferrin 0,229 family that is found abundantly in human 0,000 seminal plasma; it is produced and secreted 0,000 (80%) by Sertoli cells (3). It is sensitive to 0,000 systemic and site inflammatory changes, 0,000 and is involved in transport of iron ions in 0,000 the systemic or site compartments (4). 0,000 Distribution of the mean values of the 0,000 parameters evaluated in case and control 0,000 groups can be observed in Figure 1. 0,000 The similar age (p = 0.229) and eugonadal 0,000 status (p = 0.000) (Table 1) of the studied 0,000 individuals ensures greater reliability, and it lowers the impact on the analysis and interpretation of these variables. The male hormonal profile most commonly observed in patients in HD includes elevated serum levels of FSH, LH, and decreased levels of TT in response to the inhibitory action of one or more hypothalamic-pituitary-gonadal axis sites (5). These changes are promoted by factors such as uremia, oxidative stress (OS) and pro-inflammatory cytokines present in HD (4). The hormones profile (Table 1) in the case group in our study followed partially the pattern described above and found by other Authors (6, 7) that is high levels of FSH and LH although TT levels were within the limits of normality (eugonadics). Absence of clinical hypogonadism, in thesis, minimizes the effect of hormonal factor in the pathophysiology of the changes found in the ST level and seminal parameter. In the present study there was no relationship (P > 0.05) between ST levels and hormones (Table 2) which is corroborated by studies of Fuse (8) and Ber (9). However, there are studies that show as Tfs was inversely correlated with serum levels of LH, FSH and prolactin (10, 11). ST levels found were significantly lower in the cases in relation to control in agreement with previous studies conducted by different researchers in non-uremic populations with suspected sub/infertility. Kosar et al. (12) found values of 58.1± 14.4 μg/ml vs 108.4 ± 17.5 μg/ml (p < 0.0001); Bharshankar and Bharshankar (13) 2.63 ± 1.76 mg/dl vs 5.35 ± 2.07 mg/dl (p < 0.001) and Saeed et al. (14) 54.0 μg/ml (50.0-60, 0) vs 74.0 μg/ml (69.080.0) (p < 0.01). The explanation of the decrease in mean ST levels in unhealthy men in sub/infertility studies are not well known, but it is hypothesized that it is due to the action of interleukin-6 (IL6) in testis to reduces transferrin secretion in Sertoli cells (15). All sperm cell parameters evaluated (Table 1) were significantly lower in the case group than in the control group (p = 0.000), corroborating partially the results of other authors (16, 17) that did not found significant differences for all the elements of the SP (16, 17). However there is a study that did not show a significant difference in ST levels between healthy subjects and those with seminal quality alterations (18). There was a statistically significant correlation (Table 2) between ST and all ele-

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Seminal transferrin and seminal quality

FSH: follicle stimulating hormone; LH: luteinizing hormone.

Figure 1. Distribution of mean values of all parameters tested in the group and control group.

ments of the SP (p < 0.05). However, these correlations were not linear in comparative studies with non-uremic population of other authors. Bharshankar and Bharshankar (13) found only a statistically significant correlation between ST and percent of motile sperms (p < 0.05). Fuse et al. (8) found only a statistically significant correlation between sperm concentration and ST level (r = 0.56; p < 0.05). The FI is a general index to evaluate the semen quality, which was better than any single semen parameter (2). In the present study we found a FI significantly lower in the case group than in the control group (Table 1) in

according with the results of other Authors in uremic populations as Xu et al. (16) who found a value of 0.68 (2.08) vs 7.72 (13.51) (p < 0.05) and Xu et al. (17) who reported a value of 0.23 (0.76) vs 13.02 (14.26) (p < 0.001). The positive relationship of ST with sperm concentration and fertility index in the present study can explain up to 72.2% (R2) (p = 0.000) and 61.9% (R2) (p = 0.000) of the cases, respectively, by the simple linear regression model. This reinforces the hypothesis of its association with SPs. The explanation for changes identified in SPa and ST level are multifactorial (19). But there is evidence of the importance of cytokines and other immune regulatory factors in Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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G. Pereira Silva, F. Pirani Carneiro, V. Pereira Xavier Grangeiro

the regulation of testicular function (steroidogenesis and spermatogenesis) during pathophysiological states as well as under normal physiological conditions (20). Cytokines are interconnected with multiple factors, including steroid hormones, the redox system, and systemic or local inflammation (15). The HD patients are characterized by increased levels of oxidative stress and inflammation with the relationship between inflammation and oxidative stress leading to overproduction of reactive oxygen species (ROS) (21). These factors are likely to represent an important component for the development of SP changes (21). It is postulated that hypercytokinemia generated in patient HD can profoundly affect vascular testicular permeability and to achieve interstitial compartment of the testis (22). This causes directly profound changes in the physiology of the blood-testis barrier (BTB) and/or stimulate the testicular macrophages to produce differents pro and anti-inflammatory cytokines, promoting blockage of the paracrine/autocrine testicular regulation systems (22). In the male reproductive system there is a variety of cytokines in human seminal plasma, with differences in cytokine concentrations between fertile and infertile men and negative correlations between some cytokine levels and SP (22). The relationship between inflammation and oxidative stress is confirmed and both processes contribute with adverse effects on the structural and functional integrity of sperm, resulting in changes in the sperm function and in male infertility by protein, glycogen, lipid and DNA peroxidation that can partially justify changes in the seminal parameters (15). Pro- and anti-inflammatory cytokines and other inflammatory mediators are largely responsible for the changes observed in seminal plasma (23). IL-6 is a multifunctional cytokine involved in many changes identified in the tubular and interstitial compartments testicular with reflection on the seminal quality (23). It has been suggested that it is a potent inhibitor of the seminiferous epithelium (23), modulating ST production by Sertoli cells (20) and inducing persistent testicular resistence to LH action and/or suppression of cell steroidogenesis in the Leydig cells (24), On the other hand, IL-6 has other important functions which play an important role in maintaining the function of Sertoli cells, germ cells, regulating the dynamics of BTB via delaying BTB-constituent proteins degradation (22). Overexpression of IL-6 (systemic inflammation) could disrupt the integrity of the Sertoli cell and BTB, making foreign molecules to reach germ cells (22). Alteration of the permeability of BTB seems to be the most important event in the pathophysiology of changes in the semen of patients with seminal parameter changes (22). The cytokines produced by the complex systemic inflammation/oxidative stress, frequently observed in these patients might modulate the activity of the prooxidative and antioxidative systems (25). The oxidative stress is responsible for permanent peroxidative damage to spermatozoa by means of protein complexes called ion-responsive elements and ion regulatory proteins (ERIs/PRIs) (25). These proteins are responsible for the post-transcriptional regulation of proteins linked

Archivio Italiano di Urologia e Andrologia 2018; 90, 1

to uptake iron (transferrin receptor 1 -RTf1) and storage iron (ferritin) (25). When altered, they promote changes in intracellular iron ion levels and morpho-functional changes in seminal quality by toxic effect on germ cells (25). That breakdown of the intratesticular pro-and antiinflammatory cytokine balance promoted by different cytokines as the IL-6 contributes significantly by changes in the permeability of BTB to important alterations in autocrine/paracrine autoregulation mechanisms of interaction between surrounding germ cells, Sertoli and Leydig cells (26). The changes promoted by cytokines result in an immunopathological microenvironment that can change the testicular immune privilege and justify partially the changes in ST levels and their association with seminal quality and fertility index in this group of patients.

CONCLUSION

Although the multifactoriality in etiology of sub/infertility, our results suggest that seminal quality is associated with ST levels and what ST can be used the initial investigation of subfertility/infertility of patients undergoing chronic hemodialysis with alteration in seminal quality. This study presents the limitations of the absence of supplementary measurement of total seminal antioxidant capacity and of the reduced sample.

REFERENCES

1. Organization WH. WHO laboratory manual for the examination and processing of human semen. 2010. 2. Harvey C. A fertility index derived from semen analysis. J Clin Pathol. 1953; 6:232-6. 3. Franca LR, Hess RA, Dufour JM, et al. The Sertoli cell: one hundred fifty years of beauty and plasticity. Andrology. 2016; 4:189212. 4. Akchurin OM, Kaskel F. Update on inflammation in chronic kidney disease. Blood Purif. 2015; 39:84-92. 5. Palmer BF, Clegg DJ. Gonadal dysfunction in chronic kidney disease. Rev Endocr Metab Disord. 2017; 18:117-130. 6. Zedan H, Kamal EE, El Shazly A, et al. Impact of renal failure and haemodialysis on semen parameters and reproductive hormones. Human Andrology. 2013; 3:16-20. 7. Lehtihet M, Hylander B. Semen quality in men with chronic kidney disease and its correlation with chronic kidney disease stages. Andrologia. 2015; 47:1103-8. 8. Fuse H, Satomi S, Okumura M, Katayama T. Seminal plasma transferrin concentration: relationship with seminal parameters and plasma hormone levels. Urol Int. 1992; 49:158-62. 9. Ber A, Vardinon N, Yogev L, et al. Transferrin in seminal plasma and in serum of men: its correlation with sperm quality and hormonal status. Hum Reprod. 1990; 5:294-7. 10. Irisawa C, Nakada T, Kubota Y, et al. Transferrin concentration in seminal plasma with special reference to serum hormone levels in infertile men. Arch Androl. 1993; 30:13-21. 11. Meeker JD, Godfrey-Bailey L, Hauser R. Relationships between serum hormone levels and semen quality among men from an infertility clinic. J Androl. 2007; 28:397-406.

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Seminal transferrin and seminal quality

12. Kosar A, Sarica K, Ozdiler E. Effect of varicocelectomy on seminal plasma transferrin values: a comparative clinical trial. Andrologia. 2000; 32:19-22. 13. Bharshankar RN, Bharshankar JR. Relationship of seminal plasma transferrin with seminal parameters in male infertility. Indian J Physiol Pharmacol. 2000; 44:456-60. 14. Saeed S, Khan FA, Rahman SB, et al. Biochemical parameters in evaluation of oligospermia. J Pak Med Assoc. 1994; 44:137-40. 15. Fraczek M, Kurpisz M. Cytokines in the male reproductive tract and their role in infertility disorders. J Reprod Immunol. 2015; 108:98-104. 16. Xu L, Xu H, Zhu X, et al. Effect of uremia on semen quality and reproductive function in humans. Cell Biochem Biophys. 2012; 62:29-33. 17. Xu LG, Xu HM, Zhu XF, et al. Examination of the semen quality of patients with uraemia and renal transplant recipients in comparison with a control group. Andrologia. 2009; 41:235-40. 18. Eneroth P, Lizana J, Bygdeman M. Lactoferrin and transferrin levels in the seminal plasma of infertile men. Protides of the Biological Fluids. 1984; 31:149-53. 19. Coutton C, Fissore RA, Palermo GD, et al. Male Infertility:

Genetics, Mechanism, and Therapies. Biomed Res Int. 2016; 2016:7372362. 20. Guazzone VA, Jacobo P, Theas MS, Lustig L. Cytokines and chemokines in testicular inflammation: A brief review. Microsc Res Tech. 2009; 72:620-8. 21. Tucker PS, Scanlan AT, Dalbo VJ. Chronic kidney disease influences multiple systems: describing the relationship between oxidative stress, inflammation, kidney damage, and concomitant disease. Oxid Med Cell Longev. 2015; 2015:806358. 22. Zhang H, Yin Y, Wang G, et al. Interleukin-6 disrupts bloodtestis barrier through inhibiting protein degradation or activating phosphorylated ERK in Sertoli cells. Sci Rep. 2014; 4:4260 23. Salman DTA-WD. Evaluation the effect of Interleukin-6 and Tumor Necrosis Factor in semen quality of infertile men with varicocele. Kufa Journal for Nursing Sciences | ‫مولعلل ةفوكلا ةلجم‬ ‫ةيضيرمتلا‬. 2016; 6. 24. Tremblay JJ. Molecular regulation of steroidogenesis in endocrine Leydig cells. Steroids. 2015; 103:3-10. 25. Zhao S, Zhu W, Xue S, Han D. Testicular defense systems: immune privilege and innate immunity. Cell Mol Immunol. 2014; 11:428-37. 26. Fijak M, Bhushan S, Meinhardt A. The Immune Privilege of the Testis. Immune Infertility: Springer; 2017; p. 97-107.

Correspondence Gilmar Pereira Silva (Corresponding Author) gilpsilva2006@gmail.com Urologist physician PhD, University of Brasilia Hotel Sector North, Block D, Apartment 1716, Fusion Building, 70701- 040 Brasilia, Federal District, Brazil Fabiana Pirani Carneiro fabianapirani@hotmail.com Professor PhD, Faculty of Medicine of the University of Brasília Brasilia, Federal District, Brazil Vitor Pereira Xavier Grangeiro vitorpxavierg10@gmail.com Academic of the Faculty of Medical Sciences João Pessoa, Paraiba, Brazil Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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DOI: 10.4081/aiua.2018.1.54

ORIGINAL PAPER

How do vegetable oils (hazelnut and canola) affect the reproductive system in male rats? Bülent Kati 1, Fatih Oguz 2, Ismet Yilmaz 3, Ender Akdemir 4, Ramazan Altintas 2, Nusret Akpolat 5, Mehmet Cagatay Taskapan 6 1 Harran

University, Faculty of Medicine, Urology Department, Sanliurfa, Turkey; University, Faculty of Medicine, Urology Department, Malatya, Turkey; 3 Inonu University, Faculty of Pharmacy, Pharmacology Department, Malatya, Turkey; 4 Lokman Hekim Hospital, Urology Clinic, Van, Turkey; 5 Inonu University, Faculty of Medicine, Pathology Department, Malatya, Turkey; 6 Inonu University, Faculty of Medicine, Medical Biochemistry Department, Malatya, Turkey. 2 Inonu

Source(s) of Support No: This study was supported by Inonu University, Scientific Research Projects no: 2011/152 Presentation at a Meeting: This work is presented in EAU 8th South Eastern European Meeting held in Sofia on 26 - 27 October 2012

Summary

Objective: Vegetable oils have an important place in our daily diet. This study starts from this point to investigate the effects of canola oil and hazelnut oil in the male reproductive system in rats. Material and methods: 30 male rats were used in this 16-week study. The animals were divided into three groups: the animals in group I served as the control group, while the animals in group II and group III were fed with hazelnut and canola oil, respectively. The testes of all rats were excised for histopathologic evaluation and immunohistochemical (IHC) evaluation with a standard method. Blood samples were obtained for determination of serum hormone levels. Results: No significant differences were noted with respect to behavior or weight among the three groups. Rats in the canola oil group (group III) had higher luteinizing hormone (LH) and higher testosterone levels than rats in the control group. Rats who received hazelnut oil (group II) exhibited similar findings, with these levels being higher than they were in the control group. No statistical differences were shown for histopathology or IHC testosterone antibody levels across all treatment groups. Conclussion: Canola oil was shown to have a greater effect on serum LH and testosterone compared to the control group and the group fed with hazelnut oil. Further investigation is required into how these oils affect serum hormone and sperm activity.

KEY WORDS: Canola oil; Hazelnut oil; Reproductive system; Testosteron. Submitted 21 February 2018; 24 February 2018

INTRODUCTION

Vegetable oils have an important place in our daily diet. Commonly used sunflower and olive oil have been widely used since long time. In recent times it has been able to meet our everyday needs in hazelnut oil and canola oil (rapeseed oil), which are increasingly used in areas where they are particularly grown. Canola is a plant with bright yellow flowers that belongs to the Brassicaceae family. Originally from the Mediterranean area and Northern Europe, B. napus is commonly known as rapeseed, and was identified in

2000 BC as a high-erucic acid crop (1). The oil from rapeseed contained > 40% erucic acid, and hesitation existed about this high acid content (as observed in animal studies). High-erucic acid rapeseed oil used to be produced in North America solely in small quantities for industrial, nonfood use (2-3). However, in 1976, Canadian scientists were able to improve the quality of previous cultivars of rapeseed by growing the plant traditionally, yielding a conversion that allowed commercial consumption In 1979, Canada registered the word “canola” to describe a new seed found to yield an oil; this oil included a smaller amount of erucic acid and glucosinolates. Inherently, canola has specific cut-of levels of erucic acid (< 2%) and glucosinolates (< 30 umol/g) for consumption both in humans and in animals (4). In 1985, the United States Food and Drug Administration (FDA) accepted canola oil as “generally recognized as safe” (GRAS) as a dietary component (5). Canola has become one of the most important oilseed crops worldwide over the past 40 years; currently, canola oil is the third-largest vegetable oil by volume, after palm and soybean oil (3). hazelnut (Corylus avellana L.) is a well-recognized tree nut worldwide. Hazelnuts are mainly produced in Turkey, Italy, Spain, the USA, Portugal and France. Hazelnut oil includes a high amount of both monounsaturated and polyunsaturated fatty acids as well as tocopherols (6). Hazelnut oil contains 74.2%-83.1% oleic acid and linoleic acid. Therefore, the incorporation of hazelnut oil in meat products may have favourable efects on the health of consumers (7). Oils have an important place in the structure of the reproductive hormone system. The main hormones of the male reproductive system are mainly testosterone with follicle stimulating hormone (FSH) and luteinizing hormone (LH). There are very few studies on the effects of these oils on the male reproductive system. Because of that; the aim of our study is to investigate the effects of canola oil and hazelnut oil on the male reproductive system, with a focus on evaluating the effects on serum hormone levels and testis histopathology. No conflict of interest declared.

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Canola and nut oils effects on reproductive system

MATERIALS

AND METHODS

The selection and preparation of animals In this study, 30 four-month-old Sprague-Dawley rats were used. Inonu University Faculty of Medicine, Experimental Animal Research and Production Center provided the rats for study subjects. During the four-month study period, the average weight of the rats was 236.71 ± 19.18 gr. The study was executed according to the rules of the National Health Institute at Inonu University Experimental Research Laboratory, and was performed with the consent of the Animals Ethics Committee of the Inonu University Faculty of Medicine Ethics Committee (2011/05/18). Animals were sheltered in groups of five in standard-sized (40 by 60 cm) cages. The subjects were given 7 days to adapt to their new environment, then separated into 3 groups of 10 rats. Specially prepared hazelnut oil (12% concentration) and canola oil (12% concentration also), along with the standard food containing dry pellets and tap water, was used as the diet. Indoor lighting was tuned for 12 h of light and 12 h of darkness. Heat and moisture were set to 22°C ± 2°C and 50% ± 10%, respectively. Preparations for the experiment After the animals were separated into groups, each group was divided into half and sheltered in 2 separate cages. Any additional process was applied to the first group (Group 1); the second group was fed with the 12% hazelnut oil added to the foodoil (Group 2). The third group was fed with food that included 12% canola oil (Group 3). External factors often have an impact on testicular functioning. The photoperiod is one of these factors: long photoperiods increase testicular functioning, while short periods reduce it (8). In order to avoid any morphological changes among the groups caused by the various light amounts, all rats were exposed to the rotating 12-h light/12-h dark environment in the lab. Reproduction of sperm gradually increases up to the 75th day and the testicular weight increases up to the 100th day. When the first spermatozoa were found at the epididymis tail, about when the rats were 50 days old, they were considered adult (mature) (9). All of the rats used in our experiment were fed for approximately 4 months so that they would become 6-month-old adults and have the highest sperma reproduction. The intent in this design was to eliminate the variance in the sperma reproduction and the epididymal spermatozoa number caused by age. Preparation of the food As in the previous studies, the food was prepared considering the daily oil need. Pellet food was supplemented with the 12% oil (canola or hazelnut) (8-10). It was used to feed rats after the addition of appropriate fat to the amount of feed and control of homogenous distribution. The total absorption was ensured and, after a checking process, daily food of 18-24 g/rat was placed into the food reservoir. In order to keep the food fresh, a small amount of new food was prepared every week and the drinking water was provided via fresh tapwater adlibitum. Biochemical method of analysis The blood taken for the biochemical analysis was put into

the tubes and centrifuged at 3500 rpm for 15 minutes. The obtained serum was put into separate tubes and numbered for use with each group. Serum samples were evaluated using previously provided ELISA kits specific for rats that measured FSH (Cusabio Biotech Co., Ltd), LH (Cusabio Biotech Co., Ltd), and Testosterone (DRG International, Inc, United States) with the Basic Radim Immunoassay Operator (BRIO) (Radim spa, Pomezia, Italy) device. Histopathological and immunohistochemical research method After separation by surgical dissection, the testicles were placed in Bouin’s fixative for histopathological evaluation. The testis tissue was chopped with 2-mm apertures using microtome knives; routine tissue observation was practiced by sectioning one slice. Five-micron sections were derived from the paraffin-embedded blocks formed from tissue samples. After the process of deparaffinization, the sections were dyed with hematoxylin-eosin (HE). In the course of histopathological evaluation, the architectural structure was examined by the help of magnifying method beforehand. Subsequently, the size and the number of the seminiferous tubules, the thickness of the tubule basal membranes, the relative share and types of germ cells in the seminiferous germs, the degree of interstitial fibrosis, and the existence of the Leydig cells are evaluated in the course of a general examination of the testis cross-section. The evaluation was standardized by using the quantitative Clinical Scoring Method of 1 to 10 for each seminiferous tubule as suggested by Johnsen (11). Four-micron sections were obtained and placed onto polysine slides forimmunohistochemical dyeing, which was performed automatically using the Lecia Bond Max (Leica Microsystems Inc. U.S.A) device. Testosterone primary antibody (GeneTex, USA) was used as the primary antibody. The strength of the testosterone antibody dyeing was evaluated as a semi-quantitative method; the absence of dye was assigned zero points, while the most powerful dyeing was assigned a score of 3 points. Statistical method of analysis SPSS 15.0 for Windows (SPSS Inc., Chicago, Illinois) was used for statistical analysis. The Kolmogorov-Smirnov test was used to measure the correspondence of the different parameters and the normal distribution curve. A correspondence was observed between the LH, testosterone, and Johnsen scores as well as between the rats’ pre-experimental and post-experimental testicular weights and the normal distribution curve (P > 0.05). On the other hand, no correspondence existed between the FSH hormone distribution and the normal distrubtion curve (P < 0.05). The Kruskal-Wallis, one-way analysis of variance (ANOVA), and post-hoc Tukey tests were used for statistical analyses in the groups that corresponded with the normal distribution curve. P < 0.05 was assumed to be significant for all evaluations. Values are given as average ± standard deviation (mean ± SD).

RESULTS

All of the rats were kept alive till the end of the experiment. Rats’ pre-experiment and post-experiment (afer 16 Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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B. Kati, F. Oguz, I. Yilmaz, E. Akdemir, R. Altintas, N. Akpolat, M. Cagatay Taskapan

Groups→ Pre-experiment average weight (g) Post-experiment average weight (g)

Groups↓ hormones→ Control Hazelnut oil Canola oil

Groups Control Group Hazelnut Group Canola Group Total

Control group AO ± SS 247.2 ± 23.10 325.0 ± 32.47

LH (mIU/ml) AO ± SS 10.86 ± 5.47 13.68 ± 3.99 14.95 ± 4.55

Hazelnut group AO ± SS 228.10 ± 34.00 316.00 ± 27.39

Canola group AO ± SS 252.50 ± 50.46 345.50 ± 43.19

Testosterone (ng/ml) AO ± SS 1.29 ± 0.45 1.88 ± 0.68 2.53 ± 0.74*

Johnsen Score Averages (AO ± SS) 9.37 ± 0.27 9.21 ± 0.31 9.26 ± 0.20 9.28 ± 0.25

weeks of feeding) average weights are given in Table 1. No variance existed between the groups’ inital weights or with these weights during and at the end of the experiment (P > 0.05). The average wet weight of the removed testicles was measured as 1.37 ± 0.80 g for the control group, 1.34 ± 0.13 g for the hazelnut oil group, and 1.48 ± 0.21 g for the canola oil group; there was no significant difference between any 2 of the 3 groups for this parameter (P = 0.103). Furthermore, no signficant statistical difference existed in the levels of serum FSH among the groups (P > 0.05) (Table 2). The levels of serum LH for rats fed with either hazelnut or canola oil did increase, but this increase was not statistically significant (P > 0.05). When the levels of serum testostosterone of the 3 groups were compared, there was a statistically significant increase in the canola group (P < 0.05). The slight increase in the hazelnut group was not significant (P > 0.05) (Table 2). Histological examination of the testis The testis were removed for histopathological analysis

P 0.327 0.177

FSH (Min-Med-Max) 12.97 - 26.38 -77.24 21.74 - 30.90 - 38.44 19.06 - 31.91 - 9.33

Table 1. Increase in the weights of the rats after 16 weeks of feeding.

Table 2. Average values of serum hormone LH and testosterone * (P = 0.001).

Table 3. Johnsen Testicle Biopsy Scores for each group and group averages (P = 0.362).

and preserved within the 10% Bouin’s fixative. The testicular parenchyma of the rats (covered by tunica albuginea, Leydig cells, and interstital connective tissues) were examined in the seminiferous tubules and interstitial. In the histopathological analysis, 10 cross-cut seminiferous tubules were randomly scored 1 to 10 for each rat testicle according to Johnsen scoring criteria. After that, the average value for each rat was calculated, with total group scores and averages obtained (Table 3). No significant difference was found among the Johnsen score averages (P > 0.05). Furthermore, no significant difference existed between the immunohistochemical dyeing strength of total tissue testostosterone antibody of the 3 groups (Figure 1).

DISCUSSION

Oils are one of the most significant nutrients in that they have essential roles in the human diet and conduct vital activity in the body. The positive or adverse effects of canola and hazelnut oil on the body have not been precisely determined, although their consumption have

Figure 1. Sample of interstisial painted testosterone antibody group and scores. a) Immunohistochemical staning intensity canola oil group 20X (Score 3). b) Immunohistochemical staning intensity hazelnut oil group 40X (Score 2). c) Immunohistochemical staning intensity control group 20X (Score 1). a.

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Canola and nut oils effects on reproductive system

been continuously increasing in people’s diets worldwide. Limited and not conclusive scientific evidence would suggest some benefit for canola oil consumption, but results from studies implementing diets containing canola oil in experimental animal models have provided us with conflicting data (10-12). A study by Okuyama and colleagues using steroid hormones, canola and soybean oils for a 3-month period in hypertensive rats who were prone to stroke compared various elements in the rats at the end of the 3-month period, although they did not evaluate the impact of the 2 oils on the reproductive system. As a result, while the testostosterone values measured in the testicles of rats in the canola group were found to be low compared to those in the soybean group, corticosteroid and estradiol levels in the tissues demonstrated no significant difference. This difference was assumed to arise from a pathophysiology found in rats with hypertension (13). In our study, serum testosterone level increased while testosterone antibody values measured in the test were similar to the control group. Multiple other studies exist on the effects of canola and other oils over periods ranging from 3 to 7 months. Infants fed with and without canola oil from the ages of 4 weeks to 7 months did not exhibit significant differences in height and length based on whether they consumed the oil as part of their diets (14). Similarly, in our study, weight difference was not shown in rats fed with canola oil and hazelnut oil after 4 months period. de Almeida and colleagues evaluated the effects of a diet containing canola oil on the morphology of seminiferous tubules of young rats (15). With evaluation of FSH, LH, and testosterone levels, significant and important information was found in terms of the determination of potential malfunctioning of the reproduction pathophysiology and the conditions of the hypothalamus-hypophyseal axis. In our study, serum testostosterone levels in the groups receiving canola oil were higher compared to the control group (P < 0.05). Higher levels were also found in the hazelnut group, although it was not statistically significant compared to the control group (P > 0.05). No significant differences were found among the 3 groups in terms of testicular and body weight (P > 0.05). FSH, prompted by the hypothalamus and released by the anterior pituitary gland, stimulates sertoli cells in the seminiferous tubules, speeding up sperm production of spermatids. Furthermore, it was effective in the development and maintenance of FSH sufficent testicular function in men. Within our study; no significant difference was found among the FSH values of the 3 groups (P > 0.05). LH, prompted by the hypothalamus (GnRH) and released by the anterior pituitary gland, stimulates the release of testostosterone in the interstitial Leydig cells. In our study, LH levels in the hazelnut and canola oil groups were found to be higher compared to the control group, although it was not assumed to be statistically significant (P > 0.05). These results can be attributed to the assumption that these kinds of oils can enhance the stimulation of GnRH via the effects from the hypothalamus or that the oils can generate a slight LH stimulus by

directly influencing the anterior pituitary gland. The increased level of testostosterone, especially in the canola group fed with the oils supplied with direct LH, indicates that the results may be explained by the actions of the hypothalamus-hypophyseal axis. New experimental studies are needed to fully understand the effects of the hypothalamus-hypophyseal way. The effects of testosterone on erectile dysfunction and libido indicated that testostosterone has a considerable contribution to maintenance of libido and sexual function (16). The fact that these oils have no significant effect on FSH compared to the control group increases the probability that these hormones are more effective in exerting their effects coming from the hypophysis as opposed to the hypothalamus. There are not many publications examining the effects of these oils on the reproductive system. The effects of hazelnut and canola oil on testicle histopathology were not indicated beforehand. Histopathologic examination of the 3 groups’ testicular tissue did not reveal significant differences according to evaluation using Johnsen scoring (P > 0.05). Thus, no pathological adverse events related to use of these everyday oils in the diet were shown in this study. Furthermore, no statistically significant differences between the 3 groups were revealed as a result of the semi-quantitative immunohistochemical evaluation of testicle-tissue dyeing intensity (P > 0.05).

CONCLUSION

The effects of vegetable oils, which we often use in our daily life, on the reproductive system can be affected by various mechanisms by affecting the hormones. Additional studies are needed for the determination of the exact effect of this condition on the tissues and its influence on spermiogenesis.

ACKNOWLEDGMENTS

We thank to the biologist Fatma Ozyalin for his assistance in the care and application of the ELISA kits used in this study.

REFERENCES

1. Australian Government Department of Health and Aging Office of the Gene Technology Regulator. The Biology of Brassica napus L. (Canola).Version 2: 2008. http://www.ogtr.gov.au/internet/ogtr/publishing.nsf/content/canola3/$FILE/biologycanola08_2.pdf 2. Dupont J, White PJ, Johnston KM, et al. Food safety and health effects of canola oil. J Am Coll Nutr. 1989; 8:360-375. 3- United States Department of Agriculture. Economic Research Service – Canola. https://www.ers.usda.gov/topics/crops/soybeansoil-crops/canola.aspx 2017. 4. Mag T. Canola oil processing in Canada. J Am Oil Chem Soc. 1983; 60:380-384. 5. Lin L, Allemekinders H, Dansby A, et al. Evidence of health benefits of canola oil. Nutr Rev. 2013; 71:370-85. 6. Ozdemir M, Ackurt F, Kaplan M, et al. Evaluation of new Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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B. Kati, F. Oguz, I. Yilmaz, E. Akdemir, R. Altintas, N. Akpolat, M. Cagatay Taskapan

Turkish hybrid hazelnut (Corylus avellana L.) varieties; fatty acid composition, a-tocopherol content, mineral composition and stability. Food Chem. 2001; 73:411-415.

12. Junker R, Kratz M, Neufeld M, et al. Effects of diets containing olive oil, sunflower oil, or rapeseed oil on the hemostatic system. Thromb Haemost. 2001; 85:280-6.

7. Ozdemir, F. Akıncı, I. Physical and nutritional properties of four major commercial Turkish hazelnut varieties. J Food Eng, 2004; 63:341-347.

13. Okuyama H, Ohara N, Tatematsu K, et al.Testosterone-lowering activity of canola and hydrogenated soybean oil in the stroke-prone spontaneously hypertensive rat. J Toxicol Sci. 2010; 35:743-7.

8. Kus I, Songur A, Ozogul C, et al. Effects of photoperiod on the ultrastructure of Leydig cells in rat. Arch Androl. 2004; 50:193-200. 9. Robb GW, Amann RP, Killian GJ. Daily sperm production and epididymal sperm reserves of pubertal and adult rats. J Reprod Fertil. 1978; 54:103-7. 10. Cai J, Jang JY, Kim J, et al. Comparative Effects of Plant Oils on the Cerebral Hemorrhage in Stroke-Prone Spontaneously Hypertensive Rats. Nutr Neurosci. 2014; 19:318-326. 11. Johnsen SG. Testicular biopsy score count-method for registration of spermatogenesis in human testes: Normal values and results in 335 hypogonadal males. Hormones. 1970; 1:2-25.

Correspondence Bülent Kati, MD, Assistant Professor of Urology bulentkati@harran.edu.tr Department of Urology, Harran University, Faculty of Urology 63300, Sanliurfa, Turke Fatih Oguz, MD foguz@hotmail.com Inonu University, Turgut Ozal Medical Center, Urology, Malatya 44100 Turkey Ismet Yilmaz, MD ismetyilmaz44@hotmail.com Inonu University, Faculty of Pharmacy,, Malatya 44100 Turkey Ender Akdemir, MD ender_dr@yahoo.com Lokman Hekim Hospital, Urology Clinic, Van, 65100 Turkey Ramazan Altintas, MD ramazan449@yahoo.com Inonu University, Turgut Ozal Medical Center, Urology, Malatya 44100 Turkey Nusret Akpolat, MD nusretakpolat@hotmail.com Inonu University, Turgut Ozal Medical Center, Pathology, Malatya 44100 Turkey Mehmet Cagatay Taskapan, MD mctaskapan@hotmail.com Inonu University, Turgut Ozal Medical Center, Biochemistry Malatya 44100 Turkey

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14. Rzehak P, Koletzko S, Koletzko B, et al. GINI Study Group. Growth of infants fed formula rich in canola oil (low erucic acid rapeseed oil). Clin Nutr. 2011; 30:339-45 15. Furriel Gomes de Almeida A, Soares da Costa CA, Gaspar de Moura E, et al. Effects of soybean or canola oil intake on seminiferous tubules structure in young rats. Nutr Hosp. 2012; 27:1668-9. 16. Isidori AM, Giannetta E, Greco EA, et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a metaanalysis. Clin Endocrinol (Oxf). 2005; 63:280-293.

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DOI: 10.4081/aiua.2018.1.59

ORIGINAL PAPER

The role of diallyl thiosulfinate associated with nuciferine and diosgenin in the treatment of premature ejaculation: A pilot study Tommaso Cai 1, Andrea Cocci 2, Giamartino Cito 2, Bruno Giammusso 3, Alessandro Zucchi 4, Francesco Chiancone 5, Maurizio Carrino 5, Francesco Mastroeni 6, Francesco Comerci 7, Giorgio Franco 8, Alessandro Palmieri 9 1 Department

of Urology, Santa Chiara Regional Hospital, Trento, Italy; of Urology, University of Florence, Florence, Italy; 3 Department of Andrology, Policlinico Morgagni, Catania, Italy; 4 Department of Urology, University of Perugia, Perugia, Italy; 5 Department of Urology, Cardarelli Hospital, Naples, Italy; 6 Department of Urology, Azienda Ospedaliera Papardo, Messina, Italy 7 Urologist, Bologna, Italy; 8 Department of Urology, Sapienza University of Rome, Rome, Italy; 9 Department of Urology, University of Naples, Federico II, Naples, Italy. 2 Department

Summary

Objective: To assess the efficacy and safety of an association of diallyl thiosulfinate with nuciferine and diosgenin in the treatment of a group of patients suffering from premature ejaculation (PE), primary or secondary to erectile dysfunction (ED). Materials and methods: From July 2015 to October 2016, 143 patients (mean age 25.3; range 18-39) affected by PE completed the study and were finally analyzed in this phase I study. All patients, after clinical assessment and laboratory evaluation were asked to take an association of diallyl thiosulfinate with nuciferine and diosgenin as oral tablet, once a day, on alternate days, for three months. At the baseline and after three months of treatment, each patient was asked to complete the following questionnaires: International Index of Erectile Function (IIEF-5), Premature Ejaculation Diagnostic Tool (PEDT), Male Sexual Health Questionnaire (MSHQ). Results: A statistical significant improvement in terms of erectile function, comparing the IIEF-5 value at baseline and follow-up visit was found (respectively IIEF-5: 8.7 vs 14.01; p < 0.001). Moreover, at follow-up visit, 97/143 men (67.8%) referred a subjective improvement of the erection quality and a better control of the ejaculation (PROs). The IELT improved too between the baseline evaluation and the follow-up visit (p < 0.001). Conclusion: In conclusion, our study, even if supported by preliminary results, showed how Diallyl Thiosulfinate, Nuciferine and Diosgenin is able to improve the control of ejaculation in patients suffering from PE, primary or secondary to ED without any significant adverse effects.

KEY WORDS: Diosgenin; Muciferine; Thiosulfinate; Plant extracts; Premature ejaculation; Treatment. Submitted 6 December 2017; Accepted 12 December 2017

INTRODUCTION

Premature ejaculation (PE) is defined as uncontrolled ejaculation either before or shortly after sexual penetration (1). It is a very common male sexual dysfunction

with prevalence rates of 20-30%, probably affecting every man at some point in his life (2, 3). It may result in unsatisfactory sexual intercourse for both partners, decreasing sexual self-confidence and self-esteem and resulting in an overall reduction of quality of life (QoL) (4). Lifelong PE occurs within 30-60 seconds after vaginal penetration with nearly every coitus, interesting about > 85% of men affected by this dysfunction, whereas about 10-20% of men ejaculate within 1-2 minutes (5). Acquired PE is commonly due to sexual performance anxiety (6), psychological or relationship problems (6), erectile dysfunction (ED) (7), occasionally prostatitis (8), hyperthyroidism (9), or during withdrawal/detoxification from prescribed (10) or recreational drugs (11). In addition, men with this dysfunction are usually older, have a higher mean body max index and a greater incidence of comorbid disease and ED associated to lifelong, variable and subjective PE (12, 13). Although the pathophysiologic mechanism of lifelong PE is not fully understood, it is shown that psychosocial, as well as organic factors play a key role in the aetiology (14-16). Several studies demonstrated that patients with PE have more dorsal penile nerves, increasing glands penile hypersensivity and hyperexcitability (17). Moreover, they also usually have other abnormal autonomic reflex pathways for the ejaculatory process, including shorter bulbo-cavernosal latency time and higher bulbo-cavernosal evoked potentials (18, 19). For this reason, pharmacologic therapy that reduce glands penile hypersensivity should be effective for the treatment of PE. Medications, counselling and sexual techniques, that may delay ejaculation, can help the patients to improve sexual intercourse. However, a combination of these factors could be the best choice of treatment to improve efficacy and minimize relapse (20). Behavioural therapy essentially include the “stop-start program” developed by Semans (21), and its modification, the “squeeze” technique, pro-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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T. Cai, A. Cocci, G. Cito, B. Giammusso, A. Zucchi, F. Chiancone, M. Carrino, F. Mastroeni, F. Comerci, G. Franco, A. Palmieri

posed by Masters and Johnson (22). All these approaches need the partner’s cooperation for a long time, resulting often difficult in the long term (23). Pharmacological therapy includes: selective serotonin reuptake inhibitors (SSRIs) antidepressants (24); dapoxetine (25); anaesthetic creams (26) and phosphodiesterase type 5 inhibitors (PDE5i) (27). Also some natural compounds (i.e. Satureja montana, Tribulus terrestris, Phyllantus emblica) proved to be efficient in improving sexual quality of life in patients with PE (28). The role of nutraceuticals seems, then, interesting in the management of PE. The aim of this study was to assess the efficacy and safety of Diallyl Thiosulfinate, Nuciferine and Diosgenin (CAMPEDEX-5®) in the treatment of patients affecting by PE, primary or secondary to ED.

MATERIALS

AND METHODS

Study design From July 2015 to October 2016, we enrolled, in a pilot study, a total of 154 patients, affecting by PE, primary or secondary to ED. Each patient signed a written fully informed consent statement before being enrolled in the study and accepted the trial voluntarily. After enrolment, all patients were asked to take CAMPEDEX-5® oral tablet, once a day, on alternate days, for three months (Figure 1). After 30 days all contacted by phone in order to be sure about the adherence to study protocol. After 3 months, all patients were evaluated with clinical evaluation and questionnaires in order to test the treatment efficacy and safety. Inclusion and exclusion criteria All men had been in stable, monogamous, heterosexual relationship with at least one sexual intercourse a week with a compliant female partner. Exclusion criteria were: age < 18 years, history of a psychiatric or neurological disorder, alcohol or drug abuse, previous genitourinary system trauma or surgery, spinal cord injury, previous radiotherapy, thyroid diseases, hypogonadism, currently taking a drug known to affect sexual function, such as hormonal therapy for prostate cancer. Baseline evaluation The aetiology of PE was determined, in all cases, by a complete in-depth medical history, physical examina-

tion, hormonal evaluation and patient self-administered questionnaires on sexual function, even submitted to the partners. All the patients received a urological visit that considered the development of external genitalia, the presence of phimosis and/or prepuce anomalies. At the baseline, we collected the following hormonal profile from all patients: serum follicle-stimulating hormone (FSH) concentrations, prolactin levels, thyroid stimulating hormone (TSH), luteinizing hormone (LH) and blood total testosterone (TT). Each patient was asked to complete the following questionnaires: International Index of Erectile Function (IIEF-5), Premature Ejaculation Diagnostic Tool (PEDT) and Male Sexual Health Questionnaire (MSHQ). Questionnaires and PE status evaluation The IIEF-5 scale was used in order to evaluate the erectile function in the last six months considering the severity of ED, classified as follow: severe (IIEF-5 ≤ 7), moderate (IIEF-5 between 8 and 11), mild-moderate (IIEF-5 between 12 and 16), mild (IIEF-5 17-21), absent (IIEF5 between 22 and 25). PEDT help to identify men who may have a problem with ejaculating too soon during sexual activity, considering the ejaculation as the release of semen after penetration. PEDT investigated the severity of PE, classified as follow: absence of PE (PEDT ≤ 8), probably PE (PEDT 9-10), certainly present PE (PEDT ≥ 11) (29). MSHQ-EjD is an abridged version of the 25item MSHQ, seen as a validated, self-administered instrument for assessing the primary domains of erection, ejaculation, and sexual satisfaction in aging men. MSHQ-EjD described three ejaculatory function items, investigating force (“in the past month, how would you rate the strength or force of your ejaculation?”), volume item (“in the past month, how would you rate the amount or volume of semen or fluid when you ejaculate?”), frequency item (“in the past month, how often have you been able to ejaculate or “cum” when having sexual activity?), and one ejaculation bother item (“if you had any ejaculation difficulties or have been unable to ejaculate, have you been bothered by this?”) (30). Ejaculatory function score, which is the sum of the ordinal responses to the three items, ranges from 1 to 15, while bother scores ranges from 0 to 5. Furthermore, we collected the Intravaginal Ejaculation Latency Time (IELT), as the time from vaginal penetration until ejaculation (31). It was timed on a stopwatch by ‘start’ (penetration) to ‘stop’ (ejaculation). IELT was asked

Figure 1. The figure shows the study schedule. IIEF-5: International Index of Erectile Function; PEDT: Premature Ejaculation Diagnostic Tool; MSHQ-EjD: Male Sexual Health Questionnaire; IELT: Intravaginal ejaculation latency time; PROs: Patients-Reported Outcomes.

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Nutraceuticals and premature ejaculation

both to men and their partners, trying to be honest in recording the time and it was calculated as mean from that perceived by the men and that perceived by partners. They were instructed to calculate and record the exact time after ejaculation. Follow-up evaluation At 3 months follow-up evaluation, all patients underwent urological examination and the same laboratory and questionnaires evaluation as at the baseline time. In addition, we evaluated the Patients-Reported Outcomes (PROs). PROs are defined as a report that comes directly from the patient about the status of his health condition without amendment or interpretation of the patient’s response by a clinician or anyone else (32). The “outcomes” in PRO were interpreted broadly to reflect a variety of information reported directly by the patient, investigating the presence of a subjective improvement of erection quality and a positive change of the control of PE. Also health-related QoL, functional status and treatment adherence were collected.

Table 2. Outcome variables before and after treatment. Outcomes variable Baseline IIEF-5 (mean score) 8.7 PEDT (mean score) 15 MHSQ-EjD (ejaculatory function mean score) 9 MHSQ-EjD (bother mean score) 5 IELT (mean score) [min] 45.5

Follow-up 14.01 10

P < 0.001 < 0.1

< 0.1

3 123.7

< 0.1 < 0.001

Outcome measures and statistical analysis All clinical, laboratory and parameters and questionnaires were compared at the baseline (before to begin treatment) and at follow-up visit (after three months of treatment). All statistical analysis was performed using the IBM SPSS version 20.0 (SPSS Inc, Chicago, IL, USA). P < 0.05 was considered statistically significant.

(respectively IIEF-5: 8.7 vs 14.0; p < 0.001). Median total PEDT score changed from 15 (baseline) to 10 (follow-up). Regarding MSHQ-EjD, the majority of patients reported, at the end of treatment, a reduction of awkwardness during sexual intercourses (bother score: 5 vs 3) and an improvement of ejaculatory function disorders (ejaculatory function score: 9 vs 12). IELT shown a clean improvement, increasing significantly from 45.5 sec to 123.7 sec, respectively at baseline and follow-up visit (p < 0.001) (Figure 2). Moreover, at follow-up visit, of all 143 patients, 97/143 men (67.8%) referred a subjective improvement of the erection quality and a better control of the ejaculation (PROs). During the study, no treatment emergent adverse events occurred, let alone some patients interrupted the drug assumption for concomitant therapies or co-morbidities.

RESULTS

DISCUSSION

Of all 154 men enrolled, 143 patients completed the study voluntarily, 11 patients withdrew the study for personal reasons. 81/143 men (56.6%) had a clinical presentation of lifelong PE, while 62/143 men (43.3%) presented a secondary PE, caused by sexual performance anxiety, psychological or relationship problems and occasionally prostatitis. 44/143 patients (30.7%) had ED associated. The mean age was 25.3 years old (range 18-39). At baseline and follow-up visit, all hormonal parameters collected were in the normal range (Table 1). How shown in Table 2, at the follow-up visit, the patients shown a statistical significant improvement in terms of erectile function, comparing the IIEF-5 value at baseline and follow-up visit

Table 1. Clinical and laboratory characteristics of all analyzed patients. Demography, clinical and laboratory characteristics at baseline Enrolled patients n° 143 Age (mean) (range) 25.3 (18-39) Clinical presentation Primary PE 81 Secondary PE 62 Associated ED 44 Total testosterone (ng/ml) 14.3 FSH (IU/L) 5.3 LH (IU/L) 6.8 TSH (mIU/L) 2.3 Prolactin (ng/ml) 7.8

Main finding In this study, we demonstrated how the assumption of organic compounds derived from natural substances is able to improve the quality of erections and the control of ejaculation, increasing the mean ejaculation latency time. In particular, we tested the following combination of Diallyl Thiosulfinate (20 mg), Nuciferine (137.5 mg) and Diosgenin (45 mg). Results in the context of previous studies Thiosulfinates are allylsulfide compounds including allicin, diallyldisulfide, diallyltrisulfide, S-allylmercaptocysteine and S-allylcysteine, a class of phytochemical organosulfurs found essentially in garlic and other vegetables from Alliumspecies (33). Allicin, or Diallyl Thiosulfinate, is the most important and representative active ingredient of garlic (Allium sativus). This substance is formed when the clumps that make up the bulbs are cut, chewed or otherwise crushed. Following these mechanical actions, an enzyme, called allinase, releases from the vacuolary juices, acting on an aminoacid, the allyl, transforming it into allicin. Diallyl Thiosulphinate can increase the concentration of intracellular glutathione, a substance consisting of three amino-acids (cysteine, glutamic acid and glycine). Through a series of reactions, cysteine is transformed in hydrogen sulphide (H2S) produced at the arterial level with particular reference to peripheral circulation. H2S acts as a real proerogenous gaseous mediator which, through the opening Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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T. Cai, A. Cocci, G. Cito, B. Giammusso, A. Zucchi, F. Chiancone, M. Carrino, F. Mastroeni, F. Comerci, G. Franco, A. Palmieri

Figure 2. The figure shows the results at the follow-up evaluation by using questionnaires before (pre) and after (post) treatment. IIEF-5: International Index of Erectile Function; PEDT: Premature Ejaculation Diagnostic Tool; MSHQ-EjD: Male Sexual Health Questionnaire; IELT: Intravaginal ejaculation latency time; PROs: Patients-Reported Outcomes.

of potassium channel ATP, resulting in increased CA+ ion transfer, produces through a precise hyperpolarization mechanism on smooth muscle cells, a relaxation effect on them. The relaxation of the peripheral smooth muscle also causes the recall of blood resulting in an erection phenomenon (34). Diosgenine is the most important active principle of Dioscorea (Dioscorea villosa), also known as wild yam, a plant belonging to the Dioscoreacee family. It is therefore an important precursor of steroids, present in nature in the form of diocin glycoside or other heterosides that are then hydrolysed in acidic environments and has therefore always been used by the pharmaceutical industry as a raw material for the production of hormones, such as DHEA. Small amounts of DHEA are also produced by testicles, ovaries and glial cells. DHEA circulates bloodstream especially as a sulfate (DHEA-S); in the plasma about 80% of this sulphate is bound to albumin, while the remaining 20% is linked to lipoproteins. The amount of DHEA contained in the human body is related to the age of the subject. After birth there is a significant decrease in plasma levels of DHEA. Starting at five years, levels are rising again to reach the peak of the age of twenty-five; From the age of twenty-five, there is a progressive decrease in the concentration of DHEA in the body; this decline begins to become rapid from forty years. At eighth decade, the level does not exceed 10% of the maximum reached twenty-five years. Because of this decrease in plasma levels with age, many authors have

Archivio Italiano di Urologia e Andrologia 2018; 90, 1

suspected that DHEA was heavily involved in aging-regulating processes, so DHEA administration was recommended as an anti-aging method. DHEA appears to be involved in many biological functions including sexual activity regulation and stimulation, myelin production and activation of the G6PD-H enzyme that helps to reduce fat cells (35). Nuciferine is an alkaloid extracted from the plants Nymphaea caerulea and Nelumbo nucifera. It has a pharmacological profile of action associated with dopamine receptor blockade. Specifically, Nuciferine is a partial antagonist of D2-like receptor, a subtype of Dopamine receptors which activation is associated with ejaculation and micturition stimulus (36). It induces sedation, hypothermia, ptosis, and catalepsy, if present in higher doses; it inhibits spontaneous motor activity, conditioned avoidance response, amphetamine toxicity and stereotypy. A clinical trial on rats showed that Nuciferin, at doses ranging from 25 to 50 mg per kg intraperitoneal, is able to produce sedation levels from moderate to marked and ptosis. The authors have therefore concluded that probably Nuciferin acts by blocking dopaminergic receptors: in a further study it has been shown that this substance is able to inhibit amphetamine-induced stereotype, which, as is known, is mediated by the stimulation of dopaminergic receptors (36). This present study showed that IELT significantly increased after treatment with CAMPEDEX-5ÂŽ. Moreover, Diallyl Thiosulfinate, Nuciferine and Diosgenin

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Nutraceuticals and premature ejaculation

proved effective in improving the quality of erections, increasing significantly IIEF-5. Topical agents, for the treatment of PE, can reduce the hypersensivity of the glands penis, but can induce localized irritation, including pain, burning, delayed ejaculation and loss of penile sensation (37). Furthermore, in our study, the treatment with CAMPEDEX-5® was well tolerated by all patients, no showing any side effect reported during the period study. However, the limitation of the study is related to the methodology used, as it was not a case-control study. More studies should be carried out to clarify the precise role of the active ingredients in CAMPEDEX-5® and their interactions.

CONCLUSIONS

Our study, though based on results obtained from a pilot study, shown how Diallyl Thiosulfinate, Nuciferine and Diosgenin are able to improve the control of ejaculation in patients suffering from PE, primary or secondary to ED, significantly improving IIEF and IELT rates. The drug had thus proven to be safe and effective in the treatment of PE, without having clinically relevant side effects.

REFERENCES

1. Becker JV, Stinson JD. Premature ejaculation section of Human sexuality and sexual dysfunctions. In RE Hales et al., eds., The American Psychiatric Publishing Textbook of Psychiatry, 5th ed., 2008; pp. 711-728. Washington, DC: American Psychiatric Publishing. 2. Laumann EO, Nicolosi A, Glasser DB, et al. Sexual problems among women and men aged 40-80 y: prevalence and correlates identified in the Global Study of Sexual Attitudes and Behaviors. Int J Impot Res. 2005; 17:39-57. 3. Porst H, Montorsi F, Rosen RC, et al. The Premature Ejaculation Prevalence and Attitudes (PEPA) survey: prevalence, comorbidities, and professional help-seeking. Eur Urol. 2007; 51:816-823 4. Rosen RC, Althof S. Impact of premature ejaculation: the psychological, quality of life, and sexual relationship consequences. J Sex Med. 2008; 5:1296-1307. 5. Waldinger MD. History of Premature Ejaculation. In: Jannini E, McMahon CG, Waldinger MD, editors. Premature Ejaculation. From Etiology to Diagnosis and Treatment. Springer-Verlag Mailand, 2013:5-24. 6. Hartmann U, Schedlowski M, Krüger TH. Cognitive and partnerrelated factors in rapid ejaculation: differences between dysfunctional and functional men. World J Urol. 2005; 23:93-101. 7. Laumann EO, Nicolosi A, Glasser DB, et al. Sexual problems among women and men aged 40-80 y: prevalence and correlates identified in the Global Study of Sexual Attitudes and Behaviors. Int J Impot Res. 2005; 17:39-57 8. Screponi E, Carosa E, Di Stasi SM, et al. Prevalence of chronic prostatitis in men with premature ejaculation. Urology. 2001; 58:198-202. 9. Carani C, Isidori AM, Granata A, et al. Multicenter study on the prevalence of sexual symptoms in male hypo- and hyperthyroid patients. J Clin Endocrinol Metab. 2005; 90:6472-9. 10. Adson DE, Kotlyar M. Premature ejaculation associated with citalopram withdrawal. Ann Pharmacother. 2003; 37:1804-6.

11. Peugh J, Belenko S. Alcohol, drugs and sexual function: a review. J Psychoactive Drugs. 2001; 33:223-32. 12. Basile Fasolo C, Mirone V, Gentile V, et al. Premature ejaculation: prevalence and associated conditions in a sample of 12,558 men attending the andrology prevention week 2001--a study of the Italian Society of Andrology (SIA). J Sex Med. 2005; 2:376-82. 13. Porst H, McMahon CG, Althof SE, et al. Baseline characteristics and treatment outcomes for men with acquired or lifelong premature ejaculation with mild or no erectile dysfunction: integrated analyses of two phase 3 dapoxetine trials. J Sex Med. 2010; 7:223142. 14. Xin ZC, Choi YD, Seong DH, Choi HK. Sensory evoked potential and effect of SS-cream in premature ejaculation. Yonsei Med J. 1995; 36:397-401. 15. Xin ZC, Chung WS, Choi YD, et al. Penile sensitivity in patients with primary premature ejaculation. J Urol. 1996; 156:979-981. 16. Paick JS, Jeong H, Park MS. Penile sensitivity in men with premature ejaculation. Int J Impot Res. 1998; 10:247-250. 17. Zhang HF, Zhang CY, Li XH, et al. Dorsal penile nerves and primary premature ejaculation. Chin Med J (Engl). 2009; 122:3017-3019. 18. Vignoli GC. Premature ejaculation: new electrophysiologic approach. Urology. 1978; 11:81-82. 19. Xin ZC, Choi YD, Rha KH, Choi HK. Somatosensory evoked potentials in patients with primary premature ejaculation. J Urol. 1997; 158:451-455. 20. Perelman MA. A new combination treatment for premature ejaculation: a sex therapist's perspective. J Sex Med. 2006; 3:10041012. 21. Dinsmore WW, Hackett G, Goldmeier D, et al. Topical eutectic mixture for premature ejaculation (TEMPE): a novel aerosol-delivery form of lidocaine-prilocaine for treating premature ejaculation. BJU Int. 2007; 99:369-375. 22. Kockott G. Human sexual inadequacy--behavior therapy and the Masters and Johnson technique. Adv Biosci. 1973; 10:219-224. 23. Waldinger MD. Premature ejaculation: state of the art. Urol Clin North Am. 2007; 34:591-599 24. Cooper K, Martyn-St James M, Kaltenthaler E, et al. Interventions to treat premature ejaculation: a systematic review short report.Health Technol Assess. 2015; 19:1-180. 25. Premature ejaculation: Dapoxetine; Nice advice, May 2014. 26. Martyn-St James M, Cooper K, Ren K, et al. Topical anaesthetics for premature ejaculation: a systematic review and meta-analysis. Sex Health. 2015 Nov 25. 27. Chen J, Keren-Paz G, Bar-Yosef Y, Matzkin H. The role of phosphodiesterase type 5 inhibitors in the management of premature ejaculation: a critical analysis of basic science and clinical data. Eur Urol. 2007; 52:1331-9 28. Sansalone S, Russo GI, Mondaini N, et al. A combination of tryptophan, Satureja montana, Tribulus terrestris, Phyllanthus emblica extracts is able to improve sexual quality of life in patient with premature ejaculation Arch Ital Urol Androl. 2016; 88:171176. 29. Huang YP, Chen B, Ping P, et al. The premature ejaculation diagnostic tool (PEDT): linguistic validity of the Chinese version. J Sex Med. 2014; 11:2232-8. 30. Rosen RC, Catania JA, Althof SE, et al. Development and valiArchivio Italiano di Urologia e Andrologia 2018; 90, 1

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dation of four-item version of Male Sexual Health Questionnaire to assess ejaculatory dysfunction. Urology. 2007; 69:805-9. 31. Waldinger MD, Quinn P, Dilleen M, et al. A multinational population survey of intravaginal ejaculation latency time. J Sex Med. 2005; 2:492-7. 32. U S. Food and Drug Administration. Guidance for Industry Patient Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. Federal Register. 2009; 74:65132-3. 33. Gu X, Zhu YZ. Therapeutic applications of organosulfur compounds as novel hydrogen sulfide donors and/or mediators. Expert Rev Clin Pharmacol. 2011; 4:123-33.

Correspondence Tommaso Cai, MD (Corresponding Author) ktommy@libero.it Department of Urology, Santa Chiara Hospital Largo Medaglie d'Oro 9, Trento, Italy Andrea Cocci, MD Giamartino Cito, MD Department of Urology, University of Florence, Florence, Italy Bruno Giammusso, MD Department of Andrology, Policlinico Morgagni, Catania, Italy Alessandro Zucchi, MD Department of Urology, University of Perugia, Perugia, Italy Francesco Chiancone, MD Maurizio Carrino, MD Department of Urology, Cardarelli Hospital, Naples, Italy Francesco Mastroeni, MD Department of Urology, Azienda Ospedaliera Papardo, Messina, Italy Francesco Comerci, MD Urologist, Bologna, Italy Giorgio Franco, MD Department of Urology, Sapienza University of Rome, Rome, Italy Alessandro Palmieri, MD Department of Urology, University of Naples, Federico II, Naples, Italy

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34. Das I, Khan NS, Sooranna SR. Potent activation of nitric oxide synthase by garlic: a basis for its therapeutic applications. Curr Med Res Opin. 1995; 13:257-63. 35. Liu K, Zhao W, Gao X, , et al. Diosgenin ameliorates palmitateinduced endothelial dysfunction and insulin resistance via blocking IKKĂ&#x; and IRS-1 pathways. Atherosclerosis. 2012; 223:350-8. 36. Farrell MS, McCorvy JD, Huang XP, et al. In vitro and in vivo characterization of the alkaloid nuciferine. PLoS One. 2016; 11:e0150602. 37. Choi HK, Jung GW, Moon KH, et al. Clinical study of SS-cream in patients with lifelong premature ejaculation. Urology. 2000; 55:257-261.

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DOI: 10.4081/aiua.2018.1.65

CASE REPORT

Robotic perineal radical prostatectomy with high prostate volume •

Volkan Tugcu, Abdulmuttalip Simsek, Ismail Yigitbasi, Mustafa Gürkan Yenice, Selcuk Sahin, Ali Ishsan Tasci •

Bakirkoy Dr. Sadi Konuk Research and Training Hospital, Department of Urology, Istanbul, Turkey.

Summary

Background: Minimally invasive techniques are ever improving and are preferred more. Many techniques were developed in radical prostatectomy operations. Robotic radical prostatectomy with the perineal approach is a new technique. Case presentation: A 66-year-old male patient presented because of lower urinary tract symptoms, a PSA value of 5.5 ng/ml was detected, prostate biopsy was performed under transrectal ultrasound guide, a Gleason 3+3 adenocarcinoma on 3/12 foci was reported at pathology. Robotic perineal radical prostatectomy (r-PRP) operation was performed in the patient who had a prostate volume of 130 cc with middle lobe and a body mass index of 32 without additional disease. The duration of operation was 140 minutes in total and the duration at the console was 95 minutes, the amount of bleeding was 85 cc and no intraoperative complication was detected. Conclusion: r-PRP is a technique that can be applied safely without prolonging the operation period and without additional morbidity to the patient, preserving the oncologic and functional outcomes in patients with surgical history and large prostate volume.

(RRP) showed prolonged operation time and hospitalization (3). Since each technique has its own difficulties and limitations, it is only when the factors of the prostate do not affect the operation and when the comorbidities of the patient are also taken into account, the situation becomes more difficult and the development of new techniques will be inevitable. Robotic perineal radical prostatectomy (r-PRP) was developed and applied by Tugcu et al to 15 patients, indicated that this technique can be safely applied in centers with advanced robotic surgery experience (4). This technique with the perineal approach, is applied to a narrow surgical field without incision of endopelvic fascia and without abdomen involvement. When evaluating the surgical steps, a question comes to mind whether this technique is applicable to large prostates. In this case report, we aimed to prove that this technique can be safely applied to prostates with a large volume.

KEY WORDS: Robotic perineal radical prostatectomy; High prostate volume.

PRESENTATION

Submitted 15 January 2018; 20 January 2018

INTRODUCTION

AND BACKGROUND

Since description of radical prostatectomy technique which has high morbidity and mortality, many methods have been used up to that time and the results have been presented. With the acquisition experience, the morbidity and mortality are reduced in parallel with the development of the technology and these operations can be performed safely in experienced centers with minimally invasive techniques. Despite the introduction of many new methods, some factors of the disease may cause this surgical technique to change, to apply another surgical technique or to give up the surgeon. One of these factors is the size of the prostate and when applied with different methods, prostate size can affect the duration of operation, amount of bleeding, postoperative urinary incontinence and erectile dysfunction (1). When open radical prostatectomy (ORP) compared to other techniques, it has been reported that the amount of bleeding is significantly increased as a negative factor (2). According to the data of the literature, laparoscopic radical prostatectomy (LRP) and robotic radical prostatectomy

OF CASE

A 66-year-old male patient presented because of lower urinary tract symptoms, a PSA value of 5.5 ng/ml was detected, prostate biopsy was performed under transrectal ultrasound guide and a Gleason 3+3 adenocarcinoma on 3/12 foci was reported at pathology. At multiparametric magnetic resonance imaging (Figure 1a) of the patient, who had a laparotomy history due to ileus (Figure 1b), there was no extraprostatic spread when the PIRADS 3 lesion was detected, Radical-PRP Figure 1a. Screening middle lobe.

Figure 1b. Laparotomy incision due to ileus.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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•

V. Tugcu, A. Simsek, Ismail Yigitbasi, M. Gürkan Yenice, S. Sahin, A. Ihsan Tasci

operation was performed in the patient who had a prostate volume of 130 cc with middle lobe and a body mass index of 32 without additional disease. The duration of operation was 140 minutes in total and the duration of the console was 95 minutes, the amount of bleeding was 85 cc and no intraoperative complication was detected. The drainage catheter and urethral catheter of the patient with no postoperative complication were removed on 2nd and 7th postoperative day, respectively, and the patient was discharged the same day of catheter removal.The pathology score was Gleason 3 + 3 adenocarcinoma and the surgical margin was negative. Surgical technique The patient is taken to the exaggerated lithotomy position with 15 degrees of Trendelenburg. A urethral catheter is placed and the bladder is emptied. A sterile glove is placed in the rectum and the sides of the glove are stitched to the perineal skin. Thus, we aim to avoid rectum damage by using digital rectal examination during perineal dissections. A 6 cm semilunar incision is bilaterally made between tubercula ischiadica. The perineal dissection is terminated when the dissection margin reaches to the membranous urethra and the apex of the prostate is seen. Subcutaneous tissue laying under the incision borders is dissected deeply over the superficial perineal fascia to place the GelPOINT® (Applied Medical, Rancho Santa Margarita, CA, USA). Once the robotic system is docked (Figure 2), dissection is started from prostate apex and extended in to the lateral sides of the prostate and then deepened inferiorly to reveal the Denonvilliers’ fascia covering the seminal vesicle compartment. Once the Denonvilliers’ fascia is incised, vasa deferentes are bilaterally revealed, dissected and cut. Seminal vesicles are completely dissected and revealed. Then the membranous urethra is dissected and cut. The lateral prostatic pedicles are dissected and controlled using Hem-o-Lock® clips. After completing the lateral dissections of prostate bilaterally, the bladder neck is identified and incised with monopolar scissors, sparing and leaving intact the dorsal vein complex. Dissection was extended towards the bladder neck. Anterior bladder neck was incised using monopolar scissors. After dissection the bladder neck, the middle lobe of the prostate was observed and a vicryl suture was placed for traction of the middle lobe of the prostate (Figure 3a). With proper resection margin, posterior border of the bladder neck was cut and prostate fully dissected from the bladder (Figure 3b). Two of 4/0 V-Loc™ (Covidien, Mansfield, MA, USA) sutures are used in a running fashion starting from the Retzius side to rectal side of the bladder neck. The first suture is started at 12 o'clock on the bladder neck from outside to inside and then continued the

Figure 2. Docking of the robotic system.

Archivio Italiano di Urologia e Andrologia 2018; 90, 1

Figure 3a. Strap vicryl suture.

Figure 3b. Dissection from the bladder neck.

Figure 4. Specimen.

urethra from inside to outside clockwise down to 6 o’clock. A second barbed suture is used in the same setting but in reverse clockwise. Once the anastomosis is completed a 22 Ch urethral catheter is replaced. The bladder is filled by 200 cc saline to test the anastomosis for leakage. After observing the anastomosis is water tight, robotic system is undocked and a Jackson Pratt drain is placed. Specimen was sent to the pathology laboratory for examination (Figure 4).

DISCUSSION

Today, despite the large prostate volumes, in the experienced centers, radical prostatectomy has been successfully applied with many techniques. When we look at risk factors for prostate cancer, obesity and hypertension are at the forefront, therefore radical prostatectomy for large prostate volumes often is accompanied by obesity, hypertension and other comorbid factors. Consequently it is necessary to cope with the additional comorbidities and the negative factors related to previous abdominal surgery. Sarle et al. reported that with retropubic approach the posterior border of the prostate base is very difficult to view, especially in patients with large median lobes, ureteral orifices are almost impossible to view and the risk of injury is high, especially in the antegrade approach, and seminal vesicle dissection prolonged the duration of the operation (5). Despite the narrow surgical field with perineal approach, in our technique, large prostate was easily dissected with appropriate surgical margins on the apex, base and lateral planes, even if a large median lobe was present. Approaching the posterior borders of the prostate from the inferior side allows to safely dissect them by using used strap vicryl suture without affecting the operation time with the ureters protected by direct vision.

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Robotic perineal radical prostatectomy

When large prostates are dissected from the bladder, large defects may form in the bladder neck and require additional reconstructive intervention to anastomose bladder neck to the urethra and can adversely affect continence (6). Eden et al. have proposed 60 cc as the highest prostate volume for open perineal radical prostatectomy (7). Regardless of how large the prostate, in our technique the anterior and posterior borders of the bladder can be easily visualized from perineal approach and the prostate can be easily dissected without creating large defects in the bladder neck. Our technique allows to visualize the trigone and bilaterally the ureteral orifices. In patients who have large prostate, orifices can be protected by direct vision and bladder neck resection can be safely performed. At the same time, the endopelvic fascia is completely preserved, the bladder neck defect is optimal for anastomosis and is not dissected from the surrounding tissues. All these advantages facilitate radical prostatectomy of large prostates in order to preserve the anatomic structure at the maximum extent and contribute to functional outcomes. This technique is safely applied to large prostates with maximum respect for anatomy with its advantages.

CONCLUSION

Robotic-PRP is a technique that can be applied safely without prolonging the operation period and without

additional morbidity to the patient, preserving the oncologic and functional outcomes in patients with previous surgical history and large prostate volume.

REFERENCES

1. Smith JA Jr, Chan RC, Chang SS, Herrell SD, et al. A comparison of the incidence and location of positive surgical margins in robotic assisted laparoscopic radical prostatectomy and open retropubic radical prostatectomy. J Urol. 2007; 178:2385-2389. 2. Hsu EI, Hong EK, Lepor H. Influence of body weight and prostate volume on intraoperative, perioperative, and postoperative outcomes after radical retropubic prostatectomy. Urology. 2003; 61:60-1. 3. Link BA, Nelson R, Josephson DY, et al. The impact of prostate gland weight in robot assisted laparoscopic radical prostatectomy. J Urol. 2008; 180:928. 4. Tugcu V. Akca O, Simsek A, Yigitbasi I, et al. Robot-assisted radical perineal prostatectomy: first experience of 15 cases. Turk J Urol, 2017; 43:476-83. 5. Sarle R, Tewari A, Hemal AK, Menon M, Robotic-assisted anatomic radical prostatectomy: technical difficulties due to a large median lobe. Urol Int. 2005; 74:92-94. 6. Zorn KC, Orvieto MA, Mikhail AA, et al. Effect of prostate weight on operative and postoperative outcomes of robotic-assisted laparoscopic prostatectomy. Urology. 2007; 69:300-305. 7. Eden CG. Minimal access radical prostatectomy: how is it shaping up? BJU Int. 2008; 101:791-792.

Correspondence Volkan Tugcu, MD Abdulmuttalip Simsek, MD (Corresponding Author) simsek76@yahoo.com Ismail Yigitbasi, MD Mustafa Gürkan Yenice, MD Selcuk Sahin, MD Ali Ihsan Tasci, MD Bakirkoy Dr. Sadi Konuk Research and Training Hospital, Department of Urology Zuhuratbaba, Tevfik Saglam Cad. NO:11, Bakirkoy, Istanbul, Turkey •

•

Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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DOI: 10.4081/aiua.2018.1.68

CASE REPORT

Bilateral synchronous testicular seminoma: A rare presentation of a rare disease Pedro SimĂľes de Oliveira, Tiago Ribeiro de Oliveira, SĂŠrgio Pereira, David Martinho, TomĂŠ Lopes Hospital de Santa Maria, Urology Department, Lisbon, Portugal.

Summary

Objective: To present a case of a bilateral synchronous testicular seminoma in a young male clinical stage IIB. Material and method: A 37 years old man presented a bilateral testicular mass with elevated tumoral markers. Histology of frozen section revealed bilateral seminoma and bilateral radical orchiectomy was performed. Result: Enhanced chest and abdominopelvic staging CT scan revealed a lymphadenopathy of 30 mm within the inter-aortocava nodal chain (stage IIB). Patient received three cycles of BEP. Three months later 18F-FDG PET showed no evidence of hypermetabolic activity and serum tumoral markers were normal. Conclusion: Bilateral testicular germ cell tumors are a rare disease. Management of this tumors is controversial. Bilateral radical orchiectomy is the standard of care, nevertheless, in order to preserve fertility and androgen production, an organsparing surgery can be attempted in selected cases. Although prognosis is good, with overall survival rates similar to patients with unilateral disease, life-long close follow-up may be advocated due to relapse risk.

KEY WORDS: Seminoma; Bilateral; Synchronous. Submitted 28 October 2017; 19 November 2017

INTRODUCTION

Testicular germ cell tumors (TGCTs) are the most common malignancy diagnosed in males aged 20 to 40, nevertheless they are a rare disease representing only 5% of all urologic tumors (1). Risk factors in the development of testicular tumors include history of cryptorchidism or undescended testis, Klinefelter syndrome, testicular cancer in the first-degree relatives, presence of tumor or intratubular germ cell neoplasia (TIN) in the contralateral testis, and infertility (1). Bilateral TGCTs (BTT) are even more rare, representing 1-2% of all cases at diagnosis. Approximately 35% of these bilateral tumors are synchronous and the majority are seminomas, being histologically identical almost always (1). Management of this tumors is controversial. Bilateral radical orchiectomy via an inguinal incision is considered the standard of care in cases of synchronous testis cancer with impaired pre-operative testos-

terone levels (1). In order to preserve fertility and androgen production, organ-sparing surgery can be attempted when tumor volume is less than 30% of the testicular volume and surgical rules are respected (1). In those cases, the rate of associated germ cell neoplasia in situ (CIS) is high (up to 82%). Follow-up schedule is the same for patients with unilateral testis cancer (1). Life-long follow-up may be advocated because of a small risk for late relapse and close clinical control, with ultrasound of the testis, may be recommended for patients undergoing testis-preserving surgery (1). We present a rare case of a young male with bilateral voluminous testicular masses representing synchronous seminoma clinical stage IIB.

CASE

REPORT

A 37 years old man, without any known risk factor, presented as an outpatient with chief complaints of bilater-

Figure 1. A) Intra-operative image showing bilateral radical orchiectomy via inguinal incision; B) Pathological examination: nests of seminoma surrounded by bands of fibrous tissue infiltrated with lymphocytes (arrow); C) Enhanced chest and abdominopelvic CT scan revealing a lymphadenopathy of 30 mm within the inter-aorto-cava nodal chain (arrow); D) 18F-FDG PET showing no evidence of hypermetabolic activity.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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Bilateral synchronous seminoma

al scrotal swelling and heaviness, since last three months. On local examination swelling was present over bilateral hemiscrotum, hard in consistency, surface was irregular and it was associated with restricted mobility. Transillumination was negative. There were no palpable inguinal neither supraclavicular lymph nodes. Testis ultrasound revealed multiple bilateral solid nodules occupying about 50% of each testicle. Serum tumor markers were LDH 322 U/L, AFP 1.3 ng/ml and hCG 29 U/L. Testosterone was 453 ng/dL. Patient underwent inguinal exploration and bilateral testicular biopsy for frozen section histological examination which revealed bilateral seminoma (Figure 1A). A bilateral radical orchiectomy was performed with insertion of bilateral testicular prosthesis. Pathological examination confirmed bilateral seminoma with invasion of tunica albuginea and vascular and lymphatic invasion (pT2) (Figure 1B). Postoperatively, serum tumoral markers were normal (LDH 166 U/L, AFP 1.3 ng/ml and hCG 0.3 U/L). Patient initiated testosterone replacement therapy. Enhanced chest and abdominopelvic staging CT scan revealed a lymphadenopathy of 30 mm within the interaorto-cava nodal chain (stage IIB) (Figure 1C). Patient was referred to Oncology and received three cycles of BEP (bleomycin, etoposide and cisplatin). Three months later 18F-FDG PET showed no evidence of hypermetabolic activity (Figure 1D) and serum tumoral markers were normal.

CONCLUSIONS

BTT are rare and therefore literature is scarce, mainly case reports or small series, restricting management strategies for these patients. Patients with BTT, present with different problems requiring careful management to permit a good quality of life. Bilateral radical orchiectomy is the standard of care treatment, nevertheless this approach has a vast impact on fertility and can render patients dependent on life-long testosterone supplementation (1). In 1997 Heidenreich et al. (2) presented a series of 13 patients with BTT who underwent testis-sparring surgery. Six of the 13 patients underwent testicular radiation for CIS and five patients had adjuvant local therapy.

A testicular biopsy was taken 6 months post-operatively and revealed Sertoli cells only in all patients who had received radiation therapy. Only one patient had local recurrence 9 months after tumor enucleation. Testis-sparing surgery must be performed whenever possible, when tumor volume is less than 30% of the testicular volume and surgical margins are respected (1), although multiple testicular biopsies are advocated in this setting in order to identify the presence of CIS and tumor multifocality (1). The occurrence of CIS is a factor suggesting the need for irradiation therapy which can result in loss of fertility and hormonal function of the remaining part of the testicle, the important factors affecting patients’ quality of life (1). Holzbeierlein et al. (3) reported a series of 58 patients with bilateral testicular tumors treated at the Memorial Sloan Kettering Cancer Center between 1950 and 2001, ten had synchronous tumors while 48 had metachronous tumors, being seminoma the most frequent histology. The authors suggested that these patients had favorable outcomes when compared with patients with unilateral tumors and the prognosis was mainly determined by tumor histology and metastatic disease. Although these patients usually present with a higher stage disease, they have an excellent prognosis with overall survival rates comparable with those with unilateral disease. Follow-up is the same as unilateral disease, nevertheless life-long close follow-up is advisable due to the small risk of late relapse (1).

REFERENCES

1. Campobasso D, Ferretti S, Frattini A. Synchronous bilateral testis cancer: clinical and oncological management. Contemp Oncol (Pozn). 2017; 21:70-76. 2. Heidenreich A, Höltl W, Albrecht W, et al. Testis-preserving surgery in bilateral testicular germ cell tumours. Br J Urol. 1997; 79:253-7. 3. Holzbeierlein JM, Sogani PC, Sheinfeld J. Histology and clinical outcomes in patients with bilateral testicular germ cell tumors: The Memorial Sloan Kettering Cancer Center experience 1950 to 2001. J Urol. 2003; 169:2122-5.

Correspondence Pedro Simões de Oliveira, MD (Corresponding Author) pedrosimoesdeoliveira@gmail.com Tiago Ribeiro de Oliveira, MD tiagoribeirooliveira@sapo.pt Sergio Pereira, MD sergioahpereira@gmail.com David Martinho, MD martinho_david@hotmail.com Tomè Lopes, MD tomematoslopes@gmail.com Avenida Professor Egas Moniz 1649-035 Lisbon, Portugal Archivio Italiano di Urologia e Andrologia 2018; 90, 1

Anastasiou_Stesura Seveso 27/03/18 09:33 Pagina 70

DOI: 10.4081/aiua.2018.1.70

CASE REPORT

Conservative management of a bladder leiomyosarcoma in a 43-year-old patient Aikaterini Anastasiou, Ioannis Katafigiotis, Spyridon Skoufias, Ioannis Anastasiou, Constantinos Constantinides 1st University Urology Clinic, Laiko Hospital, Athens, Greece.

Summary

Leiomyosarcoma of the bladder is an aggressive and rare tumor, with less than 200 reported cases. The treatment of bladder leiomyosarcoma is controversial although in most cases an aggressive surgical therapy is preferred. Usually, a radical cystectomy is performed, as it is considered to have a better disease-specific survival rate. A 43-year-old man presented to our Urology Department with painless macroscopic hematuria. He was submitted to transurethral resection of the tumor. The transurethral resection was complete and revealed only this small single lesion and the rest of the bladder was normal with no other lesion or suspicious lesion. The final histology revealed leiomyosarcoma of the bladder. Due to his age and the aggressiveness of the tumor after a thorough and detailed discussion with the patient a conservative management with aggressive follow up was decided. The patient a year after the diagnosis is in perfect condition without sign of a recurrence or metastastes.

KEY WORDS: Bladder leiomyosarcoma; Bladder carcinoma; Rare bladder tumor; Non urothelial bladder cancer. Submitted 13 October 2017; Accepted 19 November 2017

INTRODUCTION

Leiomyosarcoma of the bladder is an aggressive and rare tumor, with less than 200 reported cases (1). It relates to 1% of all bladder malignancies (1). Patients have a median age of 65 years, at diagnosis (2), with no clear evidence of any sex prevalence. The prognosis of the tumor is poor, with an approximately 46 months survival (1). We present a case of a 43-year-old man with leiomyosarcoma of the bladder.

CASE

The urine cytology was negative for malignancy. He was submitted to flexible cystoscopy, during which a single small exophytic lesion in the left lateral bladder wall, was revealed. The patient also underwent computed tomography (CT), which was negative for metastases. He was submitted to transurethral resection of the tumor. The transurethral resection was complete and revealed only this small single lesion and the rest of the bladder was normal with no other lesion or suspicious lesion. The final histology revealed leiomyosarcoma of the bladder (Figure 1). Due to his age and the aggressiveness of the tumor after a thorough and detailed discussion with the patient a conservative management with aggressive follow up was decided. One month after the surgery, a new biopsy from the scar of the previous operation and random biopsies were also performed, all of which were negative. Three months postoperatively the cystoscopy was negative for recurrence. He was submitted to a third cystoscopy with random biopsies after six months again with negative results for malignancy (10 months after the first operation). The patient a year after the diagnosis is in perfect condition without sign of a recurrence or metastastes. The next cystoscopy and CT tomography of the abdomen are planned in six months. Figure 1. Neoplastic spindle cells with concomitant neo-vascular angiogenesis and sparks lymphocytic presence.

REPORT

A 43-year-old man presented to our Urology Department (1st University Urology Clinic, Laiko Hospital) with painless macroscopic hematuria. He had no other symptom and no other co morbidities. The patient was a heavy smoker, but he did not have any other risk factors. The ultrasound of the bladder was normal and the rest of the general examinations of the blood and urine were normal apart from the presence of blood in the urine.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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Bladder leiomyosarcoma

DISCUSSION

Leiomyosarcoma of the bladder is a very rare type of bladder tumor. The annual age-adjusted incidence rate is only 0.23 cases per 1,000,000 and there is no significant change over time (2). It is considered to be the most common bladder sarcoma, however it only accounts for 0.1% of all non-urothelial tumors (2). Different risk factors as the use of cyclophosphamide and ketamine may lead to the development of the disease (1). Furthermore, the exposure to local pelvic radiotherapy or systemic chemotherapy and the use of tobacco seems to be the most common etiological factors, due to genetic alterations (1). Our patient was a heavy smoker without any other co-morbidity. The pathophysiology of bladder leiomyosarcoma is not clear. The main symptoms are gross hematuria, dysuria, urinary frequency and abdominal pain (2). Hematuria is the most common symptom, and in our case, was the main and only symptom. The treatment of bladder leiomyosarcoma is controversial although in most cases an aggressive surgical therapy is preferred. Usually, a radical cystectomy is performed, as it is considered to have a better disease-specific survival rate (1, 2). Other treatment modalities that have been suggested are the partial cystectomy, the transurethral resection of a bladder tumor (TURBT) for small local tumors usually as a part of a multimodality treatment, or radiotherapy (2). Neoadjuvant or adjuvant chemotherapy is also applied (2). Neoadjuvant chemotherapy is used in patients with locally advanced disease. The most common neoadjuvant regimens are doxorubicin, ifosfamide, cisplatin, adriamycin, and vincristine with favorable outcomes (1). For the treatment of smaller leiomyosarcomas (< 4 cm) a partial cystectomy is preferred, as it provides therapeutic efficacy, but also a better quality of life to the patient, compared to more radical surgeries (1, 3). In our case, considering the young age of our patient (43 years old), after a thorough discussion a conservative management avoiding aggressive surgical methods but combined with a close follow-up

was decided. Finally, there is no consensus regarding the prognosis of the disease or the follow-up of the patients. Patients with bladder leiomyosarcomas usually have a very poor prognosis with a median survival time of 46 months, with a survival rate of 62% in 5 years (1, 3). Important prognostic factors are the presence of tumorfree margins, local invasiveness, tumor size and the tumor grade. The poor prognosis of leiomyosarcoma is attributed to the fact that more than 60% of tumours are aggressive, and lead to metastasis, some of them even in a low stage. The overall local recurrence percentage of the disease is 16% recurring mainly in the pelvis . Our patient a year after the diagnosis is in perfect condition without sign of a recurrence or metastastes.

CONCLUSION

Leiomyosarcoma of the bladder is a rare tumor that is difficult to diagnose and treat. The disease is considered to be highly aggressive. As a result a radical treatment, with detrimental effects to the quality of life of the patient is usually considered as necessary. However, a more conservative management of the patient should be considered, when treating a young person especially with small solitary lesions, but with a strict follow-up. Prognosis is generally poor.

REFERENCES

1. Fakhoury M, Hwang RR, Silletti J, Bjurlin MA. Bladder leiomyosarcoma: A rare, but aggressive diagnosis. Curr Urol. 2016; 9:166-168. 2. RodrĂguez D, Preston MA, Barrisford GW, et al. Clinical features of leiomyosarcoma of the urinary bladder: analysis of 183 cases. Urol Oncol. 2014; 32:958-65. 3. Slaoui H, Sanchez-Salas R, Validire P, et al. Urinary bladder leiomyosarcoma: primary surgical treatment. Urol Case Rep. 2014; 2:137-8.

Correspondence Aikaterini Anastasiou, MD (Corresponding Author) aikatianast@gmail.com Ioannis Katafigiotis, MD katafigiotis.giannis@gmail.com Spyridon Skoufias, MD spyskouf@hotmail.com Ioannis Anastasiou, MD ekati2@otenet.gr Constantinos Constantinides, MD ckonstan@med.uoa.gr 1st University Urology Clinic, Laiko Hospital Agiou Thoma 17, Athens 11527, Greece

Archivio Italiano di Urologia e Andrologia 2018; 90, 1

Di Franco_Stesura Seveso 27/03/18 09:33 Pagina 72

DOI: 10.4081/aiua.2018.1.72

CASE REPORT

Metastasis of the epididymis and spermatic cord from pancreatic adenocarcinoma: A rare entity. Description of a case and revision of literature Carmelo Agostino Di Franco 1, Bruno Rovereto 1, Daniele Porru 1, Valeria Zoccarato 1, Cesare Regina 1, Tiziano Cebrelli 1, Nicolò Fiorello 1, Alessandra Viglio 2, Lavinia Galvagno 3, Carlo Marchetti 1, Andrea Ringressi 1, Davide Barletta 1, Giovanni Giliberto 1 1 Department

of Urology, University Hospital IRCCS Policlinico S.Matteo of Pavia, Italy; of Pathology, University Hospital IRCCS Policlinico S.Matteo of Pavia, Italy; 3 Language and Translation Services, Enna, Italy. 2 Department

Summary

Introduction: Metastatic epididymal and spermatic cord adenocarcinoma from epithelial tumors are a rare condition. The most frequent primary cancers are prostate, lung, kidney, gastrointestinal tumors and breast. In literature, there are very low number of cases reporting metastasis from pancreatic cancer to epididymis and spermatic cord. Case description: We report a case of 70-years old man with history of left orchiectomy for undescended testicle, who presented to our department with a palpable nodule in the right scrotum. Scrotal ultrasound revealed an inhomogeneous hypoechoic nodule of epididymis and/or spermatic cord. Neoplastic markers showed high levels of CEA (carcinoembryonic antigen) and bHCG (beta Human Chorionic Gonadotropin). The patient underwent right surgical scrotal exploration with orchifunicolectomy. Pathologic examination revealed pathologic tissue showing rare glandular structures. Immunohistochemistry profile was compatible with malign epithelial neoplasm with glandular differentiation. Total body CT-scan revealed pathologic tissue in pancreas between head and body and a suspect pathologic lesion in liver and 18-FDG PET-scan confirmed the pancreatic neoplastic mass and a suspect secondary hepatic lesion. Biopsy of pancreatic pathologic area was positive for ductal pancreatic adenocarcinoma. The patient was sent to oncologic evaluation and started chemotherapy. Conclusions: Malignancies of epididymis and spermatic cord are rare entities and, in literature, very low number of cases of metastasis from pancreatic carcinoma to epididymis and spermatic cord are described. Early differential diagnosis is fundamental mostly in those patients with age range unusual for testis cancers.

KEY WORDS: Spermatic cord cancer; Metastasis; Pancreatic cancer; Adenocarcinoma; Epididymis cancer; Scrotal tumour. Submitted 6 January 2018; 24 February 2018

INTRODUCTION

Metastatic epididymal and spermatic cord adenocarcinoma from epithelial tumors are a rare condition. The most frequent primary cancers with metastasis to epididymis and spermatic cord are prostate, lung, kidney, gastrointestinal tumors and breast cancers (1-2). In literature,

there are few reports regarding epididymis and spermatic cord metastasis in gastric cancers (3-5), colorectal cancers (6-8), prostate cancer (9) and pancreatic adenocarcinoma (2). In particular, very low number of cases reported metastasis from pancreatic cancer to epididymis and spermatic cord. We report a case of 70-years old man with history of left orchiectomy for undescended testicle in young age, who presented to our department with a palpable nodule in right scrotum. The patient underwent right radical orchifunicolectomy finding adenocarcinoma of epididymis and spermatic cord probably secondary to gastrointestinal cancer; a total body CT-scan showed a suspect pancreatic lesion that a biopsy confirmed to be a ductal pancreatic adenocarcinoma.

CASE

REPORT

A 70-years old man presented with right scrotal palpable nodule without pain or other symptoms, with history of left orchiectomy in young age for undescended testis. Scrotal ultrasound revealed an inhomogeneous hypoechoic nodule of epididymis and/or spermatic cord with small calcifications. Neoplastic markers showed carcinoembryonic antigen (CEA) and beta Human chorionic gonadotropin (bHCG) respectively 9,7 ng/ml (reference ≤ 5.5 ng/ml) and 6.7 mUI/ml (reference ≤ 2.5 mUI/ml). The patient underwent right surgical scrotal exploration with orchifunicolectomy. Pathologic examination revealed a neoplastic mass of around 2 centimetres at epididymis and spermatic cord. Microscopically, pathologic tissue showed rare glandular structures, with slit-like and papillary pattern and presence of mitosis with associated desmoplastic reaction. Immunohistochemistry profile was positive for cytokeratin AE1 AE3, polyclonal CEA, cytokeratin 7, BerEp4 (Ep-CAM/ Epithelial Specific Antigen) and negative for alpha-fetoprotein, OCT3/4 (octamer-binding transcription factor), D240, Placental Alkaline Phosphatase (PLAP), CD30. This histopathologic pattern was compatible with malign epithelial neoplasm with glandular differentiation. Based on rarity of primary epididymis and spermatic cord No conflict of interest declared.

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Metastasis of the epididymis and spermatic cord

Figure 1. Contrast CT-scan showed a pancreatic neoplastic lesion between the pancreatic head and body and suspect hepatic secondary lesions.

Figure 2. 18 FDG PET-scan showed a pancreatic metabolic lesion compatible with neoplastic mass.

REFERENCES

1. Algad F, Santaularia JM, Villavicencio H. Metastatic tumour of the epididymis and spermatic cord. Eur Urol. 1983; 9:56-9. 2. Kanno K, Ohwada S, Nakamura S, et al. Epididymis metastasis from colon carcinoma: A case report and a review of the Japanese literature. Jpn J Clin Oncol. 1994; 24:340-4. 3. Irisawa C, Yamaguchi O, Shiraiwa Y, et al. A case of metastatic tumor of the spermatic cord from gastric carcinoma. Hinyokika Kiyo. 1989; 35:1807-1809. 4. Pozzobon D, Caldato C, Pavanello M, Di Falco G. Metastatic gastric neoplasm in the spermatic cord: report of a case. ChirItal. 2001; 53:729-32. 5. Schaefer I. M, Sauer U, Liwocha M, et al. Occult gastric signet ring cell carcinoma presenting as spermatic cord and testicular metastases: “Krukenberg tumor” in a male patient. Pathol Res Pract. 2010; 206:519-521. 6. Shida Y, Miyata Y, Igawa T, et al. A case of metastatic tumor of spermatic cord from ascending colon carcinoma. Hinyokika Kiyo. 2006; 52:733-5.

tumors, the Pathologist suggested a differential diagnosis with other epithelial cancers. We performed a total body CT-scan that revealed pathologic tissue in pancreas between head and body and a suspect pathologic lesion in the left hepatic lobe of 26 millimetres and another suspect metastatic hepatic lesion in VII segment of 12 millimetres (Figure 1). 18-FDG PET-scan confirmed the pancreatic neoplastic mass and a suspect secondary hepatic lesion (Figure 2). Patient performed endoscopic ultrasound and biopsy of pancreatic pathologic area that was positive for ductal pancreatic adenocarcinoma. The patient was sent to oncologic evaluation and started chemotherapy with Gemcitabine and Abraxane i.v according the scheme day 1, 8, 15 of a 28 days cycle.

CONCLUSION

Generally, malignancies of epididymis and spermatic cord are rare entities, with few cases of both primary cancers and secondary ones. In literature, very low number of cases of metastasis from pancreatic carcinoma to epididymis and spermatic cord are described and usually they are associated with a poor prognosis. Early differential diagnosis is fundamental mostly in those patients with age range unusual for testis cancers. In these cases, at the time of diagnosis, it would be correct to suspect and exclude an “extra-scrotal” origin of the disease.

7. Polychronidis A, Tsolos C, Sivridis E, et al. Spermatic cord metastasis as an initial manifestation of sigmoid colon carcinoma: Report of a case. Surg Today. 2002; 32:376-7. 8 Melone F, Olmastroni M, Petacchi D, et al. Metastatic tumor of the spermatic cord from a primary silent colorectal adenocarcinoma. Minerva Urol Nefrol. 1997; 49:57-61. 9. Bawa AS, Singh R, Bansal VK, Punia RS. Spermatic cord metastasis from prostatic cancer. J Postgrad Med. 2003; 49:97-98. Correspondence Carmelo Agostino Di Franco, MD (Corresponding Author) carmelo_difranco@tiscali.it Bruno Rovereto, MD Daniele Porru, MD Valeria Zoccarato, MD Cesare Regina, MD Tiziano Cebrelli, MD Nicolò Fiorello, MD Carlo Marchetti, MD Andrea Ringressi, MD Davide Barletta, MD Giovanni Giliberto, MD Bruno Rovereto, MD Department of Urology, University Hospital IRCCS Policlinico S.Matteo, Pavia, Italy Alessandra Viglio, MD Department of Pathology, University Hospital IRCCS Policlinico S.Matteo, Pavia, Italy Lavinia Galvagno, Prof. Language and Translation Services, Enna, Italy Archivio Italiano di Urologia e Andrologia 2018; 90, 1

Boschian_Stesura Seveso 27/03/18 09:34 Pagina 74

DOI: 10.4081/aiua.2018.1.74

CASE REPORT

Pulmonary recurrence from prostate cancer and biochemical remission after metastasis directed therapy. A case report Riccardo Boschian 1, Michele Rizzo 1, Lorenzo ZandonĂ 2, Carlo Trombetta 1, Giovanni Liguori 1 1 Department 2 Institute

of Urology, University of Trieste, Trieste, Italy; of Pathological Anatomy and Histology, University of Trieste, Trieste, Italy.

We report a case of a 69-years-old man who presented with a solitary 1 cm nodule in the lower lobe of the left lung almost 3 years after radical prostatectomy for pT3aN0M0, Gleason score 4+3 disease, without evidence of osseous or lymphatic spread. Surgical resection of the pulmonary lobe confirmed the metastatic nature of the lesion, with subsequent reduction of serum PSA to undetectable levels. After 2 years from the metastasis resection, serum PSA is still undetectable, without the necessity of additional treatments. Solitary pulmonary metastases from prostate cancer (Pca) are rare in clinical practice, with only 29 previous cases described besides the one that we present.

of the left lung, strongly suggesting a tumor. The patient was suspected to have a secondary lung metastasis. Since there was no evidence of metastatic disease in the remaining workup, the patient elected to undergo a thoracoscopic segmental resection with lymph node dissection. Histopathological examination revealed Pca metastasis with negative lymph nodes (Figure 1). Subsequently, PSA serum level dropped to undetectable levels (less than 0.05 ng/ml) and remained undetectable for more than 36 months.

KEY WORDS: Prostate cancer; Recurrence; PSA.

The incidence of lung metastases from Pca is reported from 5% to 27%; however, it is a very rare condition in the absence of gross osseous or lymphatic involvement (1). Wallis and colleagues, in their recent literature review, found a total of only 18 cases of solitary metastatic Pca to lung and 15 cases of multiple metastases without osseous or lymphatic involvement (2). Until now, androgen deprivation therapy (ADT) is the cornerstone of treatment for PCa patients diagnosed with metastatic progression following primary treatment, although the optimal timing and schedule of ADT is still under debate in this setting (3).

Summary

Submitted 9 August 2017; 21 September 2017

INTRODUCTION

Isolated lung metastases in prostate cancer (Pca) has been reported in less than 1% of cases and its proper treatment is still debated (1). We report a case, of an isolated solitary pulmonary recurrence of PCa after radical prostatectomy that was resected, resulting in a 3 years disease-free follow-up.

CASE

REPORT

A 69-year-old man comes to our observation after the diagnosis of a pG7 (4+3) prostate cancer. The PSA level was 5.1 ng/ml. In February 2011, the patient underwent open Radical Prostatectomy with pelvic lymph node dissection. The pathology specimen demonstrated bilateral disease, Gleason Score 4+3, focal evidence of surgical margins infiltration, negative seminal vescicles and negative pelvic lymph nodes. There was no evidence of vascular invasion (pT3aN0M0). The patient then underwent adjuvant radiotherapy at the dose of 70 Gy in 35 fractions. For three years postoperatively, the patientâ&#x20AC;&#x2122;s PSA serum level was undetectable. Then it rose to 0.4 ng/ml. We then applied 18-fluoro-2-deoxyclucos positron emission tomography (FDG-PET-CT) which revealed selective accumulation in a 1 cm nodule in the inferior lobe

DISCUSSION

Figure 1. Histopathological examination revealed prostate cancer metastasis.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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Pulmonary recurrence from prostate cancer and biochemical remission after metastasis directed therapy. A case report

As in other solid tumours, it is more likely that oligometastatic patients have a better prognosis and a better survival compared with patients with extensive metastatic disease. As a matter of fact, in a 2014 retrospective study on 1.206 patients referred for radiotherapy of the prostate (bed) following diagnosis of Pca, patients with a single metastasis had a 5-yr cancer-specific survival of 90% (95% CI, 71-100) compared with only 32% (95% CI, 12-52) in patients with more than one metastasis (4). Therefore, local cancer treatments could be curative in a proportion of patients with metastases. Our patient had a solitary pulmonary metastasis that resulted in a complete response after surgical excision without androgen withdrawal. To date, only 6 cases of successful resection of a solitary lung metastases after radical prostatectomy for Pca have been reported (5). To the best of our knowledge, this patient was the first in which metastases directed therapy was successfully performed only by surgery, without any ADT.

CONCLUSION

In conclusion, the diagnosis of a solitary pulmonary metastasis from Pca with an otherwise negative metastatic workup is atypical and presents a therapeutic issue of the role of metastasectomy. Metastasis-directed therapy is a promising approach and

might be offered to selected patients with good results. This case focuses the importance of regular PSA followup after PCa therapies. However due to the low numbers of cases reported in literature, the absence of trials and the heterogeneity of patients treated, this should not be considered the standard therapy.

REFERENCES

1. Bubendorf L, SchĂśpfer A, Wagner U, et al. Metastatic patterns of prostate cancer: An autopsy study of 1,589 patients. Hum Pathol. 2000; 31:578-83. 2. Wallis CJ, English JC, Goldenberg SL. The role of resection of pulmonary metastases from prostate cancer: a case report and literature review. Can Urol Assoc J. 2011; 5:E104-8. 3. Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014; 65:467-79. 4. Ost P, Decaestecker K, Lambert B, et al. Prognostic factors influencing prostate cancer-specific survival in non-castrate patients with metastatic prostate cancer. Prostate 2014; 74:297-305. 5. Maebayashi T, Abe K, Aizawa T, et al. Solitary pulmonary metastasis from prostate cancer with neuroendocrine differentiation: a case report and review of relevant cases from the literature. World J Surg Oncol. 2015; 13:173.

Correspondence Riccardo Boschian, MD (Corresponding Author) rboschian@gmail.com Michele Rizzo, MD mik.rizzo@gmail.com Carlo Trombetta, MD trombcar@units.it Giovanni Liguori, MD gioliguori33@gmail.com Department of Urology, University of Trieste, Trieste, Italy Lorenzo ZandonĂ , MD lorenzan84@libero.it Institute of Pathological Anatomy and Histology, University of Trieste, Trieste, Italy

Archivio Italiano di Urologia e Andrologia 2018; 90, 1

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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.

Istruz_Stesura Seveso 27/03/18 09:35 Pagina 2

Gr and Hot el Salerno, 24 - 26 Maggio 2018

Giovedì, 24 Maggio 2018

Venerdì, 25 Maggio 2018

SALA TAFURI TAFURI 08.30 - 13.30 LIVE SURGERY In diretta via satellite HD dalle sale operatorie della Clinica Malzoni Neuromed di Avellino

SALA TAFURI TAFURI 08.45 - 11.00 TUMORE PROST TA ATA: il GOM in azione

SALA 1 - Basse vie urinarie Energy Free B-TUEP Bipolar TUEP HoLEP Green Light Laser VapoEnucleation

SALA 2 - Alte vie urinarie Rimozione stent e RIRS con digitale monouso RIRS con LITHOVUE

SALA 3 - Protesica Impianto di protesi peniena tricomponente titan OTR Impianto di sling Virtue per incontinenza urinaria maschile

11.00 - 11.50 CARCINOMA DELLA VESCICA NON MUSCOLO INV VA ASIVO 11.50 - 12.50 IPERTROFIA PROST TA ATICA E TUTELA DELLA VESCICA 12.50 - 13.20 PRESENT TAZIONE E PREMIAZIONE COMUNICAZIONI 14.30 - 16.10 IL DOLORE PELVICO CRONICO NON HA SESSO: RESPONSABILIT TÀ DEI PROCESSI INFIAMMA AT TORI CRONICI

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SALA 4 - Laparoscopia Chirurgia laparoscopica per endometriosi pelvica massiva con coinvolgimento ureterale

14.30 - 15.30 LA CALCOLOSI URINARIA : NON SOLO CHIRURGIA 15.45 - 17.35 LA SALUTE SESSUALE: ASPETTI INNOVATIVI

16.10 - 17.45 VIDEO ACADEMY AND NEW TECHNOLOGY

24 - 25 Maggio 2018 SALA A ATENA TENA 13.00 - 14.30 Corso teorico pratico con Simulatori Alte vie urinarie Basse vie urinarie Robot Laser

TRATTATO ITALIANO di NUTRACEUTICA CLINICA

Istruz_Stesura Seveso 27/03/18 09:35 Pagina 3

È pubblicato il primo Trattato Italiano di Nutraceutica Clinica, un progetto della Società Italiana di Nutraceutica Clinica (SINut) e di Edizioni Scripta Manent. Uno strumento di formazione ed aggiornamento professionale per gli specialisti della nutraceutica e per tutti i professionisti interessati a nutrizione, alimentazione funzionale ed integrazione alimentare, argomenti concretamente trasversali a tutte le discipline specialistiche, compresa l’Urologia.

Contenuti 616 Pagine 38 Capitoli su principi attivi, integratori alimentari, preparati a base di piante officinali, alimenti funzionali, probiotici, prebiotici, alimenti naturalmente ricchi di componenti bioattivi 61 Autori e Co-Autori, tra i quali, in ambito urologico: 1. Giuseppe Morgia e Tommaso Castelli: “Nutraceutica in urologia” Oltre all’urologia, tutte le discipline specialistiche interessate alla Nutraceutica: Gastroenterologia

Sistema nervoso centrale e periferico

Metabolismo ed Endocrinologia

Dermatologia e Cosmeceutica

Malattie cardiache e cardiovascolari

Immunologia e flogosi

Epatologia

Ginecologia

Flebologia

Disturbi di ossa ed articolazioni

Geriatria

Otorinolaringoiatria

Disturbi dell’umore

Oculistica

Insonnia

Medicina dello sport

Tutti gli argomenti correlati alla ricerca: Aspetti normativi ed iter di approvazione

Aspetti clinici

Farmacotossicologia, qualità e sicurezza

Innovazione, ricerca e biotecnologie

Bibliografia ricca ed attuale Immagini, tabelle e figure originali Highlights riassuntivi

Edizioni Scripta Manent, Milano – 2017 Prezzo: Euro 100,00 (IVA inclusa)

Per informazioni su prenotazione, costi e condizioni di acquisto, inviare un’e-mail a: trattato.nutraceutica@gmail.com In alternativa, è possibile chiamare i seguenti numeri: 02 70608060 e 345 0816384.

PIstruz_Stesura Seveso 27/03/18 09:35 Pagina 4

TRATTATO ITALIANO DI

NUTRACEUTICA CLINICA a cura di

Arrigo F. G. Cicero SocietÃ Italiana di Nutraceutica

coadiutori

Alessandro Colletti e Francesco Di Pierro

Istruz_Stesura Seveso 27/03/18 09:35 Pagina 5

AVVIATISSIMO STUDIO MEDICO ELEGANTEME ENTE ARREDATO ZONA SAN MARCO (Brera) MILANO CON SERVIZIO DI PORTINERIA

CERCA MEDICO INTERESSATO A SVOLGERE PROPRIA ATTIVITÃ&#x20AC; PROFESSION NALE, A TEMPO PARZIALE IN ORARI DA CONCORDARE, PER CONDIVISION NE SPESE GESTIONE SI PREGA CONTATTARE SEGRETERIA renata.brambilla@fastwbnet.it PRECISANDO QUALIFICA E NUMERO TELEFONICO

Cop ok_Layout 1 03/04/18 11:03 Pagina 2

School 2018

Società Italiana

Cop ok_Layout 1 03/04/18 11:03 Pagina 1

s w ces i t o N Ac u a. i en w.a p O ww

ISSN 1124-3562

Vol. 90; n. 1, March 2018

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. 1 March 2018

ORIGINAL PAPERS 1

Semirigid ureteroscopy prior retrograde intrarenal surgery (RIRS) helps to select the right ureteral access sheath Ioannis Boulalas, Mauro De Dominicis, Lorenzo Defidio

A new technique of ultrasound guided percutaneous renal biopsy by perforated probe and perpendicular needle trajectory Simone Brardi, Gabriele Cevenini, Angelo Giovanni Bonadio

Injection therapy for chronic prostatitis: A retrospective analysis of 77 cases Attila Toth, Frederico Maria Guercini, Dawn Marta Feldthouse, Jun Chao Zhang

The impact of prostate artery embolization (PAE) on the the physical history and pathophysiology of benign prostatic hyperplasia (BPH) Konstantinos Stamatiou