Archivio Italiano di Urologia e Andrologia - Vol. 92 - n. 4 - 2020

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ISSN 1124-3562

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. 92; n. 4 December 2020

Vol. 92; n. 4, December 2020

ORIGINAL PAPERS 275

Overview of the italian experience in surgical management of bladder cancer during first month of COVID-19 pandemic Carmen Maccagnano, Lorenzo Rocchini, Emanuele Montanari, Giario Natale Conti, Giovanni Petralia, Federico Dehò, Kadi-Ann Bryan, Roberto Contieri, Rodolfo Hurle

282

Urological emergency activities during COVID-19 pandemic: Our experience Elisa Cicerello, Mario S. Mangano, Giandavide Cova, Alessio Zordani

286

Outcome and quality of life of patients with augmented bladder or urinary diversion after kidney transplantation Giulia Pozza, Massimo Iafrate, Mariangela Mancini, Cristina Silvestre, Francesca Neri, Lucrezia Furian, Paolo Rigotti, Tommaso Prayer Galetti

291

Attitudes and perceptions towards multiparametric magnetic resonance imaging of the prostate: A national survey among Italian urologists Arnaldo Stanzione, Massimiliano Creta, Massimo Imbriaco, Roberto La Rocca, Marco Capece, Fabio Esposito, Ciro Imbimbo, Ferdinando Fusco, Giuseppe Celentano, Luigi Napolitano, Francesco Mangiapia, Vincenzo Mirone, Nicola Longo

297

The safety and feasibility of the simultaneous use of 180-W GreenLight laser for prostate vaporization during concomitant surgery Roberto Castellucci, Michele Marchioni, Giuseppe Fasolis, Francesco Varvello, Pasquale Ditonno, Gaetano Di Rienzo, Francesco Greco, Vincenzo Maria Altieri, Antonio Frattini, Giovanni Ferrari, Luigi Schips, Luca Cindolo

302

Penile prosthesis and complications: Results from 577 implants Diego Pozza, Andrea Marcantonio, Augusto Mosca, Carlotta Pozza

309

Mini invasive approaches in the treatment of small renal masses: TC-guided renal cryoablation in elderly Oscar Selvaggio, Giovanni Silecchia, Matteo Gravina, Ugo Giovanni Falagario, Giovanni Stallone, Luca Macarini, Giuseppe Carrieri, Luigi Cormio

314

Physiopathology of the diabetic bladder Tatiana Bolgeo, Antonio Maconi, Marinella Bertolotti, Annalisa Roveta, Marta Betti, Denise Gatti, Carmelo Boccafoschi

CASE REPORTS 318

Giant hydronephrosis secondary to ureterocele with duplex system in adults: Report of a case Andrea Solinas, Luca Cau, Massimiliano Fanari, Ignazio Flaviani, Francesco Manca, Maurizio Melis

321

Complications of endourological procedures and their treatment Aldo Franco De Rose, Eugenio Di Grazia, Vincenzo Magnano San Lio, Khaled Refaai, Martina Beverini, Alberto Caviglia, Davide Di Mauro, Giuseppe Giordano, Islam O. Koraiem, Guglielmo Mantica, Diego Meo, Mohamed Ramadan, Mostafa Sakr, Carlo Terrone

LETTER TO EDITORS 326

Erectile disfunction medical treatment with phosphodiesterase 5 inhibitors (PDE5i) in patients with retinitis pigmentosa and side effects Andrea Cocci, Andrea Romano, Girolamo Morelli, Davide Frediani, Andrea Sodi, Giorgio Ivan Russo

328

Observational study on the effects of a topical formulation in patients with premature ejaculation Giuseppe Quarto, Luigi Castaldo, Giovanni Grimaldi, Alessandro Izzo, Raffaele Muscariello, Sisto PerdonĂ continued on page III

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Official Journal of SIA, SIEUN, UrOP, SSCU 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,

Department 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 Vita-Salute 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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XXIII Congresso Nazionale

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ORIGINAL PAPERS, REVIEW & CASE REPORTS 330

Perineural invasion in prostate needle biopsy: Prognostic value on radical prostatectomy and active surveillance Nuno Ramos, Alexandre Macedo, João Rosa, Miguel Carvalho

335

Effects of butein on renal ischemia/reperfusion injury: An experimental study Mehmet Akif Ramazanoglu, Tuncay Toprak, Mehmet Remzi Erdem, Gulistan Gumrukcu, Hatice Kucuk, Feridun Sengor

340

Protective effect of cordycepin on experimental renal ischemia/reperfusion injury in rats Hasan Riza Aydin, Cagri Akin Sekerci, Ertugrul Yigit, Hatice Kucuk, Huseyin Kocakgol, Seyfi Kartal, Yiloren Tanidir, Orhan Deger

345

Which factors affect the success of pediatric PCNL? Single center experience over 20 years Volkan Izol, Nihat Satar, Yildirim Bayazit, Fatih Gokalp, Nebil Akdogan, Ibrahim Atilla Aridogan

350

Clinical results of shock wave lithotripsy treatment in elderly patients with kidney stones: Results of 1433 patients Cevahir Ozer, Mehmet Ilteris Tekin

353

How urologists deal with chronic prostatitis? The preliminary results of a Mediterranean survey Konstantinos Stamatiou, Vittorio Magri, Gianpaolo Perletti, Evangelia Samara, Georgios Christopoulos, Alberto Trinchieri

357

Modeling the contribution of the obesity epidemic to the temporal decline in sperm counts Alex Kasman, Francesco Del Giudice, Eugene Shkolyar, Angelo Porreca, Gian Maria Busetto, Ying Lu, Michael L. Eisenberg

362

Antioxidant treatment of increased sperm DNA fragmentation: Complex combinations are not more successful Cevahir Ozer

366

Role of total motile sperm count in the evaluation of young men with bilateral subclinical varicocele and asthenospermia Georgios Tsampoukas, Athanasios Dellis, Antigoni Katsouri, Dominic Brown, Konstantinos Deliveliotis, Mohamad Moussa, Noor Buchholz, Athanasios Papatsoris

371

Erectile dysfunction in common neurological conditions: A narrative review Mohamad Moussa, Athanasios G. Papatsoris, Mohamed Abou Chakra, Baraa Dabboucy, Youssef Fares

386

Comparison of penile prosthesis types' complications: A retrospective analysis of single center Erdem Kisa, Mehmet Zeynel Keskin, Cem Yucel, Murat Ucar, Okan Yalbuzdag, Yusuf Ozlem Ilbey

390

Primitive small cell carcinoma of the prostate. Case report and revision of the literature Pietro Pepe, Ludovica Pepe, Mara Curdman, Michele Pennisi, Filippo Fraggetta

392

An urological cause of hypoglycaemia: A case report of the Doege-Potter syndrome Nuno Ramos, Rodrigo Ramos, Celso Marialva, Eduardo Silva

394

Renal papillary hypertrophy, a rare cause of recurrent gross hematuria; Case report and review of literature hmad Beltagy, Mohamed Elsaqa, Islam Koraiem, Ahmed Abulfotooh Eid

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ORIGINAL PAPER

DOI: 10.4081/aiua.2020.4.275

Overview of the italian experience in surgical management of bladder cancer during first month of COVID-19 pandemic Carmen Maccagnano 1, Lorenzo Rocchini 2, Emanuele Montanari 2, Giario Natale Conti 1, Giovanni Petralia 3, Federico Dehò 4, Kadi-Ann Bryan 5, Roberto Contieri 6, Rodolfo Hurle 6 1 Department

of Surgery, Section of Urology, ASST Lariana, Nuovo Ospedale Sant’Anna, San Fermo della Battaglia (CO), Italy; of Surgery, Division of Urology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; 3 Urology Unit, Niguarda Hospital, Milan, Italy; 4 Unit of Urology, ASST Sette Laghi-Circolo e Fondazione Macchi Hospital; 5 Rogue-Valley Urology, Medford, Oregon, US; 6 Department of Urology, Istituto Clinico Humanitas IRCCS Clinical and Research Hospital, Rozzano (MI), Italy.

2 Department

Summary

Objective: Overview of bladder cancer (BC) management in Italy during the first month of the COVID-19 pandemic (March 2020) with head to head comparison of the data from March 2019, considered “usual activity” period. The aim is to analyze performance of different Italian Centers in North, Center and South, with a special eye for Lombardy (the Italian epicenter).

Patients and methods: During April 2020, a survey containing 14 multiple-choice questions focused on general staffing and surgical activity related to BC during the months of March 2019 and March 2020 was sent to 32 Italian Centers.

Statistical analysis was performed using IBM SPSS Statistics (v26) software. A Medline search was performed, in order to attempt a comparative analysis with published papers.

Results: 28 Centers answered, for a response rate of 87.5%.

Most of the urology staff in the Lombardy region were employed in COVID wards (p = 0.003), with a statistically significant reduction in the number of radical cystectomies (RC) performed during that time (p = 0.036). The total amount of RC across Italy remained the same between 2019 and 2020, however there was an increase in the number of surgeries performed in the Southern region. This was most likely due to travel restrictions limiting travel the North. The number of Trans-Urethral Resection of Bladder Tumors (TURBT) (p = 0.046) was higher in Academic Centers (AC) in 2020 (p = 0.037).

Conclusions: The data of our survey, although limited, represents a snap shot of the management of BC during the first month of the COVD-19 pandemic, which posed a major challenge for cancer centers seeking to provide care during an extremely dynamic clinical and political situation which requires maximum flexibility to be appropriately managed.

KEY WORDS: COVID-19; Urology; Pandemic; Outbreak; Bladder cancer; Non-muscle invasive bladder cancer; Trans-urethral resection of bladder tumor; Cystectomy; Hematuria.

Submitted 2 June 2020; Accepted 20 July 2020

INTRODUCTION

Bladder cancer (BC) represents 3% of all malignancies, with 549.000 new cases and 199.000 deaths were

reported worldwide in 2018 (1). This is generally associated with high levels of morbidity and mortality especially in patients over 70yrs. In the United States about 47% are estimated to be Ta/Tis at initial presentation, 21% stage I, 11% stage II, 4% stage III, and 6% stage IV disease (2). The cornerstones of BC surgical treatments are represented by trans-urethral resection of bladder tumours (TURBT) and radical cystectomy (RC).

Some papers were recently published regarding mortality risk from COVID-19 and BC: 63% of patients (pts) had one comorbidity (such as hypertension, cardiovascular, or pulmonary), 32% had two or more comorbidities, and the risks of dying from BC or from a competing disease were similar at 5 yrs after diagnosis (3, 4).

On March 11th, 2020, after the World Health Organization declared the disease caused by the novel Coronavirus SARS-COV-2 a pandemic, the exponential increase in the number of affected individuals led to a rapid reallocation of economic, infrastructural and health care resources, with redistribution of those medical/surgical, including urologic oncology, prioritizing urgent and emergent needs (5). This takes into consideration the evidence that almost 30% of individuals older than 65 years are at risk for developing acute respiratory distress syndrome after contracting COVID-19 and approximately 20% of asymptomatic individuals infected with COVID-19 may die after an elective operation (6, 7). However, the effect of this prioritization, as well as the clinical consequences of postponing surgical procedures, on patients and health care systems remains actively debated, despite recently published recommendations (7-12) (Table 1).

Additionally, as demonstrated by Liang et al. and Moschovas et al., the increasing risk of COVID-19 related complications in cancer patients has to be considered specifically, noting that a significantly higher proportion of patients will require ventilation in the Intensive Care Unit (ICU), with some dying as a consequence of these complications (13, 14).

Moreover, 25% of pts requiring high-priority surgery are considered at increased perioperative risk, which can be partially defined by cancer-related immunocompromised state and consequent higher susceptibility to

No conflict of interest declared.

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C. Maccagnano, L. Rocchini, E. Montanari, G.N. Conti, G. Petralia, F. Dehò, K.-A. Bryan, R. Contieri, R.Hurle

Table 1.

International Scientific Societies recommendations about surgical management of BC during pandemic.

Scientific Society Italian Society of Urology (SIU) (https://www.siu.it) (9)

European Association of Urology (EAU) (https://uroweb.org/wp-content/uploads/EAUGuidelines-Office-Rapid-Reaction-Group-An-organisationwide-collaborative-effort-to-adapt-the-EAU-guidelinesrecommendations-to-the-COVID-19-era.pdf) (10)

National Comprehensive Cancer Network (NCCN) (https://www.nccn.org/covid-19/pdf/Cancer_Services_ Patient_Prioritization_Guidelines.pdf) (11) American Urological Association (https://www.facs.org/covid-19/clinical-guidance/triage) (12)

TURBT Low priority (deferrable) • TURBT after instillations • TURBT in low risk pts for progression Intermediate priority TURBT in pts with small recurrences High priority: • Pts with high risk of progression • 2nd look TURBT for HG or T1 Low priority (defer by 6 months): • Small papillary recurrences (< 1 cm) and history of Ta/1 low grade tumour; • 2nd TURBT in pts with visibly complete initial TURBT of T1 lesion with muscle in the specimen.

Intermediate priority (treat before end of 3 months): Any primary tumour or recurrent papillary tumour > 1 cm and without hematuria or without history of HG NMIBC High priority (treat within 6 weeks) • Pts with bladder lesion and intermittent macroscopic hematuria or history of high-risk NMIBC; • 2nd TURBT in pts with visibly residual tumour after initial resection and large or multiple T1HG at initial resection without muscle in the specimen Possible postponing low risk pts Not postponing high risk pts

Cystectomy Never postpone

High risk: TURBT as scheduled Not- high risk: Postpone in 4-12 weeks

High risk cancer: Cystectomy as scheduled Not- high risk cancer: Postpone in 4-12 weeks

infections, compared to general population (5, 15).

Furthermore, it is important to consider the most valuable resource that is personnel, as we observed a 30% shortage of health care workers due to hospital-acquired COVID-19 infection (16, 17).

We report on the surgical management of BC in different regions of Italy (with focus on Lombardy, as the Italian epicenter) during the first month of COVID-19 outbreak (March 2020), with head to head comparison with data from March 2019.

MATERIALS

Table 2.

Main characteristics of centers who answered to survey.

Characteristic Total amount of centers who answered Academic Centers Emergency Room Non COVID-centers (nCC) Institutes located in North Institutes in Lombardy Institutes located in Centre Institutes located in South

Number 28/32 (87.5%) 15/28 (53.6%) 24/28 (85.7%) 4/28 (14.3%) 14/28 (50%) 11/28 (39.3%) 7/28 (25%) 7/28 (25%)

AND METHODS

A survey containing 14 multiple choice questions, focused on surgical activity related to BC carried out in March 2019 and March 2020, was sent to 32 Italian Centers (see appendix 1) during the first week of April 2020. We also queried medical staffing at these facilities: total amount of Urologists (including resident physicians) and percentage dedicated to COVID wards for each institute. 28 Centers answered (Table 2). To note, non COVID-centers (nCC) were defined as hospitals where only pts with negative nasopharyngeal swab and negative chest CT-scans were admitted. Statistical analysis of the data was performed using IBM SPSS Statistics (v26) software. We evaluated the geographic differences between Lombardy (the epicenter of pandemic), Northern centers outside Lombardy, Center and South. Moreover, we evaluated differences between academic (AC) and non-academic centers (NAC), according to location. We evaluated the number of RC, TURBT, operative blocks (OB) dedicated to urology and number of surgical procedures performed during March 2019 and

276

Cystectomy has to be performed within 3 months since the diagnosis in case of: • pts with highest risk NMIBC; • pts with BCG unresponsive tumor or BCG failure.

Archivio Italiano di Urologia e Andrologia 2020; 92, 4

March 2020. We also compared the differences between AC and NAC. All the variables in this survey are nominal (categorical), so we tested the statistical differences between centers and location using chi-square test through crosstab function in our software.

RESULTS

Table 3 reported data about centers and their distribution across Italy.

Several different statistical differences emerged comparing Lombardy hospitals and rest of Northern Italy in March 2020: number of OB dedicated to urology (p = 0.027); number of surgical procedures per OB (p = 0.018); number of TURBT (p = 0.012); number of hemostatic TransUrethral Resection (hTUR) (p = 0.010). These differences were no relevant considering Lombardy centers among Northern group.

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Bladder cancer and Pandemic in Italy in March 2019

Table 3.

Lombardy vs North vs Centre and South Italy centers.

Lombardy North Italy Central Italy South Italy Total numbers Number 11/28 (39.3) 3/28 (10.7%) 7/28 (25%) 7/28 (25%) Covid free yes 2/11 (18.2%) 0/3 2/7 (28.6%) 0/7 4/28 (14.3%) no 9/11 (81.8%) 3/3 5/7 (71.4%) 7/7 24/28 (85.7%) Academic Hospital yes 4/11 (36.4%) 2/3 (66.7%) 5/7 (71.4%) 4/7 (57.1%) 15/28 (53.6%) no 7/11 (63.6%) 1/3 (33.3%) 2/7 (28.6%) 3/7 (42.9%) 13/28 (46.2%) Emergency room: yes 9/11 (81.8%) 3/3 5/7 (71.4%) 7/7 24/28 (85.7%) no 2/11 (18.2%) 0/3 2/7 (28.6%) 0/7 4/28 (14.3%) staff: < 10 5/11 (45.5%) 1/3 (33.3%) 3/7 (42.9%) 1/7 (14.3%) 10/28 (35.7%) 10-20 5/11 (45.5%) 0/3 1/7 (14.3%) 5/7 (71.4%) 11/28 (39.3%) > 20 1/11 (9.1%) 2/3 (66.7%) 3/7 (42.9%) 1/7 (14.3%) 7/28 (25%) Medical Doctors employed in Covid wards: < 30% 5/11 (45.5%) 3/3 7/7 7/7 22/28 (78.6%) 30%-50% 3/11 (27.3%) 0/3 0/7 0/7 3/28 (10.7%) > 50% 3/11 (27.3%) 0/3 0/7 0/7 3/28 (10.7%) Operating block dedicated to Urology Division during March 2020: 0 4/11 (36.4%) 0/3 0/7 0/7 4/28 (14.3%) 1-2 1/11 (9.1%) 0/3 1/7 (14.3%) 2/7 (28.6%) 4/28 (14.3%) >2 6/11 (54.5%) 3/3 6/7 (85.7%) 5/7 (71.4%) 20/28 (71.4%) Operating block dedicated to Urology Division during March 2019: 0 0/11 0/3 0/7 0/7 0/28 1-2 1/11 (9.1%) 0/3 1/7 (14.3%) 3/7 (42.9%) 5/28 (17.9%) >2 10/11 (90.9%) 3/3 6/7 (85.7%) 4/7 (57.1%) 23/28 (82.1%) Number of operation performed per operating block during March 2020: 1 4/11 (36.4%) 0/3 0/7 0/7 4/28 (14.3%) 2-3 4/11 (36.4%) 3/3 5/7 (71.4%) 5/7 (71.4%) 17/28 (60.7%) >3 3/11 (27.3%) 0/3 2/7 (28.6%) 2/7 (28.6%) 7/28 (25%) Number of operation performed per operating block during March 2019: 1 0/11 0/3 0/7 1/7 (14.3%) 1/28 (3.6%) 2-3 7/11 (63.6%) 2/3 (66.7%) 3/7 (42.9%) 6 (85.7%) 18/28 (64.3%) >3 4/11 (36.4%) 1/3 (33.3%) 4/7 (57.1%) 0/7 9/28 (32.1%) Number of trans-urethral resection performed during March 2020: <5 6/11 (54.5%) 0/3 0/7 1/7 (14.3%) 7/28 (25%) 5-15 4/11 (36.4%) 3/3 4/7 (57.1%) 3/7 (42.9%) 14/28 (50%) >15 3/11 (27.3%) 0/3 3/7 (42.9%) 3/7 (42.9%) 7/28 (25%) Number of trans-urethral resection performed during March 2019: <5 0/11 0/3 0/7 1/7 (14.3%) 1/28 (3.6%) 5-15 4/11 (36.4%) 1/3 (33.3%) 3/7 (42.9%) 3/7 (42.9%) 11/28 (39.3%) > 15 7/11 (63.6%) 2/3 (66.7%) 4/7 (57.1%) 3/7 (42.9%) 16/28 (57.1%) Number of cystectomy performed during March 2020: 0 6/11 (54.5%) 0/3 0/7 3/7 (42.9%) 9/28 (32.1%) 1-5 3/11 (27.3%) 2/3 (66.7%) 4/7 (57.1%) 3/7 (42.9%) 12/28 (42.9%) >5 2/11 (18.2%) 1/3 (33.3%) 3/7 (42.9%) 1/7 (14.3%) 7/28 (25%) Number of cystectomy performed during March 2019: 0 4/11 (36.4%) 0/3 2/7 (28.6%) 6/7 (85.7%) 12/28 (42.9%) 1-5 2/11 (18.2%) 1/3 (33.3%) 2/7 (28.6%) 1/7 (14.3%) 6/28 (21.4%) >5 5/11 (45.5%) 2/3 (66.7%) 3/7 (42.9%) 0/7 10/28 (35.7%) Number of patients evaluated for hematuria during March 2020: <5 7/11 (63.6%) 0/3 1/7 (14.3%) 3/7 (42.9%) 11/28 (39.3%) 5-10 1/11 (9.1%) 2/3 (66.7%) 2/7 (28.6%) 3/7 (42.9%) 8/28 (28.6%) > 10 3/11 (27.3%) 1/3 (33.3%) 4/7 (57.1%) 1/7 (14.3%) 9/28 (32.1%) Number of patients evaluated for hematuria during March 2019: <5 2/11 (18.2%) 0/3 2/7 (28.6%) 2/7 (28.6%) 6/28 (21.4%) 5-10 3/11 (27.3%) 0/3 1/7 (14.3%) 3/7 (42.9%) 7/28 (25%) > 10 6/11 (54.5%) 3/3 4/7 (57.1%) 2/7 (28.6%) 15/28 (53.6%) Number of patients undergone to tur for hemostatic/diagnostic purpose during March 2020: 0 7/11 (63.6%) 0/3 1/7 (14.3%) 1/7 (14.3%) 9/28 (32.1%) < 50% 4/11 (36.4%) 3/3 4/7 (57.1%) 4/7 (57.1%) 15/28 (53.6%) > 50% 0/11 0/3 2/7 (28.6%) 2/7 (28.6%) 4/28 (14.3%) Number of patients undergone to tur for hemostatic/diagnostic purpose during March 2019: 0 2/11 (18.2%) 0/3 2/7 (28.6%) 1/7 (14.3%) 5/28 (17.9%) < 50% 7/11 (63.6%) 1/3 (33.3%) 3/7 (42.9%) 3/7 (42.9%) 14/28 (50%) > 50% 2/11 (18.2%) 2/3 (66.7%) 2/7 (28.6%) 3/7 (42.9%) 9/28 (32.1%)

p 0.518 0.140 0.518

Compared to other hospitals across Italy during March 2020, Lombardy was the only region where a consistent number of urology staff were reassigned to COVID wards (p = 0.003) and four centers had no OB dedicated to urology (p = 0.027).

Table 4 describes differences in surgical activity, as well as patients with hematuria referred to emergency room (ER) in different parts of Italy in March 2019 and March 2020. A statistically significant reduction of the amount of RC in Lombardy (p = 0.036) was seen, as well as an increasing number of RC performed in the South (p = 0.030). The total amount of RC remained the same in 2019 and 2020, as more centers performed these opera-

0.288

0.003

0.027

0.329

0.018

0.688

0.012

0.664

0.123

0.688

0.072

0.937

0.010

0.412

Table 4.

Comparison of 2019 and 2020 activity in Lombardy, North, Centre and South of Italy.

Lombardy p North p Central p South p Operating block dedicated to Urology Division during March 2020: 0 4/11 (36.4%) 0/3 0/7 0/7 1-2 1/11 (9.1%) 0/3 1/7 (14.3%) 2/7 (28.6%) >2 6/11 (54.5%) 0.382 3/3 N.A. 6/7 (85.7%) 0.143 5/7 (71.4%) 0.714 Operating block dedicated to Urology Division during March 2019: 0 0/11 0/3 0/7 0/7 1-2 1/11 (9.1%) 0/3 1/7 (14.3%) 3/7 (42.9%) >2 10/11 (90.9%) 3/3 6/7 (85.7%) 4/7 (57.1%) Number of operation performed per operating block during March 2020: 1 4/11 (36.4%) 0/3 0/7 0/7 2-3 4/11 (36.4%) 3/3 5/7 (71.4%) 5/7 (71.4%) >3 3/11 (27.3%) 0.441 0/3 N.A. 2/7 (28.6%) 0.286 2/7 (28.6%) 0.286 Number of operation performed per operating block during March 2019: 1 0/11 0/3 0/7 1/7 (14.3%) 2-3 7/11 (63.6%) 2/3 (66.7%) 3/7 (42.9%) 6 (85.7%) >3 4/11 (36.4%) 1/3 (33.3%) 4/7 (57.1%) 0/7 Number of trans-urethral resection performed during March 2020: <5 6/11 (54.5%) 0/3 0/7 1/7 (14.3%) 5-15 4/11 (36.4%) 3/3 4/7 (57.1%) 3/7 (42.9%) >15 3/11 (27.3%) 0.125 0/3 N.A. 3/7 (42.9%) 0.629 3/7 (42.9%) 0.629 Number of trans-urethral resection performed during March 2019: <5 0/11 0/3 0/7 1/7 (14.3%) 5-15 4/11 (36.4%) 1/3 (33.3%) 3/7 (42.9%) 3/7 (42.9%) > 15 7/11 (63.6%) 2/3 (66.7%) 4/7 (57.1%) 3/7 (42.9%) Number of cystectomy performed during March 2020: 0 6/11 (54.5%) 0/3 3/7 (42.9%) 9/28 (32.1%) 1-5 3/11 (27.3%) 2/3 (66.7%) 3/7 (42.9%) 12/28 (42.9%) >5 2/11 (18.2%) 0.036 1/3 (33.3%) 0.667 1/7 (14.3%) 0.327 7/28 (25%) 0.030 Number of cystectomy performed during March 2019: 0 4/11 (36.4%) 0/3 6/7 (85.7%) 12/28 (42.9%) 1-5 2/11 (18.2%) 1/3 (33.3%) 1/7 (14.3%) 6/28 (21.4%) >5 5/11 (45.5%) 2/3 (66.7%) 0/7 10/28 (35.7%) Number of patients evaluated for hematuria during March 2020: <5 7/11 (63.6%) 0/3 1/7 (14.3%) 3/7 (42.9%) 5-10 1/11 (9.1%) 2/3 (66.7%) 2/7 (28.6%) 3/7 (42.9%) > 10 3/11 (27.3%) 0.264 1/3 (33.3%) N.A. 4/7 (57.1%) 0.068 1/7 (14.3%) 0.421 Number of patients evaluated for hematuria during March 2019: <5 2/11 (18.2%) 0/3 2/7 (28.6%) 2/7 (28.6%) 5-10 3/11 (27.3%) 0/3 1/7 (14.3%) 3/7 (42.9%) > 10 6/11 (54.5%) 3/3 4/7 (57.1%) 2/7 (28.6%) Number of patients undergone to tur for hemostatic/diagnostic purpose during March 2020: 0 7/11 (63.6%) 0/3 1/7 (14.3%) 1/7 (14.3%) < 50% 4/11 (36.4%) 3/3 4/7 (57.1%) 4/7 (57.1%) > 50% 0/11 0.166 0/3 N.A. 2/7 (28.6%) 0.190 2/7 (28.6%) 0.033 Number of patients undergone to tur for hemostatic/diagnostic purpose during March 2019: 0 2/11 (18.2%) 0/3 2/7 (28.6%) 1/7 (14.3%) < 50% 7/11 (63.6%) 1/3 (33.3%) 3/7 (42.9%) 3/7 (42.9%) > 50% 2/11 (18.2%) 2/3 (66.7%) 2/7 (28.6%) 3/7 (42.9%)

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tions in 2020, due to travel restrictions. Some statistically significant difference was observed comparing AC and NAC, with number of medical doctors, including residents, employed in COVID wards being greater in AC (p = 0.001). To note, the number of TURBT (p = 0.046) and number of RC was superior in AC in March 2020 (p = 0.037). Moreover, the AC differed in the number of interventions performed per OB (p = 0.015) and number of hTUR (p = 0.014), in favor of 2019. On the other hand, in NAC we did not observe any statistically differences in term of surgical performance from 2019 to 2020, except for the number of TURBT, which was higher in March 2019 (p = 0.022).

Finally, we tested the differences between AC and NAC in the different parts of Italy. In Lombardy, we did not find any statistical differences between AC and NAC in 2019 and in 2020 regarding: number of OB per week, number of interventions performed per OB, number of TURBT nor number of RC. We did not observe any differences in Lombardy between AC and NAC about patients referred to ER with hematuria requiring hTUR during March 2020 and 2019.

We did not find any statistical differences regarding the aforementioned parameters in the other three centers in the North (outside Lombardy).

In the Center regions, we saw statistical differences only in number of pts evaluated for hematuria (p = 0.030) and number of hTUR in 2019 (p = 0.030), with higher numbers performed in AC. Of note, 2 NAC included in this survey did not have emergency rooms.

Finally, there was no statistical differences in the aforementioned items in the Southern regions.

DISCUSSION General performance of Italian centers during the first month of Pandemic In Italy, from February, 27th to April 28th, 199,470 cases and 25.215 confirmed COVID-19-related deaths were reported (18). At the same time, a significant shortage of health care personnel was observed, with 20.831 health workers (10%) being affected by confirmed COVID-19 infection (5, 15, 18, 19).

The rapidly increasing number of pts affected by the SARS-Cov-2 virus have exerted significant pressure on the healthcare systems of Western countries in general, with an emphasis on maintaining emergency and essential services. The need to dedicate major economic, infrastructural and health care resources to assist SARS-Cov2 patients during the first weeks of the outbreak resulted in a rapid reallocation of staff, wards and equipment from several medical disciplines not primarily involved in the management of these pts (5, 20).

As a result, several facilities had to retrain or re-assign personnel to COVID-Related Activities (CRA), even if this was outside of their primary designation. The majority of hospital wards were converted to COVID-dedicated units and surgical were cases reduced because personnel and resources were reassigned.

In our study, all centers maintained 70% of their urological staff for “usual” urological activities and only 30%

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were reassigned for CRA. Overall more physicians at AC, including residents, were assigned to COVID wards (p = 0.001). It is important underlying that, in the global emergency scenario caused by COVID-19 pandemic, the Urology residents’ training has been critically affected (especially for residents attending the final year of training), with a significant proportion of residents experiencing a severe reduction (> 40%) or complete suppression (> 80%) of training both for “clinical” activities and “surgical” activities, as reported by Amparore et al. (21).

While this involvement was particularly evident in Lombardy, with Urologists involved in CRA in more than 50% of the hospitals, in the Centre and Southern Italy, < 30% of Urologists were assigned to CRA. We can therefore hypothesize that the greater the number of physicians on staff during the usual activity period, the greater the number assigned to CRA during the pandemic.

The data of our survey supports the findings of Naspro (8) and Montorsi (22), from Giovanni XXIII Hospital in Bergamo and San Raffaele Hospital in Milan, respectively (two of the primary centers for COVID-19 management during the pandemic). Naspro reported that, during the 10 days of the first cases of SARS-Cov2, two-thirds of the hospital beds were occupied by pts with COVID-19.

Within two weeks, urological surgical volume was reduced to 30%, then 15% and then totally halted as of March 19. With the progression of the outbreak, all nonemergent urology surgeries were cancelled, with few exceptions for emergent and some urgent cases (8).

During our investigation we identified four non-COVID centers (nCC): two in the North and two in the Center.

As expected, the number of urological procedures in nCC was almost identical to that of the same period in 2019. Referring pts to high-volume centers and surgeons potentially allows fast discharge and reduced number of complications (14, 23, 24). This organization also allowed for the residency program to proceed without interruptions in teaching program (25, 26).

There were no nCC in the South in our Survey, but we know that they have been created. This may be partly justified by the reduced number of COVID pts in Southern Italy (18).

Except in the South, where numbers were mildly increased, the total amount of surgical procedures were comprehensively reduced during 2020, with a wider geographic distribution of urological procedures. These is likely a direct result of strict travel restrictions during pandemic, which prevented patients living in the South from seeking medical care in the North of Italy, which was prevoiusly the norm.

A structural reorganization is essential during this time, as key elements, such as the duration of emergency, economic and social consequences, or the viral persistence in the population, are unknown (5). Therefore, rationing resources becomes mandatory, in order to ensure continuity of healthcare for COVID-free patients (27).

Nevertheless, the Italian situation has to be considered as peculiar: preservation of COVID-19-free areas within mixed facilities turned out to be impossible: both caregivers and pts can bring the infection while asymptomatic, contributing to further nosocomial spread.

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Bladder cancer and Pandemic in Italy in March 2019

Overview on surgical management of bladder cancer during pandemic When the COVID-19 outbreak expanded into Western Countries during the last weeks of February 2020, there were no recommendations about management of oncological surgical procedures, including urology. During the following weeks, several International and National Scientific Societies have published suggestions based on expertsâ&#x20AC;&#x2122; opinions, using limited data available and with currently unknown impact on urologic practice (Table 1) (9-12).

Campi et al. recently found that approximately two thirds of pts with genitourinary malignancies do not require high-priority surgery, and 25% of pts requiring high-priority surgery are considered at high perioperative risk.

This increasing risk is partially defined by the immunocompromised cancer-related state, which leads to increased susceptibility to infectious diseases compared to general population (15). During this pandemic, the risk of COVID-19 related complications, including ICU admissions, requiring mechanical ventilation and death, has been calculated to be 3.5 folds higher than usual (28).

Conversely, Wang et al. have highlighted the risk for cancer pts who do not receive adequate and timely medical treatments during an outbreak, resulting in a potentially dangerous delay of uro-oncologic surgeries, with a final impact on the short and intermediate-term progression and mortality rates (19, 29, 30).

Trans-urethral resection of bladder tumor According to the aforementioned Recommendations, TURBT for Low Grade Non Muscle Invasive Bladder Cancer (LG NMIBC) can be delayed in maximum 6 months during the COVID-19 outbreak. In case of High Grade (HG) NMIBC, the recommendations of all Societies advise against postponing interventions, due to the risk progression to muscle invasion/metastases in 15-40% and the Cancer Specific Mortality of around 10-20% (30, 31). In case of re-resection, the indications should be carefully evaluated, considering COVID-19 local incidence, patientsâ&#x20AC;&#x2122; risk factors, BC risk, characteristics of initial TURBT, not forgetting the limited surgical capacity during pandemic.

The potential risk of stage migration due to postponing TURBT should always be taken into consideration.

Finally, most NMIBC patients should be considered at high risk of presenting with severe forms of COVID-19 that might require admission to an ICU and invasive ventilation. In this particular context, the urologist has a responsibility to evaluate the potential benefits and risks of performing TURBT at the time (32). Naturally, our results showed a decrease in total amount of TURBTs in March 2020 when compared to March 2019, especially in NAC (p = 0.022).

These data agree with those recently published by Oderda et al. who reported a a restriction for TURBT of about 46% (15, 33). To note, the number of TURBT performed (p = 0.046) was superior in AC in 2020 (p = 0.037), probably due to superior number of medical staff and/or the presence of residents. Unfortunately, we did not collect detailed data about TURBT; thus, we cannot comment on this specific issue.

Radical cystectomy RC should be prioritized to other urologic oncology procedures and never be postponed according to all recommendations during the crisis (Table 1). Delays exceeding 90 days between diagnosis/TURBT and RC are associated with worse survival (7, 34).

The intervention should be considered in patients at low risk of COVID-19 mortality and with high-risk disease features: presence of high-grade pT1 plus Tis, or tumors with lympho-vascular invasion, variant histology (eg, micro-papillary disease), residual grade 3/high-grade urothelial carcinoma on re-resection, or pT1 stage (3537). The total amount of RC was decreased during the pandemic in Italy, consistent with a reduction of 46% in major uro-oncological surgeries across Europe.

Nevertheless, RC remained the second most common procedure performed during the COVID-19 outbreak (11.7% of all urological procedures) (15, 33).

In our survey, more centers performed this operations in 2020 vs 2019, with an increase in geographic availability of RC across Italy. To note, the number or RC performed in the South Centers during March 2020 did not decrease comparing to 2019; in common times Italian pts move routinely from the Southern regions to the North to address medical needs, as aforementioned. This trend was impacted by travel restrictions during outbreak, leading especially AC to perform RC. Surgical management of emergency room accesses due to hematuria The total amount of pts with hematuria and hTUR have generally decreased during COVID-19 outbreak, perhaps attributable to avoidance of the ER during the pandemic. In fact, while all the hospitals have performed hTUR in < 50% of cases during both 2019 and 2020, during 2019 more centers performed hTUR in up to 50% of cases. Considering differences in Centres, there was a difference in the number of pts evaluated for hematuria (p = 0.030) and number of hTUR in 2019 (p = 0.030) in favor of AC. Of note, two centers in this area did not have emergency rooms.

The number of hTUR increased only in the South centers and these data can be explained by the access to ER only in case of life-threatening hematuria and by travel restrictions. All these data can be justified by the general reduction of ER admissions because of non-COVID reasons.

Lombardy overview During pandemic, most of the centers were dedicated to the management of COVID-19 and had an ER with medicals staff involved in CRA in more than 50% of the hospitals (p = 0.003). Consequently, the number of urological OB diminished, also considering that four centers had not any OB dedicated to urology, comparing to other hospitals across Italy (p = 0.027). On the other hand, there were more than two OB per week dedicated to urology in the most of the hospitals. However, the total amount of TURBT and RC diminished, similarly to the rest of Italy, even if these operations were more homogeneously distributed across the region, and this is demonstrated by the fact the number of centers which performed from 1 to 5 procedures increased.

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CONCLUSIONS

The survey data supports the findings of the most recent papers, showing a global reduction in number of BC surgical procedures due to the prioritization given to COVID19 pts management. However, we can affirm that the reduction was not so significant if we look at the different regions, especially the Southern ones. In fact, during pandemic, patients seek care at the nearest medical institution, not only for COVID-19 related reasons, overriding the strict travel limitations and leading to an improvement of “local” BC surgical management in the South.

Altogether, these data demonstrate the significant efforts were made by Italian Urologists to proceed with urgent surgical procedures despite COVID-19 outbreak. In our opinion, the improvement of management of pts may be optimized by having COVID-dedicated hospitals to guarantee high-quality, timely, and safe treatments to oncological patients. This leads to appropriate cure both for COVID and COVID-free pts who are affected with urologic cancer and should not have a delay in definitive management. The “overlapping” of COVID- and nonCOVID wards could not ameliorate the management of all pts, because of the risk of transmitting infections by both pts themselves and medical/nursing staff, despite all the strict preventive measures.

Finally, COVID-19 pandemic represents an important challenge and learning opportunity for cancer centers, in the context of an extremely dynamic clinical and political situation which requires maximum flexibility to be appropriately faced. For example, telemedicine can represent an alternative for both multidisciplinary and follow-up visits, as suggested by the preliminary experience of Ambrosini et al. (38).

Our real-life data from several centers across Italy, despite limited, may represent an important insight into the BC surgical management in times of emergency, giving food for thought about the near future, which will likely be characterized by a prolonged coexistence with SARS-Cov-2 epidemic all over the world.

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24. Lei S, Jiang F, Su W, et al. Clinical characteristics and outcomes of patients undergoing surgeries during the incubation period of COVID-19 infection EClinicalMedicine. 2020; 21:100331.

25. Gabrielson AT, Kohn TP, Clifton MM. COVID-19 and the Urology Match: Perspectives and a Call to Action. J Urol. 2020; 204:17-19.

26. Vargo E, Ali M, Henry F, Kmetz D, et al. Cleveland Clinic Akron General Urology Residency Program's COVID-19 Experience.

Urology. 2020; 140:1-3.

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Bladder cancer and Pandemic in Italy in March 2019

27. Leonardi R, Bellinzoni P, Broglia L, et al. Hospital care in Departments defined as Covid-free: A proposal for a safe hospitalization protecting healthcare professionals and patients not affected

by Covid 19. Arch Ital Urol Androl. 2020; 92:67-72.

34. Ueda M, Martins R, Hendrie PC, et al. Managing cancer care during the COVID-19 pandemic: agility and collaboration toward a common goal. J Natl Compr Canc Netw. 2020:1-4.

29. Wang H, Zhang L. Risk of COVID-19 for patients with cancer.

Lancet Oncol. 2020; 21:e181.

35. Sylvester RJ, van der Meijden AP, Oosterlinck W, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006; 49:466-5; discussion 475-7.

30. Klaassen Z, Kamat AM, Kassouf W, et al. Treatment strategy for newly diagnosed T1 high-grade bladder urothelial carcinoma: new insights and updated recommendations. Eur Urol. 2018; 74: 597608.

36. Gontero P, Sylvester R, Pisano F, et al. Prognostic factors and risk groups in T1G3 non-muscle-invasive bladder cancer patients initially treated with bacillus Calmette-Guerin: results of a retrospective multicenter study of 2451 patients. Eur Urol. 2015; 67:74-82.

31. Thomas F, Noon AP, Rubin N, et al. Comparative outcomes of primary, recurrent, and progressive high-risk non-muscle-invasive bladder cancer. Eur Urol. 2013; 63:145-54.

32. Lenfant L, Seisen T, Loriot Y, Rouprêt M. Adjustments in the use of intravesical instillations of Bacillus Calmette-Guérin for high-risk non-muscle-invasive bladder cancer during the COVID-19 pandemic. Eur Urol. 2020; pii: S0302-2838(20)30302-X.

37. Veskimae E, Espinos EL, Bruins HM, et al. What is the prognostic and clinical importance of urothelial and nonurothelial histological variants of bladder cancer in predicting oncological outcomes in patients with muscle-invasive and metastatic bladder cancer? A European Association of Urology Muscle Invasive and Metastatic Bladder Cancer Guidelines Panel Systematic Review. Eur Urol Oncol. 2019; 2 :625-642.

33. Oderda M, Roupret M, Marra G, et al.The Impact of COVID19 outbreak on uro-oncological practice across Europe: which burden of activity are we facing ahead ? Eur Urol. 2020; pii: S03022838(20)30299-2.

38. Ambrosini F, Di Stasio A, Mantica G, et al. COVID-19 pandemic and uro-oncology follow up: a “virtual” multidisciplinary team strategy and patients’ satisfaction assessment Arch Ital Urol Androl.

2020; 92:78-79.

28. Puliatti S, Eissa A, Eissa R, et al. COVID-19 and Urology: a comprehensive review of the literature. BJU Int. 2020; 125:E7-E14.

Correspondence Carmen Maccagnano, MD, FEBU (Corresponding Author) carmen.maccagnano@gmail.com Giario Natale Conti, MD giario.conti@gmail.com Department of Surgery - Section of Urology ASST Lariana, Nuovo Ospedale Sant’Anna Via Ravona, 20, 22042 San Fermo della Battaglia (CO) Lorenzo Rocchini, MD lorenzo.rocchini@gmail.com Department of Surgery - Division of Urology Emanuele Montanari, MD, Professor of Urology emanuele.montanari@unimi.it Department of Surgery – Division of Urology and Department of Clinical Sciences and Community Health Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico Padiglione Cesarina Riva - Via della Commenda 15 - 20122 Milan, Italy Giovanni Petralia, MD giovannipetralia@hotmail.com Urology Unit, Niguarda Hospital Piazza Ospedale Maggiore, 3 20132, Milan, Italy Federico Dehò, MD federico.deho@asst-settelaghi.it Unit of Urology; ASST Sette Laghi-Circolo e Fondazione Macchi Hospital Viale Luigi Borri, 57 - 1100 Varese, Italy Kadi-Ann Bryan, MD kadiann.bryan@gmail.com Rogue-Valley Urology - Providence Plaza, Suite 280 1698 E. McAndrews Road - Medford, Oregon 97504 Roberto Contieri, MD contieri.ro@gmail.com Rodolfo Hurle, MD rodolfo.hurle@humanitas.it Department of Urology - Istituto Clinico Humanitas IRCCS Clinical and Research Hospital Via Manzoni, 56 - 20089, Rozzano (MI), Italy

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ORIGINAL PAPER

Urological emergency activities during COVID-19 pandemic: Our experience Elisa Cicerello, Mario S Mangano, Giandavide Cova, Alessio Zordani Urology Unit, Department of Surgery, Caâ&#x20AC;&#x2122; Foncello Hospital, Treviso, Italy.

Submitted 26 May 2020; Accepted 12 June 2020

rapidly spreading worldwide until it reached the pandemic stage declared by WHO on March 11th (1, 2).

After China, Italy was initially the country that was hit the hardest across Europe. The first case was documented on January 30th, but the emergency started only a few days later. Since March 8th 2020 following the Decreto del Presidente del Consiglio (DPCM), the whole country was on lockdown (3). By February 21st, the time when this paper was first drafted, 162.488 cases of COVID-19 have been diagnosed causing a total of 21.067 deaths, 28.011 critically ill patients, and 3.186 patients hospitalized in intensive Care Unit (ICU). In the Veneto region, whose first cluster was found on February 21st in Voâ&#x20AC;&#x2122; Euganeo (Padua), until today, 14.884 cases and 959 COVID-19 deaths have been reported (3).

Although this pandemic is causing an health emergency unprecedented in the Western countries, hospitals started facing the demand to dedicate all medical and logistical resources to the assistance of COVID-19 patients and to provide only treatments of urgent procedures or non-deferrable oncological interventions. This has inevitably caused a redistribution of all medical activities that are not directly involved in the management of COVID-19 patients. During the COVID-19 pandemic, urgent and non-deferrable activities have been kept as such, while non-urgent outpatient visits and surgical activities have been deferred until the end of pandemic (4). However, even those urgent operations have been limited, for instance, non-deferrable oncological operations in high anesthetic risk (ASA 3-4) patients became difficult to plan due to a lack of beds in intensive care unit (ICU). Thus, surgical treatments are reserved mainly to low anesthetic risk patients (ASA 1-2) for surgical procedures around renal (TCC), urinary tract urothelial cancer (UTUC), bladder and prostate cancer for high risk patients not eligible for radiation, while procedures for any other neoplasms have been postponed. When possible, alternative treatments for prostate cancer were proposed (5, 6).

This paper will report the experience of an Urology Unit (Azienda Sanitaria 2 - Marca Trevigiana) in Treviso, in the Veneto region, about urgent inpatient and outpatient activities during COVID-19 pandemic.

INTRODUCTION

MATERIALS

Summary

Background: The Coronavirus Disease (COVID-19) is causing a significant health emergency which is overturning dramatically routine activities in hospitals. The outbreak is generating the need to provide assistance to infected patients and in parallel to treat all nondeferrable oncological and urgent benign diseases.

A panel of Italian urologists agreed on possible strategies for the reorganization of urological routine practices and on a set of recommendations that should facilitate a further planning of both inpatient visits and surgical activities during the COVID19 pandemic. According to this only urgent benign and nondeferrable oncological activities have been kept.

Materials and methods: We have considered urgent outpatient visits requested by Emergency Department (ED) or by General Practitioner (GP) and emergency surgical procedures performed in our Urology Unit from March 9th to April 14th 2020, during COVID-19 pandemic. These figures have been compared to those observed last year from March 9th to April 14th 2019.

Results: Our data show that urgent care visits decreased during COCID-19 pandemic (from 293 to 179). Urgent care visits of patients who accessed directly to the ED decreased (from 219 to 107) whereas the number of urgent care visits referred

by GP remained unchanged (74 vs 72). Consequently, the rate of visits from ED decreased from 75% to 60% and the rate of visit requested by GP increased from 25% to 40% (p = 0.001).

Particularly, the rate of visits for renal colic, LUTS and other not precisely defined disorders from ED decreased and the corresponding rates of visits of patients referred by GPs increased significantly (p = 0.0001, p = 0.0180 and p = 0.0185, respectively). The rate of visits for acute urinary retention, hematuria, sepsis, acute scrotum, cystitis, prostatitis and genito-urinary trauma from ED and GP remained unchanged. Finally, urgency endourology and surgical activities have been stable in relation to the same period last year.

Conclusions: Urological emergency activities during COVID19 pandemic are more appropriate since urgent outpatientsâ&#x20AC;&#x2122; visits required by ED are decreased and emergency surgical and endourological procedures are stable.

KEY WORDS: Coronavirus disease 2019 (COVID-19); Pandemic; Emergency; Endourology; Surgery; Urology.

Since December 31st 2019 Coronavirus Disease (COVID19) was notified by Chinese authorities and has been

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AND METHODS

For the aim of this observational study, we have considered all outpatients admitted to our Unit for urgent visit No conflict of interest declared.

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required by Emergency Department (ED) or by General Practitioner (GP) from March 9th to April 14th 2020, which include: renal colic, acute urinary retention, hematuria, urosepsis, genito-urinary trauma, acute scrotum, cystitis, prostatitis, urosepsis, low urinary tract symptoms (LUTS) and other not precisely defined urinary disorders. Emergency endourological procedures for obstruction of upper urinary tract, urosepsis or renal colic refractory to medicaments and surgical operations for acute scrotum or genito-urinary trauma have been analyzed. These figures have been compared to those visited between March 9th and April 14th 2019, a year before the COVID-19 outbreak. Statistical analysis was carried out by chi-square test as well as Studentâ&#x20AC;&#x2122;s test.

RESULTS

These data show that urgent care visits requested by ED reduced during COVID-19 pandemic, if compared to those registered in the same time span last year (219 vs 107), while those addressed by GP were stable (74 vs 72).

Consequently, the rate of visits from ED decreased from 75% to 60% and the rate of visit requested by GP increased from 25% to 40% (p = 0.001) (Table 1).

A reduction of urgent care visits of patients who accessed the ED for renal colic (-36) , acute urinary retention (-8), hematuria (-12), cystitis (-10) and other not definitely disorders (-11) has been observed in the COVID period in comparison to the same period of the last year, while other urgent care visits for urosepsis (=0), prostatitis (+4), genitourinary trauma (-2) and acute scrotum (-2) remained stable.

Urgent care visits referred by GPs, instead, showed no difference for acute urinary retention (+1), hematuria

(-3), urosepsis (+2), acute scrotum (-1), prostatitis (-1), genito-urinary trauma (-1) between the pandemic period and the previous year.

An increase of visits for renal colic (+7) and a decrease of visits for LUTS (-6) and cystitis (-8) have been registered.

The rate of visits for renal colic, LUTS and other not precisely defined disorders from ED decreased and the corresponding rates of visits of patients referred by GPs increased significantly (p = 0.0001, p = 0.0180 and p = 0.0185, respectively). The rate of visits for acute urinary retention, hematuria, sepsis, acute scrotum, cystitis, prostatitis and genito-urinary trauma from ED and GP remained unchanged.

Ultimately, there was no difference between the two periods for urgent endourological and surgical procedures (Table 2).

DISCUSSION

COVID-19 pandemic has revolutionized clinical activities in several Urological Units. The unfortunate scenario of this pandemic required to address all health medical resources to COVID-19 patients. Hence, several Urological Units have been closing and urologists have been asked to support new COVID-19 wards that opened across the country.

According to urological guidelines (5, 6), in our Unit no urgent activities have been drastically cancelled. With regard to undeferrable oncological activities, the need of anesthesiologists, mechanic ventilator and intensive care beds for COVID-19 patients, has also delayed oncological operations in high risk patients (ASA 3-4). In fact, major surgeries such as radical cystectomy for bladder neoplasm, required in most cases post-operative surveillance in Intensive Care Unit (ICU), something that during the COVID-19 pandemic Table 1. is not available.

Emergency outpatient visits required by Emergency Department (ED) This allowed us to treat low risk anesthetic and General Practitioners (GP) before and during COVID-19 pandemic. patients (ASA 1-2) and perform only partial (PN) or radical nephrectomy (RN), radiBefore COVID-19 During COVID-19 Delta Sig ED vs GP cal nephroureterectomy (RNU), radical cysED GP Tot ED GP Tot P tectomy (RC) or transurethral resection Urgent inpatient visit 219 (75%) 74 (25%) 293 107 (60%) 72 (40%) 179 -114 0.0010 (TURB) for non-muscle invasive high risk Renal colic 56 (85%) 10 (15%) 66 20 (54%) 17 (46%) 37 -29 < 0.0001 bladder cancer and radical prostatectomy Acute urinary retention 32 (78%) 9 (22%) 41 24 (71%) 10 (29%) 34 -7 NS (RP) for high risk patients not eligible for Hematuria 32 (67%) 16 (33%) 48 20 (61%) 13 (39%) 33 -15 NS radiation. Alternative therapies for other Urosepsis 12 (60%) 8 (40%) 20 12 (55%) 10 (45%) 22 +2 NS patients with prostate cancer have been Acute scrotum 11 (65%) 6 (35%) 17 9 (64%) 5 (36%) 14 -3 NS proposed (radiotherapy or androgenic depCystitis 11 (55%) 9 (45%) 20 1 (50%) 1 (50%) 2 -18 NS rivation). All robotic and laparoscopic proProstatitis 6 (67%) 3 (33%) 9 10 (83%) 2 (17%) 12 +3 NS cedures have been cancelled according to Genitourinary trauma 4 (50%) 4 (50%) 8 2 (40%) 3 (60%) 5 -3 NS COVID-19 recommendations to avoid LUTS 38 (76%) 12 (24%) 50 3 (33%) 6 (67%) 9 -41 0.0180 virus widespread and to reduce or optiOther disorders 17 (94%) 1 (6%) 18 6 (55%) 5 (45%) 11 -7 0.0185 mize operating time (7). All inpatient and outpatient procedures for benign diseases have been deferred until the end of the Table 2.

Emergency endourological and surgical procedures performed before COVID-19 emergency, and only urgent and during COVID-19 pandemic. activities have been preserved.

In our experience, the dramatic decrease of Nephrostomy Catheter Catheter Testicular Genito-urinary Abscess urgent outpatientsâ&#x20AC;&#x2122; visits addressed by ED tube mono J double J torsion trauma drainage during COVID-19 pandemic could suggest Before COVID-19 3 3 6 1 1 1 that those are often non necessary, while During COVID-19 4 4 2 2 1 0 those recommended by GP seemed to be Archivio Italiano di Urologia e Andrologia 2020; 92, 4

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more appropriate since they required emergency procedures. For instance, urgent visits for hematuria were required by GP only in cases of gross hematuria with clot retention and anemia, such as in the case of urological neoplasms or radiotherapy pelvis. Hospital admission with a quick correction of anemia and vesical catheter placement, and local irrigation of hemostatic solution are necessary and radiological or urological procedures must be performed in cases those local treatments do not work on the patient. Urgent visit for hematuria required by ED decreased, probably because most of the cases were single and asymptomatic episodes: in such cases people’s fear and COVID-19 lock down reduced ED admission.

This suggests that single and asymptomatic hematuria could be evaluated by sonogram or computerized tomography (CT) at home and urological follow-up should be postponed. Thus, unmodified urgent visit for prostatitis

by ED have been addressed only for symptomatic prostatitis (strong urgency and frequency, urinary retention, prostate abscess and fever) that need urgent hospitalization: cystostomy, catheter placement and appropriate injecting antibiotic therapy are necessary to avoid urosepsis. Urgent visits for prostatitis addressed by GP have been stable probably because GP has continued to treat common and uncomplicated prostatitis at home.

Besides, urgent inpatient visit for acute scrotum (testicular torsion or scrotal abscess), genito-urinary trauma and urosespsis, required both by GP and ED are unmodified during COVID-19 pandemic because they should require urgent endourological or surgical treatments.

Overall, the decrease of urgent visits for acute urinary retention required by ED has been difficult to understand.

A hypothesis could be that strong dysuria is often confused with urinary retention and during COVID-19 lock down, when dysuria was not considered urgent problem, patients did not show up to ED at all. On the contrary, urgent outpatient visit addressed by GP for urinary retention before and during pandemic were stable because considered more urgent, which could explain the difference between the two group. Furthermore, the decrease of outpatient urgent visit for cystitis required both by GP and ED could suggest that these can be successfully treated with adequate antibiotic therapy and other preventive measures avoiding urological visit. Only in case of relapses or fever, non urgent urological evaluation could be performed and radiological follow-up required. The decrease of LUTS visits, both commissioned by ED and GP could suggest that this is usually a “misnomer”: they are not specific urinary symptoms and cannot imply urgent urological diseases. Finally, urgent visit of other non-definite disorders might have been due to variations in code status limitations.

The reduction of urgent inpatient visits for renal colic sent by ED suggests that these are not necessary and renal colic could be confused with flank pain of other origin; GP, instead, sent patients mainly showing symptomatic urolithiasis (obstruction of the upper urinary tract, urosepsis or acute pain refractory to medical therapy): almost everyone was admitted to hospital where urgent endourological procedures were required. A percutaneous nephrostomy in local anesthesia was per-

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formed in case of severe obstruction of the upper urinary tract and fever. Ureteral catheter Mono J was used with severe sepsis or in anticoagulant therapy patients, while catheter Double J was placed in most of the cases that showed renal colic refractory to medical treatment.

When possible, uncomplicated stones located in pelvic ureter were removed, while in all other cases, patients were discharged with ureteral stent Double J and the treatment was deferred until the end of COVID-19 pandemic.

Surgical procedures were performed for acute scrotum (testicular torsion, trauma or abscess) or genito-urinary trauma that cannot benefit from conservative treatment or radiological embolization. All these procedures performed during COVID-19 pandemic were not different from these required in emergency during the same period last year because urgent urological problems were unaltered. Endourological and surgical procedures were performed by expert urologists to minimize time and complications (8). Every patient even if asymptomatic underwent COVID-19 screening before emergency procedure. Enhanced Recovery After Surgery protocols has been adopted after each treatment and during hospital stay (9-11).

We could assert that emergency urological procedures during COVID-19 were stable, only urgent outpatient visits were registered and this is probably due to people’s fear of COVID-19 as well as to the strict lockdown imposed by DPCM, which order to “STAY AT HOME”.

Additionally, General Pratictioners’ activity has not diminished, on the contrary, it continues to take care of patients identifying those who really need hospitalization. This observation suggest that some patients could even be successfully treated at home by GP.

CONCLUSIONS

Even though Urologists are not involved in the first line during the COVID-19 pandemic, patients treated with urological emergencies are still present and consistent.

Urgent urological procedures become necessary especially in episodes of complicated urolithiasis or testicular torsion or genitourinary trauma, in order to prevent obstructive renal failure and urosepsis and the loss of organs, respectively.

More specifically, the risk of underestimated patients with complicated urolithiasis seems to be low or absent since symptomatic renal colic have sent to urological unit

by GP. In conclusion, COVID-19 pandemic has suddenly revolutionized Urological activities, but it can also teach how to use ED properly after this pandemic.

REFERENCES

1. Soharabi C, et al. World Health Organization declares global emergency: a review of the 2019 novel coronavirus (COVID-19). Int J Surg. 76:71-76.

2. WHO. Novel Coronavirus (COVID-199 situation. WHO https./experience argis.com/experience/685d0ace52164f8a5beeeee 1b9125cd.

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3. Decreto del Presidente del Consiglio dei Ministri 8 Marzo 2020: Ulteriori disposizioni del decreto-legge 23 febbraio 2020. n. 6, recante misure urgenti in materia di contenimento e gestione dell’emergenza epidemiologic da COVID-19. (20°01522)(GUSerie Generale n.59 del 08-03-2020).

4. Italian Ministry of health. Nuovo coronavirus.www. salute.gov.it/ nuovo coronavirus.

5. Ficarra V, Novara g, Abrate A, et al. Urology practice during COVID-19 pandemic. Minerva Urol Nephrol. 2020; 72:369-375.

6. European Association of Urology Guidelines. Available at https:/uroweb.org/guidelines.

7. Zhen MH, Boni L, Fingerhut A. Minimally invasive procedures on the novel coronavirus outbreak: lessons learned in China and Italy.

Ann Surg. 2020; 272:e5-e6.

8. Porpiglia F, Checcucci E, Amparore D, et al. Slowdown of urology resident’s learning curve during COVID-19 emergency. BJU Int. 2020;,125:E15-E17.

9. Enhnanced Recovery After Surgery Society Guideline. Available at https: /erassociety.org/guidelines/list -of-guidelines/ 10. Leonardi R, Bellinzoni P, Broglia L, et al. Hospital care in Departments defined as COVID-free: A proposal for a safe hospitalization protecting healthcare professionals and patients not affected

by COVID-19. Arch Ital Urol Androl. 2020; 92:67-72.

11. Tafuri A, Minervini A, Celia A, et al. Comment on: Hospital care in Departments defined as COVID-free: A proposal for a safe hospitalization protecting healthcare professionals and patients not affected by COVID-19. Arch Ital Urol Androl. 2020; 92:80-81.

Correspondence Elisa Cicerello, MD (Corresponding Author) elisa.cicerello@tin.it Mario S, Mangano, MD Giandavide Cova, MD Alessio Zordani, MD Urology Unit, Department of Surgery, Ca’ Foncello Hospital, Treviso, Italy.

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ORIGINAL PAPER

DOI: 10.4081/aiua.2020.4.286

Outcome and quality of life of patients with augmented bladder or urinary diversion after kidney transplantation Giulia Pozza 1, Massimo Iafrate 2, Mariangela Mancini 2, Cristina Silvestre 1, Francesca Neri 1, Lucrezia Furian 1, Paolo Rigotti 1, Tommaso Prayer Galetti 2 1 Department 2 Department

of Surgery, Renal and Pancreas Transplant Unit, University of Padua, Padua, Italy; of Surgery, Oncology, and Gastroenterology, Urology Clinic, University of Padua, Padua, Italy.

Summary

Objective: The aim of the study was to assess results and quality of life after kidney transplant in adult patients with previously bladder augmentation or urinary diversion due to significant lower urinary tract dysfunction.

Materials and methods: This cross-sectional study examines the outcome of 19 renal allografts transplanted in patients with augmented bladder or urinary diversion over a ten years period; moreover we submitted SF36 questionnaire to evaluate quality of life of these patients and compared the results with the general population.

Result: Between January 1, 2005 and 31 December 2015 we performed 19/1093 renal transplantations in patients with abnormal lower urinary tract previously treated with bladder augmentation or bladder recycling. Current post-transplant follow-up was 47 months (range 18-188). No patient developed any episode of acute or chronic rejection. Mean serum creatinine after one year from transplant was 102 umol/L. Overall survival is 94.8% at the end of follow-up and graft survival is 89.6%. No significant differences emerged between patients undergoing transplant with lower urinary tract dysfunction and patients without, regarding to recurrent urinary tract infection. There was not statistically significant difference for vitality (p = 0.8088) and mental health (p = 0.8668).

Conclusions: Presence of a previously augmented bladder or other lower urinary tract dysfunction treated in kidney transplant patients doesnâ&#x20AC;&#x2122;t worsen the final outcome. Mental health and the vitality of these patients are similar to the general population.

KEY WORDS: Kidney transplant; Bladder augmentation; Urinary diversion; Quality of life.

Submitted 21 August 2020; Accepted 2 September 2020

INTRODUCTION

The most common causes of lower urinary tract dysfunction (LUTD) are posterior urethral valves, myelomeningocele, sacral agenesis and other congenital genitourinary anomalies. These pathologies are responsible for renal failure in approximately 15% of patients with end-stage renal disease (ESDR); this percentage increased to 2030% in pediatric population with ESDR (1, 2). For a long time, patients with LUTD were considered high-risk recipients because just as LUTD may lead to destruction of native kidneys, it also may adversely affect graft sur-

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vival and function (3). Now, the improvements in medical management and the development of novel surgical techniques have improved renal transplantation outcomes in these patients (4, 5).

The general strategy, when necessary, is to correct the dysfunction by providing an adequate low-pressure urinary reservoir (bladder augmentation or urinary diversion) with a competent urethral control mechanism to ensure continence and complete bladder evacuation by voiding or clean intermittent catheterization (6).

Patients with end-stage renal disease and a poorly compliant bladder who did not response satisfactorily to conservative therapy (clean intermittent catheterization and anticholinergics) will require augmentation cystoplasty creating a low-pressure reservoir to protect the future renal transplant. Enterocystoplasty using segments of ileum or colon is the most commonly used technique. Moreover, if the patient cannot do clean intermittent catheterization through the urethra, a Mitrofanoff or Monti procedure is necessary to permit adequate bladder empty (7).

Current knowledge regarding timing of this surgery is based on a small number of studies with small sample sizes. Most authors advise performing augmented bladder before renal transplantation to provide the best possible environment for the transplanted kidney (8).

Unfortunately, only few patients can take early kidney transplantation while most patients require renal replacement therapies and during the waiting period became anuric and do not use the lower urinary tract (9). In order to overcome this problem if augmented bladder is performed before renal transplantation and the patient has anuria, a daily bladder irrigation protocol with saline solutions must be established. The aim of daily bladder irrigation is both to maintain adequate bladder volume and to remove any enteric secretions decreasing the incidence of stones and infections in bladders augmented with the intestine (10).

Noteworthy many studies have supported that bladder augmentation is a well-established method of treating severe bladder dysfunction in children with ESRD who will undergo kidney transplantation. However, there is still some debate about the safety of renal transplantation in the presence of bladder augmentation because of a theoretical increased risk of UTI in these immunosuppressed patients, leading to pyelonephritis and graft loss (11, 12).

No conflict of interest declared.

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Since 1948, when World Health Organization defined health as being not only the absence of disease and infirmity, but also the presence of physical, mental and social well-being, the interest in evaluation of quality of life is increased. In case of transplantation, the goal is not only to ensure the survival of patients or preserve physical health but also mental health (13). To our knowledge, in literature there are no reports of quality of life evaluation in this subgroup of transplanted patients.

In this cross-sectional study, we examine our experience over a ten years period with renal transplantation in 19 patients with augmented bladder or other urinary diversion to evaluate the quality of life of these patients.

nal iliac vessels. When the transplant was performed from a living donor, an end to end anastomosis of the renal artery to the internal iliac artery was used. For uretero-neocystostomy, a Lich-Gregoire technique was applied after positioning a ureteral stent.

Ureterocutaneostomy is a simple operative procedure in which the ureter can be easily passed to the cutaneous level and implanted performing a triangular cutaneous flap in order to avoid stenosis. All patients were followed up on our integrated transplant and urologic outpatient clinic and carefully trained by nurses in clean intermittent catheterization (CIC). Anticholinergic drugs were prescribed as an integration to CIC to obtain low urine reservoir pressure.

MATERIAL

Statistical analysis Statistical analyses were performed using the SPSS-2019 software. Questionnaire results were shown as mean (standard deviation) while the other continuous variables were shown as media (range). Continuous variables were compared using t-test for independent variables. Dichotomous variables were compared with chisquare test. A p-value of less than 0.05 was considered to show a statistically significant result.

AND METHODS

Study design This is a cross-sectional study involving all the consecutive patients undergoing kidney transplant and previously submitted to surgery for lower urinary tract dysfunction. All patients gave informed consent before being enrolled in this study. A retrospective review of clinical charts was performed to collect data on the patient kidney function, immunosuppressive therapy and assess the presence of febrile urinary tract infections after renal transplantation or asymptomatic bacteriuria. The primary end-point of the study was to assess the outcome of kidney transplant, in particular evaluating the urinary tract infection (UTI). UTI was defined as positive urine culture associated with clinical symptoms, indeed asymptomatic bacteriuria was defined as positive urine culture without clinical manifestations. To assess quality of life the SF-36 (short form health survey 36) was selfadministered.

Questionnaire The SF-36 questionnaire is a non-disease specific questionnaire that has been used to evaluate health-related quality of life for many years. It is self-administered and contains eight scales: physical functioning (PF), functioning-physical role (PR), bodily pain (BP); general health (GH), vitality (VT), social functioning (SF), role functioningemotional (RE), and mental health (MH). Raw scores range from 0 to 100, with higher scores indicating a better quality of life (QoL) (14). The SF-36 has been extensively validated in transplanted patients (15) and in kidney transplant recipients (16).

The final scores were compared with those of general Italian population controls (17).

Surgical procedures Bladder augmentation was obtained using an intestinal segment (usually ileum) which is opened and sewed into a patch and connected to an opening in the bladder.

When necessary, a Mitrofanoff technique was applied in order to void the bladder with intermittent catheterization and consist in the creation of a tunnel from the bladder to the cutaneous level using the appendix.

All patients underwent kidney transplantation in the right iliac fossa; in most cases an end to side anastomosis was performed from the kidney vessels to the exter-

RESULTS Patients characteristics at transplant A total of 1093 renal transplants in adults were performed at our institution between January 1, 2005 and 31 December 2015, including 19 transplantations (1.7%) performed in patients with abnormal lower urinary tract previously treated with bladder augmentation or bladder recycling. The patients were 13 man and 6 women, with median age of 35 (23-52) years. All patient had end stage renal failure as a consequence of urological abnormalities.

The abnormalities were: neuropathic bladders (5), primary vesicoureteral reflux (3), bladder exstrophy (3), posterior urethral valves (4), others (4) (Table 1). In 14 cases an augmentation enterocystoplasty with ileal segment was performed; one patient had a colon conduit; one ureterocutaneostomy; the other three performed bladder recycling of their native bladder through the Mitrofanoff or a cystostomy. All patients were anuric before transplant.

Four of the 19 transplants were from a living donor and 8 of the 19 transplants were retransplanted (second or third). All patients received continuous antibiotic prophylaxis after transplantation with TrimethoprimSulfamethoxazole daily until six months post-operatively for prevention of Pneumocystis infection.

Patients follow-up Current post-transplant follow-up was 47 months (range 18-188). No patient developed any episode of acute or chronic rejection and the mean serum creatinine after one year from transplant was 102 umol/L. Overall survival is 94.8% at the end of follow-up and graft survival is 89.6%. Two major complications were registered. In one case graft was lost due to infection in the surgical site that necessitated the removal of the transplanted kidney three days after renal transplantation. Latter case was an Archivio Italiano di Urologia e Andrologia 2020; 92, 4

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Table 1.

The characteristics of the 19 kidney recipient patients with urinary tract dysfunctions studied here.

Patient

Sex

Urologic abnormalities

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

M F M F M F M M F M M M M F M M M F M

Primary vescicoureteric reflux Neuropathic bladder Bladder extrophy Others Neuropathic bladder Others Others Neuropathic bladder Bladder extrophy Primary vescicoureteric reflux Posterior urethral valves Primary vescicoureteric reflux Posterior urethral valves Neuropathic bladder Neuropathic bladder Posterior urethral valves Bladder extrophy Others Posterior urethral valves

Type of surgical procedure Ileal cystoplasty Ileal cystoplasty Ureterocutaneostomy Colon conduit Ileal cystoplasty Ileal cystoplasty Ileal cystoplasty Ileal cystoplasty Ileal cystoplasty Mitrofanoff Ileal cystoplasty Ileal cystoplasty Ileal cystoplasty Ileal cystoplasty Ileal cystoplasty Cystostomy Ileal cystoplasty Ileal cystoplasty Cystostomy

Age at the Age at the urologic kidney procedure transplant 10 35 19 45 26 42 19 35 n.a.

23 n.a.

52 8 32 22 32 27 45 4 27 10 28 30 42 26 26 19 36 11 29 n.a.

41 44 49 43 60 24 27

ileal obstruction due to abdominal adhesions that necessitated a surgical procedure with intestinal resection.

In this case post-operative course was characterized by onset of severe acute pancreatitis and sepsis which causes patientâ&#x20AC;&#x2122;s death.

Table 2.

The scores on the eight scales of the of the kidney transplantation patients with bladder augmentation who completed 36-item short-form Health Survey (SF36) questionnaire: physical functioning (PF), role-physical (RP), bodily pain (BP); general health (GH), vitality (VT), social functioning (SF), role-emotional (RE), and mental health (MH).

288

Patient 1 2 3 4 5 6 7 8 9 10 11 12 13

PF 45 40 50 85 90 100 70 85 95 100 100 100 90

RP 0 25 100 50 100 100 75 100 50 75 100 100 100

BP 41 100 72 74 41 100 51 72 51 84 84 100 100

GH 50 65 22 47 92 62 85 77 67 42 87.15 50 52

VT 55 100 85 70 75 80 80 75 60 45 90 50 60

SF 50 87.5 87.5 87.5 87.5 62.5 87.5 75 75 50 100 100 50

RE 0 100 100 66.7 0 66.7 100 100 100 66.7 100 100 0

MH 56 100 80 68 80 72 72 80 76 40 100 100 52

Mean St. dev.

80.8 22.1

75 33.8

74.6 22.6

61.4 20.3

71.2 16.3

76.9 18.3

69.2 41.8

75.1 18.5

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Figure 1.

A comparison of the mean scores of the SF36 questionnaire of the study and control groups.

Urinary tract infection occurrence Recurrent urinary tract infections (UTI) were diagnosed in 4/17 patients (23.5%) during the post-transplant observation period, while in patients undergoing transplant without lower urinary tract dysfunction, during the follow-up UTI were diagnosed in 206 patients (p = 0.528).

Asymptomatic bacteriuria was diagnosed in 9/17 patients (53%). After kidney transplantation, ten patients necessitate intermittent self-catheterization and all these patients were previously treated with an augmentation enterocystoplasty.

Quality of life outcome Thirteen patients fulfilled the SF-36 questionnaire and results are shown in Table 2. Recipients reported a lower score than Italian general population for PF (p < 0,0001), PR (p = 0,0007), BP (p = 0,0046), GH (p < 0,0001), RE (p = 0,0462) and SF (p = 0,0200). There was not statistically significant difference for VT (p = 0,8088) and MH (p = 0,8668) as shown in Figure 1.

DISCUSSION

Treatment of patients with end-stage renal disease due to refractory lower urinary tract dysfunction is certainly not a new issue; nevertheless, it is still a source of dilemma even in transplant units with extensive experience.

In our Unit, over a ten years period, we performed 1093 kidney transplantation but only in 19 patients (1.7%), the cause of end stage renal disease (ESRD) was a lower urinary tract dysfunction (LUTD) refractory to medical treatment. In these patients augmentation enterocystoplasty or complete bladder replacement has been shown to be effective in order to achieve a low-pressure reservoir (18, 19) suitable for kidney transplant. Before transplantation, all patients with small contracted bladder should be evaluated with a urodynamic functional study for their voiding problems (21, 22) in order to perform a kidney transplant only in patients with low bladder voiding pressure. When a low volume and high-pressure bladder is found out an enterocystoplasty or complete bladder replacement is advised before kidney transplant.

In our population, at a median 47 months (range 18188) post-transplant follow-up, no patient developed any episode of acute or chronic rejection and mean serum creatinine after one year from transplant was 102

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Augmented bladder or urinary diversion after kidney transplantation

umol/L. Overall patients’ survival is 94.8% at the end of follow-up and graft survival is 89.6%. Based on our data reservoir recycling seems to have a key role in maintaining, following enterocystoplasty or complete bladder replacement, a low-pressure reservoir with good compliance. Moreover after kidney transplant clean intermittent catheterization (CIC) is required in patients with augmented bladder to obtain complete voiding (20) to reduce post voiding residual. In our experience all our 10 patients with augmented bladder required CIC, except for one woman who is able to void bladder spontaneously and one man who underwent an endoscopic incision of prostate. Among our 19 patients with previous LUTD symptomatic urinary tract infections were diagnosed in 23.5% of cases during the post-transplant period while UTI incidence in our general population of transplanted patients was 18.8% (206 cases).

Noteworthy asymptomatic bacteriuria was diagnosed in 9/17 patients (53%) and therefore a careful CIC prevented symptoms in 29.5% of our patients. Despite the need of CIC recipients reported according SF-36 questionnaire a lower score than Italian general population for physical functioning (PF - P < 0.0001), functioningphysical role (PR - P = 0,0007), bodily pain (BP - P = 0.0046), general health (GH - P < 0.0001), role functioning-emotional (RE - P = 0.0462) and social functioning (SF - P = 0.0200). There was not statistically significant difference for vitality VT (P = 0.8088) and mental health (MH - P = 0.8668). The observed data are remarkable because SF-36 questionnaire gives an objective evaluation of patients’ quality of life using a tool extensively validated in transplanted patients (15) and in kidney transplant recipients (16).

To our knowledge this is the first report in literature on quality of life of transplanted kidney patients with an augmentation enterocystoplasty in adult patients. Our data analysis showed that kidney-transplanted patients with previous lower urinary tract dysfunction reported a lower score than Italian general population for physical functioning, physical role health problems, bodily pain, general health, emotional role of health problems and social functioning. Indeed, there were not statistically significant difference for vitality and mental health.

Physical quality of life is lower in transplanted patients with bladder augmentation than in general population due to the often complex clinical and surgical history. In our Center we try to promote physical activity for all transplanted patients in order to obtain better patients physical well-being. The reason of a worst bodily pain is unclear but could be explained also by the necessity to perform many self-catheterization daily. Therefore, a correct education of the patients to the urological maneuver, seems to be important.

The good results obtained in the field of vitality and mental health could be explained by a careful selection of the patients and a continuous urological and psychological support after the transplantation. It has to be remarked that these patients before kidney transplantation were often treated with complex surgical procedure to correct lower urinary tract dysfunction and after kidney transplantation need to learn how to void correctly the bladder. Despite all these difficulties after

a careful preoperative evaluation, detailed information and continuous support, our patient obtained a good quality of life.

Our study has some limitations. The first limit of our study is the small sample size due to the rarity of the lower urinary tract dysfunction with end-stage renal disease. The second limit is the lack of an adequate control group and for this reason we used the SF-36 norms for Italian population as control. For this comparison was necessary to use parametric statistics even if the sample size of the study group was rather low.

CONCLUSIONS

This study shows that the presence of a previously augmented bladder or urinary diversion in kidney transplant patients doesn’t worsen the final outcome of kidney transplantation. Careful clean intermittent catheterization (CIC) markedly reduces symptomatic UTI incidence without compromising patients’ quality of life. The SF36 validate quality of life questionnaire demonstrates that mental health and vitality of these patients are similar to the general population. Physical status and transplant outcome in patients with abnormal lower urinary tract previously treated with bladder augmentation or bladder recycling can be increased through a continuous outpatient support and education programs.

REFERENCES

1. Rigamonti W, Capizzi A, Zacchello G, et al. Kidney transplantation into bladder augmentation or urinary diversion. Long-term results. Transplantation. 2005; 80:1435.

2. Mendizabal S, Estornell F, Zamora I, et al. Renal transplantation in children with severe bladder dysfunction. J Urol. 2005; 173:226.

3. Koo HP, Bunchman TE, Flynn JT, et al. Renal transplantation in children with severe lower urinary tract dysfunction. J Urol. 1999; 161:240.

4. Lopez Pereira P, Martinez Urrutia MJ, Lobato R, Jaureguizar E. Renal transplantation in augmented bladders. Curr Urol Rep. 2014; 15:431.

5. Ghirardo G, Midrio P, Zucchetta P, et al. Renal transplantation in children weighing < 15 kg: does concomitant lower urinary tract dysfunction influence the outcome? Pediatr Neprhol. 2015; 30:1337.

6. Chun JM, Jung GO, Park JB, et al. Renal transplantation in patients with a small bladder. Transplantation proceedings. 2008; 40:2333.

7. Barry JM. Kidney transplantation into patients with abnormal bladders. Transplantation. 2004; 77:1120.

8. Sullivan ME, Reynard JM, Cranston DW. Renal transplantation into the abnormal lower urinary tract. BJU Int. 2003; 92:510.

9. Fontaine E, Gagnadoux MF, Niaudet P, et al. Renal transplantation in children with augmentation cystoplasty: long-term results. J Urol. 1988; 140:1129.

10. Hatch DA, Koyle MA, Baskin LS, et al. Kidney transplantation in children with urinary diversion or bladder augmentation. J Urol.

2001; 165:2265.

11. Pereira DA, Barroso U, Machado P, et al. Effects of urinary tract infection in patients with bladder augmentation and kidney transplantation. J Urol. 2008; 180:2607.

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12. Jesus LE, Pippi Salle JL. Pre-transplant management of valve bladder: a critical literature review. J Pediatr Urol. 2015; 11:5.

13. Wright Pinson C, Feurer I, Payne JL, et al. Health-related quality of life after different types of solid organ transplantation. Ann Surg. 2000; 232:597.

14. Ware JE, Snow KK, Gandek B. SF-36 health survey. Manual and interpretation guide. Boston, MA, USA: The Health Institute, New England Medical Center, 1993.

15. Liem YS, Bosch JL, Arends LR, et al. Quality of life assessed with the Medical Outcomes Study Short Form 36-item Health Survey of patients on renal replacement therapy: a sys-tematic review and meta-analysis. Value Health. 2007; 5:390.

16. Weber M, Faravardeh A, Jackson S, et al. Quality of life in elderly kidney transplant recipients. JAGS. 2014; 62:1877.

17. Apolone G, Mosconi P. The Italian SF-36 Health Survey: translation, validation and norming. J Clin Epidemiol. 1998; 51:1025.

Correspondence Giulia Pozza, MD Mariangela Mancini, MD Cristina Silvestre, MD Francesca Neri, MD Lucrezia Furian, MD Paolo Rigotti, MD Department of Surgery, Renal and Pancreas Transplant Unit, University of Padua, Padua (Italy) Massimo Iafrate, MD (Corresponding Author) massimo.iafrate@unipd.it Prayer Galetti Tommaso, MD Department of Surgery, Oncology, and Gastroenterology Urology Clinic, University of Padua Via Giustiniani 2 35128 Padua (Italy)

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18. Sheldon CA, Gonzalez R, Burns MW, et al. Renal transplantation into the dysfunctional blad-der: the role of adjunctive bladder reconstruction. J Urol. 1994; 152:972.

19. Mitchell ME, Piser JA. Intestinocystoplasty and total bladder replacement in children and young adult: follow up in 129 cases. J Urol. 1987; 138:579.

20. Bianco M, Medina J, Pamplona M, et al. Outcome of renal transplantation in adult patients with augmented bladders.

Transplant Proc. 2009; 41:2382.

21. Kashi SH, Wynne KS, Sadek SA, et al. An evaluation of vesical urodynamics before renal transplantation and its effect on renal allograft function and survival. Transplantation 1994; 57:1455.

22. Marshall FF, Smolev JK, Spees EK, et al. The urological evaluation and management of pa-tients with congenital lower urinary tract anomalies prior to renal transplantation. J Urol. 1982; 127:1078.

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ORIGINAL PAPER

DOI: 10.4081/aiua.2020.4.291

Attitudes and perceptions towards multiparametric magnetic resonance imaging of the prostate: A national survey among Italian urologists Arnaldo Stanzione 1, Massimiliano Creta 2, Massimo Imbriaco 1, Roberto La Rocca 2, Marco Capece 2, Fabio Esposito 2, Ciro Imbimbo 2, Ferdinando Fusco 3, Giuseppe Celentano 2, Luigi Napolitano 2, Francesco Mangiapia 2, Vincenzo Mirone 2, Nicola Longo 2 1

Department of Advanced Biomedical Sciences, University of Naples “Federico II”, Naples, Italy; of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples "Federico II", Naples, Italy; 3 Department of Woman Child and of General and Specialist Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy.

2 Department

Summary

Objective: We aimed to assess the attitudes and perceptions towards multiparametric magnetic resonance imaging (mpMRI) of the prostate among Italian urologists.

Material and Methods: A national, web-based survey was performed. A questionnaire composed of 18 multiple choice questions was e-mailed to 941 currently active urologists, members of the Italian Society of Urology. Preserving anonymity, respondents’ demographics were collected (e.g. geographic region, type of workplace, prostate procedures performed) as well as data concerning their attitudes and perceptions towards mpMRI (e.g. indications deemed appropriate, degree of confidence in mpMRI results). Data were expressed as raw numbers and percentages of survey answers.

Results: In total, 98 responses were received (participation rate = 10.4%). Respondents mostly worked in urban areas (96%) and primarily in hospital settings (89%), while 48% of them worked in southern Italy. 97% of respondents considered mpMRI useful to detect Prostate Cancer (PCa) in patients with prior negative biopsy, 64% in biopsy-naïve patients and 60% for PCa pre-operatory staging. About half (42%) of the participants declared that mpMRI results frequently lead them to change PCa management strategy. Standardization of mpMRI acquisition and reporting was partially unsatisfactory.

Reported waiting time for mpMRI scans was longer than 4 weeks for 51% of respondents. The major limitation of this survey includes the small number of participants.

Conclusions: Prostate mpMRI is used by Italian urologists mainly for detection and for pre-operative staging of PCa. Further improvements in terms of mpMRI availability and report standardization are required.

KEY WORDS: Multiparametric magnetic resonance imaging; Prostate cancer; Prostate imaging reporting and data system; Prostate biopsy; Survey.

Submitted 5 July 2020; Accepted 3 September 2020

INTRODUCTION

Multiparametric magnetic resonance imaging (mpMRI) of the prostate has emerged as a valuable tool for the detection of clinically significant prostate cancer (PCa) and the

acceptance of this novel technology within the urology community has steadily increased (1). Current European Association of Urology (EAU) Guidelines strongly recommend prostate mpMRI before re-biopsy in patients with persistent suspicion of PCa despite a prior negative biopsy and before confirmatory biopsy in PCa patients on active surveillance (AS) (2). Further potential applications of prostate mpMRI include detection of PCa in biopsy naïve patients, PCa staging prior to treatment and suspicion of local PCa recurrence (1, 2).

The technique has undergone progressive refinements over time regarding acquisition protocol, image interpretation and reporting (3, 4).

In 2012, the European Society of Urogenital Radiology established clinical guidelines for the acquisition, interpretation, and reporting of prostate mpMRI in order to allow an adequate level of standardization and consistency (5). These recommendations, popularly referred to as Prostate Imaging - Reporting and Data System (PI-RADS), were based on literature evidence and consensus expert opinion (5).

In 2014, the PI-RADS version 2 was officially launched (6). Currently, the standard mpMRI protocol combines morphological information derived from high spatial resolution T2-weighted images, and functional data concerning cell density (diffusion weighted imaging [DWI) with apparent diffusion coefficient [ADC) maps) and vascularization (dynamic contrast-enhanced imaging) (7).

Despite the efforts to improve prostate mpMRI adoption and quality of reports, the acceptance and the standardization of the procedure in everyday clinical practice still suffer from many limitations. Indeed, mpMRI is not readily available at all institutions, and facilities’ adherence to technical standards is variable and sometimes suboptimal (8).

Attitudes and perceptions toward prostate mpMRI vary across countries and, to date, these aspects have not been investigated in Italy (9-12). The goal of the present survey was to investigate patterns of attitudes and perceptions among practicing Italian urologists with regard to the use of mpMRI to manage PCa as well as mpMRI availability and reporting quality.

No conflict of interest declared.

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MATERIALS

AND METHODS

Questionnaire An online survey consisting of 18 multiple choice questions (formulated in Italian with the aim of increasing the response rate) was designed using the Google Form application included in the Google Drive office suite (Google LLC). The questionnaire was composed of two sections: a first one to assess respondents’ demographics and a second one to evaluate their attitudes and perceptions (i.e. prescription attitudes; mpMRI availability; reporting quality; sequences considered useful in clinical practice; perceptions toward the usefulness of the procedure; impact of mpMRI results on the decision making process; management of PI-RADS 3 lesions; type of targeted prostate biopsy performed or recommended). In particular, questions about demographics included: years since completion of residency, type and location of medical practice, execution of prostate biopsies, and number of prostatectomies performed monthly. mpMRI availability was addressed by asking about average waiting time for the exam. Questions about attitudes toward mpMRI indications investigated the following potential settings: biopsy naïve patients, patients with clinical suspicious PCa despite a previous negative biopsy, pre-treatment staging, suspicion of local recurrence, AS. Questions about reporting quality addressed: the description of the sequences used, the adoption of the PI-RADS version 2 scoring system, and the presence of a segmentation map with clear identification of the index lesion in the reports received. Questions about perceptions toward the clinical utility of prostate mpMRI were formulated to assess the perceived reliability of PI-RADS v2 in identifying clinically significant PCa, and the utility in the evaluation of local stage and recurrences. Some questions required a single answer while others gave the respondents the choice to select as many answers as they felt appropriate.

Table 1.

Survey demographics and mpMRI of the prostate availability.

Question How many years since you completed residency?

n (%) < 10 years 10-30 years > 30 years

42 (43) 46 (47) 10 (10)

Academic hospital Community hospital Private practice

51 (52) 36 (37) 11 (11)

Urban Non urban

94 (96) 4 (4)

North Center South

28 (29) 23 (23) 47 (48)

Yes Not On average, how many radical prostatectomies are performed monthly in your Center? < 10 10-20 > 20 On average, how long do your patients wait for a mpMRI? < 2 weeks 2-4 weeks > 4 weeks

69 (70) 29 (30)

What type of practice do you work in primarily?

What type of setting do you practice in?

In which Region do you practice in?

Do you perform prostate biopsy?

40 (41) 32 (33) 26 (26) 13 (13) 35 (36) 50 (51)

mpMRI: multiparametric Magnetic Resonance Imaging

graphic groups and according to mpMRI availability.

Statistical analyses were two-sided using a significance level of 0.05. All statistical analyses were performed with SPSS version 17.0 (SPSS, Inc., Chicago, IL) software.

RESULTS

A total of 98 responses were received from the survey within 30 days of the initial request (participation rate = 10.4%). Table 1 shows demographic data of the respondents and information about average waiting time for prostate mpMRI. Ninety percent of respondents (n = 88)

Data collection Invitations to participate in this anonymous survey were emailed on 28 January 2019 to 941 current Italian Society of Urology (SIU) members who gave the Figure 1. approval to the use of their e-mail address.

Attitudes toward the prescription of mpMRI of the prostate in the various All survey participants were practicing urolclinical settings. ogists in Italy. For those who had not completed the survey, four follow-up reminder e-mail invitations were sent over the following 2 weeks. The survey was closed on 28 February 2019. All respondents had to fully complete the questionnaire before submission since all questions were flagged as mandatory. After submission, users could not review neither amend their answers.

Both personal contact information and data collected were not accessible to third parties.

Data analysis Data were expressed as raw numbers and percentages of survey answers. Chi square and Fisher’s exact tests were used to assess variability in responses between demo-

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Italian survey on prostate mpMRI

Table 2.

Urologists’ attitudes and perceptions toward mpMRI of the prostate.

Question When do you prescribe or consider useful to prescribe a mpMRI of the prostate?

Biopsy naïve patients Before re-biopsy Pre-operatory staging Suspicion of local recurrence Active surveillance Which of the following sequences do you consider useful for your clinical practice?

High resolution T2-weighted alone Axial DWI with ADC maps alone Axial perfusion alone High resolution T2-weighted + Axial DWI with ADC maps High resolution T2-weighted + Axial perfusion Axial DWI with ADC maps + Axial perfusion High resolution T2-weighted + Axial DWI with ADC maps + Axial perfusion High resolution T2-weighted + Axial DWI with ADC maps + Axial perfusion + Spectroscopy Axial DWI with ADC maps + Axial perfusion + Spectroscopy High resolution T2-weighted + Axial DWI with ADC maps + Spectroscopy How do you manage PI-RADS 3 lesions?

No further investigations Secondary interpretation in referral centers Targeted prostate biopsy as for PI-RADS 4 and 5 lesions Targeted prostate biopsy only in cases of high clinical suspicious Standard biopsy How often results from mpMRI change your strategy?

Almost always Often Sometimes Hardly ever Which technique of targeted prostate biopsy do you perform or advise?

Visual-cognitive Software-assisted registration MRI-TRUS MRI guidance In your clinical practice, how do you rate the reliability of PI-RADS v2 in identifying clinically significant PCa? Highly reliable Reliable Unreliable In your clinical practice, how do you rate the reliability of mpMRI in local staging of PCa? Highly reliable Reliable Unreliable In your clinical practice, how do you rate the reliability of mpMRI in the evaluation of local recurrence?

Highly reliable Reliable Unreliable

Table 3.

Indications to mpMRI according to demographic features and mpMRI availability. n (%) 63 (64) 95 (97) 59 (60) 21 (21) 24 (24) 9 (9) 3 (3) 3 (3) 24 (25) 2 (2) 7 (7) 39 (40) 8 (8) 2 (2) 1 (1) 1 (1) 25 (26) 25 (26) 20 (19) 27 (28) 5 (5) 36 (37) 52 (53) 5 (5) 46 (47) 49 (50) 3 (3) 21 (21) 75 (76) 2 (2) 24 (24) 69 (70) 5 (5) 11 (11) 68 (69) 19 (20)

ADC: Apparent Diffusion Coefficient; DWI: Diffusion Weighted Imaging; mpMRI: multiparametric Magnetic Resonance Imaging; PI-RADS: Prostate Imaging - Reporting and Data System.

completed residency less than 30 years before the survey. About half of them (48%, n = 47) worked in Southern Italy, 96% (n = 94) in urban areas, and 89% (n = 87) primarily in a hospital setting. Seventy percent of respondents (n = 69) declared to personally perform prostate biopsy and about half of them (51%, n = 50) declared that their patients wait more than 4 weeks for a prostate mpMRI. Urologists’ attitudes toward prostate mpMRI prescription in various clinical scenarios are reported in Table 2. The prevalence of indications for prostate mpMRI in the settings explored are shown in

Biopsy Before PreSuspect Patients naive repeat operatory local active patients biopsy staging recurrence surveillance (n = 63) (n = 95) (n = 59) (n = 21) (n = 24) Years since completition of residency < 10 (n = 42) 10-30 (n = 46) > 30 (n = 10) p Setting of practice Academic hospital (n = 51) Community hospital (n = 36) Private practice (n = 11) p Region North (n = 28) Center (n = 23) South (n = 47) p Do you perform biopsy?

Yes (n = 69) No (n = 29) p Radical prostatectyomies performed in the < 10 (n = 40) working center 10-20 (n = 32) per month > 20 (n = 26) p Waiting time for mpMRI < 2 weeks (n =13) 2-4 weeks (n = 35) > 4 weeks (n = 50) p

28 (66.7%) 41 (97.6%) 26 (61.9%) 27 (58.7%) 44 (95.7%) 25 (54.3%) 8 (80.0%) 10 (100%) 8 (80.0%) 0.419 1.000 0.316

8 (19.0%) 10 (21.7%) 3 (30.0%) 0.682

11 (26.2%) 12 (26.1%) 1 (10.0%) 0.657

33 (64.7%) 50 (98.0%) 30 (58.8%) 23 (63.9%) 36 (100%) 22 (61.1%) 7 (63.6%) 9 (81.8%) 7 (63.6%) 0.999 0.032 0.999

14 (27.5%) 6 (16.7%) 1 (9.1%) 0.333

14 (27.5%) 8 (22.2%) 2 (18.2%) 0.792

23 (82.1%) 26 (92.9%) 18 (64.3%) 10 (43.5%) 23 (100%) 17 (73.9%) 30 (63.8%) 46 (97.9%) 24 (51.1%) 0.016 0.438 0.162

2 (7.1%) 5 (21.7%) 14 (29.8%) 0.060

8 (28.6%) 4 (17.4%) 12 (25.5%) 0.652

42 (60.9%) 68 (98.6%) 40 (58.0%) 21 (72.4%) 27 (93.1%) 19 (65.5%) 0.276 0.208 0.486

15 (21.7%) 6 (20.7%) 0.907

17 (24.6%) 7 (24.1%) 0.958

19 (47.5%) 39 (97.5%) 24 (60.0%) 25 (78.1%) 30 (93.8%) 19 (59.4%) 19 (73.1%) 26 (100%) 16 (61.5%) 0.014 0.483 0.985

11 (27.5%) 6 (18.8%) 4 (15.4%) 0.495

8 (20.0%) 10 (31.3%) 6 (23.1%) 0.533

8 (61.5%) 12 (92.3%) 5 (38.5%) 23 (65.7%) 33 (94.3%) 24 (68.6%) 32 (64.0%) 50 (100%) 30 (60.0%) 0.962 0.139 0.166

4 (30.8%) 7 (20.0%) 10 (20.0%) 0.463

6 (46.2%) 6 (17.1%) 12 (24.0%) 0.114

Figure 1. In particular, the following values were found: suspicious PCa in patients with prior negative biopsy (97%, n = 95), suspicious PCa in biopsy naïve patients (64%, n = 63), pre-operatory staging (60%, n = 59), active surveillance (24%, n = 24), suspicious local recurrence (21%, n = 21). Geographic region and number of radical prostatectomies performed per month were significant factors influencing the prescription of prostate mpMRI in biopsy-naïve patients while setting of practice was the only factor influencing the prescription of prostate mpMRI in the re-biopsy setting (Table 3).

Results from questions investigating the quality of reports received are showed in Table 4. Most respondents (81%, n = 79) declared to receive reports including a list of the sequences acquired and evaluated. The percentages of respondents declaring to receive often or almost always a report interpreted using PI-RADS v2 guidelines and including a prostate segmentation map with the index lesions highlighted were 88% (n = 86) and 78% (n = 76), respectively. mpMRI sequences judged as useful are showed in Table 2. Forty percent of respondents (n = 39) judged useful the combination of high resolution T2-weighted, axial DWI with ADC maps, and axial perfusion sequences.

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Table 4. mpMRI data reporting.

Question Do mpMRI reports you receive include a list of MRI sequences acquired and evaluated?

Yes Not How often the mpMRI reports you receive are interpreted (and lesions scored) using the PI-RADS v2 guidelines?

Almost always Often Sometimes Hardly ever How often the mpMRI reports you receive include a prostate segmentation map with the index lesions highlighted?

Almost always Often Sometimes Hardly ever

n (%) 79 (81) 19 (19) 62 (63) 24 (25) 11 (11) 1 (1) 45 (46) 31 (32) 14 (14) 8 (8)

mpMRI: multiparametric Magnetic Resonance Imaging; PI-RADS: Prostate Imaging - Reporting and Data System.

rences were 97%, 94% and 79%, respectively. Overall, 42% of them declared to change often or almost always PCa management strategy based on mpMRI results.

In total, only 26% of respondents declared to prescribe targeted biopsy in cases of PI-RADS 3 lesions as for PIRADS 4 and 5 lesions. The percentages of respondents declaring to perform or advise targeted prostate biopsy with software assisted registration MRI-ultrasound, visuTable 5.

Targeted biopsy modality of choice.

Visual-cognitive Software-assisted MRI guidance (n = 46) registration MRI-TRUS (n = 3) (n = 49) Years since completition of residency < 10 (n = 42) 10-30 (n = 46) > 30 (n = 10) p Setting of practice Academic hospital (n = 51) Community hospital (n = 36) Private practice (n = 11) p

19 (45.2%) 24 (52.1%) 3 (30.0%) 0.429

21 (50.0%) 21 (45.6%) 7 (70.0%) 0.398

2 (4.7%) 1 (2.1%) 0 (0%) 0.714

28 (54.9%) 13 (36.1%) 5 (45.4%) 0.225

23 (45.0%) 20 (55.5%) 6 (54.5%) 0.292

0 (0%) 3 (8.3%) 0 (0%) 0.125

7 (25.0%) 13 (56.5%) 26 (55.3%) 0.024

19 (67.8%) 10 (43.4%) 20 (42.5%) 0.088

2 (7.1%) 0 (0%) 1 (2.1%) 0.436

33 (47.8%) 13 (44.8%) 0.786

33(47.8%) 16 (55.1%) 0.506

3 (4.3%) 0 (%) 0.552

22 (55%) 18 (56.2%) 6 (23.0%) 0.017

18 (45.0%) 13 (40.6%) 18 (69.2%) 0.071

0 (0%) 1 (3.1%) 2 (7.6%) 0.183

6 (46.1%) 18 (51.4%) 22 (44%) 0.818

7 (53.8%) 17 (48.5%) 25 (50.0%) 0.999

0 (0%) 0 (0%) 3 (6.0%) 0.372

Region North (n = 28) Center (n = 23) South (n = 47) p Do you perform biopsy?

Yes (n = 69) No (n = 29) p RP performed in the working center per month< 10 (n = 40) 10-20 (n = 32) > 20 (n = 26) p Waiting time for mpMRI < 2 weeks (n = 13) 2-4 weeks (n = 35) > 4 weeks (n = 50) p

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al cognitive, and MRI guidance techniques were 50%, 47%, and 3%, respectively. Geographic region and number of radical prostatectomies performed per month were significant factors influencing the adoption of visual cognitive technique (Table 5).

DISCUSSION

The adoption of prostate mpMRI to detect and characterize prostate lesions and to tailor the management of PCa patients has evolved over the last 10 years (11, 1315). Currently, however, the availability of this technology, the quality of reporting, and urologists’ perceptions and attitudes toward significantly varies across countries and some authors have stressed the need to integrate prostate mpMRI teaching courses into the training of urologists (16). To the best of our knowledge, we performed the first survey examining prostate mpMRI availability, quality of reports as well as urologists’ attitudes and perceptions toward this diagnostic modality in Italy.

The response rate elicited was within the range of surveys on this topic (10, 11, 17). Respondents seemed to look favorably upon use of prostate mpMRI, as 100% of them declared to prescribe or consider useful to prescribe it in at least one setting. By comparison, the survey published by Muthigi and coworkers in 2017 found only 85.7% of urologists declaring to use prostate mpMRI in their practice (9).

The top settings for the use of prostate mpMRI was in patients with persistent PCa suspicion despite a prior negative biopsy (97%), followed by PCa suspicion in biopsy naïve patients (64%) and pre-operatory staging (60%). Accordingly, most of respondents had a positive perception toward the ability of mpMRI to identify clinically significant PCa and to provide an adequate local staging. The high percentage of respondents declaring to prescribe mpMRI in patients with persistent PCa suspicion despite a prior negative biopsy confirms the results from previous surveys from other counties (9, 11).

Indeed, 89.5% of respondents in the survey by Muthigi and coworkers declared to prescribe prostate mpMRI in this clinical scenario (9). To date, there is strong evidence demonstrating that mpMRI-guided biopsy increases the detection rate for clinically significant PCa when compared to standard biopsies and current EAU Guidelines strongly recommend mpMRI prior to repeat biopsy (2). Interestingly, we found that urologists working in private practice setting were less prone to prescribe mpMRI before repeat biopsy.

The percentage of respondents prescribing mpMRI on biopsy naïve patients was higher if compared with published evidence. Indeed, previous surveys reported percentages of utilization of prostate mpMRI in this setting ranging from 36.8% to 53% (9, 11). Evidences about prostate mpMRI in this setting are contradictory and current Guidelines provide only weak recommendations for the adoption of mpMRI in patients undergoing their first biopsy (2). However, results from the recent randomized multicenter PRECISION trial involving 500 biopsy-naïve patients with suspected PCa support the role of pre-biopsy prostate mpMRI and recommendations may change in the future (18). mpMRI is considered as the imaging modality of choice for local staging (19). Sixty percent of

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Italian survey on prostate mpMRI

respondents in the present survey declared to prescribe mpMRI for pre-operatory staging. This finding is in line with published evidences as previous surveys from other countries reported percentages of utilization of mpMRI in this setting ranging from 38% to 85% (9, 11, 17).

Only a small percentage of respondents declared to prescribe prostate mpMRI in the clinical setting of AS (24%) and suspect local recurrence (21%). mpMRI has emerged as a valuable diagnostic modality in both patient selection and monitoring for men who undergoing AS for PCa and its use in this clinical scenario is gradually increasing (20-22). Current EAU Guidelines strongly recommend prostate mpMRI in men on AS before confirmatory prostate biopsy if not done before the first biopsy (2). However, multiple barriers have been reported to counteract the widespread use of mpMRI for AS including quality, cost and access to care (20). Accordingly, receipt of mpMRI among PCa patients on AS significantly vary across demographic, geographic, and socioeconomic strata (21). The percentage of respondents prescribing mpMRI in AS setting we reported is lower if compared to data obtained from published surveys. Indeed, 85% of French urologists and 66% of urologists working in the United States declared to utilize mpMRI in this setting (11, 17). Moreover, although published surveys involving urologists working France and in the United States demonstrated that the percentage of urologists prescribing prostate mpMRI in patients enrolled in AS was significantly higher among those working in academic hospitals, we failed to confirm this finding (11). Similar to AS setting, the percentage of urologists involved in the present survey that declared to prescribe mpMRI in patients with suspicious of local recurrence was lower when compared to those from other surveys. Indeed, 51% of French urologists declared to prescribe mpMRI with the intent to detect local recurrence following radical treatments (11).

Urologists prescribing prostate mpMRI need to be confident regarding the report they receive, as both their decision-making process and the quality of targeted prostate biopsy they perform mainly depends on the count, location, and radiographic stage of lesions identified by the radiologist (16, 23). Interestingly, about 22% of respondents in the present survey declared to receive reports that sometimes or hardly ever include a prostate segmentation map with the index lesions highlighted, 19% declared to receive reports that do not include a list of MRI sequences acquired and evaluated, and 12% declared to receive reports that sometimes or hardly ever are interpreted using the PI-RADS v2 guidelines. Taken together, these results underline the need to further improve in our Country the process of standardization of prostate mpMRI reporting.

We collected evidences about urologistsâ&#x20AC;&#x2122; point of view concerning mpMRI acquisition protocol and relevance of included sequences. The answers collected seem to indicate that the urologists might not be completely aware of the dominant sequence structure of the PI-RADS v2 guidelines. Indeed, fewer than half responders (40%) correctly identified the currently recommended protocol suggesting that the major revision of the original PIRADS has not been universally embraced among urolo-

gists. Furthermore, it should also be noted that a relatively high percentage (25%) of urologists indicated that a protocol without the perfusion sequence could be considered adequate for their patients. This is somewhat in line with a current trend advocating for the need of shorter, cheaper and less invasive MRI protocols and reinforces the ongoing debate about the role of perfusion sequences in prostate imaging (24-26).

The management of undetermined, PI-RADS 3 lesions has represented a controversial issue for many years.

Accordingly, the attitude of respondents is heterogeneous with only 26% of them recommending targeted biopsies as for PI-RADS 4 and 5 lesions and 20% performing targeted biopsies only in cases of high clinical suspicious.

More recent EAU Guidelines, updated in March 2019, consider prostate lesions with a PI-RADS score â&#x2030;Ľ 3 as positive and strongly recommend performing targeted plus systematic biopsy in biopsy naĂŻve patients and targeted biopsy only in patients with prior negative biopsy (2).

The modality with which prostate lesions identified by mpMRI are targeted at biopsy vary considerably. Visualcognitive and software-assisted registration MRITransrectal ultrasound guidance were the most frequently adopted guidance modalities by respondents in the present survey with MRI-guidance being adopted by only 3% of interviewed. Of note, the adoption of visualcognitive guidance was significantly lower in Northern Italy and in centers where more than 20 radical prostatectomies are performed monthly. Of note, the modality of lesion targeting during prostate biopsy represents a controversial and evolving issue (27-29). Beyond technical aspects, tumor multifocality is frequently involved in the discrepancies between findings from mp-MRI, prostate biopsy, and surgical specimens (29). Although MRI-guidance may represent a promising technique of biopsy guidance, it is still considered a time-consuming and expensive procedure and further investigations are needed to identify the ideal candidates (30).

The major limitation of this survey includes the small number of participants. However, the response rate is within published ranges. Secondly, respondents are not fully representative of the overall community of Italian urologists as those working in private practice setting and rural areas are poorly represented. Moreover, like any survey, participant responses were limited to the available choices.

CONCLUSIONS

This survey shows that prostate mpMRI is routinely used by urologists in Italy mainly before biopsy and for preoperative staging purposes. mpMRI availability and report standardization are suboptimal.

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21. Fam MM, Yabes JG, Macleod LC, et al. Increasing utilization of multiparametric magnetic resonance imaging in prostate cancer active surveillance. Urology. 2019; 130:99-105.

4. Manfredi M, Mele F, Garrou D, et al. Multiparametric prostate MRI: technical conduct, standardized report and clinical use.

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22. Höffkes F, Arthanareeswaran VK, Stolzenburg JU, Ganzer R. Rate of misclassification in patients undergoing radical prostatectomy but fulfilling active surveillance criteria according to the European Association of Urology guidelines on prostate cancer: a high-volume center experience. Minerva Urol Nefrol. 2018; 70:588-593.

5. Barrett T, Turkbey B, Choyke PL. PI-RADS version 2: what you need to know. Clin Radiol. 2015; 70:1165-76.

6. Turkbey B, Rosenkrantz AB, Haider MA, et al. Prostate Imaging Reporting and Data System Version 2.1: 2019 Update of Prostate Imaging Reporting and Data System Version 2. Eur Urol. 2019; 76:340-351.

7. Tewes S, Mokov N, Hartung D, et al. Standardized reporting of prostate MRI: comparison of the Prostate Imaging Reporting and Data System (PI-RADS) Version 1 and Version 2. PLoS One. 2016; 11:e0162879.

8. Esses SJ, Taneja SS, Rosenkrantz AB. Imaging facilities' adherence to PI-RADS v2 minimum technical standards for the performance of prostate MRI. Acad Radiol. 2018; 25:188-195.

9. Muthigi A, Sidana A, George AK, et al. Current beliefs and practice patterns among urologists regarding prostate magnetic resonance imaging and magnetic resonance-targeted biopsy. Urol Oncol.

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10. Manley BJ, Brockman JA, Raup VT, et al. Prostate MRI: a national survey of Urologist's attitudes and perceptions. Int Braz J Urol. 2016; 42:464-71.

11. Renard-Penna R, Rouvière O, Puech P, et al. Current practice and access to prostate MR imaging in France. Diagn Interv Imaging.

2016; 97:1125-1129.

12. Bukavina L, Tilburt JC, Konety B, et al. Perceptions of prostate MRI and fusion biopsy of radiation oncologists and urologists for patients diagnosed with prostate cancer: results from a national survey. Eur Urol Focus. 2020; 6:273-279.

24. Stanzione A, Cuocolo R, Cocozza S, et al. Detection of extraprostatic extension of cancer on biparametric MRI combining texture analysis and machine learning: preliminary results. Acad Radiol.

2019; 26:1338-1344.

25. Cuocolo R, Stanzione A, Rusconi G, et al. PSA-density does not improve bi-parametric prostate MR detection of prostate cancer in a biopsy naïve patient population. Eur J Radiol. 2018; 104:64-70.

26. Salvaggio G, Calamia M, Purpura P, et al. Role of apparent diffusion coefficient values in prostate diseases characterization on diffusion-weighted magnetic resonance imaging. Minerva Urol Nefrol.

2019; 71:154-160.

27. Pepe P, Pepe L, Panella P, Pennisi M. Can multiparametric ultrasound improve cognitive MRI/TRUS fusion prostate biopsy.

Arch Ital Urol Androl. 2020; 92:89-92 28. D'Agostino D, Mineo Bianchi F, Romagnoli D, et al. MRI/TRUS FUSION guided biopsy as first approach in ambulatory setting: Feasibility and performance of a new fusion device. Arch Ital Urol Androl. 2020; 91:211-217.

29. Lourenço M, Pissarra P, E Brito DV, et al. Lesion location agreement between prostatic multiparametric magnetic resonance, cognitive fusion biopsy and radical prostatectomy piece. Arch Ital Urol Androl. 2020; 91:218-223.

13. Tu X, Lin T, Cai D, et al. The optimal core number and site for MRI-targeted biopsy of prostate? A systematic review and pooled analysis. Minerva Urol Nefrol. 2020; 72:144-151.

30. D'Agostino D, Mineo Bianchi F, Romagnoli D, et al. Comparison between "In-bore" MRI guided prostate biopsy and standard ultrasound guided biopsy in the patient with suspicious prostate cancer: Preliminary results. Arch Ital Urol Androl. 2019; 91:87-92.

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Correspondence

15. Russo F, Manfredi M, Panebianco V, et al. Radiological Wheeler staging system: a retrospective cohort analysis to improve the local staging of prostate cancer with multiparametric MRI. Minerva Urol Nefrol. 2019; 71:264-272.

Arnaldo Stanzione, MD - arnaldostanzione@yahoo.it Massimo Imbriaco, MD - mimbriaco@hotmail.it Department of Advanced Biomedical Sciences, University of Naples “Federico II”, Via Pansini 5, 80131 Naples (Italy)

16. Kasivisvanathan V, Ambrosi A, Giganti F, et al. A dedicated prostate MRI teaching course improves the ability of the urologist to interpret clinically significant prostate cancer on multiparametric MRI. Eur Urol. 2019; 75:203-204.

Massimiliano Creta, MD (Corresponding Author) - max.creta@gmail.com Roberto La Rocca, MD - robertolarocca87@gmail.com Marco Capece, MD - drmarcocapece@gmail.com Fabio Esposito, MD - fabioesposito025@gmail.com Ciro Imbimbo, MD - ciro.imbimbo@unina.it Giuseppe Celentano, MD - dr.giuseppecelentano@gmail.com Luigi Napolitano, MD - nluigi89@libero.it Francesco Mangiapia, MP - mangiapippo@libero.it Vincenzo Mirone, MD - mirone@unina.it Nicola Longo, MD - nicolalongo20@yahoo.it Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples "Federico II" - Via Pansini 5, 80131 Naples (Italy)

17. Tooker GM, Truong H, Pinto PA, Siddiqui MM. National survey of patterns employing targeted MRI/US guided prostate biopsy in the diagnosis and staging of prostate cancer. Curr Urol. 2019; 12:97-103.

18. Kasivisvanathan V, Rannikko AS, Borghi M, et al. MRI-targeted or standard biopsy for prostate-cancer diagnosis. N Engl J Med. 2018; 378:1767-1777.

19. Caglic I, Kovac V, Barrett T. Multiparametric MRI - local staging of prostate cancer and beyond. Radiol Oncol. 2019; 53:159-170.

20. Glass AS, Dall' Era MA. Use of multiparametric magnetic resonance imaging in prostate cancer active surveillance. BJU Int. 2019; 124:730-737.

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Archivio Italiano di Urologia e Andrologia 2020; 92, 4

Ferdinando Fusco, MD - ferdinando-fusco@libero.it Department of Woman Child and of General and Specialist Surgery, University of Campania "Luigi Vanvitelli" - 80131 Naples (Italy)

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DOI: 10.4081/aiua.2020.4.297

ORIGINAL PAPER

The safety and feasibility of the simultaneous use of 180-W GreenLight laser for prostate vaporization during concomitant surgery Roberto Castellucci 1, Michele Marchioni 2, Giuseppe Fasolis 3, Francesco Varvello 3, Pasquale Ditonno 4, Gaetano Di Rienzo 4, Francesco Greco 5, Vincenzo Maria Altieri 5, Antonio Frattini 6, Giovanni Ferrari 7, Luigi Schips 2, Luca Cindolo 8 1 Department

of Urology ASL Abruzzo 2 Chieti, Italy; of Urology, SS Annunziata Hospital, “G. D’Annunzio” University, Chieti, Italy; 3 Department of Urology, “S. Lazzaro” Hospital, Alba, Italy; 4 Department of Emergency and Organ Transplantation, Urology and Andrology Unit II, University of Bari, Bari, Italy; 5 Department of Urology, Humanitas “Gavazzeni”, Bergamo, Italy; 6 Department of Urology, “Ercole Franchini” Hospital, Montecchio Emilia, Italy; 7 Department of Urology, “Hesperia” Hospital, Modena, Italy; 8 Department of Urology, Private Hospital Villa Stuart, Rome, Italy.

2 Department

Summary

Objectives: To explore the safety and feasibility of photo-selective vaporization of the prostate (PVP) with GreenLight XPS 180 Watt laser (GL-180W XPS) combined with other surgical procedures.

Material and methods: Data on patients in whom GL-180-W XPS was performed to relieve lower urinary tract symptoms/ benign prostatic hyperplasia (LUTS/BPH) symptoms were extracted from a multi-institutional database (2011-2016).

Patients were stratified into two groups. In the first all patients who had GL-180-W XPS with a concomitant procedure during the same surgical session were included as cases while those who underwent GL-180-W XPS PVP only were included as control.

Results: A total of 487 patients were included. Fifty-eight (11.9%) patients underwent concomitant procedures.

Multivariable linear regression models failed to find an association between concomitant procedures and longer laser time (p = 0.4). Similarly, multivariable linear regression models failed to find an association between concomitant procedures and laser time even when the analyses were repeated and stratified into endoscopic (p = 0.6) and open/laparoscopic (p = 0.4) procedures. Multivariable logistic regression models failed to demonstrate any association between concomitant procedures and early complications (OR:1.39, CI: 0.379-2.44, p = 0.2), late complications (OR:1.84, CI:0.78-3.98; p = 0.1) and acute urinary retention (OR:1.84, CI:0.78-3.98; p = 0.1).

When the analyses were repeated and the concomitant procedures stratified into endoscopic and open/laparoscopic ones, they yielded virtually the same results.

Conclusions: GL-180-W XPS PVP could be safely performed in concomitant endoscopic or open/laparoscopic surgery. These results should be taken into consideration in the counseling of the patient who might choose to undergo simultaneous procedures.

KEY WORDS: GreenLight laser; Concomitant procedures; LUTS/BPH; Simultaneous surgery.

Submitted 24 March 2020; Accepted 21 August 2020

INTRODUCTION

Lower urinary tract symptoms (LUTS) are strongly associated with ageing (1) and might be the most evident consequence of benign prostatic hyperplasia (LUTS/BPH).

LUTS/BPH, when related to bladder outlet obstruction (BOO), are often caused by benign prostatic enlargement (BPE) (2). A surgical treatment is often necessary in LUTS/BPH patients who experience low efficacy of pharmacological therapies or want to discontinue these therapies (3). Moreover, some patients may have already progressed and/or experienced LUTS/BPH complications, such as bladder diverticula or vesical calculi before surgery (4). Furthermore, since patients with LUTS/BPH are usually aged, other conditions such inguinal hernia may require supplementary surgical treatment (4).

Nowadays, photoselective vaporization of the prostate (PVP) with GreenLight XPS 180 Watt laser (GL-180-W XPS) (American Medical Systems, Minnetonka, Minnesota, USA) is considered a valid alternative to TURP, thanks to its safeness and efficacy (5). Moreover, the GL-180-W XPS PVP guarantees an early discharge and limits the need for blood transfusion (6-8). Currently, little evidence on the safety, efficacy and feasibility of PVP with other concomitant procedures are available. This evidence derived mostly from single center or case series reports (9, 10).

The aim of this study is to evaluate the safety and feasibility of GL-180-W XPS PVP combined with other surgical procedures. Moreover, we aim to test the effect of simultaneous procedures on perioperative outcomes, functional outcomes and complication rates.

MATERIALS

AND METHODS

Data on patients in whom PVP was performed to relieve LUTS/BPH symptoms were abstracted from a multi-institutional database (2011-2016). Patients were stratified into two groups. In the first group, all patients who had PVP with a concomitant procedure during the same surgical session were included as cases. In the second group,

L. Cindolo and G. Ferrari do surgical tutorship for AMS and received honoraria for their tutorship.

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R. Castellucci, M. Marchioni, G. Fasolis, F. Varvello, P. Ditonno, G. Di Rienzo, F. Greco, V.M. Altieri, A. Frattini, G. Ferrari, L. Schips, L. Cindolo

all patients who underwent only simple PVP were included as controls. PVP procedures were performed according to the techniques previously described by Gomez-Sancha and following the surgeonsâ&#x20AC;&#x2122; preferences (11).

The characteristics of patients collected at the time of surgery were age, LUTS/BPH drug therapy, antiplatelet/anticoagulant therapy, ASA score. Moreover, prostate volume, PSA levels, International Prostate Symptom Score (IPSS), maximum urinary flow (Qmax) and indwelling catheter history before surgery were recorded. Intra- and perioperative data, including anesthesia type, laser time, energy used, catheterization time and postoperative stay were noted. The laser time referred only to the time from the beginning to the end of laser prostate vaporization. All the patients underwent an outpatient clinic visit at least after 3 months and then annually. During the follow-up visit, IPSS, Qmax, and PSA levels were recorded.

The Patient Global Impression of Improvement (PGI-I) was evaluated with the PGI-I scale (12). Complications were collected and classified as early (within 30 post-operative days) or late (after 90 days). Early complications were classified according to the Clavien-Dindo system (13, 14).

Our study has been reported in line with the STROCCS criteria (15). Written informed consent was obtained from all subjects and for this study ethical committee approval was given.

Statistical analysis Descriptive statistics relied on median and interquartile ranges for qualitative covariates and on count and percentages (%) for categorical variables. Differences between groups were assessed with the chi-square test for categorical variables and the Mann-Whitney U test for continuous variables. Three sets of analyses were performed. First, multivariable linear regression models examined the effect of concomitant procedures on the laser time. Second, separate multivariable logistic regression models tested the effect of concomitant procedures on the rates of early complications, late complications and acute urinary retention.

Third, all the analyses were repeated after using a different coding that stratified the concomitant procedures into endoscopic versus open/laparoscopic ones. All the multivariable models were adjusted for age and prostate volume.

All statistical tests were two-sided. The level of significance was set at p < 0.05. Analyses were performed using the R software environment for statistical computing and graphics (version 3.4.3; http://www.r-project.org/).

RESULTS Preoperative and post-operative descriptive analyses In total 487 patients were included. Out of them 58 (11.9%) underwent a PVP and a concomitant procedure during the same anesthesia. Twenty-nine endoscopic and 29 open/laparoscopic concomitant procedures were performed (Table 1). Patients who underwent concomitant procedures had a more frequent history of an indwelling catheter (36.2 vs. 21.2%, p = 0.02). Moreover, patients with concomitant procedure were more frequently treated for LUTS/BPH symptoms (31 vs. 18.4%, p = 0.02) (Table 2). Patients who underwent PVP in association with

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Table 1.

Concomitant procedures.

Concomitant procedure Vescical lithotripsy Internal Urethrotomy TURB Vescical botulinum Inguinal hernia repair Colecistectomy Hydrocelectomy Laparoscopic bladder diverticulectomy

Numbers of procedures 13 8 5 3 24 2 2 1

Kind of surgery Endoscopic Endoscopic Endoscopic Endoscopic Laparoscopic/open Laparoscopic/open Laparoscopic/open Laparoscopic/open

Table 2.

Demographic and clinical characteristics of patients before photo-selective vaporization of the prostate stratified according to the surgical procedure (PVP vs PVP + concomitant procedures). Quantitative variables are reported as median and interquartile ranges (IQR). Qualitative variables are reported as count and percentages (%).

Overall (n = 487) Preoperative parameters Age, years 70 (64-76) Follow-up duration, months 17 (11-23,5) Prostate volume, mL (missing = 3) 60 (43.8-80) PSA, ng/mL (missing = 58) 2.7 (1.3-4.5) Qmax, mL/s (missing = 116) 8 (6-10) IPSS (missing = 118) 25 (21-28) ASA score 1-2 259 (53.2) 3-4 93 (19.1) Unknown 135 (27.7) History of catheterization 112 (23) BPH therapy 5-ARI 15 (3.1) Alfa-blocker 236 (48.5) Combination therapy 139 (28.5) None 97 (19.9)

PVP (n = 429)

PVP + Concomitant procedures (n = 58)

p-value

70 (64-77) 18 (11-24.6) 60 (45-80) 2,7 (1.3-1.4) 8 (6,1-10) 25 (21-28)

70.5 (65.2-76) 14.5 (8-19.8) 52 (40-74) 2.5 (1-5.1) 7.6 (6.3-10) 26 (20.5-33.5)

0.8 < 0.001 0.05 0.7 0.2 0.05 0.05

220 (51.3) 83 (19.3) 126 (29.4) 91 (21.2)

39 (67.2) 10 (17.2) 9 (15.5) 21 (36.2)

12 (2.8) 207 (48.3) 131 (30.5) 79 (18.4)

3 (5.2) 29 (50) 8 (13.8) 18 (31)

0.02 0.02

other endoscopic procedures were more frequently diagnosed with smaller prostate glands (median volume 50.0 vs. 60.0 mL; p = 0.020) and had more frequently an history of indwelling catheter (41.4 vs. 21.2%, p = 0.012 (Supplementary Table 1).

After the surgery, significant statistical differences were found for the indwelling catheter time which was longer in patients who underwent concomitant procedures (2 vs.

1 day, p = 0.006). Moreover, the DIPSS was slightly wider for patients who underwent concomitant procedures (-20 vs. -18, p = 0.03) than in those who underwent simple PVP (Table 3). No differences between the two groups were found in terms of an early and late complication rate (p = 0.3 and p = 0.07 respectively) (Table 3).

Acute urinary retention occurred in 8.4 and 15.5 patients after simple PVP and PVP with concomitant procedure, respectively (p = 0.1). DUFM was not statistically significant different between two groups (p = 0.4). Most of the patients (56.7%) had no complications at all; among patients with complications the wide majority was graded as Clavien-Dindo I (40.7%) (Tables 3, 4). Consistently we found no statistically significant differences in terms of

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Green Light laser and concomitant surgery

Supplementary Table 1.

Demographic and clinical characteristics of patients before photoselective vaporization of the prostate stratified according to the surgical procedure (PVP vs PVP + other endoscopic procedures). Quantitative variables are reported as median and interquartile ranges (IQR). Qualitative variables are reported as count and percentages (%).

Age, years Prostate volume, mL PSA, ng/mL Qmax, mL/s IPSS ASA score - 1-2 - 3-4 - Unknown History of catheterization BPH therapy - 5-ARI - Alfa-blocker - Combination therapy - None

PVP (n = 429) 70.0 (64.0, 77.0) 60.0 (45.0, 80.0) 2.7 (1.3, 4.4) 8.0 (6.1, 10.0) 25.0 (21.0, 28.0)

PVP + Other endoscopic procedures (n = 29) 72.0 (67.0, 76.0) 50.0 (35.0, 67.2) 1.4 (1.0, 3.6) 8.6 (7.0, 11.0) 23.0 (20.0, 30.0)

220 (51.3%) 83 (19.3%) 126 (29.4%) 91 (21.2%)

17 (58.6%) 3 (10.3%) 9 (31.0%) 12 (41.4%)

12 (2.8%) 207 (48.3%) 131 (30.5%) 79 (18.4%)

3 (10.3%) 14 (48.3%) 8 (27.6%) 4 (13.8%)

Table 3.

Demographic and clinical characteristics of patients during and after photoselective vaporization of the prostate stratified according to the surgical procedure (PVP vs PVP + concomitant procedures). Quantitative variables are reported as median and interquartile ranges (IQR). Qualitative variables are reported as count and percentages (%).

p-value 0.546 0.020 0.133 0.573 0.954 0.477

0.012 0.163

Supplementary Table 2.

Demographic and clinical characteristics of patients during and after photoselective vaporization of the prostate stratified according to the surgical procedure (PVP vs PVP + other endoscopic procedures). Quantitative variables are reported as median and interquartile ranges (IQR). Qualitative variables are reported as count and percentages (%).

PVP PVP + Other endoscopic procedures p-value (n = 429) (n = 29) Laser time (min) 27.0 (18.0, 38.2) 20.5 (17.0, 33.5) 0.250 Energy used (Kj) 247.1 (157.1, 360.0) 193.0 (148.8, 337.7) 0.442 Discharge day 2.0 (1.0, 2.0) 2.0 (1.0, 2.0) 0.838 Catheter removal day 1.0 (1.0, 2.0) 2.0 (1.0, 3.0) 0.079 Δ PSA, ng/mL -1.3 (-2.9, -0.2) -0.7 (-1.8, -0.3) 0.207 Δ Qmax, mL/s 11.0 (7.0, 14.0) 8.2 (1.8, 12.8) 0.076 Δ IPSS -18.0 (-23.0, -14.0) -16.0 (-25.0, -13.0) 0.691 Acute urinary retention 36 (8.4%) 5 (17.2%) 0.106 Late complications 73 (17.0%) 8 (27.6%) 0.149 Early complication 182 (42.4%) 12 (41.4%) 0.912 Satisfaction 0.617 Not satisfied 16 (3.7%) 2 (6.9%) Satisfied 388 (90.4%) 26 (89.7%) Unknown 25 (5.8%) 1 (3.4%) Clavien-Dindo classification 0.356 0 247 (57.6%) 17 (58.6%) 1 170 (39.6%) 11 (37.9%) 2 2 (0.5%) 0 (0.0%) 3a 2 (0.5%) 1 (3.4%) 4a 8 (1.9%) 0 (0.0%)

main postoperative outcomes when PVP patients were compared to those who had PVP in association with other endoscopic procedures (Supplementary Table 2).

Multivariable linear regression models Multivariable linear regression models failed to find an association between concomitant procedures and longer laser time (coefficient 1.59, -1.90 to 5.08; p = 0.4).

Overall (n = 487)

PVP PVP + Concomitant p-value (n = 429) procedures (n = 58)

Peri- and post-operative features Laser time (min) (missing = 26) 27 (18-37) 27 (18-38.2) 25 (18.4-34.2) Energy used (Kj) (missing = 5) 246.6 247.1 (157.1-360) 242.4 (169.0-336.1) Discharge day 2 (1-2) 2 (1-2) 2 (1-2) Catheter removal day 1 (1-2) 1 (1-2) 2 (1-2,8) Δ PSA, ng/mL -1.3 (-3 to -0.3) -1.3 (-2.9 to -0.2) -1.1 (-3.0 to -0.5) Δ Qmax, mL/s 11 (7-14) 11 (7-14) 12.6 (8.6-13.7) Δ IPSS -18 (-24 to -14) -18 (-23 to -24) -20 (-27.5 to -14) Acute urinary retention 45 (9.2) 36 (8.4) 9 (15.5) Late complications 89 (18.3) 73 (17) 16 (27.6) Early complication 211 (43.3) 182 (42.4) 29 (50) Satisfaction Not satisfied 20 (4.1) 16 (3.7) 4 (6.9) Satisfied 439 (90.1) 388 (90.4) 51 (87.9) Unknown 28 (5.7) 25 (5.8) 3 (5.2) Clavien-Dindo classification 0 276 (56.7) 247 (57.6) 29 (50) 1 198 (40.7) 170 (39.6) 28 (48.3) 2 2 (0.4) 2 (0.5) 0 (0) 3a 3 (0.6) 2 (0.5) 1 (1.7) 4a 8 (1.6) 8 (1.9) 0 (0)

0.6 0.7 0.7 0.006 0.5 0.4 0.03 0.1 0.07 0.3 0.5

0.4

Table 4.

Early and late complications according to the surgical procedure (PVP vs PVP + concomitant procedures). Qualitative variables are reported as count and percentages (%).

Early complications Fever (< 38°C) Fever (≥ 38°C) Burning urination Bladder tenesmus Urge Urge incontinence Stress incontinence Capsule perforation Hematuria Acute urinary retention Urinary tract infections Blood transfusion Cardiovascular acute event Minor cardiovascular event Major acute cardiovascular event Late complications Urethral stenosis Bladder neck contracture Prostatic fossa sclerosis Urinary stress incontinence Re-intervention Persistent irritative symptoms Urethral stenosis Bladder neck contracture

Overall 13 (2.7) 15 (3.1) 74 (15.2) 37 (7.6) 42 (8.6) 47 (9.7) 36 (7.4) 6 (1.2) 16 (3.3) 45 (9.2) 7 (1.4) 3 (0.6) 13 (2.7) 5 (1) 8 (1.6)

PVP 12 (2.8) 11 (2.6) 61 (14.2) 32 (7.5) 36 (8.4) 37 (8.6) 30 (7) 5 (1.2) 16 (3.7) 36 (8.4) 7 (1.6) 3 (0.7) 13 (3) 5 (1.2) 8 (1.9)

PVP + Concomitant procedures 1 (1.7) 4 (6.9) 13 (22.4) 5 (8.6) 6 (10.3) 10 (17.2) 6 (10.3) 1 (1.7) 0 (0) 9 (15.5) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)

14 (2.9) 18 (3.7) 8 (1.6) 27 (5.5) 10 (2.1) 28 (5.7) 14 (2.9) 18 (3.7)

11 (2.6) 14 (3.3) 8 (1.9) 23 (5.4) 7 (1.6) 22 (5.1) 11 (2.6) 14 (3.3)

3 (5.2) 4 (6.9) 0 (0) 4 (6.9) 3 (5.2) 6 (10.3) 3 (5.2) 4 (6.9)

Similarly, multivariable linear regression models failed to find an association between concomitant procedures and Archivio Italiano di Urologia e Andrologia 2020; 92, 4

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R. Castellucci, M. Marchioni, G. Fasolis, F. Varvello, P. Ditonno, G. Di Rienzo, F. Greco, V.M. Altieri, A. Frattini, G. Ferrari, L. Schips, L. Cindolo

Table 5.

Multivariable logistic regression (adjusted for prostate volume and patient age), concomitant procedures endoscopic and other vs. standard.

Outcomes Early complications

Standard Endoscopic Laparoscopic/open Late complications Standard Endoscopic Laparoscopic/Open Acute urinary retention Standard Endoscopic Laparoscopic/open

Odds ratio (95% confidence interval) Univariable p-value Multivariable p-value Reference 0.96 (0.44-2.04) 1.92 (0.90-4.22)

0.9 0.09

Reference 0.99 (0.45-2.16) 1.91 (0.89-4.21)

0.9 0.09

Reference 1.86 (0.75-4.21) 1.86 (0.75-4.21)

0.15 0.15

Reference 1.95 (0.77-4.49) 1.85 (0.75-4.20)

0.1 0.2

Reference 2.27 (0.73-5.89) 1.75 (0.49-4.81)

0.1 0.3

Reference 1.91 (0.60-5.11) 1.76 (0.49-4.97)

0.2 0.3

laser time even when the analyses were repeated and the concomitant procedures stratified into endoscopic (coefficient 1.21, -3.50 to 5.92, p = 0.6) and open/laparoscopic (coefficient 1.99, -2.88 to 6.85, p = 0.4) ones.

Multivariable logistic regression models Multivariable logistic regression models failed to demonstrate any association between concomitant procedures and early complications (OR: 1.39, CI: 0.38-2.44, p = 0.2), late complications (OR: 1.84, CI: 0.78-3.98; p = 0.1) and acute urinary retention (OR: 1.84, CI: 0.78-3.98; p = 0.1).

When the analyses were repeated and the concomitant procedures were stratified into endoscopic and open/laparoscopic ones, they yielded virtually the same results (Table 5).

DISCUSSION

We hypothesized that PVP combined with other surgical procedures is feasible and safe. To test our hypothesis, we compared functional and surgical outcomes of patients who underwent PVP combined with other surgical procedures, with those who underwent PVP only. Data were abstracted from a large multi-institutional database. Our analyses showed several important findings.

First, the proportion of patients with a history of catheterization was higher in the concomitant procedure group compared to the standard procedure group (36.2 vs.

21.2%). However, the proportion of patients not pharmacologically treated was also higher in the concomitant procedure compared to the standard procedure (31.0 vs.

18.4%). This finding is of interest because suggests that patients undergoing concomitant procedures could be less compliant to chronic treatments or physicians less prone to prescribe medications in those who are candidate to combination surgery with an history of indwelling catheter. It is worth of consideration the fact that in patients with a history of an indwelling catheter, the use of an alpha-blocker reduces the risk of acute retention after catheter removal (16). Moreover, the use of combination therapy in LUTS/BPH patients reduces the risk of complications (17). Taken together these observations suggest that it might be of importance for more complex patients, such as those candidates for concomitant procedures, to

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continue or start LUTS/BPH therapy in order to reduce the risk of complications after surgery. Unfortunately, the granularity of our dataset do not allow to specifically investigate this hypothesis, thus larger and prospective studies investigating the effect of LUTS/BPH treatment in concomitant procedure candidates are warrant.

Second, in a multivariable linear regression model no statistically significant differences were found in laser time between the concomitant procedure and standard procedure groups. We relied on this parameter as a surrogate of surgical difficulties that may occur when more than one procedure is performed. Indeed, when concomitant procedures are performed before the PVP, especially for endoscopic treatments (i.e. vesical lithotripsy or internal urethrotomy), bleeding or access difficulties are always a possibility. Moreover, it is worth of consideration that in our study the two groups (simple PVP and concomitant procedure) had similar prostate size. In consequence, our findings suggest that the most important predictor of laser time is the prostate size. Thus, physicians should not worry to perform concomitant procedures, that do not affect the effectiveness of PVP. The latter is confirmed again by our results, which also showed no detrimental effect of concomitant procedures on overall early complications, late complications or acute urinary retention in multivariable logistic regression models. Results were virtually the same even when all the multivariable models were adjusted to the different nature of concomitant surgical procedures (standard, endoscopic and laparoscopic/open) in specific analyses.

Our findings suggest that PVP performance is not affected by other surgical procedures. Such evidence is clinically meaningful considering that almost 10% of patients need more than one treatment, according to our series. This finding corroborates those of smaller and/or more historical series. Patel et al. in a smaller single institutional series (N = 372, 38 underwent concomitant procedures) also showed no enucleation and morcellation time differences in patients who underwent HOLEP with concomitant procedures (4). Similarly, the feasibility of GL-180-W PVP in combination with various other procedures was shown in small series or case reports (9, 10, 18, 19).

More specifically, De la Torre et al. explored the feasibility of Green Light laser 80 or 120 W prostate vaporization and bladder lithotripsy with holmium laser in 19 patients. The authors showed that there was a significant improvement in terms of Qmax, post-micturition residual volume, and IPSS after surgery with no intra- o post-operative complications (10). In a similar study Hora et al. reported no perior post-operative complications in 8 patients who underwent laparoscopic bladder diverticulectomy and Green Light Laser HPS 120 W or XPS 180 W vaporization of prostate in one operative session (19). Taken together, our study as well as those previously discussed, show the feasibility of laser surgery and more specifically of GL-180-W PVP concomitantly with other procedures (9, 10, 18-20).

Third, despite the fact that preoperative IPSS was similar in a concomitant procedure compared to the standard, â&#x2C6;&#x2020;IPSS was wider in the concomitant procedure compared to the standard procedure (-20 vs. -18). This finding corroborates the results of previous investigators that showed a larger improvement in terms of IPSS in patients who underwent

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Green Light laser and concomitant surgery

a concomitant procedure compared to a standard procedure (4). This finding is a novelty in the field of GL-180W XPS PVP. Indeed, to the best of our knowledge no previous studies have investigated functional outcomes after GL-180-W XPS PVP with concomitant not urological surgical procedures. For example, De la Torre et al. related the use of Green Light laser 80 or 120 W prostate vaporization and bladder lithotripsy with holmium laser, Hora et al. Green Light Laser HPS 120 W or XPS 180 W with bladder diverticulectomy and Cindolo et al related the feasibility of GL-180-W XPSPVP associated to robotassisted laparoscopic diverticulectomy (9, 10, 19).

It might be hypothesized that in patients with concomitant pathological conditions the relief from multiple comorbidities may exert a positive effect also on IPSS, which is wider than in patients with LUTS/BPH only.

Nevertheless, this study has several limitations. The major limitations are related to its retrospective study and the fact that non-randomized design and different surgical experience could not be controlled in the analytic phase. Further limitations included the not standardized pre- and post-operative patient management.

Similarly, the assessment and management of the complications may vary according to the different centres.

CONCLUSIONS

Our study underlines how GL-180-W XPS PVP could be safely performed in concomitant endoscopic or open surgery. These results should be taken into consideration in the counseling of the patient who might choose to undergo simultaneous procedures. Further studies are warranted to confirm our results.

REFERENCES

1. Abrams P, Chapple C, Khoury S, et al. International consultation on new developments in prostate cancer and prostate diseases. Evaluation and treatment of lower urinary tract symptoms in older men. J Urol 2013;189:S93-S101. https://doi.org10.1016/j.juro. 2012.11.021.

2. Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society.

Urology. 2003; 61:37-49.

3. Cindolo L, Pirozzi L, Sountoulides P, et al. Patient’s adherence on pharmacological therapy for benign prostatic hyperplasia (BPH)-associated lower urinary tract symptoms (LUTS) is different: is combination therapy better than monotherapy? BMC Urol. 2015; 15:96.

4. Patel A, Nunez R, Mmeje CO, Humphreys MR. Safety and feasibility of concomitant surgery during holmium laser enucleation of the prostate (HoLEP). World J Urol. 2014; 32:1543-1549.

5. Cindolo L, Marchioni M, Emiliani E, et al. Bladder neck contracture after surgery for benign prostatic obstruction. Minerva Urol Nefrol. 2017; 69:133-143.

6. Sountoulides P, Tsakiris P. The Evolution of KTP Laser Vaporization of the Prostate. Yonsei Med J. 2008; 49:189.

7. Ben-Zvi T, Hueber P-A, Liberman D, et al. GreenLight XPS 180W vs HPS 120W laser therapy for benign prostate hyperplasia: a prospective comparative analysis after 200 cases in a single-center study. Urology. 2013; 81:853-858.

8. Castellan P, Castellucci R, Schips L, Cindolo L. Safety, efficacy and reliability of 180-W GreenLight laser technology for prostate vaporization: review of the literature. World J Urol. 2015; 33:599-607.

9. Cindolo L, Ingrosso M, Marchioni M, et al. Robot-assisted laparoscopic bladder diverticulectomy and greenlight laser anatomic vaporization of the prostate. Int Braz J Urol. 2017;43.

10. de la Torre G, Barusso G, Chernobilsky V, et al. Outpatient simultaneous treatment of benign prostatic hyperplasia and bladder lithiasis with GreenLightTM and holmium laser. J Endourol. 2012; 26:164-167.

11. Gomez Sancha F, Rivera VC, Georgiev G, et al. Common trend: move to enucleation—Is there a case for GreenLight enucleation?

Development and description of the technique. World J Urol. 2015; 33:539-547.

12. Hossack T, Woo H. Validation of a patient reported outcome questionnaire for assessing success of endoscopic prostatectomy.

Prostate Int. 2014; 2:182-187.

13. Mamoulakis C, Efthimiou I, Kazoulis S, et al. The modified Clavien classification system: a standardized platform for reporting complications in transurethral resection of the prostate. World J Urol. 2011; 29:205-210.

14. De Nunzio C, Lombardo R, Autorino R, et al. Contemporary monopolar and bipolar transurethral resection of the prostate: prospective assessment of complications using the Clavien system.

Int Urol Nephrol. 2013; 45:951-959.

15. Agha RA, Borrelli MR, Vella-Baldacchino M, et al. The STROCSS statement: Strengthening the Reporting of Cohort Studies in Surgery. Int J Surg. 2017; 46:198-202.

16. Fisher E, Subramonian K, Omar MI. The role of alpha blockers prior to removal of urethral catheter for acute urinary retention in men. Cochrane database Syst Rev. 2014:CD006744.

17. Roehrborn CG, Barkin J, Siami P, et al. Clinical outcomes after combined therapy with dutasteride plus tamsulosin or either monotherapy in men with benign prostatic hyperplasia (BPH) by baseline characteristics: 4-year results from the randomized, double-blind Combination of Avodart and Tamsulosin (CombAT) Trial BJU Int. 2011; 107:946-954.

18. Tufek I, Mourmouris P, Argun OB, et al. Robot-assisted bladder diverticulectomy with concurrent management of bladder outlet obstruction. Urol Int. 2016; 96:432-437.

19. Hora M, Eret V, Stránský P, et al. Laparoscopic urinary bladder diverticulectomy combined with photoselective vaporisation of the prostate. Videosurgery Other Miniinvasive Tech. 2015; 1:62-67.

20. Brassetti A, DE Nunzio C, Delongchamps NB, et al. Green light vaporization of the prostate: is it an adult technique? Minerva Urol Nefrol. 2017; 69:109-118.

Correspondence Roberto Castellucci, MD - roberto.castellucci@gmail.com Via Nazionale Adriatica nord 99 - Pescara (Italy) Michele Marchioni, MD - mic.marchioni@gmail.com Luigi Schips, MD - luigischips@hotmail.com Via dei Vestini 1 - Chieti, Italy Giuseppe Fasolis, MD - info@poliambulatoriosanpaolo.it Francesco Varvello, MD - segreteria@francescovarvello.it C.so Entoria 16 - Alba, Italy Pasquale Ditonno, MD - ditonno@urologia.uniba.it C.so V. Emanuele II, Bari- Italy Gaetano Di Rienzo, MD - dirienzo@urologia.uniba.it Via Lucera 4 Bari - Italy Francesco Greco, MD - francesco.greco@gavazzeni.it Vincenzo Maria Altieri, MD - vmaltieri@alice.it Via Gavazzeni 1 - Bergamo, Italy Antonio Frattini, MD - antoniofrattini@gmail.com Via Donatori di Sangue - Guastalla, Italy Giovanni Ferrari, MD - gferrari@hesperia.it Via Arquà 80 - Modena, Italy Luca Cindolo, MD - lucacindolo@virgilio.it Via Trionfale 5952 - Roma, Italy Archivio Italiano di Urologia e Andrologia 2020; 92, 4

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DOI: 10.4081/aiua.2020.4.302

ORIGINAL PAPER

Penile prosthesis and complications: Results from 577 implants Diego Pozza 1, Andrea Marcantonio 1, Augusto Mosca 2, Carlotta Pozza 3 1 Studio

di Andrologia e di Chirurgia Andrologica, Roma, Italy; Urology and Andrology Unit, S. Sebastiano Hospital, Frascati, Italy; 3 Department of Experimental Medicine, Sapienza University, Roma, Italy.

2

Objective: Penile Prosthetic Surgery is already well characterized but the problems connected with possible complications still need to be evaluated and discussed.

Material and Methods: The Authors revaluated their experience in Penile Prosthetic Surgery involving 577 patients (18 - 86 years, mean age 51.3 years) operated by the same surgeon since 1984. We implanted 199 silicone-semi-rigid (Small Carrion, Implantal, Eurogest, Subrini, SSDA GS), 200 malleable (Jonas, Omniphase, Duraphase, AMS600, MentorColoplast Genesis, Vedise) and 178 inflatable (Mentor: Mark II, Alpha I, Titan OTR; AMS: mono-component Hydroflex, Dynaflex; bi-component Ambicor; multicomponent: 700 Ultrex, 700 CX, 700 LGX) prostheses.

Operative, postoperative, infectious and malfunctioning complications have been recorded. A total of 156 patients drop out at follow-up and we may not exclude possible late complications treated at different hospitals.

Results: The recorded complications and the therapeutic modalities utilized to treat them are examined. Operative complications were recorded in 2 malleable prostheses (MPP) and in one inflatable prosthesis (IPP).

Postoperative complications have been recorded in three cases of MPP (1.5%) and in 9 IPP (5.0%) and were strictly connected to general medical co-morbidities as diabetes mellitus (DM), coronary artery dysfunction (CAD), and Peyronie’s disease (PD). In three cases of IPP implantation, hematomas were related to the blunt surgical maneuvers utilized to insert the reservoir or the scrotal pumps.

Infectious complications were mostly observed in patients with DM: 4 patients with MPP (1.0%) and 15 patients with IPP (8.4%). Malfunction rate of the prostheses in our series was really disappointing considering that 13/17 cases (77%) of mono-component IPP broke while in patients with multicomponent IPP the percentage of malfunction has been of 13/161 (8%) and malfunction was observed in only one case of MPP. We were forced to explant the prostheses in 2 patients with MPP (0.5%) and 40 with IPP (22%).

However, after excluding 17 mono-component IPPs, the percentage of explants of multicomponent IPP (23 patients, 4.2%) is in line with other significative experiences.

Conclusion: The number of complications of PPS are similar to those reported by well qualified urological institutions. In our experience a scrupulous antibiotic therapeutic schedule, avoiding direct contact between the prostheses and the patient’s skin, reduced time of surgery with surgeon’s experience positively influenced the results.

Summary

302

In a limited number of patients medical treatment or minimal surgical acts allowed to solve the complications preserving the prostheses and avoiding the prosthetic explant.

KEY WORDS: Penile prosthesis surgery; Complications; Infections.

Submitted 14 June 2020; Accepted 26 August 2020

INTRODUCTION Since the first penile prosthetic implants, in 1972 (1-3), the relevant problems related to surgical technique, durability of materials and prosthetic mechanisms (4-7), the high risk of infections (8-11) and the possible traumas related to an incorrect use of the prostheses continue to be object of medical consideration (12).

With the increase of operated cases (13, 14), the surgical ability has significantly improved; in parallel medical companies have introduced new materials that last longer over time and are less subject to wear and tear.

Despite these improvements, the possibility that the insertion of a prosthesis could lead to dangerous and harmful maneuvers still exists. We have to consider that the particular weakness of the cavernous and perineal tissues such as may occur after pelvic surgery or radiation therapy, the structural alterations in Peyronie’s Disease (PD) and the presence of comorbidity such as Diabetes Mellitus (DM) or Coronary Artery Disease (CAD) continue to make Penile Prosthetic Surgery (PPS) a risky surgery (15-17).

MATERIALS

AND

METHODS

From 1984 to 2020 over 39,000 patients (pts) (age 6-90 years) with urological and/or andrological problems presented to our outpatient clinic for consultation. Out of them, 9540 patients (25.1%) complained of Erectile Dysfunction (ED). After an accurate taking of medical history and clinical evaluation we requested appropriate diagnostic tests (routine blood tests, hormonal evaluation, ColorDuplexSonography, sometimes Magnetic Resonance imaging, cavernometry and neurologic tests).

We then prescribed currently available therapies (psychotherapy, hormones, venous surgery, vasoactive intracavernous injections, oral phosphodiesterase type 5 No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2020; 92, 4

Penile Prostheses Complications

inhibitors, Medical Urethral System for Erection (MUSE) or alprostadil urethral creams, vacuum).

To 952 patients who had no satisfactory results with the first line therapies used, we suggested a Penile Prosthesis (PP). The Italian National Health System did not refund the costs of such surgery and therefore, until a few years ago, patients had to cover the not-negligible expenses for the cost of prostheses, clinics, and surgeons. For these reasons, the type of prosthesis to implant was selected also considering their economic cost. Of 952 patients, 577 (age 18-86 years) accepted the prosthetic solution of their ED. We began to implant PP in 1984 performing the surgical procedures in different private clinics in Rome.

We implanted 199 silicone semi-rigid (Small Carrion, Implantal, Eurogest, Subrini, SSDA GS), 200 malleable (Jonas, Omniphase, Duraphase, AMS600, Mentor/ Coloplast Genesis, Vedise) and 178 inflatable (Mentor: Mark II, Alpha I, Titan OTR; AMS: Hydroflex, Dynaflex, Ambicor, 700 Ultrex, 700 CX, 700 LGX) prostheses.

We systematically used an antibiotic therapy (AbThe) with Ciprofloxacin 1 g/day since 3- 4 days before surgery until 7-10 days after; Gentamicin Sulfate 150 mg/bid starting from the day of surgery until the day after, Ceftriaxone 2gr/iv just before surgery and 1gr/day until 7 days after (16).

Patients were hospitalized the night before or the morning of surgery. Genital skin was shaved 1-2 hours before surgery. Spinal anesthesia was mostly used; local anesthesia with sedation, for semi-rigid or malleable prostheses, was performed in 40 patients. The time of the surgery varied between 35 to 120 minutes. In cases of PD with significant curvature Wilson’s maneuver (14), plaque’s incision or excision with heterologous grafting were performed. Patients were discharged the day after surgery; patients implanted with inflatable prosthesis (IPP) or living outside Rome 2-3 days later. Follow-up visits were performed, generally, after 7 days, 4 weeks and 1 year. A total of 156 patients dropped out at followup and we cannot exclude possible late complications.

patient was discharged after 2 days. After 3 months, the scrotal pump malfunctioned and the IPP had to be removed. At that time, during surgery, we discovered the erroneous placement of the right cylinder. The new IPP was correctly replaced and the postoperative course had no problems. After 8 years the patient is still fine and satisfied with the IPP. Crural Perforation During the cavernous dilation in a young patient suffering from Corporal Veno Occlusive Dysfunction (CVOD), we caused the perforation of the right crus with pathological progression of scissors and Hegar’s dilators beyond the crus. No evident perineal hematoma happened. We decided to conclude the procedure inserting a Rear Tip Extender (RTE) into the cavernous crus and, through a small perineal incision, we affixed it with stitches to the albugineal tunica. We inserted the Eurogest cylinders, 21 cm into the left and 19 cm into the right space. We did not record significant postoperative complications. The patient after 6 years continues to be satisfied.

POSTOPERATIVE

COMPLICATIONS

Superficial Ecchymosis – Hematomas Postoperative formation of blood effusions or hematomas is a common surgical complication. For this reason, the patient is always advised to suspend anticoagulants and/or aspirin 7-10 days before surgery.

Cutaneous bruising and superficial hematomas tend to disappear in a few weeks (Figure 1). We recorded scrotal hematomas in 6 patients: 3 patients after peno-scrotal access and 3 patients after blunt dilation performed to place the scrotal pump after infra-pubic incision. Until 1992, we did not use any suction drainage, but after the first episode of voluminous hematoma we begun to place a suction drainage (12) that we generally remove 16-24 hours after surgery in all cases of IPP. We do not use drainage in cases of malleable prostheses (MPP) (13).

RESULTS We recorded a series of operative, late postoperative, mechanical, infectious and removal complications that we report below.

OPERATIVE

Figure 1. Postoperative local and diffuse ecchymosis.

Simple medical treatment.

COMPLICATIONS

Perforation of the cavernosal septum In 2 patients, during cavernosal dilation we perforated the septum inserting the two cylinders in the same cavernous space. In one case we were immediately aware of the incorrect location of the cylinders. In the second case, we discovered the incorrect insertion during the final suture steps. We managed to correct the defect by placing the cylinder in the correct cavernous space.

In both cases, no significant immediate or postoperative complications were recorded.

In 1 case of AMS 700CX IPP implantation, the rear part of the right cylinder was improperly positioned in the left cavernous root. The IPP functioned regularly and the

Case 1 A 52 year-old patient had to remove an IPP for malfunction after 8 years. The removal and repositioning of a new AMS700CX prosthesis did not present any problem. After 16 hours, next morning, the drainage had aspirated 15-20 cc of blood. We deflated the cylinders that had been left swollen since operation. The patient had to be dismissed Archivio Italiano di Urologia e Andrologia 2020; 92, 4

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D. Pozza, A. Marcantonio, A. Mosca, C. Pozza

in the late afternoon so we maintained the drainage. In the hours after we noticed an abundant blood collection in the vacuum cleaner and hematic suffusion at the base of the penis. We brought the patient back to the Operating Room (OR) but we did not find any bleeding vessel. Blood was seeping out of an incomplete suture of the cavernous body. We applied a stitch, inflated the prosthetic cylinders and the bleeding completely stopped. The drainage was removed after 24 hours and the patient was discharged maintaining fully inflated cylinders for 15 days. After 5 years the patient is satisfied.

Case 2 A 31 years-old patient, developed a voluminous hematoma of the penis and scrotum after IPP with drainage in suction. After 10 hours, at night, the volume of the scrotum and the base of the penis begun to increase for a voluminous hematoma (Figure 2). We immediately checked him in the OR but we failed to identify obvious sources of bleeding. Multiple local and scrotal washes were performed. We kept fully inflated the cylinders and maintained the drainage for 3 days until the patient was discharged. The cylinders were kept inflated for 10 days. After surgery, the patient was diagnosed with an unknown coagulative disease.

Figure 2. Relevant hematoma after Coloplast inflatable penile prosthesis with drainage due to unrecognized coagulationâ&#x20AC;&#x2122;s problem. An immediate surgical revision was performed. No damages to the patient and the inflatable penile prosthesis.

Case 3 & 4 Two patients (72 and 74 years old) with DM and CAD, after Radical Prostatectomy (RP), received an IPP. In the 2 cases the drainage was negative at discharge but after 7-10 days, with the resumption of aspirin and anticoagulant treatment (Coumadin), they complained of scrotum bulge with pain and difficulty in finding the scrotal pump. In one case we preferred to operate on to drain a scrotal hematoma with rapid healing. In the second, less evident, case, we solved the problem after a month with medical therapy.

Apical Extrusion After 4 years from implantation of an AMS700Cx IPP for PD with mild dorsal curvature, a 56 years old patient complained of persistent pain in the glans. The glans appeared deformed. Suspecting an apex extrusion, it was decided to operate on. After sub-coronal incision, we

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detected the extrusion of the right prosthetic cylinder, however, not in contact with the outside (Figure 3A).

A small medium-penile incision was performed and the right prosthetic cylinder was fully removed (Figure 3B).

We changed the 2 cm RTE with a 1 cm RTE. The apex of the right cavernous body was closed by applying a patch of Marlex tissue like a hood. After reinserting the cylinder the corporotomy was sutured and the glans fixed to the albuginea. The cylinders were maintained inflated for 10 days. In 2020, the patient continues to be satisfied.

Figure 3. A: Extrusion of the right cylinder of inflatable penile prosthesis under the glans; B: Removal and shortening of right cylinderâ&#x20AC;&#x2122;s rear tip extender. Repairing of the cavernous tip with Marlex hood.

Apical Extrusion with removal Case 1 In a 56 years old patient with DM, an Hydroflex cylinder perforated the apex of the right cavernous body after 8 months from implantation (Figure 4A). The IPP did not work so we removed the 2 cylinders. After dismissal, the patient was lost at follow-up.

Case 2 In a 36 years old patient, with DM and CAD and CVOD, we implanted a couple of Implantal 120 MPP in 2003.

The patient got married, he fathered a son and after 6 years he began to feel a constant pain in the glans. In a few days the cylinder came out. We extracted the prosthetic cylinder, washed with antibiotic solution and did not insert a new cylinder for the risk of infection. After 3 months the patient reported that he had no more pain being able to have penetrative intercourses with his wife.

He refused a possible re-intervention to reposition the missing prosthetic cylinder mainly for economical reasons (Figure 4B).

Case 3 In a 65 years old patient with DM, an infection of the IPP begun to develop after 35 days. The evolution of the infection was aggressive, not modified by complex antibiotic treatment, till the extrusion of the right cylinder due to necrosis of cavernous body. It was immediately explanted (Figure 4C).

Skin erosion due to connection tubes A 66 years old patient with DM received in 1999 an IPP with penoscrotal incision. After 7 years he begun to feel pain near the peno-scrotal scar where the presence of the connecting tubes was always felt. After the pain, local bulging appeared with leakage of serous not infected

Penile Prostheses Complications

Figure 4.

A: Apical extrusion of Hydroflex penile prosthesis covered by the glans, probably without infection.

B: Complete extrusion of implantal cylinder.

C: Complete extrusion of inflatable penile prosthesis after severe cavernosal infection in a patient with diabetes mellitus.

Figure 5.

Scrotal superficial extrusion of inflatable penile prosthesis tubing without infection.

Simple surgical repair of the scrotal tissues.

Figure 6. Two urethral stones extracted in a patient with inflatable penile prosthesis after renal colic.

Figure 7.

Preputial edema in IPP due to infra-pubic incision.

Figure 8.

Scrotal pump surrounded by clear fluid under the neocapsule.

material (Figure 5). A lozenge incision was made, under local anesthesia and sedation; the tube, after antibiotic washes, was sunk into the dartos tissue of the scrotum.

The skin was closed. Antibiotic therapy was started.

After discharge, the patient did not complain any local and general symptoms.

Urinary urethral stones A 76 years old patient with CAD and hyperuricemia, had an IPP in 2004. He had a frequent sexual activity being very satisfied. In 2017 he had an episode of renal colic with hematuria. The medical practitioner (MP) who visited him during the first episode, unaware of the hydraulic prosthesis, at sonography excluded kidney stones but diagnosed a “paravesical liquid cyst”.

The patient the next day continued to suffer pain and hematuria and presented to our clinic. The IPP worked properly. The “paravesical liquid cyst” at sonography revealed to be the prosthetic reservoir that emptied and filled normally. Through palpation and sonography we found 2 round stones obstructing the urethra. Local anesthesia with lidocaine was performed, followed by a small meatal incision that made possible the extraction of the urinary stones (Figure 6). A Foley catheter was inserted till the bladder without any obstacle. After 2 days a flexible cystoscopy excluded other bladder stones.

In 2020 the patient continues to utilize the prosthesis.

Preputial edema In the last 3 years we begun again to utilize the infrapubic incision to implant IPP. In 7/ 12 patients we observed, in the first post-op week a significant edema of the foreskin with patient’s discomfort and difficulties in discovering the glans. General and local steroid therapy determined a normalization of the edema in a few weeks. In one patient (Coloplast IPP), the difficulty in discovering the glans persisted after one month and the patient preferred to be submitted to circumcision. We observed this problem also in several patients operated in the past for different indications utilizing the infrapubic incision. We cannot exclude an interruption of lymphatic vessels draining of the penile foreskin due to the “pubic” incision (Figure 7).

Altered position of the scrotal pump In 3 patients we observed, during the first visit after surgery, an irregular positioning of the scrotal pump with difficulty to find and activate it.

Case 1 A 54 years-old patient, after IPP, wasn’t able to perceive the pump, to activate and to deflate the cylinders. After several controls without obtaining a correct position of the pump we decided to re-operate on the patient; after antibiotic therapy, re-incision of the scrotum and freeing of the pump from adhesions we positioned it in the correct way. We did not observe any postoperative complication, neither infections.

Case 2 A 72 years-old patient, after IPP, wasn’t able to activate the prosthesis because one tube was fixed to the pump and was not possible to detach it even with physical maneuvers performed after local anesthesia. We perArchivio Italiano di Urologia e Andrologia 2020; 92, 4

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formed a surgical revision after usual antibiotic therapy.

The pump was repositioned in the right way. The patient had no complications. After 4 years the IPP is functioning (Figure 8).

Case 3 A 66 years-old patient after radical prostatectomy had in 2012 an IPP with infrapubic access. He observed that the pump was positioned transversally, at the base of the scrotum, bur normally functioning. In front of the proposal to re-operate on to position the pump in the correct way, the patient refused due to the risks of infection.

After 3 years the patient was however satisfied.

Case 4 A 60 years-old hypertensive patient, after IPP observed a progressive formation of a painful liquid swelling of the scrotum. The ultrasound was not conclusive so we performed surgery, after antibiotic therapy, and we found a very large amount of clear fluid collected into the pseudo capsule covering the pump (Figure 9). We removed the capsule and repositioned the pump between the testicles.

No complication was registered.

Pump malfunction and substitution Two patients (56 and 60 years old) after IPP complained of malfunction of the pump that doesnâ&#x20AC;&#x2122;t inflate the cylinders. In OR, after incision of the scrotum, we observed that the tubes were broken at their base, near the pump, with leaking of the fluid. In both patients we disconnected the pumps, checked the correct function of cylinders and reservoir and we substitute only the pump making three new tube connections. No infection occurred; the IPPs worked perfectly and the patients were both satisfied after 2 and 4 years (Figure 9).

cations (14-16). In our series we recorded 22 cases of severe infections in 6/399 MPP (1.5%) and in 16/177 IPP (8.9%) that were not managed with complex antibiotic treatment.

We reported most of our complications in patients with DM (16/22, 73%) even if we tried to perform Penile Implant after regularization of glycemic values with insulin or oral antidiabetics.

Scrotal pump abscess Case 1 A 72 years-old patient with DM, 2 years after an IPP implantation, begun to report scrotal pain, fever, and leakage of purulent material from the peno-scrotal scar.

We informed the patient of the possible removal of the prosthesis but we started the treatment by cleaning the scrotal wound with gentamicin 80 mg and iodopovidone solution twice a day for 7 days and by starting systemic antibiotic treatment.

After 7 days the leakage of purulent secretion stopped and the wound closed. The patient begun to utilize the pump after 15 days. Since then he has no further complaints (Figures 10A, B).

Case 2 A 58 years-old patient with DM and CAD, after an IPP for PD and ED, begun to experience pain in the scrotum

Figure 9. Removal of the pumps of inflatable penile prosthesis and their substitution after 3 years.

INFECTIONS The risk of infection continues to be the main problem for PPS. Surgeons and medical companies tried to find the better strategy, the medical behavior, the drugs, the instruments to reduce the incidence of infective compli-

Figure 10. A: Painful scrotum and purulent secretion from the pump; B: After local infusion of gentamicin for 7 days closure of the skin with complete recovery; C: Purulent abscess of the scrotal pump in a patient with diabetes mellitus after 36 days from implantation of inflatable penile prosthesis. Removal of the inflatable penile prosthesis.

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Penile Prostheses Complications

Figure 11. A: Purulent secretion at the basis of the penis 15 days after implantation of inflatable penile prosthesis; B: Repeated local instillations of antibiotic; C: Complete resolution after 20 days.

Figure 12. Malleable penile prosthesis implantation and plaque grafting in a 42 years old patient with Peyronieâ&#x20AC;&#x2122;s disease. Initial leakage of serous-corpusculated secretion.

Repeated instillations of antibiotic with complete resolution.

Figure 13. Malfunction of inflatable penile prosthesis.

A: Aneurism of inflatable penile prosthesis AMS700Ultrex cylinder; B: Leakage of fluid from one cylinder of AMSHydroflex; C: Rupture of the outer layer of AMS700Ultrex; D: Leakage of fluid from one cylinder of AMS700.

Case 3 A 62 years-old patient with DM and CAD, in 2004 was submitted to AMS700 implant. Usual antibiotic treatment was administered. After 15 days the patient begun to complain pain at the basis of the penis, septic fever, and a yellowish lesion at the basis of the penis.

A yellowish creamy purulent secretion begun to drain.

When we inflated the cylinders the volume of purulent fluid drain increased.

Suspecting an infection of the IPP we suggested to the patient the possibility to explant the IPP. The patient, mainly for economical reasons, refused such an immediate hypothesis. We started with a local injection of iodopovidone and gentamicin 150 mg. After injecting fluid we inflated the cylinders forcing the fluid to exit.

We repeated this maneuver several times, every 8 hours.

The quantity of drain was reduced and we injected only gentamicin. After 12-15 days the skin opening closed and we maintained the cylinders fully inflated for 10 days without secretion, fever and pain. We had the possibility of checking the patient regularly till 2012 (Figures 11A, B, C).

Case 4 A 45 years-old patient presented with PD, curvature and ED. He was submitted to subcoronal incision, excision of the plaque, heterologous grafting and MPP. After 2 weeks he developed fever, pain at the glans and pouring of purulent fluid. We organized an explant and in meanwhile, we decided to inject a solution of gentamicin and iodopovidone every 8 hours into the hole of the suture.

After one week, pain and fever were decreased and the fluid drainage stopped. After 2-3 days without secretion we closed the hole. (Figures 12A, B). After 2 years the patient is fully satisfied.

MALFUNCTION

and septic fever after 30 days. In few days, scrotal pump appeared outside with purulent secretion. We decided to remove the entire IPP on suspicion of contamination of the whole system. The patient for economical reasons refused a new IPP (Figure 10C).

We recorded malfunctions in 13/17 mono-component IPP (2 leakings of fluid from the cylinders, 3 ruptures of the outer layer and 8 ineffective pumps). In multi-component IPP we recorded aneurysmatic dilation (Figure 13A) of the cylinders in 2 AMS700Ultrex, 3 leakage of fluid at the cylinder level (Figure 13B, D), 3 ruptures of the connecting tubes and 4 ruptures on the outer layer (Figure 13C).

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REMOVAL We had to remove most (13/17; 76.4%) of single component IPP (AMS Hydroflex and Dynaflex), for malfunction. For the high percentage of malfunctions these prostheses have been retired from the market (19).

We explanted in only 2 patients the broken pump of IPP reconnecting the tubes and refilling the reservoir.

In 23/160 (14.3%) IPP the whole system was removed for malfunction or infections. In 15/168 (8.9%) cases we observed infections non treatable with medical therapy.

In 6/144 (4.1%) MPP and in 23/177 (12.9%) IPP we registered infections with subsequent removal of all parts of the IPP. In 2 pts we re-implanted the IPP after 3 months and MPP in 2 pts. In the last 3 years, probably due to the selection of the patients, the skill of the surgical team, the shortening of operating procedures and the improved prosthetic materials the number of complications has greatly reduced.

CONCLUSIONS The event of complications related to PPS is still present.

Our clinical and surgical experience confirms that with experience some complications tend to decrease as is the case of all surgical practices. Particularly, we never observed major complications reported in other series as perforations of adjacent organs (20). The problem of infections and malfunctions of IPP persists and could always lead to the removal of prostheses which for the patient and surgeon always represents a bad and sad defeat. We were able to verify that some technical or infectious complications could be resolved with a limited surgery without necessarily having to perform an explant.

We also believe that a close relationship between patient and surgeon is extremely important both to manage the course of the patient with penile prosthesis and to face and resolve possible complications.

penile implant infections, device reliability, and optimizing cosmetic outcome. Curr Urol Rep. 2014; 15:413-6.

9. Dhabuvala C. In vitro assessment of antimicrobial properties of rifampicin-coated Titan Coloplast penile implants and comparison with inhibizone. J Sex Med. 2010; 7:3516-9.

10. Lokeshwar SD, Madhusoodanan V, Kava B, Ramasamy R. A surgeon guide to various antibiotic dips available during penile prosthesis implantation. Curr Urol Rep. 2019; 20:11.

11. Christodoulidou M, Pearce I. Infection of penile prostheses in patients with diabetes mellitus. Surg Infect. 2016; 17:2-8.

12. Jani K, Smith C, Delk JR 2nd, et al. Infection retardant coating impact on bacterial presence in penile prosthesis surgery: a multicenter study. Urology. 2018; 119:104-8.

13. Madiraju SK, Wallen JJ, Rydelek SP, et al. Biomechanical studies of the inflatable penile prosthesis: a review. Sex Med Rev. 2019; 7:369-75.

14. Wilson SK, Delk JR. Historical advances in penile prostheses. Int J Imp Res. 2000; 12:101-7.

15. Whelan P, Levine LA. Additional procedures performed at time of penile prosthesis implantation: a review of current literature. Int J Impot Res 2020; 32:89-98.

16. Pozza D, Pozza M, Musy M, Pozza C. 500 penile prostheses implanted by a surgeon in Italy in the last 30 years. Arch Ital Urol Androl. 2015; 87:216-21.

17. Hebert KJ, Kohler TS. Penile prosthesis infection: myths and realities. World J Mens Health. 2019; 37:276-87.

18. Kramer A, Goldmark E, Greenfield J. Is a closed-suction drain advantageous for penile implant surgery? The debate continues. J Sex Med. 2011; 8:601-12.

19. Anafarta K, Yaman O, Aydos K. Clinical experience with Dynaflex penile prostheses. Urology. 1998; 52:1098-100.

20. Deger M, Kizilgok B, Aridogan IA, Tansug MZ. Management of erosion of inflatable penile prosthesis reservoir into bladder. A different approach. Arch Ital Urol Androl. 2019; 91:43-45.

REFERENCES 1. Pearman RO. Insertion of a silastic penile prothesis for the treatment of organic sexual impotence. J Urol. 1972; 107:802-6.

2. Scott FB, Bradley WE, Timm GW. Management of impotence erectile. Use of inflatable prostheses. Urology. 1973; 2:80-82.

3. Small MP, Carrion HM, Gordon JA. Small Carrion penile prosthesis. New implant for management of impotence. Urology. 1975; 5:479-86.

4. Pozza D, Rossello Barbara M, Carrion H. L’utilizzazione del Cavernotomo di Carrion-Rossello per l’impianto di protesi intracavernose. Acta Urol Ital. 1993; 2:87-8.

5. Ehlers M, McCormick B, Coward RM, Figler BD. Innovating incrementally: development of the Modern Inflatable Penile Prosthesis. Curr Urol Rep. 2019; 20:4.

6. Scherzer ND, Dick B, Gabrielson AT, Alzweri LM, Hallstrom WJG. Penile prosthesis complications: planning, prevention, and decision making. Sex Med Rev. 2019; 7:349-59.

7. Bayrak O, Erturhan S, Seckiner I, et al. Comparison of the patient’s satisfaction underwent penile prosthesis; Malleable versus Ambicor: single center experience. Arch Ital Uro Androl. 2020; 92:25-9.

8. Mulcahy JJ, Kramer A, Brant WO, et al. Current management of

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Correspondence Diego Pozza, MD (Corresponding Author) Studio di Andrologia e di Chirurgia Andrologica Via B. Gozzoli, 82C, 00142 Roma (Italy) diegpo@tin.it Andrea Marcantonio, MD Via B. Gozzoli, 82, 00142 Roma (Italy) md.andreamarcantonio@gmail.com Augusto Mosca, MD Via Tuscolana 2, 00040 Frascati (Italy) moscaugusto@gmail.com Carlotta Pozza, MD Via B. Gozzoli, 82, 00142 Roma (Italy) carlotta.pozza@gmail.com

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DOI: 10.4081/aiua.2020.4.309

ORIGINAL PAPER

Mini invasive approaches in the treatment of small renal masses: TC-guided renal cryoablation in elderly Oscar Selvaggio 1, Giovanni Silecchia 1, Matteo Gravina 2, Ugo Giovanni Falagario 1, Giovanni Stallone 3, Luca Macarini 2, Giuseppe Carrieri 1, Luigi Cormio 1, 4 1 University

of Foggia, Department of Urology and Organ transplantation, Foggia, Italy; of Foggia, Department of Radiology, Foggia, Italy; 3 University of Foggia, Department of nephrology, Foggia, Italy; 4 Department of Urology, Bonomo Teaching Hospital, Andria (BAT), Italy.

2 University

Summary

Background: Today, the goal of surgery is to achieve oncological efficacy with the lowest complication rate. Computed Tomography (CT)-guided cryoablation is proposed as a safe and effective technique. We report, our series of small renal masses treated with cryoablation in elderly (> 70 years).

Methods: From May 2014 to April 2019, 32 patients with median (IQR) age of 75.5 years (range 71-80) with small renal masses (< T1a) diagnosis, clinical anesthesia contraindications to nephron-sparing surgery or patientâ&#x20AC;&#x2122;s will previous informed consent have been selected at our Urology Department. All patients underwent CT-guided cryoablation, preceded by needle biopsy. The cryoablation consisted in a procedure with an argon/helium gas-based system under local anesthesia. The follow-up included CT abdomen at 3, 6 and 12 months. The definition of incomplete treatment was the persistence of the lesion contrast enhancement (CE) at the end of the scan; the definition of relapse was the appearance of the CE to the 6-month control CT. Results: The median follow-up was 30 months (IQR 1-59).

The median size of the tumor was 3.85 cm (IQR 1.6-4.5).

All patients underwent lesion biopsy resulting in diagnosis of Renal Cell Carcinoma (RCC) in 29 patients (90.7%) and oncocytoma in 3 patients (9.3%). A median of 2 cryoprobes (IQR 13) was used and 2/3 cycles of freeze-thaw of the duration of 10 minutes or 5 minutes were performed. Complications were: 3 asymptomatic transitional perirenal effusion, 2 lumbar pain well-controlled by analgesic drug. Hospital stay was 2 days (range 1-3). No case showed incomplete treatment and local relapse or metastates at the CT abdomen-pelvis with contrast medium at 12 months.

Conclusions: This study shows the efficacy and safety of percutaneous cryoablation of small renal masses in elderly population. The procedure is easy to perform, with low complication rates and well tolerated by the elderly patients.

KEY WORDS: Percutaneous renal cryoablation; Kidney cancer; Small renal masses; Elderly; Mini invasive.

Submitted 10 May 2020; Accepted 10 June 2020

INTRODUCTION

Extensive application of modern imaging techniques has led to more frequent incidental diagnosis of small renal masses (SMRs) (1-3) with an increasing incidence by an

average of 3% to 4% every year (3, 4). Kidney cancer represents today 3% of all tumors diagnosed in male and female over 70 years old (5).

A growing body of evidence support the importance of treatments preserving kidney function (6, 7).

Additionally, since 25% of SMRs are benign cortical tumors (eg. Oncocytoma and angiomyolipoma) and another 25% are indolent with limited metastatic potential (eg. Chromophobe, type 1 papillary renal cancer), several options for management of clinically localized renal masses have been reported, including active surveillance, thermal ablation and surgery that include radical and partial nephrectomy (8). Active surveillance is an option for patients presenting small renal masses (< 4 m, clinical stage T1a) with a low likelihood of aggressive malignancy, procedure-limiting comorbidity, and/or limited life-expectancy (9). Nephron-sparing surgery (NSS) is considered the gold standard treatment for renal cell carcinoma (RCC) preferred for lesions less than 7 cm in diameter (clinical stage T1) (9).

In order to of decrease pain, morbidity, kidney function damages, hospital stay, and operative time, various minimally invasive modalities for NSS have been evaluated (6, 7, 10-12). Thermal ablation, which may include cryoablation or radiofrequency ablation, may be used for small clinically localized masses (clinical stage T1a) and can be performed laparoscopically or percutaneously (9).

EAU guidelines suggest active surveillance, radiofrequency ablation and cryoablation for the treatment of elderly and/or comorbid patients with small renal masses, however the quality of the available data does not allow definitive conclusions regarding morbidity and oncological outcomes of cryoablation and radiofrequency ablation and the Strength rating of this recommendation remain week (9). The aim of this study was to present our initial experience in terms of efficacy and safety of CT-guided percutaneous cryoablation for small renal masses.

MATERIALS

AND METHODS

Study population After Istitutional review board approval we retrospectively reviewed our prospectively kidney cancer database to evaluate outcomes of patients treated with CT-

No conflict of interest declared.

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guided percutaneous cryoablation. The following inclusion criteria were used: tumor diameter < 4 cm (T1a); comorbidity or clinical anesthesia contraindications to nephron-sparing surgery; residual renal masses in patients already undergoing surgery; kidney solitary condition; informed consent. Exclusion criteria were lack of percutaneous access window, disease extending into renal vein or invading adjacent organs and tumor larger than 4 cm in a candidate for surgical treatment.

All patients were seen in the clinic before ablation, history was recorded, physical examination was performed, relevant baseline laboratory values were measured, and dual-phase renal CT imaging was performed. All patients were counseled regarding all the treatment options available, after that a written informed consent was obtained.

CT-guided percutaneous cryoablation All procedures were performed by the same team of urologists and interventional radiologists on a specific TC General Electric Medical System Brightspeed. All patients were premedicated intravenously with 2 g cefazolin and ciprofloxacin 400 mg versus cotrimoxazole 2 fl in the case of allergy. Patients were positioned prone or side, to facilitate probe insertion through a better percutaneous access window; for example, caused by descent of adjacent organs most often represented by bowel, on the CT bed and the ipsilateral flank was prepared and draped in a sterile fashion. A pre-procedural non-enhanced CT image was obtained to document tumor size and decide on access, number of probes and need for thermal protection for adjacent organs (hydrodissection). CT fluoroscopy was used to determine the optimum access site, with the help of a CT-mounted laser beam. The skin and underlying tissues were anesthetized with 10-15 ml of lidocaine 200 mg, then a tiny incision (2-3 mm) was made. Before percutaneous cryoablation, all the patients underwent CT-guided needle biopsy of the lesion according to the current recommendation and at least 2 good quality biopsy cores using an 18G needle were taken (9). The cryoprobes were then inserted according to preoperative plans in order to create an “iceball” that would cover the lesion and provide at least 5 mm of ablation beyond the tumor margins. The cryoprobe advancement toward the mass and the extent of the iceball was monitorated intermittently with CT fluoroscopy. The tip of probe was positioned through the mass until to distal inner border of the lesion. The operations were performed using Argon/helium gas-based system (Endocare, HealthTonics Inc., Austin TX, USA). Such system uses a compressed argon for freezing and compressed helium for active thawing. With two exceptions, in which 1.7 mm diameter cryoprobes were used, all procedures were performed with 2.4 mm diameter cryoprobes. The number of cryoprobes used varied as a function of the lesion’s size: 8 patients treated with 1 probe, 18 pts with 2 probes, 6 pts with 3 probes. In seven cases, we have had a non-target organ (usually colon) that was closer than 1 cm to the tumor margin. In these cases, a Chiba’s needle was inserted in the “fascia” of Gerota and sterile water, mixed to 5-7 cc of contrast medium, was infused to keep the non-target organ away from the iceball.

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Technical success was defined as completion of three ablation cycle: a 10-minutes freeze, 10-minutes active thaw and 10-minutes repeat freeze with the iceball covering the entire lesion and extending at least 5 mm beyond its border.

At the end of the procedure, a CT image with contrast medium was performed to evaluate the complete cover of the lesion and possible local bleeding. The definition of incomplete treatment is the persistence of the CE at the end of the same. The patient was transferred to the recovery area and kept under observation. A blood count was performed 6 hour after the procedure and on postop day 1 before discharge. Patients were discharged home unless overnight observation was deemed necessary as a result of complications or severity of symptoms.

Complications were recorded using the Clavien-Dindo Classification and Grade I and II complications were Follow-up visits Follow-up visits were scheduled at 3-, 6-, 12-, 18-, 24and 36- months after the procedure. A physical examination was performed along with measurement of relevant laboratory values. Additionally, a dual-phase renal CT study was obtained at each follow-up visit. In order to minimize X-Ray exposure follow-up images were acquired using a Low dose protocol (low kilovolt, low milliampere). Additionally, only sequences of the treatment region were taken during the procedure and at follow-up. All studies were read by the same interventional radiologist and compared to the baseline study. Nonenhancement of the cryolesion was considered the primary radiographic hallmark of successful cryoablation.

Response to treatment was based on tumor enhancement and size on sequential images. Complete lack of enhancement of a previously enhancing mass was considered complete response. Response based on tumor size was less reliable initially, as many masses did not change in size on the first 3 months imaging study despite a gradual decrease thereafter. The existence of enhancement areas in the residual tumor mass after 6 months was considered an indication of local failure.

Statistical analysis Outcomes of this study were cancer recurrence, metastasis and complications after percutaneous cryoablation.

Descriptive statistics was performed for the overall population. Continuous variables were reported as median and interquartile whereas categorical variables were reported as rates.

Statistical analyses were performed using Stata-SE 14 (StataCorp LP, College Station, TX, USA).

RESULTS

Preoperative characteristics of the study population are shown in Table 1.

Final population included 20 men and 12 women with a median (IQR) age of 75.5 years (range 71-80 years) treated at our institution between May 2014 to April 2019.

The median (IQR) size of the tumors was 3.85 cm (range 1.6-4.5). Of the 32 treated patients, 30/32 (93.7%) had an incidentaloma and 2/32 (6.3%) were post-radiofre-

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Table 1.

Patient demographics and tumor characteristics of 32 patients.

Variable Age, years Tumor diameter, cm Gender, n (%) Male Female Side Right Left ASA score n (%) 1 2 3 Tumor location, n (%) Upper Middle Lower Diagnosis, n (%) Incidentaloma Radiofrequency failure

Cryoablation n = 32 75.5 (71-80) 3.85 (1.6-4.5) 20 (62.5%) 12 (37.5%) 14 (43.7%) 18 (56.3%) 6 (18.8%) 21 (65.6%) 5 (15.6%) 8 (25.0%) 11 (34.4%) 13 (40.6%) 30 (93.7%) 2 (6.3%)

Table 2.

Perioperative and postoperativecharacteristics.

Variable Hospital stay (d) Hystological outcomes to biopsy, n (%) Clear cells RCC Chromophobe RCC Type I Papillary RCC Oncocytoma Follow-up, months Complications, n (%) Minor Major Recurrence of tumor Metastasis

Cryoablation n = 32 2 (1-3) 20 (62.5%) 3 (9.3%) 6 (18.7%) 3 (9.3%) 30 (8-59) 5 (15.6%) 0 (0.0%) 0 (0.0%) 0 (0.0%)

quency ablation relapses. Biopsy histological findings were the following: clear cell Renal Cell Carcinoma (RCC) 20/32 (62.5%); chromophobe RCC 3/32 (9.3%); Type 1 papillary 6/32 (18.7%); oncocytoma 3/32 (9.3%) (Table 2).

An average 2 cryoprobes (IQR: 1-3) have been used, depending on the size of the tumor, and were performed 2 cycles of freeze-thaw of the duration of 10 minutes each in 25 patients, and 3 cycles of 5 minutes each in 7 patients. 1.7 and 2.4 mm cryoprobes were used to minimize injury to the colon, we used thermal protective maneuvers in seven cases (21.8%). There were no cases of non-target organ damage. Complications were: 3 effusion not clinically significant, transitional and perirenal which subsided spontaneously without intervention, 2 regressed back pain with analgesic therapy. No patient developed ablation related infection such as renal abscess, pyelonephritis or sepsis. Percutaneous cryoablation of small renal cell carcinoma was accomplished safely in all 32 cases. No episodes of urinary extravasation, significant gross hematuria or urinary obstruction occurred. No other major operative complications were encountered. Median hospital stay was 2 days (IQR: 13). Median follow-up after the procedure was 30 months (IQR: 8-59); In none case, incomplete treatment and local relapse or metastases at CT abdomen-pelvis with contrast medium at 3, 6 and 12 months was detected.

None of the 32 patients had clinical evidence of recurrent disease (confirmed with no enhancement within resolved tumor masses) at last follow-up. Median tumor size before treatment was 3.16 cm (IQR: 1.6 to 5.5) (Figure 1).

After treatment, cryo-lesions size continued to decline over time. The relative reduction of the lesion size compared to preoperative values was 21.77% at 3-month follow-up (median size: 2.47 cm; IQR: 0.9 to 4.8), 31.93% at six-month follow-up (median size: 2.2 cm; IQR: 0.6 to 4.5 cm) and 45.91% at one-year follow-up (median size: 1.71 cm; IQR: 0.6 to 3.5 cm).

Figures 2 and 3 show the gradual decrease in the larger diameter of the lesions and the corresponding decrease in terms of percentage compared to the initial dimensions.

The temporary increase in diameter of the cryolesions immediately following cryoablation is most likely due to edema in the tissue surrounding the tumor. The levels of postoperative creatinine were identical with preoperative levels.

Figure 1.

Tumor in the middle right renal before cryoablation a); subsequent treatment b); lesion after 6 months c); lesion after 1-year d).

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O. Selvaggio, G. Silecchia, M. Gravina, U.G. Falagario, G. Stallone, L. Macarini, G. Carrieri, L. Cormio

Figure 2.

Tumor size variation evaluated using CT scans at 3, 6, 12 months of follow-up.

The figure represents tumor size of 24 patients with a follow-up of at least 12 months. Each group of three columns represents a patients and age is specified below.

Figure 3.

Percentage variations in the major diameter of injuries.

DISCUSSION

The choice between conservative or radical treatment for organ confined RCC in men over 70 years is a debated topic. In the last decades, the standard of care has slowly been expanding from radical nephrectomy to include robotic partial nephrectomy, laparoscopic nephrectomy, laparoscopic ablation and finally percutaneous ablation (14, 15). Several questions such as efficacy and safety treatment, life expectancy, and cancer-specific survival advantage need to be taken into account. Image guided percutaneous ablation is especially attractive for patients with small renal masses and a solitary kidney or multiple tumors, non-surgical candidates, pre dialysis patients and patients with diseases that may cause multiple RCC as von Hippel-Lindau disease or hereditary RCC. Limited data are currently available in literature for assessing the role of percutaneous renal cryoablation. Silverman et al. described a large number of percutaneous renal cryoablations under general anesthesia with MRI guidance (16).

Image guidance for percutaneous renal cryoablation is alternated between MRI, CT, and ultrasound (US). In the

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case of MRI, the question is that system is expensive and limited in use but the ability of real time guidance and visualization of the iceball in multiple planes are the advantage, allowing the operator to achieve the safety margins of the cryolesion. Bassignari et al. reported the practicability of US-guided percutaneous renal cryoablation to aim for future performance of this treatment by a urologist alone without the interventional radiologist because urologists have ultrasound experience (17). Results of this study from our cohort of patients showed that CT-guided percutaneous cryoablation resulted in complete response for lesions as large as 4 cm. In all cases, it has a high efficacy rate, and its few complications are not only similar to those of other treatment modalities, but also appear to be reversible.

Percutaneous cryoablation with use of CT has the benefit of delaying/avoiding the end-stage renal disease by causing less renal injury. Another advantage is to perform percutaneous cryoablation under spinal anesthesia avoiding the major complications or side effects that could derive from a general anesthesia considering that many patients have plurimorbidity as well as advanced age. Other advantages of percutaneous cryoablation are faster recovery, repeatable, and lower cost. Among all percutaneous ablative techniques, cryoablation has gained particular interest for small kidney cancer for painless during the treatment and it provides real-time image feedback of the ablation zone, especially when performed with CT guidance.

Furthermore, cryoablation is less likely to result in significant treatment-related injury because the extracellular matrix is less permanently destroyed by freezing, thereby allowing for epithelial regrowth and repair. The study pointed out that percutaneous cryotherapy provides, in elderly patients with small kidney cancer, an acceptable efficacy and safety in the absence of recurrence of disease and risk of metastasis in the short to medium follow-up (median follow-up: 30 months). This result is particularly encouraging considering that Andrews et al. (18) highlights that there are no statistically significant differences in terms of local recurrence, metastases and risk of death from RCC among partial nephrectomy, radiofrequency ablation and cryoablation for cT1a patients. Pierorazio et al. (8) shows similar cancer specific survival among partial nephrectomy and thermal ablations (radiofrequency and cryoablation), with some differences in renal functional and peri/postoperative outcomes that should be considered when choosing a management strategy, particularly in elderly patient. Kitley et al. demonstrated in cT1a that cryotherapy had a lower overall survival than partial nephrectomy however at multivariable analisys adjusting for age and Charlson Comorbidity Index, the rates of survival for the two treatments were similar (19).

Additionally, overall survival of patients based on tumor size prove similar rates of survival for tumors smaller than 2 cm. To our knowledge, these data suggest that elderly men with small renal cancer can take advantage from this local treatment. This is of clinical relevance in view of the

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TC-guided renal cryoablation in elderly

fact that, as mentioned above, partial and ever more radical nephrectomy is usually not offered to elderly patients due to the risk of treatment-related complications, though their occurrence, like for most surgical procedures, is much linked to case volume (20). At the end, our data is similar to those published by Atwell et al., who reported a technical success and efficacy rate of 95% with a median follow-up of 8 months (21). Several guidelines and commentaries have highlighted the need for longer follow-up of ablation patients. Our study has limitations: all patients were referred from a urology department so may have introduced a selection bias. Additionally, even though the behavior of RCC is unpredictable, it is generally as low-growing cancer, and longer follow-up would be required to confirm the high degree of efficacy we documented in the present study.

CONCLUSIONS

Published preliminary results have shown that imageguided percutaneous cryoablation for small renal cancer is probably as safe and effective as laparoscopic cryoablation.

Results of this study confirm the very high efficacy rate and acceptable morbidity associated with this CT-guided percutaneous cryoablation. Nonetheless, CT-guided percutaneous cryoablation offers compelling advantages compared with other treatment modalities, particularly in elderly patients, and has shown high efficacy rates and low risk for minor/major complications.

REFERENCES

1. Jayson M, Sanders H. Increased incidence of serendipitously discovered renal cell carcinoma. Urology. 1998; 51:203-5.

2. Homma Y, Kawabe K, Kitamura T, et al. Increased incidental detection and reduced mortality in renal cancer--recent retrospective analysis at eight institutions. Int J Urol. 1995; 2:77-80.

3. Decastro GJ, McKiernan JM. Epidemiology, clinical staging, and presentation of renal cell carcinoma. Urol Clin North Am. 2008; 35:581-92.

4. Saad AM, Gad MM, Al-Husseini MJ, et al. Trends in renal-cell carcinoma incidence and mortality in the United States in the last 2 decades: A SEER-based study. Clin Genitourin Cancer. 2019; 17:4657 e5.

5. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68:394-424.

6. Falagario UG, Martini A, Pfail J, et al. Does race impact functional outcomes in patients undergoing robotic partial nephrectomy?

Transl Androl Urol. 2020; 9:863-869 7. Martini A, Falagario UG, Cumarasamy S, et al. Defining risk categories for a significant decline in estimated glomerular filtration rate after robotic partial nephrectomy: implications for patient follow-up. Eur Urol Oncol. 2019:S2588-9311(19)30104-X. 8. Pierorazio PM, Johnson MH, Patel HD, et al. Management of renal masses and localized renal cancer: systematic review and meta-analysis. J Urol. 2016; 196:989-99.

9. Ljungberg B, Albiges L, Bensalah K, et al. EAU Guidelines on Renal Cell Carcinoma 2018. European Association of Urology Guidelines 2018 Edition, Vol. presented at the EAU Annual

Congress Copenhagen 2018. Arnhem, The Netherlands European Association of Urology Guidelines Office, 2018.

10. Gill IS, Novick AC, Soble JJ, et al. Laparoscopic renal cryoablation: initial clinical series. Urology. 1998; 52:543-51.

11. Gill IS, Desai MM, Kaouk JH, et al. Laparoscopic partial nephrectomy for renal tumor: duplicating open surgical techniques.

J Urol. 2002; 167:469-7.

12. Ukimura O, Kawauchi A, Fujito A, et al. Radio-frequency ablation of renal cell carcinoma in patients who were at significant risk.

Int J Urol. 2004; 11:1051-7.

13. 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.

14. Corongiu E, Grande P, Di Santo A, et al. Safety and efficacy of retroperitoneal sutureless zero ischemia laparoscopic partial nephrectomy for low nephrometry score masses. Arch Ital Urol Androl. 2019; 91:157-162.

15. Tiscione D, Cai T, Luciani LG, et al. Sutureless laparoscopic partial nephrectomy using fibrin gel reduces ischemia time while preserving renal function. Arch Ital Urol Androl. 2019; 91:30-34.

16. Silverman SG, Tuncali K, vanSonnenberg E, et al. Renal tumors: MR imaging-guided percutaneous cryotherapy--initial experience in 23 patients. Radiology. 2005; 236:716-24.

17. Bassignani M, Moore Y, Watson L, Theodorescu D. Pilot experience with real-time ultrasound guided percutaneous renal mass cryoablation. J Urol. 2004; 171:1620-3.

18. Andrews JR, Atwell T, Schmit G, et al. Oncologic Outcomes Following Partial Nephrectomy and Percutaneous Ablation for cT1 Renal Masses. Eur Urol. 2019; 76:244-51.

19. Kitley W, Sulek J, Sundaram C, Bahler CD. Treatment trends and long-term survival associated with cryotherapy and partial nephrectomy for small renal masses in the National Cancer Database using propensity score matching. J Endourol. 2019; 33:408-14.

20. Kandasami SV, Mamoulakis C, El-Nahas AR, et al. Impact of case volume on outcomes of ureteroscopy for ureteral stones: the clinical research office of the endourological society ureteroscopy global study. Eur Urol. 2014; 66:1046-51 21. Atwell TD, Farrell MA, Callstrom MR, et al. Percutaneous cryoablation of 40 solid renal tumors with US guidance and CT monitoring: initial experience. Radiology. 2007; 243:276-83.

Correspondence Oscar Selvaggio, MD oscarsel@libero.it Giovanni Silecchia, MD Ugo Giovanni Falagario, MD Giuseppe Carrieri, MD Luigi Cormio, MD University of Foggia, Department of Urology and Organ Transplantation Viale Pinto 1, 71100 Foggia (Italy) Matteo Gravina, MD Luca Macarini, MD University of Foggia, Department of Radiology, Foggia, Italy Giovanni Stallone, MD University of Foggia, Department of Nephrology, Foggia, Italy

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DOI: 10.4081/aiua.2020.4.314

ORIGINAL PAPER

Physiopathology of the diabetic bladder Tatiana Bolgeo 1, Antonio Maconi 1, Marinella Bertolotti 1, Annalisa Roveta 1, Marta Betti 1, Denise Gatti 1, Carmelo Boccafoschi 2 1 Azienda 2 Clinica

Ospedaliera SS. Antonio e Biagio e C. Arrigo, Alessandria, Italy; Città di Alessandria Policlinico di Monza, Alessandria, Italy.

Summary

Objective: To investigate the incidence of diabetic cystopathy in relation to age, gender, type of diabetes, duration of diabetic disease and clinical evidence of peripheral neuropathy and to analyze the physiopathology of the various forms of diabetic cystopathy due to sensory impairment, motor-sensory impairment, motor impairment and hyperreflexia.

Materials and methods: In a retrospective multicenter cohort study the medical records of a cohort of 126 diabetic patients with (128 patients) or without (48 patients) urological symptoms were analyzed. Patients were observed at the Città di Alessandria Clinic of Policlinico di Monza and/or at the outpatient clinic of Alessandria Hospital from June 2018 to June 2020. The study excluded patients with central and/or peripheral neuropathy, spina bifida (mylomeningocele or meningocele) or spina bifida occulta; with persistent urinary infections; in anticholinergic treatment for enteric dysfunctions; in medical treatment for cervical-prostatic-urethral obstruction; with vaginal and/or rectal prolapse of II, III, IV degree; with previous spinal or pelvic surgery including radical prostatectomy, Wertheim hysterectomy or colorectal surgery. All the patients were studied with computed tomography (CT) scan of the urinary tract, voiding cystourethrography (VCUG), uroflowmetry, cystomanometry with intrinsic pressure assessment and compliance evaluation, electromyography (EMG) of the anal sphincter, pressure flow analysis, urethral pressure profile and, when advised, pharmacological tests.

Results: Out of 126 diabetic patients, 48 did not show any signs or symptoms of urine voiding dysfunction; 30 were men and 18 women with an average age of 62.6 years; 20 had type I diabetes and were in treatment with insulin and 28 type II diabetes treated with oral hypoglycemic medication.

The remaining 78 patients (48 men and 30 women), with an average age of 64.8 years, presented urological symptoms; 31 had type I diabetes and 47 had II type diabetes.

Conclusions: Diagnosis of the various forms of diabetic cystopathy and early treatment decreases complications and consequently accesses to outpatient facilities and hospital admissions, resulting in an improved quality of life.

KEY WORDS: Diabetic neuropathy; Neurological bladder; Diabetes mellitus; Urodynamics.

Submitted 13 October; Accepted 16 November

INTRODUCTION

Changes in diabetic patients’ bladder functions are part of the wider field of autonomic diabetic neuropathy, but

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from the neuropathophysiological point of view, the importance of the condition is not yet entirely specified.

Diabetic neuropathy is the most common and disturbing complication of diabetes, it leads to the highest morbidity and mortality rates, therefore producing an enormous economic burden in treatments. Clinical evaluation and treatment of diabetic peripheral neuropathy has multiple options and patients with diabetic neuropathy should be screened for autonomic neuropathy, as there is a high degree of coexistence of the two complications (1).

Nevertheless, this disease is also of great interest in relation to the high morbidity and occasional fatal consequences (2). This assumption motivated the investigation to verify the rate of diabetic cystopathy in relation to the type of diabetes and the correlation or not with a neuro-urological subjective symptomatology (3). While diabetes as a metabolic disease is of easy recognition, diabetic cystopathy develops insidiously and symptoms may not appear until the disease is already in an advanced stage (1). The consequences of diabetes on bladder function have been known since 1864 (4), but subsequently in literature often conflicting data were reported, due to both the selection of patients according to different diabetic and urological criteria, as to the occasional diversity in definitions of diabetic cystopathy, not always compliant and identical. In fact, the incidence of “bladder dysfunction” in diabetic patients varies from 37% to 67% (5). Before presenting the study and making assessments on the incidence of diabetic cystopathy it is relevant to consider some predictive factors such as age, gender, type and degree of diabetes, factors that may have caused a (unintended) patient selection, linked to the characteristics of the study population. Only with this foresight, it will be possible to attempt comparative assessments between the various authors who have so far treated the problem. Some studies include in the definition of diabetic cystopathy sensory impairment (1), others sensory and sensory-motor impairment (6), others in addition to the previous also consider the apparently isolated motor impairment of the detrusor (hyperreflexia, contractility devoid) without compulsory and prevailing sensory impairment (7).

In the present case study, patients suffering from diabetic cystopathy (in the broad interpretation of the term as diabetic autonomic neuro-bladder) were considered as patients that had sensitive impairment, sensitive-motor impairment, isolated motor impairment and detrusor “hyperreflexia”. Particular attention was paid to identify No conflict of interest declared.

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Diabetic bladder

other coexistent illnesses and diseases, especially the presence of cervical-prostatic-urethral obstructions. The diagnostic tools used to evaluate the type of diabetic cystopathy include urodynamic evaluation (uroflowmetry, cystomanometry with intrinsic pressure assessment and compliance evaluation, electromyography (EMG) of the anal sphincter, pressure-flow study, urethral pressure profile and when advised pharmacological tests), ultrasound and computed tomography (CT) scan of the urinary tract and voiding cysto-urethrography.

When assessing the association between autonomic neuropathy and cervical-prostatic obstruction, differential urodynamic diagnosis can be difficult and maybe sometimes even impossible. Conversely after the removal of the obstruction (clinically and urodynamically proven) it is easier to evaluate bladder sensitivity and residual detrusorial contraction function associated to diabetic cystopathy. During follow up, ultrasound examinations were used to assess the post-void residue. Patients were separately evaluated according to the type of diabetes and time-period of onset or first clinical diagnosis. From literature, it does not emerge a precise nosology of diabetic neuropathies and even less of diabetic cystopathy that was generically considered as an alteration of bladder function that can be independent or linked to autonomic visceral neuropathy.

The aim of this study was to assess in a cohort of patients the incidence of the above described bladder dysfunctions (diabetic cystopathy) in relation to predictive factors such as age, gender, type and timing of diabetic onset.

METHODS

In this retrospective multicentre cohort study, the clinical records of 126 diabetic patients treated at â&#x20AC;&#x153;CittĂ di Alessandria Clinicâ&#x20AC;? and/or at out-patient clinic of the Alessandria Hospital from June 2018 to June 2020 were reviewed.

Exclusion criteria included: patients with central and/or peripheral neuropathy (Parkinson. multiple sclerosis, stroke, etc.); patients with Spina Bifida (mylomeningocele or meningocele) or Spina Bifida Occulta; patients with persistent urinary infections; patients in anticholinergic treatment for enteric dysfunctions; patients in medical treatment for cervical-prostatic-urethral obstruction; patients with vaginal and/or rectal prolapse of II, III, IV degree; patients with previous spinal or pelvic surgery including radical prostatectomy, Wertheim hysterectomy or colorectal surgery.

RESULTS

Out of the 126 diabetic patients observed, 48 did not show signs or symptoms of dysfunctional voiding; 30 were men and 18 women; the average age was 62.2 years; 20 presented type I diabetes and were on treatment with insulin and 28 had type II diabetes and were on oral hypoglycemic treatment. The remaining 78 patients showed urological symptoms; 48 were men and 30 women; average age was 64.8 years; 31 presented type I diabetes and 47 type II diabetes.

The 78 diabetic patients with urological symptoms were

Table 1.

Results of urodynamic evaluation in patients with diabetes type I and II. Urodynamic results Sensory impairment Motor - Sensory impairment Motor impairment Hyperreflexia without obstruction Obstruction Normal Totale

Type I diabetes 11 5 5 1 22 4 5 31

Type II diabetes 12 5 6 8 31 13 3 47

Tot 53

Tot 78

divided into subgroups according to the type of diabetes and the presence or not of diabetic cystopathy that was differentiated in its various forms by urodynamic evaluation (Table 1).

Sensory impairment was identified in 11 patients with type I diabetes and in 12 patients with type II diabetes (a prostatic obstruction not pharmacologically treated was associated in 2 patients with type I diabetes and in 3 patients with type II diabetes, respectively). A mixed motor-sensory impairment was identified in 5 patients with type I diabetes and in 5 patients with type II diabetes (in 2 of the latter, a non-pharmacologically treated cervical-prostatic obstruction was also identified). Isolated motor impairment without sensory implication were identified in 5 type I diabetic patients and in 6 type II diabetic patients (in 1 of the latter a non-pharmacologically treated cervical-prostatic obstruction was also present).

In total, the association between diabetic cystopathy and cervical-prostatic-urethral obstructive disease was present, in 8 patients. The diagnosis of bladder outlet obstruction was conveyed on clinical and radiological data, pressure flow studies and urethral pressure profilometry (UPP), although in presence of hypocontractility or acontractility of the detrusor the flow-pressure relationship was not very significant. In 5 out of 8 cases, postvoiding residue was more than 10% (sign of decompensation). In these cases the presence of neuropathy was outstanding because when they were urodynamically studied after the removal of the cervical-prostatic obstruction hypo-contractility or a-contractility of the detrusor responded to treatment with parasympatheticmimetic drugs.

Detrusor hyperreflexia (with unstable contractions but with normal urethral resistances) was present in 1 patient with type I diabetes and in 8 type II diabetic patients. Urodynamic examination was essential to identify this group, because it allowed to exclude obstructive anatomical and/or functional factors.

The urodynamic examination also played an important role in evaluating a group of 17 patients with cervicalprostatic-urethral obstruction without any sign of diabetic cystopathy, these patients evidenced normal bladder sensitivity but detrusor hyper-contractility.

In 8 other patients (5 with type I and 3 with type II diabetes) the urodynamic evaluation did not identify any impairment allowing to consider these patients as normal for bladder function.

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T. Bolgeo, A. Maconi, M. Bertolotti, A. Roveta, M. Betti, D. Gatti, C. Boccafoschi

Altogether, diabetic cystopathy was present in 71% (22/31) of patients with type I diabetes and 66% (31/47) of patients with type II diabetes.

Peripheral somatic neuropathy was clinically present in 20 out 78 patients with urological symptoms. Fifteen of these (75%) also had diabetic cystopathy, while only 65% of the remaining 58 patients without clinically detectable signs and symptoms of somatic neuropathy, evidenced bladder dysfunctions indicative of diabetic cystopathy. Only in 15 of patients with diabetic cystopathy (about 28%) a peripheral somatic neuropathy was clinically demonstrated.

To evaluate the relationship between the duration of diabetic disease and the incidence of autonomic cystopathy, the patients included in the present study, were divided into two groups according to whether the diabetic disease had been diagnosed for less than 5 years (28 patients) or more than 5 years (50 patients).

The average age of the two groups was not significantly different being respectively 62 and 66 years.

Of the recently diagnosed patients, 16 out of 28 (57%) presented diabetic cystopathy, while 37 out of 50 (74%) of the remaining with long-lasting diabetes showed signs of cystopathy.

In 37/53 (70%) of the patients with diabetic cystopathy, the diabetic disease was present from more than 5 years.

Figure 1.

Urodynamic trace of a case of diabetic cystopathy with impairment restricted only to the sensory pathways (modified

by Boccafoschi C, Maurel A Appunti sui parametri e le metodiche in urodinamica. Minerva Medica; 1986)

Figure 2.

Urodynamic trace in a case of diabetic cystopathy with impairment of the motor-sensory pathways (modified by Boccafoschi C, Maurel A Appunti sui parametri e le metodiche in urodinamica. Minerva Medica; 1986)

DISCUSSION

The multiple aspects of the diabetic bladder can be due to both the variety of neurological impairments specific of the disease that affect the nervous system at various levels, as to the altered pathophysiology of the organ affected by neuro-impairment (8). The autonomic and somatic diabetic neuropathy has probably a multifactorial origin. The multiplicity of locations and extent of impairment can therefore explain why there are different types of diabetic neurological bladder (9).

In our case study of diabetic patients with urological symptoms, a neurogenic bladder dysfunction was identified in 66% of cases.

The total of the patients included 23 patients who presented exclusively sensory impairment, 10 patients with motor-sensory impairment, 11 patients with exclusive motor impairment and 9 patients with hyperreflexia (without obstruction) (Figures 1-4).

Seventeen of the remaining patients presenting with urological symptoms (22%) had cervical-prostatic obstruction and 8 patients (10%) were urodynamically normal.

Diabetic cystopathy, as neurogenic bladder dysfunction caused by autonomic diabetic neuropathy, occurs with remarkable frequency (42% of the 126 diabetic patients studied) particularly if urological symptoms are present (68% of this group of 78 patients).

In our series, type of diabetes (insulin dependent versus non-insulin dependent) was not associated with an higher risk of diabetic cystopathy, that was observed in 71% of symptomatic patients with type I diabetes and 66% of symptomatic patients with type II diabetes.

Consequently, it seems that the insulin dependence of diabetes is not the determining factor of onset of autonomic cystopathy. On the contrary, Frimodt-Møller (10),

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Figure 3.

Urodynamic trace in a case of diabetic cystopathy with impairment restricted only to the motor pathways (modified by Boccafoschi C, Maurel A Appunti sui parametri e le metodiche in urodinamica. Minerva Medica; 1986).

Figure 4.

Urodynamic trace in a case of diabetic cystopathy with detrusor hyperreflexia (modified by Boccafoschi C, Maurel A Appunti sui parametri e le metodiche in urodinamica. Minerva Medica; 1986).

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evaluating a different series, obtained different results showing a higher incidence of cystopathy in insulin dependent diabetics (48%) than in diabetics on oral hypoglycemic treatment or treated only with diet (25%).

Conversely, their series was not comparable with our series because of lower mean age of patients, higher prevalence of patients treated with insulin (80%) and longer duration of the diabetic disease.

The most relevant neurological disease related to diabetes in addition to autonomic neuropathy is peripheral somatic neuropathy, with the association between diabetic cystopathy and peripheral neuropathy reported in percentages varying from 14% to 80% (11-13).

The association between peripheral neuropathy and diabetic cystopathy was demonstrated in 19% of the cases with symptomatic diabetes. The rate of cystopathy was high in neuropathic patients (75%) but this was not true for the opposite. In fact, only 28% of patients with diabetic cystopathy showed clinically demonstrable peripheral neuropathy as if the impairment of the visceral autonomic nervous system precedes in time that of the peripheral autonomic system or that of the somatic nerves.

This is confirmed by the data relating the rate of cystopathy (and neuropathy) and the duration of the diabetic disease, especially if it is above 5 years. Cystopathy is in fact, present in 74% of diabetic patients that have been afflicted with the disease for more than 5 years, compared to only 57% of the patients who have been afflicted with diabetes for less than 5 years.

CONCLUSIONS

In literature, up to the present day, all the studies have addressed symptomatic and non-symptomatic diabetic patients from an urological perspective.

Urodynamic techniques can successfully study the pathophysiology of the diabetic bladder and allow identifying four types of diabetic cystopathy: sensory pathway impairment, motor-sensory pathway impairment, motor pathway impairment and impairment to control detrusorial reflex resulting in hyperreflexia. The urodynamic evaluation can also identify cases of simple cervical-prostatic obstruction without signs of diabetic cystopathy.

Nevertheless, particular problems arise when there is an association between diabetic cystopathy and cervical-prostatic-urethral obstruction. The urodynamic evaluation of detrusor contractility function, urethral function and bladder sensitivity makes it possible to convey a precise diagnosis, even if in a number of cases it becomes necessary to repeat the test after having surgically removed the cervical-prostatic-urethral obstruction. In the assessment of bladder sensitivity, the urodynamic evaluation is limited and it may be useful to integrate it with the measurement of the threshold of electrical perception or with the study of evoked potentials. The complexity of nerve structures that control bladder functioning and the possibility that diabetes can impair them with multiple mechanisms (dis-metabolic, toxic, micro- or macro- angiopathic) and at multiple levels of the central and peripheral nervous system, makes questionable the claim that the impairment responsible for diabetic cystopathy is due exclusively to peripheral impairment. Conversely, being

central impairment alone not confirmed, mixed forms should be accepted as the more frequent.

In the future, it could be worthwhile the use of dynamic brain Magnetic Resonance studies.

These results may have clinical applicability in identifying patients with diabetic cystopathy and guide patient counselling with treatment decision-making.

REFERENCES

1. Feldman EL, Callaghan BC, Pop-Busui R, et al. Diabetic neuropathy. Nat Rev Dis Primers. 2019; 5:42.

2. Deli G, Bosnyak E, Pusch G, et al. Diabetic neuropathies: diagnosis and management. Neuroendocrinology. 2013; 98:267-80.

3. Ziegler D. Painful diabetic neuropathy: treatment and future aspects. Diabetes Metab Res Rev. 2008; 24 Suppl 1:S52-7.

4. Tanik N, Tanik S, Albayrak S, et al. Association between overactive bladder and polyneuropathy in diabetic patients. Int Neurourol J. 2016; 20:232-239.

5. Duby JJ, Campbell RK, Setter SM, et al. Diabetic neuropathy: an intensive review. Am J Health Syst Pharm. 2004; 61:160-73.

6. Bossi L, Caffaratti E. Bladder complications in neuropathic diabetic patients. Clinical and radiological study. Minerva Radiol.

1968; 13:40-7.

7. Bradley WE. Cerebro-cortical innervation of the urinary bladder.

Tohoku J Exp Med. 1980; 131:7-13.

8. Bolgeo T. Caring for bladder dysfunctions in patients with Parkinsonâ&#x20AC;&#x2122;s disease. Arch Ital Urol Androl. 2011; 83:112-5.

9. Boccafoschi C, Maurel A. Appunti sui parametri e le metodiche in urodinamica. Minerva Medica; 1986.

10. Frimodt-Møller C. Diabetic cystopathy: epidemiology and related disorders. Ann Intern Med. 1980; 92:318-21.

11. Freeman R. Diabetic autonomic neuropathy. Handb Clin Neurol.

2014; 126:63-79.

12. Carone R, Frea B, Tizzani A, Borgno M. Neurologic bladder in diabetes. Etiopathogenetics and treatment. Minerva Urol. 1979; 31:91-3.

13. Kiani J, Moghimbeigi A, Azizkhani H, Kosarifard S. The prevalence and associated risk factors of peripheral diabetic neuropathy in Hamedan, Iran. Arch Iran Med. 2013; 16:17-9.

Correspondence Tatiana Bolgeo Antonio Maconi Marinella Bertolotti Annalisa Roveta Marta Betti Denise Gatti Azienda Ospedaliera SS Antonio e Biagio e C. Arrigo, Alessandria (Italy) Carmelo Boccafoschi, MD (Corresponding Author) cboccafoschi@virgilio.it Clinica CittĂ di Alessandria Policlinico di Monza, Alessandria (Italy)

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CASE REPORT

Giant hydronephrosis secondary to ureterocele with duplex system in adults: Report of a case Andrea Solinas, Luca Cau, Massimiliano Fanari, Ignazio Flaviani, Francesco Manca, Maurizio Melis Department of Surgery, Urology Unit, ATS Sardegna - ASSL Carbonia, Ospedale Sirai, Carbonia, Italy.

Summary

Giant hydronephrosis in adults is a rare entity. It is defined as an extensive dilatation of the pyelocaliceal cavities occupying a large part of the abdominal cavity. Giant hydronephrosis is usually due to pelvi-ureteric junction obstruction and is usually diagnosed in children and infants. Ureterocele, which is a cystic dilatation of the terminal ureter, often drains the upper part of the kidney in patients with a duplex system. Massive hydronephrosis in a patient with duplex system and obstructive ureterocele was described by Aeron et al. in 2017. A thorough search of the major medical databases disclosed that no other cases have been reported since. We describe a second case of unilateral complete duplex system with ureterocele and massive hydronephrosis of the upper moiety in an adult man with intermittent abdominal pain associated with constipation and a decrease in appetite. The renal function of the left kidney was 8% of total function by radionuclide renal scan. The patient subsequently underwent left laparoscopic nephrectomy.

KEY WORDS: Massive hydronephrosis; Ureterocele; Duplex system; Nephrectomy.

Submitted 29 April 2020; Accepted 6 June 2020

INTRODUCTION

Ureterocele is a cystic dilatation of submucosal distal ureter. It is rare in adults but presents a higher incidence in infants and young children. Ureterocele usually affects the upper moiety in case of complete duplication of the pelviureteric system and presents as abdominal pain and infection (1, 2). Massive hydronephrosis in adults is a rare entity and is easy to be misdiagnosed. It is defined as an extensive dilatation of the pyelocaliceal cavities occupying a large part of the abdominal cavity. In 1939 Stirling defined massive hydronephrosis as the presence of more than 1000 mL or 1.6% of body weight of fluid in the renal collecting system or the involvement of five vertebral heights. The aim of this paper is to present the second case of a massive hydronephrosis in an adult male affecting the duplex system associated with ureterocele.

CASE

REPORT

A 63-year-old man with a history of left lumbar pain which had not been investigated was referred to our urology unit with an abdominal palpable mass and pain. He had diffuse abdominal pain, persistent constipation and a

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decrease in appetite but no urological symptoms or signs or fever. He had no history of hematuria or urinary tract infection. Clinical examination showed an asymmetric abdominal palpable mass with a smooth surface.

The mass extended from the left lumbar region to the pelvic region crossing the midline. Laboratory blood investigations were unremarkable. Ultrasound showed fluid-filled mass occupying all left abdominopelvic region and pressing the digestive structures. Computerized tomography revealed massive hydronephrosis of the left upper pole moiety, measuring around 28 x 15 x 17 cm, with normally enhancing renal parenchyma at the region of lower pole (Figures 1, 2). Pelvic section revealed dilated and tortuous upper pole moiety ureter with cystic focal dilatation in its submucosal part as it entered the bladder suggestive of ureterocele (Figure 3).

Radionuclide renal scan showed a hydronephrotic left kidney with decreased global glomerular filtration rate of the left side and overall impaired function of the left kidney (8%). Radionuclide renal scan (Figure 4) documented a marked reduction in the size of the left kidney and poor parenchymal uptake in the corticomedullary phase, followed by delayed excretion, reflecting a reduced pyelocalyceal function. The left curve was considerably lower than the right and showed marked phase delay.

The total glomerular filtration rate was 63.2 mL/min, 58.2 mL/min (92%) in the right kidney and 5 mL/min (8%) in the left. The patient underwent complete endoscopic excision of the ureterocele for decompression of the system.

Complete endoscopic excision of the ureterocele exposed a wide gaping ureteral meatus. Retrograde pyelography was not performed nor was a stent inserted. In line with Weigert-Meyer rule, another ureteral meatus, draining the lower moiety, was detected superolateral to the first.

The next day an abdominal ultrasound scan, performed with the bladder catheter in situ, revealed complete resolution of the hydronephrosis of upper pole moiety and collapse of the ureterocele. The ultrasound scan performed after catheter removal demonstrated that the hydronephrosis had formed again, indicating the presence of ureteral reflux, which was demonstrated by a micturating cystourethrogram in the upper tract but not in the lower moiety or in the right kidney. Owing to the poorly functioning left kidney a left laparoscopic nephrectomy was performed about 3 months after ureterocele excision. Post-operative suites were simple and the No conflict of interest declared.

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Hydronephrosis and ureterocele

Figure 1.

Abdominal CT scan in coronal and sagittal view showing giant hydronephrosis of the left upper pole moiety occupying almost the whole abdomen with normal renal parenchyma in the region of lower pole (white arrow) dislocated by hydronephrosis and dilated tortuous upper pole moiety ureter.

Figure 2.

Contrast-enhanced abdominal CT scan showing giant hydronephrosis of the left upper pole moiety in axial view with normal renal parenchyma at the region of lower pole (white arrow) dislocated by hydronephrosis.

Figure 3.

Contrast-enhanced abdominal CT scan.

Pelvic section revealing dilated upper moiety ureter with cystic focal dilatation in its submucosal part as it enters the bladder (white arrow).

patient was discharged uneventfully on the 4th postoperative day. After three months the patient is asymptomatic and has normal renal function. Histology confirmed hydronephrosis, diffuse compression atrophy of the renal parenchyma and chronic interstitial nephritis.

DISCUSSION

In 1939 Stirling defined massive hydronephrosis as the presence of more than 1000 mL or 1.6% of body weight of fluid in the renal collecting system. In 1979 Crooks et al. defined radiographic criteria for massive hydronephrosis as the kidney occupying the hemi-abdomen which also meets or crosses the midline and has a height of about 5 vertebral bodies (3). With higher standards of medical care massive hydronephrosis is now a rare urological entity, occurring predominantly in children. The commonest cause is congenital pelvi-ureteric-junction obstruction which occurs in 80% of cases (4) followed by stones.

Other less common causes include congenital ureteral narrowing, ureteropelvic tumors, trauma, renal ectopia, retroperitoneal fibrosis, obstructive megaureter (5), ureteric atresia, polar or aberrant vessels. More than 600 cases have been reported worldwide to date, most of them in the last 15 years (6). Massive hydronephrosis is a slowly progressive disease and a huge abdominal mass or distended abdomen may be the only sign. Patients may remain asymptomatic until late phase. Its wide differential diagnosis includes intraperitoneal cysts (mesenteric or choledochal), retroperitoneal cysts (renal or adrenal or pancreatic pseudocysts), pseudomixoma, ovarian cysts/tumors, ascites (7). It usually presents with vague symptoms such as fatigue, dyspepsia or nausea, mild diffuse abdominal pain or uncomfortable feeling and persistent constipation, urinary tract infection, renal insufficiency or hematuria after trauma in adults (5). Ureterocele is a cystic dilation of the distal ureter. It is a congenital anomaly associated with other anomalies such as a duplicated system and other diseases. Most of the ureteroceles are diagnosed in utero or during the postpartum screening for congenital malformations (1) while in adult patients it is rare and usually asymptomatic.

Ureterocele can be associated with a single or a duplex system, the latter being more common. Most adult ureteroceles are in single system, intravesical and located on the trigone of bladder.

Ureterocele in a duplex system most commonly involves the upper pole moiety and hydronephrosis is usually due to obstruction at the lower end.

Figure 4.

Radionuclide renal scan depicting a reduced size and a markedly reduced parenchymal uptake in the left kidney.

The left nephrographic curve is considerably lower than the contralateral curve and shows marked phase delay.

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A. Solinas, L. Cau, M. Fanari, I. Flaviani, F. Manca, M. Melis

According to Weigert-Meyer rule, in patients with a duplex system the upper moiety ureter drains into the bladder more medial and inferior to the lower moiety ureter.

This was also the case of our patient. Ureterocele causing obstruction in adults is uncommon. Even uncommon is the association of the massive hydronephrosis with the duplex system in adults. Until now, there is only one case of giant hydronephrosis of upper pole moiety in a duplex system associated with ureterocele reported in the literature (1). The management of ureterocele is controversial, which is related to the type of presentation and postoperative morbidity. Endoscopic approach, for short operation time and acceptable outcomes, is considered as the gold standard for intravesical ureterocele. The goals of endoscopic techniques are to decompress the obstructed system minimizing the incidence of postoperative reflux (1).

Other procedures like upper polar nephrectomy or ureterocele excision and common sheath reimplantation are required on the basis of the renal function of an involved moiety, persistent obstruction or vesico-ureteral reflux of the upper tract and occurrence of new vesico-ureteral reflux post-procedure. In our case, endoscopic ureterocele resection was successful in decompressing the dilated system and ureterocele but in consideration of persistent vesico-ureteral reflux of the upper tract and owing to the poorly functioning left kidney we decided to perform a laparoscopic nephrectomy. The interest of our case lies in the combination of rare adult giant hydronephrosis and two uncommon abnormalities: duplex system and obstructive ureterocele.

CONCLUSIONS

The most important aspect of management is early diagnosis with accurate preoperative delineation of anatomy of the affected kidney. It is still not easy to differentially diagnosis. It usually presents with vague symptoms such as fatigue, dyspepsia or nausea, urinary tract infection, renal insufficiency or hematuria after trauma in adults

Correspondence Andrea Solinas, MD (Corresponding Author) sol.andrea@tiscali.it Luca Cau, MD luca.cau@atssardegna.it Massimiliano Fanari, MD massimiliano.fanari@atssardegna.it Ignazio Flaviani, MD ignazio.flaviani@atssardegna.it Francesco Manca, MD franc.manca@atssardegna.it Maurizio Melis, MD maurizio.melis@atssardegna.it S.C. Urologia, ATS Sardegna - ASSL Carbonia Ospedale Sirai, Via Ospedale, 09013 Carbonia (Italy)

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(8). It is not likely to consider a massive hydronephrosis diagnosis firstly. Nowadays, diagnostic instruments such us CT scan and ultrasonography have facilitated an accurate diagnosis of hydronephrosis. For this reason, the clinician and radiologist could readily diagnose and provide appropriate therapy. Adult obstructing ureterocele is uncommon, while adult massive hydronephrosis combined with a duplex system is highly uncommon.

The case of our patient, who exhibited all three abnormalities, deserves to be shared with the scientific community.

REFERENCES 1. Aeron R, Sokhal AK, Kumar M, Sankhwar S. Giant hydronephrosis in a case of ureterocele with duplex system: an entity yet not reported. BMJ Case Rep. 2017. DOI:10.1136/bcr-2017-221379.

2. Merlini E,Lelli Chiesa P. Obstructive ureterocele-an ongoing challange. World J Urol. 2004; 22:107-14.

3. Crooks KK, Hendren WH, Pfister RC. Giant hydronephrosis in children. J Pediatr Surg. 1979; 14:844-50.

4. Yang WT, Metreweli C. Giant hydronephrosis in adults: the great mimic. Early diagnosis with ultrasound. Postgrad Med F. 1995; 71:409-12.

5. Solinas A, Pau AC, Ayyoub M, Frongia M. Primary obstructive megaureter in adults: management strategy in a young woman. Arch Ital Urol Androl. 2010; 82:192-4.

6. Guanghui Hu, Min luo, Yunfei Xu. Giant hydronephrosis secondary to ureteropelvic junction obstruction in adults: report of a case and review of literature. Int J Clin Exp Med. 2015; 8:4715-17.

7. Kaura KS, Kumar M, Sokhal AK et al. Giant hydronephrosis: still a reality!. Turk J Urol. 2017; 43:337-44.

8. Kaya C, Pirincci N, Karaman MI. A rare case of an adult giant Hydroureteronephrosis due to ureterovesical stricture presenting as a palpable abdominal mass. Int Urol Nephr. 2005; 37:681-83.

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DOI: 10.4081/aiua.2020.4.321

CASE COLLECTION

Complications of endourological procedures and their treatment Aldo Franco De Rose 1, Eugenio Di Grazia 2, Vincenzo Magnano San Lio 3, Khaled Refaai 4, Martina Beverini 1, Alberto Caviglia 1, Davide Di Mauro 2, Giuseppe Giordano 3, Islam O. Koraiem 4, Guglielmo Mantica 1, Diego Meo 3, Mohamed Ramadan 4, Mostafa Sakr 4, Carlo Terrone 1 1 Department

of Urology, Policlinico San Martino Hospital, University of Genova, Genova, Italy; Policlinico Vittorio Emanuele, Ospedale S. Marco, Catania, Italy; 3 Unit of Diagnostic and Interventional Radiology ARNAS “Garibaldi-Nesima”, Catania, Italy; 4 Department of Urology, Alexandria University, Egypt.

2 Azienda

Summary

Endourological treatment for urinary stones and other obstructive urinary tract diseases is minimally invasive but in some cases it involves serious complications. This collection of cases describes some complications of endourological procedures and how they were treated.

Case 1: A case of right ultrasound-guided percutaneous nephrostomy found to be misplaced in the inferior vena cava.

The case was safely managed, but it showed that ultrasound guidance alone may be insufficient so it is recommended that percutaneous nephrostomy should be always placed under fluoroscopic control, either alone or in combination with ultrasound guidance.

Case 2: A case of renal subcapsular hematoma occurring on retrograde intrarenal surgery at high perfusion pressure.

The hematoma was drained under combined ultrasonic and radiological guidance. Post treatment recovery was uneventful. Large stone size, severe ipsilateral hydronephrosis, long operation time, higher hydrostatic pressure of the irrigating solution and low ureteral wall compliance are supposed to be risks factors associated with renal subcapsular formation. Management strategy should be tailored to patient’s clinical conditions. In hemodynamically stable patients, large hematoma drainage is recommended to prevent further complications and favours early recovery.

Case 3: A case of double J stent fracture discovered one month after the insertion to relieve obstruction from a 1 cm stone in the right proximal ureter. The distal fragment of the stent was removed by cystoscopy while the proximal fragment was removed by semirigid ureteroscopy in two sessions due to fever and extensive calcification.

Case 4: A mini-invasive technique for transurethral replacement of completely encrusted urinary stents in female patients. This technique allows the interventional radiologist to replace obstructed urinary stents by avoiding more invasive and traumatic urological procedures with sedation.

KEY WORDS: Percutaneous nephrostomy; Inferior vena cava (IVC); Retrograde intrarenal surgery (RIRS); Renal subcapsular hematoma; Ureters; Stents; Ureteral calculi; Fluoroscopy.

Submitted 17 July 2020; Accepted 30 September 2020

CASE 1 MISPLACED

PERCUTANEOUS NEPHROSTOMY TUBE IN THE INFERIOR VENA CAVA

Khaled Refaai, Mohamed Ramadan, Islam O. Koraiem, Mostafa Sakr

INTRODUCTION

Percutaneous nephrostomy (PCN) is a useful tool for temporary drainage of obstructed kidney even with sterile hydronephrosis (1). Depending on the image guidance, PCN can be an effective and safe procedure. However, significant morbidity due to the development of complications can still occur. Potentially serious complications include severe bleeding, septicemia and injury to adjacent organs as bowel perforation, splenic injury, pleural injury or liver injury (2). Major complications rate up to 7% have been reported. Intravenous misplacement of a urologic catheter is an uncommon complication of percutaneous renal surgery and improper management of it could lead to serious consequences. Different techniques can be used for insertion of PCN. The most commonly used techniques are either Seldinger’s technique which include puncture of kidney by a needle then insertion of guide wire and dilatation over this wire to form a wide track enough for passage of nephrostomy catheter or one-stab technique (Bonnano Technique) using a pigtail Teflon catheter mounted on a hollow 18G needle which has a sharp beveled edge to be directly inserted in the pelvicalyceal system (3). PCN insertion can be either under ultrasound (US) guidance or combined US and fluoroscopy guidance. Less commonly usage of CT can be used especially in abnormal anatomy, ectopic kidney and transplanted kidney (4) Contrast enhanced US can be used in non-dilated kidneys (5). Combined use of ultrasound and fluoroscopy is expected to achieve better results in terms of success rate and decrease in the occurrence of major complications of percutaneous nephrostomy insertion (6). US alone can be used safely in PCN insertion in case of marked dilatation of pelvicalyceal system especially in one stab technique and also can be used in puncture and dilatation in cases of pregnancy or hypersensitivity to contrast material but by well experienced surgeons (3).

No conflict of interest declared.

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CASE

REPORT

A 30-year-old female patient presented to the outpatient clinic with high grade fever and mild right loin pain.

Examination revealed mild right loin tenderness.

Laboratory blood tests results showed serum creatinine level of 1.5 mg/dl and white blood cells count of 13.5 x 103/ml and urine analysis showed pus cells more than 100/HPF. Patient was admitted to hospital and subsequent imaging confirmed the presence of stones in the right kidney with moderate hydronephrosis and thickening of renal pelvis wall reflecting inflammatory stricture.

Decision was made to insert a percutaneous nephrostomy (PCN) tube in the right kidney to drain infected hydronephrosis and to ease the later percutaneous nephrolithotomy procedure. Right PCN tube was successfully inserted under ultrasound (US) guidance under cover of broad spectrum antibiotics to be modified after results of urine culture and sensitivity test. Seldingerâ&#x20AC;&#x2122;s technique under US guidance was usually used to insert nephrostomy tube. A 18 gauge 25 cm long Chiba needle was used to make puncture under US guidance and Teflon dilators starting from 8 to 14 F over guidewire were used for blind dilatation of the track to insert a 12 F Amecath nephrostomy tube. Few days later, the PCN tube slipped and decision was made to reinsert the tube. The same urologist reinserted the tube under US guidance following the usual recommended steps. However, after insertion continuous flow of venous blood was unexpectedly noticed. The tube was clamped and fixed and as the patient was vitally stable she was directly transferred to undergo a computed tomography (CT) scan that demonstrated the PCN tube passing within the right renal vein through a segmental renal vein to reach the inferior vena cava (IVC) (Figure 1).

The tube was kept clamped and the patient remained vitally stable and decision was made to remove the tube in the operatory room (OR) under vision to be ready for any Case 1 - Figure 1.

Computed tomography scan demonstrating nephrostomy tube passing within the right renal vein through a segmental renal vein to reach the inferior vena cava.

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consequences. Exploration was done and PCN was safely removed without any subsequent bleeding, renal stones were extracted through a nephrotomy and double J stent was inserted. On post-operative day 2, patient developed mild respiratory distress. Pulmonary embolism was suspected. However, radiology and laboratory workup was negative. Patient recovered with conservative management and was discharged safely on postoperative day 5.

CONCLUSIONS

Percutaneous nephrostomy tube should be inserted by welltrained urologists with combined usage of both US and fluoroscopic guidance. In case of intravenous tube misplacement, simple removal is safe and feasible. However, OR team should be ready for any unexpected event.

CASE 2 SUBCAPSULAR

HEMATOMA AFTER

RIRS

Eugenio Di Grazia, Davide Di Mauro

INTRODUCTION

Retrograde intrarenal surgery (RIRS) is usually safe and effective for managing < 2 cm kidney stones.

Complications rate is generally low and not severe. Major complications occur in fewer than 0.1% of cases and among these renal subcapsular hematoma (RSH) is exceedingly rare and reported in few papers in literature (7-9).

We believe that, although rare, subcapsular hematoma of the kidney deserves attention from endourologists for its severity. We report on a case of renal RSH occurred in a patient after RIRS performed by an experienced endourologist to manage intrarenal kidney stone disease. The presentation, common characteristics, risk factors, management and review of the literature are discussed.

CASE

REPORT

A 32-year-old patient had a 3-month long-standing stent deployed at Emergency Unit to relieve left kidney stone obstruction. CT scan before stent placement showed a 1.2 cm pyelic stone causing hydronephrosis and another 7 mm stone located at the lower calyx. The patient was scheduled for RIRS. The patient was one pack/day smoker and his body mass index (BMI) was 18.4 Kg/m2.

Preoperative evaluation showed no comorbidities. Urine culture was negative, blood testing showed haemoglobin (Hb) 15.4 g/dl, white blood count (WBC) 8.520, creatinine 0.78 mg/dl and normal coagulation tests. After removal of the calcified stent, flexible ureteroscopy (FU) was started with cystoscopic insertion of a hydrophilic safety wire.

Then, using a 7 F semirigid ureteroscope, the ureter was inspected toward the ureteric pelvic junction (UPJ) showing long-standing stent inflammation and no stones along the ureter. We failed to deploy a 10/12 Fr ureteral access sheath (UAS) because of low ureteral wall compliance.

A 7.5 Fr flexible fiberoptic ureteroscope and holmium laser with 200 Âľm fiber were used for lithotripsy.

Irrigation was located at 80 cm from the operating table and manual intermittent forced irrigation with a 20cc syringe was used when necessary to ameliorate visibility.

After about 30 minutes operating time the procedure was aborted because of scope friction with the ureter not per-

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mitting to manage the stone properly. A double J stent was replaced and a mini percutaneous nephrolithotomy (miniPCNL) was planned at a later time after appropriate patient counselling. After RIRS, the patient experienced persistent low-grade fever between 37.3 and 38 °C and a stepwise increase in WBC count in the following days, despite 5 days carbapenems antibiotics full-therapy, and Hb dropped to 12.5 g/dl. Other clinical signs such as loin pain or hemodynamic instability were not observed. CT scan showed a 5.6 x 3.1 x 11.4 cm left RSH not supplied by active bleeding (Figure 1). Clinical symptoms and hemodynamic stability induced to manage the complication by placing an 8 F percutaneous nephrostomy catheter in the urinary system and another drainage in the RSH under ultrasonic and radiological guidance. The previously placed ureteral stent was removed to avoid possible ureteral reflux to the affected kidney during urination.

At first the drainage of the RSH drained about 50cc, then drained about 10cc per day. Culture test on the aspirate was negative. Drainage ceased to be productive in the fifth day post procedure and it was removed. Post-treatment recovery was uneventful, Hb stabilized within 10 g/dl, fever ceased in the second postoperative day and patient was discharged in the fourth postoperative day.

MiniPCNL was performed 2 months later through the same nephrostomy tract when RSH was completely healed. Informed consent was obtained by the patient for the reporting of the case.

Case 2 - Figure 1.

CT scan showing a 5.6 x 3.1 x 11.4 cm left renal subcapsular hematoma not supplied by active bleeding.

CONCLUSIONS

After RIRS, RSH is an anecdotal complication caused by fornix rupture and bleeding. Several factors are supposed to favors the risk of renal rupture when high perfusion pressure of irrigation is used. Low pressure irrigation and UAS deployment are recommended to prevent this severe complication. Management strategy is tailored to patient’s clinical conditions. In hemodynamically stable patients, large hematoma drainage is recommended to prevent further complications and favors early recovery.

CASE 3 RETRIEVAL OF BROKEN DJ URETERIC STENT A RARE ENDOUROLOGICAL NIGHTMARE

malposition, migration and encrustation. These events require further management that sometimes might be challenging for the endourologist. DJ stent fracture is a possible but rare complication that is reported in literature in very few cases (10-13), mostly related to long time before removal. We present a rare case of DJ stent fracture discovered one month after the insertion.

CASE

PRESENTATION

In February 2020 a 72-year-old man presented to another hospital with fever and right renal colic. He performed a CT scan of the abdomen that found a 1 cm stone in the right proximal ureter, just under the pyelo-ureteral joint.

A ureteral double J (DJ) stent was placed. After one month the man was admitted to our first aid with fever and right renal colic. Complete blood count, renal function tests, and serum electrolytes measurement were performed and an increase in white blood cells and creatinine was found (WBC 12.40 x 10^9/L, creatinine 2.6 mg/dL, eGFR 24 ml/m’/1.73 mq, C-Reactive Protein 41.2 mg/L). The urine culture was positive for Staphylococcus Epidermidis and Hominis. He resulted negative at the COVID-19 swab. The patient underwent another abdominal CT scan which showed a right hydronephrosis in addition to the abovementioned stone. Furthermore, the previously positioned DJ stent was broken, with the proximal tip of the stent correctly positioned in the right renal pelvis while the distal half was completely migrated in the bladder (Figure 1A).

Despite this, the overall appearance of the right kidney was healthy, with cortical thickness within the limits and presence of moderate perirenal edema. The patient underwent ureterorenoscopy. At the preliminary cystoscopy two fragments of the distal end of the stent were found and were removed with grasping forceps (Figure 1B). After that, the right ureteral meatus was identified and a safety guidewire was positioned. A pyelography with a minimal dose of contrast was done and then a ureteral catheter was advanced along the ureter inducing the push up of the stone. Purulent urine was drained. The semi rigid ureterorenoscope was introduced up to the renal pelvis and the proximal end of the known stent was found there.

The stent was taken with a forceps and the removal procedure started, however at the level of the vascular cross the curl of the stent got stuck. Considering the emergency and the septic state of the patient we didn’t proceed to laser lithotripsy of the calcified portion of the stent and therefore a mono J urethral stent was placed. After two weeks of Case 3 - Figure 1.

A. CT scan showing the broken DJ stent in situ.

B. DJ stent after the retrieval.

Aldo Franco De Rose, Martina Beverini, Alberto Caviglia, Guglielmo Mantica, Carlo Terrone

INTRODUCTION

Double-J ureteral stents are commonly used to manage urinary obstructions and their insertion is one of the basic endourological procedure. Even though ureteric stenting is usually a simple and fast maneuver, it is not completely devoid of troubles and complications such as Archivio Italiano di Urologia e Andrologia 2020; 92, 4

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antibiotic therapy, once the phlogistic indexes were normalized, the ureterorenoscopy was repeated and the last portion of the stent and the stone were removed after laser lithotripsy. A double J stent was placed. The patient tolerated the procedure very well and there were no complications. On the following day, the patient was discharged home with the indication to continue the antibiotic therapy and remove the new stent outpatiently a week later.

CONCLUSIONS

Broken DJ ureteric stent is a rare endourological complication. It can be safely removed with minimal morbidity and mortality by an experienced endourologist. To minimize further complications, hospitalization and costs it is preferable, when possible, to perform the removal of the broken DJ stent in one time. It is advisable to perform the surgery in two times in case of complications such as fever or extensive stent calcification.

• Klemmer clamp standard or angled • 8 Fr plastic double J ureteral stent, 20-22-24 cm length (Percuflex, Boston Scientific, Ratingen, Germany) After accurate disinfection, with a Lidocaine Gel 2,5% soaked Klemmer clamp the bladder’s tip of the ureteral stent is recovered (Figure 1). The proximal portion of the stent (cutting the tip) is externalized and knotted with a silk thread (Figure 2). A metal wire is advanced as far as possible inside the stent until it reaches the obstructed portion and keeping the whole system strained, a coaxial introducer sheath is advanced to reach the ureteral meatus (Figure 3). It is important to do this operation in 2 people, one gently advancing the introducer, the other one holding the catheter under tension through the silk thread. The stent is then removed while maintaining Case 4 - Figure 1.

The bladder tip of the ureteral stent was recovered by a jelly soaked Klemmer clamp.

CASE 4 A MINI-INVASIVE

TECHNIQUE FOR TRANSURETHRAL REPLACEMENT OF ENCRUSTED URINARY STENTS IN FEMALE PATIENT. DESCRIPTION OF THE TECHNIQUE AND CLINICAL RESULTS

Vincenzo Magnano San Lio, Diego Meo, Giuseppe Giordano

INTRODUCTION

Ureteral stent placement is a procedure for maintaining ureteral patency in various benign or malignant conditions (14). It may be a short-term bridge waiting for definitive therapy as in the case of ureteral stones or a long-term stenting for benign or malignant ureteral strictures (15). Plastic stents are the mainstay of long-term treatment. These stents are prone to obstruction and fouling by urinary salt precipitation (15). Traditionally their replacement has been performed cystoscopically, although an alternative is the replacement of urinary stents with a transurethral approach that is performed in the angiography room whose effectiveness is well described in the literature (16). However, complete stent obstruction makes it impossible its replacement on a metal guidewire or an hydrophilic guide wire.

We report the effectiveness of a transurethral recovery technique that allows, while maintaining access to the ureter, to remove the encrusted stent and replace it with an analogue by transurethral technique.

Technique The material needed to replace an encrusted ureteral stent is: • 0,035 inch x 145 Superstiff PTFE coated guidewire (Amplatz, Boston Scientific, Ratingen, Germany) • 0,035 inch x 180 standard coated hydrophilic guidewire (Radifocus Guidewire M, Terumo, Tokyo, Japan) • 9 Fr peel away introducer sheath 15,5 cm length or 9 Fr super flex sheath vascular introducer (cutting his terminal valve) • 3-0 silk thread • 4 Fr Bern shaped catheter (Bern, Boston Scientific, Ratingen, Germany; Ber, Cordis, Miami, FL, USA) • Lidocaine Gel 2,5%

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Case 4 - Figure 2.

The proximal portion of the stent (cutting the tip) was externalized and knotted with a silk thread.

Case 4 - Figure 3.

A metal wire was advanced as far as possible inside the stent until it reached the obstructed portion and keeping the whole system strained, a coaxial introducer sheath was advanced to reach the ureteral meatus. The stent was then removed while maintaining access to the ureter.

Case 4 - Figure 4.

The renal pelvis was reached with an hydrophilic guide and a 4 Fr Bern catheter. The wire was replaced by a superstiff PTFE coated guidewire.

Finally, the new ureteral stent was positioned.

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access to the ureter. The renal pelvis is reached, with a hydrophilic guide and a 4 Fr Bern catheter, and the wire is replaced by a superstiff PTFE coated guidewire.

A metal guidewire is advanced up to the renal pelvis inside the introducer sheath and a new 8 Fr stent is positioned (Figure 4). We developed a novel recovery technique with silk thread and use of a 9 Fr vascular introducer sheath which allowed us to remove the obstructed stents while maintaining access to the ureter.

CASE

SERIES

3. Venyo A, Fatola C, Adegbite D, Khan A. Nephrostomy in pregnancy a district general hospital experience over five years. Journal of Biomedical Graphics and Computin. 2014; 5:10.5430/jbgc.v5n1p1.

4. Ghani KR, Patel U, Anson K. Computed tomography for percutaneous renal access. J Endourol. 2009; 23:1633-9.

5. Liu BX, Huang GL, Xie XH, et al. Radiology. 2017; 285:293-301.

6. Bhatt S, Verma P, Grover Ret al. Success, effectiveness and safety of combined sonographic and fluoroscopic guided percutaneous nephrostomy in malignant ureteral obstruction. Int J Radiol Radiat Ther. 2017; 3:165-70.

From January 2013 to January 2020, 402 urinary stents were replaced with a transurethral approach in 325 women with obstructive urinary disorders (benign and malignant). Out of them 363 were recovered with a standard transurethral approach using a metal guidewire, but 39 stents were obstructed by encrustations making impossible to replace them with a standard technique. In 38 cases it was possible to replace the obstructed stents. The technique failed in one patient because we were unable to advance the access sheath through the ureteral orifice.

Encrusted ureteral stents were replaced in 22 women.

The number of procedures performed on each patient, who had an encrusted stent, varied from one to three.

Technical success was achieved in 97.4% procedures.

The mean fluoroscopic time was 3 minutes and 25 seconds (range 2 minutes, 31 seconds - 13 minutes, 32 seconds). Twenty patients had urinary infection associated with obstruction due to an occluded stent. There were 6 cases of transient minor hematuria that resolved spontaneously within 1-2 days after the procedure. There were no major complications. Some patients complained of mild pain in the urethra and lower abdomen region when the stent tip was grasped or the stent was removed, but none of them required pain management other than drugs used as part of the pretreatment. In one case a significant stone incrustation in the bladder portion of the stent did not allow for the execution of this technique, therefore we broke the incrustation with the Klemmer clamp once the proximal portion of the stent was externalized and therefore the stent could be replaced.

7. Yahsi S, Tonyali S, Ceylan C, et al. Intraparenchymal hematoma as a late complication of retrograde intrarenal surgery. International Braz J Urol. 2017; 43:367-370.

CONCLUSIONS

Correspondence

In conclusion, fluoroscopically guided transurethral replacement of encrusted ureteral stents in women is a feasible and safe alternative to cystoscopy. Performing this exchange procedure reduces costs compared to cystoscopic exchange of the ureteral stent in the operating room. This technique allows to replace obstructed urinary stents avoiding more invasive and traumatic urological procedures with sedation.

REFERENCES

1. Mittal V, Biswas M, Lal S. Percutaneous nephrostomy or double J stenting, which is better modality for obstructive uropathy-a descriptive study. Int J Res Med Sci. 2017; 4:3486-91.

2. Dyer RB, Assimos DG, Regan JD. Update on interventional uroradiology. Urol Clin North Am. 1997; 24:623-52.

Note: Supplementary Discussion and References are published online as Supplementary Materials at https://www.pagepressjournals.org/index.php/aiua/index

8. Kozminski MA, Kozminski DJ, Roberts WW, et al. Symptomatic subcapsular and perinephric hematoma following ureteroscopic lithotripsy for renal calculi. Journal of Endourology. 2015; 29:277-282.

9. Bai J, Li C, Wang S, et al. Subcapsular renal haematoma after holmium:yttrium-aluminum-garnet laser ureterolithotripsy. BJU International. 2012; 109:1230-1234.

10. Chua ME, Morales ML Jr. Spontaneous fracture of indwelling polyurethane ureteral stents: A case series and review of literature.

Can Urol Assoc J. 2012; 6:386-392.

11. Ray RP, Mahapatra RS, Mondal PP, Pal DK. Long-term complications of JJ stent and its management: A 5 years review. Urol Ann. 2015; 7:41-45.

12. El-Faqih SR, Shamsuddin AB, Chakrabarti A, et al. (1991) Polyurethane internal ureteral stents in treatment of stone patients: morbidity related to indwelling times. J Urol. 146:1487-1491.

13. Zisman A, Siegel YI, Siegmann A, Lindner A. Spontaneous ureteral stent fragmentation. J Urol. 1995; 153(3 Pt 1):718-721.

14. Park SW, Cha IH, Hong SJ, et al. Fluoroscopy-guided transurethral removal and exchange of ureteral stents in female patients: technical notes. J Vasc Interv Radiol. 2007; 18:251-6.

15. McCarthy E, Kavanagh J, McKernan S, et al. Fluoroscopically guided transurethral removal and/or replacement of ureteric stents in women. Acta Radiol. 2015; 56:635-40.

16. Carrafiello G, Coppola A, De Marchi G, et al. Trans-Urethral Ureteral Stent Replacement Technique (TRUST): 10-Year Experience in 1168 Patients. Cardiovasc Intervent Radiol. 2018; 41:610-617.

Aldo Franco De Rose, MD - aldofrancoderose@libero.it Martina Beverini, MD (Corresponding Author) - martina.beverini@live.it Alberto Caviglia, MD - caviglialberto@gmail.com Guglielmo Mantica, MD - guglielmo.mantica@gmail.com Carlo Terrone, MD - carlo.terrone@med.uniupo.it Department of Urology, Policlinico San Martino Hospital, University of Genova Largo Rosanna Benzi 10, 16132 Genova Davide Di Mauro, MD (Corresponding Author) - davidedimauro84@virgilio.it Eugenio Di Grazia, MD - eugeniodigrazia@hotmail.com Azienda Policlinico Vittorio Emanuele, Ospedale S. Marco, Catania (Italy) Magnano San Lio Vincenzo, MD Meo Diego, MD (Corresponding Author) - diegomeo@hotmail.it Giordano Giuseppe, MD Unit of Diagnostic and Interventional Radiology ARNAS â&#x20AC;&#x153;Garibaldi-Nesimaâ&#x20AC;?

Via Palermo 636, 95122 Catania (Italy) Khaled Refaai, MD - javacup16@gmail.com Mohamed Ramadan, MD Islam O. Koraiem, MD (Corresponding Author) - drislamosama@live.com Mostafa Sakr, MD Uro-oncology Unit, Department of Genito-Urinary Surgery, Faculty of Medicine, Alexandria University 74 Albert st, Smouha, 5359472, Alexandria, Egypt Archivio Italiano di Urologia e Andrologia 2020; 92, 4

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LETTER TO EDITOR

DOI: 10.4081/aiua.2020.4.326

Erectile disfunction medical treatment with phosphodiesterase 5 inhibitors (PDE5i) in patients with retinitis pigmentosa and side effects KEY WORDS: Erectile dysfunction; Medical treatment; Side effects.

Submitted 29 April 2020; Accepted 10 June 2020

To the Editor Retinitis pigmentosa represents a heterogeneous group of degenerative hereditary pathologies of the retinal photoceptors, some forms mainly affect the cones and others the rods (1). The prevalence of the disease is of 1 case per 30005000 inhabitants (1), in 80-90% of cases these are forms with prevalent involvement of the rods (RCD) and in 10-20% of cases of forms with prevalent involvement of the cones (CRD) (2). In 85% of the cases these are isolated forms, while in 15% of syndromic forms (2), the most common syndromic form is Usher's syndrome, in which retinitis pigmentosa is associated with neurosensory deafness (3). An extensive search of Medline, Embase and Scopus databases was conducted to retrieve English-language articles published up to 31 Dec 2019, assessing side effect of PDE5i. The protocol was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement.

All studies have been included. Congress meetings, editorial comments and review papers were excluded: Further exclusion criteria were full texts not available in English. Two reviewers (G.I.R. and A.C.) independently assessed the eligibility of the identified papers and any disagreements were discussed with a third reviewer (G.M.).

In the early stages of RCD disease patients show predominantly decreased night and peripheral vision, associated with photophobia. Patients with CRD complain of photophobia and reduced central vision. In both cases, disease evolution and specific symptoms are difficult to predict and depend on genetic and environmental factors.

PDE-6 Phosphodiesterase 6 is an isoenzyme of PDE that is found in the retina and is involved in the transduction of the signal, some forms of retinitis pigmentosa are related to mutations on this enzyme (4). PDE5 is the molecular target of several drugs used in the treatment of erectile dysfunction, but some of these drugs have off-target actions on PDE6 and may therefore be contraindicated (2).

PDE5 Inhibitors (5-7) Phosphodiesterase is an enzyme responsible for the hydrolysis of cGMP, a molecule that allows the erection of the penis thanks to its vasodilatory action on smooth vasal muscle cells. The smooth muscle cells of the corpora cavernosa of the penis express the isoenzyme PDE5. Inhibitory drugs specific to PDE5 are used for the treatment of erectile dysfunction: by inhibiting the enzyme they stop the hydrolysis of cGMP and thus promote vasodilation and erection. Off-target action of PDE5 inhibitors can result in several adverse reactions. Of particular interest are the adverse reactions related to the action on retinal PDE6, which may contraindicate treatment in patients with retinitis pigmentosa, where the functioning of the photoceptors is already impaired (Tables 1, 2).

Sildenafil Sildenafil is the most used inhibitor of PDE5, its action is not entirely specific for PDE5 but has a slight affinity for PDE6 retinal, in fact 9% of patients report among the adverse reactions, photosensitivity and alterations in color vision (5, 8).

The intake of sildenafil may cause transient alterations in the electroretinogram, so it is not recommended for patients with retinitis pigmentosa (4, 5).

Verdenafil Verdenafil is a molecule similar to sildenafil but more potent (7) and more selective than sildenafil, so higher doses are needed for adverse reactions related to the action on PDE6 to occur, which are therefore very rare.

Tadalafil Tadalafil has a chemical structure different from that of sildenafil and verdanafil, it has very little action on PDE6 so it does not cause adverse reactions for off-target effect on that isoenzyme (9).

Avanafil Avanafil has recently been approved for the treatment of erectile dysfunction, it is a very selective pyrimidine derivative

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No conflict of interest declared.

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Retinitis pigmentosa and PDE5i

for PDE5, which therefore does not cause adverse reactions related to the action on PDE6 (10, 11). Following a single 200 mg dose of Avanafil, no changes in colour perception were detected, however, the observation was made in a small sample and the data may not be significant. Similar results were also obtained in larger studies with larger doses of medication (12).

Other adverse reactions Other side effects were headache, dyspepsia, skin flush for sildenafil (4); headache, dyspepsia, skin flush, rhinitis, lengthening of QT for verdenafil (13, 14); headache, dyspepsia, back pain for tadalafil (5); headache, skin flush, nasal congestion, muscle cramps, postural hypotension for avanafil (10, 11).

Although there is no evidence in the literature that the administration of PDE5i in patients with retinitis pigmentosa may or may not lead to an aggravation of the disease, in the light of the knowledge on the pharmacodynamics of PDE5i and on the etiopathogenesis of retinitis pigmentosa, it seems appropriate, as a precaution, to avoid administering to these patients the least selective drugs for PDE5 and opt instead for the most selective ones. In case of patient presenting retinitis pigmentosa and organic or post-operative erectile dysfunction, the possibility of PDE5i treatment should not be excluded. This kind of patient should be analyzed and should undergo specific genetic tests to assess the presence or absence of mutations in gene coding for PDE6 expressed at retinal level. In conclusion the presence of PDE6 mutation allows us to avoid oral treatment with PDE5i.

REFERENCES

1. Pagon RA. Retinitis pigmentosa. Surv Ophthalmol. 1988; 33:137-77.

2. Parmeggiani F, Sato G, De Nadai K, Romano MR, Binotto A, Costagliola C. Clinical and rehabilitative management of retinitis pigmentosa: Up-to-Date. Curr Genomics. 2011; 12:250-9.

3. Boughman JA, Vernon M, Shaver KA. Usher syndrome: definition and estimate of prevalence from two high-risk populations. J Chronic Dis. 1983; 36:595-603.

4. Basu A, Ryder REJ. New treatment options for erectile dysfunction in patients with diabetes mellitus. Drugs. 2004; 64:2667-88.

5. Hakky TS, Jain L. Current use of phosphodiesterase inhibitors in urology. Turkish J Urol. 2015; 41:88-92.

6. Setter SM, Iltz JL, Fincham JE, Campbell RK, Baker DE. Phosphodiesterase 5 inhibitors for erectile dysfunction. Ann Pharmacother. 2005; 39:1286-95.

7. Kuthe A. Phosphodiesterase 5 inhibitors in male sexual dysfunction. Curr Opin Urol. 2003; 13:405-10.

8. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med. 1998; 338:1397-404.

9. Eardley I,Cartledge J. Tadalafil (Cialis) for men with erectile dysfunction. Int J Clin Pract. 2002; 56:300-4.

10. Limin M, Johnsen N, Hellstrom WJG. Avanafil, a new rapid-onset phosphodiesterase 5 inhibitor for the treatment of erectile dysfunction.

Expert Opin Investig Drugs. 2010; 19:1427-37.

11. Alwaal A, Al-Mannie R, Carrier S. Future prospects in the treatment of erectile dysfunction: focus on avanafil. Drug Des Devel Ther. 2011; 5:435-43.

12. Wang R, Burnett AL, Heller WH, Omori K, Kotera J, Kikkawa K. Selectivity of avanafil, a PDE5 inhibitor for the treatment of erectile dysfunction: implications for clinical safety and improved tolerability. J Sex Med. 2012; 9:2122-9.

13. Hellstrom WJG, Gittelman M, Karlin G, Segerson T, Thibonnier M, Taylor T. Vardenafil for treatment of men with erectile dysfunction: efficacy and safety in a randomized, double-blind, placebo-controlled trial. J Androl. 2002; 23:763-71.

14. Carson CC. Cardiac safety in clinical trials of phosphodiesterase 5 inhibitors. Am J Cardiol. 2005; 96:37M-41M.

Andrea Cocci 1, Andrea Romano 1, Girolamo Morelli 2, Davide Frediani 2, Andrea Sodi 3, Giorgio Ivan Russo 4 1 Department

of Surgery, Urology Section,University of Florence, Florence, Italy; of Surgery, Urology Section, University of Pisa, Pisa, Italy; 3 Department of Surgery, Ophthalmology Section, University of Florence, Florence, Italy; 4 Department of Surgery, Urology Section, University of Catania, Catania, Italy.

2 Department

Correspondence Andrea Cocci, MD Andrea Romano, MD (Corresponding Author) - romano.andrea7895@gmail.com Department of Urology, University of Florence - San Luca nuovo padiglione 16/settore C/Piano II - Largo Brambilla 3-50134 Firenze (Italy) Girolamo Morelli, MD Davide Frediani, MD Department of Surgery, Urology Section, University of Pisa, Pisa (Italy) Andrea Sodi, MD Department of Surgery, Ophthalmology Section, University of Florence, Florence (Italy) Giorgio Ivan Russo, MD Department of Surgery, Urology Section, University of Catania, Catania (Italy)

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LETTER TO EDITOR

DOI: 10.4081/aiua.2020.4.328

Observational study on the effects of a topical formulation in patients with premature ejaculation KEY WORDS: Premature Ejaculation; Clove oil; Zanthoxylum Buongeanum; Aloe; Bisabolol; ejaculation.

Submitted 13 November 2020; Accepted 19 November 2020

To the Editor Premature ejaculation (PE) has been defined as the inability to control or delay ejaculation, resulting in dissatisfaction or distress of the patient (1).

Although PE is the most frequent sexual dysfunction, it is still underdiagnosed. An accurate clinical history is the best diagnostic approach that, in the majority of cases, is enough to differentiate between primary and acquired PE. Nowadays, treatment is not curative but is effective in increasing the intravaginal ejaculatory latency time (IELT), improving the sexual satisfaction of the couple. Combination of behavioural techniques with pharmacotherapy is the best way of treatment.

Major pharmacological treatments of PE include selective serotonin reuptake inhibitors antidepressants (dapoxetine, paroxetine) and topical anesthetics (2).

From 2019 it has been introduced in the Italian market a new product for the topical natural approach of PE, containing clove oil, Zanthoxylum bungeanum fruit extract with aloe and bisabolol.

The aim of the present study was to evaluate the efficacy and the tolerability this topical formulation in patients of different age with PE. An observational study was conducted in order to evaluate efficacy and tolerability of the topical formulation Endep® Spray in patients with premature ejaculation (PE).

Patients with clinical diagnosis of PE were enrolled in this observational study. All the patients underwent clinical evaluation including administration of Premature Ejaculation Diagnostic Tool (PDT) and International Index of Erectile Function (IIEF-5) questionnaires (3, 4).

The patients were assigned to use Endep® Spray (two puff before the sexual intercourse) for 30 days. The main outcome measure, evaluated by questionnaire, was the PEDT score; the secondary outcome was the improvement in the IIEF-5 score and the product tolerability evaluated along the whole study period. Eligible sunjects were ≥ 18 and ≤ 75 years of age with diagnosis of PE according to the European Association of Urology (EAU) guidelines. Patients with supposed or recognized intolerance towards one or more components of the product and patients with prostatic or urethral inflammatory and non-inflammatory pathology (prostatitis, urethritis) were excluded from the study. Endep® Spray contains clove oil, Zanthoxylum bungeanum fruit extract, aloe and bisabolol in the formulation of a sprayble hyperfluid emulsion. All patients were asked to apply one or two puff of the product in the penis area, 10 minutes before the sexual intercourse and were asked to massage the area till the product was completely absorbed.

Twenty-eight patients with diagnosis of PE were enrolled and treated in this observational study. PEDT and IIEF-5 scores were collected before and after the treatment with and data were analysed. The data show non normal distribution, therefore the Wilcoxon test was used.

At baseline visit (T0) and after 30 days of treatment (T30) patients were evaluated and asked to complete the two selfadministered questionnaires. At follow up examination after 30 days of treatment (T30) PEDT score showed a strong significant variation (median decrease -3.5; p = 0.0002). IIEF showed a significant but marginal variation (median increase +1.5).

Correlation with patients age and weight were checked by Pearson correlation test PEDT variation values showed a clear correlation with weight (p = 0.009); if weight was lower, the decrease in the PEDT score was greater. IIEF variation showed no correlation.

No correlation was found with the marital status (Wilcoxon test). All patients correctly used the product, showing a 100% compliance to the study protocol without any adverse effect.

The aim of the present study was to evaluate the efficacy of a sprayable hyperfluid emulsion in patients with premature ejaculation which has been recently marketed in Italy. The formula contains Clove oil, Zanthoxylum bungeanum fruit extract, Aloe, Bisabolol.

Zanthoxylum bungeanum Maxim is a natural desensitizer; the extract (Zanthalene) is obtained from the fruit of Sichuan pepper, a Chinese spice known for its chemestetic properties. In vitro investigations on a nerve-muscle preparation have shown that Zanthalene has a transitory action on the neuromuscolar synaptic transmission. This activation quick-

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No conflict of interest declared.

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Premature ejaculation improvement

ly leads to the depletion of the neurotransmitter. The action is mediated by the voltage-dependent Na+ channels, by closing them at the suggested dosages and, in this way, by blocking the electric signal. Hydroxy-a-sanshool has demonstrated in vivo to show an interesting activity on thermal and tactile sensitivity (5, 6). Eugenol is a volatile phenolic constituent of clove essential oil obtained from Eugenia caryophyllata buds and leaves. It is a functional ingredient of numerous products which have been used in the pharmaceutical, food and cosmetic industry. The wide range of eugenol activities includes antimicrobial, anti-inflammatory, analgesic and antioxidant (7).

Eugenol has anaesthetic properties, due to its ability to inhibit movement of sodium ions in peripheral nerves. Methyl eugenol is a potential candidate as an effective local anesthetic and analgesic. The antinociceptive and anesthetic effects of methyl eugenol result from the inhibitory action of methyl eugenol on peripheral Na+ channels (8).

In the formulation Endep® Spray, which is a sprayable hyperfluid emulsion, the clove oil and the the Zanthoxylum bungeanum fruit extract are associated with aloe and bisabolol with soothing and emollient action .

In this observational study we evaluate the efficacy of the topical application of the product in patients with premature ejaculation. We found that the topical application on demand is able to improve PEDT score in patients with premature ejaculation aged between 18 and 75 years, without adverse events or reduction of the vaginal sensitivity of the female partner. However, this study shows some limitations related to the lack of a control group and the small number of patients; for this reason it can be considered as a preliminary observation for future studies and evaluations.

In conclusion, in this observational study, we found that the topical treatment with Endep® Spray used before sexual intercourse significantly improves the PEDT score in patients with premature ejaculation.

Endep® Spray - IDI Integratori Dietetici Italiani, Italy

REFERENCES

1. Parnham A, Serefoglu EC. Classification and definition of premature ejaculation. Transl Androl Urol. 2016; 5:416-23.

2. Hu QB, Zhang D, Ma L, et al. Progresses in pharmaceutical and surgical management of premature ejaculation. Chin Med J (Engl). 2019; 132:2362-2372.

3. Althof SE. Patient reported outcomes in the assessment of premature ejaculation. Transl Androl Urol. 2016; 5:470-4.

4. 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.

5. Bryant BP, Mezine I. Alkylamides that produce tingling paresthesia activate tactile and thermal trigeminal neurons. 1999. 25; 842:45260.

6. Lennertz RC, Makoto Tsunozaki, Bautista DM, Stucky CL. Physiological basis of tingling paresthesia evoked by hydroxy-alpha-sanshool.

J Neurosci. 2010; 24; 30:4353-61.

7. Nejad SM, Özgünes H, Basaran N. Pharmacological and Toxicological Properties of Eugenol. Turk J Pharm Sci. 2017; 14:201-206.

8. Wang ZJ, Tabakoff B, Levinson SR, Heinbockel T. Inhibition of Nav1.7 channels by methyl eugenol as a mechanism underlying its antinociceptive and anesthetic actions. Acta Pharmacol Sin. 2015; 36:791-9.

Giuseppe Quarto, Luigi Castaldo, Giovanni Grimaldi, Alessandro Izzo, Raffaele Muscariello, Sisto Perdonà Division of Urology, IRCCS Fondazione G. Pascale, Naples, Italy.

Correspondence Giuseppe Quarto, MD (Corresponding Author) giuseppe.quarto@gmail.com Luigi Castaldo, MD Giovanni Grimaldi, MD Alessandro Izzo, MD Raffaele Muscariello, MD Sisto Perdonà, MD Division of Urology, IRCCS Fondazione G.Pascale, Naples (Italy)

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DOI: 10.4081/aiua.2020.4.330

ORIGINAL PAPER

Perineural invasion in prostate needle biopsy: Prognostic value on radical prostatectomy and active surveillance Nuno Ramos, Alexandre Macedo, João Rosa, Miguel Carvalho Urology Department, Garcia de Orta Hospital, Almada, Portugal.

Summary

Purpose: The aim of this study was to evaluate the clinical impact of perineural invasion (PNI) in prostate biopsy in patients submitted to radical prostatectomy and on active surveillance (AS).

Materials and methods: We performed a single center, retrospective, cohort study on patients diagnosed with clinically localized prostate cancer and submitted to radical prostatectomy between January 2010 and December 2016. We evaluated clinical and anatomopathological characteristics from the biopsy and radical prostatectomy specimen and correlated with biochemical recurrence (BCR) using a survival analysis. We also evaluated the impact of PNI in patients with criteria for active surveillance.

Results: The cohort analyzed consists of 107 patients, with a mean age of 63.1 years and a mean PSA prior to biopsy of 7.8 ng/ml. In prostate biopsy, 66.4% of the patients had a Gleason score of 6, 30.9% had a Gleason score of 7, and 2.7% had a Gleason score of 8 or higher, with PNI being detected in 57 (53.3%) of the patients. Regarding the anatomopathological characteristics of the surgical specimen, invasion of the seminal vesicles was observed in 6.5%, lymph nodes involvement in 9.3% and positive surgical margins in 27.1% of the cases.

During follow-up, BCR was recorded in 24.3% of cases.

Clinicopathological features were stratified according to the presence or absence of PNI, with statistical significance in relation to the Gleason Score (p = 0.001), pathologic T stage (p = 0.001), D’Amico risk (p = 0.002) and upstaging of the Gleason score (p = 0.045). The survival analysis revealed a relationship between PNI and BCR (hazard ratio = 2.98; 95% CI: 1.36-6.58; p = 0.007). Regarding the men potentially eligible for AS, the presence of PNI on the biopsy presented a significant relation with Gleason upgrade (p = 0.004) and extraprostatic extension (p = 0.017).

Conclusions: The presence of PNI in prostate biopsy is related to adverse anatomopathological factors, being a potential predictor of BCR and have a possible role in the selection of patients for AS.

tive treatment options such as radical prostatectomy (RP), external beam radiotherapy and brachytherapy to conservative management strategies including active surveillance (AS) (2-5). Despite the use of adequate therapy in localized PCa, approximately 18% of patients will eventually experience biochemical recurrence (BCR) (1, 6).

Pathological stage, preoperative prostate-specific antigen (PSA) levels and Gleason score (GS) are widely used as risk factors for BCR (7). In other hand, AS has been increasingly adopted to prevent overtreatment in men with low-risk prostate cancer (8). This strategy pretends to identify patients with clinically indolent tumors and avoid or delay definitive treatment, without compromising survival (9). Although the concept of AS is well established, there is no consensus regarding the optimal characteristics of patients who should be managed by this strategy. Therefore, there is a growing interest in the identification of new clinicopathological features in prostate needle biopsy specimens to improve the evaluation of the likelihood of BCR, as improving the selection of patients to AS (2, 4, 10). In this setting, perineural invasion (PNI) has been increasingly recognized as prognostic marker (11). PNI is a histopathologic finding representing the infiltration of cancer cells in, through and/or around nerves and is present in 7%-43% of prostate needle biopsies with PCa (4, 12, 13). PNI has been implicated in PCa cell proliferation and extraprostatic spread, and the presence of PNI has been shown to be associated with adverse oncological outcomes (1416). Despite of PNI being a potential determinant in PCa behaviour, the association between PNI and PCa progression is still a subject of debate. Due to the uncertainty regarding the role of PNI, we performed a study to evaluate the association of PNI in prostate needle biopsy with adverse pathological findings on RP specimens, as well the impact on BCR. We also pretend to evaluate the role of PNI in patients’ selection for AS (11).

KEY WORDS: Prostate cancer; Active Surveillance; Prostatectomy.

Submitted 22 July 2020; Accepted 3 September 2020

INTRODUCTION

Prostate cancer (PCa) is the second most commonly diagnosed cancer in men and the third cause of cancer related death (1, 2). The best treatment strategies in clinically localized PCa remains unclear and varies from defini-

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MATERIALS

AND METHODS

We performed a single center retrospective cohort study, on male patients, who underwent RP due to clinically localised PCa, from January 2010 to December 2016. All patients underwent a 12-core biopsy prior to RP and presence or absence of PNI was assessed. PNI was defined as the histopathologic finding of circumferential No conflict of interest declared.

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Perineural invasion in prostate needle biopsy

or longitudinal tracking of PCa cells along a nerve, within the perineural space. PNI was not always reported on pathology reports and we excluded patients with unknown PNI status to minimize the potential for misclassification bias. Clinical and the biopsy parameters were evaluated, including age, PSA level prior to surgery, prostate volume, number of positive cores, total percent of core involvement and GS. We also assessed histopathologic finding on RP specimens: GS, margin positivity, stage, seminal vesicle involvement and lymphatic invasion.

The primary objective of this study was to report the association between PNI in prostate needle biopsy and adverse pathological findings on RP specimen, specifically, the presence of extraprostatic extension, surgical Gleason upgrading, positive surgical margin, and lymph node involvement. Gleason upgrading was defined as pathologic GS higher than the GS in the prostate biopsy.

A sub-analysis was focused on evaluating the role of PNI on BCR following RP, defined as two successive postoperative PSA values of 0.2 ng/mL or greater. A secondary objective of this study, was to evaluate the impact of PNI in prostate needle biopsy on the selection of patients for AS. The AS cohort was based on the patients who performed RP but could be potentially selected for AS, defined according to the Epstein criteria (clinical stage ≤ T2a, PSA density < 0.15 ng/mL, PSA < 10 ng/mL, biopsy Gleason score ≤ 6, ≤ 2 positive biopsy cores, and ≤ 50% cancer involvement in any biopsy core). A descriptive analysis on the study population was performed.

Categorical data were compared using Pearson's chisquared test and continuous variables with Student t-test.

The biochemical recurrence-free survival was calculated through the Kaplan-Meier analysis. To estimate the prognostic value of PNI we used Cox proportional hazard regression. A two-sided p value < 0.05 was considered as statistically significant. Statistical analysis was performed using SPSS®, version 23.0 (SPSS Inc., Chicago, IL, USA).

RESULTS

A total of 107 patients were included in the study, of whom 57 (53.3%) had PNI of the biopsy specimens.

The demographic and the clinical characteristics of the patients are shown in Table 1. Patient age ranged from 48 to 73 years (mean, 63.1 years; standard deviation (SD), 5.3 years). Preoperative serum PSA levels ranged from 1.51 to 21.9 ng/mL (mean, 7.8 ng/mL; SD, 3.9 ng/mL) and the clinical T stage was T1c in 48 (44.9%) of the patients, T2a in 28 (26.2%), T2b in 20 (18.7%) and T2c in 11 (10.3%). According to D’Amico risk classification 65 (60,7%) patients were low risk, 29 (27,1%) intermediate risk and 13 (12,2%) high risk.

From the prostate biopsy specimens, 71 (66.4%) had a Gleason score of 6, 33 (30.9%) had a Gleason score of 7, and 3 (2.7%) had a Gleason score of 8 or higher. The mean number of cores involved by tumor was 4.83 (SD, 1.5), and the mean percent of core involvement was 25.8% (SD, 20%).

Pathologic findings at RP are summarized in Table 2.

Regarding the RP specimens, 25 (23.4%) showed extraprostatic extension and 29 (27.1%) had positive

Table 1.

Demographic, clinical and prostate biopsy characterization.

PNI absence PNI presence Total p (n = 50, 46.7%) (n = 57, 53.3%) (n = 107) Age, mean (years) 62.4 (SD 5.2) 63.7 (SD 5.4) 63.1 (SD 5.38) 0.189 PSA level (ng/ml) 7.64 (SD 3.6) 7.94 (SD 4.5) 7.8 (SD 3.9) 0.53 Prostate volume(mean, gr) 46.5 (SD 17.5) 45.1 (SD 14.8) 45.8 (SD 16.1) 0.46 GS biopsy 0.036 6 39 (78%) 32 (56.1%) 71 (66.4%) 7 10 (20%) 23 (40.3%) 33 (30.9%) ≥8 1 (2%) 2 (3.6%) 3 (2.7%) Number of positive cores (mean) 4.56 (SD 2.36) 5.07 (SD 2.77) 4.83 (SD 2.5) 0.31 Percent of core involvement (mean) 19.48% (SD 17%) 31.3%(SD 20.95%) 25.8% (SD 20%) 0.04 Clinical stage 0.019 T1c 23 (46%) 25 (43.9%) 48 (44.9%) T2a 20 (40%) 8 (14%) 28 (26.2%) T2b 6 (12%) 14 (24.6%) 20 (18.7%) T2c 1 (2%) 10 (17.6%) 11 (10.3%) Age, PSA level prior surgery, clinical stage and anatomopathological characteristics from biopsy stratified in two groups: patients with PNI absence and patients with PNI presence in the biopsy. Categorical data were compared using Pearson's chi-squared test and continuous variables with Student t-test.

Table 2.

Clinical and histopathologic finding on RP specimens’ characterization.

PNI absence PNI presence (n = 50, 46.7%) (n = 57, 53.3%) D’Amico risk Low Intermediate High Gleason score 6 7 ≥8 Pathological stage pT2a pT2b pT2c ≥ pT3 GS upgrading Lymphatic invasion SV invasion Extraprostatic extension Margin positivity BCR

Total (n = 107)

p 0.002

38 (76%) 10 (20%) 2 (4%)

27 (47.4%) 19 (33.3%) 11 (19.3%)

65 (60.7%) 29 (27.1%) 13 (12.2%)

34 (68%) 16 (32%) -

20 (35.1%) 34 (59.6%) 3 (5.3%)

71 (66.4%) 33 (30.9%) 3 (2.7%)

8 (16%) 5 (10%) 33 (66%) 4 (8%) 8 (16%) 3 (6%) 1 (2%) 4 (8%) 8 (16%) 9 (18%)

7 (12.3%) 1 (1.8%) 27 (47.4%) 22 (38.6%) 18 (31.6%) 7 (12.3%) 6 (10.5%) 21 (36.8%) 17 (29.8%) 22 (38.6%)

15 (14%) 6 (5.6%) 60 (56.1%) 26 (24.3%) 26 (24.2%) 10 (9.3%) 7 (6.5%) 25 (23.4%) 25 (23.4%) 31 (29%)

0.001

0.001

0.065 0.27 0.11 0.001 0.09 0.032

Clinical and histopathologic finding on RP specimens stratified in two groups: patients with PNI absence and patients with PNI presence. Categorical data were compared using Pearson's chi-squared test and continuous variables with Student t-test. SV-seminal vesicle.

margins. The seminal vesicles were invaded in 7 (6.5%) cases and lymph nodes were involved in 10 (9.3%).

Surgical GS upgrading was observed in 26 (24.2%) patients. The mean follow-up time was 71 months (SD 25.3 months) and, in this period, 26 (24.3%) men experienced BCR. Clinical and anatomopathological characteristics from the biopsy and RP specimen were stratified according to the presence or absence of PNI. Significant differences were found, patients with PNI presented higher GS on biopsy and RP specimen (p = 0.036 and p = 0.001), Archivio Italiano di Urologia e Andrologia 2020; 92, 4

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Figure 1.

Kaplan-Meier curve and Log rank test.

Biochemical recurrence-free survival in patients with or without PNI.

Table 3.

Association between disease characteristics and biochemical recurrence-free survival.

Univariate (95% IC) P value

HR

1 3.01

(1.34 -6.76)

0.008

1.65

(1.04-2.60)

0.032

1 4.02

(1.98-8.15)

0.0001

1.26

(0.48-3.27)

0.64

1 3.89

(1.90-7.94)

0.0001

3.51

(1.45-8.52)

0.005

1 2.98

(1.36-6.58)

0.007

1.64

(0.7-3.86)

0.25

HR GS in RP specimen <7 â&#x2030;Ľ7 Extraprostatic extension absence presence Surgical margin negative positive PNI absence presence

Multivariate (95% IC) P value

Univariate and multivariate Cox models. CI: confidence interval; HR: hazard ratio; GS: Gleason score.

Table 4.

Clinical and histopathologic finding on active surveillance patients.

Age, mean (years) PSA level (ng/ml) Prostate volume (mean, gr) GS upgrading extraprostatic extension

PNI absence PNI presence Total (n = 16, 55.2%) (n = 13, 44.8%) (n = 29) 62.5 (SD 4.9) 63.3 (SD 6.7) 62.86 (52-73) 7.31 (SD 4.9) 7 (SD 4.1) 7.1 (SD 4.2) 56.9 (SD 24.5) 48.7 (SD 18.4) 53.3 (SD 22) 1 (6.3%) 7 (53.8%) 8 (27.6%) 4 (30.8%) 4 (13.8%)

p 0.362 0.41 0.31 0.004 0.017

CSub-group of patients potentially selected to active surveillance. Clinical and histopathologic finding stratified in two groups: patients with PNI absence and patients with PNI presence in the prostate biopsy.

higher percent of core involvement (p = 0.04), higher clinical and pathologic T stage (p = 0.019 and p = 0.001), higher Dâ&#x20AC;&#x2122;Amico risk (p = 0.002) , extraprostatic extension (p = 0.001), and higher BCR (p = 0.032) comparing with patients without PNI. On other hand, no

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significant differences were identified with respect to age (p = 0.189), preoperative PSA (p = 0.53), number of positive cores (p = 0.31), GS upgrading (p = 0.065), surgical margin involvement (p = 0.09), lymph node invasion (p = 0.27) and seminal vesicles involvement (p = 0.11).

The Kaplan-Meier curve (Figure 1) revealed a poorer recurrence-free survival in patients with PNI (Log rank test p = 0.04). On univariate Cox analysis (Table 3), PNI was associated with BCR (HR: 2.98, 95% CI: 1.366.58, p = 0.007), as GS on RP specimen (HR: 3.01, 95% CI: 1.34-6.76, p = 0.008), surgical margin positivity (HR: 3.86, 95% CI: 1.907.94, p = 0.0001) and presence of extraprostatic extension (HR: 4.02, 95% CI: 1.98-8.15 p = 0.0001). However, the prognostic role of PNI disappeared in multivariate analysis when adjusted for other predictive factors.

In the cohort, a total of 29 men submitted to RP were potentially eligible for AS, of whom 13 (44.8%) had biopsy PNI. The characteristics of this subgroup are listed in Table 4.

A significant relation between PNI and GS upgrade (p = 0.004) and extraprostatic extension (p = 0.017) was found in the AS group.

DISCUSSION

The evaluation of pathological features that may predict oncologic outcomes are important for counselling patients and therapy selection, as treatment options in PCa differ according to defined risk groups (17). PNI was identified as a possible significant marker of adverse pathologic findings in localized PCa, however, the oncological significance and prognostic value is still controversial, with inconsistent results among studies (13).

The incidence of PNI in biopsy specimens in the present study is similar to that reported by Ravery et al. (53,3% VS 47%) (18, 19). Although, a wide range of incidences have been reported in the literature due to variation in pathologic definitions and interpretation of PNI (16).

There are many challenges in looking for PNI and a negative result may either indicate that there no nerves identified in the biopsy or that nerves were present without invasion (2).

On our study, PNI presence on the biopsy cores was associated with adverse parameters in RP specimens, including higher GS, higher pathologic T staging and extraprostatic extension. Such associations were also reported in a recent meta-analysis were PNI was a significant marker to predict high stage disease (4).

Despite hypothesized that spread along intraprostatic nerves may facilitating extraprostatic tumoral extension, there are controversial results in studies investigating the correlation between PNI and BCR. Jeon et al. and Kang et al. showed that PNI is associated with adverse pathologic findings and is an independent predictor for BCR in PCa patients who undergo RP (6, 20). The same results were observed by Yu et al. and Wong et al. in patients who undergo external beam radiotherapy (21, 22). On the

Perineural invasion in prostate needle biopsy

contrary, Reeves et al. and Freedland et al. reported that PNI is not correlated with BCR in PCa after RP (23, 24).

In our cohort, we found an association between PNI and BCR on univariate but not on multivariate analysis. This questions whether PNI is an independent prognostic factor or just a risk factor for BCR, since significance is lost when PNI presence is controlled for other biopsy parameters, such as Gleason score and extraprostatic extension (25). One possible explanation for these findings is that PNI may only be an important prognostic factor in a specific sub-group of patients. Dâ&#x20AC;&#x2122;Amico et al. found that biopsy PNI showed statistical significance on multivariate analysis only in the low risk group and Quinn et al. reported that biopsy PNI was a significant prognostic factor on multivariate analysis of patients with PSA values more than 10 ng/ml (26, 27).

In the same setting, rather than evaluated the presence or absence of PNI, quantification could have a better predictive value. Maru et al. found that PNI diameter > 0.25 mm was an independent prognostic indicator for biochemical recurrence on multivariate analysis (28).

Moreover, Sun et al. demonstrated that multifocal PNI, rather than unifocal PNI, is correlate to shorter biochemical recurrence-free survival in patients with PCa (10).

AS has been widely accepted as an observational strategy, in the last decade, in response to the over-treatment of men with low-risk PCa (16). The selection of patients is based on pathologic findings on needle core biopsy. At present, biopsy PNI is not included in the established criteria for AS selection, thus, whether PNI is potentially associated with worse prognosis and preclude a conservative management is not known. In our analysis, the presence of PNI in patients who met criteria for AS has been associated with adverse pathologic findings at prostatectomy, including GS upstaging and extraprostatic extension. These finding suggest a potential role for biopsy PNI in identifying men at risk for progression on AS. This evidence is corroborated by a retrospective review of the REduction by Dutasteride of clinical progression Events in Expectant Management (REEDEM) study, with 302 men on AS, who describe that PNI is an independent predictor of clinical progression (73% after 2 years) (29). Similarly, in a cohort of 165 men on AS, Cohn et al. reported that biopsy PNI remained a significant predictor for AS failure after adjustment biopsy parameters such as tumour length (30). While these data suggest that patients with biopsy PNI on initial biopsy may not be good candidates for AS, future study is required to assess prognostic value of this pathologic finding.

Several limitations should be acknowledged in this study.

First, the small number of cases, similar to other series published, limits the statistical power of the conclusions.

Second, the study design, as a single-institution retrospective analysis with risk of unmeasured bias, does not allow to generalize the conclusions. Third, prostatectomy specimens did not undergo a centralized review, so there may be variability in the reporting of PNI. Ideally, a multicenter randomized prospective study with a larger sample would answer many questions raised in our study.

Fourth, we only report PNI as a binary variable because quantitative measures of PNI were not included in pathology reports. Finally, a short follow-up with a mean of 71 months can undervalue the BCR.

CONCLUSIONS

In conclusion, despite the limitations listed above, this study recognizes the clinicopathological importance and potential prognostic value of PNI in PCa. The presence of PNI on prostate biopsy cores is an important predictive of aggressive disease in patients submitted to RP with clinically localized PCa and an indicator of BCR in univariate analysis. Additionally, among men who met criteria for AS, biopsy PNI is associate with GS upgrade and extraprostatic extension and could have a role in the selection of patients for AS. A large prospective study with longer follow-up is needed to confirm these results.

REFERENCES

1. Zhang LJ, Wu B, Zha ZL, et al. Perineural invasion as an independent predictor of biochemical recurrence in prostate cancer following radical prostatectomy or radiotherapy: a systematic review and meta-analysis. BMC Urol. 2018; 18:5.

2. Ahmad AS, Parameshwaran V, Beltran L, et al. Should reporting of peri-neural invasion and extra prostatic extension be mandatory in prostate cancer biopsies? correlation with outcome in biopsy cases treated conservatively. Oncotarget. 2018; 9:20555-20562.

3. Vargas SO, Jiroutek M, Welch WR, et al. Perineural invasion in prostate needle biopsy specimens. Correlation with extraprostatic extension at resection. Am J Clin Pathol. 1999; 111:223-228.

4. Celik S, Bozkurt O, Demir O, et al. Effects of perineural invasion in prostate needle biopsy on tumor grade and biochemical recurrence rates after radical prostatectomy. Kaohsiung J Med Sci. 2018; 34:385-390.

5. Erdem S, Verep S, Bagbudar S, et al. The clinical predictive factors and postoperative histopathological parameters associated with upgrading after radical prostatectomy: A contemporary analysis with grade groups. Prostate. 2020; 80:225-234.

6. Jeon HG, Bae J, Yi JS, et al. Perineural invasion is a prognostic factor for biochemical failure after radical prostatectomy. Int J Urol.

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7. Barsky AR, Kraus RD, Carmona R, et al. Investigating association of perineural invasion on prostate biopsy with Gleason score upgrading at prostatectomy: A multi-institutional analysis. Cancer Med. 2020; 9:3383-3389.

8. Verep S, Erdem S, Ozluk Y, et al. The pathological upgrading after radical prostatectomy in low-risk prostate cancer patients who are eligible for active surveillance: How safe is it to depend on bioptic pathology? Prostate. 2019; 79:1523-1529.

9. Ediz C, Akan S, Temel MC, Yilmaz O. The importance of PSADensity in active surveillance for prostate cancer. Arch Ital Urol Androl. 2020; 92:136-141.

10. Kraus RD, Barsky A, Ji L, et al. The Perineural Invasion Paradox: Is Perineural Invasion an Independent Prognostic Indicator of Biochemical Recurrence Risk in Patients With pT2N0R0 Prostate Cancer? A Multi-Institutional Study. Adv Radiat Oncol.

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12. Strom P, Nordstrom T, Delahunt B, et al. Prognostic value of perineural invasion in prostate needle biopsies: a population-based study of patients treated by radical prostatectomy. J Clin Pathol.

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13. Zhao J, Chen J, Zhang M, et al. The clinical significance of perineural invasion in patients with de novo metastatic prostate cancer.

Andrology. 2019; 7:184-192.

chemical recurrence-free survival in patients with prostate cancer treated with definitive external beam radiotherapy. Urology. 2007; 70:111-116.

14. Zareba P, Flavin R, Isikbay M, et al. Perineural Invasion and Risk of Lethal Prostate Cancer. Cancer Epidemiol Biomarkers Prev.

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23. Reeves F, Hovens CM, Harewood L, et al. Does perineural invasion in a radical prostatectomy specimen predict biochemical recurrence in men with prostate cancer? Can Urol Assoc J. 2015; 9:E252255.

15. Kuang AG, Nickel JC, Andriole GL, et al. Both acute and chronic inflammation are associated with less perineural invasion in men with prostate cancer on repeat biopsy. BJU Int. 2019; 123:91-97.

16. Wu S, Lin X, Lin SX, et al. Impact of biopsy perineural invasion on the outcomes of patients who underwent radical prostatectomy: a systematic review and meta-analysis. Scand J Urol. 2019; 53:287-294.

17. Camur E, Coskun A, Kavukoglu, et al. Prostate volume effect on Gleason score upgrading in active surveillance appropriate patients.

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20. Kang M, Oh JJ, Lee S, et al. Perineural Invasion and Lymphovascular Invasion are Associated with Increased Risk of Biochemical Recurrence in Patients Undergoing Radical Prostatectomy.

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21. Wong WW, Schild SE, Vora SA, Halyard MY. Association of percent positive prostate biopsies and perineural invasion with biochemical outcome after external beam radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2004; 60:24-29.

22. Yu HH, Song DY, Tsai YY, et al. Perineural invasion affects bio-

Correspondence Nuno Ramos, MD (Corresponding Author) nuno.ramos@hgo.min-saude.pt nunoandre33@gmail.com Alexandre Macedo, MD alex.m.macedo89@gmail.com JoĂŁo Rosa, MD jpmrosa@yahoo.com Miguel Carvalho, MD uro.miguelcarvalho@gmail.com Urology Department, Garcia de Orta Hospital Av. Torrado da Silva, 2801-951, Almada (Portugal)

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24. Freedland SJ, Csathy GS, Dorey F, Aronson WJ. Percent prostate needle biopsy tissue with cancer is more predictive of biochemical failure or adverse pathology after radical prostatectomy than prostate specific antigen or Gleason score. J Urol. 2002; 167:516-520.

25. Trpkov C, Yilmaz A, Trpkov K. Perineural invasion in prostate cancer patients who are potential candidates for active surveillance: validation study. Urology. 2014; 84:149-152.

26. D'Amico AV, Wu Y, Chen MH, et al. Perineural invasion as a predictor of biochemical outcome following radical prostatectomy for select men with clinically localized prostate cancer. J Urol. 2001; 165:126-129.

27. Quinn DI, Henshall SM, Brenner PC, et al. Prognostic significance of preoperative factors in localized prostate carcinoma treated with radical prostatectomy: importance of percentage of biopsies that contain tumor and the presence of biopsy perineural invasion.

Cancer. 2003; 97:1884-1893.

28. Maru N, Ohori M, Kattan MW, et al. Prognostic significance of the diameter of perineural invasion in radical prostatectomy specimens. Hum Pathol. 2001; 32:828-833.

29. Moreira DM, Fleshner NE, Freedland SJ. Baseline Perineural Invasion is Associated with Shorter Time to Progression in Men with Prostate Cancer Undergoing Active Surveillance: Results from the REDEEM Study. J Urol. 2015; 194:1258-1263.

30. Cohn JA, Dangle PP, Wang CE, et al. The prognostic significance of perineural invasion and race in men considering active surveillance. BJU Int. 2014; 114:75-80.

DOI: 10.4081/aiua.2020.4.335

ORIGINAL PAPER

Effects of butein on renal ischemia/reperfusion injury: An experimental study Mehmet Akif Ramazanoglu 1, Tuncay Toprak 2, Mehmet Remzi Erdem 3, Gulistan Gumrukcu 4, Hatice Kucuk 5, Feridun Sengor 6 1 Department 2 University

of Urology, Rize State Hospital, Rize, Turkey; of Health Sciences, Turkey. Fatih Sultan Mehmet Training and Research Hospital, Department of Urology, Istanbul,

Turkey;

3 Department

of Urology, Istanbul Kolan Hospital, Istanbul, Turkey; of Pathology, Haydarpaşa Numune Training and Research Hospital, Istanbul, Turkey; 5 Department of Pathology, Kanuni Training and Research Hospital, Trabzon, Turkey; 6 Department of Pathology, University of Kırklareli, Faculty of Kırklareli, Turkey.

4 Department

Summary

Objectives: Renal ischemia/reperfusion (I/R) injury is a common cause of acute kidney injury. The aim of this study was to investigate the effect of butein on renal I/R injury.

Materials and methods: Twenty-seven rats were randomly allocated to three groups (n = 9): a sham group, a renal I/Runtreated (control) group, and a renal I/R-butein group.

The sham group underwent only opening and closing of the peritoneum. In the control group, an experimental I/R model was created and 1 cc isotonic saline was applied to the peritoneum. In the butein group, the experimental I/R model was created and 1 mg/kg butein was administered intraperitoneally 15 minutes before the beginning of ischemia. The left kidneys of the rats were histopathologically examined for tissue damage caused by I/R. Results: Histopathological examination of the tissue damage revealed that all kidneys in the sham group were normal. By contrast, 2 in the control group (22.2%) had small focal damaged areas, 1 (11.1%) had < 10% cortical damage, 5 (55.6%) had 10-25% cortical damage, and 1 (11.1%) had 25-75% cortical damage. The butein group had 1 (11.1%) normal kidney, 2 (22.2%) with small focal damaged areas, 4 (44.4%) with < 10% cortical damage, and 2 (22.2%) with 10-25% cortical damage. Tissue damage was significantly lower in the sham group than in the control and butein groups (p < 0.01).

No statistically significant differences were observed in the histopathology of the control and butein groups (p > 0.05).

Conclusions: Intraperitoneal administration of butein had no significant effect on renal tissue injury.

KEY WORDS: Butein; Oxidative stress; Renal ischemia; Reperfusion injury; Rat. Submitted 19 June 2020; Accepted 28 July 2020

INTRODUCTION

Ischemia/reperfusion (I/R) injury is a common cause of renal injury arising from a variety of clinical circumstances, including partial nephrectomy, renal transplantation, renal artery angioplasty, hydronephrosis and iatrogenic trauma (1, 2). The pathologic processes underlying this injury are complex and involve inflam-

mation, reactive oxygen radicals, apoptosis and necrosis (3, 4). Tissues that have undergone I/R are subjected to pro-inflammatory processes of cytokine release and the production of reactive oxygen radicals (ROR) by neutrophils (5). The production of ROR is considered a key reason for uncontrolled oxidative stress during the reperfusion period (4). Thus, oxidative stress is extremely important in renal I/R injury (6), and targeting its processes is an ideal therapeutic approach.

The importance of I/R injury preventing during nephron sparing surgery is major issue in urology practice. Serum creatinine can increase and glomerular infiltration rate can decrease after nephron sparing surgery even in the patients who have healthy contralateral kidney. To preserve better kidney function leads lowering the risk of development of metabolic or cardiovascular disorders (7). To date, many pharmacological agents such as Nacetylcysteine (8), Allopurinal (9) or Mannitol (10) have been identified to decrease I/R injury after nephron sparing surgery. Another potential compound that can target I/R injury is butein, a polyphenolic compound which has reported biological activities ranging from antioxidant properties (11) to anti-fibrogenic, anti-inflamatory (12). It can also exert a protective effect on ischemia or I/R damage (13).

Against this background, we hypothesized that butein using may reduce I/R injury in rats by its anti-oxidative effects. To the best of our knowledge, there is no information about of the anti-oxidative effects of butein in rat model of renal I/R injury.

MATERIALS

AND METHODS

All experimental and surgical procedures were approved by the Institutional Animal Care and Use Committee of University of Bezmialem (Istanbul, Turkey) (Approval Number/ID: 2016/134).

The procedures complied with the Guide for the Care and Use of Laboratory Animals and were conducted according to animal care guidelines (14). A total of 27 male WistarAlbino (WA) rats (8 weeks old, weight 220-250 g) were purchased from the University of Bezmialem (Istanbul,

No conflict of interest declared.

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Mehmet Akif Ramazanoglu, Tuncay Toprak, Mehmet Remzi Erdem, Gulistan Gumrukcu, Hatice Kucuk, Feridun Sengor

Turkey). The animals were kept in captivity under the same nutritional and environmental conditions. Rats were entrained under a 12:12 h light: dark cycle with stable temperature (21 ± 2°C) and humidity (60 ± 10%). The rats had food and sterile water available ad libitum.

Experimental design The WA rats were randomly divided into three groups (n = 9 in each group): 1. Sham group: After sterile conditions were obtained, a midline laparotomy was performed. The left kidney pedicle was then dissected. No other procedure was performed, and the incision was closed in two layers.

2. Control group (Renal I/R injury and plasebo group): After sterile conditions were obtained, a midline laparotomy was performed. Isotonic saline (1 mg/kg) was applied intraperitoneally 15 minutes before the beginning of arterial clamping. The left kidney pedicle was clamped with an artery clamp for 45 minutes. After 45 minutes of left renal ischemia, the occlusion clamp was removed and the incision was closed in two layers.

3. Renal I/R injury and butein group: After sterile conditions were obtained, a midline laparotomy was performed. Butein (1 mg/kg) was applied intraperitoneally 15 minutes before the beginning of arterial clamping.

The left kidney pedicle was clamped with an artery clamp for 45 minutes. After 45 minutes of left renal ischemia, the occlusion clamp was removed and the incision was closed in two layers.

Butein was sourced from Farmasina Medical and Chemical Products Company (Kayışdağı, Ataşehir, Istanbul).

Induction of renal I/R injury The rats were anesthetized with an intraperitoneal injection of ketamine (100 mg/kg, Ketalar, Eczacıbasi, Turkey) and xylazine (10 mg/kg). The midline laparotomy and dissection of the left kidney pedicle were then performed as already described, followed by the I/R procedure for the control and butein groups. All procedures were performed under sterile conditions. The rats were sacrificed 24 h after completion of the reperfusion procedure and kidney samples were obtained.

Histological analysis Renal tissues were extracted from rats in all groups (24 h after surgery), as well as following intraperitoneal injection of butein (1 mg/kg) in the butein group. Kidney tissue was embedded in paraffin and 5 μm tissue sections were taken for Hematoxylin and Eosin (H&E) staining. An independent pathologist blinded to the treatment groups, analyzed three different tissue sections from rats in each treatment group, using a Zeiss Axio Imager A2 microscope (Carl Zeiss AG, Germany).

The histological evaluations of the renal tissue were graded as follows: 0, normal; 0.5, small focal damage areas; 1, areas of tubular epithelial cell necrosis and desquamation, including < 10% of cortical tubules; 2, similar changes, including 10-25% cortical tubules; 3, similar changes including 25-75% cortical tubules; and 4, similar changes including > 75% cortical tubules. This scoring system is shown in Table 1 (15).

Statistical analysis

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Archivio Italiano di Urologia e Andrologia 2020; 92, 4

Table 1.

Scoring system for renal histopathology.

Score 0 0.5 1 2 3 4

Histopathological pattern Normal Small focal damaged areas < 10% Cortical damaged zone 10–25% Cortical damaged zone 25–75% Cortical damaged zone > 75% Cortical damaged zone

Statistical analysis was performed using the SPSS 22 software. Before starting to study, we performed power analysis. The power analysis showed that 9 subjects per group would be needed to have a 80% chance of achieving statistical significance at the p < 0.05 level.

The Kolmogorov-Smirnov test was performed to determine the normality of data. The results are expressed as mean ± SD. Mann-Whitney U and Kruskal-Wallis tests were performed for comparison of two and three independent samples, respectively. A p value below 0.05 was considered statistically significant.

RESULTS

Histopathological examination of tissue damage revealed that all rats in the sham group had normal kidneys. By contrast, 2 rats in the control group (22.2%) had small focal damaged areas, 1 (11.1%) had < 10% cortical damage, 5 (55.6%) had 10-25% cortical damage, and 1 (11.1%) had 25-75% cortical damage. The butein group had 1 rat (11.1%) with normal kidneys, 2 (22.2%) with small focal damaged areas, 4 (44.4%) with < 10% cortical damage, and 2 (22.2%) with 10-25% cortical damage. Renal cortical damage was significantly lower in the sham group than in the control and butein groups (p < 0.01). No statistically significant difference was noted in the histopathology of the control and butein groups (p > 0.05).

Histopathologic results for the experimental animals were shown in Table 2. Histological images of the damage according to the scoring system for the rat renal cortex sections after IR injury were shown in Figures 1-4 Table 2.

Histopathologic results for the experimental animals.

Normal Small focal damaged areas < 10% damaged cortical zone 10–25% damaged cortical zone 25–75% damaged cortical zone Min-max (median) pa Sham-Control groupb Sham-Butein groupb Control-Butein groupb

Sham group n (%) 9 (100) 0 0 0 0 0–0 (0) 0.001** 0.001** 0.001** 0.105

a Kruskal-Wallis test; b Mann-Whitney U test; **p < 0.01.

Control group n (%) 0 2 (22.2) 1 (11.1) 5 (55.6) 1 (11.1) 0.5-3 (2)

Butein Total group n (%) 1 (11.1) 10 (37.0) 2 (22.2) 4 (14.8) 4 (44.4) 5 (18.5) 2 (22.2) 7 (25.9) 0 1 (3.7) 0-2 (1) 0-3 (0.5)

Effects of butein in renal I/R injury

Figure 1.

Normal cortex (Histopathologic score = 0).

and dissociation of histopathologic tissue damage according to groups was shown in Figure 5.

DISCUSSION

The complicated pathogenesis of renal I/R injury is due to the broad range of effects on vascular endothelial and tubular epithelial cells (16). These effects are characterized by the cellular accumulation of waste products, imbalances in electrolytes and acid-base levels (17).

Renal I/R injury induces an inflammatory response by Figure 2. triggering the immune systems. An infiltration of leukoCortical focal cytes then occurs in the site of inflammation, followed by necrose areas activation of tubular epithelial cells (18, 19). The influx (Histopathologic of neutrophils and macrophages into injured renal tissue score = 1). results in the secretion of pro-inflammatory cytokines, including TNF-a, HMGB1, IL-6, and IL-1b (20), while the infiltrated cells themselves reduce blood flow in the kidney and disrupt microcirculation (21). Significant increases in pro-inflammatory cytokine levels have been reported following renal I/R injury in rats (22).

In the present study, butein was examined for its potenFigure 3. tial effects on regulating renal I/R injury. We considered More common that butein may serve a protective role in the rat model cortical necrose of renal I/R injury model by regulating the level of areas (Histopathologic inflammatory cytokines. Butein is an important herbal score = 2). polyphenol in traditional Japanese and Korean medicine, where it has been used as an analgesic, antibiotic, antithrombotic, anticancer, and anti-inflammatory medicine (23). It has demonstrated a broad spectrum of activity in both in vivo and in vitro models, including antineoplastic, anti-inflammatory, and antioxidant effects (24), but the mechanism underlying its antiinFigure 4. flammatory properties is unclear.

Extensive cortical necrose areas The present evidence suggests that butein inhibits many (Histopathologic enzymes and pro-inflammatory mediators and that it score = 3). also suppresses macrophage-mediated inflammation.

One study performed in macrophage culture showed suppression of lipopolysaccharide-dependent nitrite and PGE2 production by butein and a pronounced antiinflammatory effect (25). Application of butein to cell cultures resulted in COX-1 and COX-2 inhibition (11).

Lee and colleagues suggested the use of butein as a treatment for intestinal Figure 5. inflammation, as butein reduced the Dissociation of histopathologic tissue damage according to groups. expression of IL-8 in intestinal epithelial cell cultures (26). Butein also reduced E-selectin expression in human umbilical vein cells and expression of ICAM-1 and VCAM-1 in endothelial cells (27).

In addition, butein inhibited proinflammatory gene activity by inhibiting NFkBeta activation and inhibited the release of TNF-a, IL-6 and IL-8 (28).

Many studies have shown that butein neutralizes and inhibits production of ROR and protects the cells from ROR damage. In living organisms, ROR arise as a result of normal biological metabolism and they can distort the structures of DNA, fats, proteins and carbohydrates. The best known of these oxygen Archivio Italiano di Urologia e Andrologia 2020; 92, 4

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radicals are the superoxide anion, hydrogen peroxide, and hydroxyl radicals. Cheng et al. used CCl4 to cause cellular damage to the liver and then tried to repair this cellular damage using butein and a-tocopherol. Butein showed a similar antioxidant effect to that of a-tocopherol, but butein had the advantage of eliciting an effect at lower doses (11).

I/R-induced damage differs histologically in some respects from chemically induced damage. For example, the arterial circulation in the renal cortex is somewhat suppressed following I/R, due to tubulo-glomerular arteriolar vasoconstriction, cellular swelling, tubular obstruction, and vascular occlusion arising from extravasation of white blood cells and erythrocytes from the external medulla. The proximal tubules affected by I/R are damaged due to warm ischemia during recirculation and this leads to regression of the renal function when circulation returns to its original state. During re-infusion, the tubular lumen diameter increases, while punctures from the proximal tubules block the tubules, creating resistance to fluid ingestion in the handle and proximal tubules.

The result is a decrease in tubular reabsorption due to cellular damage, while capillary expansion increases the intratubular pressure in the external medullary collecting tubes. Subsequently, in addition to a 12% reduction in blood flow, the GFR is also reduced by 90% (29).

The tubular tissue undergoes atrophy, the tubular lumen diameter increases, the tubules undergo hyalinization, and reactive atypia, brushy edge loss, cellular swelling, nucleus deformity, and leukocyte infiltration are observed.

In our study, histopathologic evaluation of the tissue response to butein in the renal I/R rat model was compared with the non-butein control group and the sham group. Histopathologically significant differences were found between the sham group and the other groups, but no statistically significance was noted histopathologically between the I/R rats treated with butein or the saline control (p > 0.05).

The current study has two major limitations: Plasma concentrations of creatinine and urea were not measured, and no biochemical analysis of renal tissue was performed.

CONCLUSIONS

The intraperitoneal administration of butein to the rat experimental I/R model did not result in a statistically significant effect on renal tissue I/R injury. Nevertheless, this study is important since, to the best of our knowledge, it is the first study in the literature to test butein for effects on renal I/R. Further meaningful results can be obtained in comparative studies of different applications of butein.

REFERENCES

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2. Snoeijs MG, Vink H, Voesten N, et al. Acute ischemic injury to the renal microvasculature in human kidney transplantation. Am J Physiol Renal Physiol. 2010; 299:F1134-F40.

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3. Zhang J, Zou Yr, Zhong X, et al. Erythropoietin pretreatment ameliorates renal ischaemia-reperfusion injury by activating PI3K/Akt signalling. Nephrology. 2015; 20:266-72.

4. Wang L, Liu X, Chen H, et al. Effect of picroside II on apoptosis induced by renal ischemia/reperfusion injury in rats. Exp Ther Med. 2015; 9:817-22.

5. Barinaga M. Forging a path to cell death. Science 1996; 273:735-7.

6. Eltzschig HK, Eckle T. Ischemia and reperfusion—from mechanism to translation. Nat Med. 2011; 17:1391.

7. Ljungberg B, Bensalah K, Canfield S, et al. EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol. 2015; 67:913-24.

8. Conesa EL, Valero F, Nadal JC, et al. N-acetyl-L-cysteine improves renal medullary hypoperfusion in acute renal failure. Am J Physiol Regul Integr Comp Physiol. 2001; 281:R730-R7.

9. Rhoden E, Telöken C, Lucas M, et al. Protective effect of allopurinol in the renal ischemia–reperfusion in uninephrectomized rats.

Gen Pharmacol. 2000; 35:189-93.

10. Feitoza CQ, Câmara NO, Pinheiro HS, et al. Cyclooxygenase 1 and/or 2 blockade ameliorates the renal tissue damage triggered by ischemia and reperfusion injury. Int Immunopharmacol. 2005; 5:79-84.

11. Cheng Z-J, Kuo S-C, Chan S-C, et al. Antioxidant properties of butein isolated from Dalbergia odorifera. Biochim Biophys Acta.

1998; 1392:291-9.

12. Lee SH, Nan J-X, Zhao YZ, et al. The chalcone butein from Rhus verniciflua shows antifibrogenic activity. Planta Med. 2003; 69:990-4.

13. Lu M, Wang S, Han X, Lv D. Butein inhibits NF-kB activation and reduces infiltration of inflammatory cells and apoptosis after spinal cord injury in rats. Neurosci Lett. 2013; 542:87-91.

14. Council NR. Guide for the care and use of laboratory animals: National Academies Press; 2010.

15. Altintas R, Polat A, Vardi N, et al. The protective effects of apocynin on kidney damage caused by renal ischemia/reperfusion. J Endourol. 2013; 27:617-24.

16. Basile DP, Friedrich JL, Spahic J, et al. Impaired endothelial proliferation and mesenchymal transition contribute to vascular rarefaction following acute kidney injury Am J Physiol Renal Physiol. 2011; 300:F721-F33.

17. Huber TB, Edelstein CL, Hartleben B, et al. Emerging role of autophagy in kidney function, diseases and aging. Autophagy. 2012; 8:1009-31.

18. Land WG. The role of postischemic reperfusion injury and other nonantigen-dependent inflammatory pathways in transplantation.

Transplantation. 2005; 79:505-14.

19. Serteser M, Koken T, Kahraman A, Yilmaz K, Akbulut G, Dilek ON. Changes in hepatic TNF-a levels, antioxidant status, and oxidation products after renal ischemia/reperfusion injury in mice. J Surg Res. 2002; 107:234-40.

20. Ysebaert DK, De Greef KE, Vercauteren SR, et al. Identification and kinetics of leukocytes after severe ischaemia/reperfusion renal injury. Nephrol Dial Transplant. 2000; 15:1562-74.

21. Bolisetty S, Agarwal A. Neutrophils in acute kidney injury: not neutral any more. Kidney Int. 2009; 75:674-6.

Effects of butein in renal I/R injury

22. Dessing MC, Pulskens WP, Teske GJ, et al. RAGE does not contribute to renal injury and damage upon ischemia/reperfusioninduced injury. J Innate Immun. 2012; 4:80-5.

tor a-induced interleukin 8 and matrix metalloproteinase 7 production by inhibiting p38 kinase and osteopontin mediated signaling events in HT-29 cells. Life Sci. 2007; 81:1535-43.

23. Kang DG, Lee AS, Mun YJ, et al. Butein ameliorates renal concentrating ability in cisplatin-induced acute renal failure in rats.

Biol Pharm Bull. 2004; 27:366-70.

27. Takano-Ishikawa Y, Goto M, Yamaki K. Inhibitory effects of several flavonoids on E-selectin expression on human umbilical vein endothelial cells stimulated by tumor necrosis factor-a. Phytother Res. 2003; 17:1224-7.

24. Wang Y, Chan FL, Chen S, Leung LK. The plant polyphenol butein inhibits testosterone-induced proliferation in breast cancer cells expressing aromatase. Life Sci. 2005; 77:39-51.

25. Jung CH, Kim JH, Hong MH, et al. Phenolic-rich fraction from Rhus verniciflua Stokes (RVS) suppress inflammatory response via NF-kB and JNK pathway in lipopolysaccharide-induced RAW 264.7 macrophages. J Ethnopharmacol. 2007; 110:490-7.

26. Lee SH, Seo GS, Jin XY, et al. Butein blocks tumor necrosis fac-

28. Jang JH, Yang ES, Min K-J, Kwon TK. Inhibitory effect of butein on tumor necrosis factor-a-induced expression of cell adhesion molecules in human lung epithelial cells via inhibition of reactive oxygen species generation, NF-kB activation and Akt phosphorylation. Int J Mol Med. 2012; 30:1357-64.

29. Yin M, Kurvers HM, Tangelder G, et al. Intravital microscope studies of the ischemically injured rat kidney during the early phase of reperfusion. Transplant Proc. 1995; 27:2847-8.

Correspondence Mehmet Akif Ramazanoglu, MD (Corresponding Author) maramazanoglu@hotmail.com Rize State Hospital, Department of Urology Eminettin mah. Atatürk caddesi, merkez, 53020 Rize (Turkey) Tuncay Toprak, MD drtuncay55@hotmail.com University of Health Sciences, Turkey. Fatih Sultan Mehmet Training and Research Hospital, Department of Urology, Istanbul (Turkey) Mehmet Remzi Erdem, MD remzierdem@gmail.com Department of Urology, Istanbul Kolan Hospital, Istanbul (Turkey) Gulistan Gumrukcu, MD Department of Pathology, Haydarpasa Numune Training and Research Hospital, Istanbul (Turkey) Hatice Kucuk, Assistant Professor dr.hatice.kucuk@hotmail.com Department of Pathology, Kanuni Training and Research Hospital, Trabzon (Turkey) Feridun Sengor, Professor fsengor2004@yahoo.com Department of Urology, University of Kırklareli, Faculty of Kırklareli, (Turkey)

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DOI: 10.4081/aiua.2020.4.340

ORIGINAL PAPER

Protective effect of cordycepin on experimental renal ischemia/reperfusion injury in rats Hasan Riza Aydin 1, Cagri Akin Sekerci 2, Ertugrul Yigit 3, Hatice Kucuk 4, Huseyin Kocakgol 1, Seyfi Kartal 5, Yiloren Tanidir 2, Orhan Deger 6 1 Department

of Urology, University of Health Sciences, Trabzon Kanuni Training and Research Hospital, Turkey; University School of Medicine, Department of Urology, Istanbul, Turkey; 3 Karadeniz Technical University, Department of Biochemistry, Trabzon, Turkey; 4 Department of Pathology, University of Health Sciences, Trabzon Kanuni Training and Research Hospital, Turkey; 5 Department of Anesthesia and Reanimation, University of Health Sciences, Trabzon Kanuni Training and Research Hospital, Turkey; 6 Karadeniz Technical University, Department of Biochemistry, Trabzın, Turkey.

2 Marmara

Summary

Aim: To date, various molecules have been investigated to reduce the effect of renal ischemia/reperfusion (I/R) injury. However, none have yet led to clinical use. The present study aimed to investigate the protective effect of cordycepin (C) on renal I/R injury in an experimental rat model.

Materials and methods: Twenty-four mature Sprague Dawley female rat was randomly divided into three groups: Sham, I/R, I/R+C. All animals underwent abdominal exploration. To induce I/R injury, an atraumatic vascular bulldog clamp was applied to the right renal pedicle for 60 minutes (ischemia) and later clamp was removed to allow reperfusion in all rats, except for the sham group. In the I/R + C group, 10 mg/kg C was administered intraperitoneally, immediately after reperfusion. After 4 hours of reperfusion, the experiment was terminated with right nephrectomy. Histological studies and biochemical analyses were performed on the right nephrectomy specimens. EGTI (endothelial, glomerular, tubulointerstitial) histopathology scoring and semi-quantitative analysis of renal cortical necrosis were used for histological analyses and superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), total oxidant status (TOS) for biochemical analyses.

Results: Histopathological examination of the tissue damage revealed that all kidneys in the sham group were normal. The I/R group had higher histopathological scores than the I/R + C group. In the biochemical analysis of the tissues, SOD, MDA, TOS values were found to be statistically different in the I/R group compared to the I/R + C group (p: 0.004, 0.004, 0.001 respectively).

Conclusions: Intraperitoneal cordycepin injection following ischemia preserve renal tissue against oxidative stress in a rat model of renal I/R injury.

KEY WORDS: Cordycepin; Ischemia/reperfusion injury; Kidney; Rat. Submitted 19 October 2020; Accepted 27 October 2020

INTRODUCTION

Renal ischemia is one of the important causes of acute renal failure. Acute renal failure is an important public health problem with high morbidity, mortality, and cost

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worldwide (1). Hypotension, shock, sepsis, renal artery embolism, trauma, renal transplantation, and partial nephrectomy are the main conditions that cause renal ischemia. Renal tissue damage develops with the failure of oxygen and nutritional support of kidney cells due to a complete stop or decrease of blood flow.

Ischemia/reperfusion (I/R) is defined as restoring blood flow after it is interrupted. In the case of reperfusion following renal ischemia, tissue damage continues.

Necrosis, apoptosis, free oxygen radicals, and inflammation have been described as the main mechanisms that are responsible for I/R kidney damage. However, the mechanism of development of I/R kidney damage is not clear (2, 3). Various agents have been studied to protect the kidney from I/R damage. Doxycycline (by decreasing pro-inflammatory cytokine levels), ascorbic acid (by reducing antioxidant activity), leptin (by decreasing TNF alpha level and by increasing nitric oxide levels), iloprost (by suppressing lipid peroxidation) and levosimendan (antioxidant and NO/release) have been shown to have protective effects on I/R kidney damage (4).

Cordycepin (C) is an adenosine analog and reported as the first nucleoside antibiotic isolated from Cordycepin militaris culture. Cordycepin has been shown to have protective effects on testicular I/R injury in rats, and its anti-inflammatory, anti-tumor and antioxidant properties have been reported (5-7). In this study, we aimed to investigate the effects of Cordycepin on experimental renal I/R injury.

MATERIALS

AND METHODS

24 male Sprague-Dawley female rats (8 weeks old, weight 230-300 g) were obtained from the Karadeniz Technical University Laboratory Animals Research Centre (Trabzon, Turkey). The study was approved from the Animal Experiments Local Ethics Committee of Karadeniz Technical University (Trabzon, Turkey) (Approval Number/ID: 2018/21). The same environment and nutritional conditions were provided for all animals. Rats were entrained under a 12:12 h dark: light cycle (lights on 6 am-6 pm) with stable temperature (21 ± 2°C) and No conflict of interest declared.

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humidity (60 ± 5%). The rats had sterile water and food available ad libitum.

Experimental protocol and surgical procedure The protocol is described in the previous study (8). Rats were randomly and equally divided into 3 groups; sham group, I/R group, I/R+C group. Ketamine hydrochloride (100 mg/kg, Ketalar, Eczacibasi, Turkey) and xylazine (10 mg/kg) were used intraperitoneally for anesthesia.

A midline laparotomy incision was performed, and the right renal pedicle was dissected. Then, right renal ischemia was performed with bulldog clamp for 60 minutes in I/R and I/R+C groups. The clamp was removed for reperfusion and the renal artery pulse was visually confirmed. In the I/R+C group, 10 mg/kg Cordycepin was administered intraperitoneally following the beginning of reperfusion and saline in the I/R group. After controlling the bleeding, the skin layers were sutured. In the sham group, rats underwent a similar surgical procedure without renal occlusion. The rats were sacrificed 4 hours after reperfusion and the right nephrectomy was performed. Renal tissues were prepared for biochemical analyses and histopathological examination.

Histological analysis After the kidney tissue samples were fixed in 10% formaldehyde for 24-48 hours, routine histological followup was performed. Serial sections of 5-micron thickness were taken from the paraffin-embedded tissues.

Subsequently, the samples were stained with hematoxylin-eosin and I/R related changes were evaluated under the light microscope. Besides, sections were taken from each paraffin block, and Periodic acid-Schiff (PAS) and Masson trichrome stain were applied for evaluation of fibrosis and Bowman capsule thickening. The histological evaluations of the renal tissue damage were graded as described in the study of Medeiros et al. (Table 1) (9). EGTI scoring system was also used (Table 2) for histological analyses (10). This system examines histological damage in 4 separate sections: Endothelial, Glomerular, Tubular, and Interstitial. The histological evaluations were made by examining each section one by one and considering the areas where the damage was most severe.

Biochemical analysis The tissues were first cleaned by saline solution and stored at -80 °C until the analysis time. In the analysis process, first they were homogenized in cold phosphate buffer solution (PBS) (0.05 M, pH 7.4), and were centrifuged at 3000 rpm for 10 min to remove debris and to obtain clear supernatant fraction. Then, the analyses were performed in this fraction. Malondialdehyde (MDA), Total Oxidant Status (TOS), as well as enzyme activities of Superoxide Dismutase (SOD) and Catalase (CAT) were measured in this fraction. MDA levels in tissue samples were determined using the method described by Mihara and Uchiyama. Tetramethoxypropane was used as a standard, and tissue MDA levels were calculated as nmol/g wet tissue (11). TOS levels were determined using a colorimetric TOS kit as previously described by Erel (12). CAT activity was measured by modifying the method based on the

measurement of the absorbance of ammonium molybdate with H2O2 at 405 nm. CAT standard (Sigma C9322) was used as a standard, and tissue CAT activity was calculated as nmol/g protein (13). The SOD enzyme activity was determined by the method of Sun and Oberley. This method is based on the measurement of the absorbance of the purple-colored formazan molecule at 560 nm resulting from the reduction of nitroblue tetrazolium of O2.formed by the xanthine-xanthine oxidase system. Tissue SOD activity was calculated as nmol/g protein by using SOD standard (Sigma S8160) (14).

Statistical analysis The data were transferred to SPSS 22 (Statistical Package for the Social Sciences) computer package program and evaluated statistically. Compliance with normal distribution was checked by the Kolmogorov-Smirnov test. One way ANOVA and post-hoc Tukey tests were used for the evaluation of more than two independent groups that fit the normal distribution, and the Kruskal-Wallis test was used for the evaluation of more than two parameters that did not fit the normal distribution, and Mann WhitneyU test was used for the binary parameter that did not fit the normal distribution. The values obtained were expressed as mean ± standard deviation (x ± SD) and p < 0.05 was considered statistically significant.

Table 1.

Scoring system for renal histopathology.

Score 0 0.5 1 2 3 4

Histopathological pattern Normal Small focal damaged areas < 10% Cortical damaged zone 10–25% Cortical damaged zone 25–75% Cortical damaged zone > 75% Cortical damaged zone

Table 2.

The EGTI histological (Endothelial, Glomerular, Tubular, Interstitial) scoring system.

Tissue type Tubular

Endothelial

Glomerular

Tubulo/Interstitial

Damage Score No damage 0 0 Loss of Brush Border (BB) in less than 25% of tubular cells.

Integrity of basal membrane 1 Loss of BB in more than 25% of tubular cells, Thickened basal membrane 2 (Plus) Inflammation, cast formation, necrosis up to 60% of tubular cells 3 (Plus) necrosis in more than 60% of tubular cells 4 No damage 0 Endothelial swelling 1 Endothelial disruption 2 Endothelial loss 3 No damage 0 Thickening of Bowman capsule 1 Retraction of glomerular tuft 2 Glomerular fibrosis 3 No damage 0 Inflammation, haemorrhage in less than 25% of tissue 1 (Plus) necrosis in less than 25% of tissue 2 Necrosis up to 60% 3 Necrosis more than 60% 4

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H. Riza Aydin, C. Akin Sekerci, E. Yigit, H. Kucuk, H. Kocakgol, S. Kartal, Y. Tanidir, O. Deger

RESULTS

All rats in the sham group had normal renal tissue in the histopathologic examination. However, as shown in Table 3, 2 (25%) rats in the I/R group had small focal damaged areas, 3 (47.5%) < 10% cortical damage, 2 (12.5) had 10-25 % cortical damage and 1(12.5%) had 25-75% cortical damage. In I/R+C group, 5 (62.5%) had small focal damaged areas, 1 (12.5%) had < 10% cortical Table 3.

Cortical damage score of all rats according to the groups.

Rats 1 2 3 4 5 6 7 8

Sham Group 0 0 0 0 0 0 0 0

I/R Group 0.5 1 3 2 2 0.5 1 1

I/R+C Group 0.5 2 0,5 0.5 0.5 0.5 1 2

damage and 2 (25%) had 10-25% cortical damage. EGTI scores of the rats in each group are shown in Table 4, separately. Histological images are shown in Figure 1.

The biochemical analysis results are shown in Table 5.

SOD in the I/R group decreased significantly compared to the I/R+C group (p = 0.004) but was similar in the sham and I/R+C groups (p: 0 = 749). CAT in the I/R group was lower than the sham and I/R+C groups but not statistically significant (p = 0.056). MDA and TOS in the I/R group increased significantly compared to the I/R+C group (p = 0.004, p = 0.001) but were similar in the sham and I/R+C groups (p = 0.055, p = 0.324).

DISCUSSION

Ischemia-reperfusion injury of the kidney continues to be an important clinical condition since it is not an effective agent that has been used in the treatment (1).

Although the formation of I/R damage is a complex process that is not fully understood, significant progress has been made in this regard. The main components of this complex pathophysiological condition are inflammation, oxidative stress-lipid peroxidation, mitochondrTable 4. ial dysfunction, nitrite, and nitric oxide, the complement ECTI scores of all rats according to the groups. system, and the renin-angiotensin system.

Rats Sham Group I/R Group I/R+C Group Homeostatic control of kidney functions is dependent on 1 0 6 5 the production of mitochondrial adenosine triphosphate 2 0 5 3 (ATP), nitric oxide (NO), and reactive oxygen species 3 0 4 3 (ROS), but is only possible with adequate oxygen supply 4 0 6 5 to the kidney tissue (15). Circulatory impairment causes 5 0 5 5 hypoxia and oxidative stress in the kidney tissue and sub6 0 6 2 sequent NO, ROS, and oxygen imbalance. Ischemic dam7 0 4 4 age inhibits the Na-K ATPase enzyme bound to the cell 8 0 4 7 membrane, as a result, intracellular H2O and sodium increase and edema develop (16).

Interstitial edema and vascular permeability cause a furTable 5. ther reduction in blood flow.

Results of superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), total oxidant capacity (TOC) of groups.

In addition, oxidative stress and increased prostaglandin synthesis in damaged tubules further disrupts oxygen Mean ± SD Sham Group I/R Group I/R+C Group P value transmission and causes the local no-reflow phenomenon (n: 8) (n: 8) (n: 8) (17, 18). The long-term consequence of microvascular cirSOD (U/Gprotein) 46.39 ± 2.65 28.84 ± 6.74 45.76 ± 6.91 0.004* culation disorder is the development of hypoxia and final0.749** ly renal fibrosis as a result of Transforming growth factorCAT (U/Gprotein) 7.19 ± 1.02 4.37 ± 0.74 6.46 ± 1.16 0.056 beta (TGF-β) stimulation with decreased Vascular endotheMDA (nmol/Gtissue) 39.8 ± 4.9 65.5 ± 3.5 45.6 ± 2.8 0.004* lial growth factor (VEGF) response secondary to the 0.055** decrease in peritubular capillary density (19). The inflamTOS (µmol/L) 8.5 ± 1.74 17.8 ± 3.33 15.83 ± 1.53 0.001* matory cascade is triggered with I/R damage, which fur0.324** * I/R vs I/R+C. ** sham vs I/R+C. ther aggravates the kidney damage. The main mediators of inflammatory damage are chemokines. Chemokines regulate pro-inflammatory cytokine Figure 1. activity, adhesion molecule Histological images of the rat renal cortex sections. expression, leukocyte infiltraa) Glomerular damage: Glomerular Fibrosis (x40 Masson Trichrome) (Score: 3), tion and activation. IL 6 and b) Glomerular damage: Glomerular retraction (x40 Masson Trichrome) (Score: 2), TNF-alpha are cytokines that c) Tubular damage: necrosis up to 60% in tubule cells, tubular dispersion (x40 HE) (Score: 3), play a major role in the develd) Tubulo/interstitial damage: Inflammation, hemorrhage in less than 25% (x40 HE) opment of renal dysfunction in tubulo/interstitial damage area (Score: 1), e) Normal cortex (x20 HE)) (Score: 0).

(4). Activation of the Janus A B C D E kinase/signal transducer and activator of transcription (JAK/STAT) pathway mediates the release of multiple proinflammatory cytokines that

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cause progression of renal I/ R injury (20). Various agents have been studied in reducing inflammation in I/R injury.

Dexmedetomidine (a highly selective α2-adrenoreceptor agonist) has a cytoprotective effect by reducing the level of IL6 and TNF alpha by inhibiting the phosphorylation of JAK/STAT proteins (21). Nicotine has a renoprotective effect by reducing leukocyte infiltration and chymokine release with its anti-inflammatory cholinergic properties (22). Celastrol (Tripterygium wilfordii), also found in China (china herb), is used in chronic nephritis and autoimmune diseases with its anti-inflammatory and antioxidant properties. Although Celastrol has been reported to have a positive effect on I/R damage by suppressing neutrophil infiltration, lipid peroxidation, and proinflammatory mediator synthesis such as cyclooxygenase-2 (COX2), there are also counter studies reporting that it increases I/R damage by COX-2 upregulation and prostaglandin E2 synthesis (23, 24).

ROS produced in excess during I/R injury causes changes in mitochondrial oxidative phosphorylation, ATP consumption, intracellular calcium increase and membrane phospholipid protease activation (25-27). This process causes damage to the lysosome membrane, leakage of lysosome enzymes and deterioration of the cell structure (28).

Free oxygen radicals that cause lipid peroxidation are generated during the reperfusion phase of I/R injury.

Lipid peroxidation and oxidative damage contribute to apoptosis and cell death by making DNA and protein damage. In addition, down-regulation of the antioxidant enzyme system consisting of catalase, superoxide dismutase and glutathione peroxidase enzymes may be responsible for I/R damage (25-27).

Studies have shown that free radical scavengers and antioxidants can be beneficial in protecting against I/R damage. Propofol, melatonin, ulinastatin, picroliv, naringin, and aqueous garlic extract, are some of the antioxidants and radical scavengers that have been of interest to researchers (4).

In our study, the biochemical and histopathological effects of cordycepin (3'-deoxyadenosine) on renal I/R injury in a rat model were investigated. Cordycepin is widely used in the treatment and prevention of many diseases (circulatory, immune, respiratory, and glandular systems illness) in East Asian countries (29).

Cordycepin has been reported to be an effective antiinflammatory and antioxidant (7). Cordycepin exerts its anti-inflammatory and analgesic effect by inhibiting IL1β, IL-6, TNF-α, induced nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) enzymes (5). It has been reported that ROS production induced by plateletderived growth factor (PDGF) can be reduced by cordycepin and it attenuates neointima formation in vascular smooth muscles in rats (29, 30). Also, Li et al. reported that cordycepin showed a renoprotective effect by inhibiting myofibroblast activation (31).

In previous studies, Cordycepin's protective effect on the brain and testis in ischemia-reperfusion injury was reported (7, 32). In the study of Han F et al., the effectiveness of Cordycepin at different doses (2 mg/kg, 4 mg/kg, 8 mg/kg) in rats with renal ischemia-reperfusion injury was investigated (33). In this study, in which Cordycepin was administered with oral gavage for 7

days, it was reported that increasing doses reduce pathological damage, oxidative stress, and apoptosis. In the same study, serum creatinine and BUN values were observed to be statistically lower in the Cordycepin treated groups compared to the I/R group. In our study, unlike the study of Han et al., 20 mg/kg Cordycepin was administered intraperitoneally at the beginning of reperfusion, and nephrectomy was performed 4 hours later.

In the biochemical analysis, SOD, MDA, and TOS values were found to be statistically different in the C + I/R group compared to the I/R group. As a limitation of the study, serum creatinine and BUN values were not measured since we did not perform left nephrectomy.

CONCLUSIONS

Intraperitoneal Cordycepin administration has been shown to support the endogenous antioxidant defense system and reduce oxidative stress in renal ischemia/reperfusion injury in rats.

ACKNOWLEDGEMENT

We would like to thank the Scientific Research Council of the University of Health Sciences, Turkey (BAP) for the financial support. The BAP project number assigned to this study is 2018/065. The project leader of the study is Assoc. Prof. Hasan Riza Aydin.

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19. Basile DP, Donohoe D, Roethe K, Osborn JL. Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function. Am J Physiol Renal Physiol. 2001; 281:F887-99.

20. Yang N, Luo M, Li R, et al. Blockage of JAK/STAT signalling attenuates renal ischaemia-reperfusion injury in rats. Nephol Dial Transplant. 2008; 23:91-100.

21. Si Y, Bao H, Han L, et al. Dexmedetomidine protects against renal ischemia and reperfusion injury by inhibiting the JAK/STAT signaling activation. J Transl Med. 2013; 11:141.

22. Yeboah M, Xue X, Duan B, et al. Cholinergic agonists attenuate renal ischemia–reperfusion injury in rats. Kidney Int. 2008; 74:62-9.

23. Chu C, He W, Kuang Y, et al. Celastrol protects kidney against ischemia-reperfusion-induced injury in rats. J Surg Res. 2014; 186:398-407.

24. Hwang HS, Yang KJ, Park KC, et al. Pretreatment with paricalcitol attenuates inflammation in ischemia–reperfusion injury via the up-regulation of cyclooxygenase-2 and prostaglandin E2.

Nephrol Dial Transplant 2013; 28:1156-66.

25. Johnson KJ, Weinberg JM. Postischemic renal injury due to oxygen radicals. Curr Opin Nephrol Hypertens. 1993; 2:625-35.

26. Paller MS. The cell biology of reperfusion injury in the kidney. J Investig Med. 1994; 42:632-9.

27. Bonventre JV. Mechanisms of ischemic acute renal failure.

Kidney Int 1993; 43:1160-78.

28. Sugiyama S, Hanaki Y, Ogawa T, et al. The effects of SUN 1165, a novel sodium channel blocker, on ischemia-induced mitochondrial dysfunction and leakage of lysosomal enzymes in canine hearts. Biochem Biophys Res Commun. 1988; 157:433-9.

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Correspondence Hasan Riza Aydin, MD, Assoc. Prof. hrizaaydin@gmail.com Huseyin Kocakgol, MD hsynkocakgl@gmail.com Department of Urology, University of Health Sciences, Trabzon Kanuni Training and Research Hospital (Turkey) Cagri Akin Sekerci, MD, Assoc. Prof. (Corresponding Author) cagri_sekerci@hotmail.com Yiloren Tanidir, MD, Assoc. Prof. yiloren@yahoo.com Marmara University School of Medicine, Department of Urology Fevzi Çakmak Mah., Muhsin Yazicioglu Cad. No:10 Ust Kaynarca/ Pendik/Istanbul (Turkey) Ertugrul Yigit, MD ertugrulyigit@ktu.edu.tr Orhan Deger, MD, Prof. odeger@ktu.edu.tr Karadeniz Technical University, Department of Biochemistry, Trabzon (Turkey)

29. Ramesh T, Yoo S-K, Kim S-W, et al. Cordycepin (3αdeoxyadenosine) attenuates age-related oxidative stress and ameliorates antioxidant capacity in rats. Exp Gerontol. 2012; 47:979-87.

Hatice Kucuk, MD dr.hatice.kucuk@hotmail.com Department of Pathology, University of Health Sciences, Trabzon Kanuni Training and Research Hospital (Turkey)

30. Won K-J, Lee S-C, Lee C-K, et al. Cordycepin attenuates neointimal formation by inhibiting reactive oxygen species–mediated responses in vascular smooth muscle cells in rats. J Pharmacol Sci. 2009; 109:403-12.

Seyfi Kartal, MD drseyfikartal@gmail.com Department of Anesthesia and Reanimation, University of Health Sciences, Trabzon Kanuni Training and Research Hospital (Turkey)

Archivio Italiano di Urologia e Andrologia 2020; 92, 4

DOI: 10.4081/aiua.2020.4.345

ORIGINAL PAPER

Which factors affect the success of pediatric PCNL? Single center experience over 20 years Volkan Izol 1, Nihat Satar 1, Yildirim Bayazit 1, Fatih Gokalp 2, Nebil Akdogan 1, Ibrahim Atilla Aridogan 1 1 Department 2 Clinic

of Urology, Faculty of Medicine, University of Çukurova, Adana, Turkey; of Urology, Osmaniye Government Hospital, Osmaniye, Turkey.

Summary

Objective: We aimed to investigate the impact of surgeons’ experience on pediatric percutaneous nephrolithotomy (PCNL) outcomes.

Materials and methods: Between June 1997 and June 2018, 573 pediatric patients with 654 renal units underwent PCNL for renal stone disease by senior surgeons. Data were divided into two groups, group-1 (n = 267), first ten years period, group-2 (n = 387); second ten years period.

Results: Mean ± SD age of patients was 7.6 ± 4.9 (1-17) years.

The stone-free rates (SFR) assessed after 4 weeks were 74.9% vs. 83.4% in group-1 vs. group-2, respectively (p = 0.03).

The mean operation time, fluoroscopy time, and the number of patients requiring blood transfusion significantly decreased in group 2 (100.4 ± 57.5 vs. 63.63 ± 36.3, 12.1 ± 8.3 vs. 8.3 ± 5.4, and 24.3% vs. 2.9%; p < 0.001, p < 0.001, and p = 0.002 in group-1 versus group-2, respectively). On multivariate analysis, increasing stone size increased operation time (p < 0.001), fluoroscopy time (p < 0.001), intraoperative and postoperative blood transfusion rates (p = 0.006 and p = 0.018, respectively), and hospital stay (p = 0.002) but was not associated with change of glomerular filtration rate (GFR) (p = 0.71). Sheath size also correlated with increased fluoroscopy time (p < 0.001), operation time (p < 0.001), intraoperative blood transfusion (p < 0.001) and hospital stay, but sheath size did not affect postoperative blood transfusion (p = 0.614) or GFR change (p = 0.994).

Conclusions: The percutaneous nephrolithotomy (PCNL) is a minimally invasive procedure and is well accepted because of its lower complication rate and high efficiency for pediatric patients. Stone and sheath size are predictive factors for blood loss and hospital stay. During 20 years, our fluoroscopy time, operation time, blood loss, and complication rates decreased, and stone-free rate increased.

KEY WORDS: Pediatric; Percutaneous; Urinary calculi; Endourology.

Submitted 24 May 2020; Accepted 30 July 2020

INTRODUCTION

Pediatric stone-disease is widespread in developing countries and Turkey (1). The surgical management of stone disease has changed because of technological advances in recent years. For renal stones smaller than 2 cm, extracorporeal shock wave lithotripsy (SWL) and ret-

rograde intrarenal surgery (RIRS) are the treatments of choice in children (2). Additionally, over the last two decades, percutaneous nephrolitotomy (PCNL), with low complications and high success rates, has become the standard treatment of choice for kidney stones > 2 cm and is an alternative procedure for stone size between 12 cm at lower pole (2, 3).

PCNL is an effective and safe procedure in pediatric patients (4-7). Nevertheless, serious complications such as bleeding requiring transfusion, organ injuries, pneumothorax, infection, and sepsis, still have been reported for this procedure (7). There are a few factors identified as affecting complications, including stone size, sheath size, number of punctures, presence of hydronephrosis, and prolonged operation time (8, 9). Recent studies of stone disease treatment showed increased success rates, and also decreased complication rates in association with increase of expertise in high volume centers (7, 8).

In this retrospective study, we aimed to evaluate the impact of surgeons’ experience on complication rates, success rates, and the management of complications along a period of more then 20 years.

MATERIALS

AND METHODS

Between June 1997 and June 2018, 573 pediatric patients with a total of 654 renal units underwent PCNL for renal stone disease. The patients with bilateral kidney stones were treated with staged procedures. All patients were assessed preoperatively with excretory urography, renal ultrasound, and/or non-enhanced spiral computerized tomography, and urine was collected for culture analysis before surgery. Written informed consent was achieved for all participants. After approvel

by Cukurova University Ethics Committee, June 2018/78, preoperative data were obtained, including gender, age, operation time, sheath size, laterality, stone burden, hematocrit, and serum creatinine. The stone burden was calculated by the stone surface area formula.

Intraoperative and postoperative data were obtained including pre/postoperative variation of glomerular filtration rate (GFR) (calculated with Cockcroft Gault equations), drop of hemoglobin levels, transfusion rate, complications according to the Clavien classification, operative time, length of hospital stay and stone-free rate (SFR) (10, 11).

No conflict of interest declared.

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Additionally, we divided the data into two groups. In group-1, PCNL was performed in the first ten years period (1997-2007); in group-2, PCNL was performed in the second ten years period from 2008 to the present.

Surgical technique All procedures were performed by four experienced surgeons who had been working for at least 20 years in our clinic and staff surgeons under supervision of mentors.

All patients received prophylactic antibiotics preoperatively during anesthesia induction. After the placement of a 5 Fr ureteral open-end catheter, patients were positioned in a prone position with proper constructional support by silicone rolls. The pelvicalyceal system was visualized by injecting the radiographic contrast dye through the ureteric catheter. The collecting system was punctured with a needle under fluoroscopy, a guidewire was inserted, and then the urinary tract was dilated with metal or Amplatz dilatators. After placement of an 18-30 Fr sheath, a 15Fr-19Fr rigid nephroscope or 9.5 Fr rigid ureteroscope was inserted into the collecting system.

Stones were fragmented with a pneumatic lithotripter or laser and retrieved with rigid or flexible forceps or graspers. A 10 Fr nephrostomy tube was left in place if needed. We preferred the tubeless technique for selected cases such as those with short operation time, a single puncture for a tract, undamaged pelvicalyceal system, no major bleeding or residual stones at the end of the procedure.

On the second postoperative day, the patient underwent antegrade pyelography, or the nephrostomy tube was clamped if there was no residual fragment or extravasation detected by imaging. Then, the nephrostomy tube was extracted. Patients were discharged after drainage from the nephrostomy tract was stopped. If the drainage from the nephrostomy tract continued longer than seven days, it was defined as prolonged drainage, and we inserted a double J stent. When drainage was stopped for several days, patients were discharged.

Follow up The first visit for follow up was done at 4-6 weeks after discharge, including urinalysis, metabolic examination of 24-hour urine specimens, and urinary ultrasonography. Stone free rates (SFR) were evaluated at 4 week follow. We reported the result as a failure in presence of any asymptomatic residual stone fragment > 4 mm at 4 week follow up. We confirmed the result by using intravenous urography in the first-year period and nonenhanced computerized tomography in the second ten years period.

Statistical analysis SPSS, version 20.0, was used to perform statistical analysis. The Kolmogorov Smirnov test was used in the numerical computations provided the assumption of a normal distribution. For comparing the categorical measurements between the groups, the chi-square test was used. Mann-Whitney U, chi-square, ANOVA, and logistic regression were used for multivariate analysis.

Statistical significance was defined as a p-value of less than 0.05.

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RESULTS Demographic data Five hundred seventy-three pediatric patients with 654 renal units were evaluated in the study. The mean ± SD age of patients was 7.6 ± 4.9 years. The mean stone burden was 371.8 ± 459.4 (95% CI: 343.0-415.5) mm3.

There were 343 (52.5%) renal units with a single calyceal stone and 311 (47.5%) patients with multiple calyceal or staghorn stones. SFR was found 81.4% (n = 533). The mean hospital stay was 4.6 ± 4.2 days. In our practice, the usual hospital course for PCNL is 3-4 days in pediatric patients, but 173 (26.4%) patients stayed longer (7 to 27 days) due to leakage drainage, bleeding, infections, or other complications (Table 1).

Operative outcomes On multivariate analysis, the perioperative parameters such as fluoroscopy time, bleeding, and operation time were associated with stone size and sheath size.

Increasing stone size increased operation time (p < 0.001), fluoroscopy time (p < 0.001), intraoperative and postoperative blood transfusion rate (p = 0.006 and p = 0.018, respectively), and hospital stay (p = 0.002) but was not associated with GFR change (p = 0.71).

Sheath size also correlated with th parameters and increased fluoroscopy time (p < 0.001), operation time (p < 0.001), intraoperative blood transfusion (p = 0.002) and hospital stay, but sheath size did not affect postopTable 1.

Demographic data of patients.

Value 654 7.6 ± 4.9

No. of patients Age (years)a Genderb M F Lateralityb Left Right Site of stoneb Single calyx Multiple calyces Operation timea Stone free rateb

167 (62.5%) 100 (37.5%) 326 (49.8%) 328 (50.2%) 343 (52.5%) 311 (47.5%) 78.3 ± 49.0 533 (81.4%)

aData was presented as mean ± SD; bData was presented as n (%).

Table 2.

Complications causing prolonged hospital stay.

Infection and fever Leakage drainage Requiring stenting Colon perforation Collecting system perforation Bleeding Requiring blood transfusion Transcathateter angiography All data was presented as n (%).

Group 1 (1997-2007) 26 (9.7%) 10 (3.7%) 6 (2.2%) 2 (0.7%) 1 (0.3%) 78 (29.2%) 65 (24.3%) 2 (0.7%)

Group 2 (2008-2018) 15 (3.8%) 11 (2.8%) 7 (1.8%) 1 (0.2%) 4 (1.0%) 22 (5.6%) 11 (2.8%) 1 (0.2%)

p value 0.02 0.52 0.69 0.79 0.34 < 0.001 < 0.001 0.36

Success of pediatric percutaneous nephrolithotomy

erative blood transfusion (p = 0.614) or GFR change (p = 0.994). Furthermore, prolonged operation time increases fluoroscopy time (p < 0.001), intraoperative and postoperative blood transfusion (p < 0.001 and p = 0.008, respectively), and hospital stay (p < 0.001), but not associated with GFR change (p = 0.55).

Stone size and sheath size were not associated with postoperative changes of GFR. SFR was correlated with operation time (B: -0.013, p = 0.02) (Table 3). Table 4 shows the comparison of the outcomes of two subgroups of patients treated in two different period of time using different-sized instruments. Mean operation time, fluoroscopy time, and blood transfusion rate were signifiTable 3.

Multivariate analysis of SFR compared to demographic and perioperative parameters.

Age Gender Laterality Weight Stone size Operation time Fluoroscopy time Sheath size Constant

Unstandardized coefficients B Std. error p .047 .056 .399 -.024 .300 .936 -.264 .301 .380 -.017 .014 .226 -.001 .001 .108 -.013 .006 .021 .000 .000 .781 .079 .070 .259 1.367 1.614 .397

95% Confidence interval Lower Upper .939 1.170 .543 1.756 .426 1.385 .956 1.011 .998 1.000 .976 .998 .999 1.001 .944 1.241

*Depended variable was SFR.

Table 4.

Difference characteristics of two chronological groups.

Age (years)a Genderb M F Sideb Left Right Stone sizea (mm2): Sheath sizea: GFR change (mg/dl): Serum creatinine changea (mg/dl): Operation timea (min): Fluoroscopy timea (min): Hemorrhage requiring transfusionb: Stone free ratesb SF Failure Nephrostomy removal time (day): Postoperative Complications: Clavien Dindob 1 2 3a 3b 4a 5

1997-2007 (n = 267) 8.5 ± 4.9

2008-2018 (n = 387) 6.9 ± 4.7

167 (62.5%) 100 (37.5%)

210 (54.2%) 177 (45.8%)

128 (47.9%) 139 (52.1%) 480.8 ± 380.0 27.87 ± 2.8 2.6 ± 0.2 0.013 ± 0.0 100.4 ± 57.5 12.19 ± 8.3 65 (24.3%)

198 (51.1%) 189 (48.9%) 295.8 ± 196.5 24.41 ± 2.6 3.8 ± 0.3 0.001 ± 0.0 63.63 ± 36.3 8.31 ± 5.4 11 (2.9%)

200 (74.9%) 64 (24.2%) 2.93

323 (83.4%) 56 (14.8%) 2.57

39 (14.6%) 69 (25.8%) 8 (2.9%) 1 (0.3%) 2 (0.7%) 0

26 (6.7%) 15 (3.8%) 8 (2.0%) 4 (1.0%) 1 (0.2%) 0

aData was presented as mean ± SD; bData was presented as n (%).

p value

p < 0.001 p < 0.001 p = 0.425 p = 0.717 p < 0.001 p < 0.001 p = 0.002 p = 0.03 p = 0.133 p = 0.842 p = 0.001 p < 0.001 p = 0.45 p = 0.34 p = 0.36

cantly lower in group-2 (p < 0.001, p < 0.001, and p = 0.002, respectively). However, stone volume and sheath size also significantly decreased in group-2 (p < 0.001). SFR were 74.9% and 86.4% in group-1 and group-2, respectively (p = 0.03).

Reoperation rates were 18 (6.7%) versus 11 (2.9%) in group-1 vs. group-2, respectively (p = 0.01). There was no significant change between preoperative and postoperative mean GFR in both groups (2.51 ± 0.2 mL/min and 3.83 ± 0.3 mL/min; p = 0.584, p = 0.536 in group1 and group-2, respectively).

The most common complications were low-grade complications, grade I (21.3%), and grade II (29.6%). Grade I and II complications were significantly higher group-1 than group-2 (p = 0.001 and p < 0.001). Grade III-a and III-b complications were seen in 16 (2.4%) and 5 (0.7%) patients, respectively, and there was no significant difference between groups (p = 0.45, p = 0.34).

Complications and management The most common complication was bleeding in both groups (29.2% and 5.6% in group-1 and group-2, respectively). Rates of hemorrhages requiring transfusions were significantly different between the two groups (24.3% and 2.9% in group-1 and group-2, respectively, p = 0.02). Three patients underwent angiography for severe bleeding after the procedure, and a ten-year-old child underwent embolization for a pseudoaneurysm of the kidney. Twenty-six (9.7%) children in group-1 and fifteen (3.8%) in group-2 had a fever after PCNL (p = 0.07). Patients took different antibiotic regimens after a positive urine culture.

Twenty-one patients were followed up for prolonged drainage after removal of the nephrostomy tube.

Thirteen patients, six (2.2%) in group-1 and seven (1.8%) in group-2, required double-J stenting. One patient required stenting for perirenal urinoma that resolved spontaneously. Collecting system perforations were seen in five patients, one (0.3%) in group-1 and four (1.0%) in group-2. Three patients had a long-staying nephrostomy tube from four to seven days, which was extracted after no extravasation was demonstrated at anterograde pyelography. Two cases required open surgery, one underwent pyeloplasty for damaged ureter-pelviv junction (UPJ) and the other underwent a primary repair of the renal pelvis.

Two (0.7%) patients in group-1 and one (0.2%) in group2 had a colon perforation. One of them was treated with open surgery and a colostomy by the pediatric surgeon.

The colostomy was closed after three months when anastomosis was done successfully. Two patients were treated conservatively, by withdrawal of the nephrostomy tube outside the kidney into the colon as a percutaneous colostomy tube and by insertion of a double-J ureteral stent for separating nephron-colic communication.

Patients took intravenous broad-spectrum antibiotics and total parenteral nutrition. After 7-10 days, the patients started receiving oral feeding. The tube was removed after complete healing of the colon. One month after, the J stent was extracted under control of retrograde pyelography. One child underwent nephrectomy for a nonfunctioning kidney that was not producing urine in the Archivio Italiano di Urologia e Andrologia 2020; 92, 4

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postoperative days. Histopathological evaluation revealed xanthogranulomatous pyelonephritis.

DISCUSSION

Pediatric stone disease is an important issue, and the critical point for preventing recurrence and relative complications after surgery is stone clearance. There still is not a consensus on describing stone-free rates. SFR varied in the studies due to the differences between pediatric and adult kidney anatomy, variable stone size, use of different-sized instruments, and inclusion or exclusion of clinically insignificant residual fragment (CIRF) cases. A recent study by Çıtamak et al. presented their results at four years intervals over 17 years, and stone-free rates were 73.5%, 68.1%, 75.5%, and 74.0%, with no significant difference among the groups (p = 0.65) (12). Our study showed that our increasing clinical experience and use of small instruments incresed SFR after pediatric PCNL. Our SFR was significantly higher in group-2 than group-1 and reoperation rates were similar into groups. Similar to our study, Yadav et al. study reported that stone-free rates were increased over 15 years from 84.6% to 89.9% (13).

The early pediatric PCNL series were performed using adult-size instruments. The improvements in the devices and techniques of PCNL facilitated urologists to perform this procedure (14, 15). In our study, the mean sheath size decreased from 28 Fr to 24 Fr over the years. Bilen et al. compared three different sized nephroscope, and stone-free rates were 69.5%, 80%, and 90% in the 26Fr, 20Fr, and miniperc groups, respectively (p < 0.005).

The authors emphasized that the 26Fr and 20Fr groups include more patients with semi-staghorn and staghorn calculi (16). A novel systematic review showed that the minimal invasive PCNL (micro-ultra mini) success rate ranged between 85-100% (17).

In our study, the total complication rate (Clavien I-IV) was 28.4%, and there was no significant difference between the two groups. Similar results were found in the CROES study which showed that the complication rate was 23.3% (7). Novel research showed the complications were decreased over the years (33.8%, 23.6%, 19.6%, and 11.5%, respectively, for every four years, p < 0.001) (12). In the literature, the studies compared PCNL complications in children using different instruments, and the complications were graded according to the modified Clavien system, and similar to our research, most of the complications were grade I and II (5, 18, 19).

Ozden et al., in a study of 100 patients using pediatric instruments, reported an overall complication rate of 25% (18). Another study by Guven et al. reported that the total complication rate was 29.1% (n = 140), and there was no significant difference between pediatric and adult instruments (p = 0.52) (5). Additionally, Bilen et al. also showed that complication rates were not significantly different in their study comparing three different sized instruments (16). Mishra et al. examined the outcomes of miniperc (MPCNL) versus standard conventional PCNL and concluded that the MPCNL is significantly superior to PCNL in bleeding and hospital stay time (19). Similar to our study, novel papers showed that recently presented small size percutaneous accesses, such as MPCNL and micro percutaneous method (Micro-PCNL), are safer than

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classic PCNL in children (2, 20). Our study demonstrated that there had been no significant change in the treatment of complications until today, but we became less invasive due to our increased knowledge of complications.

The most common complications were bleeding and fever. Types and frequencies of complications were similar to those in adults (8, 17, 21). Zeren et al. study showed correlation of intraoperative bleeding with operation time, sheath size, and stone size (8). Our research demonstrated that stone size and operation time correlated with intraoperative and postoperative blood transfusion. We also found that a larger sheath size is related to higher intraoperative blood transfusion rates and longer hospital stay. Similar to our study, Altintaş et al. study compared three different sheath sizes (17 Fr, 24 Fr, and 26 Fr) showing that sheath size was related to increased intraoperative bleeding although there was no significant difference of preoperative and postoperative creatinine levels (p = 0.873) (22). However, controversial to our study, the literature also reported that sheath size did not affect transfusion rates (12, 16, 23).

Fever was the second common complication in our study. Previous studies reported that the postoperative fever rate was approximately present in 29% (18, 21).

Bayrak et al. reported that postoperative fever rates in their study, comparing children to adults, were 5.4% and 5.6%, respectively (24). Çelik et al. showed that postoperative fever rates were similar and reported rates of 5.9% and 6.8% using pediatric (18Fr) and adult-sized (24Fr) nephroscope, respectively (25).

In our study, postoperative fever rates were not significantly different in the two groups and similar to published literature.

Herein, we compared different-sized instruments and experience time and found that PCNL is an operatordependent procedure, which improves its results, presumably due to increased operator experience and the involvement of a team with substantial prior knowledge.

Furthermore, our results depend on advances to technology that shifted the management of stone disease to minimal invasive modalities.

We realized that we treated smaller stones in the second ten years period.

The main reasons for this finding are: • Increasing of diagnosis of patients with small stone size due to the novel radiological tools and easier access to health care services.

• In our clinic, use of a ESWL machine that uses fluoroscopy for stone localization (with no ultrasoundguided ESWL machine around the region) • Technological advancement with development of small instruments for urologic endoscopic procedures.

Limitations of the study included its retrospective nature and the absence of a metabolic evaluation and chemical analysis of the composition of the stone. The second significant limitation was insufficient data of follow up, especially on group-1 and no standardization of timing or use of imaging tools at follow up. Another limitation of the study was the performance of percutaneous pro-

Success of pediatric percutaneous nephrolithotomy

cedures by more surgeons using different instruments at different periods being the experience of each surgeon a possible source of bias. However, a strenght of the study is that the data and results were obtained from a single large volume center.

CONCLUSIONS

Our study showed that the patient cohort became younger with smaller stone sizes over time.

Concordantly, the fluoroscopy time, operation time, blood loss, and complications rates were decreased, and stone free-rates were increased with use of smaller instruments. The stone and sheath size are major factors to predict blood loss and hospital stay.

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12. Cıtamak B, Altan M, Bozacı AC, et al. Percutaneous nephrolithotomy in children: 17 years of experience. J Urol. 2016; 195:1082-7.

13. Yadav P, Madhavan K, Syal S, et al. Technique, complications, and outcomes of pediatric urolithiasis management at a tertiary care hospital: evolving paradigms over the last 15 years. J Pediatr Urol.

2019; 15:665.e1-665.e7 14. Goyal NK, Goel A, Sankhwar SN, et al. A critical appraisal of complications of percutaneous nephrolithotomy in paediatric patients using adult instruments. BJU Int. 2014; 113:801-10.

Correspondence Volkan Izol, MD Nihat Satar, MD Yildirim Bayazit, MD Nebil Akdogan, MD Ibrahim Atilla Aridogan, MD Department of Urology, Faculty of Medicine, University of Çukurova, Adana (Turkey) Fatih Gokalp, MD, FEBU (Corresponding Author) fatihgokalp85@gmail.com Osmaniye Government Hospital, Urology Clinic, 80020, Osmaniye (Turkey)

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DOI: 10.4081/aiua.2020.4.350

ORIGINAL PAPER

Clinical results of shock wave lithotripsy treatment in elderly patients with kidney stones: Results of 1433 patients Cevahir Ozer, Mehmet Ilteris Tekin Department of Urology, Baskent University, Adana, Turkey.

Summary

Objective: In this study, it was aimed to evaluate the efficacy and safety of SWL treatment in elderly patients with kidney stones.

Materials and methods: Data from a total of 3024 patients who underwent SWL treatment for urinary tract stone disease in three centers of our university were evaluated retrospectively. A total of 1433 patients in the adult age group treated for single kidney stones were included in the study. The patients were divided into 3 groups (18-40, 41-64 and ≥ 65) years depending on their age. Demographic data, stone parameters, stone-free rate (SFR) and clinically insignificant residual fragment (CIRF) rate, number of SWL sessions and complication rate were analyzed according to the age groups.

Results: The mean age of the patients was 47.38 ± 13.24 years. Stone size was significantly lower in the 18-40 years age group compared to other groups (p = 0.000) and the stones were mostly located on the right side in this age group (p = 0.007). There was no significant relationship between age groups and gender, stone localization, and number of SWL sessions.

The overall SFR was 66.4%. Although the SFR was lower (61.4%) and the rate of multiple sessions (27.2%) was higher in ≥ 65 years group, there was no statistically significant difference between age groups regarding SFR, CIRF, need for additional sessions, and complication rates.

Conclusions: Due to its similar clinical results, treatment of SWL should not be ignored as a treatment option in the geriatric patient group with kidney stones.

KEY WORDS: Kidney stones; Shock wave lithotripsy; Elderly.

Submitted 14 September 2020; Accepted 27 October 2020

INTRODUCTION

Urinary stone disease affects individuals, healthcare systems and society due to its high prevalence, recurrent and unpredictable nature and dominance in workingage adults (1). Shock wave lithotripsy (SWL), flexible ureterorenoscopy, and percutaneous nephrolithotomy are the treatment options offered by the recent guidelines for the treatment of patients with kidney stones (24). As SWL is an effective, non-invasive treatment that can be applied without general anesthesia, it remains a current treatment option (5-7).

Although many predictive factors of the success of SWL, such as urinary tract anatomy, severity of concomitant obstruction, body mass index (BMI), stone size, stone density, stone to skin distance and type of SWL device

350

used have been identified, the results regarding the effect of age are contradictory (6-9).

The purpose of this study was to evaluate the efficacy and safety of SWL treatment in elderly patients with kidney stones.

MATERIALS

AND METHODS

Data from 3024 consecutive patients who underwent SWL treatment for urinary tract stone disease since 2003, in three centers of our university, were evaluated retrospectively. A total of 1433 patients in the adult age group (≥ 18 years old) treated for single kidney stones were included in the study. The SWL decision was determined by patient and doctor preference. Informed consent was obtained from all patients.

Before the procedure, all patients were evaluated by routine blood and urine analysis, plain abdominal radiography, renal ultrasonography (US), intravenous urography and/or non-contrast computed tomography (CT). SWL was not applied in the presence of pregnancy, aortic aneurysm, morbid obesity (BMI ≥ 40), bleeding diathesis, active urinary infection and non-functional kidney on the side of the stone.

Lithostar Modularis Uro-plus (Siemens Medical Systems, Erlangen, Germany), an electromagnetic lithotripter, was used in all three centers for the SWL procedure. The procedure was applied to all patients under sedoanalgesia. After the procedure, oral analgesics were recommended to all patients.

The results of the procedure were evaluated using kidneys, ureters and bladder (KUB) radiography, US and/or CT performed 3 months after the SWL treatment.

Data interpretation and statistical analysis The patients were divided into 3 groups (18-40 years, 41-64 years and ≥ 65 years) depending on their age.

Demographic data, stone parameters, stone-free rate (SFR) and CIRF rate, number of SWL sessions and complication rate were analyzed according to age groups.

The presence of stones less than 4 mm was considered as clinically insignificant residual stone (10).

The data were analyzed using the Statistical Package of Social Science (Version 25.0; SPSS Inc., Chicago, IL, USA).

Comparisons between groups were applied using OneWay ANOVA test. The catagorical variables between the groups was analyzed by using the Chi square test. Only significant variables were included in the multiple No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2020; 92, 4

Shock wave lithotripsy in different age groups

regression analysis. Values of p less than 0.05 were considered statistically significant.

RESULTS

The mean age of the patients was 47.38 ± 13.24 years.

Stone size was significantly lower in the 18-40 age group compared to the other groups (p = 0.000) and in this age group, the stones were mostly located on the right side in this age group (p = 0.007). There was no significant difference between the age groups regarding gender, stone localization, and number of SWL sessions (Table 1).

The overall SFR was 66.4%. Although SFR was lower (61.4%) and the rate of multiple sessions (27.2%) was higher in the ≥ 65 years group, there was no statistically significant difference between the age groups regarding SFR, CIRF, need for additional sessions, and complication rates (Table 1). Since there was only a significant difference in stone size between the groups, it was evaluated by multiple regression analysis, but no significant regression model was obtained.

Mortality due to SWL procedure was not observed in any patient. Steinstrasse was observed in 22 (1.5%) patients.

Its distribution by age groups was 6 (1.3%) patients in 18-40 years group, 14 (1.7%) in 41-64 years group and 2 (1.3%) in ≥ 65 years group. Subcapsular hematoma was seen only in 1 patient in the 41-64 years group. One of the 2 patients whose operation was terminated due to arrhythmia was in the 18-40 years group and the other in the ≥ 65 years group. Hospitalization was required due to pain in 1 patient and fever in another patient in the 41-64 years group. In the 18-40 years group, 1 patient developed pancreatitis and 1 patient developed urinoma.

There was no statistically significant difference between age groups and complication rates (Table 1).

Table 1.

Characteristic features and clinical outcomes of patients.

Number (%) Gender (n, %) Male Female Stone size (mm) Side (n, %) Right Left Localization (n, %) Upper pole Middle calyx Lower pole Pelvis Number of sessions (n, %) 1 ≥2 Outcome (n, %) Stone-free CIRF Complication (n, %)

Total 18-40 years 41-64 years ≥ 65 years 1433 (100) 448 (31.3) 827 (57.7) 158 (11.0)

p 2.77

882 (61.5) 286 (63.8) 551 (38.5) 162 (36.2) 11.99 ± 5.52 10.88 ± 5.00

506 (61.2) 90 (57.0) 321 (38.2) 68 (43.0) 12.43 ± 5.66 12.80 ± 5.78

693 (48.3) 740 (51.7)

244 (54.5) 204 (45.5)

377 (45.5) 450 (55.5)

72 (45.6) 86 (55.4)

171 (11.9) 166 (11.6) 375 (26.2) 721 (50.3)

61 (13.6) 50 (11.2) 110 (24.6) 227 (50.7)

90 (10.9) 94 (11.4) 226 (27.3) 417 (50.4)

20 (12.7) 22 (14.0) 39 (24.8) 77 (45.5)

1119 (78.1) 314 (21.9)

364 (81.3) 84 (18.7)

640 (77.4) 187 (22.6)

115 (72.8) 43 (27.2)

951 (66.4) 297 (20.7) 29 (2.0)

306 (68.3) 92 (20.5) 9 (2.0)

548 (66.3) 172 (20.8) 17 (2.1)

97 (61.4) 33 (20.9) 3 (1.9)

0.000 0.007

0.688

DISCUSSION

SWL remains one of the treatment methods for the management of kidney stones. Treatment of kidney stones in elderly patients can be complicated by comorbid conditions. This makes SWL treatment a good option for elderly patients, since it can be applied in an outpatient setting without general anesthesia.

In several previous studies, it has been reported that the success rates of SWL treatment decreased in elderly patients (10, 11). In a retrospective study of 472 diseases conducted by Gokce et al., no difference was found between age groups and success rates of SWL (6). In a study by Chen et al., the SFR in elderly patients were found similar to that of non-elderly patients (41.1% vs 46.5%) (12). In our study, both SFR and CIRF rate among age groups were similar. The fact that the parameters in the evaluation of treatment success such as different age groups (> 60 years, ≥ 65 years and >/≥ 70 years) definition of success (stone-free, stone-free plus CIRF), definition of CIRF (≤ 2 mm and ≤ 4 mm), time to evaluate success (1 month, 3 months) and evaluation method of treatment result (one or more of KUB graphy, US, CT) are not homogeneous makes it difficult to comment on this issue (6, 8, 10, 12-15).

Chen et al. found that the rate of retreatment in elderly patients who received SWL for kidney stones was similar to that of non-elderly patients (38.6% vs 42.9%, p = 0.485) (12). In our study, this rate was 27.2% and there was no statistically significant difference between the other age groups.

The frequency of major complications associated with SWL in the elderly population is between 0% and 5.6% (6, 12-14, 16). In our study, this rate is 1.9% and is consistent with the literature. Whether the incidence of complications associated with SWL in the elderly population is higher than the non-elderly population is controversial. While Chen et al. had a higher risk of complications in patients ≥ 65 years, Gokce et al. did not find any significant difference (6, 12). In our study, we did not find any difference between age groups in terms of complication rates. We believe that the lack of difference may result from the patient selection bias and SWL techniques.

As in our study, the use of electromagnetic lithotriptors in the treatment of kidney stones with SWL provides better pain management (17). We think that better pain management can increase the success rate and reduce the complication rate by providing a better focus of the stone.

The prominent limitations of this study are its retrospective nature and lack of some predictive parameters such as urinary tract anatomy, severity of concomitant obstruction, BMI, stone size due to its retrospective nature. However, the large number of patients is the strength of this study.

0.065

CONCLUSIONS

0.285 0.674 0.991

Our results suggest that there is no relationship between the clinical results of SWL treatment and age. Due to its similar clinical results, treatment of SWL with similar clinical results should not be ignored as a treatment option in the geriatric patient group with kidney stones.

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ACKNOWLEDGEMENTS

The authors would like to thank Cagla Sariturk, Baskent University, Adana Dr. Turgut Noyan Medical and Research Center, Biostatistics Unit.

9. Ichiyanagi O, Nagaoka A, Izumi T, et al. Age-related delay in urinary stone clearance in elderly patients with solitary proximal ureteral calculi treated by extracorporeal shock wave lithotripsy.

Urolithiasis. 2015; 43:419-426.

REFERENCES

10. Abe T, Akakura K, Kawaguchi M, et al. Outcomes of shockwave lithotripsy for upper urinary-tract stones: a large-scale study at a single institution. J Endourol. 2005; 19:768-773.

1. Morgan MS, Pearle MS. Medical management of renal stones.

BMJ. 2016; 352:i52.

2. Turk C, Petrik A, Sarica K, et al. EAU Guidelines on interventional treatment for urolithiasis. Eur Urol. 2016; 69:475-482.

3. Assimos D, Krambeck A, Miller NL, et al. Surgical management of stones: American Urological Association/Endourological Society guideline, part II. J Urol. 2016; 196:1161-1169.

12. Chen YZ, Lin WR, Lee CC, et al. Comparison of safety and outcomes of shock wave lithotripsy between elderly and non-elderly patients. Clin Interv Aging. 2017; 12:667-672.

4. Pradere B, Doizi S, Proietti S, et al. Evaluation of guidelines for surgical management of urolithiasis. J Urol. 2018; 99:1267-1271.

13. Philippou P, Lamrani D, Moraitis K, et al. Shock-wave lithotripsy in the elderly: Safety, efficacy and special considerations. Arab J Urol. 2011; 9:29-33.

5. Knoll T, Buchholz N, Wendt-Nordahl G. Extracorporeal shockwave lithotripsy vs. percutaneous nephrolithotomy vs. flexible ureterorenoscopy for lower-pole stones. Arab J Urol. 2012; 10:336341.

14. Sighinolfi MC, Micali S, Grande M,et al. Extracorporeal shock wave lithotripsy in an elderly population: how to prevent complications and make the treatment safe and effective. J Endourol. 2008; 22:2223-2226.

6. Gokce MI, Akinci A, Akpinar C, et al. Comparison of efficacy of shock wave lithotripsy in different age groups. Journal of Urological Surgery. 2017; 4:66-70.

15. Ng CF, Wong A, Tolley D. Is extracorporeal shock wave lithotripsy the preferred treatment option for elderly patients with urinary stone? A multivariate analysis of the effect of patient age on treatment outcome. BJU Int. 2007; 100:392-395.

7. Kocakgol H, Yilmaz AH, Yapanoglu T, et al. Efficacy and predictive factors of the outcome of extracorporeal shock wave lithotripsy: a review of one-thousand-nine-hundred-ninety-seven patients.

Journal of Urological Surgery. 2019; 6:207-212.

16. Polat F, Yesil S, Ak E, et al. Safety of ESWL in elderly: evaluation of independent predictors and comorbidity on stone-free rate and complications. Geriatr Gerontol Int. 2012; 12:413-417.

8. Abdel-Khalek M, Sheir KZ, Mokhtar AA, et al. Prediction of success rate after extracorporeal shock-wave lithotripsy of renal stones--a multivariate analysis model. Scand J Urol Nephrol. 2004; 38:161-167.

17. Bianchi G, Marega D, Knez R, et al. Comparison of an electromagnetic and an electrohydraulic lithotripter: Efficacy, pain and complications. Arch Ital Urol Androl. 2018; 90:169-171.

Correspondence Cevahir Ozer, MD cevahirozer@gmail.com Mehmet Ilteris Tekin, MD ilterist@hotmail.com Department of Urology, Baskent University, Adana (Turkey)

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11. Kimura M, Sasagawa T. Significance of age on prognosis in patients treated by extracorporeal shock wave lithotripsy. Nihon Hinyokika Gakkai Zasshi. 2008; 99:571-577.

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DOI: 10.4081/aiua.2020.4.353

ORIGINAL PAPER

How urologists deal with chronic prostatitis?

The preliminary results of a Mediterranean survey Konstantinos Stamatiou 1, Vittorio Magri 2, Gianpaolo Perletti 3, Evangelia Samara 1, Georgios Christopoulos 1, Alberto Trinchieri 4 1 Urology

Department, Tzaneion Hospital, Piraeus, Greece; Secondary Care Clinic, ASST-Nord, Milan, Italy; 3 Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy; Faculty of Medicine and Medical Sciences, Ghent University, Ghent, Belgium; 4 Manzoni Hospital, Lecco, Italy.

2 Urology

Summary

Objectives: We performed a questionnaire survey to investigate various issues in the diagnosis of chronic prostatitis (CP) performed by Greek urologists and to assess some aspects of prostatitis workup in Greece. Replies were compared with those of Italian clinical research partners in an attempt to clarify the CP diagnostic approaches in Southern European Mediterranean countries.

Methods: We translated the original Italian questionnaire presented by Magri and Montanari in the frame of a urological congress held in Milan on October 26th, 2018. Τhis 5-item questionnaire explores clinical practice characteristics, attitudes, and diagnostic strategies for the management of chronic prostatitis (Chronic Bacterial Prostatitis or Chronic Prostatitis/Chronic Pelvic Pain Syndrome, according to NIH criteria). After its validation the questionnaire was uploaded in the internet and Greek healthcare professionals were invited by mail to respond. Responses were compared with those of Italian urologists, in order to determine similarities and differences in attitudes between clinicians regarding the diagnostic assessment of CP. Results: There is a wide variation in participants' preferences for diagnostic methods, laboratory tests and clinical examinations both in Italy and in Greece. In both countries many diagnostic tests performed in affected patients are only geared to exclude other treatable conditions (e.g., benign prostatic hyperplasia, bladder cancer), but more suitable methods and tests for the assessment of CP are less frequently used.

Conclusions: Urologists' choices for the diagnostic workup of CP, show a wide international or intra-national variability between Greece and Italy. Although several diagnostic tests are available to differentiate and categorize the types of CP, a large number of urologists use less suitable methods and tests.

This fact reflects both the lack of consensual vision in the literature and the difficulties encountered on a daily basis by the physicians. Under the light of this evidence, the need of studies establishing consensual guidelines for the optimal diagnosis of CP is becoming imperative.

KEY WORDS: Chronic prostatitis; Prostate; Infection; Stamey-Meyers.

Submitted 25 February 2020; Accepted 10 March 2020

INTRODUCTION

The term "chronic prostatitis" indicates syndromes which show different aetiologies and variable clinical features

being characterized by symptoms of pelvic, genital and suprapubic pain, often associated with lower urinary tract symptoms (LUTS) and sexual dysfunction. It is an easy to suspect, hard to prove condition. In fact, evaluation and diagnosis of chronic prostatitis (CP) can be confusing and challenging. Although the Meares-Stamey (MS) 4-glass test is the standard method of assessing inflammation and the presence of bacteria in the prostate, it is time consuming and not accurate enough to give a clear diagnosis of bacterial prostatitis. For this reason, it was not universally employed by urologists.

However, it is not known to which extent is infrequently used by Greek urologists and which diagnostic tests they perform in affected patients alternatively to the MS test. In order to examine Greek healthcare professionals' preferences for diagnostic investigation and testing for CP, we performed a questionnaire survey. Responses were compared with the ones given by Italian counterparts in an attempt to assess similarities or differences in the diagnostic approaches to chronic prostatitis syndromes in Southern European Mediterranean countries.

MATERIALS

AND METHODS

We translated the original Italian questionnaire presented

by Magri and Montanari in Milan on 26 October 2018 and validated its Greek version (1). This 5-item questionnaire explores practice characteristics, attitudes, and diagnostic strategies for the management of chronic prostatitis in Italy.

After its validation, the questionnaire was uploaded in the internet and Greek healthcare professionals were invited by mail to respond, in an attempt to investigate current diagnostic practices for CP in Greece. Responses were compared with those collected by our Italian research partners, reflecting the diagnostic habits of Italian urologists, as presented in the study of Magri et al. (1). The aim of this study was to assess similarities and differences in cliniciansâ&#x20AC;&#x2122; attitudes regarding the diagnostic assessment of CP. The local research ethics committee approved the study.

RESULTS

Seventy-seven Greek urologists were surveyed.

Responders diagnose chronic prostatitis in a substantial

No conflict of interest declared.

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Table 1.

Comparison of preferences of diagnostic methods.

Preferred diagnostic methods Answer choices Medical history Clinical examination (DRE) IPSS questionnaire NIH-CPSI questionnaire SHIM questionnaire (modified IIEF questionnaire) IIEF questionnaire PEDT questionnaire UPOINT questionnaire Other questionnaires Total respondents

Italy % 98.12 96.62 51.13 17.29 16.17 7.89 6.39 1.88 0.00 266

Greece % 89.6 84.4 40.2 19.4 10.3 1.29 1.29 5.19 0.00 77

Italy % 81.20 72.18 39.10 13.91 20.30 16.92 6.39 67.29 24.81 9.02 13.16 266

Greece % 57.1 49.3 2.59 1.20 11.6 1.20 11.6 74.0 2.69 0.00 1.20 77

Italy % 72.18 62.78 45.11 12.78 2.63 3.01 2.63 20.68 0.00 266

Greece % 81.8 92.20 10.30 6.49 3.88 2.59 0.00 10.3 2.59 77

Table 2.

Comparison of preferences of laboratory tests.

Preferred laboratory tests Answer choices PSA Midstream urine test Urethral swab Urethral swab after prostate massage Meares & Stamey test Meares & Stamey test with count of the number of leukocytes in VB2 and VB3/EPS Nickels’ ‘’two glass test’’ Semen culture Semen culture with count of the number of leukocytes in ejaculate Urine cytology Spermiogram Total respondents

Table 3.

Comparison of preferences of clinical tests.

Preferred clinical tests Answer choices Uroflometry Abdominal ultrasound Transrectal ultrasound Scrotal ultrasound Urodynamics Urethocystoscopy Urethrocystography Other diagnostic tests No diagnostic test Total respondents

Table 4.

Comparison of preferences of microbiological tests.

Preferred microbiological tests Answer choices Gram+ GramFungi Sexually transmitted microbes

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Italy % 83.08 86.84 56.77 77.82

Greece % 85.6 100 20.7 79.4

number of men each year (the median number of patients per specialist per month is 11 patients). Almost 72% percent of the Greek professionals use in their clinical practice the classification of "chronic prostatitis" proposed by the National Institutes of Health (NIH), which identifies two major CP conditions: Chronic Bacterial Prostatitis (CBP) and Chronic (abacterial) Prostatitis/ Chronic Pelvic Pain Syndrome (CP/CPPS). There is a wide variation in participants' preferences for diagnostic methods, laboratory tests and clinical examinations both in Italy and in Greece. In both countries many diagnostic tests performed in affected patients are geared toward excluding other treatable conditions (e.g., benign prostatic hyperplasia, bladder cancer) however more suitable methods and tests for the assessment of CP are less frequently used. A comparison between Italian and Greek survey is presented in the Tables 1-4.

DISCUSSION

CP is a common situation affecting relatively young men.

Its exact frequency is not known. As reported by Krieger et al., men in the United States with CP account for 2-5 million ambulatory physician visits per year including 8% of all appointments with a urologist. Magri and Montanari reported a frequency of 23 patients per urologist per month on average (1). Similarly to our study, Swiss urologists see a median of 10 patients per month (4). The abovementioned variations could be attributed to differences in health care policies, patients’ preference and urologists’ experience. Notably, the average age of responders to our questionnaire was significantly lower than that of the Italian study. This fact explains the lower median number of patients per Greek specialist and it may also explain the difference in the use of the NIH classification of "prostatitis" in the clinical practice between Greek and Italian specialists (62.7 vs 31.2%).

This is likely due to the fact that, compared to older colleagues, the compliance of younger urologists with clinical practice guidelines is higher. However, this might not be the case since a limited use of the NIH classification system was also reported in the UK (33%) (5) and in France (35%) (6). Large deficits in familiarity with and knowledge of CP, along with a significant uniformity in the medical approach to this condition may explain the above findings (7).

As a matter of fact, most urologists acknowledge that chronic prostatitis is the most frustrating and difficult clinical problem to deal within urology (8). This happens likely because the etiopathology of prostatitis is uncertain, several diseases of the urogenital system share common symptoms, the diagnostic work-up of prostatitis is not completely standardized, the microbiological diagnosis is partly inadequate and there are restrictions in the prescription of some clinical and laboratory tests in several countries.

As shown in Table 1, the preferred diagnostic methods (89.6 and 84.4% of Greek and 98.12% and 96.62% of Italian urologists) are medical history and physical examination alone or combined with the IPSS questionnaire.

The greatest part of them (37.6 and 41%) do not use questionnaires routinely. In general, diagnosing CP can

Mediterranean urologist and chronic prostatitis

be difficult, as the patient history and examination modalities may be quite diverse. In fact, most patients claim genitourinary pain or discomfort, though newly presented sexual dysfunction and new onset of urinary symptoms are also common. Less usual presentations include recurrent febrile infections of the urinary tract and the genital system and asymptomatic elevation of serum PSA levels (9). The physical examination is usually normal. Digital rectal examination findings suggestive of CP (painful and or edematous hardened and tender prostate) may be found in half of the cases (10). Other abnormalities that can be found during examination of the prostate, such as calculi and nodules, may impact management decisions.

Symptom assessment by the NIH-CPSI is rarely used in both Greece and Italy (17.29 and 19.4% of respondents, respectively). An even lower number (12%) was reported by Zbrun et al. (4). Actually, the NIH-CPSI was developed to assess symptoms and quality of life in men with CP/CPPS and has demonstrated good reliability and validity (11). It has been long used as the primary outcome variable in multiple trials and studies, though its role as a diagnostic tool is debatable (12). On the other hand, the questions in the NIH-CPSI provide a universal clinical assessment of CP, both in terms of initial evaluation and during therapeutic monitoring (13). Notably, UK guidelines recommend the NIH-CPSI and similar diagnostic tools such as the International Prostate Symptom Score (IPSS), the Urinary, Psychosocial, Organspecific, Infection, Neurological, and Tenderness (UPOINT) algorithm, the International Index of Erectile Function (IIEF-5) and/or the Sexual Health Inventory for Men (SHIM) scales to assess initial symptom severity and evaluate patient-tailored phenotypic differences (Level 3 recommendation) (14). They also suggest psychosocial screening with Patient Health Questionnaire-9 (PHQ-9) and/or Generalised Anxiety Disorder-7 (GAD-7) Scales as well (Level 5 recommendation) (11).

Even though the Meares and Stamey (MS) “4-glass” test is the gold standard test for the CP diagnosis, few Italian and Greek responders perform it alone (20.3% and 11.6% respectively) or in combination with leukocyte counts (16.92% and 1.2% respectively). Time and geographical trends in the use of this test may exist, since the number of Italian CP patients not subjected to the MS test was greater in the past 15 years (15). Sixty-six per cent of the Canadian practitioners’ and 80% of the US counterparts never or rarely perform the MS test in making a diagnosis of prostatitis (16, 17). In contrast, 61% of the British and 51% of the Dutch urologists are reported to be using the test (5, 18).

Kiyota et al. found that only 1.5% of Japanese urologists diagnose CP using the MS test, while almost 45% adopt the the “2-glass” pre- and post-massage test (19). A similar number was reported by Swiss urologists (4). The “2-glass” test is rarely used in both Italy and Greece (6.39 and 11.39% respectively). On the other hand, in our study, semen culture, combined or not with leukocyte counts, was by far the most popular test (76.59 and 92.1% for Greek and Italian responders respectively) and is known to be the second most used diagnostic test by Dutch urologists (18). According to Yang et al., the simple culture of

expressed prostatic secretion (EPS) is the most commonly (43.4%) performed test for the diagnosis of CP in China (20). To our knowledge, current EAU guidelines suggest semen culture not to be routinely part of the diagnostic assessment of CP. Regarding microbiology tests, both Italian and Greek responders’ preferences include both Gram-negative and Gram-positive organisms. Some clinicians and microbiologists debate the role of Gram-positive other than Enterococci (21). Currently, Gram-positive bacteria tend to be the most frequent isolates in EPS and VB3 specimens from CP patients, with coagulase-negative staphylococcal species being the most prevalent isolates in Greece (22).

In agreement with our findings, most urologist worldwide do not count the number of leukocytes in VB2 or VB3/EPS to differentiate between inflammatory and non-inflammatory chronic prostatitis/chronic pelvic pain syndrome. The proportion of urologists following this practice vary significantly worldwide (4, 17, 19). Reasons explaining these differences are practically unknown. Ku et al., suggest that the personal beliefs and professional characteristics of physicians are the most determinant factors with respect to the urologists’ preferences and routine performance or non-performance of culture tests (23). Kiyota et al. found that more than half of Japanese urologists felt pessimistic about dealing with CP (19). Although many urologists think that chronic non-bacterial prostatitis/chronic pelvic pain syndrome is not an infectious disease, they prescribe antibiotics even when no white blood cells are detected in prostate-specific specimens (4, 23).

As shown in our study, a variety of diagnostic tests are performed in patients with a suspected diagnosis of CP, in order to exclude other treatable conditions (e.g., benign prostatic hyperplasia, bladder cancer). These include imaging, endoscopy, urodynamics and PSA testing. None of them is specifically recommended in the evaluation of patients with prostatitis. However, ultrasonography and uroflowmetry are non-invasive, low cost tests for a rapid study of the anatomy of the urinary system and for a general estimation of the urinary function; hence they could be adopted in CP diagnostic work up (24).

CONCLUSIONS

Urologists' preferences for diagnostic investigation and testing for CP show considerable worldwide diversity.

Although several diagnostic tests are available to differentiate and categorize the types of CP, a large number of urologists use less suitable methods and tests. This fact reflects both the lack of consensual vision in the literature and the difficulties encountered on a daily basis by the physicians. Under the light of this evidence the need of studies establishing guidelines for its diagnosis is getting imperative.

REFERENCES

1. http://www.amcli.it/wp-content/uploads/2015/08/P20-2018_prostatiti_26_27-ottobre_def_1.pdf 2. https://docs.google.com/forms/d/1N4tnzytKSN_ehimEbPp9QfTok P1tadzQHCoDdhBtOow/edit?ts=5dbeb11e Archivio Italiano di Urologia e Andrologia 2020; 92, 4

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3. Krieger JN, Ross SO, Riley DE. Chronic prostatitis: epidemiology and role of infection. Urology. 2002; 60:8-12.

rial prostatitis and chronic prostatitis/chronic pelvic pain syndrome: a consensus guideline. BJU Int. 2015; 116:509-25.

4. Zbrun S, Schumacher M, Studer UE, Hochreiter WW. Chronic prostatitis a nationwide survey of all urologists in Switzerland. J Urol. 2004; 171:27.

15. Nickel JC, Rizzo M, Marchetti F, et al. Prevalence, characterization, diagnosis and treatment of the prostatitis patient in Italy: an opportunity to compare the European prostatitis patient to the North American experience J Urol. 2004; 171:27.

5. Luzzi GA, Bignell C, Mandal D, Maw RD. Chronic prostatitis/chronic pelvic pain syndrome: national survey of genitourinary medicine clinics. Int J STD AIDS. 2002; 13:416-419.

6. Delavierre D. Chronic prostatitis and chronic pelvic pain syndrome: a survey of French urologists. Prog Urol. 2007; 17:69-76.

7. Liu L, Yang J. Physician's practice patterns for chronic prostatitis.

Andrologia. 2009; 41:270-6.

8. Magri V, Boltri M, Cai T, et al. Multidisciplinary approach to prostatitis. Arch Ital Urol Androl. 2019; 90:227-248.

9. Stamatiou K, Karageorgopoulos D. A prospective observational study of chronic prostatitis with emphasis on epidemiological and microbiological features. Urologia. 2013; 10.5301.

10. Stamatiou K, Moschouris H. A prospective interventional study in chronic prostatitis with emphasis to clinical features. Urol J. 2014; 11:1829-33.

11. Litwin MS, McNaughton-Collins M, Fowler FJ Jr, et al. The National Institutes of Health chronic prostatitis symptom index: development and validation of a new outcome measure. J Urol.

1999; 162:369-75.

12. Roberts RO, Jacobson DJ, Girman CJ, et al. Low agreement between previous physician diagnosed prostatitis and National Institutes of Health chronic prostatitis symptom index pain measures J Urol. 2004; 171:279-283.

13. Wagenlehner FM, van Till JW, Magri V, et al. National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI. symptom evaluation in multinational cohorts of patients with chronic prostatitis/chronic pelvic pain syndrome. Eur Urol. 2013; 63:953-9.

14. Rees J, Abrahams M, Doble A, Cooper A. Prostatitis Expert Reference Group (PERG). Diagnosis and treatment of chronic bacte-

Correspondence Konstantinos Stamatiou, MD stamatiouk@gmail.com Evangelia Samara, MD Georgios Christopoulos, MD Urology Dpt, Tzaneion Hospital 2 Salepoula str, 18536 Piraeus (Greece) Vittorio Magri, MD Urology Secondary Care Clinic, ASST-Nord, Milan (Italy) Gianpaolo Perletti, PhD Department of Biotechnology and Life Sciences, University of Insubria, Varese (Italy) Alberto Trinchieri, MD Manzoni Hospital, Lecco (Italy)

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16. Nickel JC, Nigro M, Valiquette L, et al. Diagnosis and treatment of prostatitis in Canada. Urology. 1998; 52:797-802.

17. McNaughton Collins M, Fowler FJ Jr, et al. Diagnosing and treating chronic prostatitis: do urologists use the four-glass test?

Urology. 2000; 55:403-7.

18. de la Rosette JJ, Hubregtse MR, Karthaus HF, Debruyne FM. Results of a questionnaire among Dutch urologists and general practitioners concerning diagnostics and treatment of patients with prostatitis syndromes. Eur Urol. 1992; 22:14-19.

19. Kiyota H, Onodera S, Ohishi Y, et al. Questionnaire survey of Japanese urologists concerning the diagnosis and treatment of chronic prostatitis and chronic pelvic pain syndrome. Int J Urol. 2003; 10:636-42.

20. Yang J, Liu L, Xie HW, Ginsberg DA. Chinese urologistsâ&#x20AC;&#x2122; practice patterns of diagnosing and treating chronic prostatitis: a questionnaire survey. Urology. 2008; 72:548-551.

21. Krieger JN, Ross SO, Limaye AP, Riley DE. Inconsistent localization of Gram-positive bacteria to prostate-specific specimens from patients with chronic prostatitis, Urology. 2005; 66:721-725.

22. Stamatiou K, Magri V, Perletti G, et al. Chronic prostatic infection: microbiological findings in two Mediterranean populations.

Arch Ital Urol Androl. 2019; 91:177-181.

23. Ku JH, Paick JS, Kim SW. Factors influencing practices for chronic prostatitis: a nationwide survey of urologists in South Korea.

Int J Urol. 2005; 12:976-83.

24. Stamatiou K, Magri V, Perletti G, et al. Prostatic calcifications are associated with a more severe symptom burden in men with type II chronic bacterial prostatitis. Arch Ital Urol Androl. 2019; 91:79-83.

DOI: 10.4081/aiua.2020.4.357

ORIGINAL PAPER

Modeling the contribution of the obesity epidemic to the temporal decline in sperm counts Alex Kasman 1, Francesco Del Giudice 1, 2, Eugene Shkolyar 1, Angelo Porreca 3, Gian Maria Busetto 2, Ying Lu 4, Michael L. Eisenberg 1, 4 1 Department

of Urology, Stanford University School of Medicine, Stanford, California; of Maternal-Infant and Urological Sciences, “Sapienza” Rome University, Policlinico Umberto I Hospital, Rome, Italy; 3 Department of Urology, Policlinico Abano Terme, Abano Terme (PD), Italy; 4 Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California; 5 Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, California.

2 Department

Summary

Objective: Total sperm count (TSC) has been declining worldwide over the last several decades due to unknown etiologies. Our aim was to model the contribution that the obesity epidemic may have on declining TSC. Materials and methods: Obesity rates were determined since 1973 using the WHO’s Global Health Observatory data. A literature review was performed to determine the association between TSC and obesity. Using the measured obesity rates and published TSC since 1973, a model was created to evaluate the association between temporal trends in obesity/temperature and sperm count.

Results: Since 1973, obesity prevalence in the United States was increased from 41% to 67.9%. A review of the literature showed that body mass index (BMI) categories 2, 3, and 4 were associated with TSC (millions) of 164.27, 155.71, and 142.29, respectively. The contribution to change over time for obesity from 1974 to 2011 was modeled at 1.8%. When the model was changed to represent the most extreme possible contribution to obesity reported, the modeled change over time rose to 7.2%.

When stratified according to fertility status, the contribution that BMI had to falling sperm counts for all comers was 1.7%, while those presenting for fertility evaluation was 2.1%.

Conclusions: While the decline in TSC may be partially due to rising obesity rates, these contributions are minimal which highlights the complexity of this problem.

over the past 40 years (4). Additionally, several other studies in specific populations/countries have identified similar findings (5-10). However, the underlying cause or causes of the decline remains unknown. Given the complexity of spermatogenesis, there are likely multiple mechanisms behind declining sperm counts (e.g. environmental effects of chemical exposure, endocrine disruption, etc.) (11-14). Over the past four decades, the prevalence of obesity has increased over 50% in the world. As the obesity epidemic continues to worsen, the effect it may have on fertility has been increasingly investigated and several studies have been published on the topic. A systematic review by Guo et al., showed that overall for every five unit increase in BMI there was a 2.4% drop in sperm count (15). Additionally, a recent large observational study of 3,966 sperm donors showed a significant decrease in sperm count for overweight and obese men (16). However, the overall contribution the obesity epidemic has to falling total sperm counts remains unknown.

Given the public health implications of falling sperm counts, understanding the potential contributions of varying etiologies may have remains important. In the current study, we sought to model the potential contribution the US obesity epidemic could have to sperm counts over the past four decades.

KEY WORDS: Obesity; Sperm count; Total sperm count; Semen analysis.

MATERIALS

Submitted 16 September 2020; Accepted 15 October 2020

INTRODUCTION

Infertility remains an important public health concern with an estimated 15% of couples unable to conceive after 1 year of trying and therefore are labeled infertile with up to 50% having a male factor etiology (1, 2).

A such, semen analysis remains an important component of a couple’s fertility evaluation (3). With this knowledge, the overall decline in sperm count worldwide is worrisome and requires further attention. A large meta-analysis of 185 studies and data from over 42,000 men, demonstrated a 50% decline in sperm concentration and counts

AND METHODS

This systematic review was conducted according to the Systematic Review and Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines (17).

The research question was established based on the following PICO criteria: what is the contribution of the obesity epidemic to the temporal decline in sperm counts?

Furthermore, our goal was to explore the weighted influence of the US obesity on total sperm counts over the last four decades.

Obesity rates across the world were determined for the last four decades starting in 1973 up to 2011 using the World Health Organization’s (WHO) Global Health Observatory (GHO) data (https://www.who.int/gho/ncd/ risk_factors/overweight/en/). Obesity rates were quantified using body mass index (BMI). The dates, 1973-2011, were selected based

No conflict of interest declared.

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Table 1. on the real world measured sperm count data from the sysStudies utilized for obesity effect on sperm count. tematic review done by Levine et al. (4).

To determine the contribution that obesity has, on averCategory N Studies age, to total sperm count (TSC) we performed a systematic Obese 11504 Belloc (2014), Paash (2010), Shayeb (2011), Aggerholm (2008), review of the literature in PubMed, Embase, and Cochrane Duits (2010), Xiao (2013), Macdonald (2012), Chavarro (2010), from 1973-2011, without language restriction, to identify Andersen (2015), Hajshafiha (2013), Vignera (2012), Gutorova (2014), studies that examined infertility and/or male factor inferMa (2019) tility in relation to the risk of mortality. The reference lists Extreme obese 297 Hammiche (2012) of the included studies were also screened for relevant artiUSA 360 Chavarro (2010) cles. Original population-based retrospective cohort studEurope 8643 Belloc (2014), Paasch (2010), Shayeb (2011), Aggerholm (2008), ies as well as cross-sectional and case-control cohort studDuits (2010), Anderson (2015), Vignera (2012) ies were included and critically evaluated (Level of Asia 1304 Gutorova (2014), Ma (2019), Xiao (2013), Evidence: III-2, III-3). Case reports, abstracts and meeting New Zealand 372 Macdonald (2012) reports were excluded from the analysis. Search terms All comers 2852 Paasch (2010), Aggerholm (2008), Vignera (2012), Gutorova (2014) included but were not limited to: primary field: body mass Fertility evaluations 8652 Belloc (2014), Shayeb (2011), Duits (2010), Xiao (2013), Macdonald (2012), Chavarro (2010), Andersen (2015), Hajshafiha (2013) index or BMI, obesity, overweight AND, infertility, subfertility, semen parameters, or sperm parameters, sperm count, semen quality, sperm quality; secondary fields: oligospermia, azoospermia, oligozoospermia. between BMI category and sperm count to determine the A total of 26 studies were identified that examined obesiaverage sperm count based on annual BMI. BMI category, ty’s impact on male fertility. Six of these studies were the TSC was then multiplied by the appropriate obesity excluded as they did not report total sperm count. From rate and a TSC for obesity was obtained for that time perithe remaining 20 studies, BMI was categorized according od (e.g. 1973 or 2011). The rates between 1973 and 2011 to healthy weight (BMI 18.5-24.9), overweight (BMI 25were then compared and a percent change over time was 29.9), and obese (BMI > 30) using the Center for Disease calculated. Over all years, we could then evaluate changes Control’s standard definition (https://www.cdc.gov/obesiin sperm count based on temporal trends in obesity over ty/adult/defining.html). After categorization, a further 7 time. TSC was then categorized according to obesity, most studies were eliminated due to overlapping BMI categories extreme BMI contribution (e.g. the study reporting the (e.g. TSC reported together for categories 3 and 4). From strongest association between BMI and TSC), region, and these remaining 14 studies, data was extracted to obtain fertility status (unknown fertility versus those presenting the average TSC for each BMI category across studies with for fertility evaluation). Regional areas (USA, Europe, Asia, larger studies having a higher weight (Table 1).

Supplementary Table 1.

To assess the risk of bias (RoB), all Risk assessment of individual studies according to “Quality Assessment Tool included reports were independently for Observational Cohort and Cross-Sectional Studies”. reviewed using the “Quality Assessment 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Tool for Observational Cohort and CrossBelloc 2014 + + + + + + + + + NA NA Sectional Studies”, provided by the Paasch 2010 + NA + + + + + + NA NA National Institute of Health (NIH), by Shayeb 2011 + + NA + + + + + + NA NA assessing the potential risk for selecAggerholm 2008 + + + + + + + + + NA NA tion bias, information bias, measureDuits 2010 + + NA + + + + + + NA NA ment bias, or confounding bias (conXiao 2013 + + NA + + + + + + NA NA founding bias includes cointervenMacdonald 2012 + + + + + + + + + NA NA Chavarro 2010 + + + + + + + + + NA NA tions, differences at baseline in patient Hammiche 2012 + + + + + + + + + NA NA characteristics, and other issues as Andersen 2015 + + NA + + + + + + NA NA shown in Supplementary Table 1) (18).

Hajshafiha 2013 + + NA + + + + + + NA NA Studies were rated as good, fair, and Vignera 2012 + + + + + + + + + NA NA poor quality, where high risk of bias Gutorova 2014 + + NA + + + + + + NA NA translated to a rating of poor quality Ma 2019 + + + + + + + + + NA NA (“−”) and low risk of bias translated to NA: not applicable. a rating of good quality (“+”). No study Criteria 1: Was the research question or objective in this paper clearly stated?

Criteria 2: Was the study population clearly specified and defined? was considered to be seriously flawed Criteria 3: Was the participation rate of eligible persons at least 50%? according to the aforementioned criteCriteria 4: Were all the subjects selected or recruited from the same or similar populations (including the same time period)? Were inclusion and exclusion criteria for being in the study prespecified and applied uniformly to all participants? ria. Studies’ risk of performance bias Criteria 5: Were a sample size justification, power description, or variance and effect estimates provided? was low overall with absence of attriCriteria 6: For the analyses in this paper, was the exposure(s) of interest measured prior to the outcome(s) being measured? tion bias due to incomplete outcome Criteria 7: Was the timeframe sufficient so that one could reasonably expect to see an association between exposure and outcome if it existed?

Criteria 8: For exposures that can vary in amount or level, did the study examine different levels of the exposure as related to the outcome? data across all the studies.

Criteria 9: Were the exposure measures (independent variables) clearly defined, valid, reliable, and implemented consistently across all study participants?

Annual/Decade rates of body mass Criteria 10: Was the exposure(s) assessed more than once over time? index categories (i.e. normal, overCriteria 11: Were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented consistently across all study participants?

Criteria 12: Were the outcome assessors blinded to the exposure status of participants? weight, obese) were obtained from the Criteria 13: Was loss to follow-up after baseline 20% or less?

WHO for 1973 and 2011. For each Criteria 14: Were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)? year, we used our calculated association

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Obesity and sperm count

and New Zealand) were chosen based on those regions sampled in the 14 studies used. P < 0.05 were considered significant.

Figure 1.

PRISMA flow diagram.

RESULTS

The average total sperm count (TSC, millions) for increasing BMI categories 2 (normal), 3 (overweight), 4 (obese) were 164.3, 155.7, and 142.3. The average TSC (millions) for individuals above normal BMI range (e.g. categories 3 and 4) was 149. There was not enough data present in the literature for a TSC to be calculated for BMI category 1 (underweight).

Obesity has increased in prevalence of the past 40 years. In 1973, 59% of men were normal weight and 41% were obese. In contrast, in 2011 (the most recent year with available data), 32.1% were normal with 67.9% obese. Averaged across all studies, BMI categories 2, 3, and 4 were associated with TSC (millions) of 164.27, 155.71, and 142.29, respectively. The most extreme association between BMI and sperm count reported TSC (millions) of 68.6, 49.6, and 45.9 for BMI categories 2, 3, and 4, respectively (19).

Overall, the contribution to change over time for obesity from 1973 to 2011 was calculated at 1.8% (Figure 2a). When the model was changed to represent the most extreme possible contribution to obesity

reported in any given study, the modeled change over time rose to 7.2% (Figure 2a). When modeled based on regional BMI, the change for USA was 9.9%, Europe 3.1%, Asia 1.9%, and New Zealand -0.4% (Figure 2b). When stratified according to fertility status, the contribution that BMI had to falling sperm counts for men with unknown fertility status was 1. 7% while those presenting for fertility evaluation was 2.1% (Figure 2c).

Figure 2.

Model of obesity effect on sperm count stratified by overall obesity effect and largest obesity effect: (a) fertility status known versus unknown; (b) and region; (c) Reported decline for all models is based on Levine et al.

(Levine, Jørgensen, Martino, et al., 2017).

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DISCUSSION

The current report demonstrates the modest impact increasing rates of obesity may have on reported decline in semen quality. Increasing obesity rates were shown to have a small (1-10%), though measurable contribution to the overall decline with the most measured effect, logically, observed at the extreme end of obesityâ&#x20AC;&#x2122;s contribution. Additionally, the countries with higher obesity rates were shown to have a larger (~10%), though still modest, contribution to the reported 50% TSC decline over the past half century. When the obesity group was stratified by fertility status, the effect did decrease in observed men with unknown fertility versus those presenting for fertility evaluation. Overall, the contributions of rising obesity rates on declining TSC appear to be individually small and suggest that the etiology for reported declines in semen quality are likely multifactorial.

As the obesity epidemic continues to worsen globally, the health effects of each continue to gain importance (2023). Additionally, during this time period, global sperm counts have been observed to be declining with unknown mechanisms (4-8). Obesity has been postulated to be one of the mechanisms driving this especially given its implications for overall health (24). Indeed, a number of primary studies have demonstrated that as an individualâ&#x20AC;&#x2122;s BMI increases that sperm analysis parameters are affected (25-27). However, it should be noted that not all studies have found an impactful reduction in semen parameters in obese men, including a large systematic review by MacDonald, et al. (28, 29).

The etiology of this potential relationship is likely multifactorial which may explain the small effect that was measured in the current model. Increasing obesity has been associated with altered levels of both sex hormone binding globulin and testosterone as well as an increased estradiol to testosterone ratio (30-33).

Additionally, there is increased conversion of testosterone to estradiol in the setting of increased adiposity (34). All of these hormonal changes may ultimately lead to a negative effect downstream on spermatogenesis through the hypothalamic-pituitary-gonadal axis. While this may be a potential way in which sperm analysis parameters may be affected by obesity, the underlying mechanism through which increased adiposity could lead to impaired spermatogenesis is unknown. In addition, the additional body mass may insulate the scrotum contributing to rising scrotal temperature and lower sperm production.

The current model has several other limitations. The model itself is based on data from literature review and therefore is prone to both the bias of suitable articles for data extraction as well as the bias of the primary study itself. Additionally, a number of assumptions for the obesity model were made including that the measured effect of obesity overtime is constant. While other factors have been postulated to lead to declining sperm counts (e.g. chemical exposures), rigorous longitudinal surveillance did not allow modeling.

CONCLUSIONS

The current report demonstrates the modest contribution that obesity may have on declining total sperm

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counts and highlights the complex nature of infertility.

Further studies are needed to examine the underlying mechanisms behind declining total sperm counts as this has large public health implications.

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5. Huang C, Li B, Xu K, et al. Decline in semen quality among 30,636 young Chinese men from 2001 to 2015. Fertil Steril. 2017; 107:83-88.e2.

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7. Sengupta P, Nwagha U, Dutta S, et al. Evidence for decreasing sperm count in african population from 1965 to 2015. Afr Health Sci. 2017; 17:418-427 8. Mishra P, Negi MPS, Srivastava M, et al. Decline in seminal quality in Indian men over the last 37 years. Reprod Biol Endocrinol.

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11. Eisenberg ML, Li S, Cullen MR, et al. Increased risk of incident chronic medical conditions in infertile men : analysis of United States claims data. Fertil Steril. 2015; 105:629-636.

12. Mehrpour O, Karrari P, Zamani N, et al. Occupational exposure to pesticides and consequences on male semen and fertility: A review.

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14. Busetto G, Del Giudice F, Virmani A, et al. Body mass index and age correlate with antioxidant supplementation effects on sperm quality: Post hoc analyses from a double-blind placebo-controlled trial. Andrologia. 2020; 52:e13523.

15. Guo D, Wu W, Tang Q, et al. The impact of BMI on sperm parameters and the metabolite changes of seminal plasma concomitantly. Oncotarget. 2017; 8:48619-48634.

16. Ma J, Wu L, Zhou Y, et al. Association between BMI and semen quality: An observational study of 3966 sperm donors. Hum Reprod.

2019; 34:155-162.

17. Group M of OS in E (MOOSE). Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA. 2000; 283:2008-2012.

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18. National Institute of Health and Department of Health and Human Services, Quality assessment tool for observational cohort and cross-sectional studies.

28. Duits FH, Van Wely M, Van Der Veen F, Gianotten J. Healthy overweight male partners of subfertile couples should not worry about their semen quality. Fertil Steril. 2010; 94:1356-1359.

19. Hammiche F, Laven JSE, Twigt JM, et al. Body mass index and central adiposity are associated with sperm quality in men of subfertile couples. Hum Reprod. 2012; 27:2365-2372.

29. MacDonald AA, Herbison GP, Showell M, Farquhar CM. The impact of body mass index on semen parameters and reproductive hormones in human males: A systematic review with meta-analysis.

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20. Afshin A, Forouzanfar MH, Reitsma MB, et al. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med. 2017; 377:13-27.

21. Parmesan C, Yohe G. A globally coherent fingerprint of climate change. Nature. 2003; 421:37-42.

22. Del Giudice F, Kasman A, Ferro M, et al. Clinical correlation among male infertility and overall male health: A systematic review of the literature. Investig Clin Urol. 2020; 61:355-371.

23. Del Giudice F, Kasman A, De Barardinis E, et al. Association between male infertility and male-specific malignancies: systematic review and meta-analysis of population-based retrospective cohort studies. Fertil Steril. 2020; ePub ahead.

24. Heymsfield SB, Wadden TA. Mechanisms, Pathophysiology, and Management of Obesity. N Engl J Med. 2017; 376:254-266.

25. Jensen TK, Andersson AM, Jørgensen N, et al. Body mass index in relation to semen quality and reproductive hormones among 1,558 Danish men. Fertil Steril. 2004; 82:863-870.

30. Macdonald AA, Stewart AW, Farquhar CM. Body mass index in relation to semen quality and reproductive hormones in New Zealand men: a cross-sectional study in fertility clinics. Hum Reprod. 2013; 28:3178-3187.

31. Chavarro JE, Toth TL, Wright DL, et al. Body mass index in relation to semen quality, sperm DNA integrity, and serum reproductive hormone levels among men attending an infertility clinic.

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33. Keskin M, Budak S, Aksoy E, et al. Investigation of the effect of body mass index (BMI) on semen parameters and male reproductive system hormones. Arch Ital Urol Androl. 2017; 89:219-221.

26. Belloc S, Cohen-Bacrie M, Amar E, et al. High body mass index has a deleterious effect on semen parameters except morphology: Results from a large cohort study. Fertil Steril. 2014; 102:1268-1273.

34. Michalakis K, Mintziori G, Kaprara A, et al. The complex interaction between obesity, metabolic syndrome and reproductive axis: A narrative review. Metabolism. 2013; 62:457-478.

27. Eisenberg ML, Kim S, Chen Z, et al. The relationship between male BMI and waist circumference on semen quality: Data from the LIFE study. Hum Reprod. 2014; 29:193-200.

35. Levine H, Jørgensen N, Martino A, et al. Temporal trends in sperm count: a systematic review and meta-regression analysis.

Hum Reprod Update. 2017; 23:646-659.

Correspondence Alex Kasman, MD, MS Eugene Shkolyar, MD Angelo Porreca MD Department of Urology, Policlinico Abano Terme, Abano Terme (PD) (Italy) Francesco Del Giudice, MD Gian Maria Busetto MD, PhD Department of Maternal-Infant and Urological Sciences, “Sapienza” Rome University, Policlinico Umberto I Hospital, Rome (Italy) Ying Lu, PhD Department of Biomedical Data Science, Stanford University School of Medicine, Stanford (California) Michael L. Eisenberg, MD (Corresponding Author) eisenberg@stanford.edu Department of Urology, Stanford University School of Medicine, 300 Pasteur Dr., S285, Stanford, California 94305-5118

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ORIGINAL PAPER

Antioxidant treatment of increased sperm DNA fragmentation: Complex combinations are not more successful Cevahir Ozer Department of Urology, Baskent University, Adana, Turkey.

Summary

Objective: Oral antioxidant supplementation is part of the treatment of infertility associated with oxidative stress-related sperm damage.

It is possible to assume that the combined use of antioxidants will be better than single agent use. The purpose of this study was to compare the effectiveness of different antioxidant combinations in infertile men with increased sperm DNA fragmentation.

Materials and methods: We retrospectively reviewed the records of 637 patients who underwent antioxidant support therapy for increased sperm DNA damage between 2014 and 2019. Patients with DNA damage of 30% or more were included study.

Result: A total of 163 patients with follow-up data and who fulfilled the study criteria were included in the study.

There were four different treatment groups. No statistically significant differences were found between the groups. After 3 months of antioxidant treatment, there was a statistically significant decrease in sperm DNA damage in all treatment groups. However, there was no statistically significant difference between the treatment groups.

Conclusions: The complexity of the antioxidant combination may not contribute to the success of the treatment or may cause possible side effects, increase the cost of treatment and decrease patient compliance.

KEY WORDS: Infertility; Oxidative stress; Antioxidants.

Submitted 3 August 2020; Accepted 8 September 2020

INTRODUCTION

The conventional semen analysis remains the main diagnostic tool for evaluating male factor infertility (1).

However, difficulties resulting from the methodology of the conventional semen analysis significantly reduces the potential diagnostic power of this test. Furthermore, the conventional semen analysis cannot clearly identify all cases of male infertility. Although conventional semen analysis identifies some features of sperm function, it does not fully assess functional sperm competence (2). The search for a high-diagnostic method that could better predict the etiology and reproductive outcomes of male infertility resulted in a focus on sperm DNA integrity and fragmentation (3-5). The level of sperm DNA fragmentation seems to correlate negatively with pregnancy and delivery in both natural and assisted conceptions. It is also strongly associated with recurrent spontaneous abortion (6, 7).

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Oxidative stress (OS) is one of the major causes of DNA fragmentation in spermatozoa (8). This makes antioxidants a part of treatment in male infertility. Since OS can be caused by vastly different oxidants, it is possible to assume that combination therapy will be better than a single agent in antioxidant therapy (9).

The purpose of this study was to compare the effectiveness of different antioxidant combinations in infertile men with increased sperm DNA fragmentation.

MATERIALS

AND METHODS

Patients We retrospectively reviewed the records of 637 patients who underwent antioxidant support therapy for increased sperm DNA damage between 2014 and 2019. The baseline clinical evaluation for each patient included a comprehensive history and a complete physical examination.

Semen samples were collected after 2-7 days of sexual abstinence in a specially designated room in our embryology laboratory, with the aid of audiovisual stimulation.

Conventional semen analysis was performed according to the criteria of World Health Organization (WHO). DNA fragmentation in spermatozoa was measured using the terminal deoxyribonucleotidyl transferase-mediated dUTP nickend labelling (TUNEL) assay (Cell Death Detection Kit, Roche Biochemicals, Mannheim, Germany) according to the manufacturer's instructions with minor modifications. All semen tests were repeated at 3 months of treatment.

Blood samples were taken in the morning to measure follicle-stimulating hormone (FSH), luteinizing hormone (LH) and total testosterone levels at baseline and at the end of 3 months of antioxidant treatment.

Inclusion and exclusion criteria Patients with DNA damage of 30% or more were included study. Presence of varicocele, leukocytospermia, known genetic abnormality, history of chemotherapy and/or radiotherapy, history of malignancy, history of orchiectomy and/or orchiopexy and patients receiving hormonal therapy were accepted as exclusion criteria.

Ethical consideration The study was approved by Institutional Review Board (Project no: KA19/250).

No conflict of interest declared.

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Treatment of increased sperm DNA fragmentation

Data interpretation and statistical analysis Table 1.

Clinical characteristics of patients.

There were 193 patients who met the study criteria, had follow-up results and used 4 Group A Group B Group C Group D Total p different antioxidant treatment protocols. (n: 39) (n: 57) (n: 42) (n: 25) (n: 163) value Age, infertility period, history of varicocAge (years) 34.91 ± 5.94 36.16 ± 5.01 34.10 ± 4.91 36 ± 5.61 35.31 ± 5.32 0.237 electomy, cigarette smoking, alcohol conInfertility period (years) 5 (1-13) 6 (1-21) 5 (1-5) 7 (1-14) 5 (1-21) 0.211 sumption, serum FSH, serum LH and serum Smoking 15 (44.1) 26 (45.6) 29 (69) 11 (44) 81 (51.3) 0.064 testosterone levels, initial conventional Alcohol 0 (0) 4 (7) 3 (7.1) 4 (16) 11 (7) 0.127 semen parameters, and sperm DNA damage Varicocelectomy 11 (32.4) 15 (26.3) 8 (19) 7 (28) 41 (25.9) 0.609 rate before and after treatment were deterSemen parameters mined. We used propensity score-matched Volume (mL) 3 (1-6) 3 (1-7) 2.5 (1-7) 3 (1-6) 3 (1-7) 0.764 analysis to balance differences in age, duraConcentration (million/mL) 20 (8-178) 52 (5-282) 63 (3-188) 76 (0-143) 53 (0-282) 0.413 tion of infertility, smoking and alcohol use Motility (%) 55 (5-75) 55 (0-84) 52.5 (11-79) 55 (0-84) 50 (0-84) 0.983 among antioxidant treatment groups.

DNA damage (%) 47.72 ± 17.29 50.77 ± 11.26 46.71 ± 10.84 51.12 ± 18.32 49.06 ± 14.03 0.408 Power value was 76.0% for an effect size value (0.179) that was calculated for sperm DNA fragmentation at 3 month of study. With this men, Centax Pharma, Turkey) in addition to vitamin C, power value, it was found that the sample size was suffivitamin E and NAC. The multiantioxidant supplement cient. used in Group C (NeoFortil M) contains a daily dose of Statistical analysis was performed using the statistical 600 mg L-Carnitine, 250 mg L-Arginine, 120 mg vitamin package SPSS software (Version 25.0, SPSS Inc., Chicago, C, 72 mg vitamin E, 15 mg coQ10, 60 mcg selenium, 40 IL, USA). If continuous variables were normal, they were mg zinc sulfate and 800 mcg folic acid and the other one describle as the mean±standard deviation [(p > 0.05 in used in Group D (Promotil men) contains a daily dose of Kolmogorov-Smirnov test or Shapira-Wilk (n < 30)], and 2000 mg L-carnitine, 500 mg L-arginine, 200 mg vitaif the continuous variables were not normal, they were min C, 120 mg vitamin E, 100 mg coQ10, 60 mcg seledescribed as the median. Comparisons between groups nium, 60 mg magnesium, 15 mg zinc sulfate, 400 mcg were made using one way ANOVA for normally distribfolic acid, 2 mg vitamin B6, 6 mcg vitamin B12, 10 mcg uted data and Krukal Wallis test were used for the data vitamin D, 1 mg vitamin A and 2 mg beta-carotene. not normally distributed. Since analysis of variance was significant, comparisons were made using the Post Hoc Table 2. test or Mann-Whitney U test. The catagorical variables The effect of oral antioxidants on sperm DNA damage. between the groups was analyzed by using the Chi Initial DNA damage (%) 3th month DNA damage (%) p square test. Values of p < 0.05 were considered statistiGroup A 47.72 ± 17.29 29.51 ± 12.99 0.0001 cally. G-power (Version 3.1, Department of Psychology, Group B 50.77 ± 11.26 25.12 ± 13.81 0.0001 University of Düsseldorf, Germany) was used for post hoc Group C 46.71 ± 10.84 23.88 ± 16.07 0.0001 power analysis.

Group D Total

51.12 ± 18.32 49.06 ± 14.03

26.28 ± 18.20 26.03 ± 14.98

0.0001 0.0001

RESULTS

After the treatment groups are homogenized, a total of 163 patients with follow-up data and who fulfilled the study criteria were included in the study. All patients had no known medical problems. The medical history of the patients revealed varicocelectomy in 41 patients.

Patient characteristics are presented in Table 1.

No statistically significant differences were found between the groups with regard to age, infertility period, smoking, alcohol consumption, history of varicocelectomy, the initial semen parameters and initial sperm DNA damage rate (Table 1).

There were four different treatment groups that met the criteria. Group A received 500 mg daily vitamin C (EsterC plus, Solgar, USA), 400 IU daily vitamin E (Evicap fort, Kocak Farma, Turkey) and 600 mg daily N-acetylcysteine (NAC) (Assist plus, Bilim, Turkey). Group B received 100 mcg daily selenium (Selenium, Solgar, USA) and 100 mg daily coenzyme Q10 (coQ10) (Coenzyme Q-10, Solgar, USA) in addition to vitamin C, vitamin E and NAC. Group C received commercial multiantioxidant supplement (NeoFortil M, Tani Pharma, Turkey) in addition to vitamin C, vitamin E and NAC. Group D received another commercial multiantioxidant supplement (Promotil

Figure 1.

Change in DNA damage according to treatment groups.

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C. Ozer

After 3 months of antioxidant treatment, there was a statistically significant decrease in sperm DNA damage in all treatment groups (Table 2 and Figure 1). However, there was no statistically significant difference between the treatment groups (p = 0.230).

None of the patients had side effects requiring discontinuation of antioxidant support treatment.

DISCUSSION

DNA fragmentation of spermatozoa occurs during spermatogenesis and maturation processes. Increased sperm DNA fragmentation appears to be associated with impaired sperm function. Aging, poor lifestyle-related habits (such as smoking, alcohol consumption, environmental radiation and pollution), diseases, drugs, inflammation and infection in the external genital tracts and varicocele may cause an increase in sperm DNA fragmentation (8,10-12). All these factors induce sperm DNA breaks by three main mechanisms: apoptosis, impairment of sperm chromatin maturation and OS (13).

OS is a condition that is associated with an imbalance between the production and removal of reactive oxygen species (ROS) and free radicals (14). Antioxidant defense system act as scavengers to neutralize free radicals and overcome the adverse results of OS (14, 15). Antioxidant system including enzymatic factors (superoxide dismutase, catalase, and glutathione peroxidase), non-enzymatic factors and low-molecular weight compounds (glutathione, NAC, vitamin E, vitamin A and C, coQ10, carnitines, myo-inositol, lycopene etc.) and nutrients (selenium, zinc, and copper) can protect the body against OS (1618). Lack of one of these leads to a reduction in the antioxidant capacity of the plasma (17). The rationale behind the use of oral antioxidant therapy is that seminal OS is due to increased ROS production and/or decreased levels of enzymatic and non-enzymatic seminal antioxidants (19, 20). To date, several studies have shown that exogenous antioxidants have the capacity to counteract oxidative damage or OS, improving sperm DNA integrity for infertile men with OS (18, 21). Many oral formulations of antioxidants are readily available in the market and are commonly used to treat men with infertility. The different oral antioxidants available belong to the exogenous antioxidant category and they include Vitamin C, Vitamin E, coQ10, NAC, carnitines, trace elements such as zinc, selenium, pentoxifylline, and a combination of these oral antioxidants (20). Numerous studies have been conducted to assess the effectiveness of oral antioxidant supplementation for the treatment of infertile men with sperm DNA damage. Most of the studies showed an improvement in one or more of seminal fluid parameters, whereas some studies reported no positive effect.

Although there is still no consensus on the type, dosage and duration of antioxidants to be used in the treatment, it appears that in the case of OS, doses of antioxidants should be higher than the usual daily dose and because the time required for the development of a mature sperm from spermatogonia is 72 Âą 4 days, should be used for at least three months (17, 22, 23).

Since OS may be due to multiple sources, it seems reasonable to assume that a combination of antioxidants tar-

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geting the male reproductive system will provide better protection than a single antioxidant (9). However, the complexation of antioxidant therapy may have potential adverse effects including reductive stres (21).

Furthermore, complex combinations may increase the cost of treatment and may decrease treatment compliance (24). According to our study including 163 patients, complexity of oral antioxidant combination treatment does not appear to contribute to treatment success.

The limitation of our study was its retrospective and non-randomized nature. Although the small sample size in the groups we compared is another limitation, sample size was found to be sufficient in post hoc power analysis. The variability of the compounds, especially in commercial combinations, is the weakness of our study.

Since placebo arm ethics is arguable in such studies, we believe that the lack of placebo arm of the study is not a limitation. Furthermore, the effect of improvement in sperm DNA damage on fertility has not been studied because the female group was not homogenous.

CONCLUSIONS

The use of oral antioxidants can help to reduce OS and to treat OS related sperm DNA damage. The use of antioxidant agent combinations is expected to be more successful in the treatment than a single agent. However, it should be noted that the complexation of the combination may not provide an additional contribution to treatment success. Therefore, possible side effects, treatment cost and patient compliance should be kept in mind when designing combination protocols.

ACKNOWLEDGEMENTS

The author would like to thank Biostatistics specialist Cagla Sariturk for her expertise and assistance in statistical analysis.

REFERENCES

1. Komiya A, Kato T, Kawauchi Y, et al. Clinical factors associated with sperm DNA fragmentation in male patients with infertility.

Scientific World Journal. 2014; 2014:868303.

2. Santi D, Spaggiari G, Simoni M. Sperm DNA fragmentation index as a promising predictive tool for male infertility diagnosis and treatment management - meta-analyses. Reprod Biomed Online.

2018; 37:315-326.

3. Bungum M. Sperm DNA integrity assessment: a new tool in diagnosis and treatment of fertility. Obstet Gynecol Int. 2012; 2012:531042.

4. Agarwal A, Said TM. Role of sperm chromatin abnormalities and DNA damage in male infertility. Hum Reprod Update. 2003; 9:331345.

5. Sakkas D, Mariethoz E, Manicardi G, et al. Origin of DNA damage in ejaculated human spermatozoa. Rev Reprod. 1999; 4:31-37.

6. Agarwal A, Cho CL, Esteves SC. Should we evaluate and treat sperm DNA fragmentation? Curr Opin Obstet Gynecol. 2016; 28:164-171.

7. Evgeni E, Charalabopoulos K, Asimakopoulos B. Human sperm

Treatment of increased sperm DNA fragmentation

DNA fragmentation and its correlation with conventional semen parameters. J Reprod Infertil. 2014; 15:2-14.

8. Wright C, Milne S, Leeson H. Sperm DNA damage caused by oxidative stress: modifiable clinical, lifestyle and nutritional factors in male infertility. Reprod Biomed Online. 2014; 28:684-703.

9. Lewis SE, John Aitken R, Conner SJ, et al. The impact of sperm DNA damage in assisted conception and beyond: recent advances in diagnosis and treatment. Reprod Biomed Online. 2013; 27:325-337.

10. Pourmasumi S, Sabeti P, Rahiminia T, et al. The etiologies of DNA abnormalities in male infertility: An assessment and review.

Int J Reprod Biomed (Yazd) 2017; 15:331-344.

11. Cai T, Wagenlehner FM, Mazzoli S, et al. Semen quality in patients with Chlamydia trachomatis genital infection treated concurrently with prulifloxacin and a phytotherapeutic agent. J Androl.

2012; 33:615-623.

12. Alargkof V, Kersten L, Stanislavov R, et al. Relationships between sperm DNA integrity and bulk semen parameters in Bulgarian patients with varicocele. Arch Ital Urol Androl. 2019; 91.

13. Moustafa MH, Sharma RK, Thornton J, et al. Relationship between ROS production, apoptosis and DNA denaturation in spermatozoa from patients examined for infertility. Hum Reprod. 2004; 19:129-138.

16. Calogero AE, Condorelli RA, Russo GI, La Vignera S. Conservative nonhormonal options for the treatment of male infertility: antibiotics, anti-inflammatory drugs, and antioxidants.

Biomed Res Int. 2017; 2017:4650182.

17. Walczak-Jedrzejowska R, Wolski JK, Slowikowska-Hilczer J. The role of oxidative stress and antioxidants in male fertility. Cent European J Urol. 2013; 66:60-67.

18. Arcaniolo D, Favilla V, Tiscione D, et al. Is there a place for nutritional supplements in the treatment of idiopathic male infertility? Arch Ital Urol Androl. 2014; 86:164-170.

19. Zini A, Al-Hathal N. Antioxidant therapy in male infertility: fact or fiction? Asian J Androl. 2011; 13:374-381.

20. Alahmar AT. Role of oxidative stress in male infertility: an updated review. J Hum Reprod Sci. 2019; 12:4-18.

21. Gharagozloo P, Aitken RJ. The role of sperm oxidative stress in male infertility and the significance of oral antioxidant therapy.

Hum Reprod. 2011; 26:1628-1640.

22. Alahmar AT. The impact of two doses of coenzyme Q10 on semen parameters and antioxidant status in men with idiopathic oligoasthenoteratozoospermia. Clin Exp Reprod Med. 2019; 46:112-118.

14. Pham-Huy LA, He H, Pham-Huy C. Free radicals, antioxidants in disease and health. Int J Biomed Sci. 2008; 4:89-96.

23. Agarwal A, Nallella KP, Allamaneni SS, Said TM. Role of antioxidants in treatment of male infertility: an overview of the literature. Reprod Biomed Online. 2004; 8:616-627.

15. Kao SH, Chao HT, Chen HW, et al. Increase of oxidative stress in human sperm with lower motility. Fertil Steril. 2008; 89:11831190.

24. McDonald HP, Garg AX, Haynes RB. Interventions to enhance patient adherence to medication prescriptions: scientific review.

JAMA. 2002; 288:2868-2879.

Correspondence Cevahir Ozer, MD (Corresponding Author) cevahirozer@gmail.com Dadaloglu Mh Serinevler 2591 Sk No: 4/A, 01250 Yuregir, Adana (Turkey)

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DOI: 10.4081/aiua.2020.4.366

ORIGINAL PAPER

Role of total motile sperm count in the evaluation of young men with bilateral subclinical varicocele and asthenospermia Georgios Tsampoukas 1, 2, 4, Athanasios Dellis 1, 3, Antigoni Katsouri 5, Dominic Brown 2, Konstantinos Deliveliotis 6, Mohamad Moussa 7, Noor Buchholz 1, Athanasios Papatsoris 1, 6 1 U-merge

Ltd. (Urology for emerging countries), London, UK; of Urology, Princess Alexandra Hospital, Harlow, UK; 3 Department of Urology, Aretaieion Academic Hospital, Athens, Greece; 4 Department of Urology, Agios Andreas Hospital, Patras, Greece; 5 Department of Pharmacy, University of Patras, Patras, Greece; 6 2nd Department of Urology, University Hospital of Athens, Athens, Greece; 7 Al Zahraa Hospital, University Medical Center, Lebanese University, Beirut, Lebanon.

2 Department

*U-merge Ltd. (Urology for Emerging Countries) is an academic urological platform dedicated to facilitate knowledge transfer in urology on all levels from developed to emerging countries. U-merge Ltd. is registered with the Companies House in London/ UK. www.U-merge.com

Summary

Introduction: In comparison to its clinical analogue, the subclinical varicocele represents a questionable entity and specific guidelines for the optimal management are lacking. In our previous study of patients with subclinical varicocele, we showed that bilateral condition is associated with risk of dyspermia. In the present study, we evaluated the risk of deterioration of semen quality in men with bilateral disease and impaired motility according to WHO criteria.

Materials and methods: Men with bilateral subclinical varicocele, not desiring fatherhood at the time of presentation, were included in study. During initial evaluation, the number of Total Motile Sperm Count (TMSC) was calculated and the patientsâ&#x20AC;&#x2122; age, total testicular volume (TTV), maximum venous size and mean resistive index (RI) of the intratesticular arteries were recorded. We classified the participants in five classes according to the TMSC reading: class A-: TMSC < 5 x 106, class A: TMSC between 5-10 x 106, class B: TMSC between 10-15 x 106, class C: TMSC between 15-20 x 106, and class D: TMSC > 20 x 106 per ejaculate. The participants were seen after 6 months for a repeat spermiogram and physical examination. If clinical varicocele was diagnosed or a new abnormality in the spermiogram was noted, the participants were excluded from the study. The remaining patients were allocated to two groups according to the repeat TMSC reading: patients sub-classified into a lower class (group 1), and patients remaining at the same class (group 2). A comparative analysis was performed between two groups.

Results: Nineteen men were included. Nine patients were subclassified (group 1). Three patients moved to A- class (< 5 x 106). Ten patients remained in the same class having no deterioration (group 2). Comparing the two groups, no statistically significant difference was recognized for age, TTV, maximum venous size on both sides, and mean RI (p > 0.05).

However, the initial reading for TMSC was 14.57 x 106 in group 1, and 22.84 x 106 in group 2, respectively.

This difference was statistically significant (p < 0.05).

Additionally, in a paired analysis there was a significant difference in TMSC after 6 months (p < 0.05), too.

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Conclusions: Young men with bilateral varicocele and asthenospermia seem to be at risk of deterioration in their semen quality after a follow-up of 6 months. The measurement of TMSC can unmask patients at risk, whereas men with the lowest readings seem to be at highest risk for deterioration. The possibility of a worsening sperm quality should be considered in the appropriate clinical context.

KEY WORDS: Varicocele; Subclinical; Total motile sperm count (TMSC); Infertility; Bilateral.

Submitted 21 June 2020; Accepted 24 August 2020

INTRODUCTION

A subclinical varicocele (SV) is defined as the radiological finding of a dilatation of the pampiniform plexus and the presence of venous reflux, in the absence of clinical varicocele (CV) on physical examination (1, 2). The condition is regarded as an early stage for the development of a clinical varicocele and activity seems to increase the risk (3, 4). In comparison to its clinical analogue, a unilateral, subclinical varicocele is considered an entity of uncertain significance, and the evidence to support treatment, even in the context of male infertility, is weak (5).

Observation, surgical treatment, embolization and empirical treatment with clomiphene citrate or bioflavonoids has been proposed as possible management options (6-8).

A special subgroup of infertile patients with right-sided subclinical and a simultaneous left-sided clinical varicocele seem to have a greater benefit from bilateral intervention in terms of improvement in semen quality and pregnancy rates in comparison to unilateral correction, implicating that the right subclinical varicocele is significant (9). In a similar clinical context, the presence of bilateral subclinical varicocele (BSV) seems to represent a distinct entity with noteworthy clinical significance. The prevalence of BSV seems to be higher in older men, whereas the condition is associated with deterioration of semen quality, especially sperm motility, during a long follow-up (10, 11). Previously, we had concluded that the presence of No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2020; 92, 4

Bilateral subclinical varicocele and asthenospermia

BSV has been associated with abnormal semen parameters in young men in comparison to unilateral SV (12). In this study, we followed a population of young men with BSV and asthenospermia in their spermiogram who did not desire fatherhood at time of presentation with a planned follow-up of 6 months. In order to evaluate their fertility capacity, we used the Total motile sperm count (TMSC) instead of classical WHO criteria. TMSC is considered a more reliable tool for the estimation of pregnancy when a male infertility factor is implicated (13). Our aim was to evaluate the risk of deterioration in semen quality and identify possible predictive factors in those patients.

MATERIALS

the spermiogram, or evidence of clinical varicocele were excluded. The two groups were compared in terms of age, maximal left vein diameter, maximal right vein diameter, total testicular volume, mean RI value, the grade of reflux, initial TMSC, FSH and testosterone.

For statistical analysis, the Shapiro-Wilk test was used to check normality, and subsequently the Student’s t-test and Mann-Whitney U-test were used accordingly for the detection of statistically significant differences between the two groups. Statistical significance value was set at a p < 0.05. A Wilcoxon matched-pairs signed rank test was used to assess the difference in the TMSC at the first assessment, and at subsequent follow-up.

AND METHODS

Inclusion criteria were males with bilateral subclinical RESULTS varicocele, having asthenospermia alone (< 32% progresNineteen patients were included in the study. The particsive motility) according to WHO 2010 criteria in their ipants’ characteristics are listed in Table 1. spermiogram and not desiring fatherhood at the time of The distribution of patients in classes initially, and at 6 presentation. The subjects were recruited during a period months is depicted in Figure 1. Nine patients were downof 2 years (November 2016 - December 2018). Exclusion graded into a lower class (group 1). Ten patients remained criteria were clinical varicocele, previous fatherhood, hisin the same class unchanged (group 2). Three patients tory of relevant surgery, present infertility concerns, active downgraded from class A to class A- (TMSC < 5 x 106). or chronic urogenital infections, signs and symptoms of A paired t-test comparing the initial TMSC and the folprimary hypogonadism, testicular microlithiasis, backlow-up TMSC readings showed a significant difference ground of cancer, and history of intake of gonadotoxic after a mean follow-up of 6.7 months (p < 0.05, Table 2). medications or steroids. The subclinical varicocele was When comparing the mean values of all the parameters diagnosed by colour Doppler ultrasound (graded as grade I as per Hirsch classification) when the clinical examination was negative, but a venous dilatation larger than Figure 1.

2mm of the pampiniform plexus with reflux during The classification of patients according to TMSC range: A- < 5 x 106. A 5-10 x 106, B 10-15 x 106, C 15-20 x 106, Valsava manoeuvre was demonstrated (14, 15). Testicular D > 20 x 106. volume was measured by the ultrasound unit according to the formula volume = 0.53 × length × width × height, and the mean value was obtained. Also, the mean resistive index (RI) of at least 3 intratesticular arteries on both sides, and the maximum vein diameter on each side were recorded. Asthenospermia was documented by two spermiograms, whereby the spermiogram with the lowest motility value was used for reference. As an objective tool for the assessment of sperm potential, the total motile sperm count was used: ejaculate volume (V) x sperm concentration (SC) x progressive motility (A + B) divided by 100%.

For the subsequent analysis, we allocated patients into five classes according to TMSC readings: • Class A-: TMSC < 5 x 106 • Class A: TMSC 5-10 x 106 • Class B: TMSC 10-15 x 106 Table 1.

• Class C: TMSC 15-20 x 106 Patients’ characteristics.

• Class D: TMSC > 20 x 106 Age MVD MVD FU RI Testosterone FSH TTV The patients were seen again after six (years) (left, mm) (right, mm) (months) (ng/dl) (mUI/ml) (ml) months with a repeat spermiogram No. 19 19 19 19 19 19 19 19 and physical examination. According Min. 18 2.1 2.1 6 0.45 401 2 24.2 to those follow-up results, we then Max. 34 3.2 2.8 8 0.64 762 7.5 37.8 formed two groups: Range 16 1.1 0.7 2 0.19 361 5.5 13.6 • Group 1: patients reclassified into Mean +/- SD 26 + 4.22 2.73 + 0.31 2.56 + 0.17 6.79 + 0.79 0.555 + 0.05 525 + 97.7 3.83 + 1.31 29.4 + 4.08 a lower category • Group 2: patients without downMedian 26 2.80 2.60 7 0.55 489 3.90 28.1 classification.

Std. error of mean 0.967 0.072 0.04 0.181 0.012 22.4 0.3 0.936 Patient who developed additional SD: Standard Deviation, MVD: maximal vein diameter, FU: Follow-up in months, RI: Resistive index, FSH: Follicle-stimulating hormone, TTV: total testicular volume. abnormalities (e.g. oligospermia) in Archivio Italiano di Urologia e Andrologia 2020; 92, 4

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Table 2.

Match-up comparison of TMSC after mean follow-up of 6.7 months. iTMSC (millions) 19 6,32 28,6 22.2 18.9 + 7.32 20 1.68

No. Min. Max. Range Mean +/- SD Median Std. error of mean P value

fTMSC (millions) 19 4,22 28.2 24 16.5 + 8.13 16.8 1.86

Wilcoxon test

0.0002*

*Difference statistically significant, p < 0.05, Number of pairs 19, Sum of positive ranks 10.50, Sum of negative ranks -179.5, two-tailed, Median of differences -3.0, iTMSC: initial Total motile sperm count, fTMSC: follow-up total motile sperm count.

Table 3.

Comparison of parameters between Group 1 and Group 2.

Parameter Age (years) MVD (right, mm) iTMSC (1 x 106) RI Testosterone (ng/dl) FSH (mUI/ml) TTV (ml) MVD (Left, mm)

Group Group 1 Group 2 Group 1 Group 2 Group 1 Group 2 Group 1 Group 2 Group 1 Group 2 Group 1 Group 2 Group 1 Group 2 Group 1 Group 2

No. 9 10 9 10 9 10 9 10 9 10 9 10 9 10 9 10

Mean T-test 25.56 t = 0.08748, df = 17 25.40 2.622 t = 1.447, df = 17 2.51 14.57 t = 2.930, df = 17 22.84 0.57 t = 1.116, df = 17 0.54 545.3 t = 0.8542, df = 17 506.7 3.22 t = 2.082, df = 17 4.37 27.69 29.97 2.8 2.85

U-value P value 0.93 0.16 0.0093* 0.27 0.40 0.052 38

0.58

40.50

0.73

*p < 0.05, statistically significant difference, MVD: Maximal vein diameter, iTMSC: initial total motile sperm count, RI: Resistive index, FSH: Follicle-stimulating hormone, TTV: Total Testicular volume.

in both groups, no significant difference was detected in terms of age, maximal vein diameter on both sides, RI, testosterone, FSH and TTV. The initial TSMC reading was however significantly different between the patients in both groups (p < 0.05) (Table 3).

DISCUSSION

We decided to study men with bilateral varicocele as we regard the condition as the full expression of varicocele disease. The prevalence has been reported as up to 80%, and differences in detection rates are the result of differences in diagnostic approach (16, 17). Moreover, bilateral varicocelectomy is superior to unilateral in terms of the main outcome of pregnancy rates (9, 18).

Furthermore, the possible common pathophysiological background (BSV and asthenospermia) and similar expectations (no fertility issues and no desire for fatherhood at that time) formed a homogenous group which gives reproducibility to our results.

We used TMSC as a marker of semen quality as it is a superior predictive tool for the main outcomes for male

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infertility in comparison to standard WHO criteria.

Specifically, the well-studied range classification into 3 groups (TMSC < 5 × 106; 5 - 20 × 106; > 20 × 106 spermatozoa, regarded as normospermia) seems to have a superior predictive value in terms of spontaneous pregnancy rates whereas the same applies for infertile couples with male factor infertility undergoing intracytoplasmic sperm injection cycles (ICSI) (19, 20). Also, TMSC can be used as a method to assess the clinical outcome of varicocelectomy in patients with clinical varicocele (CV), and predict the need of further assisted reproduction technology treatment (21). Additionally, a study found no significant differences in the improvement of TMSC after repair in men with SV comparing to men with CV whereas most of patients in the subclinical group had BSV which is relevant to our study (22). In our cohort, the paired analysis showed a significant difference between the initial and follow-up TMSC readings. This means that this group of men might be at risk of deterioration of sperm motility in the future. Also, we observed that those men experiencing deterioration had their readings below the so-called normal cut-off of 20 x 106 (14.57 x 106 vs 22.84 x 106, p < 0.05). Moreover, 3 out of 4 patients with an initial TMSC range of 5-10 x 106 were later found with a TMSC range of < 5 x 106 at follow-up.

Although these readings do not necessarily imply infertility, this range is nevertheless associated with lower chances of spontaneous pregnancy rates. In clinical practice, infertile patients with these readings might have been advised to undergo assisted-reproductive modalities (19). Thus, our results imply that patients with BSV and asthenospermia with gray-zone values of TMSC < 20 x 106, and especially those with the lowest readings may be at risk of deterioration of their semen quality.

No statistically significant difference was found between the two groups in terms of age and no specific conclusions can be drawn. Once again, the results must be linked to the appropriate clinical context, e.g. the perspective of the patients and the possible expectations of the couple. Age does not seem to be a decisive factor for dyspermia in patients with SV (23), but it does have importance in patients with low grade varicocele undergoing varicocelectomy in relation to actual venous size (24). Also, we examined the role of vein diameter on both sides and there was no significant difference between the groups. These results are in accordance with our previous study where no association was found between maximal vein diameter in men with SV and dyspermia (12). This does not sound surprising, as even in clinical forms, even grade seems to be inferior to reflux in terms of prediction of the results of varicocelectomy (25). In our study, the role of reflux was not exhaustively examined, as all of our participants by definition had Grade I varicocele (Valsava induced reflux) according to Hirsch classification, which is helpful for the diagnosis of the subclinical form but lacks pathophysiological significance in adults (26).

In young boys, pattern of grade I reflux helps stratify the risk for hypotrophy and assist the follow-up (27). In our previous study in adult men, the pattern of the reflux (lasting all the duration of the Valsava vs short-lasting reflux) had not been linked to dyspermia in adults patients with subclinical varicocele (12). Reflux is note-

Bilateral subclinical varicocele and asthenospermia

worthy though, and the shunt-type (continuous) reflux is strongly associated with testicular hypotrophy in adolescents (28), whereas prolonged reflux may also predict the outcome of varicocelectomy in adults (25). In terms of the endocrinological profile in our study participants, there was no difference between groups in testosterone or FSH. Additionally, all readings were within normal limits reflecting the normal testicular volume found in both groups. It is doubtful if SV should be expected to have any significant effect on testicular volume, and the reports are conflicting (29-31).

Furthermore, we examined the role of intratesticular RI at the cut-off of 0.6 which has been highlighted as a marker of dyspermia (32, 33). We did not focus on linked parameters Peak Systolic Velocity (PSV) and End Diastolic Velocity (EDV) as RI is not associated with the angle of recording (which is extremely demanding in tiny arteries like intratesticular ones) and, therefore, operator-independent and more reliable for the scope of our study. In our cohort, there was no difference between the two groups in terms of RI, whereas the median value in our sample could be considered as normal. This discrepancy might be reflected by the pathophysiological background. Varicocele may provoke damage in various sites in the genital tract apart from the testicle e.g. the epididymis which is vital for the motility potential of the spermatozoa and some agents are under evaluation (34-36). Even low-grade varicoceles may undermine epididymal function causing infertility issues which might be apparent even when the spermiogram is normal (37). Another intriguing aspect lies on the intercommunication between the pampiniform and the periprostatic plexus (38, 39). In the varicoceleassociated infertility, patients with deteriorated motility undergoing varicocelectomy might not experience improvement if the periprostatic plexus is apparently dilated which implicates the complexity in the pathophysiology of the condition (40). Also, the topography of the damage caused by the SV might be the reason why infertile patients with SV have low levels of oxidative stress markers (41). In our study, the participants had normal testicles, normal RI and asthenospermia; it could be assumed that if BSV was responsible for the semen deterioration, it might have caused damage in a site different than the testicles and this is why RI is within normal limits. Either way, it is doubtful if RI can assist during the evaluation of men with SV. We appreciate our study has certain limitations. First and foremost, the men involved had no fertility concerns at that time and they must not be considered infertile. Also, we did not correlate with pregnancy rates, which is the main outcome measure in the evaluation of infertile patients with varicocele and therefore, our study cannot provide safe conclusions to infertile patients with the condition. The clinical merit of our findings must be set in an appropriate clinical context of men incidentally found with bilateral SVs. Secondly, we appreciate that our sample is small. However, the presentation and the selection criteria were major limitations because as matter of fact, the participants represented an asymptomatic population who normally do not attend in the hospital.

We managed to increase the sample size through screening and by inviting young men to the cohort.

CONCLUSIONS

Despite our small sample, our results showed that young males with BSV and asthenospermia are likely to experience deterioration in their TMSC over time. Importantly, patients with borderline TMSC readings seem to be at higher risk of deterioration, and especially patients with very low readings.

Thus, these patients might not be ideal candidates for a wait & watch approach although the optimal management is unknown. Of note, there was no correlation with pregnancy rates and therefore, our observations must be utilized in the appropriate clinical context.

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11. Hallak J. Asymptomatic male currently not desiring fertility with bilateral subclinical varicocele found on ultrasound evaluation and borderline semen analysis results. Asian J Androl. 2016; 18:315.

12. Tsampoukas G, Dellis A, Papatsoris A. Bilateral disease and intratesticular haemodynamics as markers of dyspermia in patients with subclinical varicocele: A prospective study. Arab J Urol. 2019; 17:298-304.

13. Borges EJ. Total motile sperm count: a better way to rate the severity of male factor infertility? JBRA Assist Reprod. 2016; 20:47-8.

14. Hirsh AV, Cameron KM, Tyler JP, et al. The Doppler assessment of varicoceles and internal spermatic vein reflux in infertile men. Br J Urol. 1980; 52:50-56.

15. Gonda RL, Karo JJ, Forte RA, Oâ&#x20AC;&#x2122;Donnell KT. Diagnosis of subclinical varicocele in infertility. Am J Roentgenol. 1987; 148:71-75.

16. Gat Y, Bachar GN, Zukerman Z, et al. Varicocele: a bilateral disease. Fertil. Steril. 2004; 81:424-429.

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35. Milingos SD. The epidymal factor — a diagnostic approach. Int J Androl. 1985; 8:417-420.

18. Donkol RH, Salem T. Paternity after varicocelectomy: preoperative sonographic parameters of success. J Ultrasound Med. 2007; 26:593-9.

36. Mongioi L, Calogero AE, Vicari E, et al. The role of carnitine in male infertility. Andrology. 2016; 4:800-7.

19. Hamilton JA, Cissen M, Brandes M, et al. Total motile sperm count: a better indicator for the severity of male factor infertility than the WHO sperm classification system. Hum Reprod. 2015; 30:1110-21.

37. Pajovic B, Dimitrovski A, Radojevic N, Vukovic M. A correlation between selenium and carnitine levels with hypo-osmotic swelling test for sperm membrane in low-grade varicocele patients. Eur Rev Med Pharmacol Sci. 2016; 20:598-604.

20. Borges E Jr, Setti AS, Braga DP, et al. Total motile sperm count has a superior predictive value over the WHO 2010 cut-off values for the outcomes of intracytoplasmic sperm injection cycles.

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38. De Caestecker K, Lumen N, Spinoit AF, et al. Varicocele: the origin of benign prostatic hypertrophy? Testosterone dosages in the periprostatic plexus. Acta Clin Belg. 2016; 71:281-283.

21. Samplaski MK, Lo KC, Grober ED, et al. Varicocelectomy to ‘upgrade’ semen quality to allow couples to use less invasive forms of assisted reproductive technology. Fertil Steril. 2017; 108:609-612.

22. Thirumavalavan N, Scovell JM, Balasubramanian A, et al. The Impact of Microsurgical Repair of Subclinical and Clinical Varicoceles on Total Motile Sperm Count: Is There a Difference?

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23. Chen SS. Significant predictive factors for subfertility in patients with subclinical varicocele. Andrologia 2017; 49(10).

39. Gat Y, Goren M. Benign Prostatic Hyperplasia: Long-term follow-up of prostate volume reduction after sclerotherapy of the internal spermatic veins. Andrologia. 2018; 50.

40. Condorelli RA, Calogero AE, Mongioi' L, et al. Varicocele and concomitant dilation of the periprostatic venous plexus: effects on semen viscosity sperm parameters. J Endocrinol Invest. 2016; 39:543-7.

41. Ni K, Steger K, Yang H, et al. A comprehensive investigation of sperm DNA damage and oxidative stress injury in infertile patients with subclinical, normozoospermic, and astheno/oligozoospermic clinical varicocoele. Andrology. 2016; 4:816-24.

24. Shiraishi K, Takihara H, Naito K. Internal spermatic vein diameter and age at operation reflect the response to varicocelectomy Andrologia. 2001; 33:351-5.

25. Goren MR, Erbay G, Ozer C, et al. Can we predict the outcome of varicocelectomy based on the duration of venous reflux? Urology.

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26. Freeman S, Bertolotto M, Richenberg J, et al. Ultrasound evaluation of varicoceles: guidelines and recommendations of the European Society of Urogenital Radiology Scrotal and Penile Imaging Working Group (ESUR-SPIWG) for detection, classification, and grading. Eur Radiol. 2020; 30:11-25.

27. Zampieri N, Zuin V, Corroppolo M, et al. Relationship between varicocele grade, vein reflux and testicular growth arrest. Pediatr Surg Int. 2008; 24:727-30.

28. Mohseni MJ, Nazari H, Amini E, et al. Shunt-type and stop-type varicocele in adolescents: prognostic value of these two different hemodynamic patterns. Fertil Steril. 2011; 96:1091-6.

29. Sakamoto H, Ogawa Y, Yoshida H. Relationship between testicular volume and varicocele in patients with infertility. Urology.

2008; 71:104-109.

30. Akcar N, Turgut M, Adapinar B, Ozkan IR. Intratesticular arterial resistance and testicular volume in infertile men with subclinical varicocele. J Clin Ultrasound. 2004; 32:389-393.

31. Zini A, Buckspan M, Berardinucci D, Jarvi K. The influence of clinical and subclinical varicocele on testicular volume. Fertil Steril.

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32. Pinggera GM, Mitterberger M, Bartsch G, et al. Assessment of the intratesticular resistive index by colour Doppler ultrasonography measurements as a predictor of spermatogenesis. BJU Int. 2008; 101:722-6.

33. Hillelsohn JH,Chuang KW, Goldenberg E, Gilbert BR. Spectral doppler sonography: A noninvasive method for predicting dyspermia. J Ultrasound Med. 2013; 32:1427-1432.

34. Akdemir S, Gurocak S, Konac E, et al. Different surgical techniques and L-carnitine supplementation in an experimental varicocele model. Andrologia. 2014; 46:910-6.

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Correspondence Georgios Tsampoukas, MD (Corresponding Author) tsampoukasg@gmail.com scientific-office@u-merge.com Noor Buchholz, MD noor.buchholz@gmail.com U-merge Scientific Office 1, Menandrou Street, Athens 14561 (Greece) Dominic Brown, MD dominic.brown5@nhs.net Department of Urology, Princess Alexandra Hospital, Harlow (UK) Athanasios Dellis, MD aedellis@gmail.com Department of Urology, Aretaieion Academic Hospital, Athens (Greece) Antigoni Katsouri, MD a.katsr@gmail.com Department of Pharmacy, University of Patras, Patras (Greece) Konstantinos Deliveliotis, MD chdeliveli@gmail.com Athanasios Papatsoris, MD agpapatsoris@yahoo.gr 2nd Department of Urology, University Hospital of Athens, Athens (Greece) Mohamad Moussa, MD mohamad.moussa@zhumc.org.lb Al Zahraa Hospital, University Medical Center, Lebanese University, Beirut (Lebanon)

REVIEW

DOI: 10.4081/aiua.2020.4.371

Erectile dysfunction in common neurological conditions: A narrative review Mohamad Moussa 1, Athanasios G. Papatsoris 2, Mohamed Abou Chakra 3, Baraa Dabboucy 4, Youssef Fares 5 1 Urology

Department, Zahraa Hospital, University Medical Center, Beirut, Lebanon; Department of Urology, School of Medicine, Sismanoglio Hospital, National and Kapodistrian University of Athens, Athens, Greece; 3 Department of Urology, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon; 4 Department of Neurosurgery, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon; 5 Department of Neurosurgery, Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon.

2 2nd

Summary

Neurogenic erectile dysfunction (NED) can be defined as the inability to achieve or maintain an erection due to central or peripheral neurologic disease. Neurologic diseases can also affect the physical ability and psychological status of the patient. All these factors may lead to a primary or secondary NED. Medication history plays an important role since there are many drugs commonly used in neurologic patients that can lead to ED. The assessment of NED in these patients is generally evolving with the application of evoked potentials technology in the test of somatic and autonomic nerves, and functional magnetic resonance imaging.

With the electrophysiological examinations, neurogenic causes can be determined. These tools allow to categorize neurologic lesion and assess the patient prognosis. The first-line treatment for NED is phosphodiesterase inhibitors. Second-line treatments include intracavernous and intraurethral vasoactive injections. Third-line treatments are penile prostheses.

The efficacy and safety of each treatment modality depend on the specific neurologic condition. This review discusses the physiology, pathophysiology, diagnosis, and treatment of ED in multiple peripheral and central neurologic conditions, as well as for future research.

KEY WORDS: Erectile dysfunction, Neurogenic, Neurologic disability, Management.

Submitted 19 May 2020; Accepted 6 August 2020

INTRODUCTION

Erectile dysfunction (ED) is common (affecting 10-20 million men in the USA) and multifactorial disease due to organic and/or psychological factors that strongly impair the quality of life in man. During the past decade, many advances in the understanding of the pathophysiology of ED have been made and new therapeutic strategies have become available (1). ED is the inability to achieve or maintain an erection that is sufficient for satisfactory sexual performance and affects a considerable proportion of men at least occasionally. The severity of ED is often described as mild, moderate or severe according to the five-item International Index of Erectile Function (IIEF-5) questionnaire, with a score of 1-7 indicating severe ED,

8-11 moderate ED, 12-16 mild-moderate ED, 17-21 mild ED and 22-25 no ED (2). Risk factors for ED are numerous, with patients over 40 years old demonstrating a significant association between ED and cardiovascular risk factors including hypertension, dyslipidemia, diabetes mellitus (DM), coronary artery disease, and the metabolic syndrome (3). Organic causes are responsible for about 60% to 90% of all causes of ED. Most frequent pathologies involved are vasculogenic. The most common etiologies are due to low blood inflow (large vessel atherosclerosis), DM, endocrinologic disorders, neurogenic, trauma, penile disease, iatrogenic, and drugs. It was estimated that 10-19% of the organic ED are neurogenic. The main causes are intracerebral (Parkinson's disease, cerebrovascular disease, stroke, encephalitis, or temporal lobe epilepsy) or spinal cord etiologies (trauma, multiple sclerosis, myelodysplasia). Peripheral nerves are also affected in alcoholic neuropathy, diabetic neuropathy, after surgery (radical pelvic surgery), and trauma (4).

The first distinction of ED that should be established is psychogenic from organic.

Clues to suggest a psychogenic etiology include sudden onset, good quality spontaneous or self-stimulated erections, major life events, or previous psychological problems. Conversely, gradual onset, lack of tumescence, and normal libido are more suggestive of an organic etiology (5). Identification of ED can be made through questionnaires or a complete medical and sexual history.

Anamnesis and laboratory tests are sufficient in most cases to identify ED and to manage the treatment.

Supplementary tests are used in special cases or where confirmation of an etiological diagnosis is required (6).

The current standard of care for ED consists of lifestyle changes such as management of diet, diabetes, hypertension, and weight loss, along with pharmacotherapies.

The current gold standard treatment is the use of phosphodiesterase 5 inhibitors (PDE5i) (7). PDE5i are the most effective oral drugs for the treatment of ED, including ED associated with DM, spinal cord injury, and antidepressants. Intraurethral and intracavernosal injections (ICI), vacuum pump devices, and surgically implanted penile prostheses are alternative therapeutic options

No conflict of interest declared.

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when PDE5i fail. Testosterone supplementation in men with hypogonadism improves ED and libido (8).

More invasive options exist for patients who do not respond to PDE-5 i therapy or in whom it is contraindicated. Alprostadil (prostaglandin E1) causes smoothmuscle relaxation and subsequent vasodilation by acting on adenylate cyclase to increase the intracellular cyclic adenosine monophosphate (cAMP) concentration.

Prostaglandin E1 may be administered intraurethrally, where it is absorbed and transported throughout the erectile bodies. Vasoactive drugs may also be injected intracavernosally. Such therapy represents an important second-line therapy for ED. It is the most effective pharmacologic treatment but has a high dropout rate because of the associated pain (9). Penile prostheses are the only surgical therapy option maintaining its significance as a cure for ED. There are convincing long-term results with a high degree of patient and partner satisfaction, high patient acceptance, and good functional durability of the mostly three-piece inflatable devices (10).

In patients where pharmacological therapy is unhelpful or contraindicated, another option is the surgical approach. Penile vascular surgery is suitable only for healthy men with acquired ED due to isolated stenosis of extra-penile arteries without any kind of generalized vascular disease. Penile prosthesis implant is recognized, at present, as the most effective option to obtain an artificial erection satisfactory for sexual intercourse in those patients in which the pharmacological approach is contraindicated or ineffective (11). We performed a narrative review to discuss the physiology, pathophysiology, diagnosis, and treatment of ED in multiple peripheral and central neurologic conditions. We also presented the novel therapies for ED in some neurologic diseases.

MATERIALS

AND METHODS

We searched electronic databases including PubMed, the Scopus database for published studies that analyzed the role of the following Medical Subject Headings terms: Erectile dysfunction (OR) ‘sexual dysfunction’ (OR) ‘Erection’ (OR) ‘Neural control’ (AND) ‘Erection’ (OR) ‘Electrodiagnostic test’ (AND) ‘Erectile Dysfunction’ (OR) ‘Spinal cord injury’, ‘Cerebrovascular accident’, ‘Parkinson’s disease’, ‘Multiple sclerosis’, ‘Epilepsy’, ‘Herniated disc’, ‘Multiple system atrophy’, ‘Peripheral neuropathy’ (AND) ‘Erectile Dysfunction’ (OR) ‘Neurogenic Erectile dysfunction’(AND) ‘Management’.

This was done in order to ensure the comprehensive inclusion of articles related to neurogenic erectile dysfunction. The initial search resulted in 230 articles. After review, we initially excluded papers that were not relevant (85). At completion of review, articles were selected based on their clinical relevance related to the aim. Data extraction was performed by three authors (AP, MM, MA).

Neurogenic erectile dysfunction overview Neural control of erection Erectile function requires the participation of autonomic and somatic nerves (sacral parasympathetic [pelvic], tho-

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racolumbar sympathetic [hypogastric and lumbar chain], and somatic [pudendal] nerves), with the hypothalamic and limbic pathways playing significant roles.

Neurologic diseases can also challenge the physical ability of the individual to embrace, stimulate, engage in intercourse, and maintain urinary and bowel continence during sexual activity. All these factors may lead to a primary or secondary neurogenic ED (12).

From the neurons in the spinal cord and peripheral ganglia, the sympathetic and parasympathetic nerves merge to form the cavernous nerve. The somatic nerves are primarily responsible for sensation and the contraction of the bulbocavernosus and ischiocavernosus muscles. The sympathetic pathway originates from the 11th thoracic to the 2nd lumbar spinal segments and passes through the white rami to the sympathetic chain ganglia. The parasympathetic pathway arises from neurons in the intermediolateral cell columns of the second, third, and fourth sacral spinal cord segments. The preganglionic fibers pass in the pelvic nerves to the pelvic plexus. The cavernous nerves are branches of the pelvic plexus that innervate the penis.

No psychogenic erection occurs in patients with lesions above T9; the efferent sympathetic outflow is thus suggested to be at the levels T11 and T12 (13).

Sensory information from the genitals is a potent activator of pro-erectile spinal neurons and elicits reflexive erections. Some pre-motor neurons of the medulla, pons and diencephalon project directly onto spinal sympathetic, parasympathetic, and pudendal motoneurons.

They receive in turn sensory information from the genitals (14). The somatic sensory and motor innervation of the male genitalia is carried via branches of the pudendal nerve. The pudendal nerve arises from sacral spinal segments 2-4 (S2-S4). There are three branches of the pudendal nerve (dorsal nerve of the penis, perineal and inferior rectal), each carrying sensory input to the S2-S4 spinal levels from the genital structures, which is relayed through the central nervous system via ascending spinal tracts. The skeletal pelvic floor muscles receive somatic innervation mainly from the motor branches of the pudendal nerve (15).

Penile erection can be elicited by various stimuli integrated into the spinal cord and/or higher central nervous structures. The medial preoptic area (MPOA) of the hypothalamus is known to play a key role in the regulation of male sexual behavior (16). Spinal erectile centers may be activated by genital afferents or by descending commands from higher central sites. An important inhibitory pathway from the nucleus paragigantocellularis has been demonstrated. The MPOA has been demonstrated to be crucially involved in sexual behavior. It is likely that it participates in the integration of hormonal and sensory cues necessary for sexual behavior. The medial amygdala and paraventricular nucleus of the hypothalamus have also been shown to play key roles (17).

Centrally as well as peripherally, many transmitters and transmitter systems are involved. Dopamine, nitric oxide, oxytocin, and ACTH/alpha-MSH, seem to have a facilitatory role, whereas serotonin may be either facilitatory or inhibitory, and enkephalins are inhibitory.

Peripherally, the balance between contractant (noradrenaline, endothelins, angiotensins) and relaxant (NO, VIP,

Neurogenic erectile dysfunction

and related peptides, prostanoids) factors controls the degree of contraction of the smooth muscle of the corpora cavernosa and determines the functional state of the penis (18).

Psychogenic erection is a result of audiovisual stimuli or fantasy. Impulses from the brain modulate the spinal erection centers (T11-L2 and S2-S4) to activate the erectile process. Reflexogenic erection is produced by tactile stimuli to the genital organs. The impulses reach the spinal erection centers; some then follow the ascending tract, resulting in sensory perception, while others activate the autonomic nuclei to send messages via the cavernous nerves to the penis to induce erection. This type of erection is preserved in patients with upper spinal cord injury. Nocturnal erection occurs mostly during rapid-eye-movement (REM) sleep (13).

Electrodiagnostic test of genital nerves The sympathetic skin response (SSR) tests have been applied to evaluate the autonomic innervation of the genital skin. SSR are helpful in the evaluation of sexual impotence and of disorders affecting the pelvic floor as well as of well-known neuropathies (19). The SSR was useful as an indicator of the effect on efferent C fibers.

Despite SSR being a polysynaptic potential of long latency and regulated by the cerebral cortex, the present results show that it is advisable to record the latencies of SSR in the penis, where it seems to be more useful as a marker of lumbosacral and/or pudendal alterations (20).

Corpus cavernosum electromyography (CCE) has been widely done to evaluate autonomic dysfunction in patients with ED. Due to false-negative results on CCE and penile SSR testing evoked cavernous activity (ECA) seems more reliable for determining autonomic involvement in the pathophysiology of ED (21). ECA can be recorded following a brief, startling stimulus. The noxious stimulus results in a generalized, sympathetic nervous system discharge that manifests throughout the body, including the corpus cavernosum. When the discharge is carried through the cavernous nerves, it can be recorded in the corpora cavernosa. If the sympathetic innervation to the corpus cavernosum is disrupted, then ECA will not be present following the startling stimulus (22).

In the last decade, several investigators have tried to develop corpus cavernosum electromyography (CC-EMG) as a direct clinical method to evaluate the state of the penile autonomic innervation and the cavernous smooth muscle. Both basic and clinical studies have shown promising results. However, its application as a diagnostic tool with clinical relevance was hindered by insufficient knowledge of cavernous smooth muscle electrophysiology, lack of standardization, technical and practical difficulties (23).

Erectile dysfunction (ED) in patients with spinal cord injury Spinal cord injury (SCI) is not as common as many other injuries, yet its physical and psychosocial consequences are devastating. Very few people experience complete neurologic recovery after SCI. The most common etiologies of SCI were automobile crashes (31.5%) and falls (25.3%), followed by gunshot wounds (10.4%), motor-

cycle crashes (6.8%), diving incidents (4.7%), and medical/surgical complications (4.3%) (24).

SCI causes organic changes in men leading to ED, impaired ejaculation, and changes in genital orgasmic perception. A vast majority of men with both complete and incomplete SCI will require treatment for ED (25).

The effect of SCI on the sexual response depends on the level and severity of the injury, as well as personal attributes. The level and completeness of SCI are major determinants of sexual functioning. In the immediate postinjury period, both men and women lose the ability to have reflexive sexual responses. Once reflexes return, reflexive arousal in men can be achieved with genital stimulation if the sacral spinal segments and peripheral pathway conveying sensations (cauda equina) are intact.

However, these reflexive responses are usually short-lived, limited to the duration of stimulation, and often do not achieve a fully satisfactory response. If the injury is caudal to the 12th thoracic cord segment men can be expected to experience psychogenic arousal in response to visual, auditory, imaginative, tactile, and gustatory stimuli (26).

Sacral sparing refers to the preservation of sensory and/or motor function at the S4-S5 sacral segments and is used to refer to an incomplete SCI; complete SCI do not exhibit sacral sparing. One hundred percent of the men retained reflexogenic erections when the complete lesion was above the sacral segments. Subjects with injury to the conus medularis and cauda equina were able to generate erections using psychogenic and reflexogenic stimuli in 90% and 80% of cases, respectively.

The production of reflexogenic erections in this group is likely because lesions to the conus medularis or cauda equina are often partial. Lesions below T11 generally only allow filling of the corpora cavernosa via reflexogenic erections (27).

There are social and clinical factors associated with sexual dysfunction (SD) in men with traumatic SCI, as well as predictive factors for SD. Fixed partner, ejaculation, masturbation are protective factors for SD. ED, orgasmic, and infrequent sex dysfunction are predictors of SD (28). For most men with SCI, the basic mechanisms for erection are preserved, including normal vasculature and an intact S2-4 reflex arc. They are often able to have reflex erections, but not psychogenic erections. These men typically respond well to pharmacological treatments used for the management of ED in men without SCI, namely oral PDE-5i such as sildenafil, vardenafil, and tadalafil (29).

Recommendations for the management of ED in SCI men, if it is possible to obtain a satisfactory erection but of insufficient duration, use a venous constrictor band to find out if this is sufficient to maintain the erection. Otherwise, it is recommended to use Sildenafil. If Sildenafil is not satisfactory then use ICI with prostaglandin E (30).

Sildenafil seems more effective in the treatment of neurogenic ED secondary to upper motor neuron (UMN) SCI compared with that secondary to lower motor neuron (LMN) injury. Its efficacy on LMN injuries does not seem different from placebo and administration of this treatment may not be effective in SCI which has caused LMN symptoms (31). A review was conducted to assess the efficacy and safety of sildenafil treatment of ED in men with SCI. As for the general efficacy, the proportion of Archivio Italiano di Urologia e Andrologia 2020; 92, 4

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patients who reported improved erections and ability to have intercourse was as high as 94%. Up to 72% of intercourse attempts were successful. For measures of erectile function, 5 of the 6 studies showed statistically significant improvements among sildenafil-treated versus placebo-treated patients. Erectile response rates were generally higher in patients with incomplete versus complete SCI and patients with UMN versus LMN lesions (32). A post hoc analysis of pooled data from two randomized, controlled trials (RCT) of sildenafil was conducted in Europe, Australia, and Turkey. It was found that all International Index of Erectile Function outcomes, including achieving and maintaining erections and ejaculation frequency, were statistically significantly greater with sildenafil vs. placebo, including the subgroup with complete SCI (p < .01 for all comparisons). The percentage of successful intercourse attempts with sildenafil (53% vs 12%) and preference for sildenafil (96% vs. 4%) vs. placebo were significant (p < .001), including the subgroup with complete SCI (33).

A RCT was implemented to assess the efficacy of sildenafil in men with ED associated with complete or incomplete SCI and to assess its effects on quality of life (QoL).

Results showed that compared with placebo, sildenafil produced higher levels of successful sexual stimulation, intercourse success, satisfaction with sexual life and sexual relationship, erectile function, overall sexual satisfaction, and an improved Erectile Dysfunction Inventory of Treatment Satisfaction score, with no clinically relevant effects on vital signs. Sildenafil seemed more effective in patients with incomplete SCI than in those with complete SCI (34). Another study was done by Giuliano et al. to assess the efficacy and safety of oral sildenafil in men with ED caused by traumatic SCI. A total of 178 men received placebo or sildenafil 1 hour before sexual activity for 6 weeks. The 50-mg starting dose could be adjusted to 100 or 25 mg based on efficacy and tolerability. Of 143 men with residual erectile function at baseline, 111 (78%) reported improved erections and preferred sildenafil to placebo. For all men (including those who reported no residual erectile function at baseline), 127 of

168 (76%) reported improved erections and preferred sildenafil to placebo (35). A study done by Gans et al. reported that there was significant improvement in quality of erection (p < .05) if sildenafil used in SCI patients, but no change in satisfaction (36).

Another study was done determine the efficacy and safety of tadalafil when taken on demand by men with ED secondary to SCI. It conclude that tadalafil (10 mg and 20 mg) improved erectile function and was well tolerated by men with ED secondary to traumatic SCI. The 2 most common treatment-emergent adverse events in the tadalafil group compared with placebo were headache (8.5% vs. 4.5%) and urinary tract infection (7.7% vs.

6.8%) (37).

Del Popolo et al. compared the safety, time/duration effectiveness, and the impact on the QoL of tadalafil 10 mg vs. sildenafil 50 mg in the treatment of ED in SCI patients. Tadalafil allowed a majority of men in their trial to achieve both normal sexual functioning up to 24 h postdosing compared to sildenafil (p < 0.01) and improved overall sex life satisfaction as well as sexual relations with a partner (38). Soler et al. compared the efficacy and safety of sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra) for ED in SCI patients. PDE5i were effective in 85% of the patients on sildenafil, 74% of the patients on vardenafil, and 72% of the patients on tadalafil. The mean duration of erection was 34, 28, and 26 min, respectively. Adverse effects were mild, usually attenuated with continued dosing. More than 70% of the patients on vardenafil and tadalafil required higher doses of 20 mg, whereas 50 mg of sildenafil was effective in 55% of the patients. Their data indicate that sildenafil is more effective in treating ED in SCI patients (39).

Studies have shown improvements in erectile function based on IIEF score compared to placebo when PDE5i used in the treatment of ED in patients with SCI, results are summarized in Table 1 (31, 34-41).

Sánchez Ramos et al. reported that sildenafil is an effective, well-tolerated treatment for ED caused by SCI, regardless of the cause, neurological level, American Spinal Injury Association (ASIA) grade, and time since

Table 1.

Clinical trials testing the efficacy of PDE5i to treat ED in patients with SCI. Authors N. of patients Khorrami et al. (31) 105 Ergin et al. (34) 50 Giuliano et al. (35) 178 Gans et al. (36)

17

Treatment 50-100 mg sildenafil vs. placebo 50-100 mg sildenafil vs. placebo 50-mg starting dose of sildenafil adjusted to 100 or 25 mg vs. placebo Sildenafil 25mg increased by 25 mg as needed

Giuliano et al. (37)

186

Tadalafil, 10 mg titrated to 20 mg vs. placebo

Del Popolo et al. (38) Soler et al. (39)

28 240

Lombardi et al. (40)

65

Tadalafil 10 mg vs. sildenafil 50 mg 50 to 100 mg for sildenafil, from 10 to 20 mg for vardenafil and tadalafil 10-20 mg of tadalafil

Sánchez Ramos et al. (41) 170

Sildenafil 50 mg

Main results Sildenafil was effective in 82% of patients UMN disease and its efficacy was statistically higher than placebo (82 vs. 25%, p < 0.05) Sildenafil produced higher levels of successful sexual stimulation, intercourse success, erectile function, vs. placebo 132 of 166 (80%) of men reported that sildenafil improved sexual intercourse compared with 17 of 166 men (10%) reporting improvement with placebo Erectile function significantly improved (p < .05) after 5.3 +/- 2.2 months when compared with baseline or previous therapies (p < .05) Tadalafil group compared with the placebo group was significantly greater (p < .001) in mean per-patient percentage of successful penetration attempts and percentage of improved erections Tadalafil 10 mg significantly increased the percentage of successful intercourse attempts at 12–24 hours compared with sildenafil PDE5 inhibitors were effective (rigidity enough for penetration) in 85% of the patients on sildenafil, 74% of the patients on vardenafil and 72% of the patients on tadalafil Patient using tadalafil maintained significant statistical improvement in erectile function, sexual satisfaction, and overall satisfaction compared with baseline (p < 0.05) It was reported by 88.2% of the patients and 85.3% of their partners that treatment with sildenafil had improved their erections, regardless of the baseline characteristics of the spinal cord injury and erectile function

ED: erectile dysfunction, SCI: spinal cord injury, PDE5i: Phosphodiesterase Inhibitors, UMN: upper motor neuron.

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injury (41). Rizio et al. reviewed 10 articles, which used the IIEF to study satisfaction and/or efficacy of PDE5is sildenafil, tadalafil, and vardenafil in the treatment of ED. Minimal adverse effects were reported in the articles.

Of the 739 patients studied in the 10 articles, only 102 patients reported any adverse effects, most of which were mild. Headache, flushing, hypotension, nasal congestion, and dyspepsia were the most commonly noted adverse reactions. These side effects are not only found in men with SCI but also in men without SCI who have ED (42). Patients with SCI, especially those with lesions above T6, are at great risk for hypotension. Sildenafil, can exacerbate this hypotension. Sildenafil induces significant hypotension in people with cervical level injuries more so than in thoracic level injuries and can cause dizziness in both populations (43). In another study, tadalafil use in people with SCI above T6 is safe with concerning not causing hypotension; hemodynamic changes that occurred 12-36 h post-administration were compensated for by elevations in heart rate (44).

ICI of vasoactive agents and intraurethral injection has been successfully used in the treatment of ED in patients with SCI. Trial results were summarized in Table 2 (4556). A pharmacologic erection program was given to the patient with SCI, using a fixed combination of prostaglandin E1 (PGE1) and papaverine. The dosage range was 0.10 to 0.50 cc. This simplified pharmacologic erection program offers safe, well-accepted, and effective therapy for ED to SCI population with very high patient satisfaction (45). Intracavernosal papaverine injection treatment was used to treat ED in SCI patients.

Satisfactory erection sufficient for coital penetration was possible in 97% of patients (46). The ICI and self-injection of papaverine-phentolamine technique offer the possibility of achieving a full erection which continues for a few hours and disappears afterward in a group of SCI patients with erectile impotence (47).

Intraurethral prostaglandin E1 (alprostadil, MUSE) Table 2.

Clinical trials testing the efficacy of PDE5i to treat ED in patients with SCI. Authors

Agents used

Combination of PGE1 and papaverine Kapoor et al. (46) Papaverine injection Wyndaele et al. (47) Papaverine-phentolamine Bodner et al. (48) PGE1 (alprostadil, MUSE) Lebib Ben Achour et al. (49) Alprostadil, moxisylite, papaverine Tang et al. (50) PGE1 Hirsch et al. (51) PGE1 Earle et al. (52) Papaverine, papaverine plus phentolamine or PGE1 Sidi et al. (53) Papaverine hydrochloride or papaverine and phentolamine mesylate Beretta et al. (54) Papaverine Sønksen et al. (55) Papaverine Momose et al. (56) Papaverine hydrochloride Zaslau et al. (45)

Mode of administration ICI

Effective or not for ED Effective

ICI ICI IUA ICI ICI ICI

Effective Effective Effective Effective Effective Effective

ICI ICI

Effective Effective

ICI ICI ICI

Effective Effective Effective

PGE1: prostaglandin E1, ICI: intracavernosal injection, SCI: spinal cord injury, ED: erectile dysfunction, IUA: intraurethral administration.

appears to be somewhat effective in creating erections; however, these were less rigid erections than those obtained with ICI and provided less overall satisfaction. It should always be used in the patient with SCI after the placement of a constriction ring to prevent hypotension (48). A prospective study concerns 36 spinal cord injured men was implemented to confirm the efficiency of ICI in the treatment of ED in SCI patients and to determine the mean necessary dose to obtain a functional erection. The findings confirm the efficiency of ICI in the management of ED in SCI. The average doses required to obtain a functional erection was 12.3 (+/- 4.8) microgram with alprostadil and 14 (+/- 5.4) mg with moxisylyte (49). In another study, ICI of prostaglandin E1 had significantly improved the erectile condition of the patient with SCI. Patients received testing dosage starting from 5 micrograms with increasing dosage (maximum 20 micrograms) No systemic side effect or any other complication was noted except that pain at the injection site was complained of in two patients with an incomplete lesion (50).

Vacuum erection devices (VED) can be presented to SCI men along with other options for treatment of ED. A study done by Denil et al. showed that after 3 months of the use of a VED, 93% of the men and 83% of the women reported rigidity sufficient for vaginal penetration, with an average duration of 18 minutes. VED is effective in many couples in the treatment of ED in SCI patients (57). A data from another trial suggest that VED is a feasible, safe, noninvasive alternative and possibly a better initial treatment for the management of impotence secondary to SCI (58). VED use is not without a risk, two cases of subcutaneous penile hemorrhage in patients using anticoagulant therapy and one case of penile gangrene occurred in three different SCI males (59).

Penile prostheses, introduced as the first effective organic treatment for ED over three decades ago, have an important role in the treatment of ED when other nonprosthetic treatment options have proven unsatisfactory (60).

The insertion of malleable penile prostheses in patients with SCI is associated with low complication rates and good patient satisfaction. Multiple studies showed its efficacy for ED in SCI patients, results are summarized in table 3 (61-65). A trial implemented by Kim et al., where a total of 48 patients with a SCI, who underwent malleable penile prosthesis (AMS 600) insertion from 1990 to 2004 were evaluated. The overall patient satisfaction rate was 79.2%. Complications occurred in eight patients. Wound infections in four patients. Two patients were treated with conservative management, and two were managed through prostheses removal. Other complications were erosion in two patients, uncontrolled Table 3.

Clinical trials testing the efficacy of penile prosthesis in patients with SCI. Authors Kim et al. (61) Iwatsubo et al. (62) Green et al. (63) Gross et al. (64)

Type of prosthesis Effective or not for ED Malleable Effective Shirai-type silicone penile implants Partially effective Semi-rigid and inflatable prostheses Effective Semi-rigid, semi-flexible or flexible prostheses Effective

SCI: spinal cord injury, ED: erectile dysfunction.

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penile pain owing to excessive prosthesis length in one patient, and supersonic transporter deformity in one patient (61). Iwatsubo et al. reported that the prosthesis improved sexual function in 15 (41%) patients, 18 (48%) patients were unchanged and four (11%) patients were dissatisfied (62). Gross et al. reported that when paraplegic patients are able to regain sexual activity after successful implantation of a penile prosthesis, their self-confidence is increased (64).

In men with SCI, sildenafil is the most effective treatment and is widely accepted. ICI, VED therapy in SCI patients should be used according to the patient's preference and choice (65). In SCI patients, penile implants may help to keep an external condom catheter in place and provide more penile stability for intermittent catheterization. However, they have an increased risk of infection. Semirigid rods have an increased risk of erosion. Although convenient to use, PDE5i are usually not effective in lower motor injuries. The hypotensive effects of intraurethral prostaglandins and PDE inhibitors need to be considered in SCI men with injuries at or above T6.

ICI is very effective modality of therapy (66).

The Brindley procedure consists of a stimulator for sacral anterior-root stimulation and a rhizotomy of the dorsal sacral roots to abolish neurogenic detrusor overactivity.

The Brindley procedure is suitable for a selected group of skeletally mature patients with complete SCI and detrusor overactivity. Erections can be evoked in a substantial number of patients, but results vary considerably. This can be explained by the relatively low number of patients that actually use the stimulator to evoke erections for sexual intercourse (0-32%) (67). Lombardi et al. showed that 45% of men with incomplete SCI who were submitted to sacral neuromodulation reached and maintained a normal IIEF-5 score for > 3 years (68).

Erectile dysfunction (ED) in patients with Cerebrovascular accident A marked decline in sexual activity has been reported in stroke patients. SD and dissatisfaction with sexual life seem to be common both in male and female stroke patients and in their spouses. Decreased libido, sexual arousal, and satisfaction are related particularly to the presence of the hemisensory syndrome. The etiology for SD after stroke is multifactorial including both organic and psychosocial factors (69). A study found that the occurrence of ED after ischemic stroke was 77.8%, significantly higher than the common ED. Stroke and ED have common risk factors, including hypertension and hyperlipidemia (70).

Acute ischaemic stroke in brain areas contributing to male sexual function may impair erectile function depending on the lesion site. There are an associations between stroke-related ED and lesion sites in the right occipito-parietal cortex and thalamus, as well as in the left insula and adjacent temporo-parietal areas. It was demonstrated associations between the deterioration of erectile function and lesion sites in the right occipital and thalamic region, and the left parietal association area (71). Jung et al. concluded in their study that the sexual desire, erectile function, and ejaculatory function were impaired after stroke. A lack of sexual desire was the

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major cause of an absence of sexual intercourse (72). If the right hemisphere is dominant for activation and this capacity is critical for normal sexual function, a greater incidence of impaired sexual function is occurred after right than after left hemisphere stroke (73, 74).

The presence of post stroke emotional incontinence (excessive/inappropriate laughing/crying) is a factor related to decreased post stroke sexual activity, more so in chronic than in subacute stages (75). Sexual disorders after stroke are thought to be due to multiple etiologies, including both organic (lesion localization, premorbid medical conditions, and medications) and psychosocial (fear of recurrences, loss of self-esteem, role changes, anxiety, and depression) (76).

As the sexual function is an important component to quality of life and activities of daily living, physicians and rehabilitation specialists, including physical, occupational, and speech therapists, should receive training in addressing sexuality in the treatment of post-stroke patients (77).

Sexual rehabilitation needs to be an integrative part of stroke patients' rehabilitation process, preferably at the interdisciplinary level (78). Exploring individual stroke survivor counseling preferences periodically for recovery may be a useful strategy for delivering the desired information at the most appropriate time (79).

There is a lack of studies that assessed a pharmacological intervention for ED post-stroke. A RCT was implemented to assess the effectiveness of a structured sexual rehabilitation program compared with written information alone regarding sexual and psychological functioning. It concludes that the provision of written information alone appears to be as effective as a 30-min individualized sexual rehabilitation program in an inpatient setting (80). A study was done by Tibaek et al. to evaluate the effect of pelvic floor muscle training (PFMT) on measured erectile function as an indicator of sexuality in men with lower urinary tract symptoms after stroke. The data was insufficient to provide any reliable indication of benefit or risk of physical therapy targeted towards pelvic floor muscles for improving erectile function following stroke (81). Besides pharmacological treatment, one of the most important, but underestimated, success factors of ED therapy are undeniably a proper counseling, which is mandatory to provide correct information on post-stroke sexuality (82) A systemic review had demonstrated that both neuroprotective and neurorestorative effects of PDE5i in animal models of stroke, though the specific underlying signaling pathways relating to PDE5 inhibition and cGMP may remain serendipitous in some studies. There is currently limited evidence on the effects of selective PDE5i in human stroke patients (83).

Erectile dysfunction(ED) in patients with Parkinsonâ&#x20AC;&#x2122;s disease Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder affecting older American adults and is predicted to increase in prevalence as the United States population ages. Resulting from a pathophysiologic loss or degeneration of dopaminergic neurons in the substantia nigra of the midbrain and the development of neuronal Lewy Bodies. Characterized by

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both motor and non-motor symptoms, PD patients classically display rest tremor, rigidity, bradykinesia, and stooping posture (84). Sexual dysfunction is one of the more disabling and poorly investigated aspects of PD. Several variables should be considered when evaluating SD in a disease in which physical, psychological, neurobiological, and pharmacological features merge and are not easily distinguishable (85). Dopamine has a fundamental role in the mediation of erectile function, whereas testosterone deficiency has been shown to be more common among PD patients than age-matched controls. Central regulation of erectile function is dependent on dopaminergic stimulation (86). In addition, hypothalamic dysfunction is mostly responsible for SD (decrease in libido and erection) in PD, via altered dopamine-oxytocin pathways, which normally promote libido and erection (87).

The risk of PD was higher for patients with ED along with DM or hypertension than for patients without ED or counterpart comorbidities. ED has been reported as a risk factor for the development of PD (88).

Hypersexuality (HS) is usually considered to constitute a marked increase in sexual interest, arousal, and behavior, which has adverse consequences for the patient and their partner. HS, as a complication of treated PD, is rare in absolute terms, with estimates of prevalence from postal questionnaires and clinical surveys of approximately 2% to 4%( 89).

Sildenafil citrate may be considered to treat ED in patients with PD as concluded in multiple studies, results are summarized in table 4 (90-94). A study was implemented by Raffaele et al. to assess the efficacy and safety of oral sildenafil, in depressed men with idiopathic PD and ED. Thirty-three men were enrolled in a 4month prospective, open-label, fixed-dose study, and received 50 mg of sildenafil in the home setting approximately 1 hour before sexual activity, not more than once daily. At the end of the study, improved erections were reported by 84.8% of patients. Sildenafil significantly increased patients' ability to achieve and maintain erections. A clear improvement of depressive symptoms was observed in 75% of patients. Sildenafil was well tolerated in all the patients (91). In another study, there was statistically significant improvement in total Sexual Health Inventory for Men scores (23.8 +/- 2.0 vs 16.6 +/2.8; p = 0.01), overall sexual satisfaction (p = 0.03), satisfaction with sexual desire (p = 0.04) with use of sildenafil citrate for patients with PD (92). Sildenafil has no treatment effects for quality of life (p = 0.3) or PD symptoms (p = 0.86) (93).

Hussain et al. assess the efficacy and safety of sildenafil Table 4.

Clinical trials testing the efficacy of Sildenafil for ED in patients with PD. Authors N. of patients Raffaele et al (91) 33 Zesiewicz et al (92) 10 Bernard et al (93) 20 Hussain et al (94)

12

Dosage of sildenadil Effective or not for ED 50 mg Effective 50-100 mg Effective Started at 50 mg and adjusted Effective to 25, 50, or 100 mg after 2 weeks 50 mg Effective

ED: erectile dysfunction, PD: Parkinson's Disease.

citrate in men with ED and Parkinsonism due either to PD or multiple system atrophy (MSA). Sildenafil citrate (50 mg) is efficacious in the treatment of ED in both conditions; however, it may unmask or exacerbate hypotension in MSA. As PD may be diagnostically difficult to distinguish from MSA, especially in the early stages, measurement of lying and standing blood pressure before prescribing sildenafil to men with Parkinsonism was recommended (94). There were no clinical trials have studied the potential effectiveness of the other PDE-5 i (vardenafil or tadalafil) in the treatment of ED for the patient with PD. Apomorphine, a short-acting D1- and D2-like receptor agonist, is the only drug proven to have efficacy equal to that of levodopa, albeit with a shorter time to onset and effect duration. Dopaminergic side effects such as nausea, somnolence, and hypotonia, are often mild (95).

The benefit of apomorphine on sexual function in some patients suggests a possible role in the treatment of impotence in PD (96). A study was done by Heaton et al. evaluating the efficacy and side effects of apomorphine in men with no documentable organic cause of ED. Men with primarily psychogenic impotence were tested with one of four protocols of an apomorphine preparation (preliminary sublingual liquid, preliminary 5 mg tablet, aqueous nasal spray, and new 3 and 4 mg controlled absorption tablets). Seven of 10 evaluable patients responded to the sublingual liquid preparation but the majority experienced significant nausea. The preliminary 5 mg tablet and aqueous forms did not produce useful responses. The newly formulated controlled absorption 3 and 4 mg tablets were tested in 12 men. Eight of 12 (67%) developed erections (97). Its role in the management of ED has been suggested for men with PD but not totally validated.

Testosterone deficiency is associated with a decline in erectile function and testosterone levels are inversely correlated with increasing severity of ED. A significant proportion of men who fail to respond to a PDE5i are testosterone deficient (98). Testosterone deficiency may cause signs and symptoms of the nonmotor symptoms seen in PD. In a prospective open-labeled pilot study, testosterone topical gel was administered daily to testosteronedeficient men with PD. A daily dose of transdermal testosterone gel improved testosterone deficiency symptoms in men with PD. Although there were trends in improvement in other nonmotor and motor symptoms of PD (99). In contrast, the results of the TEST-PD Study demonstrated that testosterone therapy was generally well-tolerated in elderly men with PD and probable testosterone deficiency. While there was no significant difference in the motor and nonmotor scales between the testosterone therapy and placebo groups at the end of 8 weeks compared with baseline (100). Urologist should be particularly cautious in the treatment of low testosterone concentrations in men with PD until more definitive studies were done.

Pergolide substantially improved sexual function in the younger male patients who were still interested in sexual activities. In such cases, the introduction of pergolide might be a better choice than treatment with sildenafil, which usually meets several contraindications in the comArchivio Italiano di Urologia e Andrologia 2020; 92, 4

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mon PD male population (101). Dose reduction or discontinuation of a dopamine agonist is recommended when patients experience hypersexuality. Despite the lack of therapeutic options, discussing sexuality with PD patients remains essential. The hesitation of both patients and neurologists to discuss sexuality is what may cause an ongoing circle of avoidance. Routine screening for ED may break this vicious circle (102).

Erectile dysfunction (ED) in patients with multiple sclerosis Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. The main autonomic nervous system disorders include sweating abnormalities, lower urinary tract dysfunctions, gastrointestinal symptoms and, SD. Among these, SD is common, but often underestimated symptom (103). The most common complaints of sexual dysfunction in men with MS are ED (50%-75%). One well-accepted hypothesis is that SD arises from spinal cord damage due to autoimmune responses. Recently, however, experts have suggested that SD in MS may be due not only to lesions affecting the neural pathways involved in physiologic function but also to psychological factors (104). ED in men with MS is related to neurological dysfunction, psychological factors, side effects of medication, or generalized MS symptoms, such as fatigue or micturition problems, usually in combination. The question of sexual dysfunction should always be broached during routine follow-up, regardless of age and social status (105).

Sildenafil treatment for ED in men with MS was effective and well-tolerated. A study implemented by Fowler et al. to assess the efficacy and safety of sildenafil citrate in men with MS and ED. Overall, 217 men received sildenafil (25-100 mg; n = 104) or placebo (n = 113) for 12 weeks. After 12 weeks, patients receiving sildenafil had higher mean scores for IIEF achieving and maintaining an erection compared with those receiving placebo (p < 0.0001), and 89% (92/103) reported improved erections compared with 24% of patients receiving placebo (p < 0.0001) (106). Another trial was enrolling 203 patients with MS, 102 into the sidenafil group, and 101 in the placebo group. Improved erections were reported by 32.8% of patients receiving sildenafil and 17.6% of those receiving placebo. Compared with placebo, sildenafil has little effect on MS emergent ED (107). Sildenafil cannot be recommended for the routine treatment of ED in every patient with MS. Tadalafil was proved as an effective and safe treatment for males with MS suffering from ED (108).

Intracavernous self-injection of vasoactive drugs is a wellaccepted therapy for the management of ED in neurogenic disorders. Vidal et al. presented the results of a selfinjection program in seven MS patients. All patients showed an excellent erectile response and had penile rigidity sufficient for sexual intercourse during an acceptable time, with minimal complications (109). ICI of papaverine was tested in a group of 29 patients with MS and ED. Acceptable rigidity was obtained in 27 patients of whom 23 started to use self-injections as treatment.

Minor hematomas or ecchymoses were reported in 16 cases. Two patients developed penile indurations after 6

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and 19 injections respectively (110). A study confirms the safety and efficacy of self-administered intracavernous PGE-1 for neuropathic impotence including the MS patients (111).

Counseling intervention is crucial for patients with MS and ED. Those interventions consist of counseling sessions, communication with the MS medical treatment team, education, and tailoring symptomatic treatments so they interfere less with sexual function (112).

Erectile dysfunction (ED) in patients with epilepsy SD is a common comorbidity in people with epilepsy that adversely affects their quality of life. Nearly one-half of men and women with epilepsy have SD. There is limited evidence to indicate that sexual function improves in patients rendered seizure-free following epilepsy surgery. Multiple mechanisms including direct effects of epilepsy, effects of antiepileptic drugs (AED), and psychosocial factors contribute to SD in epilepsy.

Circumstantial evidence indicates that seizures and interictal epileptiform discharges can directly affect the hypothalamic-pituitary axis as well as the production of gonadal steroids. Enzyme-inducing antiseizure drugs cause SD by affecting the metabolism of gonadal steroids (113). Clinicians need to investigate such problems carefully, both because of their multifactorial nature and because patients and physicians alike may often fail to recognize or be reluctant to acknowledge them (114).

Epileptic men have been found to have an increased risk of ED of up to 57%. Certain SD have been associated with specific periods of seizure activity, and fall into two discrete categories: those directly related to the epileptic discharge period (ictal), and those unrelated in time to seizure occurrence (interictal). Hypersexuality has been connected to ictal seizure activity while hyposexuality has been linked to interictal seizure activity (115).

Various studies have described an unusually common incidence of sexual and reproductive dysfunction in patients affected by temporal lobe epilepsy (TLE).

The results of a study done by Daniele et al. suggests a reduction of sexual interest in patients with right TLE as compared with left TLE in both men and women. No significant difference was found between right and left TLE groups concerning most aspects of sexual performance (116). Evidence suggests that people with temporal lobe epilepsy have reduced genital blood flow in response to erotic stimulation; the etiology of this phenomenon is not well understood, but disruption of the limbic and frontal cortex by epileptic activity may be implicated (117). Epileptic discharges from the temporal lobe may influence the release of hormones from the hypothalamic-pituitary axis. Serum androgen concentrations in men with epilepsy are significantly low in men with seizures (118, 119).

It is noticeable that AEDs may also alter endocrine function in both men and women with epilepsy and this alteration may lead to clinically significant reproductive endocrine disorders in certain cases. In recent years, the effects of enzyme-inducing AEDs on androgen metabolism have been evoked as a possible etiologic factor.

These drugs have been found to cause an increase in total testosterone and sex hormone-binding globulin

Neurogenic erectile dysfunction

(SHBG), but a decrease in free testosterone (120). The enzyme stimulating AEDs (phenytoin, topiramate, phenobarbital, and carbamazepine) raise the hepatic synthesis of SHBG that lessens the accessibility of testosterone.

Additionally, enhanced sex hormone metabolism and contraceptive hormones are not found with the use of AEDs that do not stimulate hepatic enzymes (lamotrigine, valproate, gabapentin, and vigabatrin) (121).

Management of SD thought to be caused by anti-convulsants should include the cessation of the offending drug, and consideration of switching to alternative anti-convulsants that have been reported to improve sexual function such as oxcarbazepine, and lamotrigine (122). A study showed that switching AED treatment from carbamazepine to oxcarbazepine in men with epilepsy can reduce the ED side effects observed with carbamazepine (123).

Adding testosterone for a short time in cases of low-normal testosterone levels (300 to 400 ng/dL) seems helpful in some men who did not respond to initial treatment with PDE-5i alone and in whom testosterone therapy is not contraindicated (124). Concentrating on hormone levels alone as an explanation of SD in epilepsy represents an overly simplistic approach to the problem (125). The therapy of SD in epilepsy depends on its cause. In cases of hormonal alterations, the first step is a change of antiepileptic regimen. Instead of enzymeinductor antiepileptics and valproate, new antiepileptic drugs should be prescribed. At present, the most investigated antiepileptic drug is the oxcarbazepine with a positive effect on antiepileptic-induced male SD, however, lamotrigine seems to be also beneficial. If the hormonal and SD cannot be eliminated by drug changes, androgenic therapy or bromocriptine may be required.

Testosterone may not only be beneficial on sexual functions but can reduce also the seizure frequency (126).

Evidence suggests an influence of PDE5i on seizure susceptibility in humans. In addition, preclinical studies have demonstrated the role of nitric oxide metabolites in the facilitation of the paroxysmal phenomenon (127).

Recent evidence indicates that sildenafil may exert some central effects through the enhancement of nitric oxide (NO)-mediated effects. NO is known to have modulatory effects on seizure threshold, raising the possibility that sildenafil may alter seizure susceptibility through NOmediated mechanisms (128). Although generalized tonic-clonic seizures were reported in a healthy man after taking tadalafil, the influence of tadalafil on seizure susceptibility has not been studied so far. A study was to investigate the effect of tadalafil on seizure threshold in three acute seizure tests in mice. It concludes that tadalafil may increase the risk of myoclonic seizure and decrease the anticonvulsant efficacy of oxcarbazepine (129). In summary, PDE5i should be used with great caution in men with epilepsy.

Erectile dysfunction (ED) in patients with Herniated disc Lumbar disc herniation (LDH) is the most common pathologic condition that is responsible for radicular pain. In patients non-responsive to medical therapy disc surgery is indicated. Lumbosacral disc disease may interfere with the

nerve transmission for erection through multiple autonomic and somatic pathways (129). Braun et al. reported that herniated disc was seen in 23.2% of 8000 men with ED (130). Akbas et al. implemented a study to evaluate patients' sexual problems and sexual behavior patterns before and after surgical treatment of LDH. Forty-three patients were included in the study (mean age 41.4 years).

The frequency of sexual intercourse before the operation was reduced by 78% of cases compared with the pain-free period. The frequency of intercourse was found to have increased (p = 0.01), while the description of any type of sexual problem had decreased (p = 0.005) significantly (131). LDH largely impacted sexual desire, activity, and satisfaction. Adjustment in sexual position was required in a large number of patients to avoid discomfort during sexual activities. Surgical treatment improved the quality of sexual activities (132). In another study, ED was more frequent in patients with LDH, the treatment of LDH had positive effects on ED (133).

Akca et al. reported four patients with sexual and sphincter dysfunction, including two women and two men, aged between 20 and 52 years. All patients had a perianal sensory deficit and sexual and sphincter dysfunction. Magnetic resonance imaging (MRI) of three patients displayed a large extruded disc fragment at the L5-S1 level. A syndrome with a perianal sensory deficit, paralysis of the sphincter, and SD may occur in patients with lumbar L5-S1 disc disease. The improvement of perianal sensory deficit after surgery was counteracted by a trend toward disturbed sexual function (134). Xu et al. studied 90 male patients with intervertebral disc herniation treated by a lumbar discectomy, who were divided into three age groups of equal number: groups A (< 45 yr), B (45 55 yr) and C ( > 55 yr). They obtained the IIEF-5 scores of the patients preoperatively and at 12 months after surgery. The IIEF-5 scores at 12 months after surgery were 21.3 +/- 3.3, 16.8 +/- 1.3 and 14.1 +/- 1.0 in groups A, B and C. Group A showed better improved erectile function than B and C ([51.17 +/- 6.25 ]% vs [36.31 +/4.28]% and [22.71 +/- 5.68]%, p < 0.05). Early decompression surgery according to different etiological factors is very important for erectile function recovery in young and middle-aged male patients (135).

One of the consequences of the discopathy is pressure on the spinal cord or nerve roots that supply the genitals and sexual centers located in the cord. In addition, the accompanying pain and limitation of mobility can lead to the occurrence of SD. The pain and neurological symptoms associated with intervertebral disc disease reduce the patients' satisfaction with their sex lives. Patients with lumbosacral discopathy noted a change in sexual performance, often resulting in passivity, discouragement, weakness, or a complete lack of interest in sex.

The disorders also affect the emotional state (136). There is significant sexual impairment in men with lesions of the cauda equina or conus medullaris. This is poorly correlated with neurological and EMG findings and has received insufficient medical attention (137).

Choy et al. describe the case of two patients with ED who were treated with percutaneous laser disc decompression as outpatients. In addition to the early return of erectile function in both cases, immediate pain relief was Archivio Italiano di Urologia e Andrologia 2020; 92, 4

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achieved in the second case. Follow-up visits confirmed continued normal sexual function and lack of pain (138). Orlin et al. reported a case of a 35-year-old male with normal erectile function up until the age of 18 years subsequently suffered permanent ED for the next 17 years. CT of the lumbar spine showed a large protrusion of the intervertebral disc L5-S1. After operative removal of the protrusion, a normal erection was achieved after 15 days and urine flow improved at 1 and 2 months and became normal after 3 months. Both erectile and bladder functions continued to be normal 10 years later. Thus, the effects of long-lasting mechanical compression of parasympathetic nerves need not be irreversible (139).

Kulaksizoglu et al. assessed the effect of lumbar disc herniation surgery for low back pain on the erectile functioning. They reported that ED rates have improved in 31.7% of those previously with ED in a 3 month period after the surgery. Best results were obtained in those patients with mild ED preoperatively. Moderate and severe ED may be related to a more severe nerve injury or to vascular and/or psychiatric factors. Evaluation of erectile functioning should routinely be performed in patients with lumbosacral disc disease (140).

Erectile dysfunction (ED) in patients with multiple system atrophy Multiple system atrophy (MSA) is a sporadic and rapidly progressive neurodegenerative disorder that presents with autonomic failure in combination with Parkinsonism or cerebellar ataxia. Novel therapeutic options targeting disease modification have been investigated in clinical trials.

These include riluzole, recombinant human growth hormone, and minocycline (141). Urinary and ED symptoms are prominent early features in men with MSA. Autonomic failure, considered until recently to be the cause of ED in these men, is commonly expressed through symptoms of orthostatic hypotension. In a study conducted by Kirchhof et al., the onset of ED had preceded the onset of bladder symptoms in 58% and the onset of hypotension symptoms in 91% of these men. The earlier occurrence of ED in men with MSA suggests a lack of a causal relationship to hypotension (142).

There is an ongoing debate on the causes of ED in MSA. Impairment of dopaminergic mediated pathways in the central nervous system, which is heavily implicated in erectile function, is most likely involved. Other diseaserelated factors such as psychosocial stress, the burden of chronic illness, changed appearance, fatigue, and relative immobility contribute to ED (143).

Sildenafil citrate (50 mg) is efficacious in the treatment of ED in parkinsonism due to PD or MSA; however, it may unmask or exacerbate hypotension in MSA (94). Its administration may not be recommended in patients with symptomatic orthostatic hypotension. The use of direct injections of alprostadil, either intracavernosal or intraurethral is another option (144).

Erectile dysfunction (ED) in patients with peripheral neuropathy Peripheral nervous system (PNS) disorders may cause SD in patients of both genders. These disorders include mainly polyneuropathies (particularly those affecting the

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autonomic nervous system and localized lesions affecting the innervation of genital organs. Impaired neural control may produce a malfunction of the genital response consisting of loss of genital sensitivity, ED, ejaculation disorder, and orgasmic disorder (145). Diabetic neuropathy was diagnosed if the patients showed two or more of the following three characteristics: neuropathic symptoms decreased or disappeared Achilles tendon reflex and/or abnormal vibration perception. A study that included 287 male Japanese patients with DM type 2, age (19-65 years) was implemented to demonstrate that diabetic neuropathy is positively associated with severe erectile dysfunction among Japanese DM type 2 patients aged < 65 years (146).

The proposed mechanisms of ED in diabetic patients are represented by vasculopathy, neuropathy, visceral adiposity, insulin resistance, and hypogonadism. Both somatic and autonomic neuropathies may contribute to diabetes-induced ED due to the impairment of sensory impulses from the penis to the reflexogenic erectile center (147). In an attempt to understand better the role of vascular and neurogenic alterations in the pathophysiology of diabetic impotence, Benvenuti et al. studied 29 impotent male patients with DM. Results confirm that vascular obstruction, more than nerve damage, plays a primary role in the pathophysiology of diabetic erectile failure, and stress the importance of psychogenic factors.

The observation that some patients presented marked involvements of both arterial supply and neurological pathways only a few years, or even 1 year, after the diagnosis of the disease, indicates the need for an early screening of the vascular and neurological status, even in asymptomatic patients (148). While Hecht et al. found that the tests indicating neuropathy showed abnormalities in men with diabetic ED as frequently as in men with neuropathic ED. Some tests even suggested neuropathy more often in diabetic than in neuropathic ED (149).

The microvascular deficit in the vasa nervorum of nerve trunks and ganglia is a major trigger for a cascade of events that eventually lead to diabetic neuropathy and autonomic neuropathy. ED is a consequence of these events and if not treated early may become irreversible.

Diabetes-induced ED are often resistant to PDE5i treatment (150).

First-, second- and third-line therapy may be applied.

PDE5i treatment from the first-line options leads to smooth muscle relaxation in the corpus cavernosum and enhancement in blood flow, resulting in erection during the sexual stimulation. The use of PDE-5i in the presence of oral nitrates is strictly contraindicated in diabetic men.

All PDE-5i have been evaluated for ED in diabetic patients with convincing efficacy data. Second-line therapy includes intracavernosal, trans- or intraurethral administration of vasoactive drugs or application of a vacuum device. Third-line therapies are the implantation of penile prosthesis and penile revascularization (151).

Gene therapy strategies that can enhance NO production or NO-mediated signaling pathways, growth factormediated nerve regeneration, or K+ channel activity in the smooth muscle could be promising approaches for the treatment of ED. For the neurogenic type of ED induced by diabetes or cavernous nerve injury, genes

Neurogenic erectile dysfunction

encoding different types of neurotrophic factors, which can enhance nerve regeneration, have been proposed for ED gene therapy. The recent clinical study using nonviral gene therapy of the Ca2+ activated BK (Max-K) channel for ED patients shows great promise for future development of gene-based therapy of ED (152).

The adoption of anatomic radical prostatectomy (RP) with cavernous nerve preservation by many surgeons, the rate of postoperative recovery of erectile function sufficient for sexual intercourse has improved dramatically.

Pharmacologic rehabilitation has rapidly emerged as a clinical strategy to reduce the incidence of ED after radical prostatectomy (153). Post prostatectomy ED appears to be initiated by neuropraxia and perpetuated by cavernosal smooth muscle apoptosis. Sildenafil has been studied in a novel primary prevention modality using nightly administration after a bilateral nerve-sparing prostatectomy. In this novel approach, it affected a sevenfold improvement in return of spontaneous, normal erectile function 2 months after drug discontinuation (154).

Preclinical data and several prospective randomized trials have demonstrated the value of treating patients with oral PDE5i after surgery, with the concomitant potential benefit of early re-oxygenation of the erectile tissue. For patients who do not properly respond to PDE5is, proper counseling regarding intracavernous treatment should be considered, along with the further possibility of surgical treatment for ED involving the implantation of a penile prosthesis (155). A proper algorithm or a clinical guideline for the post RP-ED has not been established until now.

CONCLUSIONS

Sexual and function are important factors contributing to the quality of life in patients with neurologic disease.

Neurogenic ED is a complex problem. Sexual functioning should be regularly evaluated during a long-term rehabilitation program, and any existing ED should be included in the treatment plan. New drugs and treatment options may help to improve the treatment and quality of life of patients with neurologic conditions.

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nervorum and advanced glycation endproducts. Int J Impot Res. 2013; 25:1-6.

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Correspondence Mohamad Moussa, MD mohamadamoussa@hotmail.com Head of Urology Department, Zahraa Hospital, University Medical Center, Beirut (Lebanon) Athanasios G. Papatsoris, MD (Corresponding Author) agpapatsoris@yahoo.gr 2nd Department of Urology, School of Medicine, Sismanoglio Hospital, National and Kapodistrian University of Athens, Athens (Greece) Mohamed Abou Chakra, MD mohamedabouchakra@hotmail.com Department of Urology, Faculty of Medical Sciences, Lebanese University, Beirut (Lebanon) Baraa Dabboucy, MD baraa.dabboucy@gmail.com Department of Neurosurgery, Faculty of Medical Sciences, Lebanese University, Beirut (Lebanon) Youssef Fares, MD yfares@ul.edu.lb Department of Neurosurgery, Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut (Lebanon)

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DOI: 10.4081/aiua.2020.4.386

ORIGINAL PAPER

Comparison of penile prosthesis types' complications: A retrospective analysis of single center Erdem Kisa, Mehmet Zeynel Keskin, Cem Yucel, Murat Ucar, Okan Yalbuzdag, Yusuf Ozlem Ilbey Tepecik Training and Research Hospital, Urology Department, Izmir (Turkey).

Summary

Objectives: The aim of this study was to compare clinical outcomes and complication rates associated with semirigid (malleable) and inflatable penile prostheses (PPs) and investigate the factors that influence these complications.

Material and methods: The records of 131 patients who had undergone penile prosthesis implantation (PPI) in our clinic due to erectile dysfunction (ED) between January 2010 and March 2019 were retrospectively reviewed. The initial surgery included 116 primary implants and 15 men had two revision operations. Patients were assigned to two groups as semirigid (malleable) PPI (group 1) and inflatable PPI (group 2) patients, and obtained data were compared across these two groups.

Results: Group 1 included 93 patients, while Group 2 included 38 patients. Postoperative complication rates of Group 1 were 8.6% (n = 8), and Group 2 were 21% (n = 8), and the comparison of postoperative complication rates revealed a statistically significant difference between the two groups (p = 0.025).

The majority of these complications (50%) was constituted by mechanical failure associated with inflatable PPs. When patients were further segregated as those with and without diabetes type 2 (DM) and those who had and had not undergone radical pelvic surgery (RPS), the comparison of complication rates across these subgroups did not yield any significant difference.

Conclusions: We determined in this study that semirigid (malleable) PPs were associated with lower complication rates compared to the inflatable group, particularly with regard to mechanic failure, and that DM and history of RPS did not make a difference in complication rates in patients planned to undergo PPI.

KEY WORDS: Penile prosthesis; Penile prosthesis implant; Erectile dysfunction; Impotence; Radical surgery; Satisfaction.

Submitted 1 June 2019; Accepted 1 September 2019

INTRODUCTION

Penile prosthesis implantation (PPI) treatment has been offered for over 40 years with high surgical success in patients with erectile dysfunction (ED) who either do not respond to pharmacological treatments such as oral phosphodiesterase type 5 (PDE5) inhibitors and less invasive intracavernosal vasocactive agents or reject these treatments (1). Penile prostheses (PPs) are categorized into two groups as non-inflatable and inflatable prostheses.

Non-inflatable PPs are also referred to as â&#x20AC;&#x153;semirigid (mal-

386

leable)â&#x20AC;?. Inflatable prostheses are further classified into two groups as two-piece and three-piece prostheses.

Although semirigid (malleable) PPs are more durable and less expensive, they can experience more erosion as they are constantly rigid. On the other hand, inflatable PPs allow use in flaccid and erect states and offer cosmetic advantage, however, possessing a more complex structure may result in mechanical failure over time (2-6).

Currently, two-piece and three-piece PPs constitute 75% of PPI surgeries worldwide, while in our country, semirigid (malleable) PPs are used at higher rates due to the reimbursement conditions of the social security institution and the higher cost of inflatable PPs (7-11).

Although PPI surgery is associated with patient and partner satisfaction, certain complications may arise during and after this operation (12-14). These include; intraoperative complications such as urethra perforation, cavernosal crossover, and crural perforation, as well as complications encountered in the postoperative period such as wound site infection, hematoma, lower urinary tract symptoms, bending during intercourse, breakage of the prosthesis, concorde deformity, and mechanical failure, particularly in multi-piece types. Among factors that influence these complications, the role of diabetes type 2 (DM) and history of radical pelvic surgery (RPS) has been contended in the literature (10, 15-17).

The aim of this study was to evaluate the clinical outcomes and surgical complications after PPI performed at our institution on patients with various causes of ED, compare complication rates associated with semirigid (malleable) and inflatable PPs, and investigate the factors that influence these complications.

MATERIALS

AND METHODS

Approval of the institutional ethics committee was obtained. We retrospectively reviewed the records of 116 men with ED who had 131 penile prostheses implanted in our clinic due to end-stage ED between January 2010 and March 2019. The initial surgery included 115 primary implants and one revision case, who had undergone the initial operation at another institution. A further 15 men had two revision operations. Three patients with insufficient data and two cases, who had PPs implanted at another centre and demanded removal without replacement, were excluded from the study. For all the patients, demographic characteristics, duration of ED time, size of implanted PP, complications data, and patient satisfaction No conflict of interest declared.

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were evaluated. Patients were assigned to two groups as semirigid (malleable) PPI (group 1) and inflatable PPI (group 2) patients, and obtained data were compared across these two groups.

Indications for PPI were failure or intolerance of medical treatment, confirmation of ED by Doppler ultrasound, and severe ED. All men routinely underwent medical and psychiatric consultation before the surgery. The operative field was disinfected with povidone-iodine 10 min before the surgical intervention. Preoperative antibiotic prophylaxis, such as vancomycin, was given the night before the surgery and for 3 days postoperatively. Oral antibiotic prophylaxis with ciprofloxacin was continued through the 7th postoperative day. All the PPs were implanted through penoscrotal incisions. The implant and surgical sites were irrigated with gentamicin in saline prior to implantation.

The corpus cavernosum usually was dilated with Hegar dilators, though an Otis urethrotome was deemed necessary in two cases. A Foley catheter was inserted at the end of the procedure and removed 1 day later. The patients were discharged 1-2 days postoperatively.

Surgical complications were recorded in detail.

Peroperative and postoperative complications were evaluated separately and compared between the groups.

Postoperative complications were divided into two groups as ‘early’ (complications occurring within 30 days of surgery) and late (complications occurring after 30 days of surgery).

Prosthesis function was evaluated 1 month after surgery and then annually until lost to follow-up. Our patients were asked during control visits if they were satisfied, or unsatisfied with the prosthesis in general. They were evaluated at or within 12 months of the postoperative period, in most cases through face-to-face interviews.

However, in some patients who failed to visit the clinics, follow-up was assessed through telephone interviews.

Statistical analyses The groups were assessed for normal distribution using the Shapiro Wilk test. Statistical difference between the groups were analyzed with independent sample t test Mann Whitney U test. Chi-square test was used for cross comparison. A p-value < 0.05 was considered statistically significant. All analyses were made by IBM SPSS V22.

RESULTS

Data obtained from all patients were reviewed to determine duration of ED time, causes of ED, pre-prosthetic treatment of primary patients, type of implanted PP, size of implanted PP, perioperative and postoperative complications (Table 1). The most common factor implicated in the ED etiology of patients was DM with a rate of 41.2% (n = 54), followed by RPS with a rate of 20.6% (n = 27). Of 54 DM patients, 26 (48.1%) were on oral antidiabetics and 28 (51.8%) on insulin therapy. Overall perioperative complication (urethra perforation and cavernosal crossover) rate was 1.5% (n = 2). In one of these, where urethra perforation had been encountered during the cavernousal dilation stage of PPI and the procedure had been postponed, only one side of the semirigid (malleable) PP could be implanted in the second surgical ses-

sion due to difficulty in dissection. All perioperative complications were resolved during surgery, and the operations were completed successfully. The overall postoperative complication rate was 12.2 % (n = 16).

Table 1.

Demographics; duration, etiology and treatment of erectile disfunction (ED); characteristics, complications and satisfaction of penile prostheses (PPs).

Number of patients Median age, year (min-max.)

Mean ± SD Median duration of ED time, year (min-max.)

Mean ± SD Causes of ED of primary patients, n, (%) • Idiopathic • Comorbidity DM (Diabetes type 2) Hypertension Myocardial infarction By-pass surgery Chronic obstructive pulmonary disease Cerebrovascular occlusion • RPS (Radical pelvic surgery) Radical prostatectomy Radical cystectomy • Pelvic radiotherapy • Priapism • Peyronie’s disease Penis fracture Pre-prosthetic treatment of primary patients • Phosphodiesterase 5 (PDE5) inhibitors On-demand Daily • Cavernosal injection • Vascular surgery PPI • Primary implants • Revision implants Type of implanted PP, n, (%) • Semi-rigid (Malleable) prostheses • Inflatable prostheses Two-piece Three-piece Size of implanted PP, n, (%) • Median size, diameter, cm (min-max.)

• Median size, length, cm (min-max.)

Perioperative complications, n (%), Note • Urethra perforation • Cavernosal crossover • Crural perforation Postoperative complications • Early Superficial wound infection Hematoma located on scrotum • Late Bending during intercourse Lower urinary tract symptoms Penile prosthesis breakage Concord deformity Mechanical failure Overall complications Patient satisfication, n (%) Satisfied Not satisfied

131 59 (28-74) 58.4 ± 8.3 3 (1-21) 4 ± 3.6 22 54 (41.2%) 26 11 5 2 1 24 (18.3%) 3 (2.2%) 7 1 9 1 114 101 13 1 1 116 (88.5%) 15 (11.4%) 93 (70.9%) 38 (29%) 36 (94.7%) 2 (5.2%) 10 (9-13) 18.5 (12-25) 2 (1.5%) 1, During dilatation, postpone 1, During dilatation 0 14 (10.6%) 4, Resolved with antibiotherapy 1, Resolved at follow-up 1, Revision 1, History of TURP 2, Revision 1, Revision 4, Revision 16 (12.2%) 105/131 (80.1%) 16/131 (19.8%)

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E. Kisa, M. Zeynel Keskin, C. Yucel, M. Ucar, O. Yalbuzdag, Y. Ozlem Ilbey

Revision surgery was needed for 11.4% (15/131) of the PPs inserted. Of these 15 patients who underwent revision PPI, 12 had undergone the primary surgery at our clinic and three at external centers. The median time until PPI revision was determined as 36 months (1-192 months). Overall, 80.1% (105/131) of the men were satisfied with the results.

Group 1 included 93 patients, while Group 2 included 38 patients. The comparison of data from Group 1 and Group 2 patients have been summarised in Table 2. In Group 1, one patient had to be implanted with differentsized PPs on the right and left sides, whereas in Group 2, six patients were implanted with PPs of discrepant sizes.

Postoperative complication rates of Group 1 were 8.6% (n = 8), and Group 2 were 21% (n = 8), and the comparison of postoperative complication rates revealed a statistically significant difference between the two groups (p = 0.025).

Table 2.

Study outcomes by type of prosthesis.

Median age, year (min-max.)

Mean ± SD Median duration of ED time, year (min-max.)

Mean ± SD Size of implanted PP, n, (%) • Median size, diameter, cm (min-max.)

• Median size, length, cm (min-max.)

Perioperative complications, n (%) • Urethra perforation • Cavernosal crossover • Crural perforation Postoperative complications - Early Superficial wound infection Hematoma located on scrotum - Late Bending during intercourse Lower urinary tract symptoms Penile prosthesis breakage Concord deformty Mechanical failure Overall complications

Semirigid PPI (n = 93) 59 (38-74) 58.6 ± 7.5 3 (1-20) 4.2 ± 3.5

Inflatable PPI (n = 38) 61 (28-69) 58.1 ± 9.8 2 (1-21) 3.7 ± 4

10 (9-13) 12.5 (12-12.5) 2 (2.1%) 1 (1%) 1 (1%) 0 6 (6.4%)

18.5 (12-25) 19 (14.5-22) 0 0 0 0 8 (21%)

2 0

2 1

1 1 2 0 0 8 (8.6)

0 0 0 1 4 8 (21%)

p 0.667 0.229

0.256 0.349 0.502

0.025

0.074

Table 3.

Comparison of overall complication rates of patients with and without diabetes type 2 (DM).

No complication Overall complications

DM (n = 73) 66 (90.4%) 7 (9.5%)

DM (n = 58) 49 (84.4%) 9 (5.5%)

p 0.421

Table 4.

Comparison of overall complication rates of patients with and without radical pelvic surgery (RPS).

No complication Overall complications

388

DM (n = 73) 86 (86%) 14 (14%)

DM (n = 58) 29 (93.5%) 2 (6.4%)

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p 0,356

Among postoperative complications, mechanical failure was detected in four patients, all of whom were Group 2 patients who had inflatable (two-piece) PPIs. When patients were further segregated as those with and without DM and those who had and had not undergone RPS, the comparison of complication rates across these subgroups did not yield any significant difference (Tables 3, 4).

DISCUSSION

PPI has been used effectively in patients who do not respond to oral therapies such as PDE5 inhibitors and to intracavernosal injection therapy (1). Although this treatment method offers high patient and partner satisfaction, it may be associated with certain perioperative and postoperative complications (2-13). Among these complications, most notable are the PP infections and mechanical failure that arise in the postoperative period.

In the recent years, technological advancements in PPs and advances in the surgical procedure technique have resulted in a partial decrease in these rates (18).

Although inflatable PPs are utilized more commonly across the world, semirigid (malleable) PPs have been utilized at greater rates in our country due to low economic status of the patients, high cost of inflatable PPs, and reimbursement conditions of the social security institution (7-11). In this study, we aimed to compare the complication rates associated with semirigid (malleable) and inflatable PPs that we implant at our clinic as well as to compare these rates between patients with and without DM and patients with and without history of RPS. The two groups demonstrated no statistical differences with regard to perioperative complications.

Comparison of postoperative complication rates across groups revealed a statistically higher rate for the inflatable group. The majority of these complications was constituted by mechanical failure associated with inflatable PPS. Also, the comparison of complication rates in patients with or without DM or history of RPS showed no difference of overall complication rates.

Although semirigid (malleable) PPs are less expensive and more durable, they are disadvantaged in terms of cosmetic appearance due to a constant state of erection. On the other hand, inflatable PPs offer more physiological erections but may lead to mechanical failure in the postoperative period. In the literature, mechanical failure rates vary from 0-5% for semirigid (malleable) PPs to 23% for inflatable PPs (2, 3, 10, 13). A study conducted by Lotan et al. reported that the complication-free rate was 87% for semirigid (malleable) PPs, whereas it was 50% for inflatable PPs (19). In our study, while no difference was detected between the groups with regard to perioperative complications, a statistically higher postoperative complication rate was determined in the inflatable group (21%) compared to the semirigid (malleable) group (6.4%). Half of the postoperative complications in the inflatable group were accounted by mechanical failure.

In the literature, whether post-PPI infective complications are more prevalent among patients with DM has been controversial. Although there are publications that corroborate the role of DM as a risk factor for postoper-

Comparison of penile prosthesis types' complications

ative infections, there are also contradictory studies.

Penidri et al. stated in their metanalysis that DM could be a risk factor for PP infection, although this could not be completely clarified (15). The relation of RPS history with perioperative and postoperative complication rates has also been contended in the literature. In a study by Cuneyd et al., erosion rates in semirigid (malleable) PPs were higher in the RPS group, compared to patients with other comorbidities, however, postoperative complication rates were reported to be similar across groups.

They connected these high erosion rates to fibrosis that develops in the cavernosal tissue after RPS (10). On the other hand, in a study by Lane et al., it was stressed that three-piece PP surgery had comparable postoperative complication rates in patients with and without RPS history, and therefore, could be utilized safely in these patients (17). In our study, there were no differences between patients with and without DM and between patients with and without history of RPS with regard to perioperative and postoperative complication rates.

The limitations of our study include its dependence on retrospective data, lack of partner satisfaction data as it could not be evaluated for all patients, and absence of long-term follow up data of patients.

CONCLUSIONS

PPI surgery has been performed worldwide in the treatment of ED, on patients who do not respond to oral and intracavernosal therapies. Although inflatable PPs possess a more cosmetic and physiological structure, they cannot be used in all patients in our country due to their higher cost and the reimbursement conditions of our social security system. Semirigid (malleable) PPs constitute the most commonly utilized PPs at our clinic despite certain disadvantages. In conclusion, we determined in this study that semirigid (malleable) PPs were associated with lower complication rates compared to the inflatable group, particularly with regard to mechanic failure, and that DM and history of RPS did not make a difference in complication rates in patients planned to undergo PPI.

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11. Anafarta K, Safak M, Beduk Y, et al. Clinical experience with inflatable and malleable penile implants in 104 patients. Urol Int. 1996; 56:100-104.

12. Scherzer ND, Dick B, Gabrielson AT, et al. Penile prosthesis complications: planning, prevention, and decision making. Sex Med Rev. 2019; 7:349-359.

13. Ko OS, Bennett NE Jr. Ambicor two-piece inflatable penile prosthesis: background and contemporary outcomes. Sex Med Rev. 2018; 6:319-327.

14. Levine LA, Estrada CR, Morgentaler A. Mechanical reliability and safety of, and patient satisfaction with the Ambicor inflatable penile prosthesis: results of a 2 center study. J Urol. 2001; 166:932-7.

15. Pineda M, Burnett AL. Penile prosthesis infections - A review of risk factors, prevention, and treatment. Sex Med Rev. 2016; 4:389398.

16. Bishop JR, Moul JW, Sihelnik SA, et al. Use of glycosylated hemoglobin to identify diabetics at high risk for penile periprosthetic infections. J Urol. 1992; 147:386-388.

17. Lane BR, Abouassaly R, Angermeier KW, et al. Three-piece inflatable penile prostheses can be safely implanted after radical prostatectomy through a transverse scrotal incision. Urology. 2007; 70:539-42.

18. Chung E. Penile prosthesis implant: scientific advances and technological innovations over the last four decades. Transl Androl Urol.

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Correspondence Erdem Kisa, MD, FEBU (Corresponding Author) drerdemkisa@hotmail.com Mehmet Zeynel Keskin, MD zeynel_akd@hotmail.com Cem Yucel, MD meclecuy@hotmail.com Murat Ucar, MD drmuratucar@hotmail.com Okan Yalbuzdag, MD drozgurcakmak577@yahoo.com Yusuf Ozlem Ilbey, MD ozlemyusufilbey@hotmail.com Tepecik Training and Research Hospital, Urology Department, Yenis¸ehir Mah, Gaziler Cad. No:468, Konak/Izmir (Turkey) Archivio Italiano di Urologia e Andrologia 2020; 92, 4

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DOI: 10.4081/aiua.2020.4.390

CASE REPORT

Primitive small cell carcinoma of the prostate.

Case report and revision of the literature Pietro Pepe 1, Ludovica Pepe 1, Mara Curdman 2, Michele Pennisi 1, Filippo Fraggetta 2 1 Urology

Unit - Cannizzaro Hospital, Catania, Italy; Unit - Cannizzaro Hospital, Catania, Italy.

2 Pathology

Summary

A Caucasian man 84 years old was admitted to our Department for acute renal failure secondary to severe bilateral hydronephrosis; moreover, the patient referred chronic fatigue and was anuric from two days. Serum creatinine and PSA values were equal to 9.6 mg/dl and 4.8 ng/ml and digital rectal examination was highly suspicious for prostate cancer. In emergency, the patient underwent bilateral application of percutaneous renal nephrostomies to restore kidney function and, after three days, was submitted to ultrasound-guided extended transperineal biopsy; the histology showed the presence of a prostatic small cell carcinoma (SCC) fulfilling the World Health Organization criteria. The patient underwent clinical staging including chest and abdominal computed tomography evaluation and total body scan that did not demonstrated distant metastases and/or others primitive tumors; in addition, cystoscopy and urinary cytology were negative. The patient underwent multidisciplinary evaluation, but he died 20 days from the diagnosis for progressive clinical worsening (physical and cognitive impairments) before beginning oncological treatment.

In conclusion, primitive SCC represents a very rare cancer provided of poor prognosis; only the execution of prostate biopsy combined with an accurate specimen analysis allow to make the correct diagnosis and therapeutic treatment.

KEY WORDS: Prostate cancer; Small cell cancer; Prostate small cell cancer; Neuroendocrine small cell prostate cancer.

inguinal hernia repair. The patient had not familiarity for prostate cancer (PCa) and assumed antihypertensive and alfa-blocker drugs. At admission, the patient referred chronic fatigue and was anuric from two days, serum creatinine and PSA values were equal to 9.6 mg/dl and 4.8 ng/ml, respectively; moreover, digital rectal examination was highly suspicious for PCa. In emergency, the patient underwent bilateral application of percutaneous renal nephrostomies to restore kidney function. After three day the patient was submitted to ultrasound-guided extended transperineal biopsy (6); the histology showed the presence of a prostatic SCC fulfilling the World Health Organization criteria that involved all the 12 needle cores (Figure 1). The immunohistochemical analysis was positive for chromogranin, synaptophysin and focally for thyroid transcriptation factor 1 (TTF-1); Ki67 expression was equal to 85% (Figure 2), conversely, CK7 and p63 were negative (7). The patient underwent clinical staging including chest and abdominal computed tomography (CT); evaluation and total body scan those did not demonstrated distant metastases and/or others primitive tumors; in addition, cystoscopy and urinary cytology were negative. The patient underwent multidisciplinary evaluation, but he died 20 days from the diagnosis for progressive clinical worsening (physical and cognitive impairments) before beginning oncological treatment. Autopsy was not performed.

Submitted 17 July 2020; Accepted 30 September 2020

INTRODUCTION

Primitive small cell carcinoma (SCC) of the prostate is a very rare (0.5% of the cases) and aggressive type of prostatic cancer and often is diagnosed at advanced stage due to early metastasis (1-5); most frequently, SCC is associated to progressive hormone-refractory prostate cancer. The biology of SCC is poorly understood but it is always implicated in the lethal progression secondary to visceral metastases and lytic bones lesions. In this study, a case of primitive prostate SCC has been reported.

CASE

REPORT

A Caucasian 84 years old man was admitted to our Department for acute renal failure secondary to severe bilateral hydronephrosis; the patient suffered from blood hypertension and was previously submitted to right

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DISCUSSION

Primitive SCC of the prostate is a rare entity and has a presentation that is distinct from its adenocarcinoma counterparts (8); unique features include an unresponsiveness to hormonal therapy, rapid progression, increased risk of lytic bone lesions, presence of visceral metastases, and low PSA in relation to disease burden.

On the other hand, the majority of prostate SCC are diagnosed in men with castration-resistant prostate cancer (CRPC) and are often characterized by the presence of neuroendocrine (NE) cancer differentiation.

The median time to development of SCC in patients with a history of prostatic adenocarcinoma is approximately 18-24 months from diagnosis, but ranges widely from few months to several years.

Primitive prostate SCC was first described by Wenk et al.

(3) and, recently, Zhang et al. (4) reported 8 cases of pure SCC; autopsy studies of men who have died from CRPC No conflict of interest declared.

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Primitive small cell carcinoma of the prostate

Figure 1.

Tumour was composed of undifferentiated cells with scant cytoplasm, infiltrating fatty tissue.

Figure 2.

Neoplastic cells showed a high proliferative fraction as highlighted by Ki67.

have reported the presence of SCC in up 10-20% of cases. The histological diagnosis of SCC is reached based on the presence of morphological features similar to those found in SCC of the lung; using immunohistochemical techniques, the small-cell component could be positive for one or more neuroendocrine markers (i.e., neuron-specific enolase, synapthosiphysin, chromogranin, and CD56) in almost 90% of the cases. Studies have demonstrated thyroid transcriptation factor 1 (TYF-1) expression in over 50% of SCCs of the prostate, 85-90% loss rate of tumor suppressor retinoblastoma protein (RB1), and 50-60% mutation rate of TP53, limiting its utility in distinguishing primary prostate SCC from metastases of other small cell cancers. Therefore, in the absence of a primary SCC at another site (for example, the lung), the finding of SCC on prostate biopsy is almost undoubtedly an indication of prostatic origin.

In the last years, gene expression in metastatic CRPC neuroendocrine SCC prostate has been tested confirming similar molecular profile with small cell lung carcinoma (8).

In addition, molecular studies have reported an increased expression of gene involved in cellular proliferation, cell cycle, neuroendocrine differentiation and mitosis.

Metzger et al. (5) reported on 657 men with neuroendocrine SCC an overall survival of 12 months. Wang et al.

(9) on 260 patients selected from Surveillance, Epidemiology, and End Results (SEER) database showed an increased incidence of prostate SCC over time that was characterized by presence of high stage (stage IV in 77.7%), nodes involvement (49%) and distant metastases (68%) with PSA values greater than 10 ng/ml only in 23% of the cases; although patients underwent chemotherapy (58.8%), surgery (25.4%) and, radiotherapy (31.9%) the observed survival rates of 1-year, 2-year, and 5-year were 42.1%, 22.1%, and 12.5%, respectively.

Although the poor prognosis, it is important to make distinction between primitive prostate SCC and NE-CRPC because therapeutic strategy changes and should be managed similarly to other non-prostatic SCC. Rarely prostatectomy or radiotherapy alone have been shown to be curative because the tumor, in the majority of the cases, is metastatic (5), moreover, prostate SCC is usually not responsive to androgen deprivation and disease

progression is not associated with rises in serum PSA values. In definitive, the best treatment remains the multidisciplinary approach by chemotherapy alone or combined with local therapy that could offer local palliation of clinical symptoms (5, 10).

In our case, the patient had a primitive prostate SCC characterized as locally advanced cancer involving bladder and kidney function in absence of documented distant metastases; therefore, we donâ&#x20AC;&#x2122;t know if the patient died from prostate SCC or from concomitant onset systemic pathologies.

In conclusion, although prostate SCC could be suspected in men with CRPC with clinical progression, primitive SCC represents a very rare cancer provided of poor prognosis and only prostate biopsy combined with an accurate specimen analysis allow to make the correct diagnosis and therapeutic treatment.

REFERENCES

1. Terada T. Small cell neuroendocrine carcinoma of the prostate: incidence and a report of four cases with an examination of KIT and PDGFRA. Prostate. 2012; 72:1150-1156.

2. Wang W, Epstein JI. Small cell carcinoma of the prostate. A morphologic and immunohistocemical study of 95 cases. Am J Surg Pathol. 2008; 32:65-71.

3. Wenk RE, Bhagavan BS, Levy R, et al. Ectopic ACTH, prostatic oat cell carcinoma, and marked hypernatremia. Cancer. 1977; 40:773-778.

4. Zhang Y, Ouyang W, Sun G, et al. Pure small cell carcinoma of prostate: A report of 8 cases. Urol Int. 2018; 101:263-268.

5. Metzger AL, Abel S, Wegner RE, et al. Patterns of care and outcomes in small cell carcinoma of the prostate: A national cancer database analysis. Prostate 2019; 79:1457-1461.

6. Pepe P, Garufi A, Priolo GD, et al. Is it time to perform only magnetic resonance imaging targeted cores? Our experience with 1,032 men who underwent prostate biopsy. J Urol. 2018; 200:774-778.

7. Pepe P, Fraggetta F, Candiano G, Aragona F. Does Ki-67 staining improve quantitative histology in preoperative prostate cancer staging? Arch Ital Urol Androl. 2012; 84:32-35.

8. Salemi M, Galia A, Fraggetta F, et al. Poly (ADP-ribose) polymerase 1 protein expression in normal and neoplastic prostatic tissue. Eur J Histochem. 2013; 57:e13.

9. Wang J, Liu X, Wang Y, Ren G. Current trend of worsening prognosis of prostate small cell carcinoma: A population-based study.

Cancer Med. 2019; 8: 6799-6806.

10. Papandreou CN, Daliani DD, Thall PF, et al. Results of a phase II study with doxorubicin, etoposide, and cisplatin in patients with fully characterized small-cell carcinoma of the prostate. J Clin Oncol. 2002; 20:3072-3080.

Correspondence Pietro Pepe, MD (Corresponding Author) piepepe@hotmail.com Michele Pennisi, MD Ludovica Pepe Urology Unit - Cannizzaro Hospital, Catania Via Messina 829, Catania (Italy) Mara Curdman, MD Filippo Fraggetta, MD Pathology Unit - Cannizzaro Hospital, Catania (Italy)

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DOI: 10.4081/aiua.2020.4.392

CASE REPORT

An urological cause of hypoglycaemia: A case report of the Doege-Potter syndrome Nuno Ramos 1, Rodrigo Ramos 2, Celso Marialva 2, Eduardo Silva 2 1 Urology 2 Urology

Department, Garcia de Orta Hospital, Almada, Portugal; Department, Portuguese Institute of Oncology, Lisbon, Portugal.

The Doege-Potter syndrome is a rare paraneoplastic syndrome presenting with hypoglycaemia due to ectopic secretion of insulin-like growth factor II (IGF-II) from a solitary fibrous tumor. The underlying tumor can be benign or malignant and rarely present in extrapleural sites. We describe the case of a 83-year-old male diagnosed with a Doege-Potter syndrome due to a kidney tumor.

Summary

KEY WORDS: Hypoglycaemia; Insulin-like growth factor; Solitary fibrous tumor.

Submitted 19 June 2020; Accepted 24 July

INTRODUCTION Solitary fibrous tumor (SFT) was first reported by Klemperer and Rabin in 1931 as a lesion that originated in the pleura (1, 2). Nevertheless, SFTs are rare mesenchymal tumors, found in various anatomic locations, with approximately 20% in extrapleural locations like liver, orbit, lung and gastrointestinal tract. These tumors occur mainly in adults, with a peak age of 60-80 years and are equally distributed between genders (3) . SFTs are rarely symptomatic and the vast majority are incidentally found. However, these tumors may also potentially cause symptoms, such as refractory hypoglycaemia, due to the production of insulin-like growth factor (IGF-II). When hypoglycaemia is associated with an SFT, it is referred as the Doege-Potter syndrome, a potentially life-threatening condition (2, 4). Majority of the tumors are benign, but 10%-20% can be malignant.

Malignancy is determined by invasive growth with an unclear boundary, high cell density, mitoses, pleomorphism and the presence of bleeding or necrosis (5).

Benign SFTs can be cured by complete surgical resection. The role of chemotherapy and radiotherapy is still unclear. We describe the case of an 83-year-old man, who underwent a surgical resection for a SFT, associated with refractory hypoglycaemia.

level was 33 mg/dl (normal range 70-109 mg/dl), being administrated continuous glucose infusion and glucocorticoid. The hypothesis of insulinoma was ruled out by serum insulin level of 12.3 ÂľUI/mL (normal < 28.0 ÂľUI/mL) and serum C-peptide level of 3.6 ng/ml (normal range 0.9-7.1 ng/ml). Plasma IGF-I and IGF-II levels were measured being respectively 29.00 ng/mL (normal: 55166 ng/mL) and 458 ng/mL (normal: 288-736 ng/mL).

The ratio IGF-II/IGF-I was higher than 10, suggestive of hypoglycaemia caused by non-islet cell tumor, the DoegePotter syndrome. Computed tomography (CT) demonstrated a large renal exophytic mass in the left kidney of 19 x 17 x 18.7 cm, heterogeneous, with little contrastenhancement, without signs of renal vein invasion neither areas of necrosis (Figure 1). Open left radical nephrectomy was performed. The postoperative course was uneventful, and hypoglycemic symptoms disappeared immediately after surgery.

Histopathological analysis revealed a tumor composed of spindle cells without atypia neither mitoses or areas of necroses. Immunohistochemical staining revealed a tumor positive for activators of transcription 6 (STAT6), CD34 and IGF-II, and negative for MDM2, AE1/AE3, EMA, S-100, SMA, and desmin (Figure 1). Based on the histological and immunohistochemical findings, a diagnosis of SFT of the kidney was made. The tumor secreted IGF II, which caused hypoglycaemia, but did not present malignant potential. On the first year of followup, the patient was observed in consultation every 3 months, remaining tumor-free based on CT scan at 6 and 12 months. Patient reported no episodes of hypoglycaemia during this period. Due to the rarity of this tumor, there are no specific guidelines available to monitor these patients. Therefore, we have used the European Association of Urology (EAU) guidelines for Renal Cell Carcinoma for subsequent follow-up.

CONCLUSIONS CASE

REPORT

A male 83 years old male patient was referred to our hospital due to a progressive increase of abdominal volume, in association with frequent episodes of syncope, as a result of hypoglycaemia. The patient had a history of arterial hypertension and was medicated with lisinopril.

Physical examination revealed the presence of a palpable mass in the left flank. On admission, his blood glucose

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SFTs can arise from a wide range of anatomic sites, both intrapleural or extrapleural, as the retroperitoneum.

Refractory hypoglycaemia may occur in 4% of SFT and is reported as Doege-Potter syndrome (6). It is caused by the inappropriate secretion of a high molecular-weight form of IGF-II (HMW IGF-II). This molecule is an incompletely processed molecule of IGF-II, derived from the tumor, which fails to form a complex with IGF-binding proteinNo conflict of interest declared.

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The Doege-Potter syndrome in urology

Figure 1.

Figure 1 Imaging, histopathological, and immunohistochemical findings.

(A, B) Computed tomography demonstrated a large tumor in the left kidney with little contrastenhancement, (C) histopathological findings: the mass is a spindle cell tumor (100Ă&#x2014;) (D, E, F) immunohistochemical findings: (D) immunohistochemistry shows positive staining for CD34 (100x), (E) positive staining for STAT6 (100x), (F) negative staining for MDM2, AE1/AE3, EMA, S100, SMA, and desmin (100x).

3. This leads to higher bioavailability compared to mature IGF-II, with activation of insulin receptors, inhibiting hepatic gluconeogenesis and increasing peripheral glucose uptake which results in hypoglycaemia (7). The detection of HMW IGF-II requires immunoblot analysis, not available at our institute. The patients with Doege-Potter syndrome, usually presents suppressed serum insulin, C peptide and low IGF-I against normal or elevated levels of IGF-II (8). CT scan and magnetic resonance imaging (MRI) are effective tools for identifying SFT, determining the invasion of the surrounding structures, revealing information on distant metastasis and for follow-up. CT imaging typically shows a smooth, well circumscribed, homogeneous mass with or without necrosis or calcifications (2).

MRI presents as a tumor with high signal intensity on T2weighted images and iso-intensity or low intensity on T1weighted images (6). Fluorodeoxyglucose positron emission tomography (FDG-PET) can also offer benefit in the diagnosis but is less often used. Definitive diagnosis of an SFT depend upon histological identification of a spindle cell tumor with alternating areas of cellularity and hypocellular collagen rich areas, as well as consistent CD34 expression and negative expression patterns for cytokeratin AE1/AE3, desmin and S-100. Although the majority of SFTs are benign, 20% may present local recurrence and metastases (9, 10). Malignant criteria include: hypercellularity (> 4 mitotic figures/10 high power fields), atypia, infiltrative growth pattern and necrosis (11). Complete tumor resection is the only definitive treatment. Due to its rarity, there are no guidelines for the treatment of metastatic or nonresectable SFT. Chemotherapy and consecutive selective embolization of the feeding vessels of the tumor can be tried to alleviate symptomatic hypoglycaemia in irresectable tumors, but they are not effective treatments.

Radiotherapy has limited value, although it has been used as an adjuvant treatment in case of incomplete surgical resection (3, 12). Symptomatic medical treatment of hypoglycaemia has been tried with some success for patients unfit for surgery (8). In our patient, hypoglycaemia disappeared after the complete radical resection. However, the return of this symptom can be a sign of tumor recurrence, which can happen in an estimated rate of 9.9% (2).

In conclusion Doege-Potter syndrome should be considered as a differential diagnosis in a patient with a known malignancy if accompanied by hypoglycaemia and SFTs have a favourable clinical outcome if complete resection is performed.

REFERENCES 1. Wada Y, Okano K, Ando Y, et al. A solitary fibrous tumor in the pelvic cavity of a patient with Doege-Potter syndrome: a case report.

Surg Case Rep. 2019; 5:60.

2. Forster C, Roumy A, Gonzalez M. Solitary fibrous tumor of the pleura with Doege-Potter syndrome: second recurrence in a 93-year-old female. SAGE Open Med Case Rep. 2019; 7:2050313X18823468.

3. Qian X, Zhou D, Gao B, Wang W. Metastatic solitary fibrous tumor of the pancreas in a patient with Doege-Potter syndrome.

Hepatobiliary Surgery and Nutrition. 2020; 9:112-5.

4. Moreira BL, Monarim MA, Romano RF, et al. Doege-Potter syndrome. Radiol Bras. 2015; 48:195-6. )5) Kim DW, Na KJ, Yun JS, Song SY. Doege-potter syndrome: a report of a histologically benign but clinically malignant case. J Cardiothorac Surg. 2017; 12:64.

6. Han G, Zhang Z, Shen X, et al. Doege-Potter syndrome: A review of the literature including a new case report. Medicine (Baltimore).

2017; 96:e7417.

7. Pant V, Baral S, Sayami G, Sayami P. Doege-Potter Syndrome, cause of nonislet cell tumor hypoglycemia: the first case report from Nepal. Int Med Case Rep J. 2017; 10:275-8.

8. Kalebi AY, Hale MJ, Wong ML, et al. Surgically cured hypoglycemia secondary to pleural solitary fibrous tumour: case report and update review on the Doege-Potter syndrome. J Cardiothorac Surg. 2009; 4:45.

9. Antonella D, Loren D, Maria C, et al. Doege-Potter syndrome by malignant solitary fibrous tumor of the liver: A case report and review of literature. World J Gastrointest Surg. 2019; 11:348-57.

10. Chen S, Zheng Y, Chen L, Yi Q. A broad ligament solitary fibrous tumor with Doege-Potter syndrome. Medicine (Baltimore). 2018; 97:e12564.

11. Fung EC, Crook MA. Doege-Potter syndrome and 'big-IGF2': a rare cause of hypoglycaemia. Ann Clin Biochem. 2011; 48:95-6.

12. Urbina-Lima AD, Roman-Martin AA, Crespo-Santos A, et al.

Solitary Fibrous Tumor of the Urinary Bladder Associated with Hypoglycemia: An unusual case of Doege-Potter syndrome. Urol Int. 2019; 103:120-4.

Correspondence Nuno Ramos, MD (Corresponding Author) nuno.ramos@hgo.min-saude.pt Garcia de Orta Hospital , Av. Torrado da Silva, 2801-951, Almada (Portugal) Rodrigo Ramos, MD Celso Marialva, MD Eduardo Silva, MD Urology Department, Portuguese Institute of Oncology, Lisbon (Portugal)

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DOI: 10.4081/aiua.2020.4.394

CASE REPORT

Renal papillary hypertrophy, a rare cause of recurrent gross hematuria; Case report and review of literature Ahmad Beltagy, Mohamed Elsaqa, Islam Koraiem, Ahmed Abulfotooh Eid Department of Urology, Faculty of Medicine, Alexandria University, Alexandria, Egypt.

Summary

Hematuria is a critical symptom that should properly be investigated. One of the rare causes is renal papillary hypertrophy. Literature review revealed only few reported cases. Biopsy in reported cases has shown hyperplasia of renal papillae with normal histology. We report a case of bilateral renal papillary hypertrophy in a 32 years old female presented with intermittent gross hematuria.

Computed tomgraphy urography, cystoscopy and selective cytology did not show any positive findings. Retrograde flexible uretero-renoscopy showed enlarged renal papillae protruding into upper and middle calyces of both kidneys with clots and active bleeding in some. Holmium:YAG Laser ablation of hypertrophic papillae showed an effective minimally invasive management of the condition.

KEY WORDS: Renal papillary hypertrophy; Hematuria; Laser ablation; Flexible ureteroscopy.

Submitted 1 May 2020; Accepted 6 June 2020

BACKGROUND

Hematuria, either gross or microscopic, should be carefully investigated. Hematuria, specifically in adults, should be regarded as a symptom of urologic malignancy till proved otherwise. All patients with hematuria, except perhaps young females with acute bacterial hemorrhagic cystitis, should be thoroughly evaluated (1).

Renal papillary hypertrophy or hyperplasia is one of the rare causes of gross or microscopic hematuria of benign origin. Few cases were reported in the literature (2-7).

In this article, we report this case presented with gross hematuria due to bilateral renal papillary hypertrophy and its minimally invasive management with Holmium:YAG laser ablation together with literature review of this rare pathology and its management.

CASE

REPORT

A 32 year old female presented with intermittent total gross hematuria with occasional clots and bilateral loin pain for 6 months. Other than history of poliomyelitis affecting her left leg with scoliosis of the spine, the patient has no evident clinical history or abnormal clinical findings. She did not complaint of bleeding elsewhere. Also, she did not receive neither anticoagulant nor anti-platelet medications.

Clinical examination showed normal blood pressure.

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Urine analysis revealed hematuria (> 100 red blood cells) without pyuria or proteinuria. Blood count, renal and liver functions and bleeding profile were normal.

Urine culture and ultrasound were unremarkable.

Multiphasic renal computed tomography (CT) showed bilateral enlarged papillae causing concave impressions in the calyces of both kidneys, a picture suspicious of hypertrophied renal papillae (Figure 1). Diagnostic cystoscopy with barbotage bladder cytology were done; both failed to show any positive finding. Diagnostic retrograde intrarenal ureteroscopy was done using 7.5 Fr flexible ureteroscopy that revealed hypertrophied renal papillae in the upper and middle calyces of both kidneys with active bleeding in some of these papillae (Figure 2).

Selective cytology of both ureters revealed no suspicious findings.

In a later setting, Holmium:YAG laser ablation of hypertrophied papillae of both kidneys was done using 7.5 Fr flexible ureteroscopy and 365 Îźm fiber at settings of 1200 mJ and 12 HZ. After 3 months follow up, the patient did not report any attacks of gross hematuria, despite the persistence of microscopic hematuria. She also described significant improvement of bilateral loin pain. Patient was consented for further process of data collection and publication.

DISCUSSION

Renal papillary hypertrophy is one of the rare causes of hematuria. Only few cases have been reported in the literature. In 1956, Lauret first reported renal papillary hypertrophy in a 9-month-old female infant after nephrectomy for suspected pelvic tumor by retrograde filling defect (2). In 1961, Moonen et al. described two cases of a 25-year-old female with microscopic hematuria and 11-year-old male with loin pain (3).

Histopathology following nephrectomy in these two reports revealed hyperplasia of renal papillae with normal histology (2, 3).

The same pathology was reported later on by only few case reports (4-7). The age of reported cases ranged between 9 months and 30 years old. To our best of knowledge, only 8 cases were reported in the literature, 6 females and 2 males. Presentations are usually gross or microscopic hematuria with or without flank pain (2-7).

However, although association with use of oral contraceptive pills was seen in 3 reported cases, our case never No conflict of interest declared.

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Renal papillary hypertrophy, a rare cause of recurrent gross hematuria

Figure 1.

CT Urography showing enlarged papillae indenting the minor calyces causing smooth filling defect.

Figure 2.

Intra renal flexible ureteroscopy showing hypertrophied renal papillae.

rograde study. Recently, diagnosis depend on direct visualization of hypertrophied papillae by retrograde flexible ureterorenoscopy. Biopsy may be omitted, as in our case, in case of multiple or bilateral lesions, negative cytology and absence of suspicious findings.

There are no definite guideline recommendations regarding management of papillary hypertrophy. Birk et al. reported the effective use of Homium:YAG laser for ablation of hypertrophied papillae in 2 cases (6). Heißler et al. suggested the use of either Holmium-YAG or ThuliumYAG laser for ablation according to their use for ablation of upper tract urothelial tumors (7). In our case, we used 365 μm Ho:YAG laser fiber for bilateral ablation.

CONCLUSIONS

Renal papillary hypertrophy is a rare cause of gross or microscopic hematuria of that should be kept in mind as differential diagnosis for recurrent hematuria of benign origin. Retrograde intrarenal laser ablation represents the most appropriate management.

REFERENCES

1. Gerber G, Brendler C. Evaluation of the Urologic Patient: History, Physical Examination, and Urinalysis. in: AJ Wein, LR Kavoussi, AW Partin (Eds.), et al, Campbell-Walsh Urology, 11th ed vol. 1, Saunders, Philadelphia (2016), chapt 1, pp. 35-59.

used oral contraceptive pills (6, 7). Histopathology, either after nephrectomy or recently with endoscopic biopsy, showed enlarged hyperplastic papillae (multiple rows of cells) with normal histology associated with dilated thin walled veins at the angles of calyces which may be responsible for bleeding (2, 3).

CT Urography, retrograde study or intravenous pyelography may show lobulated filling defects. Magnetic resonance (MR) Urogram in 2 reports showed prominent medullary pyramids with apices protruding into calyces causing enlargement and deformity at the calyceal fornices (5, 6). Diagnosis was previously reported after nephrectomy for suspected renal or urothelial tumors caused by filling defect on intravenous pyelography or ret-

2. Lauret G, Lamy M, Thieffry S, et al. Children Urology (in French). Paris: Expansion Scientifique Française, 1956.

3. Moonen WA, DE Groote F. Papillary hypertrophy. Acta Urol Belg.

1961; 29:347-50.

4. Whitaker RH, Edwards D. Congenital hypertrophy of a renal papilla. Br J Urol. 1969; 41:287-9.

5. Türkvatan A, Erden A, Ölçer T, et al. Hypertrophic renal papillae mimicking urothelial tumor. Eur J Rad Extra. 2009; 69:e121-3.

6. Birk A, Afiadata A, Upadhyay J. Bilateral renal papillary hypertrophy: A rare cause of benign essential hematuria endoscopic diagnosis and management. Int Arch Urol Complic. 2017; 3:031.

7. Heißler O, Seklehner S, Riedl C. Renal papillary hyperplasia as a cause of persistent asymptomatic microhematuria. J Endourol Case Rep. 2018; 4:1, 152-4.

Correspondence Ahmad Beltagy, MD (Corresponding Author) a_abdelkhalek11@alexmed.edu.eg Mohamed Elsaqa, MD mohamed.elsaqa@alexmed.edu.eg Islam Koraiem, MD Ahmed Abulfotooh Eid, MD drahmedaeid@doctor.com Alexandria University, Alexandria (Egypt)

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SUPPLEMENTARY MATERIALS - CASE COLLECTION

Complications of endourological procedures and their treatment A MISPLACED PCN TUBE IN THE INFERIOR VENA CAVA: A CASE REPORT AND LITERATURE REVIEW Khaled Refaai, Mohamed Ramadan, Islam O. Koraiem, Mostafa Sakr Department of Urology, Alexandria University, Egypt SUMMARY Percutaneous nephrostomy (PCN) is a great tool for temporary drainage of obstructed kidney especially when severe urinary tract infection and/or systemic symptoms are encountered. PCN insertion is not without complications, even with experienced hands. However, most of these complications are minor. One major complication is misplacement of the PCN in a major vessel. Here, we report a case of right PCN insertion under ultrasound (US) guidance that was found to be misplaced in the inferior vena cava. The case was safely managed but we conclude that PCN insertion should be done under fluoroscopy with or without US guidance by a well-trained urologist or interventional radiologist because US guidance alone may be not enough safe.

KEY WORDS: Percutaneous nephrostomy; Fluoroscopy guidance; Inferior vena cava (IVC).

DISCUSSION Percutaneous nephrostomy tube insertion is frequently used for management of obstructed kidney specifically in the presence of infected hydronephrosis. Recently, it is reported that PCN tube insertion is the best for temporary urinary diversion whatever the cause even in sterile kidney obstruction (1). Like any other procedure, complications may happen and although most of them are minor, major complications may still occur with serious consequences.

Few cases have been reported for PCN tube misplacement into IVC (Table 1). We previously reported a case of misplaced silicon Foley’s catheter during exchange of left PCN tube at our department, which was also managed by exploration with removal of catheter under vision and pyelolithotomy for stone removal. However, as the PCN tube was a silicon Foley’s catheter, the inflation of the balloon inside the IVC led to development of deep venous thrombus formation (2). Dias-Filho et al. reported a case of Foley’s catheter reaching right atrium during exchange of left nephrostomy tube over guidewire blindly (3). This case was managed conservatively by withdrawal of the catheter under monitoring with full preparation for immediate exploration if needed. Another case was reported by Lee et al. who misplaced a right PCN tube in the IVC (4).

This case was managed non surgically by withdrawal of the PCN catheter and direct right abdomen compression

by a 500 mL bottle and tight sponge. Al-Musawi et al reported a case of PCN tube passed through the kidney to the IVC and transfixing it. The case was safely managed by removal of PCN under fluoroscopy till inside the IVC then to the kidney (5). All the previous cases shared the step that the guidewire manipulation and tract dilation were done either blindly or just with US guidance for kidney puncture. In our center the recommended protocol for PCN insertion is to insert it under US guidance using Seldinger technique as a bed side procedure, so resident did not use fluoroscopy in this case as well.

Relatively more cases have been reported of intravenous misplacement of nephrostomy tubes after percutaneous nephrolithotomy (PCNL) (Table 2). Mazzucchi et al. reported two cases (6) of intravenous insertion at the end of PCNL procedures that were discovered few days later.

Catheters were withdrawn in the presence of a surgical team, with no bleeding or further complications encountered. Chen et al. (7) as well as Fu et al. (8) reported more cases following PCNL, all of them were safely managed either under image guidance (US, fluoroscopy or CT) or through exploration. All the previous reports came to the same conclusion that intravenous misplacement of a nephrostomy tube is an uncommon complication following PCN tube insertion or PCNL procedures, and conservative management with strict bed rest, intravenous antibiotics, and tube withdrawal with appropriate readiness of the operatory room (OR) team is safe and feasible.

In our case, passage of the PCN to the inferior vena cava was due to blind guidewire manipulation and blind dilatation of the tract that usually leads to serious complications. Some Authors emphasized the importance of using both US and fluoroscopy during PCN tube insertion to avoid complications (9). We also believe that, unless it is contraindicated, fluoroscopy is mandatory for accurate and safe guidewire passage and track dilatation even for nephrostomy insertion after PCNL where its position should be checked by contrast injection through it before fixation. The synergistic use of both US and fluoroscopy during PCN tube insertion may lead to negligible complication rates. We also should stress that fluoroscopy may be contraindicated in some cases like pregnancy and hypersensitivity to used contrast material. We also stress on the precautions used to minimize radiation exposure to save physician from radiations side effects like skin irritation and cancer.

ACKNOWLEDGMENTS We thank members of Endo-urology Unit, Alexandria Faculty of Medicine (Professor. Abdelrahman Zahran, Dr. Hussien Abdeldayim, Dr. Tamer Hussien, Dr. Akram Assem, Dr. Omar Elgebaly, Dr. Mostafa Said and Dr. Tarek

No conflict of interest declared.

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K. Refaai, M. Ramadan, I. O. Koraiem, M. Sakr

Hani) for providing consultation and sharing in decision making. They received no financial compensation.

REFERENCES 1. Pabon-Ramos WM, et al. Quality Improvement Guidelines for Percutaneous Nephrostomy. J Vasc Interv Radiol. 2016; 27:410-14.

2. Kotb AF, Elabbady A, Mohamed KR, Atta MA. Percutaneous silicon catheter insertion into the inferior vena cava, following percutaneous nephrostomy exchange. Can Urol Assoc JJ Assoc Urol Can. 2013; 7:E505-E07.

3. Dias-Filho AC., Coaracy GAV, Borges W. Right atrial migration of nephrostomy catheter. Int Braz J Urol Off J Braz Soc Urol. 2005; 31:470-71.

4. Lee T-H, Chen H-M, Wu W-J, et al. Successful nonsurgical management of inferior vena cava penetration as a rare complication of percutaneous nephrostomy. Urol Sci. 2014: 25:98-100.

5. Musawi MNA-A, Mahdi M, Mansor A. Inferior vena cava perforation during right percutaneous nephrostomy: a case report with critical review Iraqi Acad Sci J. 2016; 15:124-26.

6. Mazzucchi E, et al. Intravenous misplacement of the nephrostomy catheter following percutaneous nephrostolithotomy: two case reports. Clinics. 2009; 64: 69-70.

7. Chen X-F, et al.. Intravenous misplacement of nephrostomy tube following percutaneous nephrolithotomy: Three new cases and review of seven cases in the literature. Int Braz J Urol Off J Braz Soc Urol. 2014; 40:690-96.

8. Fu W, Yang Z, Xie Z, Yan H. Intravenous misplacement of the nephrostomy catheter following percutaneous nephrostolithotomy: two case reports and literature review. BMC Urol. 2017; 17, 43.

Table 1.

Reports of intravenous misplacement of a percutaneous nephrostomy tube.

Author Year Patient Side Dias Filho, et al. 2005 63 Y Female Lt Kotb, et al.

2013

Lt

IVC

Lee, et al.

2014 67 Y Female

Rt

IVC

42 Y Male

Rt

IVC

2019 30 Y Female

Rt

IVC

AL-Musawi, et al. 2016 Refaai, et al.

50 y male

Place IVC to

Catheter Foley’s cath Rightt atrium Foley’s cath

Management Removal under fluoroscopy Exploration with stone removal Foley’s cath Conservative with abdomen compression by a 500 mL bottle and tight sponge Nephrostomy Removal under fluoroscopy Nephrostomy Exploration with stone removal

Table 2.

Reports of intravenous misplacement of a nephrostomy tube after PCNL. Author Mazzucchi, et al.

Mazzucchi, et al.

Shaw, et al.

Li, et al.

Chen, et al.

Chen, et al.

Chen, et al.

Fu, et al.

Fu, et al.

Year Patient Side Place 2009 52 Y Male Lt Renal vein 2009 35 Y Female Rt IVC 2005 54 Y Male Rt IVC 2013 32 Y Female Lt IVC 2014 42 Y Male Lt IVC 2014 38 Y Female Lt IVC 2014 48 Y Male Lt Renal vein 2017 68 Y Male Rt Renal vein 2017 28 Y Male Lt Renal vein

Catheter Nephrostomy Nephrostomy Nephrostomy Nephrostomy Nephrostomy Nephrostomy Nephrostomy Nephrostomy Nephrostomy

Management Under fluoroscopy Under fluoroscopy Exploration US guided CT guided Under fluoroscopy US guided Exploration Exploration

9. Zegel H et al. Percutaneous nephrostomy: comparison of sonographic and fluoroscopic guidance. Am JRoentgenol. 1981; 137: 925-27.

SUBCAPSULAR HEMATOMA AFTER RIRS. A CASE REPORT AND REVIEW OF THE LITERATURE Eugenio Di Grazia, Davide Di Mauro Azienda Policlinico Vittorio Emanuele-Ospedale S. Marco, Catania, Italy

Figure 1.

Axial and coronal cuts of CT scan before PCN insertion.

321 B

Archivio Italiano di Urologia e Andrologia 2020; 92, 4

SUMMARY Introduction: Among major complications of retrograde intrarenal surgery (RIRS) renal subcapsular hematoma (RSH) is very severe and anecdotal. Large stone size, severe ipsilateral hydronephrosis, long operation duration, higher hydrostatic pressure of the irrigating solution and low ureteral wall compliance are supposed to be risks factors associated with RSH formation. Clinically RSH is characterized by fever, loin pain, white blood cells (WBC) increase and a significant drop in haemoglobin (HB). Diagnosis is based on CT scan. Depending on clinical and hemodynamic conditions RSH management may be conservative or may require renal exploration, super selective renal arterial embolization or simple drainage.

Case report: We report on a case of RSH which occurred on high perfusion pressure a patient after RIRS. Because of clinical symptoms and hemodynamic stability, we drained the RSH under ultrasonic and radiological guidance. Post treatment recovery was uneventful.

Conclusions: Post RIRS RSH is a very rare but severe com-

Complications in endourology

plication. Several risk factors together with barotrauma caused by high perfusion pressure during the procedure must be considered to prevent it. Management strategy is tailored to patientâ&#x20AC;&#x2122;s clinical conditions. In hemodynamically stable patients, large hematoma drainage is recommended to prevent further complications and favours early recovery.

KEY WORDS: RIRS; Renal Subcapsular Hematoma; Complications.

DISCUSSION The rate of RIRS complications is between 0 and 25% and includes fever, low back pain, urinary tract infections, sepsis, haematuria, ureteral and pelvic-mucosal lesion, steinstrasse, urinoma, ureteral avulsion, copious bleeding with the need for transfusion. Post URS/RIRS RSH is considered to be anecdotal (1). According to a review by Kozminski M et al., some preoperative risk factors correlated to RSH are high blood pressure, preoperative stenting deployed for ureteral obstruction or narrowing, and female sex (2).

In these situations, the parenchyma and the pyelocaliceal system are more prone to bleeding even for relatively small insults such as contact with the safety guide wire or a percutaneous puncture (1). Thus, blood and fluids accumulate in the subcapsular space, causing gradual separation of the capsule itself from the renal parenchyma. The physiological intrarenal pressure is around 10 mmHg. During a simple ureterorenoscopy the pressure changes to 35 (+/-10) mmHg, changing to an average of 54 (+/-18) mmHg during the lithotripsy procedure with peaks of 328 mmHg. If the RSH is large, Page's kidney disease may occur.

The underlying pathophysiology of Pageâ&#x20AC;&#x2122;s kidney is considered to be that the microvascular ischemia due to renal parenchymal compression activates the renin-angiotensinaldosterone system, consequently leading to hypertension (3). Usually, the treatment of renal hematoma is conservative in most patients, while renal exploration or super selective renal arterial embolization is accomplished in cases with continuing hemodynamic instability. However, during conservative therapy, the hematoma absorbed slowly so that the symptoms persist in most patients, and the aforementioned complications secondary to hematoma gradually may emerge. In addition, functional deterioration may result from compression especially in solitary kidney patients that can lead to acute renal failure due to SRH. After RIRS the patient had a persistent fever that began to improve with carbapenems antibiotics, although WBC remained high for several days. That was the reason why we decided during the same session to place a percutaneous nephrostomy and another drain in the RSH.

REFERENCES 1. Yahsi S, Tonyali S, Ceylan C, et al. Intraparenchymal hematoma as a late complication of retrograde intrarenal surgery.

International Braz J Urol 2017; 43:367-370.

2. Kozminski MA, Kozminski DJ, Roberts WW, et al. Symptomatic subcapsular and perinephric hematoma following ureteroscopic lithotripsy for renal calculi. Journal of Endourology. 2015; 29:277282.

3. Bai J, Li C, Wang S, et al. Subcapsular renal haematoma after holmium:yttrium-aluminum-garnet laser ureterolithotripsy. BJU International. 2012; 109:1230-1234.

RETRIEVAL OF BROKEN DJ URETERIC STENT: AA RARE ENDOUROLOGICAL NIGHTMARE Aldo Franco De Rose, Martina Beverini, Alberto Caviglia, Guglielmo Mantica, Carlo Terrone Department of Urology, Policlinico San Martino Hospital, University of Genova SUMMARY Double-J ureteral stents fracture is a possible but rare complication that is reported in literature in very few cases. We present a rare case of DJ stent fracture discovered one month after the insertion. A broken DJ stent can be safely removed with minimal morbidity and mortality by an experienced endourologist. To minimize further complications, hospitalization and costs it is preferable, when possible, to perform the removal of the broken DJ stent in one time. It is advisable to perform the surgery in two times in case of complications such as fever or extensive stent calcification.

KEY WORDS: Ureteric stent; Urolithiasis; DJ stent; Ureteric stone; Endourology.

DISCUSSION Ureteral stents are an integral part of urological practice.

They have been widely used in daily practice to prevent or relieve the ureteral obstruction, usually for short determining periods. In the literature ureteral stent fragmentation in a rare event accountable for about up to 0.3% of stenting procedures (1-3).

The exact reason for stent fragmentation is unclear (4).

Usually, stent fractures spontaneously occur after being in situ for a long time, because of hardening and the loss of tensile strength (2).

However, it is undeniable that such theory cannot be valid for our case and consequently new hypotheses must be considered: it is probable that cellular injury in response to the presence of urinary tract biomaterials may be an important determinant in the promotion and progression of encrustation which might weak the DJ stent (5). Moreover, it has been suggested that fragmentation occurs at a site previously allowed to kink during stent insertion (6). SWL, ureteroscopic laser lithotripsy, PCNL, and open surgery, either alone or in combination, are employed for the management of an encrusted or fragmented Double-J stent, depending on the location and severity of the case.

Urologists well trained and sufficiently advanced in endourology can manage this situation endoscopically, considering open surgery as a last resort when the endoscopic procedures fail (7). The case presented here is an example of fragmentation of DJ stent. Presence of partial encrustation of the broken DJ stent, multiple renal stones, and a functioning new DJ stent beside the broken one may represent technical challenges. Our approach includes a thorough preoperative imaging evaluation to decide the Archivio Italiano di Urologia e Andrologia 2020; 92, 4

321 C

K. Refaai, M. Ramadan, I. O. Koraiem, M. Sakr

treatment strategy. Calcifications over the stent can be fragmented with a laser lithotripter while carefully advancing the ureteroscope into the renal pelvis. After all the encrustations and calcification have been fragmented, the ureteral segment of the stent is gently removed with the help of grasping forceps passed through the ureteroscope under fluoroscopic guidance. After that the stent the stent was gently pull out under fluoroscopic guidance. It is important to avoid significant traction on the stent which can lead to ureteral trauma, ureteral avulsion, or further stent fracture and fragmentation (8).

recovered with a standard transurethral approach using a metal guidewire. The remaining 39 stents were obstructed by encrustations, therefore it was impossible to replace them with a standard technique.

Results: In 38 cases it was possible to replace the obstructed stents without complications. All procedures were carried out without any sedation. Patients were discharged after 30 minutes of observation from the end of the procedure.

Conclusions: This technique allows the interventional radiologist to replace obstructed urinary stents avoiding more invasive and traumatic urological procedures with sedation.

REFERENCES

KEY WORDS: Encrusted urinary stents; Replacement technique; Ureteral catheters; Fluoroscopy.

1. Chua ME, Morales ML Jr. Spontaneous fracture of indwelling polyurethane ureteral stents: A case series and review of literature.

Can Urol Assoc J. 2012; 6:386-392.

2. Ray RP, Mahapatra RS, Mondal PP, Pal DK. Long-term complications of JJ stent and its management: A 5 years review. Urol Ann. 2015; 7:41-45.

3. El-Faqih SR, Shamsuddin AB, Chakrabarti A et al. Polyurethane internal ureteral stents in treatment of stone patients: morbidity related to indwelling times. J Urol; 1991; 146:1487-1491.

4. Zisman A, Siegel YI, Siegmann A, Lindner A. Spontaneous ureteral stent fragmentation. J Urol. 1995; 153(3 Pt 1):718-721.

5. Beiko DT, Knudsen BE, Watterson JD, et al. Urinary tract biomaterials. J Urol. 2004; 171(6 Pt 1):2438-2444.

6. Mardis HK, Kroeger RM, Hepperlen TW, et al. Polyethylene double-pigtail ureteral stents. Urol Clin North Am. 1982; 9:95-101.

7. Bostanci Y, Ozden E, Atac F, et al. Single session removal of forgotten encrusted ureteral stents: Combined endourological approach.

Urol Res 2012; 40:523-529.

8. Lam JS, Gupta M. Tips and tricks for the management of retained ureteral stents. J Endourol. 2002; 16:733-741.

A MINI-INVASIVE TECHNIQUE FOR TRANSURETHRAL REPLACEMENT OF ENCRUSTED URINARY STENTS IN FEMALE PATIENT. DESCRIPTION OF THE TECHNIQUE AND CLINICAL RESULTS

Magnano San Lio Vincenzo, Meo Diego, Giordano Giuseppe Unit of Diagnostic and Interventional Radiology ARNAS â&#x20AC;&#x153;Garibaldi-Nesimaâ&#x20AC;?, Catania, Italy SUMMARY Objective: Usually the replacement of urinary stents with transurethral approach (particularly in women) is performed in angiographic room. However, complete stent obstruction makes it impossible to replace it on a metal guidewire or on hydrophilic guide wire. This transurethral recovery technique that allows, while maintaining access to the ureter, to remove the encrusted stent and replace it with an another stent with the transurethral technique.

Material and Methods: From January 2013 to January 2020 we replaced 402 urinary stents with a transurethral approach (only women) in patients with obstructive urinary disorders (benign and malignant). Out of them 363 were

321 D

Archivio Italiano di Urologia e Andrologia 2020; 92, 4

MATERIAL

AND METHODS

From January 2013 to January 2020 we replaced 402 urinary stents with a transurethral approach in 325 women with obstructive urinary disorders (benign and malignant). Patients were identified via a Picture Archive and Communications System (PACS) and patient demographics and relevant clinical data were obtained from their written medical records.

A total of 363 stents were replaced with a standard transurethral approach using a metal guidewire. The remaining 39 stents were obstructed by encrustations; therefore, it was impossible to replace them with a standard technique.

All procedures were performed in an interventional radiology suite, and written informed consent was obtained from all patients.

The mean age of the cohort was 58 years (range 32-82 years). Most ureteral stent replacements were in patients with urinary tract obstruction secondary to malignancy, other patients were suffering from benign conditions such as endometriosis, fibroids or inflammatory/infectious ureteral stenosis. Before each procedure, microscopic examination of urine, evaluation of renal function, blood count and coagulation were obtained for each patient. The mean time between the procedures of replacement was 7.2 months (SD: 6.5 months).

All procedures are carried out without any sedation.

The patients were discharged after 30 minutes of observation from the end of the procedure.

The fluoroscopic time, technical success (defined as the possibility of replacing the encrusted double J stent with a retrograde approach under fluoroscopic guidance) and the occurrence of complications were recorded.

DISCUSSION Plastic double J stents are prone to obstruction and encrustation, so it is recommended to replace the ureter stents permanently at intervals of 4-6 months or sooner if they are blocked (1-4).

The chemical components of the urine combine with the stent surface to form a matrix on which further calcification occurs resulting in encrustation. Numerous factors contribute to the speed with which this process occurs, including the material of the stent or catheter, the composition of the urine, and the indwelling time (5).

Formation of encrustations is also dependent bacterial colonization (6). When positioned, the stents are quick-

Complications in endourology

ly covered by a bacterial biofilm that along time can lead to obstruction of the flow of urine and possibly to sepsis of the urinary tract (7). Some organisms, especially Proteus species, which produce urease, cause hydrolysis of urea with increase of urinary pH which induces the deposition of calcium and ammonium magnesium phosphate crystals along this biofilm (8). Other risk factors for stent encrustation can be pregnancy (9) and history of urolithiasis (10).

Traditionally, ureteral stent replacement has been performed by cystoscopic guidance; the advantage of this approach is direct visualization. This can be done with a flexible or rigid cystoscope. Procedures by rigid cystoscope tend to be painful and can be poorly tolerated without general anesthesia (2).

Transvesical ureteric stent removal and replacement under fluoroscopic guidance was first described by Yedlicka et al.

(11). It is highly successful and in general well tolerated by patients. Pain is controlled by topical lidocaine gel for the urinary tract and, if necessary, by conscious sedation with midazolam. As confirmed by Chang et al. a significant advantage of fluoroscopically guided removal and replacement is the reduction of the general anesthetic costs associated with rigid cystoscopy (4).

Different techniques such as shock wave lithotripsy, ureteroscopy and percutaneous techniques, alone or in combination, are described for the management of encrusted ureteral stents (12, 13).

The present technique, such as that described by LopezHuertas et al. (14), is very useful for the replacement of stents without coarse calcifications on fluoroscopy where it is not possible to insert a guide inside the stent due to the encrustation of the lumen. If significant calcification is present under fluoroscopy, it is advisable to pursue other methods for removing encrusted stents. In this case, our technique is unlikely to be successful and use of excessive force could result in more serious complications, such as ureteral avulsion or stent fragmentation (14). We have used this technique to successfully treat 28 women. There were no complications, such as ureteral injury, stricture, or stent fragmentation, in any of the cases.

This study is limited by its retrospective nature and by the lack of clear documentation of procedural times.

Furthermore, we have limited our study to female patients.

urinary stents: evaluation and endourologic management. J Endourol. 2008; 22:905-12.

6. Ramsay JW, Crocker RP, Ball AJ, et al. Urothelial reaction to ureteric intubation. A clinical study. Br J Urol. 1987; 60:504-505.

7. Wollin TA, Tieszer C, Riddell JV, et al. Bacterial biofilm formation, encrustation, and antibiotic adsorption to ureteral stents indwelling in humans. J Endourol. 1998; 12:101-111.

8. Reid G, Davidson R, Denstedt JD. XPS, SEM and EDX analysis of conditioning film deposition on ureteral stents. Surf Interface Anal. 1994; 21:581-586.

9. Gertner JM, Coutan DR, Kliger AS, et al. Pregnancy as state of physiologic absorptive hypercalciuria. Am J Med. 1986; 81:451456.

10. Robert M, Boularan AM, El Sandid M, Grasset D. Double-J ureteric stent encrustations: clinical study on crystal formation on polyurethane stents. Urol Int. 1997; 58:100-104.

11. Yedlicka JW Jr, Azipuru R, Hunter DW, et al. Retrograde replacement of internal double-J ureteral stents. Am J Roentgenol.

1991; 156:1007-1009.

12. Acosta-Miranda AM, Milner J, Turk TM. The FECal Double-J: a simplified approach in the management of encrusted and retained ureteral stents. J Endourol. 2009; 23:409-415.

13. Rana AM, Sabooh A. Management strategies and results for severely encrusted retained ureteral stents. J Endourol. 2007; 21:628-632.

14. Lรณpez-Huertas HL, Polcari AJ, Hugen CM, et al. A novel technique for the removal of minimally encrusted ureteral stents. J Endourol. 2010; 24:9-11.

REFERENCES 1. Park SW, Cha IH, Hong SJ, et al. Fluoroscopy-guided transurethral removal and exchange of ureteral stents in female patients: technical notes. J Vasc Interv Radiol. 2007; 18:251-256.

2. McCarthy E, Kavanagh J, McKernan S, et al. Fluoroscopically guided transurethral removal and/or replacement of ureteric stents in women. Acta Radiol. 2015; 56:635-40.

3. Carrafiello G, Coppola A, De Marchi G, et al. Trans-Urethral Ureteral Stent Replacement Technique (TRUST): 10-Year experience in 1168 Patients. Cardiovasc Intervent Radiol. 2018; 41:610617.

4. Chang RS, Liang HL, Huang JS, et al. Fluoroscopic guidance of retrograde exchange of ureteral stents in women. AJR Am J Roentgenol. 2008; 190:1665-70.

5. Vanderbrink BA, Rastinehad AR, Ost MC, Smith AD. Encrusted Archivio Italiano di Urologia e Andrologia 2020; 92, 4

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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. 92; n. 4 December 2020

Vol. 92; n. 4, December 2020

ORIGINAL PAPERS 275

Overview of the italian experience in surgical management of bladder cancer during first month of COVID-19 pandemic Carmen Maccagnano, Lorenzo Rocchini, Emanuele Montanari, Giario Natale Conti, Giovanni Petralia, Federico Dehò, Kadi-Ann Bryan, Roberto Contieri, Rodolfo Hurle

282

Urological emergency activities during COVID-19 pandemic: Our experience Elisa Cicerello, Mario S. Mangano, Giandavide Cova, Alessio Zordani

286

Outcome and quality of life of patients with augmented bladder or urinary diversion after kidney transplantation Giulia Pozza, Massimo Iafrate, Mariangela Mancini, Cristina Silvestre, Francesca Neri, Lucrezia Furian, Paolo Rigotti, Tommaso Prayer Galetti

291

Attitudes and perceptions towards multiparametric magnetic resonance imaging of the prostate: A national survey among Italian urologists Arnaldo Stanzione, Massimiliano Creta, Massimo Imbriaco, Roberto La Rocca, Marco Capece, Fabio Esposito, Ciro Imbimbo, Ferdinando Fusco, Giuseppe Celentano, Luigi Napolitano, Francesco Mangiapia, Vincenzo Mirone, Nicola Longo

297

The safety and feasibility of the simultaneous use of 180-W GreenLight laser for prostate vaporization during concomitant surgery Roberto Castellucci, Michele Marchioni, Giuseppe Fasolis, Francesco Varvello, Pasquale Ditonno, Gaetano Di Rienzo, Francesco Greco, Vincenzo Maria Altieri, Antonio Frattini, Giovanni Ferrari, Luigi Schips, Luca Cindolo

302

Penile prosthesis and complications: Results from 577 implants Diego Pozza, Andrea Marcantonio, Augusto Mosca, Carlotta Pozza

309

Mini invasive approaches in the treatment of small renal masses: TC-guided renal cryoablation in elderly Oscar Selvaggio, Giovanni Silecchia, Matteo Gravina, Ugo Giovanni Falagario, Giovanni Stallone, Luca Macarini, Giuseppe Carrieri, Luigi Cormio

314

Physiopathology of the diabetic bladder Tatiana Bolgeo, Antonio Maconi, Marinella Bertolotti, Annalisa Roveta, Marta Betti, Denise Gatti, Carmelo Boccafoschi

CASE REPORTS 318

Giant hydronephrosis secondary to ureterocele with duplex system in adults: Report of a case Andrea Solinas, Luca Cau, Massimiliano Fanari, Ignazio Flaviani, Francesco Manca, Maurizio Melis

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Complications of endourological procedures and their treatment Aldo Franco De Rose, Eugenio Di Grazia, Vincenzo Magnano San Lio, Khaled Refaai, Martina Beverini, Alberto Caviglia, Davide Di Mauro, Giuseppe Giordano, Islam O. Koraiem, Guglielmo Mantica, Diego Meo, Mohamed Ramadan, Mostafa Sakr, Carlo Terrone

LETTER TO EDITORS 326

Erectile disfunction medical treatment with phosphodiesterase 5 inhibitors (PDE5i) in patients with retinitis pigmentosa and side effects Andrea Cocci, Andrea Romano, Girolamo Morelli, Davide Frediani, Andrea Sodi, Giorgio Ivan Russo

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Observational study on the effects of a topical formulation in patients with premature ejaculation Giuseppe Quarto, Luigi Castaldo, Giovanni Grimaldi, Alessandro Izzo, Raffaele Muscariello, Sisto PerdonĂ continued on page III