Archivio Italiano di Urologia e Andrologia - Vol. 91 - n. 4 - 2019 by Edizioni Scripta Manent

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ISSN 1124-3562

Vol. 91; n. 4, December 2019

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. 91; n. 4 December 2019

ORIGINAL PAPERS 205

Efficacy and safety of Finasteride (5 alpha-reductase inhibitor) monotherapy in patients with benign prostatic hyperplasia: A critical review of the literature Gian Maria Busetto, Francesco Del Giudice, Daniele D’Agostino, Daniele Romagnoli, Andrea Minervini, Bernardo Rocco, Alessandro Antonelli, Antonio Celia, Riccardo Schiavina, Luca Cindolo, Benjamin I. Chung, Jae Heon Kim, Martina Maggi, Alessandro Sciarra, Ettore De Berardinis, Angelo Porreca

211

MRI/TRUS FUSION guided biopsy as first approach in ambulatory setting: Feasibility and performance of a new fusion device Daniele D’Agostino, Federico Mineo Bianchi, Daniele Romagnoli, Marco Giampaoli, Paolo Corsi, Alessandro Del Rosso, Riccardo Schiavina, Eugenio Brunocilla, Angelo Porreca

218

Lesion location agreement between prostatic multiparametric magnetic resonance, cognitive fusion biopsy and radical prostatectomy piece Mario Lourenço, Pedro Pissarra, Duarte Vieira e Brito, Miguel Eliseu, Joao Pedro Peralta, Arnaldo Figueiredo, Cristina Marques

224

“In-bore” MRI prostate biopsy is a safe preoperative clinical tool to exclude significant prostate cancer in symptomatic patients with benign prostatic obstruction before transurethral laser enucleation Angelo Porreca, Daniele D’Agostino, Mario Vigo, Paolo Corsi, Daniele Romagnoli, Alessandro Del Rosso, Riccardo Schiavina, Eugenio Brunocilla, Walter Artibani, Marco Giampaoli

230

Is Fast Track protocol a safe tool to reduce hospitalization time after radical cystectomy with ileal urinary diversion? Initial results from a single high-volume centre Daniele Romagnoli, Riccardo Schiavina, Lorenzo Bianchi, Marco Borghesi, Francesco Chessa, Federico Mineo Bianchi, Andrea Angiolini, Carlo Casablanca, Marco Giampaoli, Paolo Corsi, Daniele D’Agostino, Eugenio Brunocilla, Angelo Porreca

237

Does duration of stenting increase the risk of clinical infection? Tuncay Toprak, Aytaç Şahïn, Musab Ali Kutluhan, Korhan Akgul, Yavuz Onur Danacioglu, Mehmet Akif Ramazanoglu, Ayhan Verit ̈ ztürk, Nurullah Hamidi, İsmail Selvi, Halil Başar, Levent Peşkircioğlu Taha Numan Yıkılmaz, Erdem O

241

Evaluation of sexual dysfunction prevalence in infertile men with non-obstructive azoospermia

245

Effect of body mass and physical activity at younger age on the risk of prostatic enlargement and erectile dysfunction: Results from the 2018 #Controllati survey Fabio Parazzini, Walter Artibani, Giuseppe Carrieri, Luca Carmignani, Salvatore Voce on behalf of the #Controllati study group continued on page III

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Official Journal of SIA, SIEUN, UrOP and GUN EDITORIAL BOARD EDITOR IN CHIEF Alberto Trinchieri (Milan, Italy)

ASSOCIATE EDITORS Emanuele Montanari, Department of Urology, IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Italy – Gianpaolo Perletti, Department of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, University of Insubria, Varese, Italy; Department of Human Structure and Repair, Ghent University, Ghent, Belgium - Angelo Porreca, Robotic Urology and Mini Invasive Urologic Surgery Unit, Abano Terme Hospital, Abano Terme, Italy

EXECUTIVE EDITORIAL BOARD Alessandro Antonelli, Department of Urology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), Verona, Italy - Antonio Celia, Department of Urology, San Bassiano Hospital, Bassano del Grappa, Italy - Luca Cindolo, Department of Urology, Villa Stuart Hospital, Rome, Italy - Andrea Minervini, Department of Urology, University of Florence, Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy Bernardo Rocco, Department of Urology, University of Modena and Reggio Emilia, Modena, Italy - Riccardo Schiavina, Department of Urology, University of Bologna, Bologna, Italy

ADVISORY EDITORIAL BOARD Pier Francesco Bassi, Urology Unit, A. Gemelli Hospital, Catholic University of Rome, Italy – Francesca Boccafoschi, Health Sciences Department, University of Piemonte Orientale in Novara, Italy – Alberto Bossi, Department of Radiotherapy, Gustave Roussy Institute, Villejuif, France – Paolo Caione, Department of Nephrology-Urology, Bambino Gesù Pediatric Hospital, Rome, Italy – Luca Carmignani, Urology Unit, San Donato Hospital, Milan, Italy – Liang Cheng, Department of Urology, Indiana University School of Medicine, Indianapolis, IN; Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN – Giovanni Colpi, Retired Andrologist, Milan, Italy – Giovanni Corona, Department of Urology, University of Florence, Careggi Hospital, Florence, Italy – Antonella Giannantoni, Department of Surgical and Biomedical Sciences, University of Perugia, Italy – Paolo Gontero, Department of Surgical Sciences, Molinette Hospital, Turin, Italy – Steven Joniau, Organ Systems, Department of Development and Regeneration, KU Leuven, Belgium – Frank Keeley, Bristol Urological Institute, Southmead Hospital, Bristol UK – Laurence Klotz, Division of Urology, Department of Surgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada – Börje Ljungberg, Urology and Andrology Unit, Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden – Nicola Mondaini, Uro-Andrology Unit, Santa Maria Annunziata Hospital, Florence, Italy – Gordon Muir, Department of Urology, King's College Hospital, London, UK – Giovanni Muto, Urology Unit, Bio-Medical Campus University, Turin, Italy – Anup Patel, Department of Urology, St. Mary's Hospital, Imperial Healthcare NHS Trust, London, UK – Glenn Preminger, Division of Urologic Surgery, Duke University Medical Center, Durham, NC, USA – David Ralph, St. Peter's Andrology Centre and Institute of Urology, London, UK – Allen Rodgers, Department of Chemistry, University of Cape Town, Cape Town, South Africa – Francisco Sampaio, Urogenital Research Unit, State University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil – Kemal Sarica, Department of Urology, Kafkas University Medical School, Kars, Turkey – Luigi Schips, Department of Urology, San Pio da Pietrelcina Hospital, Vasto, Italy – Hartwig Schwaibold, Bristol Urological Institute, Southmead Hospital, Bristol, UK – Alchiede Simonato, Department of Urology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy – Carlo Terrone, Department of Urology, IRCCS S. Martino University Hospital, Genova, Italy – Anthony Timoney, Bristol Urological Institute, Southmead Hospital, Bristol, UK – Andrea Tubaro, Urology Unit, Sant’Andrea Hospital, “La Sapienza” University, Rome, Italy – Richard Zigeuner, Department of Urology, Medical University of Graz, Graz, Austria

BOARD OF REVIEWERS Maida Bada, Department of Urology, S. Pio da Pietrelcina Hospital, ASL 2 Abruzzo, Vasto, Italy - Lorenzo Bianchi, Department of Urology, University of Bologna, Bologna, Italy Mariangela Cerruto, Department of Urology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), Verona, Italy - Francesco Chessa, Department of Urology, University of Bologna, Bologna, Italy - Daniele D’Agostino, Robotic Urology and Mini Invasive Urologic Surgery Unit, Abano Terme Hospital, Abano Terme, Italy - Fabrizio Di Maida, Department of Urology, University of Florence, Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy - Antonio Galfano, Urology Unit, Niguarda Hospital, Milan, Italy Michele Marchioni, Department of Medical, Oral and Biotechnological Sciences, "G. d'Annunzio" University of Chieti, Laboratory of Biostatistics, Chieti, Italy - Andrea Mari, Depart-

ment of Urology, University of Florence, Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy - Antonio Porcaro, Department of Urology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), Verona, Italy - Stefano Puliatti, Department of Urology, University of Modena and Reggio Emilia, Modena, Italy - Daniele Romagnoli, Robotic Urology and Mini Invasive Urologic Surgery Unit, Abano Terme Hospital, Abano Terme, Italy - Chiara Sighinolfi, Department of Urology, University of Modena and Reggio Emilia, Modena, Italy - Tommaso Silvestri, Urology Clinic, Department of Medical, Surgical and Health Science, University of Trieste, Trieste, Italy - Petros Sountoulides, Aristotle University of Thessaloniki, Department of Urology, Thessaloniki, Greece

SIA EDITOR Alessandro Palmieri, Department of Urology University Federico II of Naples, Italy

SIA ASSISTANT EDITORS Tommaso Cai, S. Chiara Hospital, Trento, Italy – Vincenzo Favilla, University Hospital Gaspare-Rodolico, Catania, Italy – Paolo Verze, Federico II University, Naples, Italy

SIA EDITORIAL BOARD Massimo Polito, Ospedali Riuniti di Ancona, Ancona, Italy – Paolo Capogrosso, Università VitaSalute San Raffaele, Milano, Italy – Giuseppe Sidoti, A.O. Garibaldi, Catania, Italy – Nicola Pavan, Azienda Ospedaliero-Universitaria "Ospedali Riuniti" di Trieste, Italy – Enrico Conti, Presidio Ospedaliero Levante Ligure, La Spezia, Italy – Matteo Paradiso, Ospedale Cardinal Massaia-ASL 19, Asti, Italy – Giuseppe Romano, Ospedale Civile S. Donato Arezzo-U.O. Arezzo, Italy – Antonio Vavallo, Ospedale della Murgia, Altamura, Italy – Gianni Paulis, Ospedale Regina Apostolorum, Albano Laziale, Italy – Valeria Randone, Studio privato–Sessuologo Clinico, Catania, Italy – Maria Colucci, Studio privato-Consulente in Sessuologia, Bari, Italy

SIEUN EDITOR Pasquale Martino, Department of Emergency and Organ Transplantation-Urology I, University Aldo Moro, Bari, Italy

SIEUN EDITORIAL BOARD Emanuele Belgrano, Department of Urology, Trieste University Hospital, Trieste, Italy - Francesco Micali, Department of Urology, Tor Vergata University Hospital, Rome, Italy - Massimo Porena, Urology Unit, Perugia Hospital, Perugia, Italy – Francesco Paolo Selvaggi, Department of Urology, University of Bari, Italy – Carlo Trombetta, Urology Clinic, Cattinara Hospital, Trieste, Italy – Giuseppe Vespasiani, Department of Urology, Tor Vergata University Hospital, Rome, Italy – Guido Virgili, Department of Urology, Tor Vergata University Hospital, Rome, Italy

UrOP EDITOR Carmelo Boccafoschi, Department of Urology, Città di Alessandria Clinic, Alessandria, Italy

UrOP EDITORIAL BOARD Renzo Colombo, Department of Urology, San Raffaele Hospital, Milan, Italy – Roberto Giulianelli, Department of Urology, New Villa Claudia, Rome, Italy – Massimo Lazzeri, Department of Urology, Humanitas Research Hospital, Rozzano (Milano), Italy – Angelo Porreca, Department of Urology, Polyclinic Abano Terme, Abano Terme (Padova), Italy – Marcello Scarcia, Department of Urology, "Francesco Miulli" Regional General Hospital, Acquaviva delle Fonti (Bari), Italy – Nazareno Suardi, Department of Urology, San Raffaele Turro, Milano, Italy.

GUN EDITOR Arrigo Francesco Giuseppe Cicero, Medical and Surgical Sciences Department, Sant’Orsola-Malpighi University Hospital, Bologna, Italy

GUN EDITORIAL BOARD Gianmaria Busetto, Department of Urology, Sapienza University of Rome, Italy – Tommaso Cai, Department of Urology, Santa Chiara Regional Hospital, Trento, Italy – Elisabetta Costantini, Andrology and Urogynecological Clinic, Santa Maria Hospital of Terni, University of Perugia, Terni, Italy – Angelo Antonio Izzo, Department of Pharmacy, University of Naples, Italy – Vittorio Magri, ASST Nord Milano, Milano, Italy – Salvatore Micali, Department of Urology, University of Modena and Reggio Emilia, Modena, Italy – Gianni Paulis, Andrology Center, Villa Benedetta Clinic, Rome, Italy – Francesco Saverio Robustelli della Cuna, University of Pavia, Italy – Giorgio Ivan Russo, Urology Department, University of Catania, Italy – Konstantinos Stamatiou, Urology Department, Tzaneio Hospital, Piraeus, Greece – Annabella Vitalone, Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

HONORARY EDITOR Enrico Pisani, Professor Emeritus, Institute of Urology, University of Milan, Italy

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ORIGINAL PAPERS 251

The association of Boswellia resin extract and propolis derived polyphenols can improve quality of life in patients affected by prostatitis - like symptoms Mattia Sibona, Paolo Destefanis, Marco Agnello, Beatrice Lillaz, Mattia Giuliano, Tommaso Cai, Paolo Gontero

256

Clinical and psychological outcomes of patients undergoing Retrograde Intrarenal Surgery and Miniaturised Percutaneous Nephrolithotomy for kidney stones. A preliminary study Davide Di Mauro, Valentina Lucia La Rosa, Sebastiano Cimino, Eugenio Di Grazia

CASE REPORTS 261

Preputial circumcision performed with a new mechanical stapling tool. The “langhe disposable circumcision suture device”. Preliminary experiences Diego Pozza, Carlotta Pozza, Augusto Mosca, Mariangela Pozza

263

Renal autotransplantation: A final option to preserve the kidney after an iatrogenic ureteral injury Napoleon Moulavasilis, Ioannis Katafigiotis, Dimitris Staios, Christos Nikolaidis, Spyridon Vernadakis, John Bokos, Ioannis Anastasiou

265

Solitary prostatic cancer metastasis to the testis: A case report and lessons to learn Asmaa Ismail, Hazem Elmansy, Walid Shahrour, Owen Prowse, Ahmed Kotb

267

Right open nephrectomy under combined spinal and peridural operative anesthesia and analgesia (CSE): A new anesthetic approach in abdominal surgery Michele Cotugno, Matteo Dallaglio, Luca Cantadori, Fabio Villani, Daniel Martens, Federico Cantoni, Michele Potenzoni, Salvatore Micali, M.C. Bernardo Rocco, Andrea Prati

269

Detection of significant left renal artery stenosis caused by fibromuscular dysplasia with selective angiography Ramezan Jafari, Zohreh Rostami, Mohammad Nikpoor, Mohammad Javanbakht, Mohsen Sadeghi Ghahroudi, Mahbobeh Sadat Hosseini, Behzad Einollahi

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AIMS AND SCOPE “Archivio Italiano di Urologia e Andrologia” publishes papers dealing with the urological, nephrological and andrological sciences. Original articles on both clinical and research fields, reviews, editorials, case reports, abstracts from papers published elsewhere, book rewiews, congress proceedings can be published.

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DOI: 10.4081/aiua.2019.4.205

ORIGINAL PAPER

Efficacy and safety of Finasteride (5 alpha-reductase inhibitor) monotherapy in patients with benign prostatic hyperplasia: A critical review of the literature Gian Maria Busetto 1, Francesco Del Giudice 1, Daniele Dâ&#x20AC;&#x2122;Agostino 2, Daniele Romagnoli 2, Andrea Minervini 3, Bernardo Rocco 4, Alessandro Antonelli 5, Antonio Celia 6, Riccardo Schiavina 7, Luca Cindolo 8, Benjamin I. Chung 9, Jae Heon Kim 10, Martina Maggi 1, Alessandro Sciarra 1, Ettore De Berardinis 1, Angelo Porreca 2 1 Department

of Maternal-Child and Urological Sciences, Sapienza Rome University, Policlinico Umberto I Hospital, Rome, Italy; of Urology, Policlinico Abano Terme, Abano Terme (PD), Italy; 3 Department of Urology, University of Florence, Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy; 4 Department of Urology, University of Modena and Reggio Emilia, Modena, Italy; 5 Department of Urology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), Verona, Italy; 6 Department of Urology, San Bassiano Hospital, Bassano Del Grappa, Italy; 7 Department of Urology, University of Bologna, Bologna, Italy; 8 Department of Urology, Villa Stuart Hospital, Rome, Italy; 9 Department of Urology, Stanford Medical Center, Palo Alto, CA, USA; 10 Department of Urology, Soonchunhyang University Seoul Hospital, Soon Chun Hyang University College of Medicine, Seoul, Korea. 2 Department

Summary

Background: Combination therapy with 5 alpha-reductase inhibitor (5-ARI) and alpha-blocker can be considered as a gold standard intervention for medical management of lower urinary tract symptoms related to benign prostatic hyperplasia (LUTS/BPH). On the other hand, 5-ARI monotherapy and in particular Finasteride alone is currently getting focus of attention especially due to lack of systematic reviews investigating efficacy outcomes and/or adverse events associated. Objectives: Aim of the present critical review was to analyze current knowledge of clinical efficacy and incidence of adverse events associated with 5-ARI treatment for LUTS/BPH. Materials and methods: A systematic review of clinical trials of the literature of the past 20 years was performed using database from PubMed, Cochrane Collaboration and Embase. A total of 8821 patients were included in this study and inclusion criteria for studies selection were: data from randomized clinical trials (RCTs) focusing their attention on the clinical role of Finasteride monotherapy for symptomatic BPH. Parameters of research included prostate specific antigen (PSA), prostate volume (PV), International Prostate Symptom Score (IPPS), postvoid residual urine (PVR), voiding symptoms of IPSS (voiding IPSS), maximum urinary flow rate (Qmax), and adverse events (AEs). Results: Overall 12 original articles were included and critically evaluated. Sample sizes of patient actively treated with finasteride varied from 13 to 1524 cases analyzed in a single study. Follow-up after treatments ranged from 3 to 54 months. The effect of finasteride in reducing prostate volume (PV) was moderate (standardized mean difference (SMD) effect between 0.5 to 0.8 for all trials evaluable) while the effect on IPSS score and Qmax was considered significant (SMD in the 0.2 to 0.5 variation range). No severe AEs and/or psychiatric disorders were retrieved among the studies. Sexual health dysfunctions were significantly influenced by finasteride therapy when compared with placebo treated patients. Conclusions: Although significant clinical benefits of finas-

teride monotherapy were demonstrated, the effective size of the available reports included in the analysis is limited. Additional head-to-head studies would be needed to re-evaluate clinical efficacy and safety of 5-ARI in combination or not with alpha blockers.

KEY WORDS: Benign prostatic hyperplasia; 5 alpha-reductase inhibitor; Finasteride; Side effects. Submitted 27 November 2019; Accepted 7 December 2019

INTRODUCTION

Benign prostatic hyperplasia (BPH) with lower urinary tract symptoms (LUTS) is one of the most common diseases prevalent in elderly men. Prevalence of BPH among men in their 50s and 60s is 50% rising to 90% by the age of 80s with significant consequent impact on Quality of Live (QoL) outcomes (1, 2). Five Alpha-Reductase Inhibitors (5-ARI) block the conversion of testosterone to dihydrotestosterone, which accounts for the efficacy of its use in the treatment of BPH/LUTS, by reducing prostate volume (3, 4). To date, there are two types of 5-ARIs: finasteride and dutasteride. While finasteride inhibits only type 2 5-ARI, dutasteride inhibits both type 1 and 2, but both medications have shown similar efficacy (5). Primary medical management of men with BPH/LUTS include alpha-blockers and 5-ARI as standard therapy and Serenoa repens with more limited efficacy (6-8). Combination treatment with alpha blockers have been demonstrated to be able to significantly decrease prostate volume (PV), improve International Prostate Symptom Score (IPSS), improve Qmax, decrease risk of acute urinary retention (AUR) and operative procedures related with BPH/LUTS better than finasteride alone. Even studies on 5-ARI monotherapy resulted, especially for finasteride,

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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G.M Busetto, F. Del Giudice, D. D’Agostino, et al.

in a significant improvement in all BPH related symptoms by long-term treatment (9, 10). However, decision of implementing a 5-ARI monotherapy regimen of treatment should be cautiously evaluated by urologists due to recent warning data suggesting adverse clinical implications of such drugs including the events of erectile dysfunction, decreased libido, clinically significant prostate cancer increase of incidence, gynecomastia, and anxiety (11-15). Moreover, in their recent systematic review and metanalysis Kim et al. (16) clearly raised the correlation on 5-ARI administration and possible risk for suicidal attempts and depression, showing also a considerable number of men reporting intolerable adverse effects after initiating finasteride therapy, and continuing to experience these effects after treatment withdrawal (10, 11). These peripheral or secondary effects have undesirable consequences that are collectively becoming known as post-finasteride syndrome (17-19). Considering the social burden of BPH significant symptoms on the worldwide QoL scenario in men, together with the wide prescription/assumption of these medications, more evidence is needed in order to develop better information for both clinicians and patients, which could have benefits regarding shared decision making about 5-ARI use. Aim of our analysis was to critically update current knowledge specifically for the efficacy and safety profile of finasteride 5-ARI monotherapy in men with BPH/LUTS through a critical review of available RCTs which have systematically implemented the use of finasteride as per standard of reference. In particular we analyzed the impact of finasteride monotherapy on urodynamics variables (PV; Qmax), questionnaire score (IPSS) and secondary outcomes (comparison with Placebo). At the same time, we carried out a review of the drug tolerability and sides effects profile.

MATERIALS

AND METHODS

Evidence acquisition We performed a systematic search in PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) up to Dec 2018, without language restriction, to identify clinical trials implementing the use of Finasteride as the only treatment for male with BPH/LUTS and reporting side effects related to drug assumption compared to placebo. The feature of related articles in PubMed was used to identify further papers. The reference lists of the studies included were also screened. Only original articles were included and critically evaluated. We excluded case reports as well as abstracts and reports from meetings. An expert librarian was involved in the design of the search strategy and in the conduct of the

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literature search. Accordingly, we searched publications using the following primary and secondary fields: “benign prostatic hyperplasia” and “low tract urinary symptoms” and “5 alpha-reductase inhibitor” and “finasteride” and “5ARI monotherapy” and “side effects” (primary fields); “PSA reduction” and “placebo controlled” and “randomized clinical trials” (secondary fields). For all studies, we evaluated the level of evidence (LE) according to the European Association of Urology (EAU) guidelines (Table 1) (20). Selection of the studies, criteria of inclusion, analysis of the outcomes Entry into the analysis was restricted to data collected from original studies, including data from BPH symptomatic men trials implementing finasteride as per standard of treatment compared with a placebo arm. Two authors (FDG and GMB) independently screened the titles and abstracts of all articles using predefined inclusion criteria. The full-text articles were examined independently by three authors (AP, FDG, and EDB) to determine whether or not they met the inclusion criteria. Then, two authors (FDG and BIC) extracted data from the selected articles. Final inclusion was determined by consensus of all investigators. Study inclusion criteria were: 1) randomized controlled clinical trials (RCTs) with 5-ARI and placebo administration; 2) daily 5-ARI treatment; 3) disease indication of BPH/LUTS; 4) types of functional outcomes measures including at least one of these: prostate specific antigen (PSA), prostate volume (PV), International Prostate Symptom Score (IPPS), post-void residual urine (PVR), voiding symptoms of IPSS (Voiding IPSS), maximum urinary flow rate (Qmax), and adverse events (AEs). To evaluate the effect of the different continuous variables analyzed, standardized mean difference (SMD) was identified from the studies included as was recently reported by the systematic review and metanalysis of Kim et al. on 5-ARI monotherapy in patients with BPH (21). In their analysis, SMDs were calculated as the difference between the mean change in the treatment and placebo groups divided by the pooled standard deviation (SD).

Table 1. Characteristics of the studies included in the analysis. Author

Publication Year Country

Feneley Isotalo Espana Haggstrom Kirby McConnell Roehrborn Crawford Kaplan

2000 UK, Netherland 2001 Finland 2002 Spain 2002 Sweden 2003 Europe 2003 NA 2004 USA 2006 NA 2006 USA

Kaplan Kaplan

2008 2011

USA USA

Qian

2015

China

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No. of patients Tx Placebo 18 29 30 13 239 89 1524 NA 232 281 252 768 281 295 45

9 19 10 15 253 128 1516 737 250 274 213 737 276 288 42

Mean age (year) Tx. Placebo 67.5 71 66.7 NA 63 62.6 64 61 61.8 65.1 62.6 60.7 63.9 70.1

67.5 71 69.5 NA 64 62.5 63.9 62.5 60.5 62.4 64.8 62.5 60.3 64.1 72.3

Finasteride F/U duration dose (mg) (months) NA 6 5 18 NA 9 5 3 5 13 5 54 5 48 5 54 5 54 5 5

54 54

LE 1b 1b 1b 1b 1b 1b 1b 1b 1b 1b 1b 1b 1b 1b 1b

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To identify the effect of placebo on the continuous outcomes, the ratio of means (ROM), which was a measure of relative change compared with the baseline, was reported as previously calculated by Kim et al. (21). To assess the risk of bias (RoB), all included reports were reviewed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool for diagnostic accuracy studies (22). The two reviewing authors independently assessed the methodological quality based on sequence generation, allocation concealment, blinding of patients and personnel, blinding of outcome assessors, incomplete outcome data, selective outcome reporting, and additional sources of bias.

Figure 1. PRISMA flow diagram.

RESULTS Search results The database searches initially yielded 284 articles (PubMed: 212; Cochrane: 8 and Embase: 64) from the past 20 years until Dec 2018. One-hundred-forty-six were excluded because they contained overlapping data or appeared in more than one database. Of these, 64 were subsequently removed due to duplication. On more detailed review, additional 97 papers were excluded for the following reasons: finasteride with other topics (24), other drugs and/or combination therapy (39), animal experiment (15), and review paper or editorials (19).

Full-text articles were then reevaluated and critically analyzed for the remaining 41 journal references. Of these, 29 did not meet the inclusion criteria. The remaining 12 studies were considered for our critical review (Figure 1 and Table 1). RoB assessment according to QUADAS-2 tool for each of the individual studies is illustrated in Figure 2. Study locations and types Of the 12 studies included in our review, 5 were conducted in Europe, 4 in USA, 1 in China, 1 was globally dis-

Figure 2. PRISMA flow diagram.

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Table 2. Standardized mean difference (SMD) effect for Prostate Volume (PV) change over treatment with finasteride. Author Feneley et al. Isotalo et al. Kaplan et al.

Year 2000 2001 2006

Kaplan et al. Kaplan et al.

2008 2011

Qian et al.

2015

N. Pts. treated Tx Placebo 18 9 29 19 232 250 281 274 252 213 768 737 281 276 295 288 45 42

Measure of effect SMD CI%95 -0.62 -0.80 to -0.44 -0.63 -0.80 to -0.45 -0.61 -0.77 to -0.44 -0.60 -0.75 to -0.46 -0.60 -0.74 to -0.46 -0.63 -0.76 to -0.49 -0.63 -0.75 to -0.51 -0.64 -0.76 to -0.52 -0.63 -0.74 to -0.52

Table 3. Standardized mean difference (SMD) effect for International Prostate Symptom Score (IPSS) change over treatment with finasteride. Author Kirby et al. McConnell et al. Roehrborn et al. Kaplan et al.

Year 2003 2003 2004 2011

N. Pts. treated Tx Placebo 239 253 89 128 1524 1516 281 276 295 288

Measure of effect SMD CI%95 -0.25 -0.33 to -0.18 -0.24 -0.31 to 0.17 -0.21 -0.31 to -0.11 -0.20 -0.29 to -0.11 -0.19 -0.28 to -0.11

Table 4. Standardized mean difference (SMD) effect for Maximum flow (Qmax) change over treatment with finasteride. Author Feneley et al. Isotalo et al. Kirby et al. McConnell et al. Crawford et al. Kaplan et al.

Year 2000 2001 2003 2003 2006 2011

Qian et al.

2015

N. Pts. treated Tx Placebo 18 9 29 19 239 253 89 128 NA 737 281 276 295 288 45 42

Measure of effect SMD CI%95 0.36 0.23 to 0.50 0.36 0.23 to 0.50 0.33 0.23 to 0.42 0.32 0.24 to 0.40 0.32 0.24 to 0.40 0.30 0.22 to 0.38 0.30 0.23 to 0.37 0.29 0.22 to 0.36

played while for one study was not available information regarding location. All of the studies were prospective RCTs placebo-controlled implementing finasteride as reference of standard. Study sample sizes, participant ages, and follow-up The sample sizes of patient actively treated with finasteride varied from 13 to 1524 cases analyzed in a single study. The total sample size of the twelve studies was 8821 patients. The total sample size of each individual treatment was 4096 for finasteride 4725 for placebo. Two studies did not report participantâ&#x20AC;&#x2122;s age. The range of mean age across the remaining ten studies varied from 61 to 71 years for patients undergone

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finasteride monotherapy while varied from 60 to 72 for placebo group. In the studies, the follow-up after treatments ranged from 3 to 54 months. Impact of finasteride monotherapy on Prostate Volume, International Prostate Symptom Score and Maximal Urinary Flow Rate Regarding PV, a total of 6 articles out of the 12 included reported extractable outcomes (23-34). The effect of finasteride in reducing PV compared to placebo after a median follow-up of 36 (range 6-54) months, was overall moderate (SMD effect between 0.5 to 0.8 for all trials evaluable) achieving maximum outcome in the study of Kaplan et al. (27) (-0.64; CI%95: -0.76 to -0.52). Of note, no studies reported failure in significant decrease of PV. Each trial effect for PV reduction resulted similar independently from sample sizes treated demonstrating no significant differences among studies (Feneley et al. (23), n = 18; SMD: -0.62; CI%95: -0.80 to -0.44 Vs. Kaplan et al. (24), n = 768; SMD: -0.63; CI%95: -0.75 to -0.51; p = 0.782) (Table 2). For IPSS, a total of 5 out of 12 studies were critically evaluated (27-31). All the studies reported a significant improvement in the IPSS score domains after a median follow up of 48 (range 6-54) months. The SMD effect of finasteride for IPSS score reduction was significant (SMD in the 0.2 to 0.5 variation range) varying from -0.19 (CI%95: -0.27 to -0.11) in the study of Quian et al. (28) to -0.25 (CI%95: -0.33 to -0.18) in the study of Kirby et al. (29) (Table 3). At the same time effect of finasteride on Qmax resulted in significant improvement after a median follow-up of 18 (range 6 - 54) months. Seven out of 12 studies were considered (23, 24, 27-30, 32). Improvement was considered overall small (SMD in the 0.2 to 0.5 variation range) showing minimal increase in the study of McConnel and Crawford (30, 32) who presented identical SMD of 0.32 (CI%95: 0.24 to 0.40) compared to the study of Feneley and Isotalo (23, 24) where a SMD of 0.36 (CI%95: 0.23 to 0.50) was retrieved (Table 4). Ratio of the means for PV, IPSS and Qmax, as previously calculated by the metanalysis of Kim et al. (21), for the efficacy of the placebo group according to our inclusion criteria were summarized in Table 5.

Table 5. Ratio of the means for PV, IPSS and Qmax for the studies included in the analysis. Author (year) Feneley (2000) Isotalo (2001) Kirby (2003) McConnell (2003) Roehrborn (2004) Crawford (2006) Kaplan (2008) Kaplan (2008)a Kaplan (2008)b Kaplan (2008)c Qian (2015)

No. of samples 9 19

PV 0.82 (0.52, 1.31) 0.91 (0.75, 1.11)

Ratio of mean (95% CI) IPSS

0.69 (0.63, 0.74) 0.76 (0.73, 0.80) 0.97 (0.94, 1.00)

Qmax 1.23 (0.85, 1.77) 1.09 (0.76, 1.56) 1.12 (1.06, 1.18) 1.13 (1.10, 1.16) 1.13 (1.11, 1.16)

249 214 112 161 42

1.34 (1.22, 1.46) 1.12 (1.04, 1.21) 1.20 (1.08, 1.32) 1.21 (1.16, 1.27) 0.60 (0.57, 0.63)

0.36 (0.32, 0.41)

2.79 (2.36, 3.30)

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Table 6. OR of the Adverse events (AEs) among studies enrolled for finasteride treatment compared to placebo. Complication Decreased libido Kirby (2003) Roehrborn (2004) Ejaculatory disorder Kirby (2003) Roehrbn (2004) Impotence Kirby (2003) Roehrborn (2004) Postural hypotension Kirby (2003)

Effect size OR (95% CI)

p-value

1.83 (0.62-5.4) 1.97 (1.39-2.79)

0.271 < 0.001

1.53 (0.44-5.35) 2.81 (1.62-4.87) 1.68 (1.3-2.17) 1.47 (0.64-3.38) 1.83 (1.42-2.36) 1.18 (0.27-5.12) 0.51 (0.09-2.76)

0.507 < 0.001 < 0.001 0.363 < 0.001 0.821 0.434

Analysis of significant adverse events rate for finasteride monotherapy vs. placebo Among the twelve articles included in the analysis only the experience of Kirby et al. and Roehrborn et al. (29, 31), clearly identified relationships between finasteride vs. placebo in adverse events rate. Table 6 illustrates estimated OR (CI%95) previously identified by Kim et al. (23) for AEs retrieved in these studies included in our critical review. Interestingly in their large experience Roehrborn et al. (31) are the only that demonstrated a significant correlation between finasteride assumption and increased risk of developing sexual health dysfunctions: impotence (1.83; CI%98: 1.42-2.36; p < 0.001), decreased libido (1.97; CI%95: 1.39-2.79; p < 0.001); ejaculatory disorder (2.81; CI%95: 1.62-4.87; p < 0.001) and gynecomastia (3.11; CI%95: 1.78-5.45; p < 0.001), when compared to placebo group. Of note, none of the previous AEs was statistically found to be related in the analysis of Kirby et al. (29) (Table 6). Even a comparison with other 5-ARIs (dutasteride) demonstrated an inferior effect on male sexuality (35). Relevantly, none of the studies included in the present analysis found or demonstrated any significant correlation between implementation of finasteride and development of anxiety and minor/major depression syndrome.

DISCUSSION

Androgens release and modulation profoundly regulate homeostasis of both prostate growth and differentiation, as well as sexual function and are associated with general men health, including bone metabolism regulation and cardiovascular health (36). Therefore, even if guidelines on BPH suggest the administration of 5-ARI in patients with symptomatic LUTS and/or prostate size greater than 30 ml, serious implications may derive from prescription of both dutasteride and finasteride. In this field, the overall long-term adherence to the prescribed regimen (alpha blockers or 5-ARI or combination) has been demonstrated to be generally low, but it is even more limited in patients under 5-ARI, probably due to the incidence of AEs (37). Significant higher events of heart failure compared to placebo group have been indeed described in the study of Andriole et al in 2010 looking at correlation

between 5-ARI and risk of prostate cancer development (38). Moreover, many observational studies and the recently published metanalysis by Kim et al. have shown increased incidence of possible risk for suicidal attempts and minor/major depression events (16, 39). On the other hand, the indication of treatment with 5ARI seems clear and confirmed from many available trials and review analysis. Goals of finasteride treatment are represented by preventing over the years the exacerbation of BPH and urinary retention and therefore its routinely use demonstrated to be a reliable tool able to impact clinical urinary outcomes and at the same time to improve perioperative results of patients candidate for endourological procedures such as TURP/simple prostatectomy and others. In 2015 Busetto GM et al. (40) in their observational study demonstrated how preoperative (TURP) 5ARI treatment could have improved estimated blood loss and histopathological findings of prostate vascularity by impacting on vascular endothelial growth factor (VEGF) immunoreactivity and micro-vessel density (MVD) modulation specifically in large prostates (> 50 ml). From all these observations, necessity arises to periodically update data regarding the worldwide impact of these medications and the real clinical benefit for men suffering from BPH. Moreover, new formulations of finasteride drug have been yearly introduced in the pharmacy market in the last few years demonstrating the continuous interest in the field of BPH medical therapy. We on purpose decided to restrict the field of research of the present review on a smaller window (20 years) when compared to previously published reviews articles in order to photograph the current changes in literature. Finasteride is indeed for sure the 5-ARI medication which has been more prescribed and on which are present most of the available trials in literature antecedent to year 2000. The first two RCT using finasteride noteworthy are dated 1992 when Beisland et al. (41) and Gormley et al. (42) respectively published their analysis on European Urology and New England Journal of Medicine, demonstrating, especially the last one, a significant effect despite the short term follow-up on voiding IPSS scores (OR: 0.88; CI%95: 0.80 to 0.97). Therefore, our review has been based on the results recently provided by the metanalysis published by Kim et al. (21), but with different criteria of inclusion and a shorter time frame of literature review focusing only on finasteride monotherapy. The level of evidence raised by the 12 included RCT articles was overall good (LE: â&#x2030;Ľ 2a) with homogeneous distribution in terms of sample size, balanced treatment groups and placebo arms and both urinary and AEs outcomes investigated. Finasteride monotherapy demonstrated to be able to positively and significantly impact all the urinary variables (PV, IPSS, Qmax) in all the studies included, showing a SMD effect ranging between small to moderate effect on the analyzed variable. Severe AEs were not reported, and the main issue was again the impact of the drug on sexual health life. Only Roehrborn et al. RCT (31) reported an association between finasteride and sexuality (31). Finasteride sexual side effects profile is better when compared with dutasteride (35). Even if our results did not identify any correlation among the studies included and Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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the risk of psychiatric AEs, the metanalysis of Kim et al. (16) published in 2019, investigating the risk of depression with 5-ARI, showed a not high risk but however a relevant distribution of these events which for their clinical importance needs validation by further studies.

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Correspondence Gian Maria Busetto, MD, PhD (Corresponding Author) gianmaria.busetto@uniroma1.it Del Giudice Francesco, MD Maggi Martina, MD Sciarra Alessandro, MD De Berardinis Ettore, MD Department of Maternal-Child and Urological Sciences, Sapienza Rome University, Policlinico Umberto I Hospital Viale del Policlinico 155, 00161, Rome (Italy) D’Agostino Daniele, MD Romagnoli Daniele, MD Porreca Angelo, MD Department of Urology, Policlinico Abano Terme, Abano Terme (PD) (Italy) Minervini Andrea, MD Department of Urology, University of Florence, Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence (Italy) Rocco Bernardo, MD Department of Urology, University of Modena and Reggio Emilia, Modena (Italy) Antonelli Alessandro, MD Department of Urology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), Verona (Italy) Celia Antonio, MD Department of Urology, San Bassiano Hospital, Bassano Del Grappa (Italy) Schiavina Riccardo, MD Department of Urology, University of Bologna, Bologna, Italy Cindolo Luca, MD Department of Urology, Villa Stuart Hospital, Rome (Italy) Chung Benjamin I, MD Department of Urology, Stanford Medical Center, Palo Alto, CA (USA) Kim Jae Heon, MD Department of Urology, Soonchunhyang University Seoul Hospital, Soon Chun Hyang University College of Medicine, Seoul (Korea)

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DOI: 10.4081/aiua.2019.4.212

ORIGINAL PAPER

MRI/TRUS FUSION guided biopsy as first approach in ambulatory setting: Feasibility and performance of a new fusion device Daniele Dâ&#x20AC;&#x2122;Agostino 1, Federico Mineo Bianchi 2, Daniele Romagnoli 1, Marco Giampaoli 1, Paolo Corsi 1, Alessandro Del Rosso 1, Riccardo Schiavina 2, Eugenio Brunocilla 2, Angelo Porreca 1 1 Department 2 Department

of Robotic Urological Surgery, Abano Terme Hospital, Abano Terme, Italy; of Urology, University of Bologna, Bologna, Italy.

Summary

Purpose: To evaluate the detection rate of Magnetic Resonance Imaging/Transrectal Ultrasound (MRI/TRUS) Fusion Biopsy performed in a series of patients with suspicious prostate cancer in an ambulatory setting. Materials and methods: Between March 2018 and January 2019 a series of 155 patients undergoing MRI/TRUS fusionguided biopsy were prospectively enrolled. All patients presented a suspected diagnosis for prostate cancer because of raised Prostate Specific Antigen (PSA) serum level and/or abnormal physical examination (digital rectal examination), and showed at least one suspicious area at the multiparametric Magnetic Resonance Imaging (mpMRI). Results: Of 155 patients, 58 (37.4%) were biopsy-naĂŻve, 97 (62.6%) had at least 1 previous negative TRUS-guided biopsy. The median age of the patient cohort was 66 years (IQR, 6169); the median prebiopsy PSA value was 7.1 ng/ml (IQR, 58.9). Overall, the Fusion-TB findings were positive in 94 of 155 patients with a detection rate (DR) of 60%; a significantly high DR was obtained in terms of clinically significant prostate cancer (csPCa) by Fusion-TB (61 pts; 41.9%). The overall DR in the 121 biopsy-naive patients was 60.6%. In the subgroup of the 34 patients with at least 1 previous set of TRUS-GB, overall DR was 39.3% (35/50). Conclusions: The targeted MRI/TRUS fusion-guided biopsy represents a safe and accurate approach for diagnosis of csPCa, especially in patient with previous TRUS guided biopsy negative and suspicious prostate cancer.

KEY WORDS: Prostate cancer; Magnetic Resonance; Prostate biopsy. Submitted 8 July 2019; Accepted 2 August 2019

INTRODUCTION

Prostate cancer (PCA) is the most frequent among solid tumors in the male sex, as emerges from the 2016 estimate of the American Cancer Society (1). Currently, diagnosis of PCA is one of the most debated topics in the urology literature (2) and is based on the serum dosage of prostate specific antigen (PSA) and digital rectal exploration. PSA levels can be elevated not only in the case of prostatic carcinoma but also in the case of other pathologies, such as benign prostatic hyperplasia and inflammatory states of different nature (3) with consequent risk of over-diagnosis and over-treatment. Although the intro-

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duction of PSA has radically changed the diagnosis of PCA, as amply highlighted by the literature, it is a test that has limits in terms of sensitivity and specificity; for example about 15% of men with PSA levels equal to or below 4.0 ng/ml are affected by prostatic carcinoma that in about 15% of cases is of high-grade (4). To date, the conventional diagnosis of prostatic carcinoma is performed by identifying histopathology on systematic ultrasound-guided biopsy specimens with a sensitivity of 45-70% for clinically significant PCA (5). The main disadvantages related to this method are the loss of identification of a substantial portion of patients with significant prostatic carcinoma (about 20%) linked to sampling errors, in particular at the level of the anterior prostate area (6) and the possibility of important complications following the procedure, above all related to sampling performed by trans-rectal ultrasound-guided biopsy (7). The actually limited detection rate represents an important concern and the management of patients with persistent suspected diagnosis of PCA and previous set of negative biopsies represents a continuing challenge. Magnetic Resonance Imaging (MRI) has shown a high sensitivity and specificity in diagnosing clinically significant PCA (csPCa) (5, 6) and, exploiting the use of functional studies, multiparametric MRI (mpMRI) improves the identification of PCA lesion within the gland (7, 8). A growing body of evidence suggests that mpMRI, improving the risk classification of lesions, could reduce false-negative rates and the necessity of repeat biopsies in presence of suspected PCA (8, 9); not surprisingly, a MRI targeted biopsy should be strongly applied for any patient with a prior negative set of prostate biopsy who has persistent clinical suspected diagnosis for PCA as reported by recent AUA Consensus Statement (9); more frequently MRI is used in the first diagnostic phase for PCA; for this reason the MRI-guided approach of prostatic biopsy is increasingly used. Approaches for targeted biopsy include visual estimation TRUS-GB (cognitive technique), software co-registered MRI-ultrasound fusion (fusion technique) and in-bore MRI-guided biopsy (MRI-GB). Studies from literature suggest that there was no significant advantage of MRI-GB compared with fusion technique concerning overall No conflict of interest declared.

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detection rate and clinical significant neoplasm detection rate (10) even if the main potential limitation of MRI-GB consist of impossibility to perform a simultaneous standard TRUS biopsy, especially in biopsy naive patients, since up to 16% of men with no suspicious mpMRI could reveal csCaP on systematic biopsy (11). Different software for MRI/TRUS fusion-guided biopsy systems are at the present time used: the aim of this study was to evaluate the detection rate of MRI TRUS Fusion Biopsy performed in a series of patients with suspicious PCA in ambulatory setting with a new fusion device.

MATERIALS

AND METHODS

Patients cohort and methodology Between March 2018 and January 2019 a series of 155 patients undergoing MRI/TRUS fusion-guided biopsy were prospectively enrolled. All patients had a suspected diagnosis for PCA because of elevated value of Prostate Specific Antigen (PSA) serum level and/or abnormal physical examination (digital rectal examination), and showed at least one suspicious area at the mpMRI. According to the European Society of Urogenital Radiology (ESUR) guidelines, the presence of csPCa at mpMRI was defined equivocal, likely or highly likely basing on the PIRADS-v2 (Prostate Imaging Reporting and Data Systemversion 2) score of 3/5, 4/5 or 5/5, respectively; the localization of index lesion are reported in Table 2 (12). This study was conducted under the approval of local Institutional Review Board and in the accordance with good clinical practice guidelines and the ethical principles of the Declaration of Helsinki. Primary endpoints of this study were overall detection rates of PCA (PCA DR), csPCa Detection Rate (csPCa DR). Secondary endpoints were correlations between mpMRI parameters biopsy results, comparison to definitive pathologic results of surgical specimens (when available) and complications rates. Multiparametric Magnetic Resonance Imaging and analysis MRI examination and analysis. All the MRI examinations were performed with a 32 channels 1.5 T whole body scanner (Achieva XR; Philips Medical Systems, Best, Netherlands) with a 32-channels phased-array surface coil without endorectal coil. After local three-plane acquisition, required for the correct positioning of the sequences, the morphological and functional studies were carried out. Morphological study of the prostate gland were obtained with Turbo Spin Echo (TSE) T2weighted sequences (TE 100 msec, TR 4074 msec, Slice Thickness 3 mm, Slice Spacing 0.3 mm, Field of View FOV 180 x 180 mm and matrix size 276 x 205) in the sagittal, axial and coronal planes, including seminal vesicles and the entire prostate gland. For the functional study, DWI, DCE-MRI and MRS acquisition were performed. The DWI acquisition was carried out in the axial plane, using a single-shot echo-planar imaging (SSEPI) sequence, with three b-values (0, 600 and 1500 s/mm2), slice thickness of 3 mm, FOV 180 x 180 mm and matrix size 80 x 71. The DCE-MRI was obtained using three-

dimensional (3D) T1W High Resolution Isotropic Volume Examination (THRIVE) sequence during the intravenous injection of a contrast bolus of 0.1 mmol per kilogram of body weight of Meglumine gadobenate (Multihance, Bracco Diagnostics, Milan, Italy), at flow rate of 3.5 ml/sec followed by 15 ml of saline solution. Conduct of the biopsy The biopsies were performed within three weeks from the first diagnostic mpMRI study by a single urologist with a consolidated experience in MRI Fusion-GB. All patients received oral antibiotic prophylaxis with quinolones (Ciprofloxacin 500 mg) twice a day, started the day before the procedure and prolonged for at least 2 days thereafter. Prostate biopsy procedures were conducted in an ambulatory setting with patient in lithotomic position. Peri-prostatic nerve blockade local anesthesia with lidocaine 2% was administered immediately before biopsy to each patient. Biopsies were conducted using a disposable biopsy gun with a 18-gauge needle and an Ultrasound Platform (BK ultrasound 5000) with a biplanar probe. Using the BK Ultrasound 5000 MRI-TRUS Fusion platform, Fusion-TB was performed on the previously identified suspicious area at the mpMRI using a real time alignment of the T2-weighted sequence to the TRUS image. MRI-TRUS images alignment was possible due to a tracking device consisted in a sensor coil on the TRUS probe paired with a magnetic field generator in order to register the location of the tracking device in the 3D space. At least 3 cores were taken for each lesion and the number of additional cores were based on the diameter of the lesion. The number of cores taken was related to the size of the lesions; the cores were carried out along the long axis of the lesion with a maximum of two biopsies taken for each needle. TRUS Standard Biopsy was a typical 12 cores double sextant template from lateral to medial of base, mid and apex. Only the TRUS images, with no mp-MRI target data available, were used for the standard biopsy portion of the case. After the procedure, patients were observed for 1 hour and were re-evaluated by outpatient visit after 7-10 days in order to record any potential complication. Statistical analysis Continuous variables were reported as medians with interquartile ranges (IQR) whereas categorical variables were described as frequencies with percentages. The Mann-Whitney and Pearson Chi-square test were used to compare medians and frequencies among patients with positive and negative biopsies, respectively. Uni- and multivariate logistic regression models with enter method were used to identify which covariates could predict PCA, csPCa and concordance between mpMRI index lesion and bioptic index lesion. An alpha value of 5% was set to be the threshold to determine statistical significance. Statistical analyses were conducted using SPSS® v21 (IBM Corp, Armonk, NY) for Macintosh®.

RESULTS

The clinical, radiologic, and pathologic characteristics of the entire population are listed in Table 1. Of 155 patients, 58 (37.4%) were biopsy-naïve, 97 (62.6%) had Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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at least 1 previous negative set of random TRUS-GB. The median age of the patient population was 66 years (IQR, 61-69) and median prebiopsy PSA level was 7.1 ng/ml (IQR, 5-8.9). The median number of targeted biopsies per patient was 4 (IQR, 3-4), and, accordingly, the median total number of biopsies including the standard 12-cores was 14 (IQR,12-15). At the prebiopsy mpMRI study, a total of 155 suspected lesions were identified and were scheduled for Fusion-TB. The median diameter of the index lesion was 13 mm (IQR, 9-18.1 mm). The univariate logistic regression model showed a crucial role of V2PIRADS score of index lesion in the prediction of PCA and csPCA (Tables 3, 4). Overall, the FUSION-TB findings were positive in 94 of 155 patients with a DR of 60%; a significantly high DR was obtained in terms of clinically significant PCA (csPCa) of Fusion-TB (61 pts; 41.9%). The overall DR in the 121 biopsy-naive patients was 60.6%. In the subgroup of the 34 patients with at least 1 Table 1. Design of studies of Serenoa repens for BPH treatment. Overall population Biopsy+patients Biopsy-patients p-value (n = 155) (n = 94) (n = 61) Age Median 66 IQR 61-69 PSA (ng/ml) Median 7.1 IQR 5-8.9 PSA density (ng/ml/cm3) Median 0.12 IQR 0.09-0.16 Prostate Volume (cm3) Median 55 IQR 43-75 Previous TRUS-GB (%) No 121 (78.1) Yes 34 (21.9) Index lesion diameter (mm) Median 13 IQR 9-18.1 Index lesion location (%) Anterior 44 (28.4) Posterior 111 (71.6) Index lesion site (%) Peripheral 107 (69) Central 48 (31) Index lesion PIRADS V2 score (%) 3 72 (46.5) 4 53 (34.2) 5 30 (19.4) Total cores taken per patient Median 14 IQR 12-15 Target biopsy cores taken per patient Median 4 IQR 3-4 ISUP grade group (%) Negative 61 (39.4) 1 29 (18.7) 2 26 (16.8) 3 28 (18.1) 4 11 (7.1) 5 0 (0)

66 61-70

65 61-69

0.5

7.2 5.4-9.3

7 4.6-8.8

0.9

0.13 0.1-0.17

0.11 0.08-0.13

0.03

50 40-60

58 46-80

0.2

57 (60.6) 37 (39.3)

40 (65.6) 21 (34.4)

0.6

11 8-16

13 9-16.5

0.9

27 (28.7) 67 (71.3)

17 (27.9) 44 (72.1)

0.7

65 (69.1) 29 (28.7)

42 (68.9) 19 (31.1)

0.1

29 (38.5) 41 (38.5) 24 (23.1)

43 (70.5) 12 (19.7) 6 (9.8)

< 0.001

14 12-15

13 12-15

0.96

4 3-5

4 3-4

0.9

0 (0) 29 (18.7) 26 (16.8) 28 (18.1) 11 (7.1) 0 (0)

61 (100) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

DRE: digito-rectal examination; IQR: interquartile range; PSA: prostate specific antigen; TRUS-GB: trans-rectal ultrasound-guided biopsy; MRI-GB: magnetic resonance imaging-guided biopsy.

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Table 2. Localization of Index lesion at mpMRI and bioptic results stratified according to previous biopsy status and bioptic findings. Biopsy+patients (n = 94) Biopsy näive patients (n = 97) Index Lesion Location (%) Anterior 15 (26.3) Posterior 42 (73.7) Index lesion site (%) Central 17 (29.8) Peripheral 40 (70.2) Previous negative biopsies (n = 58) Index Lesion Location (%) Anterior 12 (32.4) Posterior 25 (67.6) Index lesion site (%) Central 12 (32.4) Peripheral 25 (67.6)

Biopsy-patients (n = 61)

p-value

13 (32.5) 27 (67.5)

0.7

15 (37.5) 32 (62.5)

0.3

4 (19) 17 (81)

0.4

4 (19) 17 (81)

0.4

Table 3. Uni-variate logistic regression model predicting PCa (n = 94) at Fusion biopsy.

Age (yrs) PSA (ng/ml) PSA density (ng/ml/cm3) < 0.15 0.15 Previous TRUS-GB No Yes Index Lesion Site Peripheral Central Lesion Location Posterior Anterior Index lesion PiRADS V2 score 3 4 5 Index lesion diameter (mm) N of cores taken N of target cores taken

Univariate analysis HR (95% CI) 1.01 (0.97 -1.07) 1.08 (0.97-1.19)

p-value 0.5 0.2

Ref. 0.94 (0.47-1.87)

0.9

Ref. 1.24 (0.63-2.42)

0.5

Ref. 0.99 (0.49-1.98)

0.97

Ref. 0.98 (0.47-1.96)

0.9

Ref. 5.07 (2.28-11.24) 5.93 (2.16-16.3) 1.01 (0.96-1.07) 1 (0.86-1.16) 1.07 (0.72-1.58)

< 0.001 0.001 0.7 0.99 0.8

PCa: Prostate Cancer; HR: hazard ratio; CI: confidence interval; PSA: prostate specific antigen; TRUS-GB: trans-rectal ultrasound-guided biopsy.

previous set of TRUS-GB, overall DR was 39.3% (35/50). In the series of biopsy naïve patients whose clinically significant PCA (csPCa) was found, the location of index lesion was anterior in 26.3% (15/57 cases) while we observed a posterior lesion in 73.7% (42/57 cases). In patients with previous negative TRUS-GB whose csPCa was diagnosed the location of index lesion was anterior in 32.4% (12/37 cases) and posterior in 67.5% (25/37 cases). Overall, in the patients with a PI-RADS-v2 score of 3 of 5, 4 of 5, and 5 of 5, DR for PCAa were 40.2% (29/72), 77.0% (41/53) and 80.0% (24/30), respectively (p < 0.001). In Table 5 are reported univariate logistic regres-

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Table 4. Univariate logistic regression model predicting csPCa (n = 54) at fusion biopsy.

Age (yrs) PSA (ng/ml) PSA density (ng/ml/cm3) < 0.15 ≥ 0.15 Previous TRUS-GB No Yes Index Lesion Site Peripheral Central Index lesion PiRADS V2 score 3 4 5 Index lesion diameter (mm) N of cores taken N of target cores taken

Univariate analysis HR (95% CI) 1.02 (0.97-1.07) 1.03 (0.96-1.1)

p-value 0.2 0.4

Ref. 1.08 (0.55-2.12)

0.8

Ref. 1.57 (0.82-3.02)

0.2

Ref. 0.67 (0.33-1.33)

0.3

Ref. 3.42 (1.63-7.22) 4.86 (1.95-12.11) 1.01 (0.96-1.07) 1.03 (0.89-1.19) 1.09 (0.74-1.6)

0.001 0.001 0.6 0.7 0.7

csPCa: Clinically significant Prostate Cancer; DRE: Digito-rectal examination; HR: Hazard ratio; CI: Confidence interval; PSA: Prostate specific antigen; TRUS-GB: Trans-rectal ultrasound-guided biopsy.

Table 5. Univariate logistic regression model predicting concordance between Index lesion at mpMRI and highest cGS in the bioptic cores. Univariate analysis HR (95% CI) p-value 1.03 (0.96-1.1) 0.5 1.05 (0.92-1.2) 0.4

Age (yrs) PSA (ng/ml) PSA density (ng/ml/cm3) < 0.15 Ref. 0.15 1.45 (0.51-4.15) Previous TRUS-GB No Ref Yes 2.2 (0.77-6.23) Index lesion site Peripheral Ref. Central 0.29 (0.11-0.77) Index lesion location Posterior Ref. Anterior 0.84 (0.29-2.43) Index lesion PiRADS V2 score 3 Ref. 4 0.74 (0.26-2.08) 5 8.76 (1.01-76.08) Index lesion diameter (mm) 1.02 (0.95-1.1) N of cores taken 1.07 (0.87-1.31) N of target cores taken 0.89 (0.49-1.64)

Multivariate analysis HR (95% CI) p-value -

0.5

0.1

0.01

Ref. 0.3 (0.1-0.82)

0.02

0.8

0.6 0.05 0.6 0.5 0.7

Ref. 0.75 (0.25-2.2) 0.6 8.83 (0.99-78.93) 0.05 -

mpMRI: Multi-parametric magnetic resonance imaging; cGS: Clinical Gleason Score; HR: Hazard ratio; CI: Confidence interval; PSA: Prostate specific antigen; TRUS-GB: Trans-rectal ultrasound-guided biopsy.

sion model predicting concordance between Index lesion at mpMRI and highest Gleason score in the bioptic cores.

DISCUSSION

Several major changes have taken place in the last decade regarding the diagnosis of PCA; the introduction of new

imaging techniques (traditional radiology, nuclear medicine, etc.) is radically changing the approach to the patient with PCA (13-17). In particular the most important innovation was represented by the introduction of multiparametric magnetic resonance imaging (mpMRI) in the diagnosis and management of PCA (active surveillance, surgery, radiotherapy, etc.) (18, 19). In fact, this examination showed an elevate detection and localization rate of csPCa thus making it possible to perform selected targeted biopsies instead of systematic ultrasound guided biopsies. In any case, TRUS-GB represents the “gold-standard” technique of histological diagnosis of PCA although MRI-targeted biopsies (cognitive, fusion and “in bore” technique) significantly increased the detection of high risk PCA while decreasing the detection of low risk PCA compared with standard biopsy; moreover a lower number of cores could be required in men with suspicious MRI findings reducing also potential complications related to the procedure and all the consequence on quality of life (20-22). In our experience we have analyzed the impact of one of the targeted biopsy techniques, the MRI-US “fusion” prostate biopsy, in the diagnosis of clinically significant PCA; in particular the MRI-US “fusion” biopsy is simply described as a way to align a pre-registered MRI to an intra-procedure US in order to identify and target suspected lesions within the gland through a dedicated hardware platforms targeting areas found during mpMRI and not clearly visible during US scan. Based on our experience we can affirm that this technique had high sensitivity, accuracy and specificity than TRUS-GB and no significant difference for treatment zone between combined biopsies and targeted. The advantages are the high reproducibility and the real time feedback though counterbalanced by the high upfront cost of the device; another advantage of the fusion technique is the ability to perform a systematic biopsy during the same session. In our series of patients the MRI-US fusion biopsy showed an elevate accuracy for diagnosis of csPCa; in particular the overall DR of csPCa was 69.1% (65/94 cases); in particular we observed a statistically significant correlation between the PiRads V2 score and the presence of csPCa (p < 0.001). These results were in line with available studies in literature (23). Evaluating the detection rate of different techniques of targeted biopsy, Arsov et al. (24) compared the DR between an “in-bore” approach and a fusion approach: in particular they not observed important improvement in DR by fusion approach. In our previous experience we evaluated the role of “in-bore” MRI guided biopsy in a series of 70 patients (25); we observed an overall DR of 45.7% and in particular > 75% in csPCa. Examining this series we observed an important correlation between the location of index lesion and the finding of PCA in the sample of biopsy. Venderlink et al. highlighted that there are no significant differences between magnetic resonance and fusion-guided biopsy; the only differences were related with an increasing lesion size (26). Considering the overall DR, in a NIH study of men with previous negative biopsy, a global DR of 37.4% using MRI fision biopsy was reported by Vourganti et al. (27). Other studies highlighted as performing 12 cores Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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random biopsies the DR for csPCa is increasing respect to MRI fusion biopsy (28-30); in particular Radtke et al. reported that systematic transperineal prostate biopsy was more likely to miss Gleason > 7 PCA compared with MRI targeted biopsy (20.9% vs 12.8%) (30). This dates are apparently in contrast with the results of our study; in fact the elevate DR for clinically significant disease depends on the fact that in addition to perform a standard 12-core biopsy we have added cores in areas normally not considered (lesions of the anterior and transitional); these data support the thesis about the essential role of mpMRI and MRI guided biopsy of suspicious lesions in the algorithm for evaluating men with previous negative TRUS-GB but with ongoing suspicion for PCA. Our study has some limitations: the number of patients, exclusive inclusion of patients with positive findings at mpMRI, no follow-up data and the lack of control group.

CONCLUSIONS

In conclusion, the results from our present study confirm that the mpMRI and MRI fusion guided biopsy have the purpose to improve detection of clinically significant PCA. In particular the targeted MRI/TRUS fusion-guided biopsy represent a safe and accurate approach for diagnosis of csPCa, especially in patient with previous TRUS guided biopsy negative and suspicious PCA. Given that the experience of radiologist for mpMRI and of urologist for MRI/TRUS fusion-guided biopsy are critical, further studies are necessary to confirm these promising results.

REFERENCES

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resonance imaging and magnetic resonance imaging targeted biopsy in patients with a prior negative biopsy: a consensus statement by AUA and SAR. J Urol. 2016; 196:1613-8. 10. Wegelin O, van Melick HH, Hooft L, et al. Comparing three different techniques for magnetic resonance imaging-targeted prostate biopsies: a systematic review of in-bore versus magnetic resonance imaging-transrectal ultrasound fusion versus cognitive registration—is there a preferred technique. Eur Urol. 2017; 71:517-531 11. Filson CP, Natarajan S, Margolis DJ, et al. PCA detection with magnetic resonance-ultrasound fusion biopsy: the role of systematic and targeted biopsies. Cancer. 2016; 122:884-92. 12. Weinreb JC, Barentsz JO, Choyke PL, et al. PI-RADS prostate imaging— reporting and data system: 2015, version 2. Eur Urol. 2016; 69:16-40. 13. Schiavina R, Bianchi L, Borghesi M, et al. MRI displays the prostatic cancer anatomy and improves the bundles management before robot-assisted radical prostatectomy. J Endourol. 2018; 32:315321. 14. Vagnoni V, Bianchi L, Borghesi M, et al. Adverse features and competing risk mortality in patients with high-risk PCA. Clin Genitourin Cancer. 2017; 15:e239-e248. 15. Schiavina R, Chessa F, Borghesi M, et al. State-of-the-art imaging techniques in the management of preoperative staging and restaging of PCA. Int J Urol. 2019; 26:18-30. 16. Vagnoni V, Brunocilla E, Bianchi L, et al. State of the art of PET/CT with 11-choline and 18F-fluorocholine in the diagnosis and follow-up of localized and locally advanced PCA. Arch Esp Urol. 2015; 68:354-70 17. Schiavina R, Bianchi L, Mineo Bianchi F, et al. Preoperative staging with 11C-Choline PET/CT is adequately accurate in patients with very high-risk PCA. Clin Genitourin Cancer. 2018;16:305312. 18. Grasso AA, Cozzi G, DE Lorenzis E, et al. Multicenter analysis of pathological outcomes of patients eligible for active surveillance according to PRIAS criteria. Minerva Urol Nefrol. 2016; 68:237-41. 19. Schiavina R, Borghesi M, Brunocilla E, et al. The biopsy Gleason score 3+4 in a single core does not necessarily reflect an unfavourable pathological disease after radical prostatectomy in comparison with biopsy Gleason score 3+3: looking for larger selection criteria for active surveillance candidates. PCA Prostatic Dis. 2015; 18:270-5. 20. Porreca A, Noale M, Artibani W, et al. Pros-IT CNR study group. Disease-specific and general health-related quality of life in newly diagnosed PCA patients: the Pros-IT CNR study. Health Qual Life Outcomes. 2018; 16:122. 21. Gacci M, Noale M, Artibani W, et al. Pros-IT CNR study group. Quality of Life After PCA Diagnosis: Data from the Pros-IT CNR. Eur Urol Focus. 2017; 3:321-324. 22. Noale M, Maggi S, Artibani W, et al. Pros-IT CNR study group. Pros-IT CNR: an Italian PCA monitoring project. Aging Clin Exp Res. 2017; 29:165-172. 23. Pinto PA, Ching PH, Rastinehad AR, et al. Magnetic resonance imaging /ultrasound fusion guided prostate biopsy improves cancer detection following transrectal ultrasound biopsy and correlates with multiparametric magnetic resonance imaging. J Urol. 2011; 186: 1281-5. 24. Arsov C, Rabenalt R, Blondin D, et al. Prospective randomized trial comparing magnetic resonance imaging (MRI)-guided in bore biopsy to MRI-ultrasound fusion and transrectal ultrasound guided

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prostate biopsy in patients with prior negative biopsies. Eur Urol. 2015; 68:713-20. 25. Schiavina R, Vagnoni V, D'Agostino D, et al. "In-bore" MRIguided prostate biopsy using an endorectal nonmagnetic device: a prospective study of 70 consecutive patients. Clin Genitourin Cancer. 2017; 15:417-427. 26. Venderlink W, Van der Leest M, Van Luijtelaar A, et al. Retrospective comparison of direct in-bore magnetic resonance imaging (MRI)-guided biopsy and fusion guided biopsy in patients with MRI lesions which are likely or highly likely to be clinically significant PCA. Word J Urol. 2017; 35:1849-1855. 27. Vourganti S, Rastinehad A, Yerram NK, et al. Multiparametric

magnetic resonance imaging and ultrasound fusion biopsy detect PCA in patients with prior negative transrectal ultrasound biopsies. J Urol. 2012; 188: 2152-7. 28. Delongchamps NB, Peyromaure M, Schull A, et al. Prebiopsy magnetic resonance imaging and PCA detection: comparison of random and targeted biopsies. J Urol. 2013; 189: 493-930 29. Kuru TH, Saeb-Parsy K, Cantiani A, et al. Evolution of repeat prostate biopsy strategies incorporating transperineal and MRITRUS fusion techniques. World J Urol. 2014; 32: 945-5031. 30. Radtke JP, Kuru TH, Boxler S, et al. Comparative analysis of transperineal template-saturation prostate biopsy versus MRI-targeted biopsy with MRI-US fusion-guidance. J Urol. 2015; 193:87-94.

Correspondence Daniele Dâ&#x20AC;&#x2122;Agostino, MD (Corresponding Author) dott.dagostino@gmail.com Daniele Romagnoli, MD Marco Giampaoli, MD Paolo Corsi, MD Alessandro Del Rosso, MD Angelo Porreca, MD Department of Robotic Urological Surgery, Abano Terme Hospital Piazza Cristoforo Colombo 1, 35031 Abano Terme (PD) (Italy) Federico Mineo Bianchi, MD Riccardo Schiavina, MD Eugenio Brunocilla, MD Department of Urology, University of Bologna, Bologna (Italy)

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DOI: 10.4081/aiua.2019.4.218

ORIGINAL PAPER

Lesion location agreement between prostatic multiparametric magnetic resonance, cognitive fusion biopsy and radical prostatectomy piece Mario Lourenรงo 1, Pedro Pissarra 2, Duarte Vieira e Brito 1, Miguel Eliseu 3, Joao Pedro Peralta 1, Arnaldo Figueiredo 3, Cristina Marques 2 1 Urology

Department Portuguese Institute of Oncology Coimbra, Coimbra, Portugal; Department Coimbra Hospital University Centre, Coimbra, Portugal; 3 Urology and Kidney Transplant Department Coimbra Hospital University Centre, Coimbra, Portugal. 2 Radiology

Summary

Introduction: Prostatic multiparametric magnetic resonance (mpMRI) allows for guided prostate biopsy (PB). Objective: To evaluate localization agreement between mpMRI lesions and histology obtained by cognitive PB and radical prostatectomy (RP) surgical specimen (SS). Methods: Out of 115 consecutive cognitive biopsied patients, 37 with positive PB were studied. Sample was characterized regarding age, prostatic volume, PI-RADS, location of lesion on mpMRI, lesion dimension, total number of fragments obtain by PB, number of fragments directed to the lesion, number of fragments with prostatic adenocarcinoma (PCa) and ISUP classification. The relationship between mpMRI and SS piece was analysed in 15 patients who underwent RP. Results: Regarding agreement between mpMRI and PB, agreement of location was observed in 26 (70.3%); 7 (18.9%) presented PCa positive fragments in the suspected zone plus others in the same lobe; 3 (8.1%) in the suspected zone plus the contralateral lobe and 1 (2.7%) had no PCa in the suspected zone but had bilateral PCa. The total number of fragments with PCa was lower in cases with agreement between mpMRI and PB (p < 0.05). Regarding agreement between mpMRI and SS, 5 cases (33.3%) presented the same location as described by mpMRI, 5 (33.3%) showed ipsilateral lesions in other zones of the prostate; 4 (26.7%) presented extensive bilateral lesions on all prostate zones and 1 (6.7%) showed previously unknown contralateral lesions. None of the factors studied related mpMRI and RP (p > 0.05). Conclusions: Localization agreement of mpMRI vs PB and mpMRI vs SS was present in 26/37 (70.3%) and 5/15 (33.3%), respectively. That suggests the existence of other lesions (multifocality) not identified on mpMRI.

KEY WORDS: Prostate biopsy; Cognitive prostate biopsy; Multiparametric magnetic resonance imaging; Prostate cancer; Localization agreement; Multifocality. Submitted 4 June 2019; Accepted 6 August 2019

INTRODUCTION

The incidence of prostate cancer (PCa) has increased in the last decades, being the most common male malignant disease and a major cause of morbidity and mortality (1-3). This increase is due to the increasing use of screening techniques such as the Prostate Specific Antigen

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(PSA) testing which allows for the detection of lesions at an earlier stage including lesions that may not develop into significant disease (1, 3). PCa has high prevalence in the male population (3-4% in northern Europe) but low mortality rates (1). Currently, the standard method for the diagnosis of PCa is digital rectal exam (DRE) or PSA measurement followed by transrectal ultrasound guided prostate biopsy (PB) in suspected patients although it lacks sensitivity and specificity for lesion detection (1, 2, 4). Prostate ultrasound can demonstrate some lesions that appear hypo-echoic when compared to the normal echogenic peripheral zone. However, more than 4050% of cancerous lesions may appear as iso-echoic allowing for many false negatives even when protocols that sample normal prostate are used, such as double sextant biopsy (1, 4, 5). Due to this fact, the use of multiparametric magnetic resonance (mpMRI), applying the PI-RADS scoring system, to complement and in some cases avoid PB has increased (1, 4, 6-10). Multiparametric magnetic resonance allows for detection, characterization, staging and assessment of metabolic, morphological and cellular changes of lesions that correlate with tumour aggressiveness; mpMRI can also decrease the detection of indolent disease. The combination of mpMRI with biopsy (fusion biopsies) increases its value as a diagnostic tool (1, 4, 6, 7, 11-13). The use of mpMRI with its ability to detect lesions larger than 0.2 ml, permits in some cases the identification of multiple lesions (multifocality) of localized PCa. In fact, prostate can have coexistence of more than one lesion with different Gleason score (2, 7, 9, 14). Thus, the term Index Lesion (IL) or dominant lesion, has been introduced to define the lesion with the highest Gleason score orthe largest lesion in the case of lesions with the same Gleason score (6, 7, 14). The multifocality of PCa, expressed by the presence of satellite lesions, also underestimates the size and extent of PCa. The clinical significance of these factors is still undetermined: in high-risk patients where treatment option is radical prostatectomy (RP) they may not alter prognosis, but they are of high importance when focal treatment is regarded as an option. The use of fusion biopsy may allow for identifiNo conflict of interest declared.

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cation of more lesions and better planning of treatment (12, 15). It is theorized that the IL drives disease progression and that multifocality does not alter prognosis, although a consensus has not been achieved because of divergent results of different studies (6, 15). The use of mpMRI to guide biopsies, as a first line diagnostic tool (rather than as second line when PB fails to detect lesions) is increasing, as it is its use to determine the need of prostatic biopsy in some individuals (16). Nevertheless, a normal mpMRI does not exclude the presence of PCa because mpMRI can detect lesions with high Gleason score and miss lesions with lower Gleason and areas deemed non-suspicious can still reveal significant disease with PB (2, 4, 12, 17, 18). Correlation between mpMRI identified lesions and radical prostatectomy was found to be accurate in lesions equal or superior to 0.2 ml, validating its use for fusion biopsy and possibly guided therapy (12, 17, 19-21). In patients with a negative mpMRI, the risk of significant disease (Gleason â&#x2030;Ľ 7) is still present, although recent studies show a very high negative predictive value. Therefore, some studies still recommend PB even with negative mpMRI (12, 15, 17, 21). The interobserver variability of prostate mpMRI still represents a challenge, as rates are still very variable between studies (8, 11, 13). The aim of this work was to evaluate the correlation between lesions described in mpMRI and the histology results obtained by prostate biopsy and RP.

METHODS Patients selection A retrospective analysis of 291 consecutive diagnostic mpMRI conducted by the same team of radiologists in a tertiary hospital was performed. One hundred fifteen biopsied patients were selected, of whom 56 had a positive biopsy for prostate adenocarcinoma. The data available allowed for the evaluation of agreement between lesion location on mpMRI and PB in 37 patients or on mpMRI and RP in 15 patients (Figure 1). Data collection Clinical and biochemical data was obtained from consulting patientsâ&#x20AC;&#x2122; charts. Imaging data was obtained from analysis of reports conducted by the same team of radiologists, or by revision of images if insufficient data was present in the reports. Anatomopathological data from PB and RP was obtained from consulting reports by the medical team of the pathology department. Technical characteristics All mpMRI were conducted and described by the same team of radiologists and were revised by a single senior radiologist. Of the 291 mpMRI, 161 were conducted utilizing the PI-RADS v1 classification, while the remaining were evaluated applying the PI RADS v2. In this study, being our main endpoint the location of the tumour, no distinction between PI-RADS versions was made in order to increase available numbers. Exams were performed on a 3T MR scanner.

Figure 1. Patients method selection.

Prostate biopsies were conducted by different urologists (non-studied variable) under ultrasound guidance according to cognitive fusion. All patients were submitted to guided biopsy and systematic biopsy (with variable number of cores collected). Studied variables The sample obtained was characterized in relation to age, prostate volume, PI-RADS score, location of lesion [side (left, right, bilateral, medial), floor (apex, base, medial), zone (peripheral, transition, central, stroma)] and dimension on mpMRI. Regarding prostate biopsy it was assessed the total number of fragments obtained, the number of fragments directed to the lesion, number of fragments with PCa, ISUP classification and agreement between location of PCa in fragments in relation to mpMRI. In the 15 patients submitted to RP, the agreement between location of lesion on surgical specimen (SS) and mpMRI was evaluated. We included patients with PI-RADS score 2 that had any mpMRI modification possible to localize (hypointensity lesions in the peripheral zone; circumscribed hypointense or heterogeneous nodules) and had a positive PB. Definition of agreement Agreement between mpMRI/PB and mpMRI/SS was defined as agreement of the presence of PCa only on the regions identified by mpMRI. Statistical analysis Evaluation of the effect of variables studied on location agreement was conducted utilizing the Mann-Whitney test (utilizing the statistic program SPSS v21). The values p < 0.05 were considered statistically significant.

RESULTS Agreement in location mpMRI/PB In relation to PB, location was assessed only as side. Agreement between mpMRI/PB was of about 26 (70.3%), meaning that 11 (29.9%) presented lesions out of the suspected zone. Results concerning location of lesions are summarized in Table 1. The characterization of studied variables and its effect on agreement are summarized in Table 2. Of the factors Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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statistically significant effect. In relation to side, agreement for lesions localized on the right side, left, medial and bilateral was 33.3% (n = 2), 33.3% (n = 2), 0.0% (n = Agreement mpMRI vs PB (n = 37) Agreement mpMRI vs SS (n = 15) 0) and 50.0% (n = 1), respectively. In relaAgreement 26; 70.3% Agreement 5; 33.3% tion to the floor, agreement for lesions PCa in SZ + PCa in the same lobe 7; 18.9% PCa in SZ + ipsilateral lesions in other floors 5; 33.3% localized at the base, medium and apex PCa in SZ + PCa in contralateral lobe 3; 8.1% PCa in SZ + contralateral lesions 1; 6.7% was 33.3% (n = 2), 28.6% (n = 2) and No PCa in SZ + bilateral PCa 1; 2.7% Bilateral lesions in all floors 4; 26.7% PB = prostatic biopsy; PCa = prostate cancer; SS = surgical specimen; SZ = suspicious zone. 50.0% (n = 1), respectively. In relation to anatomical zone, agreement for lesions localized in the peripheral zone, transition zone and central zone was 36.4% (n = 4), 33.3% (n = 1) Table 2. Effect of clinical and imaging variables on agreement and 0.0% (n = 0), respectively. in location between suspicious lesion of prostate Agreement in location between mpMRI/SS for PI-RADS adenocarcinoma on mpMRI and prostate biopsy. lesion score 2,3,4 and 5 was off 0.0% (n = 0), 100% (n = 1), 50.0% (n = 2) and 33.3% (n = 3), respectively. All patients With agreement p Agreement in location for ISUP 1,2 and 5 (evaluated by (n = 37) (n = 26) SS) was 50.0% (n = 2), 33.3% (n = 4), and 0.0% (n = 0), Average age (years) 66.6 65.9 NS respectively. Average PSA (ng/ml) 9.1 10.0 NS In the five exams that showed agreement, all patients Average volume (cc) 53.5 54.4 NS presented with an ISUP SS smaller or similar to the ISUP Average number of previous PB 1.3 1.1 NS Average diameter of suspicious obtained by PB (only one patient was reclassified with lesion on mpMRI (mm) 24.3 22.9 NS ISUP 3 on PB and of ISUP 2 on SS, having the remaining Location of lesion in mpMRI NS patients maintained ISUP classification). Table 1. Agreement in location between mpMRI and lesions objectified in prostatic biopsy and by radical prostatectomy specimen.

• Right 15; 40.5% • Left 15; 40.5% • Medial 3; 8.1% • Bilateral 4; 10.8% Average total number of fragments 13.0 Average number of guided fragments 4.7 PI-RADS •2 7; 18.9% •3 3; 8.1% •4 4; 10.8% •5 23; 62.2% Average number of fragments with PCa 3.5 ISUP after PB •1 •2 •3 •4 •5 • Unknown

10; 27.0% 18; 48.6% 5; 13.5% 3; 8.1% 0; 0.0% 1; 2.7%

10; 38.5% 11; 42.3% 1; 3.8% 4; 15.4% 13.0 4.9

5; 19.2% 3; 11.5% 4; 15.4% 14; 53.8% 3

NS NS NS

Statistically significant NS

8; 30.8% 10; 38.5% 5; 19.2% 2; 7.7% 0; 0.0% 1; 3.8%

PSA = Prostatic specific antigen; PB = Prostatic biopsy; mpMRI = multiparametric magnetic resonance; PCa = prostate adenocarcinoma; NS = Non significant (p > 0.05); StS = statistically significant (p ≤ 0.05).

studied, only the total number of fragments with PCa was lower in cases with agreement between mpMRI and PB (p < 0.05). Agreement on location between mpMRI/PB for lesions PI-RADS 2,3,4 and 5 was 71.4% (n = 5), 100.0% (n = 3), 100% (n = 4) and 60.9% (n = 23), respectively. Agreement in location mpMRI/PB for lesions ISUP (PB result) 1,2,3 and 4 was 80% (n = 8), 55.6% (n = 10), 100.0% (n = 3) and 66.7% (n = 2), respectively. Agreement in location mpMRI/SS Agreement on location between mpMRI/SS was of 5 (33.3%) (Table 1). The characterization and effect of variables on agreement are summarized in Table 3, being that no variable had a

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Table 3. Effect of clinical and imaging variables on agreement between location of prostate adenocarcinoma suspicious lesion, between mpMRI and findings in surgical specimen after radical prostatectomy.

Average age (years) Average PSA (ng/ml) Average volume (cc) Average diameter of suspicious lesion on mpMRI (mm) Location of lesion in mpMRI a) Side • Right • Left • Medial • Bilateral b) Floor • Base • Medial • Apex c) Zone • Peripheral • Transition • Central PI-RADS •2 •3 •4 •5 ISUP SS •1 •2 •3 •4 •5

All patients (n = 15) 65.1 8.6 49.1

With agreement (n = 5) 63.6 10.0 53.4

26.4

23.5

6; 40.0% 6; 40.0% 1; 6.7% 2; 13.3%

2; 40.0% 2; 40.0% 0; 0.0% 1; 20.0%

6; 40.0% 7; 46.7% 2, 13.3%

2; 40.0% 2; 40.0% 1; 20.0%

11; 73.3% 3; 20.0% 1; 6.7%

4; 80.0% 1; 20.0% 0; 0.0%

3; 20.0% 1; 6.7% 2; 13.3% 9; 60.0%

0; 0.0% 1; 20.0% 1; 20.0% 3; 60.0%

2; 13.3% 12; 80.0% 0; 0.0% 0; 0.0% 1; 6.7%

1; 20.0% 4; 80.0% 4; 80.0% 0; 0.0% 0; 0.0%

p NS NS NS NS NS

PSA = Prostatic specific antigen; PB = Prostatic biopsy; mpMRI = multiparametric magnetic resonance; PCa = prostate adenocarcinoma; NS = Non significant; SS = Surgical specimen.

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In the 10 nonagreeing exams, the ISUP SS values were superior to the ISUP BP values in 5 (50.0%) of cases (regarding the five ISUP 1 patients in PB, four were reclassified as ISUP 2 in SS and one maintained ISUP classification).

DISCUSSION

Currently the use of “blind” biopsy in the search for PCa with the objective of “finding” the neoplasic lesion constitutes an exception when compared to other cancer diagnostic procedures (22). The development of mpMRI and the subsequent rise of guided prostate biopsy has been associated with excellent results in detecting significant PCa. This has various potential applications of great relevancy, such as reducing the number of unnecessary biopsies, reducing the diagnosis of indolent PCa and better planning of focal therapy (2, 19, 23). To make it possible, mpMRI has to present high sensitivity and high negative predictive values, which can be evaluated by comparing characteristics of identified lesions on mpMRI with findings obtained from prostate biopsy (guided and systematic) and with histopathological result from radical prostatectomy specimens. In this study, agreement between mpMRI and PB was 70.3%. In relation to patients without agreement, all presented multifocality. In an interesting way, we observed that all bilateral suspicious lesions on mpMRI (n = 4) presented agreement on PB. Of all factors studied, only having a small number of positive PB cores for PCa, was related to higher agreement between mpMRI and PB. This data can be explained by the fact that a higher number of positive cores can be associated to the presence of multifocal lesions not identified by mpMRI. The agreement was higher for lesions PI-RADS ≤ 3 that for lesions PI-RADS > 3 (80.0% vs. 66.7%). Agreement between location for mpMRI and SS was only 33.3% and multifocality was responsible for the lack of agreement in the 66.7% remaining patients. Interestingly, patients with non-agreeing lesions presented with an increased ISUP classification in relation to PB in 50.0% of cases (vs 0.0% of patients with agreement). None of the factors studied related to agreement (probably by the reduced sample size). The accuracy of mpMRI for detecting PCa has been widely studied. Multiple studies have shown that guided prostate biopsy of the suspected lesion on mpMRI detects more clinically significant tumours that systematic biopsy, whereas systematic biopsy detects more nonsignificant tumours. Due to this fact, most authors still recommend conducting both techniques at the same time as to increase diagnostic accuracy (2, 3, 5, 22). Given that mpMRI has a high negative predictive value (between 63 and 98% (24), various authors have defended that mpMRI can significantly reduce the number of prostatic biopsies conducted, particularly in patients with previously negative biopsy (3, 4, 21). The accuracy of mpMRI is especially high in detecting index lesions, with various recent studies showing values > 85% (7, 14, 19, 20, 25). In our study, the low correlation between lesions identified on mpMRI with biopsy and surgical specimen, was

related to multifocality, as in our methodology we considered the existence of unidentified multifocal lesions on mpMRI as nonagreeing exams. Various studies have shown that PCa is multifocal in most cases, with a variation of 57 to 91% (26-29). In this context, it is important to assess the characteristics of unidentified lesions on mpMRI, being they index or satellite lesions. Radtke et al. (19), in a study correlating surgical specimen of radical prostatectomy, objectified that 94% of lesions not identified by mpMRI presented with Gleason ≤ 3+4. In a study by Borkowetz et al. (7), that also related mpMRI to SS, mpMRI failed to identify 13% of index lesions, that in half of cases presented with a Gleason score ≥ 4+3. Baco et al. (14) obtained a diagnostic acuity of 95% for IL with biopsy guided by mpMRI, where the remaining 5% were identified by systematic biopsy. The high sensitivity obtained by combining guided biopsy with systematic biopsy was equally proved in other studies (19, 30). Le et al. (6) described the multifocality of PCa in 64% of cases, being the mpMRI detection rate for all tumours of only 47% (132/283). The sensitivity of mpMRI was higher in lesions larger than 1 cm (72%), Gleason score ≥ 7 (72%) and for index lesions (80%). In a study conducted by Tan et al., mpMRI was capable of identifying 46.7% of all tumour foci (31). Better results concerning the ability of mpMRI in detecting multifocal lesions was described by Hegde et al. (12), who described an accuracy of 62.0% in detecting satellite lesions by mpMRI ( that in 55.3% presented with Gleason score ≥ 3+4). Analysing therapeutic applications, particularly focal therapies, it is relevant to highlight that satellite lesions do not necessarily present adjacent to the index lesion, being the average distance of approximately 1 cm (32). The importance of satellite lesions is not totally explained. Currently, the most widespread idea supports that potentially metastatic and lethal PCa originates from the same aberrant progenitor cell (in other words, with the same monoclonal origin) (33, 34) and that IL (correctly identified by mpMRI) most likely originates from the same lethal parent cell (35). Nevertheless, other studies showed that non-index lesions can be responsible for local invasion (36) and for metastatic PCa (37). The identification of PCa lesions by mpMRI is dependent on multiple factors, namely lesion volume (> 1cc), Gleason score (≥ 7), histology, location (inferior to lesion located at the apex ) and of the contrast to normal adjacent tissue (14, 31). Currently another matter of debate is the influence of the technique of guided biopsy utilized, namely the difference between cognitive fusion biopsy (utilized in our work), MRI-transrectal ultrasound fusion and in-bore MRI target biopsy. A recent systematic review showed that in-bore MRI target biopsy is superior to cognitive fusion biopsy for the detection of all PCa (regardless of Gleason score), although it was not superior in detecting significant tumours. The MRI-transrectal ultrasound fusion biopsy did not show advantages in relation to cognitive fusion biopsy (38). In this study, all the exams were conducted or revised by the same radiologist, which eliminates the subjective variation in reading mpMRI. Some studies showed that Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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for index lesion the interobserver variation is not significant (15, 39), while other studies showed a clear effect of the radiologist´s experience in reading mpMRI (13). This work presents with various limitations, namely its retrospective nature and the small number of surgical specimens evaluated. Also, histology was assessed by report, which can reduce agreement concerning location (10, 15). Another limitation was the inclusion of patients with a PI-RADS score of 2, which by definition signifies a negative mpMRI (although during PB the areas of the prostate where alterations were present where considered, namely hypointensity lesions in the peripheral zone). Lastly, agreement between index lesion and satellite lesion was not evaluated, nor was histopathological characteristics for tumour foci.

13. Riney JC, Sarwani NE, Siddique S, Raman JD. Prostate magnetic resonance imaging: The truth lies in the eye of the beholder. Urol Oncol. 2018; 36:159.e1-.e5. 14. Baco E, Ukimura O, Rud E, et al. Magnetic resonance imagingtransectal ultrasound image-fusion biopsies accurately characterize the index tumor: correlation with step-sectioned radical prostatectomy specimens in 135 patients. Eur Urol. 2015; 67:787-94. 15. Steenbergen P, Haustermans K, Lerut E, et al. Prostate tumor delineation using multiparametric magnetic resonance imaging: Inter-observer variability and pathology validation. Radiother Oncol. 2015; 115:186-90. 16. Kasivisvanathan V, Rannikko AS, Borghi M, et al. MRI-targeted or standard biopsy for prostate-cancer diagnosis. N Engl J Med. 2018; 378:1767-77.

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Correspondence Mario Lourenรงo, MD (Corresponding Author) mariolourenco88@gmail.com Duarte Vieira e Brito, MD Joao Pedro Peralta, MD Urology Department Portuguese Institute of Oncology Coimbra Rua Maria Bourbon Bobone, n57, RE/Esq, Coimbra, 3030-481 Portugal Pedro Pissarra, MD Cristina Marques, MD Radiology Department Coimbra Hospital University Centre, Coimbra (Portugal) Miguel Eliseu, MD Arnaldo Figueiredo, MD Urology and Kidney Transplant Department Coimbra Hospital University Centre, Coimbra (Portugal)

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DOI: 10.4081/aiua.2019.4.224

ORIGINAL PAPER

“In-bore” MRI prostate biopsy is a safe preoperative clinical tool to exclude significant prostate cancer in symptomatic patients with benign prostatic obstruction before transurethral laser enucleation Angelo Porreca 1, Daniele D’Agostino 1, Mario Vigo 2, Paolo Corsi 1, Daniele Romagnoli 1, Alessandro Del Rosso 1, Riccardo Schiavina 3, Eugenio Brunocilla 3, Walter Artibani 1, Marco Giampaoli 1 1 Department

of Urology, Abano Terme Hospital, Padua, Italy; of Radiology, Abano Terme Hospital, Padua, Italy; 3 Department of Urology, University of Bologna, Bologna, Italy. 2 Department

Summary

Introduction: Purpose of our study was to investigate the role of a negative in-bore MRI-guided biopsy (MRI-GB) in comparison to a negative multiparametric prostate MRI (mpMRI) and a contextual negative transrectal ultrasound guided biopsy of the prostate with regard to incidental prostate cancer findings in the surgical specimen of men who underwent to Holmium Laser enucleation of prostate (HoLEP) with a preoperative suspicion of prostate cancer. Materials and methods: Data of 117 of symptomatic patients for bladder outflow obstruction who subsequently underwent to HoLEP was retrospectively analyzed form a multicentric database. All patients had a raised serum PSA and/or an abnormal digital rectal examination (DRE) with a pre-interventional mpMRI. Prostate cancer was excluded either with an en-bore MRI-GB (group "IN-BORE MRI-GB" n = 57) in case of a suspect area at the mpMRI or with a standard biopsy (group "mpMRI + TRUS-GB" n = 60) in case of a negative mpMRI. Preoperative characteristic surgical and histological outcomes were analyzed. Univariate and multivariate logistic regression model was performed to investigate independent predictors of incidental Prostate Cancer (iPCa). Results: Both groups presented moderate to severe lower tract urinary symptoms: median IPSS was 19 (IQR: 17.0-22.0) in the IN-BORE MRI-GB group and 20 (IQR: 17.5-22.0) in the mpMRI + TRUS-GB (p = 0.71). No statistically significant difference was found between the two groups besides total prostate volume with 68 cc (IQR: 58.0-97.0) in the IN-BORE MRI-GB group and 84 cc (IQR: 70.0-115.0) in the mpMRI + TRU-GB group (p = 0.01) No differences were registered in surgical time, removed tissue, catheterization time, hospital stay and complications rate. No different rates (p = 0.50) of iPCa were found in the IN-BORE MRI-GB group (14%) in comparison with mpMRI + TRUS-GB group (10 %); pT stage and ISUP Grade Group in iPCa stratification were comparable between the two groups. In multivariate analysis a statistically significant correlation with age as an independent predictive factor of iPCa was found (OR 1.14; 95% CI: 1.02-1.27; p = 0.02) while no correlations were revealed with PSA (OR 1.12; 95% CI: 0.99-1.28; p = 0.08) and a negative in-bore MRI-GB (OR 1.72; 95% CI: 0.51-5.77; p = 0.37). Conclusions: Including a mpMRI and an eventual in-bore MRIGB represents a novel clinical approach before surgery in patients with symptomatic obstruction with a concomitant sus-

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picion of PCa, leading to low rate of iPCa and avoiding unnecessary standard TRUS-GB biopsies.

KEY WORDS: Magnetic resonance imaging; Holmium laser enucleation of the prostate; Prostate biopsy; Prostatic enlargement; Prostate cancer. Submitted 29 May 2019; Accepted 2 August 2019

INTRODUCTION

One of the most common non-malignant disease in aging men is represented by benign prostate enlargement (BPE) (1) which might drives to bladder outlet obstruction (BOO) with consequent affected quality of life (QoL) leading to the necessity of a surgical procedure. During the preoperative work-up, a prostate cancer (PCa) diagnosis might be arise and whenever its presence is suspected, its exclusion is necessary since prostate cancer might represent an heavy burden in quality of life (2) and both an accurate diagnosis and risk stratification are mandatory for an adequate disease management (3, 4). In men with a raised serum prostate specific antigen (PSA) and/or abnormal digital rectal examination (DRE) the standard of care in order to rule out PCa is represented by a 10-12 core ultrasound guided transrectal biopsy of the prostate (TRUS-GB) (5) which several times leads to either false negative results or non-clinically significant PCa (6, 7). During the last years, several new imaging techniques such as magnetic resonance imaging (MRI) (8) and positron emission tomography (PET) (9), were introduced in the clinical practice in order to diagnose and stage PCa. A multiparametric Magnetic Resonance Imaging (mpMRI) of the prostate combines both functional and morphological studies and demonstrated to be a valuable tool for PCa diagnosis with high sensitivity and specificity (10). Performing a targeted biopsy to mpMRI suspect areas might reduce the numbers of necessary biopsies and lower the non-clinically significant PCA rates (11). Several targeting techniques were proposed: visual estimation TRUS-GB (cognitive technique), software co-regNo conflict of interest declared.

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istered MRI-ultrasound fusion (fusion technique) and inbore MRI-guided biopsy (MRI-GB). In-bore MRI-GB has the advantage to provide the greatest probability to sample suspected areas since is performed with a direct and real-time proof of the correct sampling (12) especially in case of high volume prostate. Holmium laser enucleation of the prostate (HoLEP) represent an endoscopic surgical technique that allows to obtain patients’ symptoms relief. HoLEP is reported to be applicable to all prostate sizes and to represent a safe, efficient and time-durable surgical solution to patients (13). Differently to other laser techniques for the treatment of symptomatic BPE, HoLEP is able to retrieve and adequate enucleated prostatic adenoma tissue, better than transurethral resection of the prostate (TURP) and comparable to open simple prostatectomy (14). Purpose of our study was to investigate the role of a negative in-bore MRIGB in comparison to a negative mpMRI and a contextual negative transrectal ultrasound guided biopsy of the prostate with regard to incidental prostate cancer findings in the surgical specimen of men who underwent to HoLEP with a preoperative suspicion of prostate cancer due to a raised PSA and/or and abnormal DRE.

PATIENTS

AND METHODS

Patients with a suspicious area at the mpMRI (PI-RADS v2 Score ≥ 3) underwent to in-bore MRI-GB (2 cores taken per suspect lesion), resulted negative for PCa and then were scheduled for HoLEP. Individuals with a negative mpMRI (PI-RADS -v2 Score < 3) underwent to an additional standard random TRUS-GB (10 or 12 cores were taken based on the prostate volume), resulted negative for PCa and then scheduled for HoLEP. Pre-operative collected data included age, total PSA, DRE, prostate and adenoma volume either at mpMRI or at transrectal ultrasound, PSA density, Qmax, IPSS, QoL, post-voided residual volume (PRV), drug assumption, previous acute urinary retention. The following peri- and post-operative parameters were evaluated: surgical time, removed tissue weight, catheterization time, hospital stay, peri-operative complications, presence of incidental Prostate Cancer (iPCa), pT stage and International Society of Urological Pathology (ISUP) Grade Group of each iPCa. Conduct of the in-bore MRI-guided biopsy (MRI-GB) Biopsies were performed by two urologists with consolidated experience in MRI-GB. Oral antibiotic prophylaxis was started one day before the procedure prolonged for at least 2 days. Peri-prostatic nerve blockade local anesthesia with lidocaine 2% was executed for patients’ pain relief. Biopsies were performed transrectally, with patients in a

Population and study design Figure 1. Data was retrospectively retrieved from a multicentric The non-magnetic MR-compatible biopsy device fixed on the table top of the magnet. database of patients affected by symptomatic BOO due to BPE who underwent to HoLEP from January 2017 to December 2018. Surgical indication was given in case of persistent bladder outflow obstruction symptoms, International Prostatic Symptoms Score (IPSS) higher than 8, peak urinary flow (Qmax) ≤ 15 ml/s, non-responsiveness to medical therapies (alfa blockers and/or 5α-reductase inhibitors 5ARI), acute and chronic urinary retention or renal function impairment due to BOO. All patients selected from the database had exclusively a pre-operative suspicion of PCa (total PSA > 4 ng/mL and /or abnormal DRE) and underwent to a pre-interventional prostate mpMRI. Multiparametric MRI was performed with a 1.5 T whole body scanner (Achieva XR; Philips Medical Systems, Best, Netherlands) with a 32-channels phased-array surface and without an endorectal coil. Morphological Figure 2. The Gadolinium-filled needle guide properly identified in a sagittal T2-weighted image studies consisted in Turbo Spin Echo (A); the dedicated software (DynaCAD, Invivo, Gainesville, FL) shows the 3D (TSE) T2-weighted sequences in adjustments through automatic calculation enabling the proper calibration of the sagittal, axial and coronal planes biopsy needle to the target lesion (B). while functional studies were obtained through Diffusion Weighted Imaging (DWI) and Dynamic Contrast Enhanced-MRI (DCE-MRI). MpMRIs were exclusively conducted in one of the two involved centers and images were evaluated by two high experienced UroRadiologists according to PI-RADSv2, based on ESUR guidelines for the evaluation and reporting of prostate mpMRI (15). Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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prone position on the 1.5 T MR scanner, using an 18-G Univariate and multivariate logistic regression model was automatic core-needle filled with Gadolinium, a non-magemployed to investigate if any preoperative factors (Age, netic portable biopsy device (DynaTRIM, Invivo, PSA, Prostate Volume, Adenoma Volume, Removed Tissue, Gainesville, FL - Figure 1) and a dedicated software packPSA density > 15, negative in-bore MRI-GB) could be corage for device tracking and target localization (DynaCAD, related with iPCa in patients who underwent HoLEP Invivo, Gainesville, FL). Oblique axial T2w images were with a suspect of PCa. aligned with the needle guide in order to allow software IBM SPSS v.22 with a 2-sided significance level set at P < registration showing three-dimensional adjustments 0.05, was used for statistical analysis. required to align the track of the biopsy needle through the needle guide and the target lesion (Figure 1). After manual calibration adjustments on the arm of the biopsy RESULTS device attached to the needle guide, sagittal T2w images in A total amount of 117 patients [IN-BORE MRI-GB (n = parallel with the long axis were obtained in order to con57), mpMRI + TRUS-GB (n = 60)] were identified and firm the correct position and the proper direction of the included in the study. Preoperative clinical patients ‘charneedle guide to the target; reconfirmation of the needle acteristics are listed in Table 1. Overall median age, PSA, track was repeated until proper alignment was obtained. prostate volume, adenoma volume and PSA density were If targeting was not certain, due to lesion size or subjective judgment of the operaTable 1. tor, subsequent axial and sagittal T2w General and preoperative clinical characteristics. images with the needle in place were Overall IN-BORE MRI-GB mpMRI + TRUS-GB P value obtained to detect needle position and be (n = 117) (n = 57) (n = 60) able to make adjustments for the next Age, years core (Figures 3a, 3b). A maximum of two Median (IQR) 65.0 (59.5-70.0) 65.0 (60.0-70.0) 65.0 (58.25-69.0) 0.44 biopsy cores were taken for each patient. PSA, ng/ml Surgical procedure The HoLEP procedure was carried out by four experienced surgeons in either one of the two centers using the Lumenis® Versa Pulse™ Holmium laser delivering laser energy with a 550-μm fiber set at 2.0 J and 60 Hz (maximum power of 120 W) and a 26Fr continuous-flow Storz laser resectoscope. A modified Gilling's technique (16) was employed and enucleated prostatic lobes were retrieved using Lumenis® VersaCut™ Morcellator System. Continuous flow irrigation until next morning through a 20F three-way catheter indwelled at the end of the surgery was placed. Catheter removal was executed at the second post-operative day in the event of no intercurred complication (e.g. hematuria, fever, acute urinary retention, etc.). Statistical analysis Overall patients (n = 117) were dived in two groups, “IN-BORE MRI-GB” (n = 57) and “mpMRI + TRUS-GB” (n = 60) respectively based on the presence of a negative in-bore MRI-GB or a negative mpMRI with a contextual negative TRUS-GB prior to HoLEP. Median values with interquartile ranges (IQR) and frequencies with proportions (%) were reported for continuous and categorical variables respectively. Differences between two groups were investigated with Mann-Whitney U test for continuous data, and chi-square test for categorical values.

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Median (IQR) 6.20 (5.40-9.90) DRE, n (%) Negative 95 (81.2) Positive 22 (18.8) Prostate volume, cc Median (IQR) 80.0 (60.0-101.0) Adenoma volume, cc Median (IQR) 47.0 (35.0-70.0) PSA Density, ng/ml/cc Median (IQR) 0.08 (0.06-0.13) PSA Density > 0.15 ng/ml/cc, n (%) No 100 (85.5) Yes 17 (14.5) Qmax, mL/sec Median (IQR) 9.6 (6.8-9.5) IPSS score Median (IQR) 20.0 (17.0-22.0) PRV, cc Median (IQR) 95 (50-150) Drug assumption, n (%) No 15 (12.2) Alfa blocker 43 (36.8) 5-ARI 12 (10.3) 5-ARI + alfa-blocker 47 (40.2) Previous acute urinary retention, n (%) No 105 (89.7) Yes 12 (10.3) PIRADS v2 Score, n (%) <3 60 (51.3) 3 36 (30.8) 4 18 (15.4) 5 3 (2.6) Site Positive Area, n (%) Anterior 48 (84.2) Posterior 9 (15.8) Site Positive Area, n (%) Right lobe 31 (54.4) Left lobe 26 (45.6)

5.96 (5.26-10.0)

6.00 (4.82-9.87)

0.66 0.37

44 (77.2) 13 (22.8)

51 (85.0) 9 (15.0)

68.0 (58.0-97.0)

84.0 (70.0-115.0)

0.01*

47 (35.0-70.0)

50.0 (37.0-73.0)

0.33

0.08 (0.07-0.15)

0.08 (0.06-0.11)

45 (78.9) 12 (21.1)

55 (91.7) 5 (8.3)

0,41 0.06

11.0 (10.2-12.0)

8.7 (8.0-11.0)

0.11

19.0 (17.0-22.0)

20.0 (17.5-22.0)

0.71

80 (52-140)

105 (42-321)

6 (10.5) 24 (42.1) 6 (10.5) 21 (36.8)

9 (15.0) 19 (31.7) 6 (10.0) 26 (43.7)

0.32 0.65

54 (94.7) 3 (5.3)

51 (85.0) 9 (15.0)

0 (0.0) 36 (63.2) 18 (31.6) 3 (5.3)

60 (100.0) 0 (0.0) 0 (0.0) 0 (0.0)

48 (84.2) 9 (15.8)

0 (0.0) 0 (0.0)

31 (54.4) 26 (45.6)

0 (0.0) 0 (0.0)

0.09 -

Continuous variables are shown as median (IQR) values while categorical as number (%). Statistically significant values are considered as p value < 0.05. PSA prostate specific antigen, DRE digital rectal examination, Qmax maximum peak urinary flow, IPSS international prostate symptoms score, QoL quality of life, PRV post-void volume, 5-ARI 5-aromatase receptor inhibitor. mpMRI multiparametric Magnetic Resonance Imaging.

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“In-bore” MRI prostate biopsy is a safe preoperative clinical tool to exclude significant prostate cancer in symptomatic patients...

Table 2. Perioperative surgical and histological outcomes. Overall (n = 117) Surgery time (min) Mean (SD) 70.0 (50.0 -95.0) Removed tissue (gr) Mean (SD) 30.0 (20.0-55.0) Catheterization time (days) Median (IQR) 2 (2 – 2) Hospital stay (days) Median (IQR) 2 (2 – 2) Peri-operative complications, n (%) No 109 (93.2) Grade* 1 5 (4.3) Grade* 2 3 (2.5) Histopathology (%) Negative 103 (88.1) iPCa 14 (12.0) pT Stage (%) pT1a 10 (71.4) pT1b 4 (28.6) ISUP Grade Group (%) Group I 11 (78.6) Group II 3 (21.4)

IN-BORE MRI-GB (n = 57)

mpMRI + TRUS-GB (n = 60)

P value

70.0 (40.0-80.0)

70.0 (55.0-100.0)

0.85

24.0 (17.0-45.0)

36.0 (24.0-70.0)

0.90

2 (2-2)

0.32

2 (2-2)

0.30

52 (91.2) 3 (5.3) 2 (3.5)

57 (90.5) 2 (6.3) 1 (3.2)

0.36

49 (86.0) 8 (14.0)

54 (90.0) 6 (10.0)

0.50

6 (75.0) 2 (25.0)

4 (66.7) 2 (33.3)

0.73

6 (75.0) 2 (25.0)

5 (83.3) 1 (16.7)

0.71

Continuous variables are shown as median (IQR) values while categorical as number (%). Statistically significant values are considered as p value < 0.05. pT stage pathologic T stage, ISUP International Society of Urological Pathology. mpMRI multiparametric Magnetic Resonance Imaging.

Table 3. Uni and multivariate logistic regression. Variables Age [continuous] (years) PSA [continuous] (ng/mL) Prostate Volume [continuous] (cc) Adenoma Volume [continuous] (cc) Removed Tissue [continuous] (gr) PSA density > 15 [yes vs no] (ng/mL/cc) Negative IN-BORE MRI-GB (yes vs no)

p value 0.03* 0.15 0.41 0.16 0.93 0.44 0.50

Univariate OR (95% CI) 1.12 (1.01-1.25) 1.09 (0.96-1.23) 1.01 (0.99-1.02) 1.02 (0.98-1.04) 1.01 (0.98-1.02) 1.73 (0.42-6.99) 1.46 (0.47-4.53)

p value 0.02* 0.08

0.37

Multivariate OR (95% CI) 1.14 (1.02-1.27) 1.12 (0.99-1.28)

1.72 (0.51-5.77)

MRI-GB magnetic resonance imaging guided biopsy. Statistically significant values are considered as p value < 0.05. OR odds ratio, CI confidence interval, PSA prostate specific antigen.

65.0 years (IQR: 59.5-70.0), 6.20 ng/mL (IQR: 5.409.90), 80.0 cc (IQR: 60.0-101.0), 47.0 cc (IQR: 35.070.0) and 0.08 ng/mL/cc (IQR: 0.06-0.13), respectively. A statistically significant difference was found between the two groups in terms of total prostate volume with 68 cc (IQR: 58.0-97.0) in the IN-BORE MRI-GB group and 84 cc (IQR: 70.0-115.0) in the mpMRI + TRU-GB group (p = 0.01). However no statistically differences were found between the two groups in terms of adenoma volume (47 cc IQR: 35.0-70.0 versus 50 cc IQR: 37.0-73.0; p = 0.33) and the other clinical preoperative characteristics. Patients in both groups presented moderate to severe lower tract urinary symptoms with affected quality of life, based on the IPSS, and a bladder outflow obstruction with decreased peak urinary flow (Qmax). Median IPSS was 19 (IQR: 17.0-22.0) in the IN-BORE MRI-GB group and 20 (IQR: 17.5-22.0) in the mpMRI + TRUSGB (p = 0.71). No statistically differences were recorded between the two groups in preoperative drug assumption and previous

acute urinary retention. The majority of patients with a negative IN-BORE MRI-GB presented either a posterior (84.2%) or a a PI-RADS-v2 Score 3 area (63.2%). Perioperative surgical outcomes, as reported in Table 2, were found to be comparable in terms of surgery time, removed issue, catheterization time, hospital stay and perioperative complication. No statistically different rates (p = 0.50) of iPCa detected in the resected tissue of IN-BORE MRI-GB group (14%) in comparison with mpMRI + TRUS-GB group (10%) were shown at final pathology examination. Comparable pT stage and ISUP Grade Group in iPCa stratification were found with pT1a stage and ISUP Grade Group I (Gleason Score 3+3) 75.0% versus 66.7% (p = 0.73) and 75.0% versus 63.3% (p = 0.71) respectively in IN-BORE MRI-GB and mpMRI + TRUS-GB group. Univariate analysis (Table 3) showed that only Age (OR 1.12; 95% CI: 1.01-1.25; p = 0.03) was correlated with iPCa after HoLEP, whereas a preoperative negative in-bore MRI-GB wasn’t statistically related to iPCa (OR 1.46; 95% CI: 0.47-4.53; p = 0.50) such as PSA Density > 0.15 ng/mL/cc (p = 0.44), PSA (p = 0.15), prostate volume (p = 0.41), adenoma volume (p = 0.16), removed tissue (p = 0.93). In a multivariate predictive model a statistically significant correlation with Age as an independent predictive factor of iPCa was also found (OR 1.14; 95% CI: 1.02-1.27; p = 0.02) while no correlations were revealed with PSA (OR 1.12; 95% CI: 0.99-1.28; p = 0.08) and a negative inbore MRI-GB (OR 1.72; 95% CI: 0.515.77; p = 0.37) (Table 3).

DISCUSSION

HoLEP represents a modern less-invasive treatment of symptomatic BPE with demonstrated safety and effectiveness with long terms results, even in a randomized study (17). Respect to other laser BPE surgery, HoLEP leads to a transurethral enucleation which sometimes the retrieval of an iPCa in the final pathology. Elkoushy et al. (18) conducted a prospective study demonstrating that active surveillance (19, 20) might be a safe clinical option in managing iPCa diagnosis after HoLEP, especially because radiotherapy or radical prostatectomy, even if necessary sometimes, often negatively affect quality of life (21). Therefore, a different novel clinical approach is necessary when a PCa suspicion is present before to schedule surgery for BPE. Purpose of our study was to evaluate the role of a negative in-bore MRI-GB in comparison to a negative mpMRI and a contextual negative transrectal ultrasound guided Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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biopsy of the prostate, before an HoLEP surgery, with regard to incidental prostate cancer findings in individuals with a preoperative suspicion of prostate cancer. All patients of our retrospective multicentric study were symptomatic due BOO secondary to BPE, had a raised serum PSA and/or an abnormal DRE, underwent to a pre-operative mpMRI and PCa was excluded either with a negative in-bore magnetic resonance imaging guided prostate biopsy (IN-BORE MRI-GB group) or an additional standard prostate biopsy to the negative mpMRI (mpMRI + TRUS-GB group). Both study groups presented pre-surgery assessments e peri-operative surgical outcomes with no statistically significant differences, besides total prostate volume but not adenoma volume, demonstrating low rates of complications, short hospital stay (median 2 days; IQR 2-2) and catheterization time (median 2 days; IQR 2-2). In the overall selected population of our study, final pathology examination showed a rate of iPCa (12%) which is comparable to the interval available in the present literature (8.1-15%) (22-24). The explanation to this range might be found in the various baseline characteristics of the patients, which usually are due to merging individuals with normal PSA and DRE to patients with suspicion of PCa. In fact Herlemann et al. (24), in a sub-analysis of their HoLEP study arm, found a 40% iPCa rate in a sub-cohort of patients with a preoperative negative TRUS-GB, highlighting the need of a different preoperative diagnostic approach when a suspect of PCa is present before BPE surgery. Several preoperative parameters, such as older age, preoperative PSA, smaller prostate volume, preoperative TRUS-GB, were pointed as possible predictor of iPCa before BPE surgery. Bhojani et al. (23) in their study demonstrated with their regression model that age prior surgery is an independent predictive factor for iPCa before HoLEP. In our experience mpMRI proved to be a valuable preoperative tool not only, as demonstrated,in planning a precise and safe nerve sparing in patients scheduled for radical prostatectomy (25), but also to exclude PCa before HoLEP either with a negative finding or using the same MRI in order to guide a precise biopsy in a suspicious area. Our reported rate of 12% of iPCa after HoLEP in patients with a suspect preoperative PCa is lower both than the 40% of the sub cohort of Herlemann et al. (24) and the recent 23.1% of 359 patients treated with HoLEP and TRUS-GB recently reported by Kim et al. (26). In our study a negative in-bore MRI-GB showed a good reliability in order to safely exclude a PCa and didn’t show any statistically difference in percentage of iPCa compared to a negative mpMRI with a contextual TRUSGB, 14% versus 10% (p = 0.50), and in pT stage and ISUP Grade Group distribution (p = 0.73 and p = 0.71 respectively). Both in univariate (OR 1.46; 95% CI: 0.474.53; p = 0.50) and multivariate (OR 1.72; 95% CI: 0.51-5.77; p = 0.37) regression analysis model a negative in-bore MRI-GB wasn’t and independent predictive factor of iPCa before HoLEP while at the same regression model age was found to significant either in univariate

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(OR 1.12; 95% CI: 1.01-1.25; p = 0.03) and multivariate (OR 1.14; 95% CI: 1.02-1.27; p = 0.02). The retrospective nature of our study and the absence of a randomization are the main limitations and secondly the two groups were not matched. Patients’ data with positive in-bore MRI-GB or TRUS-GB were not available thus a prospective randomized data collection is needed in order to confirm our preliminary results. Moreover, our data didn’t let a stratification based on an 80cc cut-off prostate volume, and lastly there is both a lack of a long-term oncologic follow-up and the comparison with the histologic gold standard for prostate cancer diagnosis (radical prostatectomy specimen) since the presence of cancer risk in the residual peripheral prostate. Despite these important limitations, our study represents a selected cohort of patients due the inclusion of only individuals with serum PSA > 4 ng/mL and/or abnormal DRE and our data represent one of the first studies available in the clinical use of a prostate mpMRI and an inbore MRI-GB before HoLEP. However, in order to deeply investigate and confirm our preliminary results randomized trials and further investigations are needed.

CONCLUSIONS

Our results show that a negative preoperative in-bore MRI guided prostate biopsy before HoLEP in patients with raised serum PSA and/or abnormal DRE leads to low rate of iPCa. Therefore, including a mpMRI and an eventual in-bore MRI-GB in a novel clinical evaluation might avoid unnecessary standard TRUS-GB biopsies and represents a novel clinical approach in patients eligible to HoLEP due symptomatic BOO secondary to BPE who presents a suspicion of PCa.

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MRI: technical conduct, standardized report and clinical use. Minerva Urol Nefrol. 2018; 70:9-21. 9. Vagnoni V, Brunocilla E, Bianchi L, et al. State of the art of PET/CT with 11-choline and 18F-fluorocholine in the diagnosis and follow-up of localized and locally advanced prostate cancer. Arch Esp Urol. 2015; 68:354-70. 10. Porpiglia F, Manfredi M, Mele F, et al. Diagnostic pathway with multiparametric magnetic resonance imaging versus standard pathway: results from a randomized prospective study in biopsy-naïve patients with suspected prostate cancer. Eur Urol. 2017; 72:282-8. 11. Schoots IG, Roobol MJ, Nieboer D, et al. Magnetic resonance imaging-targeted biopsy may enhance the diagnostic accuracy of significant prostate cancer detection compared to standard transrectal ultrasound-guided biopsy: a systematic review and meta-analysis. Eur Urol. 2015; 68:438-50. 12. Schiavina R, Vagnoni V, D’Agostino D, et al. “In-bore” MRIguided prostate biopsy using an endorectal nonmagnetic device: a prospective study of 70 consecutive patients. Clin Genitourin Cancer. 2017; 15:417-27. 13. Krambeck AE, Handa SE, Lingeman JE. Experience with more than 1,000 holmium laser prostate enucleations for benign prostatic hyperplasia. J Urol. 2013; 189(1 Suppl):S141-145. 14. Naspro R, Freschi M, Salonia A, et al. Holmium laser enucleation versus transurethral resection of the prostate. Are histological findings comparable? J Urol. 2004; 171:1203-6. 15. Weinreb JC, Barentsz JO, Choyke PL, et al. PI-RADS Prostate Imaging - Reporting and Data System: 2015, Version 2. Eur Urol. 2016; 69:16-40.

18. Elkoushy MA, Elshal AM, Elhilali MM. Incidental prostate cancer diagnosis during holmium laser enucleation: assessment of predictors, survival, and disease progression. Urology. 2015; 86:552-7. 19. Schiavina R, Borghesi M, Brunocilla E, et al. The biopsy Gleason score 3+4 in a single core does not necessarily reflect an unfavourable pathological disease after radical prostatectomy in comparison with biopsy Gleason score 3+3: looking for larger selection criteria for active surveillance candidates. Prostate Cancer Prostatic Dis. 2015; 18:270-5. 20. Grasso AA, Cozzi G, DE Lorenzis E, et al. Multicenter analysis of pathological outcomes of patients eligible for active surveillance according to PRIAS criteria. Minerva Urol Nefrol. 2016; 68:237-41. 21. Porreca A, Noale M, Artibani W, et al. Disease-specific and general health-related quality of life in newly diagnosed prostate cancer patients: the Pros-IT CNR study. Health Qual Life Outcomes. 2018; 16:122. 22. Nunez R, Hurd KJ, Noble BN, et al. Incidental prostate cancer revisited: Early outcomes after holmium laser enucleation of the prostate. Intern J Urol. 2011; 18:543-7. 23. Bhojani N, Boris RS, Monn MF, et al. Coexisting prostate cancer found at the time of holmium laser enucleation of the prostate for benign prostatic hyperplasia: predicting its presence and grade in analyzed tissue. J Endourol. 2015; 29:41-6. 24. Herlemann A, Wegner K, Roosen A, et al. “Finding the needle in a haystack”: oncologic evaluation of patients treated for LUTS with holmium laser enucleation of the prostate (HoLEP) versus transurethral resection of the prostate (TURP). World J Urol. 2017; 35:1777-82.

16. Gilling PJ, Kennett K, Das AK, et al. Holmium laser enucleation of the prostate (HoLEP) combined with transurethral tissue morcellation: an update on the early clinical experience. J Endourol. 1998; 12:457-9.

25. Schiavina R, Bianchi L, Borghesi M, et al. MRI Displays the prostatic cancer anatomy and improves the bundles management before robot-assisted radical prostatectomy. J Endourol. 2018; 32:315-21.

17. Lourenco T, Pickard R, Vale L, et al. Alternative approaches to endoscopic ablation for benign enlargement of the prostate: systematic review of randomised controlled trials. BMJ. 2008; 337:a449.

26. Kim KH, Kim SW, Son HS, et al. Role of Holmium laser enucleation of the prostate to increase cancer detection rate in patients with gray-zone PSA level. Minerva Urol Nefrol. 2019; 71:72-8.

Correspondence Porreca Angelo, MD angeloporreca@gmail.com D’Agostino Daniele, MD daniele.dagostino@casacura.it Corsi Paolo, MD paolo.corsi@casacura.it Romagnoli Daniele, MD danieleromagnoli87@gmail.com Del Rosso Alessandro, MD adelrosso@casacura.it Artibani Walter, MD prof.artibani@gmail.com Giampaoli Marco, MD (Corresponding Author) marco.giampaoli@casacura.it Robotic Urology and Mini Invasive Urologic Surgery Unit, Abano Terme Hospital Piazza Cristoforo Colombo, 1, 35031 Abano Terme (Padova) (Italy) Vigo Mario, MD Department of Radiology, Abano Terme Hospital, Padua, Italy Schiavina Riccardo, MD rschiavina@yahoo.it Brunocilla Eugenio, MD eugenio.brunocilla@unibo.it Department of Specialistic, Experimental and Diagnostic Medicine, Urology, Alma Mater Studiorum-University of Bologna, S. Orsola Hospital Via Pelagio Palagi, 9, 40138 Bologna (Italy) Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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DOI: 10.4081/aiua.2019.4.230

ORIGINAL PAPER

Is Fast Track protocol a safe tool to reduce hospitalization time after radical cystectomy with ileal urinary diversion? Initial results from a single high-volume centre Daniele Romagnoli 1, Riccardo Schiavina 2, Lorenzo Bianchi 2, Marco Borghesi 2, Francesco Chessa 2, Federico Mineo Bianchi 2, Andrea Angiolini 2, Carlo Casablanca 2, Marco Giampaoli 1, Paolo Corsi 1, Daniele D’Agostino 1, Eugenio Brunocilla 2, Angelo Porreca 1 1 Abano 2 St.

Terme Hospital, Abano Terme (PD), Italy; Orsola Malpighi Universitary Urology Clinic, Bologna (BO), Italy.

Summary

Introduction and aim: Radical Cystectomy (RC) with ileal urinary diversion is one of the most complex urological surgical procedure, and many Fast Track (FT) protocols have been described to reduce hospitalization, without increasing postoperatory complications. We present the one-year results of a dedicated protocol developed at a high volume centre. Materials and methods: The FT protocol was designed after a review of the literature and a multidisciplinary collegiate discussion, and it was applied to patients scheduled to open RC with intestinal urinary diversion. To validate its feasibility, we compared its results with data collected from a 1:1 matched population of patients who had undergone the same surgical procedure, without the implementation of the FT protocol. Results: We enrolled in the FT group 11 (55%) patients scheduled to RC with ileal conduit diversion, and 9 patients (45%) scheduled to orthotopic neobladder (Studer) substitution, while a numerically equivalent population was enrolled in the control group, matched according to age at surgery, BMI, gender, ASA score, CCI, preoperative stage and type of urinary diversion. No statistically significant difference was found in terms of pre-operatory and intra-operatory domains. Median overall age was 71 years (Inter Quartile Range - IQR: 63-76) and mean operatory time was 276 ± 57 minutes. Hospitalization time was significantly reduced in the FT group, considering oralization and canalization items we found a significant advantage in the FT group. No statistically significant difference was found in the control of the post-operatory pain. We found no difference, in terms of both early and late complications ratio, among the two populations. Complications graded Clavien ≥ 3 were found in 4 patients of the control group (20%), while in only one patient (5%) in the Fast Track group, though this difference was not statistically significant. Conclusions: The Fast Track protocol developed in this study has proven to be effective in significantly reducing hospitalization time in patients submitted to RC with intestinal urinary diversion, without increasing post-operatory complications ratio.

KEY WORDS: Radical cystectomy; Fast Track; Enhanced recovery; After surgery. Submitted 4 June 2019; Accepted 26 June 2019

INTRODUCTION

Bladder cancer (BC) represents the 7th most common cancer in male population and the 11th considering both

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sexes (1). Open RC remains the gold standard for the surgical treatment of localized muscle invasive bladder cancer (MIBC) or non-muscle invasive bladder cancer (NMIBC) resistant to topic chemo- and immunologic therapy (2, 3). RC with urinary diversion is considered one of the most complex urological surgery and is characterized by long hospital stay and high rate of postoperative morbidity and mortality. Complication rate could be up to 34.4% (and to 50% in some series) for mildmoderate grade (Clavien Dindo < 3), and up to 17.5% for severe grade (4, 5) (Clavien Dindo ≥ 3). Even if improvements in surgical procedure have reduced incidence of postoperative complication, it remains important to minimise surgical trauma and optimise perioperative care. The term “Fast Track” refers to a group of perioperative protocols aimed to standardise perioperative cares, shorten hospital stay, maintain optimal surgical treatment quality without increasing postoperative complication rate (6). They are also commonly known as Enhanced Recovery After Surgery (ERAS) protocols, as they were firstly described in general surgery. FT schemes are standardised, multimodal and multidisciplinary developed protocols aimed to enhance surgical outcomes referring to perioperative “best clinical practice” (7). The origins of ERAS protocols date back to the early 90s with the experiences of Dahl et al., with bupivacaine intratecal analgesia (8), and Kehlet et al. with epidural anaesthesia, high preoperative glucose intake and early mobilization and starting of oral diet, applied on colorectal surgery with a mean reduction of 2 days in terms of hospital stay (9). From the urologist’s point of view, FT protocols can be applied mainly to RC with ileal diversion, considering the complex operation technique, high complication rate and long mean hospital stay. Distinctive tract of the FT protocols is that they can be adapted on patient’s needs depending on perioperative management phase. Key features of FT protocols are: perioperative diet management, advanced anesthesiological technique, specific antalgic postoperative care (based on non-opioid drugs), early oral diet intake and mobilization (10). We developed a FT protocol with the aim of reducing mean hospitalization time in patients subNo conflict of interest declared.

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Fast Track protocol after radical cystectomy with ileal urinary diversion

mitted to RC with ileal urinary diversion in our centre, without increasing the complications ratio.

MATERIALS

AND METHODS

After an extensive review of literature and a multidisciplinary team consult consisting of urologists, anesthesiologists, nurses and nutritionists, we developed an ERAS protocol (see Appendix). To test the effect of this protocol, we designed a pilot observational prospective cohort study, in accordance with the principles and practice of our Review Board. The protocol focused on the reduction of postoperative nausea and vomiting, early canalization, nasogastric tube (NGT) removal, enteral feeding and mobilization, shorter hospitalization time, without significant worsening in terms of complication rate or pain management. We enrolled 20 consecutive patients candidate to open RC with ileal urinary diversion from January 2016 to April 2017 at a single high volume centre. Each operation was performed by surgeons at the end of the learning curve and with extensive experience. The indications for RC included muscle-invasive bladder carcinoma or high-grade non-muscle invasive bladder carcinoma refractory to topic intravesical immunotherapy in fit-for-surgery patients (2, 3). Preoperative radiological assessment was realized via a toraco-abdominal computed tomography with urographic reconstructions and contrast enhanced magnetic resonance of the pelvis (we adopted this accessory technique in order to have a precise and detailed study of the pelvis, as previously described) (11). Data were prospectively collected from medical records. For each patient of the study population a one-to-one propensity scorematched analysis was performed with a population selected among 64 patients who underwent RC with ileal urinary diversion, without application of the FT protocol. Each patient received detailed instructions about FT protocol at preoperative evaluation. Adherence to instructions was verified at the time of the hospital admittance. Data were prospectively collected for patients in the FT group, while, for patients of the control group, each item was retrospectively collected. Preoperative data were collected about age, Body Mass Index (BMI), American Society of Anesthesiology score (ASA Score), Charlson Comorbidity Index (CCI), smoking habits, clinical stage, grading (defined sec. WHO 2016 classification) or neoadiuvant therapy. We collected data regarding surgical approach, urinary diversion used, pelvic lymphadenectomy template, number of removed lymph nodes, global operation time (minutes) and intraoperative transfusion rate. Postoperative data collection comprehended

histological tumor features (such as stage, grading, lymph node status), hospital stay time, NGT removal

Table 1. Preoperative and intraoperative items. Number of patients, n (%) Gender, n (%) Male Female Age Median (IQR) ASA score, n (%) 1-2 3-4 CCI, n (%) 0 1-2 3-4 >4 BMI (Kg/m2) Mean ± SD Smoking attitude, n (%) No Yes Clinical stage, n (%) T0 Ta-pT1 T2 T3 Preoperative grade, n (%) G1 G2 G3 Neoadjuvant chemotherapy, n (%) No Yes Surgical approach, n (%) Open Laparoscopic PLND template, n (%) Not performed Standard Extended Super-extended Lymph node retrieved Median (IQR) Urinary diversion, n (%) Ileal conduit Ileal ortotopic neobladder (Studer neobladder) Surgical time (minutes) Mean ± SD Intraoperative transfusion, n (%) No Yes Pathologic stage, n (%) pT0 pT1-pTis pT2a-pT2b pT3a-pT3b pT4 Pathologic grade, n (%) G1 G2 G3 G4 LNI, n (%) No Yes

Overall Fast Track group 40 (100%) 20 (50%)

Control group 20 (50%)

P value -

31 (77.5) 49 (22.5)

16 (80) 4 (20)

15 (75) 5 (25)

0.7

71 (63-76)

70 (60-76)

72 (66-75)

0.6

16 (40) 24 (60)

9 (45) 11 (55)

7 (35) 13 (65)

0.5

0 (0) 7 (17.5) 15 (37.5) 18 (45)

0 (0) 4 (20) 8 (40) 8 (40)

0 (0) 3 (15) 7 (35) 10 (50)

0.8

28 ± 4.8

28 ± 4.9

28 ± 5

0.9

16 (40) 24 (60)

11 (55) 9 (45)

5 (25) 15 (75)

0.05

1 (2.5) 12 (30) 23 (57.5) 4 (10)

0 (0) 7 (35) 11 (55) 2 (10)

1 (5) 5 (25) 12 (60) 2 (10)

0.7

1 (2.5) 5 (5) 37 (92.5)

0 (0) 1 (5) 19 (95)

1 (5) 1 (5) 18 (90)

0.6

40 (100) 0 (0)

39 (97.5) 1 (2.5)

19 (95) 1 (5)

20 (100) 0 (0)

0.3

2 (5) 22 (55) 14 (35) 2 (5)

1 (5) 13 (65) 4 (20) 2 (10)

1 (5) 9 (45) 10 (50) 0 (0)

0.2

14 (10-23)

14 (12-21)

14 (8-24)

0.3

23 (57.5) 17 (42.5)

11 (55) 9 (45)

12 (60) 8 (40)

0.7

276 ± 57

260 ± 56

293 ± 54

0.06

27 (67.5) 13 (32.5)

15 (75) 5 (25)

12 (60) 8 (40)

0.3

2 (5) 9 (22.5) 7 (17.5) 15 (37.5) 7 (17.5)

1 (5) 6 (30) 3 (15) 6 (30) 4 (20)

1 (5) 3 (15) 4 (20) 9 (45) 3 (15)

0.8

2 (5 ) 2 (5) 35 (87.5) 1 (2.5)

1 (5) 1 (5) 17 (85) 1 (5)

1 (5) 1 (5) 18 (90) 0 (0)

0.8

26 (65) 14 (35)

13 (65) 7 (35)

IQR: Inter Quartile Range; VAS: Visual Analogue Scale; ASA: American Society Of Anesthesiologists; CCI: Charlson Comorbidity Index; BMI: Body Mass Index; SD: Standard Deviation; PLND: Pelvic Lymph Node Dissection; LNI: Lymph Node Invasion.

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(time and repositioning), pain control (coded by visual analogic scale [VAS] standard), time to flatus and time to defecation, lymphorrea amount, time of the start of a light diet and time to drain removal. Postoperative complications were stratified as early (before 30 days from surgery) and late complications (between 30 and 90 days from surgery). All complications were graded following the Clavien-Dindo classication. To compare results between the study population and the control group a one-to-one propensity score-matched analysis was computed by modelling a logistic regression, with the dependent variable as the odds of undergoing Fast Track protocol and independent variables such as age at surgery, BMI, gender, ASA score, CCI, preoperative stage and urinary diversion in course of surgery. Subsequently, covariate balance between the matched groups was examined. Covariates between the two groups were considered equivalent, providing a standardised mean difference ≤ 10%. The primary objective was the evaluation of the eventual reduction in hospitalization ratio, while the secondary objective was the evaluation of any difference in the early (< 30 days) and late (< 90 days) postoperative complication ratio. Statistic software R (The R Foundation) was used for statistical analysis. Chi-square test and t test were used for binomial and continuous variables, respectively.

RESULTS

11 (55%) patients of FT groups underwent ureteroileocutaneostomy, while 9 (45%) patients underwent urinary diversion with orthotopic neobladder (according to the Studer technique), while, in the control group, 12 (60%) patients received ureteroileocutaneostomy and 8 patients (40%) were submitted to orthotopic urinary diversion according to the Studer technique. Table 1 shows preoperative and intraoperative characteristics of the two study groups. The two groups were statistically homogenous, with no significant difference among them. Considering intraoperative parameters, mean operative time was 260 ± 56 min in FT group, while was 293 ± 54 min in the control group, with a difference at the limit of the statistical difference (p = 0.06). Table 2 depicts Fast Track outcomes. NGT was removed earlier in the FT group than in the control group, with a median of 20 hours versus 48 hours, respectively (p < 0.001). Just one patient (5%) of the FT group had SNG removed after the first 24 hours. No significant difference was noted in NGT repositioning rates between the two groups (15% in FT group and 5% in control group, p = 0.3).

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Table 2. Postoperative datas. Number of patients, n (%) NGT removal ( hours) Median (IQR) NGT removal after POD 1, n (%) NGT repositioning, n (%) Mobilization (hours postoperatively) Mean ± SD Postoperative nausea episodes, n (%) None 1 >1 Postoperative VAS Score Median (IQR) Time to flatus (POD) Median (IQR) Time to defecation (POD) Median (IQR) Start of a light diet (POD) Median (IQR) Last drain removal (POD) Median (IQR) Lymphorrea amount (ml) Mean ± SD Hospital stay (days) Median (IQR)

Overall Fast Track group 40 (100%) 20 (50%)

Control group 20 (50%)

P value -

24 (20-48) 18 (42.5) 4 (10)

20 (18-20) 1 (5) 3 (15)

48 (48-72) 16 (80) 1 (5)

< 0.001 < 0.001 0.3

66 ± 43

21 ± 12

106 ± 26

< 0.001

25 (62.5) 7 (17.5) 8 (20)

13 (65) 6 (30) 1 (5)

12 (60) 1 (5) 7 (35)

0.02

4 (3-4)

3 (3-4)

4 (3-4)

0.2

2 (1-3)

1.5 (1-2.75)

3 (2-3.75)

0.004

5 (3-6)

4 (3-5.75)

6 (4.5-6)

0.02

5 (2-8)

2 (2-4.5)

6.5 (6-8)

< 0.001

8 (6-9)

7 (6-9.75)

8.3 (7-9)

0.5

1720 ± 1534

1776 ± 1710

1665 ± 1380

0.8

12 (9-14)

10 (8-12)

13 (11-14)

0.005

NGT: Naso Gastric Tube; POD: Post Operatory Day; SD: Standard Deviation; IQR: Inter Quartile Range.

Table 3. Postoperative complications. Overall Fast Track group Control group P value Number of patients, n (%) 40 (100%) 20 (50%) 20 (50%) Overall perioperative (< 30 days) complications, n (%) No 31 (77.5) 14 (70) 17 (85) 0.3 Yes 9 (22.5) 6 (30) 3 (15) Clavien-Dindo classification, n (%) Grade 1 6 (66.6) 5 (83.3) 1 (33.3) 0.3 Grade 2 2 (22.2) 1 (16.7) 1 (33.3) Grade 3 1 (11.1) 0 (0) 1 (33.3) Grade 4 0 (0) 0 (0) 0 (0) Grade 5 0 (0) 0 (0) 0 (0) Type of complication (< 30 days), n (%) Dynamic Ileus 6 (66.6) 5 (83.3) 1 (33.3) 0.3 Anemization 1 (11.1) 1 (16.7) 0 (0) Wound Infection 1 (11.1) 0 (0) 1 (33.3) Deep Venous Thrombosis 1 (11.1) 0 (0) 1 (33.3) Overall postoperative (< 90 days) complications, n (%) No 36 (90) 19 (95) 17 (85) 0.3 Yes 4 (10) 1 (5) 3 (15) Clavien-Dindo classification, n (%) Grade 1 0 (0) 0 (0) 0 (0) 0.3 Grade 2 0 (0) 0 (0) 0 (0) Grade 3 4 (100) 1 (100) 2 (100) Grade 4 0 (0) 0 (0) 0 (0) Grade 5 0 (0) 0 (0) 0 (0) Type of complication (< 90 days), n (%) Lymphocele (Right Iliac Fossa) 1 (25) 1 (100) 0 0.2 Uretero-Ileal Anastomosis Stricture 2 (50) 0 2 (66.7) Laparocele 1 (25) 0 1 (33.3) Readmission within 90 days, n (%) 4 (10) 1 (5) 3 (15) 0.3

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Fast Track protocol after radical cystectomy with ileal urinary diversion

Mobilization time was significantly shorter in the FT group than in the control group (mean 21 Âą 12 hours vs 106 Âą 26 hours, respectively, p < 0.001). We observed one (5%) patient in the FT group who had more than one nausea episode postoperatively, while we noted 7 (35%) of such events in the control group (p = 0.02). Median time to flatus was 1,5 (IQR 1-3) days in the FT group and 3 (IQR: 2-3.75) days in the control group, with a statistically significant difference (p = 0.004). We also observed a significant shorter time to defecation in the FT group (4 days IQR: 3-5.75) than in the control group (6 days, IQR 4.5-6) with p = 0.02. No statistically significant difference was noted in terms of VAS scale, duration and entity of lymphorrea between the two groups. We observed a statistically significant shorter median hospital stay time in the FT group (10 days, IQR: 8-12) than in the control group (13 days, IQR: 11-14, p = 0.005). As depicted in Table 3, no statistically significant difference was noted in terms of early and late complication rate among the two groups (p = 0.3 for each type of complication, respectively). Considering early complications, only one event graded as Clavien 3 was reported (11.1%), and it was a wound infection surgically treated in the control group. Considering late complications ratio, 4 events graded as Clavien 3 were documented, 1 in the FT group (right iliac fossa lymphocele percutaneously drained), and 3 in the control group (2 cases of uretero-ileal anastomosis stricture surgically corrected, and 1 case of laparocele surgically repaired), though this difference was not statistically significant (p = 0.2). No statistically significant difference was found in terms of readmission rate within 90 days among the two groups (p = 0.3)

DISCUSSION

RC with ileal urinary diversion is a surgery historically affected by a high rate of perioperative morbidity and mortality. With the starting point set in intervention on bowel in general surgery, ERAS protocols were described in order to improve postoperative outcomes. Although a number of ERAS protocols have been built over the years, all of them found their key features on strategies to improve postoperative recovery rate and reduction of hospital stay time, without worsening postoperative complication rate. After extensive literature review and multidisciplinary meeting between urologists, anaesthetists, nurses and nutritionists, we designed a tailored ERAS protocol to be adopted at a high volume institution. In order to validate the FT protocol we designed a case-control prospective study, matching patients who underwent RC with ileal urinary diversion and who applied the protocol with patients who underwent the same kind of surgery but without implementation of the protocol. In our cohorts of RC with ileal urinary diversion, the adherence to the FT protocol permitted to obtain a significant shorter hospitalization time, without a significant increase in term of perioperative complications rate. An interesting fact is that no preoperative bowel preparation was adopted, because, as demonstrated by Shafii et al., it does not give any significant advantage (12). Moreover, the early removal of the NGT tube, in adjunction with a continuous prokinetic stimu-

lus, has proven to be feasible, in accordance to the experience of Braga (13), who demonstrated that decompression with NGT in all patients is not necessary ad is associated with an increased incidence of pulmonary complications. An important contribute to this result is represented by the perioperative dietary regimen and by the intra- and postoperative pain management. The hypercaloric and hyperglucidic preoperative dietary regimen of the FT protocol allows to create a preoperative supply of proteins and glucose in order to react to the operative stress without significantly compromise the homeostasis and improving the natural healing process. This fact seems to be the possible base for the observation that no wound infections were reported in the FT group. As a matter of fact, wound repair depends on the disponibility of adequate protein and glucose supply, which could be insufficient after a prolonged perioperative fasting period. We observed no statistically significant difference in VAS scale evaluation between the two groups, so we might affirm the non-inferiority of an opioid-free pain control regimen (based on FANS and continuous infusion via epidural catheter), in comparison with the pain control obtained with opioid drugs. Moreover, the absence of opioid administration allows to avoid typical side effects, such as a prolonged intestinal transit, which could hesitate in delayed time to flatus and time to defecation. Other aspects of our FT protocol aimed to improve intestinal function, such as administration of prokinetic drugs (metoclopramide) and of chewing-gum, as already been prove successful by Kouba et al. (14). We observed a statistically significant reduction of canalization time in FT group compared to control group, either considering median time to flatus (respectively in POD 1,5 vs POD 3, p = 0.004) and median time to defecation (respectively on POD 4 vs POD 6, p = 0.02). Moreover we observed that patients of the FT group could tolerate a solid diet regimen on POD 2, significantly sooner in comparison with patients of the control group (median POD 6.5, p < 0.001). These results could be explained by the fact that metoclopramide administration is able to reduce the incidence of nausea and vomiting episodes, and also gastrointestinal complications, as described by Pruthi (15). Another explanation for this matter could be the fact that faster bowel activity recovery might be reached also with early mobilization and early feeding, as postulated by Cerruto et al. (10). Internal peristalsis is moreover facilitated by the blocking of visceral afferents and segmental efferences, which is realized by the epidural analgesia (16). The importance of a T11 epidural catheter as a useful tool to increase microvessels perfusion (thus reducing interference with the cardiopulmonary system), has been underlined by Friedrich-Freksa, who successfully applied this technique to high-risk patients submitted to RC (17). The result of the aforementioned considerations allows patients in the FT group to be discharged 3 days before, in comparison with patients of the control group (mean 10 days vs 13 days, p = 0.005). This result is in line with the Literature, though there are discordant experiences, as the one described by Cerruto (10), who reported no statistically significant difference in mean hospital stay Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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time in patients submitted to RC with implementation of a dedicated FT protocol. A promising synergy is represented by FT protocols applied to mini-invasive surgery, a technique which is usually already characterized by a short hospital stay (18). As demonstrated by Saar et al. (19), the implementation of a FT protocol in case of robotic approach to RC provides a significant advantage in terms of return to a regular diet and use of postoperative morphine equivalents. The efficacy of FT protocols applied to mini-invasive surgery has led to the recommendation to always adopt them in case of robot assisted radical cystectomy, as written in the paper published by Wilson (20). Moreover, the use of barbed sutures (21), a typical feature of the robotic approach, might improve the postoperatory continence ratio, as described in case of robotassisted radical prostatectomy (22, 23). Another point of interest of FT protocols is the eventual reduction of both postoperative complications ratio and 90-days readmission rates. On a previous publication by Cerruto et al. on the effect of a FT protocol in patients candidates to robot-assisted RC with Padovana ileal neobladder, the authors reported a lower global rate of postoperative complications (p = 0.004) in patients adherent to the protocol (10). In our study we did not record a statistically significant difference between the two groups in terms of complications or readmission rate. Such observation is in partly due to the scarce numerosity of the group of our study. It is important to underline that no major early complication (grade 3 or superior according to the Clavien-Dindo classification) was observed in the FT group. Moreover, of the 4 (10%) major late complications observed, only 1 (5%) was in FT group, while 3 (15%) were in control group. The complication of the FT group was a lymphocele treated with ultrasound-guided percutaneous drainage, which seemed unrelated to FT protocol implementation. On the control group we observed one early and three late complications Clavien â&#x2030;Ľ 3, consisting of wound infection (early complication), two uretero-ileal anastomotic strictures (a well-documented complication of this kind of surgery) (24) and a laparocele, all of them treated with surgical revision on general anaesthesia. A limitation of the present study is the limited number of patients enrolled, though the scarce numerosity seems to be a common feature in studies concerning FT protocols applied to RC, as confirmed by a recent paper published by Freeks et al. (25).

REFERENCES

CONCLUSIONS

17. Friederich-Freksa M, et al. Cystectomy and urinary diversion in the treatment of bladder cancer without artificial respiration. Int Braz J Urol. 2012; 38:645-651.

The implementation of the FT protocol to patients submitted to RC with urinary ileal diversion is a safe and effective procedure, which allows to reduce hospitalization time without increasing postoperatory complications ratio. Further studies are needed, with larger populations, in order to definitively confirm the superiority of FT protocols over standard protocols in the perioperative management of patients submitted to this surgical procedure.

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1. Ferlay J, et al. Cancer incidence and mortality patterns in Europe: Estimates for 40 countries in 2012. Eur J Cancer. 2013; 49:13741403. 2. Babijuk M, et al. EAU Guidelines: Non-muscle-invasive Bladder Cancer, 2019. 3. Witjes JA, et al. EAU Guidelines: Muscle-invasive and Metastatic Bladder Cancer, 2019. 4. Schiavina R, et al. Perioperative Complications and Mortality After Radical Cystectomy When Using a Standardized Reporting Methodology. Clin Genitourin Cancer. 2013; 11:189-197. 5. Chung Y-R, et al. Association of statin use and hypertriglyceridemia with diabetic macular edema in patients with type 2 diabetes and diabetic retinopathy. Cardiovasc Diabetol. 2017; 16:4. 6. Geltzeiler CB, et al. Prospective Study of Colorectal Enhanced Recovery After Surgery in a Community Hospital. JAMA Surg. 2014; 149:955-961. 7. Chang SS, et al. Analysis of Early Complications After Radical Cystectomy: Results of a Collaborative Care Pathway, J Urol. 2002; 167:2012-6. 8. Dahl JB, et al. Influence of timing on the effect of continuos extradural analgesia with bupivacaine and morphine after major abdominal surgery, Br J Anaesth. 1992; 69:4-8. 9. Kehlet H, et al. Multimodal strategies to improve surgical outcome. Am J Surg. 2002; 183:630-641. 10. Cerruto MA, et al. Fast track surgery to reduce short-term complications following radical cystectomy and intestinal urinary diversion with Vescica Ileale Padovana neobladder: proposal for a tailored enhanced recovery protocol and preliminary report from a pilot study. Urol Int. 2014; 92:41-49. 11. Schiavina R, et al. MRI Displays the Prostatic Cancer Anatomy and Improves the Bundles Management Before Robot-Assisted Radical Prostatectomy. J Endourol. 2018; 32:315-321. 12. Shafii M, et al. is mechanical bowel preparation necessary in patients undergoing cystectomy and urinary diversion? BJU Int. 2002, 89:879-881. 13. Braga M, et al. ESPEN Guidelines on Parenteral Nutrition: surgery. Clin Nutr. 2009; 28:378-386. 14. Kouba EJ, Wallen EM, Pruthi RS. Gum chewing stimulates bowel motility in patients undergoing radical cystectomy with urinary diversion. Urology. 2007; 70:1053-1056. 15. Pruthi RS, et al. Fast track program in patients undergoing radical cystectomy: results in 362 consecutive patients. J Am Coll Surg. 2010; 210:93-99. 16. White PF, et al. The role of the anesthesiologist in fast track surgery: from multimedial analgesia to perioperative medical care. Anesth Analg. 2007; 104:1380-1396.

18. Porreca A, et al. Robot assisted radical cystectomy with totally intracorporeal urinary diversion: initial, single-surgeon's experience after a modified modular training. Minerva Urol Nefrol. 2018; 70:193-201. 19. Saar M, et al. Fast-track rehabilitation after robot-assisted laparoscopic cystectomy accelerates postoperative recovery. BJU Int. 2013; 112:E99-E106.

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Fast Track protocol after radical cystectomy with ileal urinary diversion

20. Wilson TG, et al. Best practices in robot-assisted radical cystectomy and urinary reconstruction: recommendations of the Pasadena Consensus Panel, Eur Urol. 2015; 67:363-75.

culofascial reconstruction and knotless vesicourethral anastomosis during robot-assisted radical prostatectomy. Minerva Urol Nefrol. 2018; 70:319-325.

21. Mineo Bianchi F, et al. Posterior muscle-fascial reconstruction and knotless urethro-neo bladder anastomosis during robot-assisted radical cystectomy: Description of the technique and its impact on urinary continence, Arch Ital Urol Androl. 2019; 91:5-10.

24. Schiavina R, et al. Laparoscopic and robotic ureteral stenosis repair: a multi-institutional experience with a long-term follow-up. J Robot Surg. 2016; 10:323-330.

22. Porreca A, et al. Robotic-Assisted Radical Prostatectomy with the Use of Barbed Sutures, Surg Technol Int. 2017; 30:39-43. 23. Porreca A, et al. Bidirectional barbed suture for posterior mus-

25. Freeks SK, et al. A prospective randomized pilot study evaluating an ERAS protocol versus a standard protocol for patients treated with radical cystectomy and urinary diversion for bladder cancer, World J Urol. 2018; 36:215-220.

Appendix Enhanced Recovery Protocol Preoperative clinical setting: within 7 days before surgery - Anestehesiological assessment - Written dietary recommendations - Diet with no restrictions Preoperative days - 24 hours before RC - Hospital admittance - Unrestricted clear fluids - Normal breakfast - No bowel preparation Perioperative phase - day of RC - Clear fluids allowed up to 2 hours before RC - Nutritional supply 2 hours before surgery (400 mL/200 calories) - Elastic compressive stockings - Ceftriaxone 2 g i.v as prophylaxis for infection Intraoperative phase - day of RC - Combined general and epidural anesthesia with intrathecal catheter left in place for the first PODs - Optimized intraoperative intravenous fluid administration - NGT insertion preoperatively ad removal at the end of surgery - Reducing intraoperative blood loss - Antiemetic prophylaxis - Infiltration of the surgical wound with local anesthetic Postoperative phase - day of RC - Ranitidine 150 mg i.v. - Metoclopramide 25 mg i.v. every 8 hours - Intravenous analgesia (paracetamol, ketorolac) - Epidural analgesia (elastomeric pump loaded with naropine) - Low molecular weight heparin (LMWH) as prophylaxis for thromboembolic events - Intravenous hydration (100 mL/h) of 10% glucose solution and electrolyte solution - Mobilization 6 hours after surgery - Free clear fluids as tolerated Postoperative phase - POD 1 - Female patients: remove vaginal pack - Active mobilization - Respiratory rehabilitation exercises - 1100 calories diet as tolerated - Free clear liquids as tolerated - Analgesia if needed (ropivacaine, paracetamol, ketorolac) - Metoclopramide 25 mg i.v. every 8 hours - Ranitidine 150 mg 1 tab/die - LMWH as prophilaxys - Chewing gum (1 piece very 2-4 hours), as tolerated Postoperative phase - POD 2 - 1500 calories diet as tolerated - Free clear fluids - Active mobilization - Drain removal (if drained < 50 mL/24 hours)

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D. Romagnoli, R. Schiavina, L. Bianchi, et al.

Epidural catheter removal Neobladder flushes 3 trimes a day (every 8 hours) Analgesia if required (paracetamol, ketorolac) LMWH as prophylaxis Metoclopramide 25 mg i.v. every 8 hours Continue ranitidine

Postoperative phase - POD 3 - Active mobilization - 1650 calories diet - Analgesia if needed (paracetamol, ketorolac) - Metoclopramide 25 mg i.v. every 8 hours - LMWH as prophylaxis - Continue ranitidine - Continue neobladder flushing Postoperative phase - POD 4 - Active mobilization - 2000 calories diet as tolerated - Analgesia if needed (paracetamol, ketorolac) - Metoclopramide 25 mg i.v. every 8 hours - LMWH as prophylaxis - Continue ranitidine - Continue neobladder flushing Postoperative phase - PODs 5 to 7 - Free diet - Active mobilization - If absence of canalization and oralization after 5 days from surgery, start total parenteral nutrition (TPN) and search for any cause - Continue neobladder flushing - LMWH as prophylaxis - Continue ranitidine Postoperative phase - PODs 8 and 9 - Ureteral stents removal - Clips removal - LMWH as prophylaxis Postoperative phase - PODs 10 and 11 - Schedule for return to home - LMWH as prophylaxis (up to 18 days after RC) Postoperative phase - POD 30 - Catheter removal (without neocystogram)

Correspondence Daniele Romagnoli, MD (Corresponding Author) danieleromagnoli87@gmail.com Marco Giampaoli, MD Paolo Corsi, MD Daniele Dâ&#x20AC;&#x2122;Agostino, MD Angelo Porreca, MD Robotic Urology and Mini Invasive Urologic Surgery Unit Abano Terme Hospital, Piazza Cristoforo Colombo 2 - Abano Terme (PD), Italy Riccardo Schiavina, MD Lorenzo Bianchi, MD Marco Borghesi, MD Federico Mineo Bianchi, MD Andrea Angiolini, MD Eugenio Brunocilla, MD Urology Unit, S. Orsola Malpighi University Hospital - Alma Mater Studiorum Via Pelagio Palagi, 9 Bologna (Italy) Francesco Chessa Carlo Casablanca St. Orsola Malpighi Universitary Urology Clinic, Bologna (BO), Italy

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DOI: 10.4081/aiua.2019.4.237

ORIGINAL PAPER

Does duration of stenting increase the risk of clinical infection? Tuncay Toprak, AytaĂ§ SĚ§ahĂŻn, Musab Ali Kutluhan, Korhan Akgul, Yavuz Onur Danacioglu, Mehmet Akif Ramazanoglu, Ayhan Verit Department of Urology, Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Turkey.

Summary

Objective: We investigated when an indwelling ureteral catheter should be withdrawn for infection and evaluated the importance of urinary cultures in identifying colonized microorganisms and define the bacterial flora encountered in the study. Moreover, this study tried to determine the clinical role of stent culture in clinical practice. Material and methods: The study was conducted between June 2018 and February 2019. Patients with ureteral stent implantation after endoscopic ureteral stone treatment were divided into two groups and each group consisted of 45 patients. Ureteral catheter was removed 15 and 30 days after ureteral stone treatment in group 1 and 2, respectively, and transferred for microbiological examination. The urine culture was obtained before and after ureteral stent implantation. The groups were compared in terms of demographics, urine and catheter cultures results. Urine analysis and catheter culture results were also compared. Results: Demographic data of patients were similar in both groups. 3 patients in group 1 and 12 patients in group 2 had positive urine culture before catheter retraction; 2 of 45 and 6 of 45 patients had positive catheter culture in group 1 and 2, respectively. Although 2 patients in group 1 and 4 patients in group 2 had urine culture sterile, they had growth in catheter culture. In Group 1, 1 of the microorganisms was E. fecalis and 1 was E. coli. In Group 2, 2 cases were E. fecalis, 3 were E. coli and 1 was MRSE. There was no significant difference between the urine analysis results of the patients before catheter retraction and catheter culture positivity. Conclusions: Pre-operative urine culture does not exclude catheter colonization, and the prolonged duration of the catheter associated with greater colonization and may be associated urinary tract infection. Ureteral catheter should be removed as early as possible.

KEY WORDS: Duration; Ureteral stents; Colonization. Submitted 15 June 2019; Accepted 23 July 2019

INTRODUCTION

Ureteral stenting is commonly used for drainage of the obstructed or infected upper urinary tract. Although ureteral stent application is not routinely recommended after each ureteroscopy (1) ureteral stents were inserted before the procedure to relieve pain to 7 to 68% of patients who underwent ureteroscopy (2). Ureteral stent is often colonized and incrustated, because it is in direct contact with urine after insertion (3) and sterile urine cultures do not exclude bacterial colonization on ureter-

al stents and postoperative urinary tract infection (4). Many studies indicated there is no significant difference between stents and urine cultures, complicating the selection of appropriate antibiotics even when bacteria are identified in urine culture (5, 6). We investigated when an indwelling ureteral catheter should be withdrawn for infection and evaluated the importance of urinary cultures in identifying colonized microorganisms and define the bacterial flora encountered in the study. Moreover, this study tried to determine the clinical role of stent cultures in clinical practice.

MATERIAL

AND METHODS

This prospective study was approved by the institutional ethics committee of Fatih Sultan Mehmet Training and Research Hospital (FSM EAH-KAEK 2019/13) and was conducted between June 2018 and February 2019. All patients gave an informed consent for participation in the study. Patients who underwent ureteral stent implantation after endoscopic ureteral stone treatment were included in this study. The patients who had positive urine culture before ureteral stone treatment and who underwent ureteroscopy for other reasons and patients who had diabetes mellitus, chronic renal diseases, or immune suppression were not included in this study. Patients were divided into two groups and each group consisted of 45 patients. At the beginning and before catheter retraction urine culture were obtained from mid-stream voided urine. Stents were inserted and removed under aseptic conditions with 22 Fr rigid cystoscope. Intravenous second-generation cephalosporin was given 30-60 minutes before stent placement. A polyurethane double J stents (DJS; Uromed, Oststeinbek, Germany) was used for insertion. Ureteral catheters were removed 15 and 30 days after ureteral stone treatment in group 1 and 2, respectively. The ureteral stents were transferred to the microbiological examination immediately. Post-operative antibiotics were not given. Urine culture and ureteral catheter culture results of patients were compared between groups. Urine analysis results and catheter culture results were also compared. Statistical analysis When evaluating the findings obtained in this study, IBM SPSS Statistics 22 for statistical analysis (SPSS IBM, Turkey)

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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T. Toprak, Aytaç Şahïn, M. Ali Kutluhan, K. Akgul, Y. Onur Danacioglu, M. Akif Ramazanoglu, A. Verit

programs were used. The conformity of the parameters to the normal distribution was evaluated by Shapiro Wilks test. For evaluation of study data, Chi-Square test was used to compare qualitative data as well as descriptive statistical methods. Significance was evaluated as p < 0.05.

RESULTS

A total of 90 patients were included in this study. Patients were randomized into two groups. Patients’ characteristics are summarized in Table 1. Male/female ratio was 1.5 in group 1 and 1.25 in group 2. The mean age was 45.6 in group 1 and 42.7 in group 2. No significant difference was observed between the groups in terms of age and gender. The urine culture of all patients was sterile before catheter insertion. Urine culture taken before catheter retraction was positive in 3 patients in group 1 and 12 patients in group 2. Table 2 shows comparison of bacterial growth between groups. Patients with positive urine culture were treated with appropriate antibiotics before ureteral catheter withTable 1. Comparison of demographic characteristics between groups. M/F (%) Age, years, mean

Group 1 (n = 45) 60/40 45.6 (min 19 , max 73)

Group 2 (n = 45) 55.5/44.5 42.7 (min 23, max 76)

P value > 0.05 > 0.05

Table 2. Comparison of bacterial growth between groups. Group 1 (n = 45) Urine culture (at the All of them sterile beginning or before ureteral catheter placement) Urine culture (after ureteral 3 positive (6.6%) catheter placement or before 12 positive (26.6%) ureteral catheter retraction) Catheter culture results 3 of them sterile of patients with positive urine culture before catheter retraction (after antibiotic treatment) Catheter culture in total 2 positive (4.4%) (1 of them women)

Group 2 (n = 45) P value All of them sterile

(2 of them women) (8 of them women)

0.01

10 of them sterile

6 positive (13.3%) (4 of them women)

0.14

Table 3. Bacteriology of the cultured ureteral stents. Enterococcus fecalis MRSE E. coli Sterile Total

Pyuria (> 5 leukocytes) Leukocyte esterase positivity Nitrite positivity

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Group 1 - n (%) 1(%2.2) 0(%0) 1(%2.2) 43(%95.5) 45(%100)

Group 1 Positive catheter culture (n = 2) 1 (%50) 0 (%0) 0 (%0)

Group 2 - n (%) 2(%4.4) 1(%2.2) 3(%6.6) 39(%86.6) 45(%100)

Group 1 Negative catheter culture (n = 43) 18 (%41.8) 4 (%9.3) 3 (%6.9)

Archivio Italiano di Urologia e Andrologia 2019; 91, 4

P value

0.82 0.65 0.69

drawal. Three patients with positive urine culture in Group 1 had no bacterial growth in catheter culture after antibiotic treatment. Two of 12 patients with positive urine culture in Group 2 had the same microorganisminduced growth in catheter culture after antibiotic treatment. Although 2 patients in group 1 and 4 patients in group 2 had urine culture sterile, they had growth in catheter culture. As shown in Table 3; one of the microorganisms isolated from urine culture in Group 1 was E. fecalis and one of was E. coli. In Group 2, 2 cases were E. fecalis, 3 were E. coli and 1 was MRSE. The urine analysis of the patients before the procedure was investigated for nitrite positivity, leukocyte esterase positivity and pyuria and compared with catheter culture results. As shown in Table 4 no statistically significant difference was found between catheter culture and urine analysis results. The duration of surgical procedures ranged from 9 to 37 minutes, but the relationship between the duration of surgery and colonization was not investigated.

DISCUSSION

Ureteral stents are usually effective and safe in order to deliver urine from kidney to the bladder. However, they can lead to various complications, one of them being urinary infection (7). After stent insertion biofilm formation starts immediately, however, the time required for bacteria to colonize the stent has not yet been defined (3). Several studies showed the ability of uropathogens such as E. coli, Proteus mirabilis, Staphylococcus epidermidis, and Enterococcus faecalis to form biofilms on ureteral stents within 24 hours (8, 9). Biofilm formation process on a ureteral catheter is well defined by some studies (10), and begins with the early development of the first membrane on the catheter. Bacteria on this membrane can more easily adhere and multiply. This environment protects bacteria from antibacterial factors (3) and bacteria appear to be more resistant to antibiotics by developing resistance genes to antibiotics (11). Consequently, it is not surprising that stent colonization is frequently encountered. In our study approximately 9% of our patients hosted one microorganism and 87.5% of these colonies included Gram-negative bacteria. This rate is similar to rates described by other publications that are below 50% for a mean catheterization time between 2 and 9 weeks (6, 12-14). Stent retention time in the ureter increases the likelihood of biofilm formation and so the duration of stenting is considered to be a critical factor for bacterial proliferation (13). However, some reports (6, 15) didn’t find a meaningful relationship between positive cultures and catheterization time. In our study, patients in group 2 had more bacterial growth in ureteral stent cultures than group 1 patients. Female gender in

Group 2 Positive catheter culture (n = 6) 3 (%50) 1 (%16.6) 2(%33.3)

Group 2 Negative catheter culture (n = 39) 21 (%53.84) 3 (%7.6) 5 (%12.8)

P value

0.86 0.47 0.19

Table 4. Comparison of catheter culture and urine analysis.

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Duration of stenting and infection

various studies was found to be associated with a high rate of sepsis as a result of the high infection rate in this population (16). As expected, in our study 62.5% of patients with positive ureteral catheter culture were women, but we have not encountered symptomatic infection or sepsis. The relationship between urine and ureteral catheter cultures is not well defined. Lojanapiwat (17) published urine culture results showing colonization in approximately two-thirds of patients, whereas Klis et al. (5) indicated a large inconsistency between urine and ureteral catheter cultures. Our data supports the discordance between preoperative urine and intraoperative stent culture. In this study, 6 patients had positive stent culture despite sterile urine culture. Sterile urine culture in the presence of foreign bodies doesn’t prevent stent colonization, and this may cause urinary tract infection (18). Although some studies have reported the opposite (15), in our study, the most common pathogen in ureteral catheter cultures were E. coli and Enterococci. In literature, there are also other publications reporting that E. coli (4, 17) and Enterococci (6) are most common in ureteral catheter culture. Kehinde et al. (19) showed that bacteriuria and ureteral stent colonization increased significantly with a longer stenting time, female gender and presence of systemic diseases such as diabetic nephropathy, chronic renal failure and diabetes mellitus and recommended that patient of these categories should have shorter stenting time and antimicrobial prophylaxis to minimize infectious complications. Another study (20) emphasized that early removal of the ureteral stent, 2 weeks after renal transplantation, reduced the rate of urinary tract infection. Although not statistically significant our study gave similar results: longer duration of stenting was associated to higher colonization rate (4.4% for stents left for 15 days versus 13.3% for those left for 30 days). None of our patients had any systemic disease therefore the study of the correlation between presence of pathologies and colonization was not made. In conclusion, our study shows that results of urine cultures do not represent the results of ureteral stent cultures. E. coli is usually isolated and should be coated with preoperative antibiotics. Our study demonstrates that the stents are colonized under natural conditions and that more awareness should be necessary before using these stents. Our findings also showed that colonization of ureteral stents was not associated with the development of symptomatic infection. We didn’t found any symptomatic infection after stent removal and we found a colonization rate of 4.4% within 15 days and 13.3% within 30 days. Limitations of our study We have given preoperative antibiotic treatment which may have affected bacterial flora. Although a study (5) showed that colonization throughout the stent is consistent, we didn’t investigate different ureteral stent segments which could be colonized by different pathogens. Our bacterial profile depends from local flora and could be not transferable to other centers. Finally, stone culture was not done although bacteria within the stone could affect ureteral colonization.

CONCLUSIONS The clinical significance of bacterial colonization of ureteral stent seems to be low, and it seems that ureteral stents are safer, especially within 15 days when colonization is very low. Urine analysis and urine culture results are not related with ureteral stent culture and prolongation of ureteral stent increases colonization. Further studies are needed to determine the optimal indwelling time of ureteral stent after endoscopic ureter stone treatment. Knowing the bacteriological flora of an institution is useful for evidence-based prophylactic and therapeutic application. It is not recommended to routinely send the stents to microbiological examination because it is not cost effective and increases the workload to the microbiology laboratory. Stents should be withdrawn immediately if no more required. Informed consent Ureteral stent is frequently inserted after ureteral stone treatment. Our study named ‘DOES STENT DURATION INCREASE THE RISK OF CLINICAL INFECTION?’ will investigate the relationship between the duration of these ureteral stents with infection. The ureteral stent of some patients will be taken 15 days after the stone treatment and some of them will be taken 30 days later and sent to the microbiological examination. Our research is multicentered and will be between September 2018 and January 2019. A total of 100 patients were planned to be included in the study. Patients will be randomized into two groups. In the event of any unintended or unexpected health problems directly or indirectly related to the research, any medical intervention will be provided by us without any charge. You are completely free to participate in the research. Failure to participate in this study will not necessarily affect your current treatment or relationship with your physician. You have the right to withdraw from the work by giving notice at any time; and if deemed necessary, you may be excluded from research by the investigator, provided that your medical condition is not harmed. If you participate in the research, you will not be charged any fees or charges for any expenses incurred in the study. The sample taken from you for research will be used only for this study. In addition, your information at the end of the research will serve only scientific purposes without your identity being disclosed. Author's contribution Toprak: Project development, Data Collection, Manuscript writing; Şahin: Data Collection, Statistical analysis; Kutluhan: Manuscript writing; Akgul: Revision; Danacıoglu: Data Collection; Ramazanoglu: Data Collection; Verit: Revision.

REFERENCES

1. Blackmur JP, Maitra NU, Marri RR, et al., Analysis of factors' association with risk of postoperative urosepsis in patients undergoing ureteroscopy for treatment of stone disease. J Endourol. 2016; 30: 963-969. Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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2. Sivalingam S, Stormont IM, Nakada SY. Contemporary practice patterns in the management of acute obstructing ureteral stones. J Endourol. 2015; 29: 736-740.

12. 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; 62:214-217.

3. Zumstein V, Betschart P, Albrich WC, et al. Biofilm formation on ureteral stents-Incidence, clinical impact, and prevention. Swiss Med Wkly. 2017; 147:w14408.

13. Kehinde EO, Rotimi VO, Al-Hunayan A, et al. Bacteriology of urinary tract infection associated with indwelling J ureteral stents. J Endourol. 2004; 18:891-896.

4. Farsi HM, Mosli HA, Al-Zemaity MF, et al. Bacteriuria and colonization of double-pigtail ureteral stents: long-term experience with 237 patients. J Endourol. 1995; 9:469-72.

14. Aydin HR, Irkilata L, Aydin M, et al. Incidence of bacterial colonisation after indwelling of double-J ureteral stent. Arch Ital Urol Androl. 2016; 87:291-4.

5. Klis R, Korczak-Kozakiewicz E, Denys A, et al. Relationship between urinary tract infection and self-retaining Double-J catheter colonization. J Endourol. 2009; 23:1015-1019.

15. Kozyrakis D, Perikleous S, Chatzistamou S-E, et al. Is there a role for double J stent culture in contemporary urology? Urol Int. 2018; 100:203-208.

6. Lifshitz DA, Winkler HZ, Gross M, et al. Predictive value of urinary cultures in assessment of microbial colonization of ureteral stents. J Endourol. 1999; 13:735-8.

16. De La Rosette J, Denstedt J, Geavlete P, et al., The clinical research office of the endourological society ureteroscopy global study: indications, complications, and outcomes in 11,885 patients. J Endourol. 2014; 28:131-139.

7. Vallejo JH, Burgos FR, Alvarez JA, et al. Double J ureteral catheter. Clinical complications. Arch Esp Urol. 1998; 51:361-373. 8. Stickler DJ. Bacterial biofilms in patients with indwelling urinary catheters. Nature Reviews Urology. 2008; 5:598. 9. Gabi M, Hefermehl L, Lukic D, et al. Electrical microcurrent to prevent conditioning film and bacterial adhesion to urological stents. Urol Res, 2011; 39:81-88.

18. Grabe M, Botto H, Cek M, et al. Preoperative assessment of the patient and risk factors for infectious complications and tentative classification of surgical field contamination of urological procedures. World J Urol. 2012; 30:39-50.

10. Reid G, Denstedt JD, Kang YS, et al. Microbial adhesion and biofilm formation on ureteral stents in vitro and in vivo. J Urol. 1992; 148:1592-1594.

19. Kehinde EO, Rotimi VO, Al-Awadi KA, et al. Factors predisposing to urinary tract infection after J ureteral stent insertion. J Urol. 2002; 167:1334-7.

11. Kiran MD, Giacometti A, Cirioni O, Balaban N. Suppression of biofilm related, device-associated infections by staphylococcal quorum sensing inhibitors. Int J Artif Organs. 2008; 31:761-70.

20. Coskun AK, Harlak A, Ozer T, et al. Is removal of the stent at the end of 2 weeks helpful to reduce infectious or urologic complications after renal transplantation? Transplant Proc. 2011; 43:813-5

Correspondence Tuncay Toprak, MD (Corresponding Author) drtuncay55@hotmail.com Aytaç Şahïn, MD draytacsahin@gmail.com Musab Ali Kutluhan, MD dr.musab151@gmail.com Korhan Akgul, MD korhanakgul@gmail.com Ayhan Verit, MD veritayhan@yahoo.com Department of Urology, Fatih Sultan Mehmet Training and Research Hospital, Istanbul (Turkey) Yavuz Onur Danacioglu, MD dr_yonur@hotmail.com Department of Urology, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Istanbul (Turkey) Mehmet Akif Ramazanoglu, MD maramazanoglu@hotmail.com Urology, Rize State Hospital, Rize (Turkey)

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17. Lojanapiwat B. Colonization of internal ureteral stent and bacteriuria. World J Urol. 2006; 24:681-683.

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DOI: 10.4081/aiua.2019.4.241

ORIGINAL PAPER

Evaluation of sexual dysfunction prevalence in infertile men with non-obstructive azoospermia Taha Numan Yıkılmaz, Erdem Öztürk, Nurullah Hamidi, !smail Selvi, Halil Başar, Levent Peşkircioğlu Department of Urology, Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital, Ankara.

Summary

Objectives: To determine the prevalence of sexual dysfunction in male partners of infertile couples and evaluate the effect of childlessness on erectile dysfunction (ED) and sexual relationship stress. Materials and methods: We collected datas of couples who attended our clinics for infertility between 2009 and 2016. Erectile dysfunction was investigated with the Questionnaires of International Index of Erectile Function-15 (IIEF-15) whereas premature ejaculation (PE) status with the Premature Ejaculation Diagnostic Tool (PEDT). The stress status of the childlessness in terms of sexual intercourse was scored by the Visual analogue scale (VAS) questionnaire. These scores were measured before and after a successful assisted reproductive treatment with the birth of the child. Results: The median age of the 193 male patients was 31 years (range 23-48). Erectile dysfunction was found in 68 (35.2%) and PE in 42 (21.7%) subjects. One hundred and forty-one couples were treated with assisted reproductive treatments. Forty eight couples had successful pregnancy. The IIEF-15 test was repeated after the birth of the child to the male partners of these couples. We observed that the IIEF-15 scores increased from 16 to 21 (p = 0.014). However there were no significant improvement on their ejaculation status (p > 0.05). The mean VAS scores of male partners was 5.2 (3-10) in the treatment period while it decreased to 4.1 (0-8) after the birth of the chils (p = 0.02). Statistically analysis showed a correlation between VAS and infertility as did IIEF-15. Conclusions: We observed that having children has a reducing effect on sexual relationship stress. Infertility is absolutely blamed on the women and men. This condition may have negative effects on male sexual performance and it is closely related with some emerging female sexual disorders. It should be taken into consideration that infertile couples may have sexual dysfunction.

KEY WORDS: Andrology; Infertility; Childlessness; Anxiety; Erectile dysfunction. Submitted 12 May 2019; Accepted 2 August 2019

INTRODUCTION

Infertility is the inability to have child after 1 year of unprotected intercouse. Fifteen percent of couples experience difficulty conceiving a child. In between one-third and one-half of these, an abnormality can be found in the male partner (1). Infertility has been described as a stressor and a life crisis for individuals or couples, which results in a lower life quality and enhanced marital conflicts (2-5). These stresses play havoc with the couple’s sex life. The physical health and emotional well-being of

many individuals and couples of reproductive age are significantly affected by infertility. Sexual function is one of the important components of health and overall quality of life (6). Thus, couples with infertility may have abnormalities of sexual function, reduced sexual activity and this leads to an increase in the numbers of past years without a baby owner (7). The relationship between sexual problems and infertility is unclear. Infertility causes many psychosexual problems such as loss of libido (with a consequent decrease in sexual activity), impotence, inhibition of orgasm and premature ejaculation (little or no control over ejaculatory response withnejaculation that may occur before vaginal entry achieved) or retarded ejaculation (difficulty ejaculating intravaginally, or at all) in male (8). In contrast, sexual dysfunction may have an etiological role on infertility. Several studies from the United States (US) have suggested that infertility does not impact on sexual or erectile function after controlling for differences in intercourse frequency and/or socio-economic factors (9-11). One the other hand, many studies from US have suggested that infertility is often associated with sexual problems in men (12). The aim of this study is determining the prevalence of sexual dysfunction in male partners of infertile couples and evaluating the effect of childlessness on erectile dysfunction (ED) and sexual relationship stress in male partners.

MATERIALS

AND METHODS

We collected data of couples who attended our clinics for infertility from 2009 to 2016. Age of couples, educational status of couples, duration of marriage, timing of obtaining first sexuality education, the number of successful or unsuccessful conception history of prior paternity, number of intercourse and sexual function were enrolled. Sexual function involved erectile dysfunction and premature ejaculation for men. Erectile dysfunction was investigated with the Questionnaires of International Index of Erectile Function-15 (IIEF-15) (11), in its Turkish translation. Male participants were invited to complete several selfreported questionnaires including modified the IIEF-15 and the modified International Index of Erectile Function (IIEF-5) which consists 5 questions: 2 regarding erectile function, 1 concerning orgasmic function, 1 question on sexual desire, and 1 on satisfaction with intercourse.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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IIEF-15, a 15-item questionnaire for the evaluation of 5 domains of male sexual function (desire, erectile function, intercourse satisfaction, orgasmic function and overall satisfaction) (13, 14). The questionnaire investigated both spontaneous sex for pleasure and sex intended to lead to pregnancy. An IIEF-15 Erectile Function domain score less than 26 was used as a cut-off for the presence of erectile dysfunction (15). According to IIEF15, score was categorized as: (score 6-10) severe ED; (score 11-16) moderate ED; (score 17-21) mild to moderate ED; (score 22-25) mild ED; (score 26-30) no ED. Premature ejaculation (PE) was determined by a questionnaire consisting of 5 separate questions called Premature ejaculation diagnostic tool (PEDT) (16). A PEDT score less than 8 indicates no PE, on the contrary PE was diagnosed. The subjects underwent standard semen analysis, according to World Health Organization criteria. Semen samples obtained by masturbation after 3-5 days of sexual abstinence. Azoospermic men were evaluated according to the clinical parameters (testicular volume and structure, serum FSH levels and testicular biopsy) and only non-obstructive azoospermia patients were included in the study. The stress status of the childlessness in terms of sexual intercourse was scored by the Visual analogue scale (VAS) questionnaire. The scores before and after the birth of the child were compared. Patients with known systematic and psychiatric diseases, taking a medicine that may cause sexual dysfunction or the ones complaining of secondary infertility were excluded from the study. All the data provided were enrolled as part of a routinely clinical procedure and, ethical approval for the study was received from the Ethics Commitee. Written informed consent was obtained from patients who participated in this study. Statistical analysis All statistical analyses were performed with Statistical Package for the Social Science (SPSS Inc, Chicago, Illinois, USA) version 16.0. Normality of tests was analyzed with the Kolmogorov-Smirnov and Shapiro-Wilk tests. The independent samples t test was used for pairwise comparisons of parameters that were distributed normally, and the Mann Whitney U-test was used for parameters that were not distributed normally. Differences were considered significant when p < 0.05.

RESULTS

The median age of the 193 male patients and their partners were 31 (range 23-48) and 27.2 (range 18-43) years, respectively. When the socio-cultural levels of male partners were examined, 59% of them were graduated from high school or university. Couples have been married for an average of 45 months (range 12-193) and the median period of infertility in these couples was 27 months (range 12-180). The average number of weekly frequency of coitus was around 2.5 (range 0.5-7). In this study, all of the cases consisted of primarily infertile couples, whereas a previously successful birth was not observed in any case. The mean number of treatments of couples prior to involvement in study was 0.6 (range 07) including oral medications, injectable fertility drugs,

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intrauterine insemination (IUI).The majority of men was in their first marriage (93%), while a minority was in their second (6%) or third marriage (1%) (Table 1). The results of the IIEF-15 questionnaire showed that 68 (35.2%) men reported an overall ED. Of these, 31 (15.5%) patients reported a mild ED (score 22-25), 25 (12.9%) patients a mild to moderate (score 17-21), 9 (4.6%) patients a moderate ED (score 11-16) and 3 (1.5 %) patients have reported a severe form (score 6-10). Premature ejaculation was seen in 42 (21.7%) patients according to PEDT score. In patients with a PEDT score > 8 acquired and lifelong PE was reported by 56.2% and 43.8% of the patients, respectively. Erectile dysfunction was not seen in 50% of cases with PE, whereas PE was not observed in cases with severe ED. Patients were divided into two groups according to presence of ED, (group 1: IIEF-15 ED score < 26 [n:68]; group 2: no ED [n:125]). The mean age of the patients was 33.1 ± 6.55 and 31.3 ± 4.93, respectively (p = 0.14). When comparing two groups there was no relationship between ED presence and education level but the education levels of men with severe and moderate ED were significantly lower than men with mild ED (p < 0.05). Age of partners was 29.4 ± 6.02 and 27.5 ± 5.15, respectively, and weekly frequency of coitus was 2.1 ± 0.84 and 2.5 ± 0.97 respectively; differences were statistically significant (p = 0.053 and 0.002, respectively). The mean number of treatment protocols applied to these couples was 2.1 (0-4). One hundred and forty-one of the couples were treated with different treatment modalities such as oral drugs, injectable fertility drugs, intrauterine insemination (IUI). Successful pregnancies were obtained in 61 cases with assisted reproduction treatments after a mean of 10 months (3-18 months). Thirteen pregnancies were terminated due to different reasons. After the treatment period, the IIEF-15 test was repeated to 48 male partners of couples having children. We observed that IIEF-15 scores increased from 16 to 21 and that improvement in IIEF-15 scores was statistically Table 1. Sociodemographic and clinical characteristics of the subjects. Age (years) Partner’s age (years) Education (%) Duration of marriage (months) Number of marriage (%)

Duration of infertility (months) Frequency of coitus (per week) Erectile dysfunction n (%) IIEF-15 score n (%)

Premature ejaculation n (%)

All patients (n: 193) 31 ± 4.2 27.2 ± 3.1 Primary/secondary High/University

41 59 45 (12-193)

First Second Third

93 6 1 27 (12-180) 2.5 (0.5-7) 68 (35.2)

No ED (26-30) Mild ED (22-25) Mild to Moderate (17-21) Moderate (11-16) Severe (6-10)

125 (64.8) 31 (15.5) 25 (12.9) 9 (4.6) 3 (1.5) 42 (21.7)

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Sexual dysfunction and non-obstructive azoospermia

Table 2. Comparison of stress levels of 48 male partners with childhood by using VAS questionnaire and ED and PE scores between childlessness and after having child. IIEF (0-30) PE (0-20) VAS (0-10)

Childlessness 16 6.3 ± 2.1 5.2 (3-10)

Having child 21 5.9 ± 1.7 4.1 (0-8)

p 0.014 0.02

significant (p = 0.014). At the same time PE was questioned by PEDT in this group of patients, but no statistical difference was observed. We evaluated the effect of having children on stress levels by VAS score. The Visual analogue scale (VAS) questionnaire was filled during the period of the use of assisted reproduction methods and in the next period after having children in order to evaluate the stress related to infertility. Their stress levels regarding sexual function in these two periods were scored as follows; 0: no stress, 10: very stressful. The mean VAS scores of male partners was 5.2 (3-10) in treatment period while the same group mean score decreased to 4.1 (0-8) when they had children (p = 0.02). Statistical analysis showed a correlation between VAS and infertility like IIEF-15 (Table 2).

DISCUSSION

Sexual dysfunctions are common problems in society. Premature ejaculation (29.3%) is the main sexual displeasure in men in the general population; ED (14.5%) follows as the second sexual health problem (17). The prevalence of infertile couples ranges from 4% to 17% and sexual dysfunction may play an etiological role in these couples (18, 19). In one study, investigating presence of ED and PE in infertile men, Lotti et al. proved that both ED and PE were higher in them compared to fertile men (20). Another study in infertile men on in vitro fertilisation treatment, found no significant difference in infertile men in terms of ED, but these patients had more depressive mood (21). In a community research by Jain et al. premature ejaculation (66%) was the most common problem and it was followed by erectile dysfunction (15%), decreased libido (11%) and orgasmic failure (8%) among the infertile men (22). In a similar study by Lotti et al. erection and ejaculation status of infertile men were evaluated with IIEF and PEDT (12). They also researched psychological status with Middlesex Hospital Questionnaire (MHQ) and prostatitis symptoms with National Institutes of Health-chronic prostatitis symptom index (NIH-CPSI). Lotti et al. found lower rates of PE and ED (15.6% and 17.8%) than in our study (21.7% and 34.7%, respectively). Also depression was significantly associated with ED and they found a positive relationship between PE and prostatitis symptoms and phobic anxiety. According to these rates, it was obvious that men who had known that they were infertile, came across with more sexual problems such as PE and ED than fertile ones. These male partners, especially living in conservative societies, have a feeling of guiltiness and weakness so sexual fuction can not be fully performed by them (23). There are many factors that can lead to the relation

between infertility and sexual dysfunction such as age, race, religion, social status, employment status, level of education and previous paternity experience. In our study, we found that education levels of men with severe and moderate ED were significantly lower than in men with mild ED, similarly to the literature (23). Kızılay et al. found a close correlation between sperm parameters and sexual dysfunction in infertile couples. According to this study, poor sperm quality for count, morphology and motility were associated with severe ED in men and a parallel increase of female sexual dysfunction was observed (24). They also reported that worse sperm parameters accompanied declines in testosterone and IIEF scores. This comparison is not possible in terms of the azoospermia of all the cases in our study. However, known azoospermic group had the worst erectile function, higher PE prevalence, lower sexual desire, orgasmic function and general health condition among all infertile males (25). In 2014, Bayar et al. examined sexual dysfunction before and after treatment in patients who received IVF treatment (26). IIEF form for male partners and FSFI form for female partners were used for determining sexual dysfunction. At the third month of IVF treatment, severity of sexual dysfunction increased to 72% of female partners and 48% of male partners. But in the subgroup analysis, there were not found significant differencies in erection status and PE. In our study we investigated the changes in ED and PE in case of couple’s having a baby and we observed that IIEF-15 scores increased from 16 to 21 in male partners after having a baby after treatment. This improvement in IIEF-15 scores was statistically significant (p = 0.014). At the same time PE was questioned by PEDT in this group of patients, but no statistical difference was observed. It had been observed that psychosexual problems rise at the maximum level when duration of childlessness lasted less than two years or more than eight years (14). Song et al. searched stress related to infertility and timed intercourse during fertile periods of male partners in infertile couples with VAS questionnaires (8). The mean VAS score of sexual relationship stress was significantly higher during fertile than non-fertile periods (3.4 vs 2.1). As the fecundity of healthy couples is about 20% per cycle, the wife and the environment create stress on men' sexual function during fertile periods (8). We investigated the effect of sexual relationship stress in infertile couples who had children after assisted reproduction procedures. To our knowledge, this is the first study to quantitatively investigate stress levels of male partners of infertile couples between the periods before after the birth of the child. In our study, after having child the VAS scores of male partners showed a statistically significant decrease to 4.1 from 5.2 during sexual intercourse. Furthermore this significant improvement was also observed on sexual functions. We observed a statistically significant increase in the mean IIEF-15 levels from 16 to 21 in case of having a baby although the same improvement was not seen in PE. Our study has some limitations. Firstly, sexual functions of female partners were not investigated. A decrease in female sexual desire may cause a negative effect on sexual function of their male partners. Secondly, we did not evalArchivio Italiano di Urologia e Andrologia 2019; 91, 4

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uate the psychological or somatic status of patients with psychiatric tests such as Middlesex Hospital Questionnaire (MHQ) or Short Form Health Survey 36 (SF-36) which can effect patients’ sexual functions. Lastly, our study did not include fertile couples as a control group. Also the retrospective design of our study is an important bias. Therefore, randomised prospective studies with large groups of infertile and fertile groups are needed to understand the main pathogenesis of male sexual dysfunction.

CONCLUSIONS

We aimed to investigate the prevalence of sexual dysfunction which included ED and PE in infertile men. Erectile dysfunction was more common in our patient group than the literature. We consider this as a repercussion of communicative obstacles encountered in conservative societies. Moreover another finding, contrasting the literature, was related to the assessment of ED, PE and quantitative stress degree related to infertility (VAS scores) after having a baby through assisted reproduction treatments. We observed that having children is a reducing effect on sexual relationship stress. Sexuality can be deprived of its amusement and erotic value in case of a known infertility status. This condition may have negative affects on male sexual performance and it is closely related with occuring female sexual disorders. It should not be forgotten that infertile couples may have sexual dysfunction.

REFERENCES

1. Lee TY, Sun GH, Chao SC. The effect of an infertility diagnosis on the distress, marital and sexual satisfaction between husbands and wives in Taiwan. Hum Reprod 2001; 16:1762-7. 2. Nene UA, Jindal UN, Dhall GI. Infertility: A label of choice in the case of sexually dysfunctional couples. Patient Educ Couns 2005; 59:234-8. 3. Brugh VM III, Lipshultz LI. Male factor infertility: Evaluation and management. Med Clin North Am 2004; 88:367-85. 4. Chevret M, Jaudinot E, Sullivan K, et al. Impact of erectile dysfunction (ED) on sexual life of female partners: Assessment with the Index of Sexual Life (ISL) Questionnaire. J Sex Marital Ther 2004; 30:157-72. 5. Speckens AE, Hengeveld MW, Lycklama a Nijeholt G, et al. Psychosexual functioning of partners of men with presumed nonorganic erectile dysfunction: Cause or consequence of the disorder? Arch Sex Behav 1995; 24:157-72. 6. Khademi A, Alleyassin A, Amini M, Ghaemi M. Evaluation of sexual dysfunction prevalence in infertile couples. J Sex Med. 2008; 5:1402-10. 7. Lapane KL, Zierler S, Lasater TM, et al. Is a history of depressive symptoms associated with an increased risk of infertility in women? Psychosom Med 1995; 57:509-13. 8. Song SH, Kim DS, Yoon TK, et al. Sexual function and stress level of male partners of infertile couples during the fertile period. BJU Int. 2016; 117:173-6. 9. Hurwitz MB. Sexual dysfunction associated with infertility. A comparison of sexual function during the fertile and the nonfertile phase of the menstrual cycle. S Afr Med J. 1989; 76:58-61. 10. Shindel AW, Nelson CJ, Naughton CK, Mulhall JP. Premature ejaculation in infertile couples: Prevalence and correlates. J Sex Med. 2008; 5:485-91.

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11. Cappelleri JC, Rosen RC, Smith MD, et al. Diagnostic evaluation of the erectile function domain of the International Index of Erectile Function. Urology. 1999; 54:346-51. 12. Lotti F, Corona G, Rastrelli G, et al. Clinical correlates of erectile dysfunction and premature ejaculation in men with couple infertility. J Sex Med. 2012; 9:2698-707. 13. Saleh RA, Ranga GM, Nelson DR, Agarwal A. Sexual dysfunction in men undergoing infertility evaluation: a cohort observation study. Fertil Steril. 2003; 79:909-12. 14. Jindal UN, Dhall GI. Psychosexual problems of infertile women in India. Int J Fertil. 1990; 35:222-5. 15. Soykan A. The reliability and validity of Arizona sexual experiences scale in Turkish ESRD patients undergoing hemodialysis. Int J Impot Res. 2004; 16:531-4. 16. Symonds T, Perelman MA, Althof S, et al. Development and validation of a premature ejaculation diagnostic tool. Eur Urol. 2007; 52:565-73. 17. Yilmaz E, Zeytinci IE, Sari S, et al. Investigation of sexual problems in married people living in the center of Konya. Turk Psikiyatri Derg. 2010; 21:126-34. 18. Tuttelmann F, Nieschlag E. Classification of Andrological disorders. In: Nieschlag E, Behre HM, Nieschlag S, eds. Andrology. Male reproductive health and dysfunction. 3nd edition. Berlin: Springer, Verlag; 2010; 87-92. 19. Krausz C. Male infertility: Pathogenesis and clinical diagnosis. Best Pract Res Clin Endocrinol Metab. 2011; 25:271-85. 20. Lotti F, Corona G, Castellini G, et al. Semen quality impairment is associated with sexual dysfunction according to its severity. Human Reproduction. 2016; 31:2668-2680. 21. Ozkan B, Orhan E, Aktas N, Coskuner ER. Depression and sexual dysfunction in Turkish men diagnosed with infertility. Urology. 2015; 85:1389-1393. 22. Jain K, Radhakrishnan G, Agrawal P. Infertility and psychosexual disorders: relationship in infertile couples. Indian J Med Sci. 2000; 54:1-7. 23. Smith JF, Walsh TJ, Shindel AW, et al. Sexual, marital, and social impact of a man’s perceived infertility diagnosis. J Sex Med. 2009; 6:2505-2515. 24. Kızılay F, Sahin M, Altay B. Do sperm parameters and infertility affect sexuality of couples? Andrologia. 2018; 50. 25. Lotti F, Corona G, Castellini G, et al. Semen quality impairment is associated with sexual dysfunction according to its severity. Hum Reprod. 2016; 31:2668-2680. 26. Bayar U, Basaran M, Atasoy N, et al. Sexual dysfunction in infertile couples: evaluation and treatment of infertility. J Pak Med Assoc. 2014; 64:138-45.

Correspondence Taha Numan Yıkılmaz, MD (Corresponding Author) - numanyikilmaz@gmail.com Erdem Öztürk, MD - drerdemozturk@gmail.com Halil Başar, MD - drhalilbasar@gmail.com !smail Selvi, MD - drismailselvi@gmail.com Department of Urology, Ankara Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital, Ankara 06200, Turkey Nurullah Hamidi, MD - drnurullahhamidi@gmail.com Atatürk Training and Research Hospital, Ankara 06200, Department of Urology Levent Peşkircioğlu, MD - drlevent@gmail.com Baskent University Ankara Education and Research Hospital, Department of Urology, Ankara, Turkey

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DOI: 10.4081/aiua.2019.4.245

ORIGINAL PAPER

Effect of body mass and physical activity at younger age on the risk of prostatic enlargement and erectile dysfunction: Results from the 2018 #Controllati survey Fabio Parazzini 1, Walter Artibani 2, Giuseppe Carrieri 3, Luca Carmignani 4, Salvatore Voce 5 on behalf of the #Controllati study group* 1 Università

degli Studi di Milano Dipartimento di Scienze Cliniche e di Comunità, IRCCS Policlinico, Milano, Italy; Italiana di Urologia (SIU), Roma, Italy; 3 Dipartimento Nefro/Urologico Clinica Urologica e Centro Trapianti di Rene, Università degli Studi di Foggia, Italy; 4 Università degli Studi di Milano, Unità Operativa Complessa, Ospedale Policlinico San Donato, Milano, Italy; 5 Divisione di Urologia Ospedale Santa Maria delle Croci, Ravenna, Italy. 2 Società

Summary

Objective: Overweight and low physical activity (PA) increase the risk of prostatic enlargement and erectile dysfunction (ED). Less clear is the role of these factors at young age on the lifelong risk. Materials and methods: During June 2018 the Italian Society of Urologists organized the month of Male Urologic Prevention “#Controllati”. Men aged 18 years or more were invited to attend urologic centers for a visit and counselling about urologic/andrologic conditions. Each participating man underwent a physical examination and was asked about urologic symptoms, sexual activity and possible related problems. Results: We analyzed data from 2786 men, aged 55.1 years (SD 10.9, range 19-97). A total of 710 (25.5%) subjects had a diagnosis of prostatic enlargement and 632 (22.7%) of DE. Overweight/obese men were at increased risk of prostatic enlargement and ED with corresponding odds ratio (0R) in comparison with normal or underweight men, being respectively 1.18 (95% Confidence Interval (CI) 1.00-1.44) and 1.69 (95% CI 1.39-2.05). The OR of prostatic enlargement in comparison with men reporting at age 25 a BMI < 25.0 was 1.22 (95% CI 1.01-1.51) for men with a BMI at 25 years of age ≥ 25; the corresponding OR value for ED was 1.17 (0.921.48). Considering total PA at diagnosis, the OR of prostatic enlargement in comparison with no or low PA, was 0.69 (95%CI 0.55-0.86) for men reporting moderate PA and 0.75 (95%CI 0.58-0.98) for those reporting intense PA. When we considered PA at 25 years of age, the OR of subsequent diagnosis of prostatic enlargement, in comparison with men reporting no/low PA at 25 years of age was 0.81 (95%CI 0.63-1.04) for men reporting moderate PA and 0.70 (95%CI 0.52-0.99) for those reporting intense PA. Conclusions: These findings underline the utility of encouraging healthy lifestyle habits among young men in order to reduce the subsequent risk of prostatic enlargement and ED.

KEY WORDS: Benign prostatic enlargement; Hypertension; Diabetes; Heart disease; Body mass index; Physical activity. Submitted 10 April 2019; Accepted 1 May 2019

INTRODUCTION

Benign prostatic enlargement (BPE) and erectile dysfunction (ED) are the two most common urologic diseases in men, the estimated prevalence of PE being about 10% in

the fourth decades increasing up to 50% thereafter and that of ED being 12% (1, 2). Among the risk factors for these two conditions, lifestyles play a major role. It is well recognized, for example, that overweight, low physical activity (PA), hypertension, hypercholesterolemia and hypertriglyceridemia increase the risk of these conditions at advanced age (3-6). Less clear is the role of these factors on the lifelong risk when they were present at younger age (7). Since 2016 the Italian Urologic Society (SIU, Società Italiana di Urologia) coordinates a huge preventive initiative: the month of Male Urologic Prevention ”#Controllati” (8, 9). In the framework of this preventive campaign data have been collected on determinants of the risk of prostatic enlargement and ED. In this paper we present the results of the 2018 initiative with a special focus on risk factors for prostatic enlargement and ED and on lifelong risk for these condition in relation to lifestyle at younger age.

METHODS

During June 2018, men aged 18 year or more were invited to attend the participating urologic centers for a free of charge visit and counselling about urologic or andrologic conditions. A pamphlet inviting men for check-up was distributed in chemists and general practitioners’ waiting rooms. An advertising campaign was also set on media. At visit, general data were recorded using a simple questionnaire. The first section of the questionnaire, including data on age, life habits height and weight, was completed by the patient. The section on PA included questions on self-reported intensity of PA (‘none’, ‘low’, ‘moderate’,‘intense’) at work and in leisure time separately. History of hypertension, diabetes, cardiopathy, hypertriglyceridemia and hypercholesterolemia were checked by the urologist. Information was also collected on body mass index (BMI) and total PA at age 25 year among men aged 30 year or more.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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F. Parazzini, W. Artibani, G. Carrieri, L. Carmignani, S. Voce on behalf of the #Controllati study group

Each participating man underwent a physical examination, including digital rectal examination (DRE), and was asked by the urologist about urologic symptoms, sexual activity and possible related problems. Diagnosis of prostatic enlargement was made by the urologist by DRE. Erectile function was assessed by asking men about their sexual performance: ED was diagnosed, according to the definition of the NIH Consensus Development Panel (10), when a man was consistently unable to attain or maintain a penile erection sufficient for satisfactory sexual performance. The 2002 ICS definitions were used for frequency, nicturia, urgency, dysuria (intermittency, slow stream, straining, terminal dribble, postmicturition dribble) incomplete emptying (11). A man was considered a smoker if he had smoked more than one cigarette/day for at least one year; ex-smoker if he had smoked more than one cigarette/day for at least one year, but had stopped more than one year before the interview, and non-smoker if he had never smoked more than one cigarette/day. Total PA was evaluated combining occupational and leisure time PA. Frequencies (%) were computed as appropriate. Odds ratios (OR), and the corresponding 95% confidence intervals (CI), adjusted for age were derived using unconditional multiple logistic regression, fitted by the method of maximum likelihood, in which the dependent variable was the presence (case) or absence (control) of the condition and the independent ones were the exposures considered in the analysis. We included in the model age considered as categorical variable (12).

RESULTS

During the 2018 campaign a total of 3092 men entered the study. After exclusion of men who underwent previous surgery for partial or complete prostatectomy and those who did not answer at least one of two questions

about PA, we analyzed data from 2786 men, aged 55.1 years (SD 10.9, range 19-97). The reason for visit was urinary symptoms in 504 (18.1%), sexual problems in 270 (9.7%), renal disease in 68 (2.4%) and prostatic problems in 429 (15.4%) (more than one reason was allowed). Prevention was the only reason for consultation in 1776 subjects (63.8%). A total of 710 (25.5%) subjects had a diagnosis of prostatic enlargement and 632 (22.7%) of DE. Table 1 shows the distribution, and the corresponding OR, of study subjects according to the diagnosis of prostatic enlargement, ED and age, smoking habits and BMI. The risk of prostatic enlargement and ED increased with age: in comparison with men aged <=40 years or less, the risk of prostatic enlargement was 2.57, 7.22, 17.97 and 39.1 in the age classes 41-50, 51-60, 61-70 and >=71, respectively. The corresponding values for ED were 1.15, 1.63, 3.06 and 4.87. Smoking increased the risk of ED: in comparison with never smokers, ex-smokers had an increased risk of ED of 1.38 (95%CI 1.11-1.69) and current smokers of 1.92 (95%CI 1.49-2.48). Overweight/obese men were at increased risk of prostatic enlargement and ED the corresponding 0R, in comparison with normal or underweight men, being respectively 1.18 (95%CI 1.00-1.44) and 1.69 (95%CI 1.39-2.05). We have also considered (among men aged 30 years or more) the role of overweight/obesity at 25 years of age on the subsequent risk of prostatic enlargement and ED. In comparison with men reporting at age 25 a BMI < 25.0, the OR of prostatic enlargement was for men with a BMI at 25 years of age ≥ 25, 1.22 (95%CI 1.01-1.51); the corresponding value for ED was 1.17 (95%CI 0.921.48). Table 2 considers the relation between prostatic enlargement and DE and urinary symptoms, hypertension, diabetes, cardiopathy, hypertriglyceridemia and hypercholesterolemia.

Table 1. Odds ratios (and corresponding 95% confidence intervals) of BPE and erectile dysfunction according to selected factors. Benign prostatic enlargement No Yes No.* (%) No.* (%) Age (years) ≤ 40 41-50 51-60 61-70 ≥ 71 Smoking habits Never Ex smokers Current smokers < 10 cig/day ≥ 10 cig/day BMI (kg/m2) < 25.0 ≥ 25.0 BMI at 25 years of age < 25.0 ≥ 25.0

Age adj OR (95%CI)

Erectile dysfunction No Yes No.* (%) No.* (%)

166 782 718 339 118

7.8 36.8 33.8 16.0 5.6

7 87 225 269 171

0.9 11.5 29.6 35.4 22.5

1° 2.57 (1.17-5.66) 7.22 (3.34-15.63) 17.97 (8.29-38.96) 35.10 (15.83-77.86)

150 736 752 413 165

6.8 33.2 33.9 18.6 7.4

23 133 191 195 124

3.5 20.0 28.7 29.3 18.6

1° 1.15 (0.71-1.85) 1.63 (1.02-2.60) 3.06 (1.91-4.90) 4.87 (2.94-8.06)

1131 624 343 127 192

53.3 29.4 16.2 8.5 12.9

342 303 103 34 67

45.1 39.9 13.6 7.5 14.8

1° 1.2 (0.98-1.47) 1.1 (0.84-1.47) 0.94 (0.58-1.53) 1.27 (0.90-1.78)

1198 668 317 130 174

54.1 30.1 14.3 8.5 11.3

275 259 129 31 85

41.3 38.9 19.4 7.6 21.0

1° 1.38 (1.12-1.69) 1.92 (1.49-2.48) 1.49 (0.96-2.29) 2.25 (1.66-3.06)

891 1172

43.2 56.8

253 453

35.8 64.2

1° 118. (1.00-1.44)

949 1189

44.1 55.2

195 436

30.8 69.0

1° 1.69 (1.39-2.05)

1293 384

62.3 18.5

443 123

62.4 17.3

1° 1.22 (1.01-1.51)

1335 381

62.0 17.7

401 126

63.4 19.9

1° 1.17 (0.92-1.48)

*Sometimes, the sums do not add up the total due to missing values; °reference category OR: odds ratio; CI: confidence interval.

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Age adj OR (95%CI)

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Lifestyle habits and prostatic enlargement

Table 2. Odds ratios (and corresponding 95% confidence intervals) of BPE and erectile dysfunction according to medical history. Benign prostatic enlargement No Yes No.* (%) No.* (%) Urinary symptoms** No 987 Yes 1136 Erectile dysfunction No 1698 Yes 425 Benign prostatic enlargement No Yes Hypertension No 1492 Yes 407 Missing 224 Diabetes No 1884 Yes 78 Missing 161 Cardiopathy No 1857 Yes 76 Missing 190 Hypertriglyceridemia No 1753 Yes 130 Missing 240 Hypercholesterolemia No 1548 Yes 301 Missing 274

adj OR (95%CI)

Erectile dysfunction No Yes No.* (%) No.* (%)

adj OR (95%CI)

46.5 53.5

101 658

13.3 86.7

1° 5.14 (3.97-6.67)

924 1292

41.7 58.3

164 502

24.6 75.4

1° 1.82 (1.47-2.25)

80.0 20.0

518 241

68.2 31.8

1° 1.27 (1.03-1.57)

1698 518

76.6 23.4

425 241

63.8 36.2

1° 1.27 (1.03-1.57)

70.3 19.2 10.6

369 275 115

48.6 36.2 15.2

1° 1.6 (1.30-2.619)

1524 457 235

68.8 20.6 10.6

337 225 104

50.6 33.8 15.6

1° 1.60 (1.29-1.99) --

88.7 3.7 7.6

599 80 80

78.9 10.5 10.5

1° 1.57 (1.08-1.85)

1964 82 170

88.6 3.7 7.7

519 76 71

77.9 11.4 10.7

1° 2.43 (1.70-3.47) -

87.5 3.6 8.9

577 74 108

76.0 9.7 14.2

1° 1.30 (1.02-1.67)

1925 80 211

86.9 3.6 9.5

509 70 87

76.4 10.5 13.1

1° 2.12 (1.47-3.06) -

82.6 6.1 11.3

586 62 111

77.2 8.2 14.6

1° 1.31 (0.92-1.85)

1830 130 256

82.6 5.9 11.6

509 62 95

76.4 9.3 14.3

1° 1.59 (1.13-2.22) -

72.9 14.2 12.9

492 143 124

64.8 18.8 16.3

1° 1.30 (1.02-1.67)

1613 315 288

72.8 14.2 13.0

427 129 110

64.1 19.4 16.5

1° 1.42 (1.11-1.81) -

*Sometimes, the sums do not add up the total due to missing values; **one or more of the followings: nocturia, urgency, dysuria (intermittency, slow stream, straining, terminal dribble, postmicturition dribble) incomplete emptying; °reference category; adjOR: adjusted odds ratio; CI: confidence interval.

Table 3. Odds ratios (and corresponding 95% confidence intervals) of premature ejaculation and erectile dysfunction according to physical activity. Benign prostatic enlargement No Yes No.* (%) No.* (%) Occupational PA None/Low Moderate (0,7-1,1) Intense Missing Leisure PA Low Moderate Intense Missing Total PA Low Moderate Intense Missing PA at 25 years of age Low Moderate Intense Missing

adj OR (95%CI)

Erectile dysfunction No Yes No.* (%) No.* (%)

adj OR (95%CI)

1002 631 657 283 160

48.3 30.4 30.5 13.6 7.7

354 198 172 80 78

49.9 27.9 27.2 11.3 11.0

1° 0.89 0.86 (0.69-1.08) 0.97 (0.72-1.31)

1035

48.1

321

50.8

1°

286 176

13.3 8.2

77 62

12.2 9.8

0.98 (0.73-1.30) -

767 893 319 97

36.9 43.0 15.4 4.7

317 272 84 37

44.6 38.3 11.8 5.2

1° 0.67 (0.55-0.83) 0.64 (0.51-0.91)

785 926 342 101

36.4 43.0 15.9 4.7

299 239 61 33

47.3 37.8 9.7 5.2

1° 0.66 (0.54-0.80) 0.48 (0.36-0.66) -

537 960 515 64

25.9 46.2 24.8 3.1

228 308 144 30

32.1 43.4 20.3 4.2

1° 0.69 (0.55-0.86) 0.75 (0.58-0.98)

544 995 545 70

25.3 46.2 25.3 3.2

221 273 114 24

35.0 43.2 18.0 3.8

1° 0.65 (0.53-0.80) 0.56 (0.43-0.72) -

401 820 773 82

19.3 39.5 37.2 3.9

160 273 244 33

22.5 38.5 34.4 4.6

1° 0.81 (0.63-1.04) 0.70 (0.52-0.99)

415 858 785 96

19.3 39.8 36.4 4.5

146 235 232 19

23.1 37.2 36.7 3.0

1° 0.78 (0.61-0.99) 0.74 (0.58-1.10) -

*Sometimes, the sums do not add up the total due to missing values; °reference category; adjOR: adjusted odds ratio; CI: confidence interval.

A history of hypertension, diabetes, cardiopathy, high cholesterol levels were significantly associated to an increased risk of prostatic enlargement in the total series.

Likewise, hypertension, diabetes, cardiopathy, high triglyceride and cholesterol levels were significantly associated to an increased risk of ED. Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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F. Parazzini, W. Artibani, G. Carrieri, L. Carmignani, S. Voce on behalf of the #Controllati study group

PA was significantly associated with a decreased risk of prostatic enlargement: considering the total PA at diagnosis, the OR of prostatic enlargement, in comparison with men reporting no or low PA, was 0.69 (95%CI 0.55-0.86) among men reporting moderate PA and 0.75 (95%CI 0.58-0.98) among those reporting intense PA. The OR of subsequent diagnosis of prostatic enlargement were, in comparison with men reporting no/low PA at 25 years of age 0.81 (95%CI 0.63-1.04) for men reporting moderate PA and 0.70 (95%CI 0.52-0.99) for those reporting intense PA at 25 years of age. Similar findings emerged when we considered ED risk.

DISCUSSION

The general results of this analysis show that low PA, high BMI and a history of hypertension, diabetes, hypercholesterolemia, cardiopathy increase the risk of prostatic enlargement. High BMI and low PA at 25 year of age increase the risk of prostatic enlargement at older ages. Similar results emerged also for the risk profile of ED. Limitations As already discussed in the papers presenting the results of 2016 and 2017 initiative (8, 9), the major flaw of this study is that the study population were men voluntarily presenting to the participating centers. The participating centers were not randomly identified among all Italian urologic centers, so they cannot be considered representative of all Italian centers. However, they were well distributed over the main areas of the country. In any case, any inference from the present analysis must be made in strictly comparative terms and strictly referred to men attending urologic services. The diagnosis of PE was based on DRE that tends to underestimate the prostatic volume (2). Any misclassification of men with or without BPE or should lower the observed associations. With regard to the diagnosis of DE, it was reported by the men and checked for standard criteria by the physician. The results of this study confirm data from different populations that have reported that high BMI, low PA and a history of hypertension, diabetes, hypercholesterolemia, increase the risk of BPE at all ages (13, 14). All these findings underline that benign BPE shares similar risk factors with metabolic syndrome and cardiovascular diseases. The etiological mechanisms that links these risk factors and prostatic growth are not completely understood. However, it has been shown that lipids (oxidized lowdensity lipoproteins) increase in vitro the secretion of growth and pro-inflammatory factors by human stromal BPE cells in culture (15). Along this line, in a clinical perspective, the addition of statins to standard therapy for benign PE lowered prostate volume (16). Further, alteration of sex steroid hormone metabolism caused by both obesity and diabetes could lead to â&#x20AC;&#x2DC;pro-inflammatoryâ&#x20AC;&#x2122; conditions, causing release of chemokines potentially associated with prostate enlargement (17). Regular PA has been consistently reported to decrease the risk of BPE. A meta-analysis has shown that moderate-to-vigorous physical activity was associated with up

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to a 25% decreased risk of benign prostatic enlargment, with the magnitude of the protective effect increasing with the higher levels of activity (18). An interesting finding from the present study is the observation that the OR of BPE and ED associated with none/low PA and high BMI at 25 years were higher than unity. Few data have been published on the role of PA at younger ages on the lifetime risk of BPE. A previous Italian case control study have reported that moderate/intense recreational physical activity (> 2 hours week) at age 30-39 decrease the risk of benign BPE of about 30%. The Authors concluded that avoidance of sedentary lifestyle through a moderate recreational PA at any age may help preventing a sizeable number (e.g., approximately 20%) of BPE cases (7). With regard to erectile dysfunction, the risk profile of ED was largely similar with that observed for prostatic enlargement. In particular, the present analysis confirms that smoking, overweight, low PA and history of diabetes, hypertension, cardiopathy, hypercholesterolemia, hypertriglyceridemia, all increased the risk of ED. All these findings underline the role of encouraging healthy lifestyle habits among young men in order to reduce the subsequent risk of prostatic enlargement and ED.

REFERENCES

1. Parazzini F, Menchini Fabris F, Bortolotti A, et al, Frequency and determinants of erectile dysfunction in Italy. Eur Urol. 2000; 37:43-9. 2. Vuichoud C, Loughlin KR. Benign prostatic hyperplasia: epidemiology, economics and evaluation. Can J Urol. 2015; 22 Suppl 1:1-6. 3. Lee S, Min HG, Choi SH, et al. Central obesity as a risk factor for prostatic hyperplasia. Obesity (Silver Spring) 2006; 14:172-9. 4. Muller RL, Gerber L, Moreira DM, et al. Obesity is associated with increased prostate growth and attenuated prostate volume reduction by dutasteride. Eur Urol. 2013; 63:1115-21. 5. Bourke JB, Griffin JP. Hypertension, diabetes mellitus, and blood groups in benign prostatic hypertrophy. Br J Urol. 1966; 38:18-23. 6. Nandeesha H, Koner BC, Dorairajan LN, Sen SK. Hyperinsulinemia and dyslipidemia in non-diabetic benign prostatic hyperplasia. Clin Chim Acta. 2006; 370:89-93. 7. Dal Maso L, Zucchetto A, Tavani A, et al. Lifetime occupational and recreational physical activity and risk of benign prostatic hyperplasia. Int J Cancer. 2006; 118:2632-2635. 8. Mirone V, Carone R, Carrieri G, et al. Urinary symptoms and sexual dysfunction among Italian men: The results of the #Controllati survey. Arch Ital Urol Androl. 2017; 89:75-80. 9. Mirone V, Carrieri G, Morgia G, et al. Risk factors for benign prostatic enlargement: The role of lifestyle habits at younger age. The #Controllati2017 initiative study group. Arch Ital Urol Androl. 2017; 89:253-258. 10. NIH Consensus Conference (1993) Impotence. Consensus Development Panel on Impotence. JAMA 1993; 270:83-90. 11. Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn. 2002; 21:167-78. 12. Baker NJ, Nelder JA. The GLIM System. Release 3. Oxford: Numerical Algorithms Group; 1978.

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Lifestyle habits and prostatic enlargement

13. Raheem OA, Parsons JK. Associations of obesity, physical activity and diet with benign prostatic hyperplasia and lower urinary tract symptoms. Curr Opin Urol. 2014; 24:10-4.

16. Lee SH, Park TJ, Bae MHm, et al. Impact of treatment with statins on prostate-specific antigen and prostate volume in patients with benign prostatic hyperplasia. Korean J Urol. 2013; 54:750-5.

14. Parsons JK, Carter HB, Partin AW, et al. Metabolic factors associated with benign prostatic hyperplasia. J Clin Endocrinol Metab. 2006; 91:2562-8.

17. Jerde TJ, Bushman W. IL-1 induces IGF-dependent epithelial proliferation in prostate development and reactive hyperplasia. Sci Signal. 2009; 2:ra49.

15. Vignozzi L, Gacci M, Cellai I, et al. Fatboosts, while androgen receptor activation counteracts, BPH-associated prostate inflammation. Prostate. 2013; 73: 789-800.

18. Parsons JK, Kashefi C. Physical activity, benign prostatic hyperplasia, and lower urinary tract symptoms. Eur Urol. 2008; 53:1228-1235.

*Participating centers: A.O.U. Città della Salute e della Scienza - Ospedale Molinette, Torino (Gontero Paolo) Arcispedale Sant'Anna Ferrara (Ippolito Carmelo) ASL Reggio Calabria (De Martin Michele) P.O. Umberto I, Nocera Inferiore (Sanseverino Roberto) ASL Presidio Ospedaliero Carmagnola, Chieri (Marino Gaetano) ASST Franciacorta - Ospedale M. Mellini (Chiari Tralce Luigi) Ospedale Mater Salutis Legnago (Curti Pierpaolo) Aurelia Hospital, Roma (Cusumano Roberto) Azienda Ospedaliera Universitaria di Sassari (Madonia Massimo) Azienda Ospedaliera "Umberto I" Siracusa (Lentini Bartolomeo) Azienda Ospedaliera Universitaria, Parma (Maestroni Umberto Vittorio) Azienda Ospedaliera, Padova (Zattoni Filiberto) Azienda Ospedaliera Gaetano Rummo Benevento (Salzano Luigi) Azienda Ospedaliera Ospedali Riuniti Papardo Piemonte, Messina (Mastroeni Francesco) Azienda Ospedaliera Policlinico di Bari (Ditonno Pasquale) Azienda Ospedaliera Policlinico di Bari (Battaglia Michele) Azienda Ospedaliera Pugliese Ciaccio Catanzaro (Pirritano Domenico) Azienda Ospedaliera S. Antonio e Biagio, Alessandria (Serao Armando) Azienda Ospedaliera S. Bortolo, Vicenza (Ferrarese Paolo) Azienda Ospedaliera S. Giuseppe Moscati, Avellino (Cicalese Virgilio) Azienda Ospedaliera Sant’Anna e San Sebastiano di Caserta (Caggiano Sergio) Azienda Ospedaliera Santa Maria Terni (Elisabetta Costantini) Azienda Ospedaliera-Universitaria - "L. Vanvitelli" Napoli (De Sio Marco) Azienda Ospedaliera-Universitaria Integrata Verona (Artibani Walter) Azienda Ospedaliera-Universitaria Mater Domini di Catanzaro (Damiano Rocco) Azienda Ospedaliera-Universitaria Policlinico G. Martino Messina (Ficarra Vincenzo) Azienda Ospedaliero-Universitaria "Policlinico - Vittorio Emanuele" Catania (Falsaperla Mari) Azienda Ospedaliero-Universitaria Careggi, Firenze (Carini Marco) Azienda Ospedaliero-Universitaria S. Luigi Gonzaga Orbassano (Porpiglia Francesco) Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara (Volpe Alessandro) Azienda Ospedaliero-Universitaria Pisana - Stabilimento di Cisanello (Selli Cesare) Azienda Ospedaliero-Universitaria Sant' Andrea, Roma (Tubaro Andrea) Ospedale Civile di Voghera (Mensi Mario) Azienda Socio Sanitaria Territoriale Santi Paolo e Carlo, Milano (Dormia Guido) Campus Università degli Studi "Gabriele d'Annunzio" Chieti (Raffaele Tenaglia) Casa di Cura Ambrosiana Cesano Boscone (Catanzaro Francesco) Casa di Cura Gibiino Catania (Ranno Christian) Casa di Cura Giovanni XXIII, Monastier di Treviso (Morana Carmelo) Casa di Cura Guarnieri, Roma (Di Marco Massimiliano) Casa di Cura Luigi Cobellis Vallo della Lucania (Cavaliere Aniello) Casa di Cura Malatesta Novello Cesena (Cuzzocrea Diego) Casa di Cura Musumeci Gecas Gravina di Catania (Leonardi Rosario) Casa di Cura Nuova Clinica Santa Rita Benevento (Coscione Mario) Casa di Cura Nuova Villa Claudia, Roma (Giulianelli Roberto) Casa di Cura Regina Pacis, San Cataldo (Cammarata Carla) Casa di Cura Romolo Hospital Rocca di Neto (Cappa Manlio) Casa di Cura S. Rita, Atripalda De Simone Elia Virginio; Casa di Cura San Camillo Messina (Bruschetta Sebastiano); Casa di Cura Santa Lucia San Giuseppe Vesuviano (Casoli Eugenio)

Casa di Cura Sileno ed Anna Rizzola, San Donà di Piave (Loiero Gaetano) Casa di Cura Trusso, Ottaviano (De Stefano Giacomo) Casa Di Cura Villa Betania, Roma (Buscarini Maurizio) Casa di Cura Villa dei Fiori, Mugnano di Napoli (Jungano Renato) Casa di Cura Villa Esther, Avellino (Di Martino Mario) Casa di Cura Villa Fiorita, Prato (Dami Andrea Cesare) Casa di Cura Villa Igea, Ancona (Cafarelli Angelo) Casa di Cura Villa Maria, Mirabella Eclano (Morelli Emilio) Casa di Cura Villa Stabia Castellammare di Stabia (Scognamiglio Giuseppe) Centro Medico Politerapica, Seriate (Paolo Belvisi) Clinica Athena Villa dei Pini, Piedimonte Matese (Dalena Giuseppe) Clinica Padre Pio, Mondragone (Sepe Giuseppe Salvatore) Clinica Pierangeli, Pescara (Pompa Paolo) Clinica Villa Pia, Roma (Campagna Adriano) Casa di Cura Pederzoli, Peschiera del Garda (Grosso Gaetano) Ospedale Generale Regionale F. Miulli, Acquaviva delle Fonti (Ludovico Giuseppe Mario) Ospedale Galliera, Genova (Introini Carlo); Fondazione Policlinico IRCCS, Milano (Montanari Emanuele); Fondazione PTV Policlinico, Tor Vergata, Roma (Vespasiani Giuseppe); Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria (Cozzupoli Pietro); Hesperia Hospital, Modena (Ferrari Giovanni); Humanitas Gradenigo, Torino (Muto Giovanni); Humanitas San Pio X, Milano (Nava Luciano); IRCCS Policlinico San Donato (Carmignani Luca); IRCCS Policlinico Milano (Elena Ricci, data analysis); IRCCS AOU San Martino IST, Genova (Terrone Carlo); Istituti Clinici Zucchi, Monza (Stefano Casellato); Istituto Clinico S. Anna, Brescia (Najati Alrabi); Istituto Europeo di Oncologia, Milano (De Cobelli Ottavio); Istituto Nazionale Tumori IRCCS "Fondazione Pascale" Napoli (Perdonà Sisto); Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo (Cisternino Antonio); Ospedale Buon Consiglio Fatebenefratelli, Napoli (Imperatore Vittorio); Ospedale Cardarelli, Napoli (Fedelini Paolo); Ospedale Carlo Urbani, Jesi (Ferrara Vincenzo); Ospedale Civico di Cristina Benfratelli , Palermo (Gianfranco Savoca); Ospedale Civile di Guastalla (Frattini Antonio); Ospedale Civile P.O. Dell'Annunziata, Cosenza (Emilio De Giacomo); Ospedale Civile Ramazzini Carpi (Barusi Maurizio); Ospedale Civile S. Giacomo, Monopoli (Vito Domenico Ricapito); Ospedale Civile San Salvatore, L’Aquila (Di Clemente Luigi); Ospedale Cottolengo, Torino (Scoffone Cesare Marco); Ospedale degli Infermi, Rimini (Montanari Francesco); Ospedale del Mare, Napoli (Zito Aniello Rosario) ; Ospedale della Murgia Fabio Perinei, Altamura (De Siati Mario); Ospedale di Bassano del Grappa (Celia Antonio); Ospedale di Belcolle, Viterbo (Rizzotto Antonio); Ospedale di Senigallia (Vincenzo Ferrara); Ospedale di Sondrio (Giumelli Pierluigi); Ospedale di Villafranca di Verona (Pecoraro Giuseppe); Ospedale Cristo Re, Roma (Lorenzo Defidio); Ospedale Don Tonino Bello Molfetta (Altomare Mauro); Ospedale Garibaldi Nesima, Catania (La Rosa Pasquale Gianfranco); Ospedale ICOT, Latina (Carbone Antonio); Ospedale L. Bonomo, Andria (Corvasce Antonio); Ospedale Madonna delle Grazie, Matera (Disabato Giuseppe); Ospedale Maggiore, Bologna (Emili Emilio); Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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F. Parazzini, W. Artibani, G. Carrieri, L. Carmignani, S. Voce on behalf of the #Controllati study group Ospedale Maria SS. Addolorata, Erboli (Tufano Antonio); Ospedale Niguarda Ca' Granda, Milano (Bocciardi Aldo); Ospedale Privato Accreditato Villa Regina, Bologna (Cuzzocrea Diego Ettore); Ospedale Villa Serena, Forlì (Zambelli Massimo); Ospedale S. Giacomo di Novi Ligure (Montefiore Franco); Ospedale S. Giovanni in Persiceto (Emilo Emili); Ospedale S. Maria della Misericordia, S. Andrea delle Fratte Perugia (Ettore Mearini); Ospedale S. Maria delle Croci, Ravenna (Voce Salvatore); Ospedale S. Raffaele Turro, Milano (Gaboardi Franco); Ospedale Sacro Cuore di Gesù Fatebenefratelli, Benevento (Ferravante Paolo); Ospedale Sacro Cuore Don Calabria, Negrar (Cavalleri Stefano); Ospedale San Bartolomeo, Sarzana (Conti Enrico); Ospedale San Biagio DomodossolaRosa Antonio; Ospedale San Camillo Forlanini, Roma (Gaffi Marco); Ospedale San Donato, Arezzo (De Angelis Michele); Ospedale San Giacomo Apostolo, Castelfranco Veneto (Luca De Zorzi); Ospedale San Giovanni Battista, Foligno (Mearini Luigi); Ospedale San Giovanni di Dio, Agrigento (Ruoppolo Michele); Ospedale San Pio da Pietrelcina, Vasto (Schips Luigi); Ospedale San Raffaele, Milano (Montorsi Francesco); Ospedale San Salvatore. Pesaro (Beatrici Valerio); Ospedale San Tommaso dei Battuti, Portogruaro (Amenta Michele); Ospedale Sant'Ottone Frangipane, Ariano Irpino (Grasso Gerardo); Ospedale Santa Maria Misericordia, Udine (Valotto Claudio); Ospedale Santa Maria Regina degli Angeli, Adria (Meneghini Agostino); Ospedale Santissima Trinità, Cagliari (De Lisa Antonello);

Correspondence Fabio Parazzini, MD (Corresponding Author) fabio.parazzini@unimi.it Dipartimento di Scienze Cliniche e di Comunità, Università di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Via Commenda 12, 20122 Milano (Italy) Walter Artibani, MD segreteria@siu.it Società Italiana di Urologia (SIU), Roma (Italy) Giuseppe Carrieri, MD giuseppe.carrieri@unifg.it Dipartimento Nefro/Urologico Clinica Urologica e Centro Trapianti di Rene Università degli Studi di Foggia (Italy) Luca Carmignani, MD luca.carmignani@unimi.it Università degli Studi di Milano, Unità Operativa Complessa Ospedale Policlinico San Donato, Milano (Italy) Salvatore Voce, MD salvatore.voce@auslromagna.it Divisione di Urologia Ospedale Santa Maria delle Croci, Ravenna (Italy)

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Ospedale Spoke, Locri (Capocasale Francesco); Ospedale SS. Capitanio e Gerosa, Lovere (Ranieri Antonio); Ospedale Vincenzo Monaldi, Napoli (Uricchio Francesco); Ospedali Riuniti di Ancona (Galosi Andrea Benedetto); Ospedali Riuniti di Foggia (Carrieri Giuseppe), Presidio Ospedaliero Cerignola (Annunziata Gennaro); P.O. S. Marta e S. Venera di Acireale (Ingrassia Antonino); P.O. Umberto I, Enna (D'Anca Michele); Policlinico Agostino Gemelli, Roma (Bassi Pierfrancesco); Policlinico di Abano Terme (Porreca Angelo); Ospedale Civile di Baggiovara (Bianchi Giampaolo); Policlinico Federico II, Napoli (Mirone Vincenzo); Policlinico S. Orsola-Malpighi, Bologna (Brunocilla Eugenio); Policlinico SS. Annunziata, Chieti (Schips Luigi); Polo Pontino - Ospedale ICOT, Latina (Carbone Antonio); Presidio Ospedaliero "Vittorio Emanuele", Gela (Condorelli Sebastiano); Policlinico “Vittorio Emanuele”, Catania (Morgia Giuseppe); Presidio Ospedale S.S. Pietro e Paolo, Borgosesia (Cipollone Giovanni), Presidio Ospedaliero Carlo Poma, Mantova (Dall'Oglio Bruno) Presidio Ospedaliero CTO - Unità Spinale Struttura di Neuro Urologia, Torino (Carone Roberto); Presidio Ospedaliero di Brescia (Simeone Claudio); Presidio Ospedaliero di Busto Arsizio (Buizza Carlo); Presidio Ospedaliero di Pescara (Renzetti Roberto); Presidio Ospedaliero Mazzini, Teramo (Vicentini Carlo); Presidio Ospedaliero Occidentale, Castellaneta (Di Lena Sebastiano); Presidio Ospedaliero Perrino, Brindisi (Brigante Salvatore); Presidio Ospedaliero S. Andrea, Vercelli (Cipollone Giovanni); Ospedale S. Maria del Prato, Feltre (Xausa Daniele); Villa Pini D'Abruzzo, Chieti (Marascia Gabriele).

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DOI: 10.4081/aiua.2019.4.251

ORIGINAL PAPER

The association of Boswellia resin extract and propolis derived polyphenols can improve quality of life in patients affected by prostatitis - like symptoms Mattia Sibona 1, Paolo Destefanis 1, Marco Agnello 1, Beatrice Lillaz 1, Mattia Giuliano 1, Tommaso Cai 2, Paolo Gontero 1 1 Department

of Urology, Department of Surgical Sciences, A.O.U. Città della Salute e della Scienza di Torino, Molinette Hospital, University of Turin, Turin, Italy; 2 Department of Urology, Santa Chiara Regional Hospital, Trento, Italy.

Summary

Objectives: Chronic prostatitis syndrome is a bothering and poorly understood condition. Many patients report genitourinary pain and Lower Urinary Tract Symptoms as a main complaint. Many different pharmacological or behavioural therapies are prescribed in daily clinical practice, but efficacy data are still lacking. The aim of our study was to test the efficacy and safety of a transrectal delivered association of Boswellia resin extract and propolis derived polyphenols for the relief of prostatitis - like symptoms. Materials and methods: Patients affected by chronic/recurrent prostatitis - like symptoms were prospectively enrolled in our study from December, 2016 to December, 2018. Patients were screened at baseline through clinical examination and validated questionnaires administration: Chronic Prostatitis Symptom Index (CPSI), International Prostate Symptom Score (IPSS), International Index of Erectile Function (IIEF). Inclusion criteria were: age ≥ 18; prostatitis symptoms persisting for at least 3 of the last 6 months; CPSI pain domain score ≥ 5; previous negative Meares-Stamey test. Treatment consisted on the administration of 1 suppository containing Boswellia resin extract and propolis derived polyphenols, once a day for 20 days. The primary endpoint of the study was the improvement of quality of life after treatment, defined by a reduction of ≥ 2 points, or ≥ 25%, of mean CPSI pain domain score, compared to baseline. Secondary endpoints were the improvement of posttreatment CPSI total score and the analysis of treatment related adverse events. All patients were re-evaluated 1 month after treatment. Results: 40 patients were enrolled in our study. Median age (Inter - Quartile Range IQR) was 51.5 (41.5-63.2) years. Mean baseline CPSI scores were: 22.15 (total score), 9.67 (pain domain), 5.15 (micturition domain) and 7.35 (quality of life domain), respectively. No significant adverse events were reported. At 1 month follow-up, CPSI scores appeared modified as follows: 16.40 (total score, p = 0.001); 6.92 (pain domain; p = 0.001; 4.02 (micturition domain, p = 0.09); 5.45 (quality of life domain, p = 0.002). Mean CPSI pain domain score reduction was -2.75 points (-28.5%). Mean CPSI total score reduction was -5.75 points (-26%). Conclusions: The association of Boswellia resin extract and propolis derived polyphenols can reduce genitourinary pain and then improve quality of life of men affected by bothersome prostatitis - like symptoms.

KEY WORDS: Prostatitis; Pain; Boswellia serrata; Propolis; Quality of life. Submitted 27 June 2019; Accepted 2 August 2019

INTRODUCTION

Prostatitis syndrome is characterised by genitourinary pain and Lower Urinary Tract Symptoms (LUTS). According to different studies, the prevalence of prostatitis in the male population ranges between 2.2% and 13.8% (1), and it is estimated that at least 50% of men have suffered from at least one episode of prostatitis in their lifetime (1). Moreover, this disease can account for up to 10% of all urological consults (2). The National Institute of Health (NIH) differentiates prostatitis into several etiologic categories. Acute bacterial prostatitis (NIH type 1) is characterized by fever and acute onset of LUTS. Conversely, asymptomatic inflammatory prostatitis (NIH type 4) is characterized by the absence of symptoms and its diagnosis is usually occasional (3). Chronic prostatitis is a pathological entity lying between the two categories, and it is basically defined as a clinical syndrome whose manifestations are prolonged over time. The aetiology of chronic prostatitis may be infectious (Chronic Bacterial Prostatitis, CBP, NIH type 2), or merely inflammatory (Chronic Prostatitis/Chronic Pelvic Pain Syndrome, CP/CPPS, NIH type 3). Nevertheless, at least from a clinical point of view, the two conditions appear to be largely overlapping (3). Chronic prostatitis remains one of the most common urologic disorders. It is often poorly understood in its causative mechanisms and usually complex to manage. Due to a lack of standardized therapeutic protocols, it is often treated with empirical pharmacological therapies, including prolonged antibiotic courses. Despite a microbiological evidence of infection is often unavailable, in fact, antibiotics are prescribed up to a third of all patients (4). Several alternative therapies have been also evaluated over time, including anti-inflammatory medications, neuromodulators, alpha-blockers, physical and cognitive - behavioural therapies, and phytotherapy. However, reliable efficacy data are still lacking. Bosexil® is a vegetal extract derived from the resin of Boswellia serrata, a plant native to India. Boswellic acids (BAs) already showed anti-inflammatory and antioxidant properties in a variety of inflammatory diseases, including rheumatoid arthritis, osteoarthritis, and asthma (5, 6), whose physio-pathological pathways could be shared with those of chronic prostatitis. On the other

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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hand, Fenolmicina P3®, a polyphenolic extract derived from beehive propolis, demonstrated anti-inflammatory, anti-microbial and antioxidant properties in several preclinical reports (7-9). The aim of our study was to test the efficacy and safety of the association of Bosexil® and Fenolmicina P3® in relieving prostatitis - like symptoms in an adult male, prospective cohort.

MATERIALS

AND METHODS

Study design and sample size definition Our study was conceived as a pilot study, characterised by an observational, non-randomized, prospective approach. The required sample size for this study was determined on the basis of the expected variation of mean Chronic Prostatitis Symptom Index (CPSI) pain domain score, compared to baseline. A size of 40 patients was needed to detect a 2 points difference, with an 80% power and a 0.05 alpha error level. Patients selection Male patients, attending our outpatient service for chronic/recurrent prostatitis - like symptoms were prospectively evaluated from December 2016 to December, 2018. A key point for the diagnosis of prostatitis was the presence of chronic perineal or genital pain, exacerbated by micturition or ejaculation. According to current European Association of Urology (EAU) Guidelines, prostatitis syndrome was suspected when symptoms persisting for 3 months or more were reported (10). Moreover, we included in the study patients with both recurrent symptoms and previous negative Meares-Stamey test. Once screened, patients’ general and urological history was investigated, and a complete urological examination, including a Digital Rectal Examination (DRE) was carried out for all candidates to enrolment, in order to confirm prostatic pain and exclude synchronous prostatic diseases, like Prostate Cancer (PCa). Moreover, they were all administered three validated questionnaires: NIH-Chronic Prostatitis Symptom Index (NIH-CPSI), International Prostate Symptom Score (IPSS) and International Index of Erectile Function (IIEF). Validated questionnaires Three international validated questionnaires were used to evaluate patients at baseline and at follow-up: • CPSI: it is an international, validated questionnaire proposed by the NIH Chronic Prostatitis Collaborative Research Network in 1999 to objectively assess prostatitis symptoms (3). It has been validated in Italian in 2005 (11). It is composed of three parts, or “individual domains”: a) pain domain, assessing the localization and amount of painful urogenital symptoms; b) micturition domain, focused on LUTS; c) quality of life domain. • IPSS: it is an international, validated questionnaire aiming to assess LUTS. It is composed of 7 questions about LUTS, plus 1 question about Quality of Life. Symptoms are classified as: mild (0 to 7 points); moderate (8 to 19 points); severe (20 to 35 points) (12). • IIEF: it is composed of 15 questions about several aspects of sexual function. It is divided into 5 domains:

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1) erectile function; 2) orgasmic function; 3) sexual desire; 4) intercourse satisfaction; 5) overall satisfaction. It allows a minimum of 5 points and a maximum of 75 (13). Inclusion criteria Inclusion criteria were: age >=18; diagnosis of chronic prostatitis-like symptoms, prolonged for >=3 months over the last six (10); CPSI pain domain score >=5; previous negative Meares-Stamey test. We excluded from the study patients affected by acute bacterial prostatitis, asymptomatic prostatitis, Benign Prostatic Hyperplasia (BPH), PCa, Inflammatory Bowel Diseases (IBD), previous intra-vesical therapies (mitomycin, BCG), recent (< 1 month) systemic antibiotic therapies or ongoing specific therapies for chronic prostatitis (including phytotherapy). Study schedule At baseline, general medical information and baseline characteristics were recorded. Moreover, NIH-CPSI, IPSS and IIEF questionnaires were administered. Subsequently, patients underwent a 20 days therapy with Bosexil® and Fenolmicina P3® suppositories (MICTALASE®). Standard therapeutic regimen was one suppository, once a day, for 20 days. Every administration (2 g suppository) contained: 1. BOSEXIL® - Boswellia Fitosoma® 2. Fenolmicina P3® - propolis derived polyphenols 3. Silicon Dioxide, lecithin, cellulose, silica and solid glycerides. All patients were re-evaluated after 30 days. At followup, they were re-administered the CPSI, IPSS and IIEF questionnaires. Results were recorded by using a dedicated database. Analysis of results Analysis of the results was based on the comparison of pre and post-treatment mean scores of the CPSI (total score and pain, micturition and quality of life domain scores), IPSS and IIEF questionnaires. The primary endpoint of the study was the improvement of quality of life, defined by a statistically and clinically significant reduction of symptoms after treatment. A reduction of at least 2 points or ≥ 25% of pain domain CPSI score was considered clinically significant. Secondary endpoints were: 1) total CPSI score statistically and clinically significant reduction, defined by at least 5 points or ≥ 25% reduction of the score after treatment. 2) evaluation of treatment’s safety. For this purpose, adverse events of any type were investigated and reported. Statistical analysis The t-test was used to compare the distribution of continue variables. The χ2 test was used to compare categorical variables. The statistical significance was obtained when a p < 0.05 value was reached. The statistical analysis was performed with SPSS version 20.0 (IBM Corp, Armonk, NY, USA). The study was conducted according to the statements of the Helsinki Declaration and the Good Clinical Practice Guidelines.

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Boswellia resin extract and propolis for prostatitis symptoms

RESULTS

DISCUSSION

Baseline 40 patients were enrolled in the study. The median (IQR) age was 51.5 (41.5-63.2) years. As concerns descriptive statistics, 2 (5%) patients were cigarette smokers; 1 (2.5%) was affected by diabetes mellitus; 8 (20%) were affected by hypertension (Table 1). Baseline data were collected for all patients through the CPSI, IPSS and IIEF questionnaires administration. Mean (SD) CPSI total score was 22.15 (6.02). Mean (SD) CPSI pain domain score was 9.67 (2.77). Mean (SD) CPSI micturition and quality of life domain scores were 5.15 (3.17) and 7.35 (2.2), respectively. Mean (SD) IPSS score was 15.55 (8.8). Mean (SD) IIEF score was 62.6 (16.5). Adherence to therapy and adverse events All patients underwent a standard therapeutic regimen. We did not register any case of withdrawal from the study. Moreover, we did not register any significant, treatment - related adverse event. Follow-up Follow-up was carried out at 1 month. Mean (SD) CPSI pain domain score was 6.92 (4.50), p = 0.001. Mean (SD) CPSI total score was 16.40 (8.97), p = 0.001. Mean (SD) CPSI micturition and quality of life domain scores were 4.02 (2.71), p = 0.09 and 5.45 (3.21), p = 0.002 respectively. Mean CPSI pain domain score reduction was -2.75 points (-28.5%). Mean CPSI total score reduction was -5.75 points (-26%). Mean (SD) post-treatment IPSS score was 12.5 (7.97), p = 0.10, while mean (SD) IIEF score was 63.85 (16.45), p = 0.74 (Results are summarized in Table 2). Table 1. Baseline characteristics of patients included in the study. Age, years, median (IQR) Cigarette smoke, n (%) Diabetes, n (%) Hypertension, n (%) Coronary Artery Disease, n (%)

51.5 (41.5-63.2) 2 (5) 1 (2,5) 8 (20) 0 (0)

Age is expressed as median and Inter Quartile Range (IQR). Total sample number (N) = 40.

Table 2. Baseline and post-treatment (1 month) results of validated questionnaires measuring prostatitis - like symptoms. CPSI total score CPSI pain domain score CPSI micturition domain score CPSI quality of life score IPSS IIEF

Baseline 22.15 (6.02) 9.67 (2.77) 5.15 (3.17) 7.35 (2.20) 15.55 (8.8) 62.60 (16.5)

1 month follow-up 16.40 (8.97) 6.92 (4.50) 4.02 (2.71) 5.45 (3.21) 12.5 (7.97) 63.85 (16.45)

p value 0.001 0.001 0.09 0.002 0.10 0.74

Results are expressed as: mean (standard deviation, SD). CPSI: Chronic Prostatitis Symptom Index; IPSS: International Prostate Symptom Score; IIEF; International Index of Erectile Function.

Chronic prostatitis still remains a poorly understood condition. Many of the underlying pathological patterns of this disease are yet to be enlightened. On the other hand, prostatitis prevalence is not negligible and its symptoms can sometimes be very bothering and negatively affecting patients’ quality of life. Poor knowledge and limited therapeutic options often make chronic prostatitis a true urological challenge. Despite microbiological definition of the disease is often lacking, prolonged antibiotic administration is still considered a gold standard treatment (10). On the other hand, due to the lack of standardized therapeutic protocols, many other pharmacological or non-pharmacological therapies, including phytotherapy, are often considered by physicians as part of a multimodal treatment, even though evidences about effectiveness and safety of these products are limited (1, 14, 15). Our study aimed to test the efficacy and safety of a transrectal delivered association of Bosexil® and Fenolmicina P3® for the treatment of chronic prostatitis symptoms. Among a wide range of other products, Boswellia serrata derivatives, like BAs and, specifically, Bosexil®, have been traditionally attributed a therapeutic potential against several chronic inflammatory diseases. More specifically, literature reports show in vitro, preclinical efficacy data concerning the use of Boswellia in different contexts as an antioxidant, revealing a positive effect on the reduction of oxidant species and inflammation (5, 6, 16). Besides propolis, rich in polyphenols, is the object of several preclinical reports that have confirmed its anti-inflammatory and antioxidant activity. Moreover, propolis shows a strong antioxidant effect, generating a synergistic effect when linked to the activity of Boswellia (7-9, 17). As concerns systemic bioavailability of this constituents after oral or transrectal administration, we still undoubtfully reckon with inconclusive data. Moreover, no comparative data between the oral and transrectal administration of Boswellia resin extracts and propolis are available to our knowledge, but the use of the transrectal way, which allows antioxidant substances to be in contact with the mucosa and antagonize oxidant species thus reducing painful symptoms, appears reasonable. Data from our study, which is the first, to our knowledge, addressing the therapeutic role of this association of compounds for the treatment of prostatitis - like symptoms, showed some significant results. First, we reported a significant post-treatment reduction of prostatitis - like symptoms, which we considered an index of quality of life improvement, as demonstrated by a statistically and clinically significant reduction of both the NIH-CPSI total score (p = 0.001) and pain domain score (p = 0.001). Moreover, we also registered a significant improvement of the CPSI quality of life domain (p = 0.002). On the other hand, we did not appreciate a similar effect against those symptoms more related to bladder outlet obstruction and BPH. In fact, the improvement of the CPSI micturition domain did not reach statistical significance (4.02 versus 5.15 p = 0.09). Our results, the most interesting of which is the significant improvement of CPSI pain domain score, find confirmation in previously published, high quality studies. Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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As a matter of fact, the use of an NIH-CPSI based evaluation of the response to treatment is a common finding in chronic prostatitis trials, even though reference levels are not clearly established and can vary highly between different studies. For example, Cai and colleagues (18) demonstrated the superiority of flower pollen extract in association with vitamins over ibuprofen, considering a ≥ 25% reduction in the NIH-CPSI total score as clinically significant. Similarly, Wagenlehner (1) and Elist (19) showed a significant improvement of the CPSI total score, CPSI “pain” domain score and QoL score as indicative of efficacy of another pollen extract, compared to placebo. In most cases, a reduction > 25-50% or > 2-5 points in NIH-CPSI total score or pain domain score, was considered significant (20). As a second strength of our study, we particularly focused on the selection of our sample. In fact, we aimed to differentiate patients affected by prostatitis - like symptoms from pure BPH or mixed patients. Considering that the two conditions, despite sometimes overlapping symptoms, can be differentiated on a clinical basis through accurate anamnestic data collection ad clinical examination, we relied on this to segregate the ones from the others, being the prostatitis patients those characterized by prevalent genitourinary pain compared to the IPB ones affected by prevalent unpainful micturition symptoms. Moreover, we used the instrument of the validated questionnaires to obtain an even more accurate patient selection, including only CPSI pain domain ≥ 5 subjects. Reflecting the good selection of the included patients and meeting our expectations, patients in our sample referred a better response of the painful, inflammatory symptoms than those more typical of noninflammatory BPH. Finally, treatment with Bosexil® and Fenolmicina P3® demonstrated completely safe. No major nor minor adverse side effects were registered. Moreover, we did not report any case of withdrawal from the study and no patients were lost to follow-up, even though longer follow-up should be advisable. Nonetheless, our study is not devoid of limitations, the major of which is the lack of randomisation and a control group. Without any doubt, the absence of a control group makes our results, showing a strong positive effect of the treatment against prostatitis symptoms, susceptible to overestimation, due to possible placebo effect. For this reason, we interpreted our data in the light of other previously published, randomized, controlled trials concerning the same issues, particularly those addressing the use of Boswellia resin extracts (21). As we found our results consistent with those reported by randomized controlled trials investigating similar compounds, we judged them highly suggestive of a real therapeutic effect. However, since our study was conceived and has to be considered as a preliminary investigation, the need for further studies concerning these compounds is to be underlined.

CONCLUSIONS

The association of Bosexil® and Fenolmicina P3® can reduce genitourinary pain and then improve quality of

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life of men affected by bothersome prostatitis - like symptoms.

REFERENCES

1. Wagenlehner FME, Schneider H, Ludwig M, et al. A Pollen Extract (Cernilton) in Patients with Inflammatory Chronic Prostatitis–Chronic Pelvic Pain Syndrome: A Multicentre, Randomised, Prospective, Double-Blind, Placebo-Controlled Phase 3 Study. Eur Urol. 2009; 56:544-551. 2. Quentin Clemens J. Male chronic pelvic pain syndrome: Prevalence, risk factors, treatment patterns, and socioeconomic impact. Curr Prostate Rep. 2008; 6:81-85. 3. Litwin MS, McNaughton-Collins M, Fowler FJ, et al. The National Institutes of Health chronic prostatitis symptom index: development and validation of a new outcome measure. Chronic Prostatitis Collaborative Research Network. J Urol. 1999; 162:369-75. 4. Taylor BC, Noorbaloochi S, McNaughton-Collins M, et al. Urologic Diseases in America Project. Excessive antibiotic use in men with prostatitis. Am J Med. 2008; 121:444-9. 5. Poeckel D, Werz O. Boswellic acids: biological actions and molecular targets. Curr Med Chem. 2006; 13:3359-69. 6. Siemoneit U, Koeberle A, Rossi A, et al. Inhibition of microsomal prostaglandin E2 synthase-1 as a molecular basis for the antiinflammatory actions of boswellic acids from frankincense. Br J Pharmacol. 2011; 162:147-162. 7. Silva JC, Rodrigues S, Feás X, Estevinho LM. Antimicrobial activity, phenolic profile and role in the inflammation of propolis. Food Chem Toxicol. 2012; 50:1790-5. 8. Ristivojevic P, Dimkic I, Trifkovic J, et al. Antimicrobial Activity of Serbian Propolis Evaluated by Means of MIC, HPTLC, Bioautography and Chemometrics. PLoS One. 2016; 11:e0157097. 9. Naito Y, Yasumuro M, Kondou K, Ohara N. Antiinflammatory effect of topically applied propolis extract in carrageenan-induced rat hind paw edema. Phytother Res. 2007; 21:452-6. 10. Fall M, Baranowski AP, Elneil S, et al. European Association of Urology. EAU Guidelines on Chronic Pelvic Pain. Eur Urol. 2010; 57:35-48. 11. Giubilei G, Mondaini N, Crisci A, et al. The Italian Version of the National Institutes of Health Chronic Prostatitis Symptom Index. Eur Urol. 2005; 47:805-811. 12. Badía X, García-Losa M, Dal-Ré R. Ten-language translation and harmonization of the International Prostate Symptom Score: developing a methodology for multinational clinical trials. Eur Urol. 1997; 31:129-40. 13. Rosen RC, Riley A, Wagner G, et al. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology. 1997; 49:822-30. 14. Cai T, Luciani LG, Caola I, et al. Effects of Pollen Extract in Association with Vitamins (Deprox 500®) for Pain Relief in Patients Affected by Chronic Prostatitis/Chronic Pelvic Pain Syndrome: Results from a Pilot Study. Urol J. 2013; 80:5-10. 15. Shoskes DA, Nickel JC. Quercetin for Chronic Prostatitis/ Chronic Pelvic Pain Syndrome. Urol Clin North Am. 2011; 38:279-284. 16. Hartmann RM, Martins MIM, Tieppo J, et al. Effect of Boswellia serrata on antioxidant status in an experimental model of colitis rats induced by acetic acid. Dig Dis Sci. 2012; 57:2038-2044. 17. Galeotti F, Maccari F, Fachini A, et al. Chemical composition and

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antioxidant activity of propolis prepared in different forms and in different solvents useful for finished products. Foods. 2018; 19; 7(3).

prostatitis/chronic pelvic pain syndrome: a randomized, doubleblind, placebo-controlled study. Urology. 2006; 67:60-3.

18. Cai T, Wagenlehner FME, Luciani LG, et al. Pollen extract in association with vitamins provides early pain relief in patients affected by chronic prostatitis/chronic pelvic pain syndrome. Exp Ther Med. 2014; 8:1032-1038.

20. Cai T, Verze P, La Rocca R,et al. The role of flower pollen extract in managing patients affected by chronic prostatitis/chronic pelvic pain syndrome: a comprehensive analysis of all published clinical trials. BMC Urol. 2017; 17:32.

19. Elist J. Effects of pollen extract preparation Prostat/Poltit on lower urinary tract symptoms in patients with chronic nonbacterial

21. Galeone G, Spadavecchia R, Balducci MT, Pagliarulo V. The role of Proxelan in the treatment of chronic prostatitis. Results of a randomized trial. Minerva Urol Nefrol. 2012; 64:135-41.

Correspondence Mattia Sibona, MD (Corresponding Author) mattia.sibona@gmail.com Paolo Destefanis, MD p.deste@gmail.com Marco Agnello, MD agnello.marco89@gmail.com Beatrice Lillaz, MD blillaz@cittadellasalute.to.it Mattia Giuliano, MD mattia.giuliano877@edu.unito.it Paolo Gontero, MD paolo.gontero@unito.it Department of Urology, Department of Surgical Sciences, A.O.U. CittĂ della Salute e della Scienza di Torino, Molinette Hospital, University of Turin, Italy Corso Bramante 88-90, 10126 - Torino, Italy Tommaso Cai, MD ktommy@libero.it Department of Urology, Santa Chiara Regional Hospital, Trento, Italy Largo Medaglie dâ&#x20AC;&#x2122;Oro 1, 38122 - Trento, Italy

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DOI: 10.4081/aiua.2019.4.256

ORIGINAL PAPER

Clinical and psychological outcomes of patients undergoing Retrograde Intrarenal Surgery and Miniaturised Percutaneous Nephrolithotomy for kidney stones. A preliminary study Davide Di Mauro 1, Valentina Lucia La Rosa 2, Sebastiano Cimino 1, Eugenio Di Grazia 3 1 Department

of Urology, University of Catania, Catania, Italy; of Psychodiagnostics and Clinical Psychology, University of Catania, Catania, Italy; 3 Unit of Urology, Garibaldi Hospital, Catania, Italy. 2 Unit

Summary

Purpose: To assess disease-specific and health-related QoL, anxiety and depression as well as satisfaction regarding retrograde intrarenal surgery (RIRS) and miniaturized percutaneous nephrolithotomy (mPCNL) intervention for kidney stones up to 2.5 cm. Secondarily, pain as well as perioperative and postoperative patient outcomes were evaluated. Methods: 60 consecutive patients with kidney stones of dimensions not exceeding 2.5 cm were enrolled in the study of which 30 underwent RIRS and 30 mPCNL. Perioperative characteristics (age, gender, body mass index (BMI), stone side and size, previous interventions for kidney stones and duration of hospitalization) and surgical outcomes (hemoglobin drop, stone-free rate, visual analogue scale (VAS), stenting time, size of ureteral access sheath (UAS) deployment, and postoperative complications) of patients were collected. Quality of life and psychological outcomes were evaluated using validated questionnaires. Results: No significant differences were found between the two groups in terms of age, gender, BMI, stone side and size (p > 0.05). Significant differences between the mPCNL and the RIRS groups were found regarding stenting time (p = 0.032) and duration of hospital stay (p < 0.001). The stone-free rates of mPCNL vs RIRS were not significantly different between the two groups (73.3% vs 66.7%, p > 0.05). Peri- and postoperative complications were not statistically different between the two groups (p > 0.05). RIRS group reported higher anxiety and depression scores compared with the mPCNL group (3 [range 0-15] vs 15 [range 6-24], p < 0.01). We found significant differences between the two groups in social (p < 0.05) and vitality (p < 0.01) scores. VAS pain score was significantly lower in the mPCNL group than in the RIRS one (p < 0.05). Conclusions: These results open new scenarios in the treatment of kidney stones up to 2.5 cm when RIRS and mPCNL have interchangeable indications. Since in our experience complications and success rate are similar, the surgical choice of switching from RIRS to mPCNL in real-time and viceversa may be proposed to the patient in the preoperative counseling.

KEY WORDS: RIRS; mPCNL; Kidney stones; Quality of life; Satisfaction. Submitted 24 September 2019; Accepted 24 October 2019

INTRODUCTION

Retrograde Intrarenal Surgery (RIRS) is recommended as the standard treatment for small to medium (< 2 cm)

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renal stones by the European Association of Urology (EAU) Guidelines. The reason is that a high stone-free rate of usually more than 90% can be achieved, which is potentially related to fewer complications in comparison with percutaneous nephrolithotomy (PCNL). Many studies attempted to treat stones of a size up to 2.5 cm with RIRS in order to decrease potential PCNL morbidity. Contrariwise, RIRS failure rates range from 8% to 10% due to a difficult impassable ureter. Additionally, the failure rate to insert a standard ureteral access sheath (UAS) is probably higher because in most failed ureteroscopies even smaller ureteroscopes cannot be inserted. In these cases, a stent needs to be placed and the procedure postponed. After the ureteral relaxed, RIRS can be repeated. Double-staged procedures are frustrating for urologists and for patients. Moreover, they increase significantly costs related to additional stone treatments and prolonged hospital stay. A real-time surgical alternative, as morbid and mini-invasive as RIRS, is needed to avoid staged-procedures. In the last few years many studies reconsidered miniaturized PCNL (mPCNL) as an alternative, which is a more effective approach compared with RIRS reporting a better stone-free rate and a similar complications rate (1). Furthermore, patients often undergo for several days postoperative ureteral stenting to prevent from complications related to residual fragments in the ureteral passage, potential ureteral edema or post UAS inflammation. Postoperative ureteral stenting has impacts on the quality of life (QoL) for patients, a fact often not considered in RIRS and mPCNL researches. The principles of evidencebased medicine recommend considering both clinicalreported outcome (CRO) parameters and patient-reported outcomes (PROs) (2). Despite the adoption of mPCNL and RIRS techniques into clinical practice, comparative clinical data, assessing patient satisfaction, taking perioperative and postoperative morbidities into account, is lacking. The primary aim of our study was to assess disease-specific and health-related QoL, anxiety and depression as well as satisfaction regarding RIRS and mPCNL intervention for kidney stones up to 2.5 cm. Secondarily, pain as well as perioperative and postoperative patient outcomes were evaluated. No conflict of interest declared.

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Outcomes of surgery for kidney stonesstones. A preliminary study

MATERIALS

AND METHODS

Study design and ethical approval The study conducted at a tertiary hospital and was carried out in accordance with the Declaration of Helsinki and the STROBE guidelines. Informed consent was obtained from all participants before the study. Study variables Perioperative characteristics (age, gender, body mass index (BMI), stone side and size, previous interventions for kidney stones and duration of hospitalization) and surgical outcomes (hemoglobin drop, stone-free rate (SFR), visual analogue scale (VAS), stenting time, size of UAS deployment, and postoperative complications) of patients treated between January 2018 and January 2019 were collected. All pre-operative imaging was accomplished by computed tomography (CT) scans with 3 mm cuts. Stone size and volumes were collated using the EAU stone volume formula (volume = π/6 Å~ Length x Width x Depth) using CT scan measurements. Stone-free rate was calculated taking stone fragments less than 4 mm by KUB radiographic or sonographic evaluation after 3 months postsurgery into account. Health Related Quality of Life (HRQoL) was evaluated using the Italian adaptation of the Wisconsin Stone Quality of Life questionnaire (WISQOL)3. It is a 28-item, selfadministered instrument designed to evaluate the effect of kidney stones on patients’ QoL. Through a 5-point Likert scale, it is possible to evaluate the following domains: activity/energy level, sleep patterns, social functioning, therapy compliance, physical symptoms, family life, intimacy, and emotional health. A higher score is associated to better QoL (3). Anxiety and depression levels were assessed through the Hospital Anxiety and Depression Scale (HADS) (4). It is a self-report questionnaire designed to detect clinical cases of depression and anxiety. It includes two subscales evaluating anxiety (HADS-A) and depression (HADS-D), respectively. Each subscale consists of 7 items to be rated on a four-point scale (0-3). The subscales have a maximum score of 21 and a score above 11 is considered clinically significant (4). Both the questionnaires were administered 6 months after surgery. Furthermore, we assessd levels of perceived pain and satisfaction regarding the treatment using a VAS 10-point scale (5). Finally, the procedures were compared regarding surgical outcomes and stonefree rate. Peri- and postoperative complications of procedures were classified using the modified Clavien-Dindo classification for PCNL surgery (6). Participants Assuming two balanced groups, a sample size of 58 patients achieve 80% of power with a significance level of 5% to detect a minimum mean difference of 0.78. 60 patients with kidney stones of dimensions not exceeding 2.5 cm were enrolled in the study of which 30 underwent RIRS and 30 mPCNL. Exclusion criteria were the age under 18 years, transplantation or urinary derivation, congenital anomalies,

renal cancer, pregnancy, cardiovascular or pulmonary comorbidities, coagulation disorders only for PCNL surgery, psychological and/or psychiatric diseases, cognitive and linguistic abilities not sufficient to understand and interpret questionnaires used in the study. Surgical techniques mPCNL and RIRS were performed under general anesthesia and antibiotic prophylaxis with Gentamicine 80 mg when preoperative urine culture was negative. Antibiotic therapy was performed according to antibiotic sensibility when urine culture was positive at least 3 days before surgery and continued 3 days afterwards. mPCNL A transurethral 5 F open-ended catheter was positioned in the ureter to inject contrast dye in the upper tract in a Galdakao-modified supine Valdivia position (7). Puncture of the calyceal system was performed under both ultrasound and fluoroscopy guidance. After placing a hydrophilic safety guide wire (Bard Nicore nitinol guidewire with hydrophilic coating. 0,035” x 150 cm stiff shaft-straight tip), a 10 F dual-lumen angiography catheter (Boston Scientific) and a second safety guide wire were inserted (SensorTM- PTFE- Nitinol Guidewire with hydrophilic tip - Boston Scientific). One-shot tract dilation was accomplished over the SensorTM guidewire with metal dilatator (Karl Storz) and a 15 or 17.5 Fr Amplatz sheath (Karl Storz) was placed. A 12 F Nephroscope (Karl Storz) was inserted through the Amplatz sheath to fragment kidney stones using dusting settings with a 500 µm fiber (0.3 J × 20-30 Hz). Residual fragments were washed out with a vacuum cleaner effect. The procedure was finished with the placement of an 8 F nephrostomy (FleximaTM-Boston Scientific) or a double J stent (BardInlay ureteral stent 6 F 24-26-28) with attached strings coming out the urethra (when tubeless mPCNL was performed). The nephrostomy was removed after confirming a free ureter passage by antegrade ureterography (2436 h after the procedure). In tubeless mPCNL, the ureteral stent was removed 3 to 7 days after the intervention pulling on the attached strings. RIRS RIRS was started with cystoscopic (Rigid cystoscope 19 F Karl Storz) insertion of a safety guide-wire (Bard Nicore nitinol guidewire with hydrophilic coating, 0,035” x 150 cm stiff shaft-straight tip) in supine lithotomic position. A 7 F semirigid ureteroscope (Karl Storz) was used to exclude intraureteral lesions, stones or insufficient ureter dilation. A second guide wire was inserted, and a 10/12 Fr UAS, (Retrace® Coloplast) was deployed over the hydrophilic guidewire inside the ureter if ureteral walls compliance permitted under fluoroscopic guidance. A 7.5 F flexible fiberoptic ureteroscope (Flex X2® - Karl Storz) was used for the complete inspection of the pelvicaliceal system. Stones were fragmented using a Holmium laser dusting set with a 200 µm fiber (Lumenis Pulse TM 120H). Some removal of fragments was not systematically performed using a nitinol basket (Zero-TipTMBoston Scientific) and postoperative stenting (7-14 days) (Bard Inlay ureteral stent 6 F 24-26-28), with an Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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attached string were used (to be extracted by pulling on the string). Statistical analysis Statistical analyses were performed using R package “Rcmdr” (version 2.5-1). A p value < 0.05 was considered statistically significant. Quantitative variables were expressed as mean ± standard deviation (SD) or as median (interquartile range: IQR), when appropriate. Categorical variables were expressed as frequencies (percentages). After testing the non-normality of the distribution of quantitative variables with the Shapiro Wilk test, nonparametric tests were used for data analysis. Chi-squared test was utilized to compare categorical variables and Mann-Whitney test to underline possible significant differences between mPCNL and RIRS for the clinical and psychological outcomes examined in this study.

RESULTS

A total of 30 patients who underwent mPCNL and 30 patients who underwent RIRS were enrolled in this study. The mean age of the patients was 55 (range 4459) years in the mPCNL group and 57.50 (range 47-61) years in the RIRS group. No significant differences were found between the two groups in terms of age, gender, BMI, stone side and size (p > 0.05). However, the two groups were significantly different in terms of previous interventions for kidney stones (p = 0.002). All the demographic data and stone characteristics of the two groups are summarized in Table 1. As shown in Table 2, significant differences between the mPCNL and the RIRS groups were found regarding stenting time (p = 0.032) and duration of hospital stay (p < 0.001). The stone-free rates of mPCNL vs RIRS were not significantly different between the two groups (73.3% vs 66.7%, p > 0.05). Peri- and postoperative complications were not statistically different between the two groups (p > 0.05). We found a significant difference regarding hemoglobin drop values in favor of RIRS, even if no patient needed blood transfusions (p < 0.001). Table 1. Demographic data and stone characteristics of the sample. mPCNL group RIRS group P value (n = 30) (n = 30) Gender Women 22 (73.3) 14 (46.7) 0.064 Men 8 (26.7) 16 (53.3) Age (yr) 55.00 [44.00, 59.00] 57.50 [47.00, 61.00] 0.415 BMI (kg/m2) 26.48 [24.02, 27.54] 25.43 [23.72, 32.33] 0.750 Previous interventions None 11 (36.7) 21 (70.0) 0.002** ESWL 2 (6.7) 4 (13.3) PCNL 7 (23.3) 0 (0.0) RIRS 10 (33.3) 4 (13.3) URS 0 (0.0) 1 (3.3) Stone side Bilateral 2 (6.7) 3 (10.0) 0.737 Right 16 (53.3) 13 (43.3) Left 12 (40.0) 14 (46.7) Stone size (cm) 2.00 [1.62, 2.50] 1.55 [1.20, 2.50] 0.219 Data are expressed as median [range] and as frequencies (percentages). *p < .05; **p < .01.

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Table 2. Postoperative parameters in study groups.

Clavien complications (%) Grade 0 Grade I Stone-free rate (%) < 4 mm > 4 mm Hospital stay (d) Stenting time (d) Hemoglobin (Hb) drop (mg/dL)

mPCNL group RIRS group (n = 30) (n = 30) 28 (93.3) 28 (93.3) 2 (6.7) 2 (6.7) 22 (73.3) 20 (66.7) 8 (26.7) 10 (33.3) 6.00 [4.00, 9.00] 2.00 [1.00, 5.00] 7.00 [0.00, 10.00] 8.00 [5.00, 14.75] 1.15 [0.9, 2.50] 0.5 [0.00, 0.7]

P value 1.000 0.779 < 0.001 0.032* < 0.001

Data are expressed as median [range] and as frequencies (percentages). * p < .05.

Table 3. Psychological outcomes in study groups. mPCNL group (n = 30) HADS (anxiety) 3.00 [0.00, 7.00] HADS (depression) 0.00 [0.00, 5.00] HADS (total) 3.00 [0.00, 15.00] QoL disease score 87.50 [50.00, 95.33] QoL emotional score 82.10 [57.10, 96.40] QoL social score 100.00 [81.30, 100.00] QoL vitality score 100.00 [66.65, 100.00] QoL total score 90.20 [67.00, 95.50] Satisfaction score 10.00 [9.00, 10.00] VAS score 2.00 [1.00, 5.75]

RIRS group P value (n = 30) 7.00 [4.00, 14.00] 0.006** 8.00 [1.00, 10.75] < 0.001** 15.00 [6.00, 24.00] 0.001** 65.60 [45.35, 85.15] 0.179 78.60 [57.10, 92.90] 0.629 84.40 [63.30, 96.90] 0.028* 50.00 [33.30, 91.70] 0.004** 68.75 [56.30, 90.43] 0.166 10.00 [7.00, 10.00] 0.098 5.00 [4.00, 7.00] 0.032*

Data are expressed as median [range]. HADS: Hospital Anxiety and Depression Scale; QoL: Quality of Life; VAS: Visual Analogue Scale. *p < .05; ** p < .01.

Table 3 describes psychological and QoL outcomes assessed in the two groups. Statistically significant differences between the mPCNL and the RIRS groups were found in terms of HADS scores reporting higher anxiety and depression scores, compared with the mPCNL group (3 [range 0-15] vs 15 [range 6-24], p < 0.01). Regarding QoL evaluated with the WISQOL questionnaire, we found significant differences between the two groups in social (p < 0.05) and vitality (p < 0.01) scores. No significant differences were found between the two groups in terms of satisfaction score (p > 0.05). VAS pain score was significantly lower in the mPCNL group than in the RIRS one (p < 0.05).

DISCUSSION

Endourologic stone management comprises several minimally invasive techniques (PCNL, mPCNL, and RIRS) and takes several factors such as success rate, complication rate, comorbidities and technological facilities into account. Percutaneous surgery was developed in 1980 using at first large access sheaths (28-30 F) facilitating irrigation, debris drainage and active removing of large stones (8). In the last decade, mPCNL has gained attention because it involves a miniaturized nephroscope and offers a nephrostomy tract size < 20 F with the aim of decreasing complications associated with tract size during conventional PCNL while providing comparable SFR (9, 10). Besides, in the last two decades an increasing interest for RIRS in the management of kidney stones up to 2 cm with successful treatment of larger stones with fewer complications com-

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pared to standard PCNL using single or staged ureteroscopic procedures has been reported 6. Despite the evolution of mPCNL and RIRS techniques into clinical practice, there is still a lack of comparative clinical data assessing patient satisfaction taking into account perioperative and postoperative morbidity. The principles of evidence-based medicine (EBM) call for the consideration of both clinicalreported outcome (CRO) parameters and patient-reported outcomes (PROs) and the present analysis was conducted with the aim of identifying and critically comparing the outcomes of mPCNL with those of RIRS in the management of kidney stones up to 2,5 cm, focusing both on clinical and psychological outcomes. In our sample, stone-free rate was similar in mPCNL compared to the RIRS group (73.3% vs 66.7%, p > 0.05). Likely, mPCNL would reach the success rate more precociously than RIRS as most of RIRS performers use laser lithotripsy between 5 and 15 W, using a dusting technique to reduce fragments to easily passible sandlike pieces. Instead, mPCNL may guarantee intraoperative stone clearance either by stone dusting or by fragments washed-out through Amplatz sheath (11). Validated Clavien-Dindo evaluation for complications did not reveal any statistically significant difference, while hospital stay was in favor for RIRS, as expected. In our experience, the length of stay is longer for the nephrostomy management in patients subjected to mPCNL, as patients remain hospitalized while the nephrostomy is still inserted. Instead, in tubeless or a totally tubeless patients hospitalization times are overlapping with those of the RIRS. Patients subjected to RIRS are discharged precociously even if they carry a stent because they do not usually require any specific support until stent removal. Stenting time was significantly different between the mPCNL and the RIRS group (7 days [range 4-5] vs 8 days [range 514.75], p = 0.032). Prolonged stenting time in subjects undergoing RIRS is required to eliminate fragments and dust after surgery, which may take an indefinite time - an aspect of ongoing debate. A complete fragment clearance with a basket is very time consuming and requires an UAS of significant diameter to obtain an intraoperative â&#x20AC;&#x153;stone-freeâ&#x20AC;? status. On the other hand, RIRS failure rates due to a difficult impassable ureter range from 8% to 10% and the failure rate to insert a standard UAS is even higher because, in most failed ureteroscopy cases even the smaller diameter ureteroscopes cannot be insert. In these cases, stent placement is necessary, which postpones the procedure. After ureteral relaxation, RIRS can be repeated. The double-staged procedures may be frustrating either for Urologists or for patients and increase costs management. Differently, in the mPCNL fragment clearance is easily obtainable during surgery, allowing to decide whether to use either a stent or nephrostomy for a few days as a precaution to prevent complications (tubeless mPCNL) or not to use tubes at all (totally tubeless). Regarding psychological outcomes, we found significant differences between the two groups regarding QoL domains of social functioning (p < 0.05) and vitality (p < 0.01). Furthermore, the RIRS group showed elevated anxiety and depression scores. Correlated to this data, also VAS pain scores were significantly lower in the mPCNL group compared with the RIRS group (p <

0.05). These data are probably due also to the discomfort related to the postoperative stenting time which was longer in patients undergoing RIRS. Indeed, it has been demonstrated that stents provoke irritating voiding symptoms, hematuria, stent incrustation and fragmentation, back pain, stent migration, infection, pyelonephritis, and ureteral trauma (12, 13). These complications may significantly affect patients QoL and could explain the data in favor of mPCNL regarding psychological outcomes (14). Even though several studies demonstrated a significant difference in terms of discomfort and distress of stented and not stented patients, deeper insights are needed. Ringel et al. reported that 32.7% of their patients had ureteral stents removed because of complications (15). These observations open new scenarios in the treatment of urinary stones for which RIRS and mPCNL have interchangeable indications. Since the complications and the success rate are similar, the surgical choice of switching from RIRS to mPCNL and viceversa may be proposed to patients during pre-operative counseling. Moreover, supine position modified according to Galdakao variant allows in the selected cases of kidney stones up to 2.5 cm, an easy, no time-consuming switch from retrograde to anterograde treatment and vice-versa when patients are unfit for one over the other technique. This could potentially prevent a double-staged procedure, not compliant ureter, UAS insertion failures, impacted stones, anatomical anomalies, inadequate laser dusting for stone physical characteristics and dilated upper tract system. Our study, if corroborated by others on this topic, introduces a new possible paradigm in the treatment of urinary stones up to 2.5 cm, for which the technique (RIRS or mPCNL) to be used is not decided in the preoperative setting, but in progress during the surgery. Strengths and limitations Our study represents an important contribution to the comparison between the surgical procedures most used in the treatment of kidney stones, not only in reference to clinical and surgical outcomes but also to psychological and QoL ones. For this reason, it may be a reference with regard to the clinical and multidisciplinary management of these patients. However, this study has some limitations. First of all, the sample is small, and it is therefore necessary to conduct further studies on larger samples to confirm the results of the study. Furthermore, some data are based on selfreported questionnaires with consequent risk of bias linked to the patient's social desirability. Finally, we did not include a specific questionnaire to assess patients experience of stenting. Further studies are needed about this topic in order to better understand the real impact of stenting on QoL and psychological wellbeing.

CONCLUSIONS

RIRS is usually considered less invasive than mPCNL and preferred in stones up to 2- 2.5 cm but in several cases planned RIRS is not feasible because of unpredictable difficulties forcing the surgeon to place a ureteral stent or nephrostomy and postpone the surgery. In our study, we reported similar outcomes in terms of Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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success-rate, complications and quality of life in up to 2.5 cm stones comparable groups undergoing RIRS and mPCNL. Interestingly, the increased stenting time in patients subjected to RIRS compared to those subjected to mPCNL significantly impacted on QoL. These observations open new scenarios in the treatment of kidney stones when RIRS and mPCNL have interchangeable indications. Since in our experience complications and success rate are similar, the surgical choice of switching from RIRS to mPCNL in real-time and viceversa may be proposed to the patient in the preoperative counseling.

7. Scoffone CM, Cracco CM, Cossu M, et al. Endoscopic combined intrarenal surgery in Galdakao-modified supine Valdivia position: a new standard for percutaneous nephrolithotomy? Eur Urol. 2008; 54:1393-403.

REFERENCES

9. Mariani AJ. Combined electrohydraulic and holmium:YAG laser ureteroscopic nephrolithotripsy of large (greater than 4 cm) renal calculi. J Urol. 2007; 177:168-73; discussion73.

1. Davis NF, Quinlan MR, Poyet C, et al. Miniaturised percutaneous nephrolithotomy versus flexible ureteropyeloscopy: a systematic review and meta-analysis comparing clinical efficacy and safety profile. World J Urol. 2018; 36:1127-38. 2. Garcia SF, Cella D, Clauser SB, et al. Standardizing patientreported outcomes assessment in cancer clinical trials: a patientreported outcomes measurement information system initiative. J Clin Oncol. 2007; 25:5106-12. 3. Penniston KL, Antonelli JA, Viprakasit DP, et al. Validation and Reliability of the Wisconsin Stone Quality of Life Questionnaire. J Urol. 2017; 197:1280-8. 4. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983; 67:361-70. 5. Heller GZ, Manuguerra M, Chow R. How to analyze the Visual Analogue Scale: Myths, truths and clinical relevance. Scand J Pain. 2016; 13:67-75.

Correspondence Davide Di Mauro, MD davidedimauro84@virgilio.it Sebastiano Cimino, MD Department of Urology, University of Catania, Catania (Italy) Valentina Lucia La Rosa, Psy. D. psicolarosa@gmail.com Unit of Psychodiagnostics and Clinical Psychology, University of Catania, Catania (Italy) Eugenio Di Grazia, MD (Corresponding Author) Unit of Urology, Garibaldi Hospital, Catania (Italy)

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6. de la Rosette JJ, Opondo D, Daels FP, et al. Categorisation of complications and validation of the Clavien score for percutaneous nephrolithotomy. Eur Urol. 2012; 62:246-55

8. Hyams ES, Munver R, Bird VG, et al. Flexible ureterorenoscopy and holmium laser lithotripsy for the management of renal stone burdens that measure 2 to 3 cm: a multi-institutional experience. J Endourol. 2010; 24:1583-8.

10. Monga M, Oglevie S. Minipercutaneous nephrolithotomy. J Endourol. 2000; 14:419-21. 11. Jackman SV, Docimo SG, Cadeddu JA, Bishoff JT, Kavoussi LR, Jarrett TW. The "mini-perc" technique: a less invasive alternative to percutaneous nephrolithotomy. World J Urol. 1998; 16:371-4. 12. De S, Autorino R, Kim FJ, et al. Percutaneous nephrolithotomy versus retrograde intrarenal surgery: a systematic review and metaanalysis. Eur Urol. 2015; 67:125-37. 13. Ucuzal M, Serce P. Ureteral Stents: Impact on Quality of Life. Holist Nurs Pract. 2017; 31:126-32. 14. Kelly T, Kelly MH. Living with ureteric stents: a phenomenological study. Br J Nurs. 2019; 28:S29-S37. 15. Ringel A, Richter S, Shalev M, Nissenkorn I. Late complications of ureteral stents. Eur Urol. 2000; 38:41-4.

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DOI: 10.4081/aiua.2019.4.261

CASE REPORT

Preputial circumcision performed with a new mechanical stapling tool. The â&#x20AC;&#x153;langhe disposable circumcision suture deviceâ&#x20AC;?. Preliminary experiences Diego Pozza 1, Carlotta Pozza 2, Augusto Mosca 3, Mariangela Pozza 1 1 Studio

di Andrologia e di Chirurgia Andrologica, Rome, Italy; of FPM, Sapienza University, Rome, Italy; 3 U.O. Urologia ed Andrologia, Osp. S. Sebastiano, Frascati, Italy. 2 Department

Summary

The Authors present their preliminary clinical experiences in performing preputial circumcision utilizing a new stapling tool.

KEY WORDS: Circumcision; Phimosis; Stapling surgical tool. Submitted 17 July 2019; Accepted 29 July 2019

INTRODUCTION

piece is fixed to the Cup under the prepuce. The two handles of the handpiece are firmly tightened so that there is a further compression and section of the cutaneous and mucosal layers. The compression of the handles determines their circular section and suture with 12 staples with perfect mechanical and hydraulic seal. After 1 minute the screw is unscrewed to distance the two parts and free the perfectly circumcised and sutured penis (Figure 2). The prepuce is wrapped with sterile gauze and a strong circular pressure is maintained with the fingers for 4-5 minutes. The penis is tightly bendaged and the pt. is returned to bed with the bandage which is maintained for at least 2-3 hours for hemostatic purposes. If there are no signs of bleeding when the bandage is removed, the patient is sent home. If, on the other hand, a bleeding is observed, a local compression or an absorbable stitch should be applied. The first 3 cases required special prudence and attention; the 17 following pts were performed with simple local anesthesia and in 3 pts (< 20 years) with sedation. Operating times varied between 5 and 7 minutes.

Male circumcision was performed since 2300 BC in Egypt (1) and is one of the most common surgical procedures performed on males for religious, ethical, sexual or medical reasons (2). Circumcision is undertaken using a variety of surgical methods (3). Since the years '80, "Stapler" tools that allow to make sections and sutures of circular and longitudinal organs in very short time have become a "standard" for many surgical branches. Genital surgery, due to the narrowness of the operative field and the limited dimensions of the organs, did not admit the use of these mechanical staplers. We want to present our preliminary experiences on the use of the "Langhe disposable circumcision suture device" (LDCSD), which is an innovative mechanical "Stapler" tool to carry out a Figure 1. A. The Box containing the LDCSD. circumcision (4).

B. The Instrument ready for use. C. The 12 staples assembled in the circular resection part.

CASE

REPORT

We utilized the LDCSD in 20 patients (pts) aged 14 to 80 years with congenital phimosis, redundant prepuce or balanopostitic outcome (Figure 1). In the Operating Room local anesthesia or anesthesiological sedation is performed according to age and clinical data of the pts. After disinfection it is checked that the preputial frenulum is sufficiently extensible, otherwise it is engraved. The part of the instrument, conformed like a small cup with a stem, is introduced under the prepuce to completely cover the gland. The prepuce is fixed to the stem with a safety buckle, the stem of the instrument is introduced into the handpiece until it protrudes. The screw is turned until the handNo conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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Figure 2. A. The prepuce is fixed around the metallic stem. B. The stem is introduced into the handpiece. C. The handpieces are strictly tightened. D. The system is disassembled; the prepuce has been cut.

We have never observed any major complications. No significant intraoperative blood loss. In 2 cases we have prudentially applied few absorbable suture stitches. Metallic staples fell spontaneously after 15-25 days. In 2 cases after 30 days we removed some staples still present with a simple and painless ambulatory maneuver. All pts reported full satisfaction concerning operative, postoperative, aesthetic and functional results (Figure 3). Figure 3. A. Result after 1 week in young patient with phimosis. B. Result in a 80 years old patient after balanoposthitis. C. The metallic staples. D. Result in a young patient after one month.

CONCLUSIONS

The LDCSD with his advantages of simple and easier manipulation, shorter operation time, fewer complications, better cosmetic results, could be considered a useful tool to carry out a rapid, aesthetic, effective and safe circumcision.

REFERENCES

1. Meijer B, Butzelaar RM. Circumcision from a historical perspective. Ned Tijdchr Geneeskd. 2000; 144:2504. 2. Bronselaer GA, Schober JM, Meyer-Bahlburg HF, et al. Male circumcision decreases penile sensitivity as measured in a large cohort. BJU. 2013; 111:820. 3. Featherstone NC, Murphy FL. Paediatric suturless circumcision and modified circumcision: video demostration. J Pediatr Urol. 2012; 8:240. 4. Lv BD, Zhang SG, Zhu XW, et al. Disposable circumcision suture device: clinical effect and patient satisfaction. Asian J Androl. 2014; 16:453.

Correspondence Diego Pozza, MD (Corresponding Author) diegpo@tin.it Mariangela Pozza, MD Studio di Andrologia e di Chirurgia Andrologica Via B. Gozzoli, 62H - 00142 Roma (Italy) Carlotta Pozza, MD Department of FPM, Sapienza University, Roma (Italy) Augusto Mosca, MD U.O. Urologia ed Andrologia, Osp. S. Sebastiano, Frascati (Italy)

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CASE REPORT

DOI: 10.4081/aiua.2019.4.263

Renal autotransplantation: A final option to preserve the kidney after an iatrogenic ureteral injury Napoleon Moulavasilis 1, Ioannis Katafigiotis 1, Dimitris Staios 3, Christos Nikolaidis 2, Spyridon Vernadakis 2, John Bokos 2, Ioannis Anastasiou 1 1 1st

Department of Urology, National and Kapodistrian University of Athens, Laiko Hospital, Athens, Greece; Transplant Unit, Laiko Hospital, Athens, Greece; 3 Urologist, Laiko Hospital, Athens, Greece. 2 Renal

Summary

Background: Ureteral injuries are not very common and can occur after many surgical procedures. Kidney salvage is desirable. Renal autotransplantation is a final option for some cases. In this case, we report an autotransplantation of the kidney after an iatrogenic injury of the ureter with totally extraperitoneal approach. Case report: A 41 years old female underwent left endoscopic ureterolithotomy with holmium laser for ureteral calculi. An iatrogenic ureteral injury, probably ureteral avulsion, occurred. After multiple interventions, she referred to us with a nephrostomy tube. Imaging was performed and left renal autotransplantation was chosen as surgical management. The approach was totally extraperitoneal. No alteration of renal function or of urine outflow was observed during the follow up. Conclusions: The report supports the safety and efficacy of renal autotransplantation.

KEY WORDS: Ureteral injury; Iatrogenic; Renal autotransplantation; Totally extraperitoneal. Submitted 7 July 2019; Accepted 20 July 2019

INTRODUCTION

Iatrogenic ureteral injuries are not a very common complication of urologic and non urologic surgery, but it can be quite challenging to correct them. Salvaging the kidney function and repairing the defect are of paramount importance. Treatment depends on the extent of the ureteral trauma and the site of the injury. Minor injuries can be treated endoscopically with ureteral stent placement, but can relapse. More serious injuries or relapses of minor injuries may require more complicated interventions such as ureteral reimplantation with psoas hitch or Boari flap, or uretero-ureteral anastomosis. Even these more advanced techniques cannot treat the proximal ureter defects, due to short length of healthy ureter (1). Renal autotransplantation is a suitable option for such cases. The first case was performed by JD Hardy in 1963 to repair a ureteral injury, but its implementation is still limited. We present a case of an iatrogenic ureteral injury with failed endoscopic management that resulted in autotransplantation of the kidney.

CASE

REPORT/CASE PRESENTATION

A 41 year old female was referred to us after a prolonged

history of multiple interventions that resulted in the permanent placement of nephrostomy tube for renal drainage. The initial intervention was endoscopic ureterolithotripsy with holmium YAG laser for an impacted ureteral calculi. After complete but strenuous stone fragmentation and removal of semirigid ureteroscope, a complete ureteral avulsion was realised. An immediate open intervention was decided and patient underwent ureteral anastomosis and ureteral stent placement. Patientâ&#x20AC;&#x2122;s post op course was uneventful and she was discharged five days later. Two months postoperatively the patient returned to the treating physicians because of abdominal pain and high fever of 38.5Â°C. Emergency imaging with a CT scan revealed a retroperitoneal abscess around the left kidney extending further to the psoas muscle. Patient underwent open drainage, recovered and was discharged again with a indwelling ureteral stent. Eight months later the patient had a relapse of fever and abdominal pain and CT scan again revealed a retroperitoneal urinoma, that was percutaneously drained. Patient was discharged again after clinical improvement with an indwelling ureteral stent and a Foley catheter for bladder drainage. Seven days later, patient complained of abdominal pain, nausea and vomiting. An ultrasound reported fluid around the kidney extending to the psoas muscle. An attempt to replace the double J stent failed, a percutaneous nephrostomy was placed instead and an ureteral catheter was placed retrogradely. Thereafter the patient was referred to our hospital. A treatment strategy was planned. Firstly, a computer tomography was performed. The report described that the ureteral catheter drained the retroperitoneal fluid. Treatment was given for 6 weeks according to antibiogram of fluid culture following antimicrobial treatment guidelines. The exact site of the urinary tract injury and the extent of the ureteral trauma were investigated thereafter with antegrade pyelography and retrograde ureterography (Figure 1). An upper ureteral defect more than 15 cm in length was demonstrated. Moreover, magnetic resonance imaging (MRI) was performed. Autotransplantation was chosen as surgical management. It was performed almost 1 year after the initial intervention (endoscopic ureterolithotripsy with holmium laser). In supine position, previous incision was revised and the approach was totally extraperitoneal (Figure 2). The kidney was completely mobilized and was harvested with

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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N. Moulavasilis, I. Katafigiotis, D. Staios, C. Nikolaidis, S. Vernadakis, J. Bokos, I. Anastasiou

Figure 1. Antegrade pyelography.

Figure 2. Extraperitoneal approach.

maximal artery and vein length. A healthy segment of the upper ureter was mobilized. The renal vessels were anastomosed to the iliac vessels to reestablish renal perfusion and blood supply to the kidney was recovered within 40 minutes. The segment of the proximal ureter was anastomosed to the bladder. No intraoperative complications occurred. Pigtail (double J stent) was left in the urinary tract for 4 weeks in order to provide safe urine flow from the transplanted kidney. Fifteen days after the autotransplantation the patient was discharged from our hospital with good state of the autotransplanted kidney and urinary tract function. Ultrasound Doppler and DTPA were used to confirm good arterial and venous flow of the transplanted kidney (Figure 3).

Figure 3. DTPA.

the injury. Renal autotransplantation is considered a suitable option for ureteral injuries especially when there is a major loss of ureteral length. Early recognition of the injury is very important because it is followed by minimally invasive procedure. Delayed recognition of injury requires treatment with extended procedures as well as high experience of the urologists. Repair of long defect of the ureter, especially of the proximal ureter, is a particularly difficult surgical challenge. There are no strict recommendations on the treatment of long ureteral lesions. The treatment choice for every case is unique. The decision for renal autotransplantation should be taken based on the extent and location of ureteral injury as well as patient preference and surgeon experience.

CONCLUSIONS

Iatrogenic ureteral injuries are relatively uncommon and the loss of a kidney is devastating. Renal autotransplantation in the setting of severe loss of ureteral length provides an option as it preserves the renal function (3). This report supports the safety and efficacy of renal autotransplantation.

COMPLIANCE

WITH ETHICAL STANDARDS

Informed consent: Written informed consent was obtained from the patient for the publication of this Case Repost/any accompanying images.

REFERENCES

1. Azhar B, Patel S, Chadha P, Hakim N. Indications for renal autotransplant: an overview. Exp Clin Transplant. 2015; 13:109-14. 2. Benson MC, Ring KS, Olsson CA. Ureteral reconstruction and bypass: experience with ileal interposition, the Boari flap-psoas hitch and renal autotransplantation. J Urol. 1990; 143:20-3. 3. Shekarriz B, Lu H, Duh Q, et al. Laparoscopic nephrectomy and autotransplantation for severe iatrogenic ureteral injuries. Urology. 2001; 58:540-3.

Correspondence Napoleon Moulavasilis, MD (Corresponding Author) napomoul@hotmail.com Ioannis Katafigiotis, MD katafigiotis.giannis@gmail.com Ioannis Anastasiou, MD ekati2@otenet.gr 1st Department of Urology, National and Kapodistrian University of Athens, Laiko Hospital Agiou Thoma str., Athens (Greece)

Thirty-two weeks after surgery, no signs of abnormalities of renal function or urine outflow were observed.

DISCUSSION

The management of major ureteral injury is always a challenge (2). It depends on the location and extent of

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Christos Nikolaidis, MD chr.nikolaidis@gmail.com Spyridon Vernadakis, MD svernadakis@yahoo.com John Bokos, MD johnbokos@gmail.com Renal Transplant Unit, Laiko Hospital, Athens (Greece) Dimitris Staios, MD dstaios@yahoo.com Urologist, Laiko Hospital, Athens (Greece)

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DOI: 10.4081/aiua.2019.4.265

CASE REPORT

Solitary prostatic cancer metastasis to the testis: A case report and lessons to learn Asmaa Ismail, Hazem Elmansy, Walid Shahrour, Owen Prowse, Ahmed Kotb Urology Department, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada.

Summary

Prostate cancer (Pca) is a complex disease. Several case series and reports have described the spread of Pca to unusual organs, like esophagus, eye and periureteric fat causing ureteropelvic junction obstruction. Spread of Pca to the testis has been reported in few case reports, however Pca was always firstly diagnosed in all published cases and testicular spread of cancer has been diagnosed during follow up of the patients. This case is unique in that, the patient initially presented with a testicular mass and histologic examination after orchiectomy allowed to diagnose prostatic cancer. This patient was 81 years old and he never had PSA screening by his family doctor. PSA was not even done initially by us considering his age and the presentation with testicular mass. This case may impact clinical practice in several ways: 1) considering Pca always in the differential diagnosis of any disease of an adult man, regardless of its presentation because we did not do that at initial patient evaluation and PSA was only measured after orchiectomy when pathology demonstrated metastatic Pca; 2) suggesting standard orchiectomy with epididemectomy for surgical castration instead of the current surgical technique of subcapsular/subepididymal orchiectomy, because our patient had cancer involving his epididymis as well; 3) suggesting to include PSMA as a part of preoperative staging for high risk Pca patients, in consideration that PSMA is proving to be a promising new imaging technique that can help diagnosing metastatic Pca in unusual locations.

KEY WORDS: Prostate cancer; Testicular metastasis; PSMA; Orchiectomy. Submitted 17 August 2019; Accepted 1 September 2019

INTRODUCTION

Prostate cancer (Pca) is a complicated disease that should be considered in the differential diagnosis of any disease in a man over 50 year old, regardless of his initial presentation. Pastore et al. (1) recently published a case of Pca presented with ocular symptoms turned to be orbital metastasis. Mittal et al. (2) described a patient that had bilateral orchiectomy for hormonal control of metastatic Pca where histology demonstrated metastatic Pca of the testis and epididymis.

CASE

REPORT

An 81- years old man presented to the urology clinic with a left hard and painless testicular mass. Tumour markers were normal and CT of chest, abdomen and pelvis was normal. He was counseled and left radical

orchiectomy was done. Pathology was metastatic adenocarcinoma likely prostatic in origin. The tumour mainly involved epididymis and lower half of the testis. The tumour did show positive immunohistochemical staining to pan-keratin, EMA, CK8/18, p53, BerEP4 and PSA, but negative for CD30, CK7, CK20, alpha-fetoprotein, placental alkaline phosphatase, hCG, CEA, vimentin, calretinin, TTF-1, and CK 5/6. There was no previous PSA testing done. PSA was then measured and transrectal ultrasound (TRUS) guided biopsy was scheduled. PSA was 66 ng/ml and TRUS guided biopsy confirmed Pca Gleason 4+4 in all cores. Bone scan was negative. The patient was counseled about his diagnosis and the absence of other evidence of metastases. External radiotherapy was started with a curative intent.

DISCUSSION

AND CONCLUSIONS

Almagro et al. (3) had the first PubMed indexed publication describing accidentally discovered Pca in the testis during bilateral orchiectomy done for hormonal control. Since then; infrequent case reports are being published describing the testicular spread of Pca. However, all available case reports included patients known to have Pca and had testicular metastasis during follow up course of cancer. Table 1 summarizes ways of presentation of testicular metastasis from Pca. This case report is unique as it describes a metastatic testicular lesion as a way to diagnose Pca. It even leads us to few questions that should be considered during management of this complex disease. Is subcapsular/subepididymal orchiectomy a valid option for surgical castration, considering the risk of epididymal silent metastasis? This Table 1. Some studies of patients with Pca presenting with testicular mass. Publications Janssen et al. (4) Menchini-Fabris et al. (5) Campara et al. (6) Kusaka et al. (7) Mittal et al. (2) Almagro et al. (3) This case report

Presentation During follow up after radical prostatectomy During hormonal treatment of metastatic Pca As a part of initial management of metastatic Pca Metastatic Pca to the testis without previous Pca diagnosis

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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patient had his cancer involving both the testis and epididymis with no clinical suspicion for epididymal involvement. Santos-Lopes et al. (8) described a case of Pca developing epididymal metastasis during follow up of Pca that was discovered because of rising PSA. Are CT bone scans sufficient for patients presenting with high risk criteria of Pca? A recent case series (9) showed that PSMA was able to detect metastatic Pca in unusual sites. Another study included 21 patients with high risk Pca proved superiority of PSMA over CT scan, bone scan and MRI, with PSMA changing management of 51% of patients (10). Prostate cancer should be always suspected in disease of adult men regardless of their presentation. Subcapsular/ subepididymal orchiectomy may not be a safe option for surgical castration. PSMA scan may be the future single routine investigation for all patients with high risk prostate cancer.

REFERENCES

4. Janssen S, Bernhards J, Anastasiadis AG, et al. Solitary testicular metastasis from prostate cancer: a rare case of isolated recurrence after radical prostatectomy. Anticancer Res. 2010; 30:1747-9. 5. Menchini-Fabris F, Giannarini G, Pomara G, et al. Testicular metastasis as isolated recurrence after radical prostatectomy. A first case. Int J Impot Res. 2007; 19: 108-9. 6. Campara Z, Simic D, Aleksic P, et al. Metastasis of prostate adenocarcinoma to the testis. Med Arch. 2016; 70:318- 20. 7. Kusaka A, Koie T, Yamamoto H, et al. Testicular metastasis of prostate cancer: a case report. Case Rep Oncol. 2014; 7:643-7. 8. Santos-Lopes S, Lobo J, Henrique R, et al. Epididymal metastasis from prostate adenocarcinoma: an unusual and challenging diagnosissuspected in gallium-68 prostate-specific membrane antigen-positron emissiontomography/computed tomography and histologically confirmed. Urol Ann. 2017; 9:89-91.

1. Pastore MR, D'Aloisio R, Cirigliano G, et al. Orbital metastasis as presenting symptom from a prostatic adenocarcinoma. Eur J Ophthalmol. 2019; 1120672119832182.

9. Dureja S, Thakral P, Pant V, et al. Rare sites of metastases in prostate cancer detected on Ga-68 PSMA PET/CT scan. A case series. Indian J Nucl Med. 2017; 32:13-15.

2. Mittal J, Dorairajan LN, Manikandan R, et al. Testicular and epididymal metastasis from prostate carcinoma: a rare manifestation of common disease. J Clin Diagn Res. 2017; 11:PD01- PD02.

10. Hirmas N, Al-Ibraheem A, Herrmann K, et al. [68Ga]PSMA PET/CT improves initial staging and management plan of patients with high-risk prostate cancer. Mol Imaging Biol. 2019; 21:574-581.

Correspondence Asmaa Ismail, MD asmaaismail@rocketmail.com Hazem Elmansy, MD hazemuro100@yahoo.com Walid Shahrour, MD walid.shahrour@gmail.com Owen Prowse, MD owenprowse@rogers.com Ahmed Kotb, MD drahmedfali@gmail.com Urology Department, Northern Ontario School of Medicine, Thunder Bay Regional Health Sciences Centre, 980 Oliver Rd, Thunder Bay, Ontario P7B 6V4 (Canada)

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3. Almagro UA. Metastatic tumors involving testis. Urology. 1988; 32:357-60.

Archivio Italiano di Urologia e Andrologia 2019; 91, 4

Cotugno_Stesura Seveso 10/01/20 09:07 Pagina 267

DOI: 10.4081/aiua.2019.4.268

CASE REPORT

Right open nephrectomy under combined spinal and peridural operative anesthesia and analgesia (CSE): A new anesthetic approach in abdominal surgery Michele Cotugno 1, Matteo Dallaglio 2, Luca Cantadori 2, Fabio Villani 2, Daniel Martens 1, Federico Cantoni 1, Michele Potenzoni 1, Salvatore Micali 3, M.C. Bernardo Rocco 3, Andrea Prati 1 1 Dipartimento

Chirurgico, U.O. di Urologia, Ospedale di Vaio-Fidenza, Fidenza, Italy; Chirurgico, U.O. di Anestesia e Rianimazione, Ospedale di Vaio-Fidenza, Fidenza, Italy; 3 Dipartimento di Chirurgia Generale e SpecialitĂ Chirurgiche, U.O. di Urologia, Azienda Ospedaliero-Universitaria di Modena, Italy. 2 Dipartimento

Summary

A case of right open nephrectomy performed under combined spinal and epidural anesthesia and analgesia was presented. This new anesthetic technique gives significant advantages to the patient by avoiding endotracheal intubation with mechanical ventilation and curare administration and by reducing the use of opioids.

KEY WORDS: Nephrectomy; Spinal; Epidural; Anesthesia. Submitted 5 June 2019; Accepted 2 September 2019

INTRODUCTION

We describe a case of right open nephrectomy with xifopubic incision in a patient undergoing initially thoracic spinal anesthesia that was later converted into peridural anesthesia and analgesia (CSE).

PATIENTS

peridural catheter was placed at T9-T10 level and the right radial artery was cannulated. Beginning of the operation was about 15 minutes after the puncture without any surgical or anesthetic problem. After about 70 minutes 15 ml of ropivacaine 0.5% was administered in the peridural catheter in fractions of 5 ml each in a total time of 30 minutes. In the meantime, peridural infusion of ketamine 50 mg + midazolam 5 mg was started at a rate of 2-3 ml/h. The patient was sedated in a light way, awake to the call and reactive to the light stimulus. He maintained sponFigure 1. Antegrade pyelography.

AND METHODS

A 57-year-old male patient with negative medical history for major internal and surgical diseases accessed our operative unit for a massive hematuria. Abdomen ultrasound showed a right renal mass suspected as heteroplasia. Subsequently he performed a computed tomography (CT) of the abdomen with evidence of an inhomogeneous and hyper-vascularized renal neoformation of 10 x 9 cm with central necrotic area and without safe cleavage from the liver. Presence of clots in the renal pelvis, numerous mesenteric and retroperitoneal adenopathies and an occasional finding of a thoracic aortic aneurysm of 4.8 cm were also demonstrated (Figures 1, 2). It was decided to perform the intervention of right nephrectomy with xifopubic incision given the size of the mass and the unsafe cleavage from neighboring structures. Anesthesiologist performed a Combined Spinal and Epidural (CSE) anesthesia and analgesia: subarachnoid puncture at T10-T11 level with Whiteacre 25G needle with administration of isobaric bupivacaine 0.5% 10 mg + dexamethasone 4 mg + ketamine 20 mg + midazolam 2 mg reaching a complete sensory and motor block up to T3 level. Immediately after the spinal puncture, a

Figure 2. Extraperitoneal approach.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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M. Cotugno, M. Dallaglio, L. Cantadori, F. Villani, D. Martens, F. Cantoni, M. Potenzoni, S. Micali, M.C. Bernardo Rocco, A. Prati

taneous breathing with nasal cannulas and low oxygen flow achieving excellent saturation values. The intervention lasted a total of 2 h and 40 minutes with blood losses of about 200 ml. Starting from the closure of the surgical wound, ropivacaine 0.2% infusion was initiated in association with midazolam 5 mg at 5 ml/h. Patient controlled analgesia (PCA) was continued with 1.5 ml boluses with lockout every 20 minutes.

RESULTS

Arterial Blood Gas (ABG) at the end of the procedure showed excellent respiratory exchanges with normocapnia, and lactate in the normal range. Post-operative course was regular. Vital parameters always remained in the normal range, gastrointestinal canalization was recovered the day after the operation, blood count was stable. Bladder catheter was removed on the third postoperative day. Subhepatic drainage and epidural catheter were removed on the fourth postoperative day. The apyretic and asymptomatic patient was discharged on the seventh postoperative day waiting for result of histological examination.

DISCUSSION

Castellani et al. were the first in Italy to describe five cases of radical cystectomy performed under continuous spinal anesthesia, a technique that represents the natural evolution of that used by us (1). Numerous authors have shown excellent perioperative outcomes in cardio-vascular, orthopedic, pelvic and abdominal surgery (2-4). It is also interesting to note that the entire procedure was Correspondence Michele Cotugno, MD (Corresponding Author) mikcot88@libero.it Daniel Martens dmastens@ausl.pr.it Federico Cantoni fcantoni@ausl.pr.it Michele Potenzoni mpotenzoni@ausl.pr.it Andrea Prati aprati@ausl.pr.it Dipartimento Chirurgico, U.O. di Urologia Ospedale di Vaio-Fidenza, Fidenza (Italy) Matteo Dallaglio madallaglio@ausl.pr.it Luca Cantadori lcantadori@ausl.pr.it Fabio Villani fvillani@ausl.pr.it Dipartimento Chirurgico, U.O. di Anestesia e Rianimazione, Ospedale di Vaio-Fidenza, Fidenza (Italy) Salvatore Micali smicali@unimore.it Maria Cesare Bernardo Rocco bernardo.rocco@gmail.com Dipartimento di Chirurgia Generale e SpecialitĂ Chirurgiche, U.O. di Urologia, Azienda Ospedaliero-Universitaria di Modena, Modena (Italy)

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conducted in opioid free mode without negative effect on pain during intra- and post-operative period. This is the first case described in Italy of open nephrectomy performed with this type of anesthesia and the excellent results obtained leads us to think that we can apply it in other future surgical procedures.

CONCLUSIONS Our opinion is that this new anesthetic technique gives significant advantages to the patient, in particular by avoiding endotracheal intubation with mechanical ventilation and curare administration and by reducing the use of opioids. The evolution (using a special device) to continuous spinal anesthesia (CSA) could lead to a further improvement of the procedure. Randomized and controlled clinical trials will be needed to confirm our initial results.

REFERENCES 1. Castellani D, Starnari R, Faloia L, et al. Radical cystectomy in frail octogenarians in thoracic continuous spinal anesthesia and analgesia: a pilot study. Ther Adv Urol. 2018; 10:343-349. 2. Michaloudis D, Petrou A, Bakos P, et al. Continuous spinal anaesthesia/analgesia for the perioperative management of high-risk patients. Eur J Anaesthesiol. 2000; 17:239-247. 3. Amin SM, and Sadek SF. Continuous spinal anesthesia for elderly patients with cardiomyopathy undergoing lower abdominal surgeries. Egypt J Anaesth. 2016; 32:535-540. 4. Jaitly VK and Kumar CM. Continuous spinal anaesthesia for laparotomy. Curr Anaesth Crit Care. 2009; 20:60-64.

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DOI: 10.4081/aiua.2019.4.269

CASE REPORT

Detection of significant left renal artery stenosis caused by fibromuscular dysplasia with selective angiography Ramezan Jafari 1, Zohreh Rostami 2, Mohammad Nikpoor 2, Mohammad Javanbakht 2, Mohsen Sadeghi Ghahroudi 3, Mahbobeh Sadat Hosseini 4, Behzad Einollahi 2 1 Department

of Radiology and Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran; and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran; 3 Atherosclerosis Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran; 4 Clinical Research Development Unit, Baqiyatallah University of Medical Sciences, Tehran, Iran. 2 Nephrology

Summary

A 22-year-old female, was referred with a history of a headache and elevated blood pressure without family history of hypertension or familial dyslipidemia. Initially, a spiral computed tomographic angiography of the renal arteries was conducted, demonstrating completely abnormal left renal artery at the medial portion of the vessel with suspicious stenosis, which was supposed to be due to fibromuscular dysplasia (FMD). Subsequently, the patient underwent selective renal angiography and balloon angioplasty. Severe stenosis was observed on the left side and moderate stenosis on the right side in the medial and proximal part of the vessels, respectively. After the diagnosis of FMD, the left side was treated by balloon and finally, the patient was discharged with good control of blood pressure by losartan/amlodipine treatment.

KEY WORDS: Fibromuscular dysplasia; Computed tomographic angiography; Selective renal angiography; Balloon. Submitted 10 August 2019; Accepted 16 October 2019

INTRODUCTION

Fibromuscular dysplasia (FMD) with renovascular hypertension (RVH) is idiopathic with unclear etiology, being a non-inflammatory and non-atherosclerotic vascular disease, which mainly involves the renal arteries leading to RVH. It less commonly affects carotids, vertebral, iliac, subclavian, and visceral arteries (1, 2). FMD is mainly observed in young women and only 10% to 20% of the cases present with renal artery stenosis (RAS), causing secondary RVH. The right RA is the prevailing site of FMD although bilateral manifestation is possible in 40% of cases and approximately bilateral FMD is seen in one-third of cases and unilateral FMD of the right RA is three times higher than FMD of the left RA (3, 4). Invasive selective renal artery angiography procedure has been considered as the gold standard for the detection and assessment of RAS caused by FMD although noninvasive diagnostic techniques such as color Doppler ultrasonography and CT angiography can discover RAS, especially when localized near to the vascular origin (5, 6). In present study, we report a 22-year-old female with a history of a headache and hypertension due to RAS caused by FMD who was successfully treated.

CASE

PRESENTATION

A 22-year-old female patient was referred to our clinic with a history of a headache and elevated blood pressure. After primary examination and relative blood pressure control (from 190/120 to 160/100 mmHg) she was hospitalized for further investigation in the hospital. Additionally, she had with no family history of hypertension or familial dyslipidemia and no history of cigarette smoking, alcohol and drug consumption. On physical examination, the patient had normal jugular venous pressure. Moreover, in her cardiac exam, there was a systolic murmur (3/6) at the apex. No bruits were heard on her abdomen and carotid regions, and also, the upper and lower extremities pulse was normal and symmetrical. Her laboratory results included: WBC: 4.600 Neutrophils 71%, Hemoglobin: 9.3 g/dl, MCV: 87 fl, MCH: 29 pg, Platelet: 360000, Liver function tests: normal, Erythrocyte sedimentation rate: 8 mm/h, C reactive protein: negative, Antinuclear antibody: negative, Rheumatic factor: negative, Anti dsDNA antibody: negative, C3: normal, C4: normal, Calcium: normal, Magnesium: normal, Creatinine: 0.8 mg/dl, Sodium: 136 mEq/dl, Potassium: 3.7 mEq/dl, 24 hr urine protein: normal, Aldosterone: 1230 ng/dl, Plasma Renin Activity: 61.5 ng/ml. At transthoracic echocardiography investigation, she had a mild enlarged left ventricular size and normal function (moderate left ventricular hypertrophy), normal right ventricle size and function, moderate to severe mitral regurgitation, mild to moderate tricuspid regurgitation, moderate aorta insufficiency. Renal ultrasonography revealed right and left kidney measuring 107 and 90 mm in length, respectively. Color Doppler ultrasound indicated that velocity at the origin of the right renal artery was 359 cm/s and at the left was 95 cm/s with a resistive index (RI) of 0.60-0.62 and 0.390.48 at the right and left renal artery, respectively. In consideration of the size difference of the two kidneys and of the reduced RI, plus the elevated serum levels of renin and aldosterone, a supplementary study with computed tomographic angiography (CTA) was recommended. A spiral CTA of the renal arteries was conducted, revealing unilateral renal FMD. The left renal artery was completely abnormal at the medial portion of the vessel with suspicious stenosis, which was related to FMD at that

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2019; 91, 4

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R. Jafari, Z. Rostami, M. Nikpoor, M. Javanbakht, M. Sadeghi Ghahroudi, M. Sadat Hosseini, B. Einollahi

Figure 1. Axial (A) coronal (B) and Volume Rendering Technique (VRT) of computed tomography (CT) scan images showing beading at mid and distal third of left renal artery with significant stenosis at midportion and sparing of origin which is compatible with Fibromuscular dysplasia (FMD).

time. A selective renal angiography was performed, demonstrating patent right renal artery without stenosis (Figire 1) and mild beading of branches of left renal artery branches. Additionally, no accessory or aberrant arterial branch was detected. She underwent selective renal angiography and balloon angioplasty. The most critical stenosis was on the left side (severe) but moderate stenosis was also seen on the right side in the proximal part of the vessel. The left side (more severely affected by FMD) was treated by balloon on the medium part of the vessel. There was a good angiographic outcome after this approach: the stenosis ameliorated notably and there were no spasms or dissections. There were no complications. After angioplasty, she was discharged with good control of blood pressure with losartan/amlodipine therapy. She was asymptomatic and in good overall clinical condition and well-controlled blood pressure was observed after discharge.

DISCUSSION

FMD as an unusual cause of arterial disease, which mainly affects females (aged 15-50 years), and regularly involves the mid or/and distal segments of the renal artery (4, 7). In accordance, our case was a 22-year-old female with a stenosis of the renal artery at the medial portion of the vessel. On the other hand, notwithstanding diverse theories involving genetic, mechanical and hormonal risk factors, cigarette smoking, cardiovascular risk factors and also, intrinsic deficiency of elastic fibers, the pathogenesis of FMD remains undisclosed (8, 9). Medical management and pharmacological therapy of hypertension in FMD should pursue the guidelines of the Joint National Committee on interdiction, inspection, assessment and remedy of high blood pressure (10). The first line therapy when managing patients with symptomatic FMD is the treatment of blood pressure that in patients with RAS needs at least one antihypertensive drug (11). Furthermore, in young patients, revascularization is an alternative in cases with hypertension

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refractory to pharmacological therapy (12). Balloon angioplasty is beneficial for the remedy of FMD in the principal renal arteries. However, nowadays it is possible to use smaller balloons and better catheter techniques (13, 14). In accordance with the above reported treatment approaches, our patient affected by FMD was treated by balloon on the medium part of the left renal vessel and was discharged with control of blood pressure using losartan/amlodipine. Finally, subsequent the angioplasty, the blood pressure in our case returned to normal on antihypertensive drugs.

CONCLUSIONS

FMD causing RAS and renovascular hypertension is fundamental to be considered in young hypertensives, even in absence of family history of hypertension. Moreover, balloon angioplasty as well as selective renal angiography is the 'gold standard' test for RAS and must be conducted when renovascular intervention is envisaged.

CONSENT

Informed patient consent was obtained.

REFERENCES

1. Geavlete O, Calin C, Croitoru M, et al. Fibromuscular dysplasia - a rare cause of renovascular hypertension. Case study and overview of the literature data. J Med Life. 2012; 5:316-20. 2. Hundae AY, Hebert CA, Schussler JM. Fibromuscular dysplasia of the renal artery as a cause of secondary hypertension. Proc (Bayl Univ Med Cent). 2013; 26:405-6. 3. Chrysant SG, Chrysant GS. Treatment of hypertension in patients with renal artery stenosis due to fibromuscular dysplasia of the renal arteries. Cardiovasc Diagn Ther. 2014; 4:36-43. 4. Zeina AR, Vladimir W, Barmeir E. Fibromuscular dysplasia in an accessory renal artery causing renovascular hypertension: a case report. J Med Case Rep. 2007; 1:58. 5. Colyer WR, Eltahawy E, Cooper CJ. Renal artery stenosis: optimizing diagnosis and treatment. Prog Cardiovasc Dis. 2011; 54:29-35.

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Left renal artery stenosis

6. Radermacher J, Chavan A, SchĂ¤ffer J, et al. Detection of significant renal artery stenosis with color Doppler sonography: combining extrarenal and intrarenal approaches to minimize technical failure. Clin Nephrol. 2000; 53:333-43.

11. Weinberg I, Gu X, Giri J, et al. Anti-platelet and anti-hypertension medication use in patients with fibromuscular dysplasia: results from the United States Registry for fibromuscular dysplasia. Vasc Med. 2015; 20:447-453.

7. Urban BA, Ratner LE, Fishman EK. Three-dimensional Volumerendered CT angiography of the renal arteries and veins: normal anatomy, variants, and clinical applications. Radiographics. 2001; 21:373-386.

12. Knorring JV, Edgren J, LepĂ¤ntalo M. Long-term results of percutaneous transluminal angioplasty in renovascular hypertension. Acta Radiologica. 1996; 37:36-40.

8. Slovut DP, Olin JW. Fibromusculardysplasia. N Engl J Med. 2004; 50:1862-1871. 9. Ralapanawa DM, Jayawickreme KP, Ekanayake EM. A case of treatable hypertension: fibromuscular dysplasia of renal arteries. BMC Res Notes. 2016; 9:6. 10. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA. 2003; 289:2560-2572.

13. Gumus B, Cevik H, Vuran C, et al. Cutting balloon angioplasty of bilateral renal artery stenosis due to Takayasu arteritis in a 5year-old child with midterm follow-up. Cardiovasc Intervent Radiol. 2010; 33:394-7. 14. Alhadad A, Mattiasson I, Ivancev K, et al. Revascularisation of renal artery stenosis caused by fibromuscular dysplasia: effects on blood pressure during 7-year follow-up are influenced by duration of hypertension and branch artery stenosis. J Hum Hypertens. 2005; 19:761-7.

Correspondence Ramezan Jafari, MD Department of Radiology and Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran (Iran) Mohammad Javanbakht, MD (Corresponding Author) mhmjvbt81@gmail.com Zohreh Rostami, MD Mohammad Nikpoor, MD Behzad Einollahi, MD Nephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran (Iran) Mohsen Sadeghi Ghahroudi, MD Atherosclerosis Research Center, Baqiyatallah University of Medical Sciences, Tehran (Iran) Mahbobeh Sadat Hosseini, MD Clinical Research Development Unit, Baqiyatallah University of Medical Sciences, Tehran (Iran)

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