Archivio Italiano di Urologia e Andrologia - Vol. 93 - n. 4 - 2021 by Edizioni Scripta Manent

ISSN 1124-3562

Vol. 93; n. 4, December 2021

ORIGINAL PAPERS 379

Is it possible to reduce the complications and mortality of patients undergoing radical cystectomy? Effectiveness of pre-operative parameters. A prospective study

Övünç Kavukoglu, Alper Coskun, Kubilay Sabuncu, Emre Çamur, Gökhan Faydaci

385

Outcomes of active surveillance for clinically localized prostate cancer in a middle eastern tertiary care center Mohammad Hout, Ali Merhe, Nassib Abou Heidar, Jose M El-Asmar, Wassim Wazzan, Bassel Bachir, Rola Jaafar, Albert El Hajj, Muhammad Bulbul

389

Diagnostic assessment program for prostate cancer: Lessons learned after 2 years and degree of compliance to Canadian guidelines Waleed Shabana, Ahmed Kotb, Daniel Tesolin, Mohammed F.K. Ibrahim, Kristi Dolcetti, Amy Boucher, Mohammed Bassuony, Kevin Ramchandar, Ahmed S. Zakaria, Hazem Elmansy, Walid Shahrour

393

Novel hormonal agents for metastatic Castration-Resistant Prostate Cancer: comparing outcomes. A single-center retrospective study Roberto Saldanha Jarimba, Miguel Nobre Eliseu, João Pedroso Lima, Vasco Quaresma, Pedro Moreira, Pedro Coelho Nunes, Edgar Tavares da Silva, Arnaldo José Figueiredo

399 404

Does transition from standard to Retzius-sparing technique in robot-assisted radical prostatectomy affect the functional and oncological outcomes?

Hakan Anıl, Kaan Karamık, Ali Yıldız, Murat Savaş

Sexual rehabilitation with intracavernous alprostadil after radical prostatectomy: Outcomes from a nursing program Alexandre Gromicho, Pedro Costa, Débora Araújo, Daniela Pereira, Luís Ferraz

408

Is robotic radical nephroureterectomy a safe alternative to open approach: The first prospective analysis Panagiotis Mourmouris, Omer Burak Argun, Lazaros Tzelves, Mustafa Bilal Tuna, Maria Gourtzelidou, Andreas Tziotis, Ali Riza Kural, Andreas Skolarikos

412 418

Does Holmium laser enucleation of the prostate (HoLEP) still have a steep learning curve? Our experience of 100 consecutive cases from Turkey

Güçlü Gürlen, Kadir Karkin

The use and applicability of machine learning algorithms in predicting the surgical outcome for patients with benign prostatic enlargement. Which model to use? Panagiotis Mourmouris, Lazaros Tzelves, Georgios Feretzakis, Dimitris Kalles, Ioannis Manolitsis, Marinos Berdempes, Ioannis Varkarakis, Andreas Skolarikos

425

Outcomes of fluoroscopy-free retrograde intrarenal surgery and predictive factors of stone-free Huseyin Kocakgol, Hasan Riza Aydin, Ahmet Ozgur Guctas, Cagri Akin Sekerci, Deniz Ozturk Kocakgol, Hamit Zafer Aksoy, Yiloren Tanidir, Huseyin Kocakgol

431

The active guidewire technique versus standard technique as different way to approach ureteral endoscopic stone treatment Alessandro Calarco, Marco Frisenda, Emilio Molinaro, Niccolò Lenci

436 441

Is there a relationship between renal scarring and neutrophil-to-lymphocyte ratio in patients with vesicoureteral reflux?

Mehmet Demir, İ􏰀smail Yağmur, Eyyup Sabri Pelit, Bülent Katı, Eser Ördek, Halil Çiftçi

In women with incontinence, the need for pressure-flow study before surgery and abnormalities in the voiding phase. An up-to-date comment on the available problem accompanied by literature

Kutluhan Erdem, Alper Coşkun, Fatih Üstün, Fatih Tarhan

continued on page III

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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 –Tommaso Cai, S. Chiara Hospital, Trento, Italy – 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 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

ORIGINAL PAPERS 445

Nocturnal polyuria in men performing uroflowmetry for lower urinary tract symptoms Emanuele Rubilotta, Daniele Castellani, Marilena Gubbiotti, Matteo Balzarro, Giacomo Maria Pirola, Rita Righetti, Pierpaolo Curti, Antonella Giannantoni, Maria Angela Cerruto, Alessandro Antonelli

450

Telementoring for communication between residents and faculty physicians: Results from a survey on attitudes and perceptions in an Academic Tertiary Urology Referral Department in Italy

Vincenzo Mirone, Massimiliano Creta, Marco Capece, Giuseppe Celentano, Gianluigi Califano, Claudia Collà Ruvolo, Lorenzo Spirito, Giovanni Maria Fusco, Luigi Cirillo, Nicola Longo, Ferdinando Fusco, Claudia Mirone, Roberto La Rocca, Luigi Napolitano

455

Professional roles of female urologists: A webinar-based survey of perceptions and obstacles to career development Sufyan Ibrahim, Amelia Pietropaolo, Nithesh Naik, Anita Patel, Milap J. Shah, Patricia Zondervan, Jean McDonald, BM Zeeshan Hameed, Bhavan Prasad Rai, Hadis Karimi, Bhaskar K. Somani, Joanne Cresswell

460

Erectile dysfunction and testosterone levels prior to COVID-19 disease: What is the relationship? Kadir Karkin, Ergün Alma

465

The effect of N-acetyl cysteine consumption on men with abnormal sperm parameters due to positive history of COVID-19 in the last three months Bahare Rafiee, Seyed Mohammad Bagher Tabei

468

475

Serenoa repens and its effects on male sexual function. A systematic review and meta-analysis of clinical trials Gianni Paulis, Andrea Paulis, Gianpaolo Perletti

481

489

Ectopic adrenal tissue in the kidney: A systematic review

Davide De Marchi, Alessandro Tafuri, Guglielmo Mantica, Aliasger Shakir , Federico Scarfò, Giovanni Passaretti, Salvatore Smelzo, Silvia Proietti, Lorenzo Rigatti, Roberta Luciano, Alessandro Antonelli, Vincenzo Pagliarulo, Leonardi Rosario, Guido Giusti, Franco Gaboardi

Drug-induced gynecomastia: A sistematic review and meta-analysis of randomized clinical trials Alberto Trinchieri, Gianpaolo Perletti, Vittorio Magri, Konstantinos Stamatiou, Margherita Trinchieri, Emanuele Montanari

LETTERS TO EDITOR 497

Comment on renal autotransplantation: A final option to preserve the kidney after an iatrogenic ureteral injury Christos Damaskos, Nikolaos Garmpis, Konstantinos Nikolettos, Alexandros Patsouras, Dimitrios Schizas, Anna Garmpi, Vasiliki E. Georgakopoulou, Athanasios Syllaios, Dimitrios Dimitroulis

499

Varicocele and varicocelectomy: Which news from the past? Nicola Zampieri

501

Preliminary results of a randomized crossover clinical trial comparing a new electromagnetic and vibrating device and alpha-blocker agents in patients affected by bladder outlet obstruction secondary to benign prostatic hyperplasia Simone Brardi, Giuseppe Romano, Gabriele Cevenini

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GENERAL INFORMATION AIMS AND SCOPE “Archivio Italiano di Urologia e Andrologia” publishes papers dealing with the urological, nephrological and andrological sciences. Original articles on both clinical and research fields, reviews, editorials, case reports, abstracts from papers published elsewhere, book rewiews, congress proceedings can be published. Archivio Italiano di Urologia e Andrologia 2021, 93, 4

III

seguici segu s g ici anche a n h qui!! nche qu i!! www.salutepertutti.it www .salutepertutti.it IIl l pod podcast cast della d ella rIvIst rIvIsta ta a Ogni settimana parliamo di salute, su come trovare piccoli accorgimenti quotidiani per mantenere il nostro bene più prezioso. La salute non è solo assenza di malattia, ma anche perper cezione di benessere, sentirsi bene ed occuparsi di cose utili e belle. Le voci di Salutepertutti.it sono Alessia Bisini e Ruben Cazzola.

DOI: 10.4081/aiua.2021.4.379

ORIGINAL PAPER

Is it possible to reduce the complications and mortality of patients undergoing radical cystectomy? Effectiveness of pre-operative parameters. A prospective study Övünç Kavukoglu, Alper Coskun, Kubilay Sabuncu, Emre Çamur, Gökhan Faydaci Department of Urology, University of Health Sciences, Kartal Dr. Lutfi Kırdar City Hospital, Istanbul, Turkey.

Objective: To evaluate the relationship between serum albumin, hematocrit (HTC), age-dependent Charlson comorbidity index, body mass index (BMI), and deleted operation time in predicting mortality and complications associated with radical cystectomy. Materials and methods: All patients planned for radical cystectomy owing to bladder cancer were investigated prospectively between 2015 and 2016 in our clinic. A total of 55 cases were included in the study. Patients' characteristics, preoperative serum albumin values, hematocrit level, age-dependent Charlson comorbidity index (CCI), body mass index and deleted operation time, drainage catheter time, gas-stool expulsion time were recorded. The patients were followed up for 90 days. Results: Age of cases, Charlson comorbidity index scores, and HCT were not different in patients with or without complications (overall) or severe complications nor in patients who died or survived after the procedure. The albumin value of the cases with observed mortality and complications was significantly lower than that of the cases with no mortality and complications. In multivariate and univariate analysis, low albumin level was established to be meaningful in predicting mortality and serious complications. The cut-off point for albumin, according to mortality, was found to be 4.1. Mortality within 90 days was 16.3% (n = 9). Conclusions: We have evaluated albumin as a marker that could indicate both mortality and the presence of severe complications after radical cystectomy and urinary diversion.

owing to provides the best cancer-specific survival in muscle-invasive patients (3, 4). RC provides excellent local control with a local recurrence rate of 4% in patients with lymph node-negative (5). RC is associated with significant complications, including death, with wide variability in reported postoperative morbidity and mortality rates. In a study of 1142 patients managed by Shabsigh et al., the serious complication rate was 13% and the mortality rate within 30 days was 1.5% (6). Although the mortality rate has decreased over the past decade, early morbidity rates have remained at ranging from 11 to 68% (3, 7, 8). Whether the disease is organ-confined to the or not and the patient's comorbidity status (age-adjusted Charlson comorbidity index - ACCI) are defined indicators of mortality and complications after radical cystectomy (9). Putting forth a marker that can predict complications can be a prominent attempt to reduce mortality and morbidity. In line with this goal, and hence that there is no prospective study on this subject in the literature, we aimed to examine the usability of serum albümin. Simultaneously, we also examined hematocrit values, agedependent Charlson comorbidity index (ACCI), BMI, and operation time.

KEY WORDS: Albumin; Bladder cancer; Complications; Cystectomy; Mortality.

All patients scheduled to view radical cystectomy for BC between 2015 and 2016 in the urology clinic of Kartal Lütfi Kırdar City Hospital were examined prospectively. A total of 60 patients underwent radical cystectomy operation, and since five patients were out of follow-up, 55 cases, six females and 49 males were included in the study. Ethics Committee Approval was obtained from our hospital's ethics committee for our study, and all subjects signed an informed consent form (IRB number 514/65/4). Patient's age, BMI, ACCI score, preoperative serum albumin, hematocrit (HCT), urea-creatinine values, operation time, pre-and post-cystectomy pathological stages, diversion type, amount of blood transfusion, type of complications, intestinal functions (gas-stool output time), the transition time to oral nutrition, total parenteral nutrition (TPN) time, the length of hospital stay, the duration of drainage catheter and reoperations, patients' mortality

Summary

Submitted Submitted 28 July 2021; Accepted 9 September 2021

INTRODUCTION

Bladder cancer (BC) is the 7th most commonly diagnosed cancer in males, while it degrades to 11th when both genders are taken into account (1); 75% of patients with BC present with disease non-muscle invasive bladder cancer at the first consult. Patients with muscle-invasive bladder tumors often present with progressed disease and approximately 20% of them are patients who progress from lower stages (2). The cancer-specific mortality rate of muscle-invasive bladder cancer (MIBC) can be predicted to increase up to 85% if left untreated (2). Radical cystectomy (RC) and pelvic lymph node dissection (PLND) is the standard treatment for localized MIBC

MATERIALS

AND METHODS

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

379

Ö. Kavukoglu, A. Coskun, K. Sabuncu, E. Çamur, G. Faydaci

and morbidity until the postoperative 90th day and their application for any reason to the hospital, were recorded for each patient. Also, they routinely were called for follow-up visits in the postoperative first and third months. We preferred a well-described method, as Clavien Dindo classification system (CCS), for evaluation of postoperative complications (10, 11). Statistical analysis was conducted using NCSS (Number Cruncher Statistical System) 2007 (Kaysville, Utah, USA). The quantitative and qualitative variables were analyzed with Student's t-test, Mann Whitney U test, Pearson chi-square test, Fisher's Exact Test, and Fisher Freeman Halton test. A p value < 0.05 was considered to indicate statistical significance.

The mean age of the patients was 65.27 ± 9.38, BMI 26.21 ± 4.17 kg/m2, HCT 37.90 ± 5.37, albumin values ranged from 2.2 to 4.9, with an average of 4.03 ± 0.55. Operation times averaged 273.15 ± 74.30 minutes and gas-stool output time 3.92 ± 1.60 days. The patients' demographic characteristics, preoperative laboratory values, postoperative results, Charlson scores, Clavien complication scores were outlined in Table 1. The majority of postoperative complications are related to

Table 1. Patients characteristics findings. Pre-operative parameters Age (years) BMI (kg /m2)

Hemoglobin Hematocrit Albumin Urea Creatinine Neoadjuvant chemotherapy radiotherapy/ Abdominal surgery Charlson score Clavien Dindo (n=39)

Peri-operative parameters Positive Surgical margin Operation time (min) Postoperative parameters Re-operation Intensive care unit time (day) Gas output time (day) Stool output time (day) Transition time to oral nutrition (day) TPN time (day) Drainage catheter staying time (day) Length of Hospital stay (day)

380

Pre-operative parameters

Gastrointestinal system Infection Genitourinary system Hematological/vascular Cardiac Wound/skin

RESULTS

Gender

Table 2. The type of complications and comparing with albumin.

Female Male

No Yes ≤2 3-4 ≥5 2 3 4 5

Min-max (median) Mean ± Ss 38-85 (65) 65.27 ± 9.38 n % Normal 45.50 Overweight 34.50 Obese 20.00 6 10.9 49 89.1 9.2-16 (12.1) 12.45 ± 1.80 27.7-48.8 (37.6) 37.90 ± 5.37 2.2-4.9 (4.1) 4.03 ± 0.55 12-135 (39) 44.65 ± 20.77 0.6-4.7 (1.1) 1.33 ± 0.87 0-4 (0) 40 72.7 15 27.3 9 16.4 28 50.9 18 32.7 15 38.5 11 28.2 4 10.3 9 23.1

No Yes 160-540 (257.5)

41 14 273.15 ± 74.30

75.9 24.1

No Yes 0-31 (1) 1-8 (3) 1-9 (4) 1-11 (4) 0-10 (4) 4-19 (8.5) 2-46 (10)

44 11 2.42 ± 5.43 2.88 ± 1.45 3.92 ± 1.60 4.00 ± 1.79 4.10 ± 2.35 9.74 ± 3.53 12.78 ± 9.65

80.0 20.0

Archivio Italiano di Urologia e Andrologia 2021; 93, 4

Pulmonary Neurological Metabolic Musculoskeletal system

No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes

Albumin > 3.5 ≤ 3.5 n (%) n (%) 26 (56.5) 3 (33.3) 20 (43.5) 6 (66.7) 32 (69.6) 3 (33.3) 14 (30.4) 6 (66.7) 43 (93.5) 8 (88.9) 3 (6.5) 1 (11.1) 42 (91.3) 8 (88.9) 4 (8.7) 1 (11.1) 44 (95.7) 8 (88.9) 2 (4.3) 1 (11.1) 42 (91.3) 5 (55.6) 4 (8.7) 4 (44.4) 41 (89.1) 7 (77.8) 5 (10.9) 2 (22.2) 43 (93.5) 5 (55.6) 3 (6.5) 4 (44.4) 41 (89.1) 8 (88.9) 5 (10.9) 1 (11.1) 45 (97.8) 9 (100.0) 1 (2.2) 0 (0.0)

Test value P χ2 = 1.624 0.281b χ2 = 4.270 0.059 b χ2 = 0.235 b0.522 b χ2 = 0.053 1.000 b 2 χ = 0.668 b0.421 b χ2 = 7.739 0.019 b * χ2 = 0.873 0.321 b χ2 = 9.746 0.002 b ** χ2 = 0.000 1.000 b χ2 = 0.199 1.000 b

b Fisher’s Exact Test; *p < 0.05; **p < 0.01.

gastrointestinal system (GIS) with a 47.3% rate (n = 26). Second most frequent complications with a 36.4% rate (n = 20) were infectiouscomplications; wound/skin-related complications followed with 14.5% rate (n = 8). In the relationship between the variety of complications and albumin value, the rate of wound/skin and neurological complications in patients with albumin below 3.5 was significantly higher than in those with a value over 3.5 (p = 0.019, p = 0.002) (Table 2). According to Clavien complication status and severity, age, Charlson comorbidity index, operation times, HCT values, gas-stool output times did not show a statistically significant difference (p > 0.05). Likewise, when the albumin values were examined according to the complication status and severity, no albumin value of 3.5 or less was observed in any of the cases without complications and with mild complication severity. Besides, the albumin value of the patients with complications was found to be significantly lower than the cases without complications (p = 0.013; p < 0.05) (Table 3). While there is no statistically significant difference between age, Charlson comorbidity index, BMI, operation time, HCT value, gas-stool output time and mortality, the same is not current for albumin. In fact, 55.6% of the cases with mortality had an albumin value of 3.5 and below, and 8.7% of the cases with no mortality had an albumin value below 3.5 (Table 4). The cut-off point for albumin considering mortality was found to be 4. Accordingly, it is significant that the albumin value of the cases with mortality is 4.1 and below. This cut-off value's sensitivity is 100%, the specificity is 52.17%, the positive predictive value is 29 and the negative predictive value is 100. The area under the ROC curve was 82% for the standard error of the area 6.7% (Figure 1).

Complications of radical cystectomy

Table 3. Comparison of operation time, BMI and albumin values according to the presence of complications and their severity.

Age (years) BMI (kg/m2) Charlson score Operasyon time Hematocrit BMI (n%) Charlson score Albumin Albumin

Min-max (median) Mean ± Ss Min-max (median) Mean ± Ss Min-max (median) Mean ± Ss Min-max (median) Mean ± Ss Min-max (median) Mean ± Ss Normal Overweight Obese ≤2 3-4 ≥5 Min-max (median) Mean ± Ss > 3.5 ≤ 3.5

Overall complications No (n = 16) Yes (n = 39) 51-77 (63) 38-85 (67) 63.56 ± 7.76 65.97 ± 9.98 22-34.1 (25.5) 17.6-36.3 (25.4) 26.46 ± 3.92 26.10 ± 4.31 2-6 (3.5) 0-8 (4) 3.62 ± 1.20 4.10 ± 1.70 180-450 (255) 160-540 (257.5) 264.69 ± 69.84 276.71 ± 76.72 33.4-46.5 (40) 27.7-48.8 (37.5) 39.63 ± 4.32 37.19 ± 5.64 7 (43.8) 18 (46.2) 5 (31.3) 14 (35.9) 4 (25.0) 7 (17.9) 3 (18.8) 6 (15.4) 9 (56.3) 19 (48.7) 4 (25.0) 14 (35.9) 3.7-4.8 (4.25) 2.2-4.9 (4) 4.26 ± 0.31 3.94 ± 0.60 16 (100.0) 30 (76.9) 0 (0.0) 9 (23.1)

Test value P t = 0.864 0.392 d t = -0.288 0.774 d Z = -1.641 0.101 a t = -0.539 0.592 d t = 1.548 0.128 d χ2 = 0.367 0.832 e χ2 = 0.706 0.716 c t = 2.563 0.013 d* χ2 = 4.415 0.046 b *

Complication severity Mild (n = 15) Severe (n = 24) 38-81 (75) 53-85 (66) 65.87 ± 11.78 66.04 ± 8.94 17.6-34.0 (23) 22.1-36.3 (25.8) 24.26 ± 4.21 27.25 ± 4.04 0-5 (4) 2-8 (4) 3.60 ± 1.40 4.42 ± 1.81 180-540 (250) 160-390 (270) 284.00 ± 97.43 271.96 ± 61.62 31.6-47.0 (37.6) 27.7-48.8 (36.45) 38.25 ± 4.99 36.53 ± 6.01 9 (60.0) 9 (37.5) 5 (33.3) 9 (37.5) 1 (6.7) 6 (25.0) 3 (20.0) 3 (12.5) 8 (53.3) 11 (45.8) 4 (26.7) 10 (41.7) 3.-4.9 (4.2) 2.2-4.8 (4) 4.23 ± 0.35 3.76 ± 0.66 15 (100.0) 15 (62.5) 0 (0.0) 9 (37.5)

Test value P t = 0.053 0.958 d t = 2.215 0.033 d * Z = -0.944 0.345 a t = -0.468 0.643 d t = -0.930 0.359 d χ2 = 2.611 0.283 c χ2 = 1.115 0.675 c t = -2.499 0.007 d ** χ2 = 7.313 0.007 b **

a Mann WhitneyUTest; b Fisher’sExact Test; c Fisher Freeman Halton Test; d Student-tTest; e Pearson Chi-SquareTest; *p < 0.05; **p < 0.01.

Figure 1. Diagnostic screening tests and ROC curve outcomes of albumin by mortality.

To examine factors that affect the severity of complications and mortality, two separate logistic regression models derived from age, BMI, albumin value, preoperative HCT value and Charlson index variables were estab-

lished. The sensitivity of these models (model 1, 2) for the cases with mortality was 44.4% and 79.2% and the specificity rate was 66.7% and 93.5%, overall accuracy was 85% and 74.4%, respectively. Additionally, albumin's oneArchivio Italiano di Urologia e Andrologia 2021; 93, 4

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Table 4. Charlson comorbidity index, BMI, HCT, and albumin values by mortality.

Age (years) BMI (kg/m2) Charlson Score Hematocrit BMI (n %) Charlson score Albumin (n %) Albumin g/dl Albumin Cut-Off

Min-max (median) Mean ± Ss Min-max (median) Mean ± Ss Min-max (median) Mean ± Ss Min-max (median) Mean ± Ss Normal Overweight Obese ≤2 3-4 ≥5 > 3.5 ≤ 3.5 Min-max (median) Ort ± Ss > 4.1 ≤ 4.1

Mortality Yes (n = 46) No (n = 9) 38-84 (65) 57-85 (70) 64.63 ± 9.45 68.56 ± 8.80 17.6-36.3 (25.4) 22.1-32 (24.8) 26.28 ± 4.30 25.83 ± 3.64 0-8 (4) 2-7 (5) 3.80 ± 1.51 4.78 ± 1.71 27.7-48.0 (37.7) 30.0-48.8 (37.5) 37.94 ± 5.27 37.71 ± 6.20 20 (43.5) 5 (55.6) 17 (37.0) 2 (22.2) 9 (19.6) 2 (22.2) 8 (17.4) 1 (11.1) 25 (54.3) 3 (33.3) 13 (28.3) 5 (55.6) 42 (91.3) 4 (44.4) 4 (8.7) 5 (55.6) 2.7-4.9 (4.2) 2.2-4.1 (3.3) 4.15 ± 0.45 3.44 ± 0.66 24 (52.2) 0 (0.0) 22 (47.8) 9 (100.0)

Test value P Z = -1.162 0.245 a Z = -0.228 0.820 a Z = -0.995 0.320 a Z = -0.262 0.794 a 2 χ = 0.835 0.725 c χ2 = 2.341 0.343 c χ2 = 12.077 0.003 b ** Z = -3.028 0.002 a ** χ2 = 8.331 0.003 b **

a Mann WhitneyUTest; b Fisher’sExact Test; c Fisher Freeman Halton Test; *p < 0.05; **p < 0.01.

Operation time was excluded.

Table 5. Logistic regression models for factors affecting mortality and complication severity.

Model 1. Mortality Age BMI Albumin Hematocrit Charlson score Charlson (2-5) Charlson (> 5) Constant Model 2. Complication severity Age BMI Albumin Hematocrit Charlson score Charlson (2-5) Charlson (> 5) Constant

Odds ratio (OR)

-0.079 -0.039 -4.294 0.242

0.412 0.792 0.005 0.036 0.457 0.919 0.569 0.230

0.924 0.961 0.014 1.273

0.766 0.717 0.001 1.016

1.116 1.289 0.272 1.595

0.825 3.128 121625.915

0.020 0.062

34.123 158.545

1.022 1.400 0.057 0.991

0.902 1.039 0.005 0.828

1.158 1.887 0.704 1.184

0.376 0.384 22.993

0.018 0.011

8.040 14.063

-0.192 1.140 11.709 0.021 0.337 -2.857 -0.010 -0.978 -0.956 3.135

0.736 0.027 * 0.025 * 0.917 0.822 0.531 0.603 0.661

Confidence interval for OR Low High

*p < 0.05.

point rising could decrease the prospect of mortality by 0.014 (1/71) times and of serious complications by 0.057 (1/17) times. Similarly, it was found that a one-unit decrease in HCT value would increase the likelihood of mortality by 1.273 times, while a one-unit increase in BMI value would increase the likelihood of severe complications by 1.4 times. b coefficients obtained in the logistic regression models (model 1, 2) are shown in Table 5.

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DISCUSSION

Radical cystectomy (RC) is the primary treatment modality for patients with muscle-invasive urothelial cancer of the bladder (1). Increasing patient age, female gender, more than two comorbidities, having undergone previous pelvic surgery, stage of the disease (extravesical disease) and obesity are factors that will increase complications and mortality (6, 7, 12-14). Also, the experience of the surgeon, perioperative blood loss and operation time are important items. Assessment of comorbidities of patients is of great significance in predicting mortality and morbidity. The American Society of Anesthesiologists (ASA) score is frequently used for this goal. However, we used the Charlson comorbidity index (CCI) in our study (15). Considering their comorbidity index, we divided the patients into three groups: 2 mild, 3-4 moderate, and ≥ 5 severe. We observed that patients with 5 and above have serious complications. In the study by Koppie et al., overall survival was demonstrated decreasing in patients with high comorbidity considering the comorbidity index, but recurrence-free survival was not affected. Again Maffezini et al. In his study, a CCI of more than 3 was found to be associated with survival (16). It is also noteworthy that patients with high comorbidities had been performed less lymph node dissection and less postoperative chemotherapy (9). The complication percentage of our study is 70.9%. This value is higher than the literature obviously. (6, 15, 1820). Whereas these literature values included 30-day morbidity and mortality, we analyzed 90-day. Although most of the complications come into being were complaints that would not be classified as serious complications, we found the serious complication rate (ClavienDindo: 3-5) 43.6% (n: 24), severe complication Clavien Dindo 4-5 23.6%. The mortality rate within 90 days postoperatively is 16.3% (n = 9). We did not find a significant relationship between mortality and complication rates with BMI, Charlson comorbidity index, preoperative hematocrit values and operation time in univariate analysis. As for the multivariate analysis, we observed that the hematocrit value is strongly related to predicting mortality and BMI is also significant in the presence of severe complications. However, it would not be wrong to say that we found the most significant results in our study when we analyzed the albumin values. Albumin is an important marker to predict mortality and severe complication in both univariate and multivariate analyses. In addition, Our results showed us that wound/skin and neurological complications were significantly higher if albumin values are low. Undernourishment is a well-known risk factor for complications (21-23). Serum albumin has been shown that is a determinant of nutritional status and is a prominent marker of prognosis and progression in many types of cancer in previous studies (24, 25). In the study by Gregg at al., they have categorized patients with preoperative albumin value of 3.5 and below, those with BMI < 18.5 and patients with pre-operative weight loss of more than 5% were as patients with malnutrition (23). In another study that had been done with similar logic, the preoperative albumin value was found to be significant in predicting complica-

Complications of radical cystectomy

tions and mortality after radical cystectomy. It was predicted that better postoperative outcomes could be achieved with preoperative nutritional support (26). The study by Djaladat et al. investigated the relationship between ASA score and albumin with survival; they established that a high ASA score was associated with increased complication rates and low serum albumin with recurrence-free overall survival. As a result of albumin being so vital, the idea of albumin supplementation to patients had come into question, but studies have shown that it does not cause better results and may cause undesirable effects (26, 27). Similarly, when the patients who were given TPN (total parenteral nutrition) and not given were investigated, no difference was obtained in the complication rates and infectious complications (such as intraabdominal abscess and peritonitis) increased in patients who received TPN (28). We can indicate the study's limitations as follows; it is a single-center study, the number of patients is insufficient, a single surgeon did not perform operations, complications, mortality and was not calculated according to the pathological stages of the patients, our follow-up period is short. We thought that it would cause us to have difficulty in distinguishing cancer-specific survival from postoperative mortality in a more extended follow-up period. Therefore, we considered that the 3-month period is optimal duration. The fact that our results are similar to the literature may bring a criticism that the study does not contribute to literature at first. Although accepting this as a self-criticism, our research was designed prospectively, point that it is different from existing studies. Another subject of criticism is that the patients' postoperative albumin values were not compared with the preoperative values. Frankly, we believe that this may be the subject of a different study. It is valuable that albumin gives such significant statistical results with a small patient population. However, it would not explain the high mortality and complications with only preoperative data-besides, the lack of patient outcomes who underwent laparoscopic and robotic surgery acceptable an issue of criticism. Our results are generally concordant with the literature. We believe that the fact that these supportive data were obtained prospectively will make our study privileged.

CONCLUSIONS

Finding a marker that predict the mortality and complications that may occur after radical cystectomy may be help to prepare the patient before surgery and manage the patient after surgery. As a result, albumin was found to be meaningful in predicting both mortality and the presence of serious complications. We believe that our results will give an opinion for future randomized controlled multicenter studies. Thus, it may be possible to minimize complications and mortality.

REFERENCES

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

2. Prout GR, Marshall VF. The prognosis with untreated bladder tumors. Cancer. 1956; 9:551-558. 3. Lawrentschuk N, Colombo R, Hakenberg OW, et al. Prevention and management of complications following radical cystectomy for bladder cancer. Eur Urol. 2010; 57:983-1001. 4. Meyer JP, Blick C, Arumainayagam N, et al. A three-centre experience of orthotopic neobladder reconstruction after radical cystectomy: revisiting the initial experience, and results in 104 patients. BJU Int. 2009; 103:680-683. 5. Morris DS, Weizer AZ, Ye Z, et al. Understanding bladder cancer death: tumor biology versus physician practice. Cancer. 2009; 115:1011-1020. 6. Shabsigh A, Korets R, Vora KC, et al. Defining early morbidity of radical cystectomy for patients with bladder cancer using a standardized reporting methodology. Eur Urol. 2009; 55:164-74. 7. Novara G, Marco VD, Aragona M, et al. Complications and mortality after radical cystectomy for bladder transitional cell cancer. J Urol. 2009; 182:914-921. 8. Bostrom PJ, Mirtti T, Kössi J, et al. Twenty-year experience of radical cystectomy for bladder cancer in a medium-volume centre. Scand J Urol Nephrol Suppl. 2009; 43:357-364. 9. Koppie TM, Serio AM, Vickers AJ, et al. Age-adjusted Charlson comorbidity score is associated with treatment decisions and clinical outcomes for patients undergoing radical cystectomy for bladder cancer. Cancer. 2008; 112:2384-2392. 10. Clavien PA, Sanabria JR, Strasberg SM. Proposed classification of complications of surgery with examples of utility in cholecystectomy. Surgery. 1992; 111:518-526. 11. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004; 240:205-213. 12. Kim HL, Steinberg GD. Complications of cystectomy in patients with a history of pelvic radiation. Urology. 2001; 58:557-560. 13. Mastroeni F, Aragona M, Caldarera E, et al. Deep venous thrombosis in patients undergoing salvage radical cystectomy. Arch Esp Urol. 2001; 54:839-841. 14. Arumainayagam N, McGrath J, Jefferson KP, Gillat DA. Introduction of an enhanced recovery protocol for radical cystectomy. BJU Int. 2008; 101:698-701. 15. Charlson ME, Pompei P, Ales KL, MacKenzie CR. J Chronic Dis. 1987; 40:373-383. 16. Maffezzini M, Fontana V, Pacchetti A, et al. Age above 70 years and Charlson Comorbidity Index higher than 3 are associated with reduced survival probabilities after radical cystectomy for bladder cancer. Data from a contemporary series of 334 consecutive patients. Arch Ital Urol Androl. 2021; 93:15-20. 17. Frazier HA, Robertson JE, Paulson DF. Complications of radical cystectomy and urinary diversion: a retrospective review of 675 cases in 2 decades. J Urol. 1992; 148:1401-1405. 18. Konety BR, Allareddy V, Herr H. Complications after radical cystectomy: analysis of population-based data. Urology. 2006; 68:5864. 19. Brannan W, Fuselier HA, Ochsner M, Randrup ER. Critical evaluation of 1-stage cystectomy--reducing morbidity and mortality. J Urol. 1981; 125:640-642. 20. Skinner DG, Crawford ED, Kaufman JJ. Complications of radical cystectomy for carcinoma of the bladder. J Urol. 1980; 123:640-643. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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21. Gibbs J, Cull W, Henderson W, et al. Preoperative serum albumin level as a predictor of operative mortality and morbidity: results from the National VA Surgical Risk Study. Arch Surg. 1999;134:36-42.

25. Gupta D, Lis CG. Pretreatment serum albumin as a predictor of cancer survival: a systematic review of the epidemiological literature. Nutr J. 2010; 9:69.

22. Djaladat H, Bruins HM, Miranda G, et al. The association of preoperative serum albumin level and American Society of Anesthesiologists (ASA) score on early complications and survival of patients undergoing radical cystectomy for urothelial bladder cancer. BJU Int. 2014; 113:887-893.

26. Garg T, Chen LY, Donat M. Preoperative serum albumin is associated with mortality and complications after radical cystectomy. BJU Int. 2014; 113:918-923.

23. Gregg JR, Cookson MS, Phillips S, et al. Effect of preoperative nutritional deficiency on mortality after radical cystectomy for bladder cancer. J Urol. 2011; 185:90-96.

27. Gore JL, Lai J, Setodji CM, et al. Mortality increases when radical cystectomy is delayed more than 12 weeks: results from a Surveillance, Epidemiology, and End Results-Medicare analysis. Cancer. 2009; 115:988-996.

24. Liu J, Dai Y, Zhou F, et al. The prognostic role of preoperative serum albumin/globulin ratio in patients with bladder urothelial carcinoma undergoing radical cystectomy. Urol Oncol. 2016; 34:484 e1-484e8.

28. Brennan MF, Pisters PW, Posner M, et al. A prospective randomized trial of total parenteral nutrition after major pancreatic resection for malignancy. Ann Surg. 1994; 220:436-444.

Correspondence Övünç Kavukoglu, MD ovunckavukoglu@hotmail.com Alper Coskun, MD (Corresponding Author) alpercoskun62@yahoo.com Kubilay Sabuncu, MD kubilaysabuncu@yahoo.com Emre Çamur, MD emre.camur@outlook.com Gökhan Faydaci, MD faydacig@yahoo.com Department of Urology, University of Health Sciences, Kartal Dr. Lutfi Kırdar City Hospital, Istanbul (Turkey)

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DOI: 10.4081/aiua.2021.4.385

ORIGINAL PAPER

Outcomes of active surveillance for clinically localized prostate cancer in a middle eastern tertiary care center Mohammad Hout 1, Ali Merhe 1, Nassib Abou Heidar 1, Jose M El-Asmar 1, Wassim Wazzan 1, Bassel Bachir 1, Rola Jaafar 2, Albert El Hajj 1, Muhammad Bulbul 1 1 Department 2 Department

of Surgery, Division of Urology, American University of Beirut Medical Center, Beirut, Lebanon; of Surgery, American University of Beirut Medical Center, Beirut, Lebanon.

Summary

Background: The aim of our study was to evaluate the outcome of active surveillance (AS) for prostate cancer for a cohort of patients at our institution. Methods: A total of 43 patients with low risk prostate cancer were enrolled in an active surveillance pilot program at our institution between 2008 and 2018. Follow up protocols included: periodic prostate specific antigen (PSA), digital rectal examination (DRE), multiparametric MRI, and prostate biopsy at one year. Pertinent parameters were collected, and descriptive statistics were reported along with a subset analysis of patients that dropped out of the protocol to receive active treatment for disease progression. Results: Out of 43 eligible patients, 46.5% had a significant rise in follow up PSA. DRE was initially suspicious in 27.9% of patients, and none had any change in DRE on follow up. Initially, prostate MRIs showed PIRADS 3, 4, and 5 in 14%, 37.2%, and 11.6% respectively, while 23.2% had a negative initial MRI. 14% did not have an MRI. Upon follow up, 18.6% of patients had progression on MRI. Initial biopsies revealed that 86% were classified as WHO group 1, while 14% as WHO group 2. With regards to the follow up biopsies, 11.6% were upgraded. 20.9% of our patients had active treatment; 44.4% due to upgraded biopsy results, 22.2% due to PSA progression, 22.2% due to strong patient preference, and 11.1% due to radiologic progression. Conclusions: For selected men with low risk prostate cancer, AS is a reasonable alternative. The decision for active treatment should be tailored upon changes in PSA, DRE, MRI, and biopsy results.

KEY WORDS: Active surveillance; Prostate cancer; Men’s health; Screening; Prostate specific antigen. Submitted 14 May 2021; Accepted 19 July 2021

INTRODUCTION

Active surveillance (AS) as a management strategy for low grade prostate cancer is a relatively new approach increasingly utilized by clinicians in the light of better comprehension of low-grade prostate cancer behavior. It is a dynamic surveillance strategy that may shift into a direct curative intervention (1). The main goal is to follow-up patients with clinical parameters such as prostate specific antigen (PSA), digital rectal examination (DRE), imaging and biopsy according to predetermined protocols. The impor-

tance of AS lies in evading unnecessary treatments, and so their potentially detrimental side effects, through careful surveillance at specific intervals to disease progression and need for intervention (1). The rationale justified by the slow and indolent course of low-grade prostate cancer (2, 3). Moreover, observational studies revealed no significant advantage in patients that underwent surgery versus active surveillance (4, 5). In particular, the PROTECT trial showed a similar 10-year Prostate cancer specific survival in patients with localized low-grade prostate cancer that underwent monitoring, surgery, or radiation therapy (6). Our purpose is to evaluate our active surveillance protocol and its outcomes in our Middle Eastern cohort over a 10year span. To our knowledge, this is the first AS outcome data reported outside of North America and Europe.

METHODS

After obtaining institutional review board approval, we performed a retrospective review of our prostate cancer patients’ data at the American University of Beirut- Medical Center (AUBMC), a Middle Eastern tertiary care center, over a span of 10 years (2008-2018). 43 of them satisfied the inclusion criteria into our institution’s active surveillance protocol. Our inclusion criteria included low risk prostate cancer defined by the following parameters: PSA less than 10, a negative DRE or a localized nodule (T1C/T2A), biopsy Gleason group grade 1 or 2 as defined by the WHO criteria, and unilateral disease involvement on biopsy. Magnetic resonance imaging (MRI) was done to characterize and guide the localization of prostatic lesions for biopsy. Consequently, targeted biopsies were taken from those lesions along with random ones. There was no exclusion criteria based on age. To note, patients that were enrolled into the AS protocol were thoroughly counseled about available treatment options including their possible side effects. Our follow-up strategy based upon a PSA and DRE every 4-6 months, an initial prostate biopsy at the time of enrollment, and a second biopsy at 1 year. Annual MRI was not initially part of the protocol, yet it was introduced in the last few years. Furthermore, an additional re-biopsy was done after the first year with evident signs of clinical progression such as a suspicious rise in PSA, change in DRE, or MRI progression which included the appearance of a new lesion, or an increased

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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complexity of a previously noted one as defined by the PIRADs system. Descriptive statistics of patients and their above parameters were reported along with a subset analysis of patients that dropped out of the protocol to receive treatment for progression of disease.

Figure 1. Mode of intervention after dropping out from active surveillance.

RESULTS

Our populations’ age ranged between 51-78 with a mean of 63.88. PSA values ranged between 1.87-15.9. At presentation, a positive DRE was present in 27.9% of included patients, whereas negative in 72.1% of them. Initial MRI’s harbored a PIRADS 3 lesions in 14% of patients, PIRADS 4 in 37.2%, PIRADS 5 in 11.6%. 23.2% of patients had a negative MRI and 14% did not have one. The Pathology grade of our patients prostate biopsy revealed a WHO group 1 in 86% of patients while a WHO group 2 in 14% of the biopsies (Table 1). Upon regular follow-up, 46.5% of patients (20/43) had a significant rise in follow-up PSA, 46.5% (20/43) had a stable PSA throughout, and 7% (3/43) did not have a folTable 1. Mean age, mean PSA, rate of positive DRE, MRI results and pathology grade of our population. Patient demographics AGE PSA DRE (negative) DRE (positive) MRI (not done) MRI (negative) MRI (PIRADS 3) MRI (PIRADS 4) MRI (PIRADS 5) Pathology grade WHO group 1 WHO group 2

Results 63.88 (51-78) 6.26 (1.87-15.9) 72.1% (31/43) 27.9% (12/43) 14% (6/43) 23.2% (10/43) 14% (6/43) 37.2% (16/43) 11.6% (5/43) 86% (37/43) 14% (6/43)

Table 2. PSA, MRI and biopsies at follow-up. Clinical parameter PSA MRI Pathology

Progressed 46.5% (20/43) 18.6% (8/43) 11.6% (5/43)

Stable 46.5% (20/43) 39.5% (17/43) 46.5% (20/43)

N/A 7% (3/43) 41.9% (18/43) 41.9% (18/43)

Table 3. Comparison of our results to various North American cohorts studied in different medical centers. Center No of patients Median age Median follow-up Overall survival Cancer specific survival Conversion to treatment (ROT) Gleason grade change (ROT) PSA increase (ROT) Positive LNS (ROT) Personal choice

386

Toronto (8) 993 68 77 80% 98% 36.50% 9.50% 11.70% 1.60%

Hopkins (29) 1298 66 60 93% 99.90% 50% 15.10% 0.40% 8%

UCSF (10) 321 63 43 98% 100% 24% 38% 26%

DISCUSSION

Canary pass AUBMC (30) 905 43 63 65 28 40 N/A 100% 19% 20.90% 11.60% 4.65%

Archivio Italiano di Urologia e Andrologia 2021; 93, 4

low-up PSA. Out of the prostate MRIs done, 18.6% (8/43) had imaging progression as per the previously stated criteria, 39.5% (17/43) of lesions were stable, and 41.9% (18/43) did not have a follow-up MRI. With regards to the follow-up biopsies, 11.6% (5/43) were upgraded to a higher WHO group, 46.5% (20/43) were either stable or at a lower group, while 41.9% (18/43) of the repeat biopsies were not done (Table 2). A descriptive analysis of the patients that dropped out of active surveillance for intervention was performed. 20.9% (9/43) of patients dropped out. Analysis according to changes in clinical parameters was performed and demonstrated the following: of the 20 patients who progressed by PSA, only 2 patients (10%) dropped out of active surveillance for intervention. Of the 8 patients that progressed on follow-up MRI, 3 patients (37.5%) dropped out for intervention. Of the 3 patients who were upgraded on followup biopsies, 2 patients (66.7%) dropped out for intervention (Figure 1). Two patients elected to drop out and seek intervention due to psychological/patient preference. Of the patients that dropped out of active surveillance, 44.4% (4/9) underwent radical prostatectomy, 44.4% (4/9) underwent radiation therapy plus ADT, and 11.1% (1/9) took ADT alone (Figure 1). Of those who underwent radical prostatectomy, 50% (2/4) were upgraded according to the final pathology, while 50% (2/4) maintained the same grade as the last biopsy result.

4.65%

According to the NCCN 2019 guidelines, inclusion criteria for active surveillance for prostate cancer includes patients with very low/low-risk disease or intermediate risk disease with low volume disease and a outcome with a life expectancy of 10 years and beyond (7, 8). Follow up criteria vary from one institution to another where most opt for a follow-up PSA every 6 months, DRE every 12 months, and biopsy every 1-2 years. Some protocols have incorporated the use of MRI every 12 months or more (NCCN) (9). Our protocol has been consistent with the above recommendations whilst gradually incorporating MRI as a valuable aid in decision making. Serum marker PSA is the frontline parameter that triggers further workup to rule out clinical progression. This was

Active surveillance for prostate cancer

similarly evident in our cohort whereby almost half (46.5%) of our patients had a significant rise in PSA that led to the decision of further investigation that included a rebiopsy +/- MRI. Of those with PSA progression, 10% (2/20) had an upgraded pathology on repeat biopsy. One remained eligible for the AS group, while the other was reclassified from low to intermediate risk group leading to an intervention. It is prudent to follow-up biannually with PSA results; however, it is rarely the sole trigger for intervention. When suspicion arises, further clinical workup is warranted via MRI and biopsy (10, 11). With regards to the initial DRE, all patients were either negative (72.1%) or suspicious to have a T2a lesion on exam (27.9%). Patients with large nodules, bilateral nodules, or involvement of seminal vesicles were excluded from active surveillance (12). Abnormal DREs are associated with an increased risk of detecting high-grade disease (12). Any sign of T3 disease or progression in the clinical stage suggested by a DRE would warrant a further investigation/intervention in patients with AS (13). Nevertheless, none of our patients revealed signs of progression upon DRE. The addition of MRI evaluation proved to be a resourceful tool in clinical decision making for AS patients (14-20). It was similarly essential for our patients. Upon follow-up, 18.6% (8/43) of our patients progressed on MRI, 37.5% (3/8) of those patients that progressed were dropped from AS. One of those (1/3), had a suspicious capsule involvement on MRI leading to direct intervention, whereas the other two (2/3) patients had a rebiopsy that revealed upgrading of disease leading to intervention. From the total number of patients, only 13% of them were not imaged with MRI despite strong recommendation. Imaging for prostate cancer, MRI has been integral for decision making in AS, as it significantly improved detection rates of suspicious lesions. Biopsy without MRI has a misclassification rate of 20-30% (14). In addition, Berglund et al. showed that an immediate confirmatory biopsy for AS patients revealed an upgrade in 27% of cases to Gleason 7 and above (15). As such, an MRI is deemed a crucial addition in the diagnostics of prostate cancer as it can accurately guide targeting of clinically significant lesions in 2/3 of men eligible for active surveillance (16). In addition, MRI has a high negative predictive value 90-100% (17), it also lacks sensitivity to low grade tumors of Gleason 6 (3+3). Therefore, on initial workup a negative MRI may omit the need for biopsy to rule out prostate cancer and may even be an attractive alternative of recurrent biopsies leading to a decreased incidence of diagnosing low grade prostate cancer (18, 19). Yet, the use of MRI for follow-up on AS patients should be subject to better defined radiological parameters (20). Biopsy results belonging to WHO group 1 or 2 is the final determinant of patient inclusion to the AS protocol of our study. On follow-up, any suspicious clinical parameter would warrant a repeat biopsy. Of those, 11.6% (5/43) were upgraded. Of the upgraded biopsies 80% (4/5) lead to an intervention. In addition, biopsy result was the trigger for intervention in 44.4% of patients that dropped out of AS. In a 41.9% (20/43) of follow-up, biopsies at one year were not done. This high percentage can be explained by lack of patient commitment to the AS protocol mainly due to discomfort from undergoing a repeat biopsy as well as false reassurance from the other non-

invasive clinical parameters. To note, none of the patients who underwent radical prostatectomy as the intervention of choice had a high-grade pathology specimen (Gleason 8 or above). Biopsy is indeed the most solid parameter for decision making. According to the PRIAS study, switch to active treatment should be guided by biopsy upgrading and/or clinical T3 disease (13). We compared our results to various North American cohorts studied in different medical centers. Despite our small sample size, our numbers were consistent with their results. Fortunately, our OS and CSS revealed no deceased patients. This could be explained by our relatively short median follow-up time of 40 months and our small sample size. Moreover, our conversion to treatment rate was 20.9% which was comparable to other cohorts (19-50%) (Table 3). Truly one of the biggest and main challenges in Prostate cancer is differentiating low risk pathology from aggressive ones. Gleason pathology is currently the most reliable method. MRI has an emerging role in aiding clinicians and is gaining popularity as new studies are in favor of its diagnostic potential. Biomarkers appear to be promising but await prospective studies to be fully endorsed (1). PCA3 and TMPRSS2:ERG may be able to assess risk of aggressive disease yet fail to reveal an independent predictive value or benefit over PSA (21). 4k score has a significant association with reclassification biopsy; however, it showed no additional benefit over PSA in guiding follow-up biopsies in AS (22). Genomic markers include 3 genetic tissue assays that are currently FDA approved. The DECIFER genomic classifier which consists of 22 genes, gives a score 0-1 and classifies patients into 3 risk groups (23). Genomic Prostate score consists of 17 genes and may potentially aid the initial decision for AS enrollment (24). Cell cycle progression test may similarly aid the decision-making process (25). None have been validated for use in AS; however, they may be incorporated in nomograms especially in deciding on AS for intermediate risk patients (26). Patients with BRCA1/2 mutations are not recommended to undergo active surveillance. When present, these mutations are associated with increased risk of nodal and distant metastasis as well as poor survival outcomes (27). Our AS protocol has some limitations. Despite an agreed upon consensus on the active surveillance protocol, there was an inter patient variability driven by patient compliance or financial/insurance coverage. In addition, treating physicians in our region are still reluctant to initiate active surveillance protocol for various reasons (28). Moreover, a bigger sample size and longer follow-up period would further solidify our findings and improve our understanding of long-term patient outcomes on active surveillance (29, 30).

CONCLUSIONS

In conclusion, active surveillance is a practical and appropriate clinical strategy that should be further employed as part of our patient care arsenal. It is a complex and demanding process for both physician and patient alike as it requires rigorous follow-up with shrewd attention to multiple combined clinical parameters as well as patient commitment and willingness to undergo periodic assessments. PSA is an essential clinical marker for Active Surveillance that may subtly guide decision making. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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MRI is a useful clinical parameter in AS that may obviate need for re-biopsy or even an initial biopsy for prostate cancer. DRE and biopsy are major contributors in halting AS and proceeding towards an intervention especially with evident disease progression either by an upgraded Gleason score or an upstaging upon exam (cT3).

REFERENCES

18. Barentsz JO, Richenberg J, Clements R, et al. ESUR prostate MR guidelines 2012. Eur Radiol. 2012; 22:746-57. 19. Dianat SS, Carter HB, Pienta KJ, et al. Magnetic resonance-invisible versus magnetic resonance-visible prostate cancer in active surveillance: a preliminary report on disease outcomes. Urology. 2015; 85:147-53.

1. Briganti A, Fossati N, Catto JWF, et al. Active surveillance for lowrisk prostate cancer: the European Association of Urology position in 2018. Eur Urol. 2018; 74:357-68.

20. Schoots IG, Petrides N, Giganti F, et al. Magnetic resonance imaging in active surveillance of prostate cancer: a systematic review. Eur Urol. 2015; 67:627-36.

2. Popiolek M, Rider JR, Andren O, et al. Natural history of early, localized prostate cancer: a final report from three decades of follow-up. Eur Urol. 2013; 63:428-35.

21. Lin DW, Newcomb LF, Brown EC, et al. Urinary TMPRSS2:ERG and PCA3 in an active surveillance cohort: results from a baseline analysis in the Canary Prostate Active Surveillance Study. Clin Cancer Res 2013; 19:2442-50.

3. Albertsen PC, Hanley JA, Fine J. 20-year outcomes following conservative management of clinically localized prostate cancer. Jama. 2005; 293:2095-101. 4. Johansson E, Steineck G, Holmberg L, et al. Long-term quality-of-life outcomes after radical prostatectomy or watchful waiting: the Scandinavian Prostate Cancer Group-4 randomised trial. The Lancet Oncology. 2011; 12:891-9. 5. Grossman DC, Curry SJ, Owens DK, et al. Screening for prostate cancer: US preventive services task force recommendation statement. JAMA. 2018; 319:1901-13. 6. Hamdy FC, Donovan JL, Lane JA, et al. 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. New Engl J Med 2016; 375:1415-24.

22. Lin DW, Newcomb LF, Brown MD, et al. Evaluating the four kallikrein panel of the 4Kscore for prediction of high-grade prostate cancer in men in the Canary Prostate Active Surveillance Study. Eur Urol. 2017; 72:448-54. 23. Klein EA, Haddad Z, Yousefi K, et al. Decipher genomic classifier measured on prostate biopsy predicts metastasis risk. Urology. 2016; 90:148-52. 24. Klein EA, Cooperberg MR, Magi-Galluzzi C, et al. A 17-gene assay to predict prostate cancer aggressiveness in the context of Gleason grade heterogeneity, tumor multifocality, and biopsy undersampling. Eur Urol. 2014; 66:550-60.

7. Klotz L. Active surveillance in intermediate-risk prostate cancer. BJU Int. 2020; 125:346-54.

25. Shore ND, Kella N, Moran B, et al. Impact of the cell cycle progression test on physician and patient treatment selection for localized prostate cancer. J Urol. 2016; 195:612-8.

8. Klotz L, Vesprini D, Sethukavalan P, et al. Long-term follow-up of a large active surveillance cohort of patients with prostate cancer. J Clin Oncol. 2015; 33:272-7.

26. Wang SY, Cowan JE, Cary KC, et al. Limited ability of existing nomograms to predict outcomes in men undergoing active surveillance for prostate cancer. BJU Int. 2014; 114:E18-e24.

9. Carroll PR, Parsons JK, Andriole G, et al. NCCN Guidelines insights: prostate cancer early detection, Version 2.2016. JNCCN. 2016; 14:50919.

27. Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013; 31:1748-57.

10. Welty CJ, Cowan JE, Nguyen H, et al. Extended followup and risk factors for disease reclassification in a large active surveillance cohort for localized prostate cancer. J Urol 2015; 193:807-11. 11. Garisto JD, Klotz L. Active surveillance for prostate cancer: how to do it ight. Oncology (Williston Park) 2017; 31:333-40. 12. Gosselaar C, Roobol MJ, Roemeling S, Schroder FH. The role of the digital rectal examination in subsequent screening visits in the European randomized study of screening for prostate cancer (ERSPC), Rotterdam. Eur Urol. 2008; 54:581-8. 13. Bokhorst LP, Lepisto I, Kakehi Y, et al. Complications after prostate biopsies in men on active surveillance and its effects on receiving further biopsies in the Prostate cancer Research International: Active Surveillance (PRIAS) study. BJU Int. 2016; 118:366-71. 14. Ploussard G, Salomon L, Xylinas E, et al. Pathological findings and prostate specific antigen outcomes after radical prostatectomy in men eligible for active surveillance--does the risk of misclassification vary according to biopsy criteria? J Urol. 2010; 183:539-44. 15. Berglund RK, Masterson TA, Vora KC, et al. Pathological upgrading and up staging with immediate repeat biopsy in patients eligible for active surveillance. J Urol 2008; 180:1964-7. 16. De Rooij M, Hamoen EH, Futterer JJ, et al. Accuracy of multiparametric MRI for prostate cancer detection: a meta-analysis. AJR 2014; 202:343-51. 17. Gaziev G, Wadhwa K, Barrett T, et al. Defining the learning curve

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for multiparametric magnetic resonance imaging (MRI) of the prostate using MRI-transrectal ultrasonography (TRUS) fusion-guided transperineal prostate biopsies as a validation tool. BJU Int. 2016; 117:80-6.

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28. El Sebaaly R, Mansour M, Labban M, et al. Survey on the practice of active surveillance for prostate cancer from the Middle East. Prostate Int. 2020; 8:41-8. 29. Tosoian JJ, Mamawala M, Epstein JI, et al. Intermediate and longerterm outcomes from a prospective active-surveillance program for favorable-risk prostate cancer. J Clin Oncol. 2015; 33:3379-85. 30. Newcomb LF, Thompson IM, Jr., Boyer HD, et al. Outcomes of active surveillance for clinically localized prostate cancer in the prospective, Multi-Institutional Canary PASS Cohort. J Urol. 2016; 195:313-20. Correspondence Mohammad Hout, MD - mh21@aub.edu.lb Ali Merhe, MD - am134@aub.edu.lb Nassib Fares Heidar, MD - na192@aub.edu.lb Jose M El-Asmar, MD - je56@aub.edu.lb Wassim Wazzan, MD - ww04@aub.edu.lb Bassel Bachir, MD - bb12@aub.edu.lb Albert El-Hajj, MD - ae67@aub.edu.lb Muhammad Bulbul, MD, Clinical Professor (Corresponding Author) mb30@aub.edu.lb Department of Urology, American University of Beirut Medical Center Riad El-Solh 1107 2020 Beirut, Lebanon Rola Jaafar, MD - rj29@aub.edu.lb Department of Surgery, American University of Beirut Medical Center, Beirut, Lebanon

DOI: 10.4081/aiua.2021.4.389

ORIGINAL PAPER

Summary

Background: In 2018, our Institute launched the Diagnostic Assessment Program (DAP) for prostate cancer. It enabled quick access to a urologist for patients presented to family physician with elevated PSA and allowed fast multidisciplinary patient care. We aim to document our data over 2 years in comparison to data before implementation of DAP and its impact on the degree of adherence to Canadian guidelines. Methods: From April 2016 to April 2020, 880 patients who were evaluated for prostate cancer at Thunder Bay Regional Health Sciences Centre (TBRHSC) were included in this study. Patients’ characteristics, clinical data, waiting times and line of treatment before and after implementation of DAP were calculated and statistically analysed. Results: The median waiting time to urology consultation was significantly reduced from 68 (IQR 27-168) days to 34 (23-44) days (p < 0.001). The time from patient’s referral to prostate biopsy decreased substantially from 34 (20-66) days to 18(1125) days after DAP (p < 0.001). After DAP, the percentage of Gleason 6 detected prostate cancers were significantly increased (19.7% to 30%) (p = 0.02). After DAP, rate for intermediate-risk patients elected for external beam radiotherapy (from 53.5% to 57.9%, p = 0.53) and radical prostatectomy (from 34.5% to 39.4%, p = 0.47) increased. More compliance to Canadian guidelines was observed in intermediate risk patients (88% vs 97.3%, p =.008). Conclusions: Implementation of DAP has led to a notable reduction of waiting time to urology consult and prostate biopsy. There is significant increase in Gleason 6 detected prostate cancer. Increased compliance to Canadian guidelines was detected in intermediate risk patients.

KEY WORDS: Prostate cancer; Diagnostic assessment program; Prostate biopsy. Submitted 21 September 2021; Accepted 17 October 2021

INTRODUCTION

Prostate cancer (PCa) is the second commonly diagnosed malignancy in men worldwide (1). The diversity in treatment options among different risk groups of prostate cancer necessitate cooperation amongst different specialities and substantial patients’ involvement (2). It is important that patients diagnosed with prostate cancer get assessed promptly, preferably in multidisciplinary clinics (MDC) that are composed of radiation oncologists, urologist and

other assisting specialists like medical oncologists, radiologists, and pathologists (3). Analysis of many MDCs versus standard community care consistently showed that MDCs were associated with “changes in staging/diagnosis, initial management plans, higher rates of treatment, shorter time to treatment after diagnosis, better survival, and adherence to clinical guidelines” (4). Patient satisfaction and feeling of well-being was also increased due to the patient feeling well informed in treatment decisions (5). The MDC approach allows multiple specialists contribute to the treatment decisions, which has been shown to remove physician bias toward the modality of treatment provided (4). The enthusiasm for unifying the referral process of prostate cancer was developed due to tendency of urologist and radiation oncologist who received the primary referral to suggest therapy that they offer (6). In 2007, a Diagnostic Assessment Program (DAP) for prostate cancer was developed in North York General Hospital and further was mandated by Cancer care Ontario for lung, colorectal and prostate cancers. The goal act of DAP is to improve timely access to care for prostate cancer patients. Early evidence showed that the DAP reduced wait times from cancer suspicion to radiotherapy by on average 2 months compared to standard community practice (7). In the efforts to reduce waiting time, multiparametric magnetic resonant imaging (mpMRI) is strongly recommended in men candidate for prostate biopsy or in men enrolled in active surveillance protocols (8). In a recent report, the surveyed physician reported less than 4 weeks waiting time to get mpMRI with further acceleration of diagnostic process (9). A DAP has been established in Thunder Bay, Ontario since 2018. It is not clear if data collected from the DAP in Southern Ontario can be extrapolated to a more rural and remote location with a different population, less healthcare resources, and vast geographical coverage. In a recent report on the influence of socioeconomic and geographical factors on prostate cancer diagnosis, only 17% of patients presented with localised prostate cancer live in rural area less than 4000 inhabitants (10). We herein report the results of a retrospective analysis of the referral process before and after the implementation of the DAP, as well as the adherence to the guidelines.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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PATIENT

AND METHODS

Electronic medical records for patients referred with suspected diagnosis of prostate cancer to our institute between 2016 and 2020 were reviewed and enrolled in this retrospective study after obtaining ethical board committee approval. In 2018, Diagnostic Assessment Program (DAP) for prostate cancer was implemented in our institute where any patient referred with elevated PSA and/or suspicious digital rectal exam was briefly evaluated by the DAP coordinator. A structured referral form for each patient was created includin patient demographics, PSA, digital rectal exam, family history of prostate cancer, and other available clinical data. Expediated approach was used for the evaluation of the patients in specialized DAP clinic. All patients were evaluated by a urologist who discussed the management plan. For patients diagnosed with prostate cancer, all clinical data were discussed in our multidisciplinary genitourinary oncology weekly meeting. Finally, these patients get two separate meetings with both the urologist and the radiation oncologist before making a treatment decision (Figure 1). Patient cohort The initial registry included all patients referred with suspected diagnosis of prostate cancer. Patients with prior diagnosis of prostate cancer were excluded from the study. Patients were stratified into 2 groups according to the date of referral. Group I included patient referred to our institute before May 2018 while group II included patient referred after that. Data obtained included patient’s age, referral date, referral reason, PSA level, date of biopsy, tumor stage, Gleason Score (GS), percent core involvement, and treatment deci-

sion. Patients were classified into three risk groups according to the D’Amico criteria (11). For elaborating the effect of DAP implementation, patients’ variables and designated treatment options were compared before and after DAP configuration in the two study groups. Moreover, within each risk group, the chosen treatment was compared with the bench-mark recommendation of the Canadian guidelines. Statistical analysis Categorical variables were presented through numbers and percentages, and compared between groups using Fisher’s exact test. The median and interquartile range (IQR) were calculated and compared using the MannWhitney test. Patients’ data was analysed using SPSS version 26 (IBM Corp., Armonk, NY). Statistical significance was defined as a two-tailed p-value less than 0.05.

RESULTS

Over the four years of the study, a total of 570 patients were included in the study. One hundred sixty-eight patients were investigated for suspicion of prostate cancer before DAP implementation and 402 of them were referred after DAP initiation and allocated to the post DAP group. Thirty-one patients had negative biopsy in the pre-DAP group while 107 patients were negative in the post-DAP group. The median age of patients in the pre-DAP and post-DAP groups was 67 and 71 years, respectively (p = 0.14). The distribution of clinicopathological data per group were presented in Table 1. By comparing the two study groups it was shown that, median waiting time for receiving urology consultation and prostate biopsy were substantially reduced (68 to 34 days and 34 to 18 days respectively, p < 0.001). Additionally, the proportion of patients who had a negative prostatic biopsy increased significantly (p = 0.03). The percentage of Gleason 6 detected prostate adenocarcinoma was increased (19.7% vs 30.5%, p = 0.02) while Gleason 7 detected one were significantly decreased (50% vs 29.6%, p = 0.002). After DAP, rate of intermediaterisk patients elected for external beam radiotherapy (from 53.5% to 57.9%, p = 0.53) and radical prostatectomy (from 34.5% to 39.4%, p = 0.47) increased.

Figure 1. Patient flow through the multidisciplinary genitourinary cancer clinic after DAP.

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Diagnostic assessment program for prostate cancer

Table 1. Comparison of frequency of demographic variables and potential risk factors in each study group. Demographic Age years Median (IQR3-IQR1) Serum PSA level (mg/dL) Median (IQR3-IQR1) Waiting time for urology consultation (days) Median (IQR3-IQR1) Waiting time for prostate biopsy (days) Median (IQR3-IQR1) Number of positive prostate biopsy core Median (IQR3-IQR1) Percentage of cancer involvement Median (IQR3-IQR1) Negative biopsy Gleason 6 Gleason 7 Gleason > 8

Pre-DAP group n = 168

Post-DAP Group n = 402

P-value

67 (69-63)

71 (72-69)

0.14

7.3 (7.6-6.5)

6.9 (7.1-6.4)

0.08

68 (168-27)

34 (44-23)

< 0.001

34 (66-20)

18 (25-11)

< 0.001

4 (6-4)

4 (7-4)

0.23

30 (50-25) 31 (18.4%) 33 (19.7%) 84 (50%) 20 (11.7%)

35 (45-30) 107 (26.6%) 123 (30.5%) 119 (29.6%) 53 (13.2%)

0.27 0.03 0.02 0.001 0.1

Following DAP, 97.3% of intermediate-risk patients received a treatment according to Canadian guidelines 1st line recommendation which was significantly higher than the rate prior to DAP (88% vs 97.3%, p = 0.008) (Figure 2, Table 2). Table 2. Primary treatment for intermediate risk category. Treatment options Active surveillance (n) Radical prostatectomy (n) Radiation therapy (n) Hormonal therapy (n)

Pre-DAP n = 84 6 (7.1%) 29 (34.5%) 45 (53.5%) 4 (4.7%)

Post-DAP n = 119 0 47 (39.5%) 69 (57.9%) 3 (2.5%)

P-value 0.47 0.53 0.7

Figure 2. Distribution of treatment choice for intermediate risk group.

DISCUSSION

A centralised, organised system with a multidisciplinary approach is critical for expediting the delivery of diagnostic cancer assessment services (12). The diagnostic assessment program is an evidence-based approach that originates from published literature, environmental scan

and the opinion of related expertise who reach to a consensus on the standard organized diagnostic assessment services in Ontario (13). One of the critical issues in approaching the prostate cancer cases is the time gap between diagnosis and the provided treatment. According to a prospective Canadian study, the median of waiting time for prostate cancer diagnosis was about 81 days (14). In an Irish prospective study evaluating rapid access diagnostic clinic, the median waiting time from referral date to urology consultation was 13 days (range, 1-37) (15). The Calgary Prostate Institute's rapid access clinic (RAC) reported a median wait time of 21 days from referral by primary care provider to prostate biopsyv (16). In our series, we reported 34 days median waiting time from referral to urology consultation. The differences in the median waiting time in the Irish (15), Calgary Institute (16) and our study may be attributed to the differences in catchment areas and the unique geographical characteristic of Northern Ontario. The area of coverage of Northwestern Ontario goes up to 526.000 Km2, with numerous remote reserves and smaller towns. The changes of Gleason grade detection in relation to changes in referral pathway have been previously studies. Gilliland et al. described Gleason grade migration in response to change in detection method from incidental finding to screening (17). In a comparative study evaluating prostate cancer rapid access diagnostic clinic, O’Kelly et al. reported a downward migration in Gleason grades with significant increase in Gleason 6 detected prostate cancer (51% vs 18%) (18). Guy et al., on the other hand, reported decrease in diagnosing low risk disease and increase in intermediate risk disease after initiation of multidisciplinary diagnostic assessment programme (5). We also identified increase in low-risk prostate cancer. These differences in results may be due to variability in studies design and discrepancies between multidisciplinary approach or diagnostic assessment program. Additionally, we think that the facilitation of the referral process has led to an increase in the number of referrals which might have caused the increase in the number of cases with low-risk prostate cancer. The higher grade prior to DAP can also be attributed to the effect of the US task force recommendation (19, 20). There is a growing interest in literature to link the multidisciplinary approach for prostate cancer management and the degree of care patients received and guidelines adherence. In a study of 630 patients from 3 tertiary care centers, Aizer et. al. reported that patients managed through multidisciplinary approach were opted to active surveillance more than patients managed by a single speciality (64% vs 30%; p < 0.001) (21). The investigators concluded that multidisciplinary approach would lead to more adherence to National Comprehensive Cancer Network (NCCN) guidelines for very low risk prostate cancer and avoidance of unnecessary treatments. In our study, we aimed to look at the intermediate risk group as the options are clearer with fewer variabilities compared to the guideline’s recommendation for the lower or higher risk groups. Another group of investigators noted significant adherence to NCCN guidelines compared to the period before initiation of multidisciplinary clinic in intermediate risk group (89.8% vs. 76%, p = 0.01), while it was not statistically significant in Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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low-risk (100% vs. 99%, p = 0.43) and high-risk patients (100% vs. 95%, p = 0.26) (22). Similarly, our results showed significant adherence to Canadian guidelines in the intermediate risk group (p = 0.008). Our study is not void of limitations. Firstly, the retrospective nature of our study is considered a design limitation. Secondly, all participants in this research were seen in our tertiary care facility, a context that facilitates the implementation of multidisciplinary clinics more easily than community hospitals with geographical restrictions. Lastly, our data analysis is limited to 4 years period and a longer time would warrant more accurate results.

CONCLUSIONS

Implementation of DAP has led to a notable reduction of waiting time to urology consult and prostate biopsy. There is significant increase in Gleason 6 detected prostate cancer. Increased compliance to Canadian guidelines was detected in intermediate risk patients.

REFERENCES

1. D’Agostino D, Corsi P, Colicchia M, et al. The pathological and clinical features of anterior lesions of prostate cancer: evaluation in a single cohort of patients. Arch Ital Urol Androl. 2020; 92:102. 2. Horwich A, Hugosson J, de Reijke T, et al. Prostate cancer: ESMO consensus conference guidelines 2012. Ann Oncol. 2013; 24:1141-62. 3. Valicenti RK, Gomella L, El-Gabry E, et al. The multidisciplinary clinic approach to prostate cancer counseling and treatment. Semin. Urol. Oncol. 2000; 18:188-191. 4. Pillay B, Wootten AC, Crowe H, et al. The impact of multidisciplinary team meetings on patient assessment, management and outcomes in oncology settings: A systematic review of the literature. Cancer Treat Rev. 2016; 42:56-72. 5. Guy D, Ghanem G, Loblaw A, et al. Diagnosis, referral, and primary treatment decisions in newly diagnosed prostate cancer patients in a multidisciplinary diagnostic assessment program. Can Urol Assoc J. 2016; 10:120. 6. Keyes M, Crook J, Morris WJ, et al. Canadian prostate brachytherapy in 2012. Can Urol Assoc J. 2013; 7:51-8. 7. Sethukavalan P, Zhang L, Jethava V, et al. Improved wait time intervals for prostate cancer patients in a multi-disciplinary rapid diagnostic unit compared to a community-based referral pattern. Can Urol Assoc J. 2013; 7:244. 8. Pepe P, Candiano G, Pepe L, et al. mpMRI PI-RADS score 3 lesions diagnosed by reference vs affiliated radiological centers: Our experience in 950 cases. Arch Ital Urol Androl. 2021; 93:139-142. 9. Stanzione A, Creta M, Imbriaco M, et al. Attitudes and perceptions towards multiparametric magnetic resonance imaging of the prostate: A national survey among Italian urologists. Arch Ital Urol Androl. 2020; 9:291. 10. Pereira-Lourenço M, Vieira E Brito D, Peralta JP, et al. Influence of sociodemographic factors on treatment's choice for localized prostate cancer in Portugal. Arch Ital Urol Androl. 2020; 92:45-49. 11. D'Amico AV, Whittington R, Schultz D, et al. Outcome based staging for clinically localized adenocarcinoma of the prostate. J Urol. 1997; 158:1422-1426. 12. Brouwers M, Crawford J, Elison P, et al. Organizational standards for diagnostic assessment programs. Toronto (ON): Cancer

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Care Ontario; 2007 Jun 15 (In review 2011 Sep). Program in Evidence-based Care Evidence-based Series Organizational Standards for DAP IN REVIEW 13. Brouwers M, Oliver TK, Crawford J, et al. Cancer diagnostic assessment programs: standards for the organization of care in Ontario. Curr Oncol. 2009; 16:29-41. 14. Grunfeld E, Watters JM, Urquhart R, et al. A prospective study of peri-diagnostic and surgical wait times for patients with presumptive colorectal, lung, or prostate cancer. Br J Cancer. 2009; 100:56-62. 15. Forde JC, O'Connor KM, Casey L, et al. A rapid access diagnostic clinic for prostate cancer: the experience after one year. Ir J Med Sci. 2011; 180:505-8. 16. Kavanagh AG, Lee JC, Donnelly B. Time to treatment of prostate cancer through the Calgary Prostate Institute rapid access clinic. Can J Urol. 2008; 15:3975-3979. 17. Gilliland FD, Gleason DF, Hunt WC, et al. Trends in Gleason score for prostate cancer diagnosed between 1983 and 1993. J Urol. 2001; 165:846-850. 18. O'Kelly F, Thomas AZ, Murray D, et al. Emerging evidence for Gleason grade migration and distance impact in prostate cancer? An analysis of the rapid access prostate clinic in a tertiary referral center: St. Vincent's University Hospital, Dublin (2009-2011). Ir J Med Sci. 2013; 182:487-91. 19. Moyer VA,US Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Int Med. 2012; 157:120-134. 20. Butler SS, Muralidhar V, Zhao SG, et al. Prostate cancer incidence across stage, NCCN risk groups, and age before and after USPSTF Grade D recommendations against prostate-specific antigen screening in 2012. Cancer. 2020; 126:717-724. 21. Aizer AA, Paly JJ, Zietman AL, et al. Models of care and NCCN guideline adherence in very-low-risk prostate cancer. J Natl Compr Canc Netw 2013; 11:1364-72. 22. Korman H, Lanni TJr, Shah C, et al. Impact of a prostate multidisciplinary clinic program on patient treatment decisions and on adherence to NCCN guidelines: the William Beaumont Hospital experience. Am J Clin Oncol. 2013; 36:121-125. Correspondence Walid Shabana, MD (Corresponding Author) waleed.shabana@gmail.com Ahmed Kotb, MD kotba@tbh.net Daniel Tesolin, MD dtesoln@nosm.ca Mohammed Ibrahim, MD ibrahimm@tbh.net Kristi Dolcetti, MD dolcetk@tbh.net Amy Boucher, MD bouchra@tbh.net Mohammed Bassuony, MD Bassunm@tbh.net Kevin Ramchandar, MD ramchnk@tbh.net Ahmed Zakaria, MD aszakari81@yahoo.com Hazem Elmansy, MD elmancyh@tbh.net Walid Shahrour, MD walid.shahrou@gmail.com Urology Department, Northern Ontario School of medicine, 146 Court Street South, Thunder Bay, ON P7B 2X6, Canada

DOI: 10.4081/aiua.2021.4.393

ORIGINAL PAPER

Novel hormonal agents for metastatic Castration-Resistant Prostate Cancer: comparing outcomes. A single-center retrospective study Roberto Saldanha Jarimba 1, Miguel Nobre Eliseu 1, João Pedroso Lima 1, Vasco Quaresma 1, Pedro Moreira 1, Pedro Coelho Nunes 1, 2, Edgar Tavares da Silva 1, 2, Arnaldo José Figueiredo 1, 2 1 Urology 2 Faculty

and Renal Transplantation Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; of Medicine, University of Coimbra, Portugal.

Summary

Introduction: Prostate cancer is the most common cancer in men, accounting for 15% of all diagnosed cancers and is the sixth leading cause of cancerrelated deaths amongst men worldwide. Abiraterone and enzalutamide were the first two novel hormonal agents approved for the treatment of metastatic prostate cancer but there is a lack of quality evidence regarding which is associated with better outcomes and who would benefit the most with one or another of these drugs. Objective: To evaluate the clinical outcomes of real-world patients submitted to treatment with novel hormonal agents, enzalutamide and abiraterone, for castration resistant metastatic prostate cancer in an academic center. Patients and methods: We retrospectively reviewed patients treated for castration-resistant prostate cancer with either abiraterone or enzulatamide between January 1, 2016 and December 31, 2019. The primary endpoints were biochemical response, biochemical progression, radiological progression, clinical deterioration (attributed to disease progression) and death. Results: Enzalutamide had a higher biochemical response rate than abiraterone in patients with mCRPC (77.1% vs 58.1%, p = 0.016). Achieving a biochemical response was associated with a lower risk of biochemical progression (OR: 0.248, p = 0.017) and death (OR: 0.302, p = 0.038). Conclusions: Enzalutamide conferred higher biochemical response rate than abiraterone in patients with mCRPC. Despite the trend to better performance of other endpoints in the enzalutamide group, it did not achieve statistical significance. Well-designed prospective studies are needed to elucidate the comparative efficacies of these agents.

KEY WORDS: Prostate cancer; Abiraterone; Enzalutamide; Castration-resistant. Submitted 7 June 2021; Accepted 15 August 2021

INTRODUCTION

Prostate cancer is the most common cancer in men, accounting for 15% of all diagnosed cancers and being the sixth leading cause of cancer-related deaths amongst men worldwide. Metastatic prostatic cancer can be roughly divided in two main clinical stages: hormone-sensitive and castrationresistant prostate cancer.

Since 1941, when Charles Huggins and colleagues uncovered the hormonal dependence of metastatic prostate cancer, androgen deprivation therapy has been the therapeutical mainstay for metastatic prostate cancer. After decades of absent novelties, we assisted to the introduction of novel hormonal agents for the treatment of castration-resistant metastatic prostate cancer. Abiraterone and enzalutamide were the first two novel hormonal agents approved for the treatment of metastatic prostate cancer and are now widely used. Abiraterone is an inhibitor of CYP17A1, an enzyme essential in the process of androgen synthesis. Enzalutamide competitively inhibits androgen binding to the androgen receptor (AR), nuclear translocation of the AR, DNA binding and coactivator recruitment. Both abiraterone and enzalutamide are first line treatments for metastatic castrationresistant prostate cancer (mCRPC), but there is a lack of quality evidence regarding which is associated with better outcomes and who would benefit the most with one or another of these drugs. Our propose was to evaluate the clinical outcomes of patients submitted to either abiraterone or enzalutamide for castration-resistant metastatic prostate cancer in our center.

PATIENTS

AND METHODS

Patients eligible for this study had a diagnosis of metastatic castration-resistant prostate cancer defined as castrate serum testosterone < 50 ng/mL and biochemical progression (three consecutives rises in prostatic specific antigen (PSA) at least one week apart resulting in two 50% increases over the nadir, and a PSA > 2 ng/mL) or radiological progression (appearance of new lesions: either two or more new bone lesions or a soft lesion using Response Evaluation Criteria in Solid Tumours (RECIST)) and initiated treatment with either abiraterone or enzalutamide between January 1, 2016 and December 31, 2019. Follow-up extended from January 1, 2016 until December 31, 2020. In 2019, we treated 358 patients diagnosed with prostate cancer, representing roughly 5.5% cases nationwide. Individual clinical cases were discussed in bi-weekly oncourology meetings. Patients with clinical criteria of poor prognosis (symptoms, short period of response under

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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androgen deprivation therapy (ADT), high metastatic burden, visceral metastasis or poor prognostic genetic mutations) were treated with taxane-based chemotherapy. The decision to begin treatment with a novel hormonal agent was taken either as first line therapy in patients with less aggressive features (asymptomatic, durable response under previous ADT, low metastatic burden and no visceral metastases) or as second line therapy in patients that progressed under first line therapy with taxane-based chemoterapy. In the absence of contraindication for either pharmaceutical drugs, patients were sequentially assigned to either enzalutamide or abiraterone group. The database used was anonymized and unstructured. Data were originally extracted from electronic medical records. Demographic and clinicopathological features (International Society of Urological Pathology (ISUP) score, M1 ab inition or progression after local treatment status, previous period of classical androgen deprivation therapy, PSA level, previous treatment of taxane-based chemotherapy and localization of metastasis) were registered at baseline. Data reported adverse events (AEs) was also available. Per local protocol, stable patients with metastatic prostate cancer under novel hormonal agents are followed with clinical and analytical evaluation including PSA measurement every 3 months by a staff expert. Occurrence of biochemical response (defined as a reduction of ≥ 50% of pretreatment PSA level after 12 weeks of treatment), PSA progression (three consecutives rises in PSA at least one week apart resulting in two 50% increases over the nadir, and a PSA > 2 ng/mL), radiological progression (appearance of new lesions: either two or more new bone lesions or a soft lesion using RECIST) diagnosed either by computed tomography (CT) scan, bone scintigraphy or G68 prostate-specific membrane antigen (PSMA) - positron emission tomography (PET), clinical deterioration and/or death and the time of their occurrence were available. The primary endpoints of this study were biochemical response, biochemical progression, radiological progression, clinical deterioration (attributed to disease progression) and death. Safety was a secondary endpoint. Follow-up was stopped when the drug was suspended due to adverse reactions or disease progression. There was no crossover. Statistical analysis Descriptive statistics of patient and pathological characteristic were calculated for all patients included in the present study, as well as by administered agent. We used a chi-square univariate analysis to assess the statistical significance of the difference between rate response in the abiraterone and enzalutamide group. Further, we used a binary logistic regression, adjusted to clinicopathological features, to quantify this association. A Cox-regression was performed to uncover predictive co-variates of biochemical progression, radiological progression and overall survival. A survival analysis using a Kaplan-Meier method was used to evaluate the risk of biochemical progression, radiological progression and overall survival and a log-rank test applied to test for significant differences. All analyses were conducted using IBM SPSS statistics

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version 23. All comparisons were made using 2-sided tests, with p < 0.05 considered statistically significant.

RESULTS

A total of 91 patients who initiated a novel hormonal agent, either abiraterone or enzalutamide, between January 2016 and December 2019 were included in the study. 56 (61.5%) patients were treated with abiraterone and the remaining 35 (38.5%) with enzalutamide. 45 (49.5%) patients were diagnosed with metastatic prostate cancer ab inition. 74.7%, 53.8% and 6.6% had bone, lymphatic, and visceral metastasis, respectively. Almost 30% of patients had been previously submitted to taxane-based chemotherapy. Mean age of the cohort was 74.4 (± 8.26) years, while the mean pretreatment PSA level was 231.51 (± 380.15) ng/mL and previous classical androgen deprivation therapy duration was 74.13 (± 54.87) months. Median follow-up time was 18.34 months. All covariates, as age, pretreatment PSA level, ISUP score, M1 ab inition or progression after local treatment status, previous period of classical androgen deprivation therapy, previous treatment of taxane-based chemotherapy and localization of metastasis were similar between the groups. Baseline demographic and clinicopathological features are shown in Table 1. Biochemical response Overall, rate of biochemical response was 61.5% in mCRPC patients. It was found to be significantly higher in the enzalutamide group than in the abiraterone group, with a rate response of 77.1% and 58.1%, respectively (p = 0.016). In binary logistic regression adjusted to clinicopathological features, enzalutamide was associated with a higher proba-

Table 1. Baseline demographic and clinicopathological characteristics by drug of mCRPC patients. Demographic and pathological features Total Abiraterone Enzalutamide (n = 91) (n = 56) (n = 35) Age (years) 74.44 ± 8.26 75.00 ± 7.01 73.54 ± 9.980 Pretreatment PSA level (ng/ml) 231.51 ± 380.16 215.40 ± 372.82 257.94 ± 401.65 Previous ADT (months) 74.13 ± 54.87 77.53 ± 61.66 68.82 ± 42.50 Follow-up (months) 18.34 ± 9.81 17.16 ± 8.71 20.68 ± 11.20 ISUP 1 9 (10%) 4 (7.3%) 5 (14.3%) 2 18 (20%) 13 (23.6%) 5 (14.3%) 3 25 (27.8%) 16 (29.1%) 9 (25.7%) ≥4 19 (21.1%) 12 (21.8%) 7 (20%) N/A 19 (21.1%) 10 (18.2%) 9 (25.7%) Status M1 ab inition 45 (50.6%) 28 (50.9%) 17 (50%) Post local treatment 44 (49.4%) 27 (49.1%) 17 (50%) Metastasis Bone 68 (74.7%) 39 (69.6%) 29 (82.9%) Ganglionar 49 (53.8%) 30 (53.6%) 19 (54.3%) Visceral 6 (6.2%) 4 (6.5%) 2 (5.7%) Post docetaxel 27 (29.7%) 15 (26.8%) 12 (34.3%) ADT: androgen deprivation therapy; PSA: prostate-specific antigen; N/A: not admitted.

P 0.416 0.717 0.882 0.276 0.612

0.934

0.158 0.947 0.788 0.446

Novel hormonal agents for metastatic castration-resistant prostate cancer: Comparing outcomes

Figure 1. Biochemical progression based on administered drug.

Figure 2. Radiological progression based on administered drug.

bility of biochemical response (OR: 3.485, p = 0.021). Biochemical response was associated with lower probability of biochemical progression (OR: 0.248, p = 0.017) and death (OR: 0.302, p = 0.038), adjusted to clinicopathological features. Subgroup analyses showed no statistically significant difference between biochemical responses in the docetaxelnaïve patients between abiraterone and enzalutamide (56.1% vs 73.9%, p = 0.158), but enzalutamide had a higher response rate than abiraterone in patients previously submitted to docetaxel (83.3% vs 40%, p = 0.019). In the subgroup of patients with metastatic prostate cancer ab inition, that progressed to mCRPC and were docetaxel-naïve, the period of previous classical hormonal

therapy was inversely associated with biochemical response (OR: 0.928, p = 0.035). Biochemical progression mCRPC patients submitted to treatment with enzalutamide and abiraterone had a biochemical progressionfree survival (bPFS) of 19.2 and 30.2 months, respectively. The difference failed to achieve statistical significance (p = 0.284). The Kaplan-Meier curves for bPFS are showed in the Figure 1. In patients who achieved a biochemical response, the bPFS was similar in both enzalutamide group and abiraterone group (24.0 vs 24.3 months, p = 0.651). No covariate factor was identified as predictor of bPFS in multivariate analysis. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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Figure 3. Overall survival based on administered drug.

Radiological progression Overall, in the mCRPC group the rPFS in patients submitted to enzalutamide was 41.2 months vs 28.57 months in the abiraterone group, but with no statistical significance (p = 0.363). The Kaplan-Meier curves for rPFS are showed in the Figure 2. Among biochemical responders, patients submitted to abiraterone had a rPFS of 32.2 months and patients treated with enzalutamide had a rPFS of 29.34 months. No statistically significant differences was achieved (p = 0.791). No covariate factor was identified as predictor of rPFS in multivariate analysis. Overall survival All cause time-to-death, in mCRPC patients, was 37.5 months in enzalutamide group and 26 months in abiraterone group, without achieving a statistically significant difference (p = 0.277). The Kaplan-Meier curves for overall survival (OS) are showed in the Figure 3. In patients in whom biochemical response was achieved, the abiraterone group had a OS of 31.27 months vs 27.30 months in the enzalutamide group, but without statistically significant difference (p = 0.994). In patients that failed to meet biochemical response criteria, OS was 31.15 months and 17.58 months in enzalutamide and abiraterone group, respectively. A statistically significant difference was not achieved (31.18 vs 17.58, p = 0.121). No covariate factor was identified as predictor of OS in multivariate analysis. AEs associated with treatment with abiraterone or enzalutamide Overall, 14 patients (14.4%) experienced drug-related adverse events (AEs), 10 (16.1%) in abiraterone group and 4 (11.4%) in enzalutamide group. The common AEs that occurred in this series were as follows: fatigue (60%) and diarrhea (20%) in abiraterone group and fatigue (100%) in enzalutamide group. Only 2 AEs ≥ grade 3 were registered, 1 in each group, causing the suspension of the drug.

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DISCUSSION

Novel hormonal agents are now a cornerstone in the treatment of castration-resistant prostate cancer. Both enzalutamide and abiraterone with prednisolone are approved therapies for men with mCRPC. These two drugs have shown clinical efficacy in multicenter phase III RCTs (1-4), yet there is a lack of evidence regarding comparative outcomes of men submitted to treatment with either of the two drugs. Findings from previous retrospective studies suggest survival advantages toward enzalutamide compared with abiraterone and prednisolone in the treatment of men with mCRPC (5), although both drugs were effective, with PSA rate response over 50%. Our analysis is consistent with prior data for better biochemical response with enzalutamide in men with mCRPC. We found that patients in the enzalutamide group had a significantly higher biochemical response than the abiraterone group, with a rate response of 51.8% and 77.1%, respectively (p = 0.016). This seems particularly relevant in patients previously submitted to taxane-based chemotherapy. In a multivariate analysis, enzalutamide was associated with a higher probability of rate response compared with abiraterone (OR: 3.485, p = 0.021). Biochemical response was associated with a lower probability of biochemical progression (OR: 0.248, p = 0.017) and death (OR: 0.302, p = 0.038). This data suggests that the higher rate of biochemical response of enzalutamide is associated with better outcomes. Respective to other endpoints (biochemical progression, radiological progression, and overall survival), there was a trend toward advantage of enzalutamide over abiraterone with no statistical significance. Data showed that in patients who achieved biochemical response, the apparent advantage of enzalutamide over abiraterone disappears. Patients who did not achieve a biochemical response had a trend to longer survival when treated to enzalutamide vs abiraterone, albeit not statistically different. As suggested in previous studies (6, 7), this may support an early change of therapeutical strategy when biochemical response is not achieved with abiraterone.

Novel hormonal agents for metastatic castration-resistant prostate cancer: Comparing outcomes

Miyake et al., retrospectively reviewed 280 docetaxelnaïve mCRPC patients. A higher PSA response rate for patients treated with enzalutamide when compared with abiraterone (70.7% vs 53.1%) was found, in line with our results. On the other hand, a better bPFS in enzalutamide group was also found, which our study failed to find. In this study, because of the drug choice was at physician discretion, there was a preference of abiraterone over enzalutamide in patients with less favorable clinicopathological features based in the results of COU-AA-302 and PREVAIL trials, respectively (8). Heo et al. performed a retrospective study that evaluated the outcomes of patients diagnosed with mCRPC treated with abiraterone and enzalutamide in post-docetaxel setting. 54 patients were evaluated (25 in abiraterone group and 29 in enzalutamide group) and a PSA rate response was seen 36% and 52% for abiraterone and enzalutamide, respectively. In our cohort the PSA rate response was similar for abiraterone (40%), but enzalutamide had a higher response rate than reported in this study (83.3%) in this subset of patients (9). Both drugs were well tolerated, with low incidence of drug-related grade ≥ 3 events. Only two patients had their treatment suspended. The type of AEs registered were in line with ones reported in COU-AA-302 and PREVAIL trials. Norris et al. retrospectively studied 198 mCRPC patients submitted to treatment with abiraterone and enzalutamide. Significantly higher PSA response rates were observed in the enzalutamide (51%) than abiraterone (36%). In our cohort the overall PSA response rate were higher, 51.8% and 77.1% in abiraterone and enzalutamide, respectively. There was no significant difference in OS between the groups with median OS of 15.3 months in abiraterone group versus 22.2 months in the enzalutamide group. The OS survival in our study was also higher for enzalutamide (37.5 months for enzalutamide and 27.30 months for abiraterone). These differences can be partially explained by the proportion of patients that were treated in post-docetaxel setting in each study, being the majority of patients in Norris et al. cohort and only 30% in ours. As seen in our cohort, higher PSA response rates were seen in the pre-docetaxel group compared to the post-docetaxel (10). Garcia et al. performed a retrospective observational study reviewing 48 patients with mCRPC (26 in abiraterone group and 22 in enzalutamide). Most patients had been submitted to docetaxel. The primary endpoint was biochemical response. Unlike our study, no statistically difference in biochemical response between abiraterone and enzalutamide was observed (53.85% and 58.85% for abiraterone and enzalutamide groups, respectively). A low number of patients treated can impair the statistical power of this study (11). Khalaf et al. retrospectively analyzed 210 patients (106 in abiraterone and 104 in enzalutamide groups), older than 80 years who received novel hormonal agents for firstline treatment of mCRPC. As in our cohort, the biochemical response was higher in patients treated with enzalutamide than abiraterone (77.9% vs 43.4%) but no OS advantage was observed. In our study the PSA response rates of docetaxel-naïve patients were similar with the

ones reported in this study (56.1% and 73.9% for abiraterone and enzalutamide, respectively) (12). Our study has some strengths: similar groups regarding clinicopathological characteristics and a relatively uniform distribution between abiraterone and enzalutamide groups (61.5% vs 38.5%). A 1:1 proportion between abiraterone and enzalutamide was not achieved due to the numerous contraindications to enzalutamide. The approval of abiraterone for treatment of mCRPC was conceded before enzalutamide by national regulatory agency, contributing to the discrepancy in the number of patients in each group. Some limitations of this study must however be noted. As a real-life study, the results can be biased by not randomized allocation of patients to different treatments. Adverse events were not systematically evaluated due to retrospective nature of this study, making security performance assessment inaccurate. The threshold and image modality (either CT and bone scintigraphy or Ga68 PETPSMA) used for staging patients in the scenario of biochemical progression was not specified, introducing some bias in radiological progression assessment. Mean followup period was relatively short. Based on our results, enzalutamide conferred higher biochemical response rate than abiraterone in patients with mCRPC. Achieving a biochemical response was associated with a lower risk of biochemical progression and death. Other endpoints tended to improve in the enzalutamide group although not significantly. Well designed prospective studies are needed to elucidate the comparative efficacies of these agents.

REFERENCES

1. Fizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012; 13:983-92. 2. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014; 371:424-33. 3. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012; 367:1187-97. 4. Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015; 16:152-60. 5. Wang X, Yang H, Hu X, et al. Comparing the clinical efficacy and safety of abiraterone and enzalutamide in metastatic castrationresistant prostate cancer: A systematic review and meta-analysis. J Oncol Pharm Pract. 2021; 27:614-622. 6. Khalaf DJ, Annala M, Taavitsainen S, et al. Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial. Lancet Oncol. 2019; 20:1730-9. 7. Hung SC, Wang SS, Li JR, et al. Outcome of Patients with Metastatic Castration-resistant Prostate Cancer After PSA Progression with Abiraterone Acetate. Anticancer Res. 2018; 38:5429-36. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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8. Miyake H, Hara T, Terakawa T, et al. Comparative assessment of clinical outcomes between abiraterone acetate and enzalutamide in patients with docetaxel-naive metastatic castration-resistant prostate cancer: experience in real-world clinical practice in Japan. Clin Genitourin Cancer. 2017; 15:313-9. 9. Heo MH, Park SH, Kim HK, et al. Overall survival beyond firstline docetaxel in patients with metastatic castrate-resistant prostate cancer treated with abiraterone acetate or enzalutamide. J Clin Oncol. 2017; 35(6_suppl):e570-e570. 10. Norris T, Walter S, Williams A, et al. Comparison of Toxicity and Efficacy Outcomes of Abiraterone and Enzalutamide in 198

Correspondence Roberto Saldanha Jarimba robertojarimba@chuc.min-saude.pt Serviço de Urologia, Centro Hospitalar e Universitário de Coimbra Rua Professor Mota Pinto 3004-561, Coimbra (Portugal) Miguel Nobre Eliseu, MD João Pedroso Lima, MD Vasco Quaresma, MD Pedro Moreira, MD Urology and Renal Transplantation Department, Centro Hospitalar e Universitário de Coimbra, Coimbra (Portugal) Pedro Coelho Nunes, MD Edgar Tavares da Silva, MD Arnaldo José Figueiredo, MD Urology and Renal Transplantation Department, Centro Hospitalar e Universitário de Coimbra & Faculty of Medicine, University of Coimbra, Coimbra (Portugal)

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Patients with Metastatic Castrate Resistant Prostate Cancer. Clin Oncol. 2017; 29:e87-8. 11. García AS, Mateos AA, Esquerdo ML, et al. 4CPS-128 Effectiveness of abiraterone acetate and enzalutamide in metastatic castration-resistant prostate cancer. Eur J Hosp Pharm. 2018; 25(Suppl 1):A101-A101. 12. Khalaf D, Zou K, Struss WJ, et al. Efficacy and tolerability of first-line abiraterone + prednisone (ABI) versus enzalutamide (ENZ) for metastatic castration-resistant prostate cancer (mCRPC) in men ≥ 80 years: A retrospective cohort study. J Clin Oncol. 2018; 36(15_suppl):5051-5051.

DOI: 10.4081/aiua.2021.4.399

ORIGINAL PAPER

Does transition from standard to Retzius-sparing technique in robot-assisted radical prostatectomy affect the functional and oncological outcomes? Hakan Anıl 1, Kaan Karamık 2, Ali Yıldız 3, Murat Savaş 4 1 Department

of Urology, Adana Seyhan State Hospital, Adana, Turkey; of Urology, Antalya Korkuteli State Hospital, Antalya, Turkey; 3 Department of Urology, Okan University Hospital, Faculty of Medicine, Istanbul, Turkey; 4 Department of Urology, Antalya Memorial Hospital, Antalya, Turkey. 2 Department

Summary

Objective: To appraise the outcomes on the Retzius-sparing robot-assisted radical prostatectomy (Rs-RARP) learning curve of a surgeon with previous experience of anterior (standard) RARP. Materials and methods: The first 50 cases during the Rs-RARP learning curve (group 1) and 50 cases after the second 100 cases with the standard approach (group 2) were comprised in the study. Patients who used zero or one safety pads were considered continent. Erectile function recuperation was characterized as the competence to achieve penetrative intercourse without receiving any medication. All patients were reevaluated at two weeks, first, third, sixth, and 12th months after surgery using IIEF-5, PSA level, and continence status. Results: Immediate continence rates following catheter removal were 32/50 (64%) in Rs-RARP group and 26/50 (52%) in S-RARP group (p = 0.224). The continence recovery rate was 48/50 (96%) in Rs-RARP group and 46/50 (92%) in the S-RARP group at 12 months follow-up (p = 0.400). Total nerve-sparing surgery was enforced in 36/50 (72%) patients for group 1 and 35/50 (70%) patients for group 2. Potency recovery was 27/43 (62.8%) in Rs-RARP and 30/44 (68.2%) for S-RARP at 12 months follow up (p = 0.597). Surgical margin positivity was detected in 6/50 (12%) cases in the Rs-RARP group and in 4/50 (8%) cases in the S-RARP (p = 0.444). Conclusions: Functional and oncological results are not negatively affected in the first 50 cases for a surgeon who is experienced in S-RARP before transition to the Rs-RARP method.

KEY WORDS: Learning curve; Radical prostatectomy; Retziussparing; Robotic surgery; Trifecta. Submitted 28 August 2021; Accepted 19 September 2021

INTRODUCTION

Prostate cancer is the most frequently diagnosed type of cancer among men and is the second most common cause of cancer-related death in men (1). Radical prostatectomy is the most commonly offered treatment modality in eligible patient groups (2). Robot-assisted radical prostatectomy (RARP) has become popular in the last two decades. The method most widely adopted by urologists is standard-RARP with an anterior approach (3). The main issue after RARP is preserving continence and erectile function, in addition to oncologic safety. Many

techniques were reported to improve continence (4-6). Recently, a new method is the Retzius-sparing (Rs) RARP applied with the posterior approach, defined by Galfano et al. (7). The basic principle of this approach is to prevent interference with anatomical structures that provide continence in the anterior region. In this context, many surgeons may consider revising their method. Additionally, it is controversial for a surgeon who has completed the learning curve with the standard approach to change their technique using the Rs-RARP approach with regard to functional and oncological results. In this study aimed to appraise the functional and oncological outcomes during the Rs-RARP learning curve for a surgeon with previous experience of the S-RARP procedure.

MATERIALS

AND METHODS

Patient selection and study design After the local institutional review board approval, the RsRARP and S-RARP surgeries applied by a single surgeon with experience in robotic surgery between 01.01.2017 and 01.01.2019 were retrospectively evaluated from a prospectively-collected database. The first 50 cases during the Rs-RARP learning curve and 50 cases after the second 100 cases with the standard approach were enrolled in the study. Surgeon participated in live surgeries before performing Rs-RARP. In addition, in the first 10 cases, patients with low-to-moderate volume prostates (≤ 60cc) without a median lobe were preferred. Patients with previous prostate and abdominal surgery, incontinence, and presence of lymph node metastasis were excluded from the study. Fifty patients who met the inclusion criteria and underwent Rs-RARP were considered group 1, and 50 patients who underwent S-RARP were group 2. Evaluated variables Preoperative evaluation included age, Charlson Comorbidity Index score (CCI), prostate-specific antigen (PSA), International Index of Erectile Function-5 (IIEF-5) score, Gleason score at biopsy, clinical T stage, prostate volume, and D’Amico risk group. Furthermore, perioperative variables and pathologi-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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cal features were noted: operative time, anastomosis duration, nerve-sparing status, intraoperative complications, estimated blood loss, presence of lymph node dissection, length of hospital stay, Foley catheter removal time, lymph node positiveness, surgical margin status, and pathological stage. Patients were followed for at 12 months for continence and potency recovery. Immediate continence evaluation was performed within 1 week after catheter removal. Patients who used zero or one safety pads were considered continent. Erectile function recovery was evaluated in the first month, initially. Erectile function recuperation was characterized as the competence to achieve penetrative intercourse without the use of any medication. All patients were reevaluated at two weeks, first, third, sixth, and 12th month after surgery using IIEF5, PSA level, and continence status. Surgical technique All robot-assisted radical prostatectomies were implemented by a single surgeon (M.S) who routinely performed over 100 RARPs per year. Our surgical principles were close to that defined by Galfano et al. (7). After the placement of 4 robot trocars and 1 assistant trocar, a 4 arms Da Vinci robot system (Intuitive surgical, LA, USA) was docked. The parietal peritoneum was incised horizontally at the anterior layer of the Douglas pouch. Seminal vesicle pedicles were identified and ligated by using Hem-o-Lok clips. Also, vas deferens were identified and incised. The avascular zone was found by entering among the Denonvillier’s fascia and the posterior prostatic fascia. The intrafascial plan was maintained and the prostate apex was reached with dissection. The bladder neck was identified and incised. At this step, we don't use cardinal stitches to identify the bladder neck, unlike Galfano and colleagues (7). The anterior surface of the prostate was separated from the Santorini plexus. Apex separation was achieved and the urethra identified and cutted. The prostate was placed in the endobag. The urethrabladder anastomosis was performed continuously with 3.0 v-lock sutures from the 12-o’clock position. Statistical analysis Variables were presented as mean±standard deviation, median and interquartile range (25th-75th, IQR), frequency, and percentage. Evaluation of categorical data was done with the chi-square or Fisher’s exact test. The conformity of the data to the normal distribution was checked with the Shapiro-wilk test. Student’s t-test or Mann-Whitney U test was used for continuous variables according to the distribution. The Kaplan Meier analysis was applied to determine erectile and continence recovery. A two-way repeated-measures ANOVA was used to compare preoperative and postoperative IIEF scores between surgical approaches. Statistical analysis was conducted with IBM SPSS Statistics for Windows, version 22.0 (IBM Corp., Armonk, NY). A p-value < 0.05 was considered as statistically significant.

RESULTS

Group 1 and group 2 comprised 50 patients with a median age of 63.5 (IQR 58-68.5) years, and 50 patients with a median age of 66 (IQR, 62-68.5) years, respectively.

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Table 1. Demoghraphics and preoperative features. Variable Median (IQR) age, years Median (IQR) CCI score Median (IQR) BMI, kg/m2 Median (IQR) PSA, ng/ml Gleason score at biopsy n (%) ≤6 7 8-10 Clinical T stage n (%) T1a-c T2a-b T2c Mean (± SD) prostate volume, mL D’Amico risk classification n (%) Low Intermediate High

Rs-RARP 63.5 (58-68.5) 2 (1-3) 27.2 (24.3-28.7) 9.7 (7.8-11.2)

S-RARP 66 (62-68.5) 2 (1-3) 28 (25-29.7) 8.0 (5-13.4)

31 (62) 13 (26) 6 (12)

32 (64) 14 (28) 4 (8)

33 (66) 15 (30) 2 (4) 60.1 ± 24.2

29 (58) 19 (38) 2 (4) 58.8 ± 22.6

23 (46) 15 (30) 12 (24)

28 (56) 14 (28) 8 (16)

P value 0.151 ͳ 0.531 ͳ 0.223 ͳ 0.183 ͳ 0.797 ӿ

0.695 ӿ

0.782 ¥ 0.516 ӿ

SD: standart deviation; IQR: interquartile range; CCI: Charlson Comorbidity Index; BMI: body mass index; PSA: prostate-specific antigen. ͳ: Mann- Whitney U test. ¥: Student’s t-test. ӿ: Chi-sqaure test Data are presented as mean (± SD) or median (IQR) and frequency (percantage).

There were statistically insignificant differences among the groups regarding preoperative demographics and clinical characteristics (Table 1). The median operative time was 162.5 (IQR 137.5-210) mins and 150 (IQR 125-220) mins for groups 1 and 2, respectively (p = 0.865). Bilateral nerve-sparing surgery was performed in 36/50 (72%) and 35/50 (70%) patients for group 1 and group 2, respectively. Intraoperatively, one patient had Table 2. Peroperative and postoperative results. Variable Median (IQR) operative time, mins Nerve sparing, n (%) Bilateral Unilateral None Lymph node dissection, n (%) Median (IQR) anastomosis time, mins Median (IQR) blood loss, mL Median (IQR) hematocrit decrease Median (IQR) discharged time, day Median (IQR) catheter removal time, day pT, n (%) T0 T2 T3a T3b-4 pN, n (%) N0 N+ Positive surgical margin, n (%) Yes No

Rs-RARP 162.5 (137.5-210)

S-RARP 150 (125-220)

36 (72) 7 (14) 7 (14) 21 (42) 20 (15-20) 150 (100-200) 4.2 (0.7-1.7) 3 (2.7-3) 8 (7-9)

35 (70) 9 (18) 6 (12) 19 (38) 20 (15-20) 100 (65-150) 3.9 (0.7-1.6) 3 (2-3.5) 8 (7-9)

0 38 (76) 7 (14) 5 (10)

1 (2) 36 (72) 8 (16) 5 (10)

20(40) 1(2)

18 (36) 1 (2)

6 (12) 44 (88)

4 (8) 46 (92)

P value 0.865 ͳ 0.843ӿ

0.683 ӿ 0.952 ͳ 0.120 ͳ 0.668 ͳ 0.588 ͳ 0.431 ͳ

0.444 ӿ

ͳ: Mann- Whitney U test. ¥: Student’s t-test. ӿ: Chi-sqaure test.

Data are presented as median (IQR) and frequency (percantage).

Transition from standard to Retzius-sparing

complete ureteral injury in the Rs-RARP group. One patient in the S-RARP group had external iliac vein injury during lymph node dissection. Both complications were managed intracorporeally. As a result of the histopathological examination of radical specimens, surgical margin positivity was detected in 6/50 (12%) cases in the RsRARP group and in 4/50 (8%) cases in the S-RARP (p = 0.444). Intra-postoperative clinical and pathological outcomes are summarized in Table 2. The median catheter discharge time was 8 days (IQR 7-9) in group 1 and 8 (IQR 7-9) days for group 2, respectively (p = 0.431). Immediate continence rates following catheter removal were 32/50 (64%) in the Rs-RARP group and 26/50 (52%) in the S-RARP group (p = 0.224). The continence recovery rate was 48/50 (96%) in the RsRARP group and 46/50 (92%) in the S-RARP group at 12month follow-up (p = 0.400). Comparison of both groups according to continence recovery using KaplanMeier methods is shown in Figure 1A. Eighty-seven patients, 43 in group 1 and 44 in group 2, who achieved preoperative sexual intercourse were included in the erectile function evaluation. The mean baseline IIEF-5 score was 21.6 ± 2.5 and 20.7 ± 2.6 in group 1 and 2,

respectively (p = 0.143). No statistically significant difference was found between the surgical approach in terms of IIEF score reductions at 12-month follow-up (p = 0.260) (Figure 1B). Potency recovery of patients who underwent bilateral or unilateral nerve-sparing surgery was 27/43 (62.8%) in group 1 and 30/44 (68.2%) in group 2 at 12 months follow up. This difference was not statistically significant (p = 0.597). Figure 1C shows the KaplanMeier curve for potency recovery at 12-months follow-up (p = 0.719). Biochemical recurrence was observed in 7/50 (14%) patients in group 1, and 6/50 (12%) patients in group 2 at median 33 (IQR 28-40) months follow-up (p = 0.766). Biochemical recurrence-free survival analysis according to surgical approaches is shown in Figure 1D.

DISCUSSION

One-third of men with localized prostate cancer undergo radical prostatectomy (8). Incontinence is an adverse effect faced by patients after radical prostatectomy. Rs-RARP recently gained popularity with early continence results. In this article, we questioned the effect of the Rs-RARP learning curve on functional and oncological results for a sur-

Figure 1. Comparison of functional and oncological outcomes between groups.

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geon who was experienced in S-RARP before. This study provided that the Rs-RARP learning curve period is not adversely affected by either functional or oncologic results. The number of cases required to achieve competence in radical prostatectomy is uncertain. Also, there is no objective parameter to be used in defining the learning curve. A study based on complications showed that the complications were significantly reduced after 150 cases (9). In another study examining the learning curve for robotic radical prostatectomy by an experienced surgeon with the open approach, they reported that self-confidence and comfort similar to open surgery were achieved after performing 250 robotic surgeries (10). In a recent study, Islamoglu et al. reported that the surgeon experienced in laparoscopy and open radical prostatectomy should have experience of at least 50 cases to achieve the optimal surgical time. However, they found that the learning curve did not affect positive surgical margin (11). Another study reported the requirement of 90 cases after intensive structured modular training to achieve optimal perioperative and functional outcomes (12). In this context, we think that the learning curve for RsRARP is person-based and will vary depending on the surgeon's previous skills in laparoscopy and S-RARP. In 2010, Galfano et al. defined Rs-RARP for the first time in their study, which they defined as the Bocciardi approach (7). The theory of this approach is that it has a positive effect on continence and erectile function by protecting structures such as the Santorini plexus, pudendal artery, and pubourethral ligament. Recent studies show that Rs-RARP is advantageous especially in terms of immediate continence (13). In their series of 200 cases, Galfano et al. reported a continence rate of 90% at 1 week and 96% at the end of 1 year (14). In a randomized controlled study comparing Rs-RARP with S-RARP, continence rates at 1 week were 71% versus 48% in favor of Rs-RARP (p = 0.01) (2). In a series of 256 cases involving surgeons on the learning curve, the immediate continence rate was reported as 82% and 90% at the end of 12 months (15). On the other hand, it was emphasized that the high continence rate seen in the early period with the Rs-RARP approach is similar to S-RARP after 12 months (12). In our study, although the continence rates in the first week were higher in the Rs-RARP group compared to the S-RARP group, no statistical difference was found. At the end of the first year, results were excellent in both groups. Sexual potency evaluation was performed in patients with preoperative penetrative sexual intercourse and patients undergoing bilateral or unilateral nerve-sparing surgery. At the end of 12 months, we found a potency rate of 62.8% in the Rs-RARP group and 68.2% in the S-RARP group. Olivero and colleagues reported a sexual potency rate of 80.4% in their study with surgeons on the RsRARP learning curve. However, they included young patients with full-nerve-sparing procedures in the analysis in this study (15). In a randomized prospective study including 3rd-month penetrative intercourse rates for 30 anterior and 30 posterior approaches by Mennon et al., rates were reported as 36.7% in the anterior group and 43.7% in the posterior group. They emphasized that at the end of the 12th month erection sufficient for penetrative intercourse increased to 69.2% in the anterior group

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and 89% in the posterior group (16). In our study, the rate of erectile function was found to be lower in the RsRARP group compared to the literature. This may be because we included patients from all age groups and patients who underwent unilateral nerve-sparing surgery. Positive surgical margin is a valuable data for evaluating oncological outcomes after radical prostatectomy. Galfano et al. found a PSM rate of 22% in the first 100 cases in their learning curve and 9% in the second 100 patients (14). Sayyid and colleagues reported that PSM after RsRARP and S-RARP were similar in accordance to pT stage subgroups (for pT2 stage: 16.7% PSM in Rs-RARP vs 13.7% PSM in S-RARP, p = 0.54; for pT3 stage: 47.1% and 47.8%, respectively, p = 0.95) (17). In another study comparing Rs-RARP and S-RARP, the rate of PSM was 10% in the S-RARP group and 28.2% in the Rs-RARP group, and this difference was statistically significant (p = 0.05). However, when pT stage subgroups were compared, no statistical significance was found (18). Also, many studies comparing Rs-RARP and S-RARP reported similar PSM rate and biochemical recurrence-free survival (8). In our study, in accordance with the literature, there was no significant difference in PSM rate between the groups. Our study has some limitations. First bias may be due to the retrospective design. Second, the study has a relatively small sample size. On the other hand, our data were collected prospectively and all surgical procedures were performed by a single surgeon.

CONCLUSIONS This study reported the outcomes for cases on the Rs-RARP learning curve of a surgeon with previous experience of S-RARP. According to the data in our study, when a surgeon who is experienced in S-RARP switches to the RsRARP method, functional and oncological results are not negatively affected in the first 50 cases. Although immediate continence was found to be lower than the literature in our study, the results are excellent at the end of 12 months. Surgeons previously experienced in the S-RARP approach can safely move to the Rs-RARP approach.

REFERENCES

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018; 68:7-30. 2. Dalela D, Jeong W, Prasad MA, et al. A pragmatic randomized controlled trial examining the impact of the Retzius-sparing approach on early urinary continence recovery after robot-assisted radical prostatectomy. Eur Urol. 2017; 72:677-685. 3. Galfano A, Secco S, Dell'Oglio P, et al. Retzius-sparing robotassisted radical prostatectomy: early learning curve experience in three continents. BJU Int. 2021; 127:412-417. 4. Patel VR, Coelho RF, Palmer KJ, Rocco B. Periurethral suspension stitch during robot-assisted laparoscopic radical prostatectomy: description of the technique and continence outcomes. Eur Urol. 2009; 56:472-8. 5. Ma X, Tang K, Yang C, et al. Bladder neck preservation improves time to continence after radical prostatectomy: a systematic review and meta-analysis. Oncotarget. 2016; 7:67463-75.

Transition from standard to Retzius-sparing

6. Kojima Y, Takahashi N, Haga N, et al. Urinary incontinence after robot-assisted radical prostatectomy: pathophysiology and intraoperative techniques to improve surgical outcome. Int J Urol. 2013; 20:1052-63.

13. Phukan C, Mclean A, Nambiar A, et al. Retzius-sparing robotic assisted radical prostatectomy vs. conventional robotic assisted radical prostatectomy: a systematic review and meta-analysis. World J Urol. 2020; 38:1123-1134.

7. Galfano A, Ascione A, Grimaldi S, et al. A new anatomic approach for robot-assisted laparoscopic prostatectomy: a feasibility study for completely intrafascial surgery. Eur Urol. 2010; 58:457-61.

14. Galfano A, Di Trapani D, Sozzi F, et al. Beyond the learning curve of the Retzius-sparing approach for robot-assisted laparoscopic radical prostatectomy: oncologic and functional results of the first 200 patients with ≥ 1 year of follow-up. Eur Urol. 2013; 64:974-80.

8. Davis M, Egan J, Marhamati S, et al. Retzius-Sparing RobotAssisted Robotic Prostatectomy: Past, Present, and Future. Urol Clin North Am. 2021; 48:11-23. 9. Ou Y-C, Yang C-R, Wang J, et al. The learning curve for reducing complications of robotic-assisted laparoscopic radical prostatectomy by a single surgeon: complications of RALP. BJU Int. 2011; 108:420-5. 10. Herrell SD, Smith JA Jr. Robotic-assisted laparoscopic prostatectomy: what is the learning curve? Urology. 2005; 66(5 Suppl):105-7. 11. Islamoglu E, Karamik K, Ozsoy C, et al. The learning curve does not affect positive surgical margin status in robot-assisted laparoscopic prostatectomy. Urol J. 2018; 15:333-338. 12. Schiavina R, Borghesi M, Dababneh H, et al. The impact of a structured intensive modular training in the learning curve of robot assisted radical prostatectomy. Arch Ital Urol Androl. 2018; 90:1-7.

15. Olivero A, Galfano A, Piccinelli M, et al. Retzius-sparing robotic radical prostatectomy for surgeons in the learning curve: a propensity score-matching analysis. Eur Urol Focus. 2021; 7:772-778. 16. Menon M, Dalela D, Jamil M, et al. Functional recovery, oncologic outcomes and postoperative complications after robot-assisted radical prostatectomy: an evidence-based analysis comparing the Retzius-sparing and standard approaches. J Urol. 2018; 199:12101217. 17. Sayyid RK, Simpson WG, Lu C, et al. Retzius-sparing roboticassisted laparoscopic radical prostatectomy: a safe surgical technique with superior continence outcomes. J Endourol. 2017; 31:1244-1250. 18. Asimakopoulos AD, Topazio L, De Angelis M, et al. Retzius-sparing versus standard robot-assisted radical prostatectomy: a prospective randomized comparison on immediate continence rates. Surg Endosc. 2019; 33:2187-2196.

Correspondence Hakan Anıl, MD (Corresponding Author) dr.hakananil@gmail.com Department of Urology, Adana Seyhan State Hospital, Adana (Turkey) Kaan Karamık, MD Department of Urology, Antalya Korkuteli State Hospital, Antalya (Turkey) Ali Yıldız, Asst. Prof., MD Department of Urology, Okan University Hospital, Faculty of Medicine, Istanbul (Turkey) Murat Savaş, Prof. Dr., MD Department of Urology, Antalya Memorial Hospital, Antalya (Turkey)

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DOI: 10.4081/aiua.2021.4.404

ORIGINAL PAPER

Sexual rehabilitation with intracavernous alprostadil after radical prostatectomy: Outcomes from a nursing program Alexandre Gromicho 1, Pedro Costa 2, Débora Araújo 2, Daniela Pereira 2, Luís Ferraz 2 1 Urology 2 Urology

Department, Centro Hospitalar do Funchal, Portugal; Department, Centro Hospitalar Vila Nova de Gaia/Espinho EPE, Vila Nova de Gaia, Portugal.

Summary

Introduction and objectives: Erectile dysfunction (ED) is a common complication after radical prostatectomy that affects quality of life. There are several therapeutic options, including intracavernous alprostadil injections (IAI). However, no specific recommendations have been made on the optimal rehabilitation strategy. In this study we evaluated a sexual rehabilitation program (SRP) with IAI for patients with ED after radical prostatectomy, assessing the rate of compliance and reasons for dropout. Methods: The sexual rehabilitation program (SRP) was offered to all patients who underwent radical prostatectomy from 1 January 2010 to 31 December 2019. The first consultations were performed by a urology specialist nurse, explaining the IAI procedure and possible complications. The program was considered successful when the patients achieved autonomy in the drug preparation with a good injection technique. A medical consultation was performed at 6 months evaluating the IAI usage and adverse events. In case of dropout, a questionnaire about reasons for dropout was performed. The primary endpoint was the rate of compliance and dropout of the program. Secondary endpoints were the reasons for dropout and adverse events. Results: 340 patients underwent radical prostatectomy at our institution, and 123 patients accepted to participate in the rehabilitation program. A total of 96 patients (78%) successfully completed the SRP, and at 6 months 60 (62.5%) still used IAI. Concerning the reasons for dropping out, the most frequent were the need of injectable therapy and pain. Regarding complications, 17 patients (13.8%) reported pain related to the injection and 1 patient (0.8%) had a priapism, managed with conservative treatment. Conclusions: Management of post-radical prostatectomy ED by a nursing program achieved good rates of patients’ self-injection accomplishment and treatment compliance. Close monitoring for dose adjustment and management of post-injection penile pain is required during the follow-up.

KEY WORDS: Radical prostatectomy; Erectile dysfunction; Sexual rehabilitation; Alprostadil.

complications, both impairing patients’ quality of life (1). ED is classically attributed to the injury of neurovascular bundles. The persistent penile hypoxia due to the loss of physiological erections may lead the cavernous fibrosis and, ultimately, a decline in erectile function (2). The use of vasoactive drugs may improve tissue oxygenation through increased penile blood flow, and prevent penile fibrosis (3, 4). Therefore, early treatment with erectogenic drugs may play an important role in sexual rehabilitation after RP. Several treatments have been proposed to manage postRP ED: intracavernous alprostadil injections (IAI), phosphodiesterase-5 (PDE-5) inhibitors and vacuum devices (4, 5). The IAI has become increasingly common, especially after Montorsi et al. (6) reported that early postoperative administration of alprostadil injections significantly increased the recovery rate of spontaneous erections after RP. The IAI is a complex procedure. It involves the preparation of the syringe, identification of the injection site and correct administration, which requires a minimum of dexterity. Moreover, the need of a penile injection and the loss of spontaneity of the sexual act may lead to patient anxiety. Most studies reported high discontinuation rates of patients treated with IAI, and the lack of explanation and lack of follow-up were important causes of treatment failure and non-compliance (7). So, it is crucial to clearly inform patients and partners about the objectives of the treatment and expectations of sexual recovery. Due to the time required to explain the IAI procedure to the patient during medical consultations and sexual counselling during the follow-up, the management of post-RP ED is challenging. Therefore, some studies reported an erectile rehabilitation program provided by a urology specialist nurse with good results (8). In this study we evaluated a sexual rehabilitation program (SRP) for patients with ED after RP, assessing the rate of compliance and reasons for dropout.

Submitted 11 August 2021; Accepted 14 October 2021

INTRODUTION

Radical prostatectomy (RP) is a therapeutic option for patients with localized prostate cancer. Erectile dysfunction (ED) and urinary incontinence are the most common

404

MATERIALS

AND METHODS

The present study is a single-center, retrospective study. The SRP with IAI was offered to all patients who underwent non-nerve sparing radical prostatectomy from 1 January 2010 to 31 December 2019. A preoperative evalNo conflict of interest declared.

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Alprostadil after radical prostatectomy

uation included a detailed medical history and sexual habits, assessing the quality of erection, libido, orgasm and ejaculation. The therapy was offered at the first post-operative consultation and initiated once the patient was interested in sexual rehabilitation, usually after proper continence control. A consultation was performed by a urology specialist nurse and the sexual partner was asked to participate as well. The first consultation evaluated the changes in the sexual habits and expectations with the treatment. The process of preparation and administration IAI, as well as the possible complications associated, were explained. Then the patients were seen once a week and information was collected about the previous administration (efficacy, side effects), the injection technique and the correct dose adjustment if necessary. The quality of erections was evaluated through the Erection Hardness Score (EHS). The program was considered successful when the patients achieved autonomy in the drug preparation with a good injection technique. In case of dropout, a questionnaire about reasons for dropout was performed. A medical consultation was performed at 6 months after completing the program, evaluating the IAI usage and adverse events. Reasons for abandoning the IAI at 6 months were also reported. The primary endpoint was the rate of compliance and dropout of the program. Secondary endpoints were the reasons for dropout and adverse events. Data were analysed using SPSS.

RESULTS

A total of 340 patients underwent radical prostatectomy at our institution, and 123 patients (36.2%) accepted to participate in the rehabilitation program. Population demographic and clinical features are show in Table 1. The median (IQR) age of the cohort was 63 (60-67) years old. The median time (IQR) between the surgery and the rehabilitation program was 6.8 (3.6-11.2) months. All patients reported being sexually active before the surgery, with 118 (95.6%) without preoperative erectile dysfunction symptoms. 36.6% of the patients were initially treated with PDE-5 inhibitors, without success. The first consultations were performed with the patient and sexual partner in 72 cases (58.5%). The alprostadil dose distribution is represented on Table 2 and 111 patients (90.2%) achieved erection hard enough for sexual intercourse after IAI (EHS 3 or 4). In general, a minimum of 3 (± 0.7) nursing consultations were performed before patients successfully completed the program. A total of 27 patients (22%) dropped out over the first consultations and did not complete the rehabilitation program. Of the 96 patients who completed the initial rehabilitation program, 60 (62.5%) still used intracavernous alprostadil at 6 months. The reasons for dropping out are described on Table 3. In most cases was the need of injectable therapy. The second most frequent reason was injection pain, despite adjusting to the lowest effective dose. Regarding complications, 17 patients (13.8%) reported pain related to the injection and 1 patient (0.8%) had a priapism, managed with conservative treatment. There was no significant difference in drop-out rates with

Table 1. Population characteristics. Characteristics (n = 123) Age (years), median (IQR) Pre-operative erectile dysfunction symptoms, n (%) Diabetes mellitus, n (%) Previous radiotherapy, n (%) Previous PDE-5 inhibitors, n (%) Time between surgery and rehabilitation program (months), median (IQR) Urinary incontinence, n (%) • No • Mild • Moderate to severe

Statistic 63 (60-67) 4 13 14.6 36.6 6.8 (3.6-11.2) 60.2 32.5 6.5

PDE-5: phosphodiesterase-5.

Table 2. Alprostadil dose distribution. Alprostadil lowest effective dose (ug) 5 10 15 20

N (%) 10 (8.4) 60 (50.4) 2 (1.7) 47 (39.5)

Table 3. Reason for dropping out the rehabilitation program. Injectable therapy Injection pain Loss of follow up Lack of sexual interest Urinary incontinence Lack of treatment efficacy

N (%) 22 (37.3) 12 (20.3) 8 (13.6) 7 (11.9) 3 (5.1) 2 (3.4)

age, diabetes mellitus, previous radiotherapy, previous PDE-5 inhibitors, time between surgery-rehabilitation program and urinary incontinence (p > 0.05).

DISCUSSION

Radical prostatectomy is one of the most frequent therapeutic options used for the management of patients diagnosed with localized prostate cancer. However, this treatment has a negative effect on patients’ quality of life, particularly affecting sexual life. In fact, some studies concluded that sexual dysfunction was an independent determinant of worse general health-related quality of life after primary treatment for prostate cancer (9). Most of the studies published in the literature evaluates the effectiveness of drugs used in erectile function recovery, but few data are available concerning the protocols and drug compliance. Intracavernous alprostadil remains the main treatment for erectile rehabilitation after radical prostatectomy, improving sexual function also in patients treated with non-nerve sparing technique (10). The beginning of IAI and patient follow-up can become problematic due to the overload of medical consultations. For these reasons Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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our department created a program aimed at sexual rehabilitation, provided with the help of urology specialist nurses. In our study, 78% (n = 96) of the patients who agreed to participate successfully completed SRP. They were able to successfully self-administer the IAI and achieved the ability to adjust the correct doses. In 58.5% the nursing consultations were performed with the couple, highlighting the role of spouses/partner in the sexual rehabilitation. The revaluation at 6 months after the program concluded that 60 patients (62.5%) still used IAI. Regarding the reasons for dropping out, the most frequent were the need of injectable therapy (patients with fear of needles and patients who refuse to undergo injectable therapy) and pain. Interestingly, the cost of the drug was never stated as a reason for dropping out. Regarding patients who abandoned therapy at 6 months, it should be noted that 4 patients (12.9%) were able to achieve erection without IAI. Therefore, despite being a potentially effective treatment, the fact that it is an injectable treatment was a major limitation for these patients. Pain was reported in only 17 patients (13.8%), especially in the first consultations, but was a major reason for dropping out in only 9 patients. The cause of post-IAI pain is not well known and its management is challenging. Patients were recommended to take analgesics 1 hour before the injection and reduce to the lowest effective dose, but in some cases that was not satisfactory. Other strategies reported in the literature were combining the IAI with a numbing product or the use a mixture of vasoactive drugs such as Trimix (combination of alprostadil, phentolamine and papaverine) (11, 12). The combination allows lower doses of each drug, reducing the adverse events. However, none of these combination drugs have a clinical authorization in the treatment of erectile dysfunction and are not available in Portugal. The dropout rate at the end of the program and at 6 months were 22% and 37.5%, respectively. For standard rehabilitation with intracavernous alprostadil, drop-out rates of 41-68% have been reported, most occurring during the first three months (1). So, our results demonstrate lower discontinuation rates than those reported for standard rehabilitation therapy, but comparable with other studies of IAI in which nursing and sexual counselling was performed and maintained (8, 13, 14). Also post-IAI pain rate was lower than in other studies. Taken together, these results may indicate that a SRP was a key factor for increasing the motivation of the couples and treatment compliance, as well for minimizing the adverse events. Although not being a primary outcome, the efficacy of IAI was also evaluated. After the first consultation, 90% of the patients achieved erections hard enough for sexual intercourse. Our results are comparable with other studies, which reported success rates ranged from 70% to 95% (3, 9, 13). Similarly, the percentage of patients without preoperative erectile dysfunction was quite high for a population with a median age of 63 years old. A possible explanation is the fact that younger patients with no preoperative symptoms of erectile dysfunction were the most motivated to initiate sexual rehabilitation. Also, the erectile dysfunction symptoms were not evaluated through

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validated questionnaires and the final results may not be accurate. Regarding the time between the surgery and the rehabilitation program, it was approximately 7 months. The reasons for the delay were not reported, but it could be due to the necessity of adjuvant radiotherapy, hormonal therapy or transient urinary incontinence, discouraging some patients from undertaking SRP. On the other hand, patient’s anxiety concerning the oncologic outcomes is usual in the first medical consultations, having a negative impact on the motivation to initiate SRP. Limitations of the study were described previously throughout the discussion, such as the absence of validated questionnaires evaluating the preoperative erectile dysfunction symptoms and injection-related pain, and the delay to initiate the ERP. Another limitation is related to the retrospective single-center, single-arm and nonrandomized design. More robust evidence is needed from multicenter, randomized and controlled trials to establish a standard sexual rehabilitation program to these patients in the future.

CONCLUSIONS

Management of post-radical prostatectomy ED by a nursing program achieved good rates of patients’ self-injection accomplishment and treatment compliance, which are the key components of sexual rehabilitation. Close monitoring for dose adjustment and management of postinjection penile pain is required during the follow-up.

REFERENCES

1. Salonia A, Bettocchi C, Carvalho J, et al. EAU Guidelines on Sexual and Reproductive Health. EAU Guidel. 2021. 2. Mulhall JP, Slovick R, Hotaling J, et al. Erectile dysfunction after radical prostatectomy: Hemodynamic profiles and their correlation with the recovery of erectile function. J Urol. 2002; 167:1371-5. 3. Raina R, Agarwal A, Zippe CD. Management of erectile dysfunction after radical prostatectomy. Urology. 2005; 66:923-9. 4. Montorsi F, Briganti A, Salonia A, et al. Current and future strategies for preventing and managing erectile dysfunction following radical prostatectomy. Eur Urol. 2004; 45:123-33. 5. Kim JH, Lee SW. Current status of penile rehabilitation after radical prostatectomy. Korean J Urol. 2015; 56:99-108. 6. Montorsi F, Guazzoni G, Strambi LF, et al. Recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil: results of a prospective, randomized trial. J Urol. 1997; 158:1408-10 7. Titta M, Tavolini IM, Dal Moro F, et al. Sexual counseling improved erectile rehabilitation after non-nerve-sparing radical retropubic prostatectomy or cystectomy - Results of a randomized prospective study. J Sex Med. 2006; 3:267-73. 8. Yiou R, Khodari M, Lingombet O, et al. Évaluation d’un programme infirmier d’education thérapeutique pour les injections intra-caverneuses d’alprostadil après prostatectomie radicale. Prog Urol. 2011; 21:283-7. 9. Gontero P, Fontana F, Zitella A, et al. A prospective evaluation of efficacy and compliance with a multistep treatment approach for

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erectile dysfunction in patients after non-nerve sparing radical prostatectomy. BJU Int. 2005; 95:359-65. 10. Moussa M, Papatsoris A, Abou Chakra M, et al. Erectile dysfunction post radical cystectomy. The role of early rehabilitation with pharmacotherapy in nerve sparing and non-nerve sparing group: A randomized, clinical trial. Arch Ital Urol Androl. 2021; 93:58-64. 11. Schramek P, Plas EG, Hübner WA, Pflüger H. Intracavernous injection of prostaglandin E1 plus procaine in the treatment of erectile dysfunction. J Urol. 1994; 152:1108-10.

12. Mulhall J, Land S, Parker M,, et al. The use of an erectogenic pharmacotherapy regimen following radical prostatectomy improves recovery of spontaneous erectile function. J Sex Med. 2005; 2:532-40. 13. Polito M, D’anzeo G, Conti A, Muzzonigro G. Erectile rehabilitation with intracavernous alprostadil after radical prostatectomy: Refusal and dropout rates. BJU Int. 2012; 110:1-4. 14. Yiou R, Cunin P, De La Taille A, et al. Sexual rehabilitation and penile pain associated with intracavernous alprostadil after radical prostatectomy. J Sex Med. 2011; 8:575-82.

Correspondence Alexandre Gromicho, MD (Corresponding Author) alexandrepgromicho@gmail.com Urology Department, Centro Hospitalar do Funchal, Portugal Adress: Av. Luís de Camões 57, 9000-177, Funchal (Portugal) Pedro Costa, MD pedro_r_costa@hotmail.com Débora Araújo, MD deboracerqueiraaraujo@gmail.com Daniela Pereira, MD filipa.pereira27@gmail.com Luís Ferraz, MD ferrasluis@gmail.com Urology Department, Centro Hospitalar Vila Nova de Gaia/Espinho EPE, Vila Nova de Gaia (Portugal)

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ORIGINAL PAPER

Is robotic radical nephroureterectomy a safe alternative to open approach: The first prospective analysis Panagiotis Mourmouris 1, Omer Burak Argun 2, Lazaros Tzelves 1, Mustafa Bilal Tuna 2, Maria Gourtzelidou 1, Andreas Tziotis 1, Ali Riza Kural 1, Andreas Skolarikos 2 1 2nd

Department of Urology, Athens Medical School, National and Kapodistrian University of Athens, Sismanogleio General Hospital, Athens, Greece; 2 Department of Urology, Acıbadem Mehmet Ali Aydınlar University, Acibadem Maslak Hospital, Istanbul, Turkey.

Summary

Purpose: To test the efficacy and safety profile of robotic radical nephroureterectomy compared to the open approach. Methods: We enrolled 45 consecutive patients who suffered from non-metastatic, upper urinary tract urothelial carcinoma from September 2019 to March 2021 and underwent radical nephroureterectomy. Patients were divided in two groups: group A consisted of 29 patients (open approach) and group B consisted of 16 patients (robotic approach). The factors which were taken into consideration were age, sex, body mass index, tumour size, side and grade, cancer stage, ASA score, operation time, drain removal time, foley time, hospitalization time, estimated blood loss, surgical margins, preoperative and postoperative creatinine, Hct and bladder recurrences. Statistical analysis was performed with the use of SPSS version 26 and p < 0.05 was the cut-off for reaching statistical significance. Results: The mean age in group 1 was 67.12 years and in group 2 68.12 years, whereas the mean body mass index (BMI) in group 1 was 26.54 kg/m2 and in group 2 25.20 kg/m2. Operative time was better in group A (124 vs 186 mins p < 0.001) and estimated blood loss were better in group B compared to group A (137 vs 316 ml p < 0.001). Length of stay (LOS) was significantly less in the robotic group (5.75 vs 4.3 days p = 0.003) and the same applied for time required for drain removal (4.5 vs 3.3 days p = 0.006). Conclusions: Robotic radical nephroureterectomy is a safe and efficient alternative to open approach. It provides a favorable perioperative profile in patients suffering from upper urinary tract carcinoma without metastasis.

KEY WORDS: Robotic radical nephroureterectomy; Open radical nephroureterectomy; Prospective analysis; Complications. Submitted 31 August 2021; Accepted 13 October 2021

INTRODUCTION

Upper urinary tract urothelial carcinoma (UUTC) represents a relatively rare entity, as it accounts for 5% of these neoplasms with an estimated annual incidence of 2 cases per 100.000 inhabitants (1), but because 60% of these malignancies are invasive at the time of diagnosis their management is of crucial importance (2). According to European Association of Urology, open radical nephroureterectomy (ORNU) with bladder cuff excision remains the gold standard treatment of high-risk UTUC, regardless of tumour

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location (3). Trying to improve safety and effectiveness of treatment, new techniques such as laparoscopy have become an effective alternative (4-6). The results have shown that both laparoscopic nephroureterectomy and hand-assisted laparoscopic nephroureterectomy had comparable, if not superior, perioperative and postoperative and similar oncological outcomes (6). Technological advances made to achieve shorter and less morbid operations, have led to the next step of UTUC treatment, which is the use of the robotic platform. Results from multiple studies and the experience of various surgeons worldwide has shown that RRNU share equivalent oncologic outcomes at short-term follow up, while also displaying very low peri-operative morbidity and complications (7, 8). Although robotic radical nephroureterectomy (RRNU) represents a promising alternative to currently existing methods of treatment, there is a surprising paucity of studies comparing RRNU and ORNU. All available data originate from retrospective studies limited by important selection biases. Our study represents the first prospective comparison of these two techniques regarding their efficacy and safety in the treatment of UTUC.

MATERIALS

AND METHODS

We enrolled 45 consecutive patients who suffered from non-metastatic, upper urinary tract urothelial carcinoma from September 2019 to March 2021 and underwent radical nephroureterectomy. The surgeries took place in two different academic centres by experienced surgeons. In the former, the operations were performed by three different surgeons, each of whom had performed more than 50 open nephroureterectomies. In the latter, all the operations were carried out by the same surgeon with a vast experience in robotic upper tract surgeries (more than 300). Patients were divided in two groups: group A consisted of 29 patients (open approach) and group B consisted of 16 patients (robotic approach). The exclusion criteria of the patients for the study were the following: patients with history of other urological managements and patients with contraindications for laparoscopic surgery. The Institutional Review Board has approved the study protocol and all patients have signed an informed consent. No conflict of interest declared.

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Robotic radical nephroureterectomy

The Da Vinci Xi System was used for the robotic procedures. We followed the same technique for performing RRNU as already published (9). Open NU procedures were based on the standard approach 2 with bladder cuff excision (10). The factors which were taken into consideration were age, sex, body mass index, tumour size, side and grade, cancer stage, ASA score, operation time, drain removal time, Foley time, hospitalization time, estimated blood loss, surgical margins, preoperative and postoperative creatinine, Hct and bladder recurrences. Complications were categorized according to Clavien Dindo system (11). Continuous variables are described as mean ± standard deviation (SD) and categorical variables as proportions. Comparison of continuous outcomes was performed using Student’s t-test for normally distributed data and Mann-Whitney test for non-normally distributed data. Distribution of data was checked using the Shapiro-Wilk test. Categorical variables were compared between the two groups, using chi-square and Fisher’s exact test, as dictated by the frequency of observations. Statistical analysis was performed with the use of SPSS version 26 and p ≤ 0.05 was the cut-off for reaching statistical significance.

RESULTS

The study included 45 patients from which 7 were female (5 in group A and 2 in group 2) and 38 males. The basic characteristics of the patients are shown in Table 1. The mean age in group 1 was 67.12 years and in group 2 68.12 years, whereas the mean body mass index (BMI) in group 1 was 26.54 kg/m2 and in group 2 25.20 kg/m2, without any statistically significant difference between them. A right sided tumor was found in 13 patients in group A and 4 patients in group B, whereas 14 patients in group A and 10 in group B had tumors in the renal calyces or pelvis. The two groups were matched in terms of ASA score (p = 0.07) and tumor size (p = 0.5). Operative time was better in group A (124 vs 186 mins p < 0.001) and estimated blood loss were better in group B compared to group A (137 vs 316 ml p < 0.001). Two patients in group A and no patient in group B required transfusion. Length of stay (LOS) was significantly less in the robotic group (5.75 vs 4.3 days p = 0.003) and the same applied for time required for drain removal (4.5 vs 3.3 days p = 0.006). The peri- and postoperative results are shown in Table 2. In group A, 16 patients suffered postoperative complications: 7 patients suffered from fever, 2 from hematoma, 3 from wound infection, 2 required transfusion, 1 from paralytic ileus and 1 suffered a myocardial infarction whereas from group B 3 patients suffered postoperative complications, 2 patients with fever and 1 with hematoma. The complications’ classification according to Clavien-Dindo score is shown in Table 3.

DISCUSSION

The use of the robotic platform for the management of UUTC has evolved since the first reports of retroperitoneal (12) and intraabdominal operations (13, 14) that may have also utilized other approaches (open or laparo-

Table 1. Basic patients characteristics. Age (years) Sex (male/female) BMI (kg/m2) Tumor size (mm) Laterality (right) Tumor location intra renal Ureter ASA score Preoperative creatinine (mg/dl) Preoperative Hct

Group A (n = 29) 67.12 (12.19) 24/5 26.54 (1.95) 36.2 (20.09) 13 14 15 2.56 (0.89) 1.16 (0.43) 38.85 (4.91)

Group B (n = 16) 68.12 (9.0) 14/2 25.20 (1.85) 33.0 (10.73) 4 10 6 2.06 (0.25) 1.23 (0.30) 41.71 (3.52)

P value 0.8 1.0 0.12 0.59 0.71 0.06 0.07 0.09 0.06

ASA score (American Society of Anesthesiologists score); BMI (body mass index). Continuous outcomes are presented as mean values (± standard deviation).

Table 2. Peri and postoperative outcomes. Operative time (min) Drain removal time (days) Foley removal time (days) Length of stay (days) Estimate blood loss (ml) Positive surgical margins Postoperative creatinine (mg/dl) Postoperative Hct Pathological T stage Ta T1 T2 T3 T4 Tumour grade Low grade High grade Bladder recurrence

Group A 124,37 (25.74) 4.5 (1.21) 11.43 (5.29) 5.75 (1.43) 316.87 (93.87) 8/29 1.4 (0.47) 31.90 (4.37)

Group B 186.25 (34.03) 3.3 (0,94) 3,37 (0.80) 4.3 (1.08) 137.5 (78.52) 0/16 1.43 (0.39) 37.71 (4.05)

5 9 1 13 1

6 2 3 5 0

8 21 3

9 7 1

P value < 0.001 0.006 < 0.001 0.003 < 0.001 0.004 0.8 0.003 0.01

0.06

0.33

Table 3. Post-operative complications. Clavien Dindo classification No complications Grade I Grade II Grade III Grade IV Grade V

Group A 13 12 3 0 1 0

Group B 13 1 2 0 0 0

P value 0.28

scopic) for the nephrectomy or the ureterectomy. The surgeon’s experience has increased and new “hybrid” techniques have emerged, eliminating the basic disadvantage of the robotic platform, namely the need for redocking to perform ureteral excision (15, 16). Robotic approach yielded satisfactory oncological outcomes, even for Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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advanced disease, with studies reporting a 5-year recurrence free survival of 57.1% in a series including 28.3% patients with pT3 and 6.7% pT4 disease (17). In the same pace, one of the biggest studies so far enrolling patients from three high volume robotic surgery centers, reported a low high grade complication rate (2.6%) with excellent intra- and post-operative results, suggesting this approach as a viable alternative to the gold standard open approach (18). The technology advancements of the robotic platform with the development of the DaVinci Xi system provided the surgeon’s more tools towards increasing experience in this approach, while decreasing operation room time (19). Recently published data in the literature, emphasize the auxiliary role of robotic radical nephroureterectomy in the management of UUTC. The next step was comparing this approach to the open technique, which remains the gold standard therapy according to global guidelines. Available data in existing literature, consist of studies that enrolled patients mainly from open and pure laparoscopic approaches, while robotic approach cases in these series represented a minority. Even though some of these studies have large sample sizes, all of them are retrospective and their level of evidence is relatively low, due to the inherited bias of the retrospective nature (20, 21). In another study, multivariate logistic regression revealed a significant favorable impact of robotic approach in postoperative complications but not for intraoperative ones (22). As for the functional outcomes of the procedure, it is documented in the literature that RNU may be a risk factor for acute kidney injury resulting in renal function decline after this procedure (23). In our cohort, in both groups, patients suffered from postoperative creatinine decline, nevertheless when the two groups were compared no statistically significant difference was found relative to this factor. A relatively recent study provided data for the oncological superiority of the robotic approach, since this approach showed significantly longer progression free, cancer specific and overall survival (p < 0.05) (6). Nevertheless, in this study the open surgeries were performed in patients of most advanced stage and with negative prognostic factors (like lymph node metastasis). A recent systematic review and meta-analysis of a vast number of patients provided useful insights on the comparison of the open, laparoscopic, and robotic approach: the RRNU showed the lowest estimated blood loss (EBL) and the ONU the highest (163 ml vs 419.99 ml) with ONU showing higher odds of transfusion. Operative time was shorter for ONU whereas RRNU showed both lower length of stay (LOS) and intraoperative complications. Nevertheless, the meta-analysis is significantly limited from the retrospective studies which were analyzed (only 1 RCT and 2 prospective studies none of which included robotic cases) and most patients included were derived from non-comparative studies. Consequently, in this meta-analysis the distribution is in favor of ONU and LRNU so the data on robotic technique might be weak (24). Our study represents the first prospective comparison between open and robotic approach. The two groups were matched for most significant factors that could affect final outcomes, except from T stage, which it is not like-

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ly to have an impact to most of perioperative outcomes. We found a favorable profile of the robotic approach when compared to its open counterpart: better LOS, EBL, Hct decrease, need for transfusions and removal of drains and catheters. We also found significant difference in positive surgical margins, but this is possible due to the most advanced stage of tumors that were operated with the open approach. The basic difference from the literature is operation time which was lesser in the open approach but again this can be justified because the robotic approach requests docking of the robot and changing of the instruments position for the ureterectomy. The small sample size comprises a limitation of this study, necessitating the conduct of larger prospective cohorts, ideally after patient randomization. Nevertheless, this limitation is partly equilibrated by the prospective nature of our study and the limitation of potential biases that it provides. Another potential limitation is the relatively short follow-up (1-5 months), but the study was designed to address the efficacy and safety of these procedures by comparing their perioperative outcomes.

CONCLUSIONS Robotic radical nephroureterectomy is a safe and efficient alternative to open approach. It provides a favorable perioperative profile in patients suffering from upper urinary tract carcinoma without metastasis. Future prospective or randomized trials can assess its efficiency versus open approach in terms of oncological outcomes.

REFERENCES

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019; 69:7-34. 2. Margulis V, Shariat SF, Matin SF, et al. Outcomes of radical nephroureterectomy: a series from the Upper Tract Urothelial Carcinoma Collaboration. Cancer. 2009; 115:1224-33. 3. Rouprêt M, Babjuk M, Compérat E, et al. European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2017 Update. Eur Urol. 2018; 73:111-22. 4. Nouralizadeh A, Tabatabaei S, Basiri A, et al. Comparison of open versus laparoscopic versus hand-assisted laparoscopic nephroureterectomy: a systematic review and meta-analysis. J Laparoendosc Adv Surg Tech A. 2018; 28:656-81. 5. Mullen E, Ahmed K, Challacombe B. Systematic review of open versus laparoscopic versus robot-assisted nephroureterectomy. Rev Urol. 2017; 19:32-43. 6. Lee H, Kim HJ, Lee SE, et al. Comparison of oncological and perioperative outcomes of open, laparoscopic, and robotic nephroureterectomy approaches in patients with non-metastatic upper-tract urothelial carcinoma. PLoS One. 2019; 14:e0210401. 7. Hu CY, Yang CK, Huang CY, et al. Robot-assisted laparoscopic nephroureterectomy versus hand-assisted laparoscopic nephroureterectomy for upper urinary tract urothelial carcinoma: a matched comparison study. BioMed Res Int. 2015; 2015:918486. 8. Campi R, Cotte J, Sessa F, et al. Robotic radical nephroureterectomy and segmental ureterectomy for upper tract urothelial carcinoma: a multi-institutional experience. World J Urol. 2019; 37:2303-11.

Robotic radical nephroureterectomy

9. Argun OB, Mourmouris P, Tufek I, et al. Radical nephroureterectomy without patient or port repositioning using the Da Vinci Xi robotic system: initial experience. Urology. 2016; 92:136-9. 10. Li WM, Shen JT, Li CC, et al. Oncologic outcomes following three different approaches to the distal ureter and bladder cuff in nephroureterectomy for primary upper urinary tract urothelial carcinoma. Eur Urol. 2010; 57:963-9.

der cuff excision for upper tract urothelial carcinoma. J Urol. 2015; 194:1561-6. 18. De Groote R, Decaestecker K, Larcher A, et al. Robot-assisted nephroureterectomy for upper tract urothelial carcinoma: results from three high-volume robotic surgery institutions. J Robot Surg. 2020; 14:211-9.

11. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004; 240:205-13.

19. Patel MN, Aboumohamed A, Hemal A. Does transition from the da Vinci Si to Xi robotic platform impact single-docking technique for robot-assisted laparoscopic nephroureterectomy? BJU Int. 2015; 116:990-4.

12. Rose K, Khan S, Godbole H, et al. Robotic assisted retroperitoneoscopic nephroureterectomy -- first experience and the hybrid port technique. Int J Clin Pract. 2006; 60:12-4.

20. Rodriguez JF, Packiam VT, Boysen WR, et al. Utilization and outcomes of nephroureterectomy for upper tract urothelial carcinoma by surgical approach. J Endourol. 2017; 31:661-5.

13. Nanigian DK, Smith W, Ellison LM. Robot-assisted laparoscopic nephroureterectomy. J Endourol. 2006; 20:463-5.

21. Tinay I, Gelpi-Hammerschmidt F, Leow JJ. Trends in utilisation, perioperative outcomes, and costs of nephroureterectomies in the management of upper tract urothelial carcinoma: a 10-year population-based analysis. BJU Int. 2016; 117:954-60.

14. Park SY, Jeong W, Ham WS, et al. Initial experience of robotic nephroureterectomy: a hybrid-port technique. BJU Int. 2009; 104:1718-21. 15. Pugh J, Parekattil S, Willis D, et al. Perioperative outcomes of robot-assisted nephroureterectomy for upper urinary tract urothelial carcinoma: a multi-institutional series. BJU Int. 2013; 112:E295300. 16. Zargar H, Krishnan J, Autorino R, et al. Robotic nephroureterectomy: a simplified approach requiring no patient repositioning or robot redocking. Eur Urol. 2014; 66:769-77. 17. Aboumohamed AA, Krane LS, Hemal AK. Oncologic outcomes following robot-assisted laparoscopic nephroureterectomy with blad-

22. Pearce SM, Pariser JJ, Patel SG, et al. The effect of surgical approach on performance of lymphadenectomy and perioperative morbidity for radical nephroureterectomy. Urol Oncol. 2016; 34:121.e15-21. 23. Tafuri A, Odorizzi K, Di Filippo G, et al. Acute kidney injury strongly influences renal function after radical nephroureterectomy for upper tract urothelial carcinoma: A single-centre experience. Arch Ital Urol Androl. 2021; 93:9-14. 24. Veccia A, Antonelli A, Francavilla S, et al. Robotic versus other nephroureterectomy techniques: a systematic review and meta-analysis of over 87.000 cases. World J Urol. 2020; 38:845-52.

Correspondence Panagiotis Mourmouris, MD, PhD (Corresponding Author) thodoros13@yahoo.com Lazaros Tzelves, MD lazarostzelves@gmail.com Maria Gourtzelidou, MD mariaeirinigr@gmail.com Andreas Tziotis, MD tziotis.and@gmail.com Andreas Skolarikos, PhD andskol@yahoo.com 2nd Department of Urology, Athens Medical School, National and Kapodistrian University of Athens, Sismanogleio General Hospital, Athens (Greece) Omer Burak Argun, MD drburakargun@gmail.com Mustafa Bilal Tuna, MD mustafabilaltuna@gmail.com Ali Riza Kural, PhD arkural@gmail.com Department of Urology, Acıbadem Mehmet Ali Aydınlar University, Acibadem Maslak Hospital, Istanbul (Turkey)

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DOI: 10.4081/aiua.2021.4.412

ORIGINAL PAPER

Does Holmium laser enucleation of the prostate (HoLEP) still have a steep learning curve? Our experience of 100 consecutive cases from Turkey Güçlü Gürlen, Kadir Karkin Department of Urology, Health Sciences University, Adana City Training and Research Hospital, Adana, Turkey.

Summary

Aim: The aim of our study is to examine the learning curve of HoLEP and to discuss our results in the light of the literature. Methods: 100 patients who had LUTS resistant to medical treatment and complicated BPH to whom HoLEP procedure had been administered regardless of the size of the prostate in the last 1 year were analysed retrospectively. To evaluate the learning curve, the patients were classified into 4 main groups of 25 consecutively operated patients beginning from the first case. The 4 main groups were divided into 2 subgroups including patients who had prostate volume below or above 80 grams. Results: The mean age of the 100 patients who had HoLEP was 64.5 years. The mean prostate volume was 99.1 cc (45-281 cc). When those with prostate smaller than 80 g are examined, Enucleation efficiency was 0.76 g/min (0.46-0.97 g/min) and Morcellation efficiency was 3.07 g/min (3.34-4 g/min). When those with prostates larger than 80 g are examined, Enucleation efficiency was 0.89 g/min (0.66-1.04 g/min) and Morcellation efficiency was 4.01 g/min (3.93-4.25 g/min). These two parameters were statistically and significantly different in all the 4 groups (p < 0.05). Conclusions: HoLEP still has a steep learning curve. It is necessary to reach the number of cases of 25-50 to reach fundamental experience.

KEY WORDS: HoLEP; Learning curve; LUTS; Enucleation efficiency; Morcellation efficiency. Submitted 9 August 2021; Accepted 10 September 2021

INTRODUCTION

Holmium laser resection of the prostate (HoLEP) was first described by Gilling et al. in 1995 and after a few years, this technique was standardized as HoLEP (1). The classical well-known gold standards for the surgical treatment of benign prostate hyperplasia (BPH) have been OP and transurethral resection of the prostate (TURP) depending on prostate size (2). HoLEP has been shown in studies to have several advantages compared to transurethral resection of the prostate (TURP), including shorter hospital stay, reduced bleeding complications and absence of TURP-syndrome (3). Furthermore, functional outcomes of HoLEP have been stated to be at least as good as after TURP, and comparable to those obtained with open prostatectomy (OP) for larger prostates (3, 4). HoLEP is one of the most commonly used endoscopic enucleation of

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prostate (EEP) intervention that is recommended by the European Association of Urology (EAU) and American Urological Association (AUA) as a minimal invasive treatment method regarding patients with BPH independently from prostate sizes (but especially prostates with volume greater than 80 ml) (5, 6). HoLEP is thus often considered as a “new gold standard” by several Authors, However, in many centers, HoLEP has not yet replaced TURP and OP (7) because HoLEP is considered as a more difficult and lengthy procedure and learning curve has been pointed out as a limitation for a high diffusion of this surgical technique already described 15 years ago (8, 9). Therefore, the prolonged learning curve has slowed acceptance of the procedure in the urological community (10). There is some literature about the learning curve of HoLEP (10, 11), but this is the first learning curve analysis in Turkey. The aim of our study is to examine the learning curve of this surgery and to discuss our results in the light of the literature.

MATERIAL

AND METHOD

Study design and patients After our study had been approved by the Ministry of Health and the local ethics committee, patients to whom HoLEP procedure was administered between March 2019 and May 2020 were analysed retrospectively. Patients who had LUTS (lower urinary tract symptom) resistant to medical treatment and complicated BPH to whom HoLEP procedure had been administered regardless of the size of the prostate in Adana City Hospital Urology Clinic in previous approximately 1 year were analysed retrospectively. The first HoLEP case was performed in March 2019. The surgeon who had great experience in endoscopic surgery, started to perform HoLEP after watching videos, reading available published articles, and being an observer in 10 cases with a mentor in an external centre. No counsellor accompanied the surgeon during the cases. HoLEP operation was performed by the same urologist on 100 patients. Informed consent was obtained from all participants. All patients were evaluated preoperatively with serum prostate specific antigen (PSA), haemoglobin (Hb), transrectal ultrasound (TRUS), digital rectal examination (DRE), urinalysis and International Prostate Symptom No conflict of interest declared.

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Does Holmium laser enucleation of the prostate (HoLEP) still have a steep learning curve?

Score (IPSS). Uroflowmetry (UFM) was done and post-void residual urine (PVR) was measured by ultrasound. The patients who had high PSA were operated one month after prostate biopsy under transrectal ultrasound guidance. The drugs of patients who were receiving antiplatelet and anticoagulant treatment were discontinued 12 hours before the operation and they were replaced with low molecular weight heparin. Enucleation time and morcellation time were recorded perioperatively and the weight of the removed tissue was measured. Patients with IPSS ≥ 8, maximum urine flow rate (Qmax) ≤ 15 mL/h, and PVR ≥ 50 mL were included in the study. On the other hand, the patients with urethral stricture, neurogenic component, prostate cancer and bladder cancer were excluded from the study. The patients were classified into 4 main groups of 25 consecutively cases beginning from the first case to determine the learning curve. Group A consisted of the first 25 patients, group B consisted of the second 25 patients, group C consisted of the third 25 patients, and group D consisted of the fourth 25 patients. The 4 main groups were divided into 2 subgroups as the patients who had prostate volume below or above 80 grams. The two subgroups were statistically compared within themselves. Surgical technique Upon the anaesthetist’s preference, the operations were performed under general anaesthesia and spinal anaesthesia. 120W Holmium: yttrium-aluminiumgarnet (Versa Pulse Power Suite, Lumenis, Yokneam Israel), resectoscope, morcellator and display screen appropriate for 26 F HoLEP (Richard Wolf GmbH, Knittlingen, Germany) were used during the surgery. After the surgery was completed, all tissues were examined histologically. A 22 F 3-way catheter was used in the patients and washing with continuous saline was performed until haematuria ceased. Control hemogram was checked at the first postoperative day. The patient was discharged from the hospital after the catheter was removed and micturition was performed after the end of haematuria of the patient. Postoperative follow-up IPSS, UFM, PVR, and quality of life (QoL) were checked during followup at 1st, 3rd, and 6th month postoperatively, and serum PSA and postoperative TRUS measurements were performed at 3rd month. Postoperative complications were graded using the Clavien-Dindo classification (12). Continence sta-

tus and post micturition symptoms (PMS) were evaluated according to the standards which are recommended by the International Continence Society (ICS) (13). Statistical evaluation SPSS (Statistical Package for the Social Sciences) 23.0 (IBM, Armonk, NY) package program was used for statistical analysis of the data. Categorical measurements were reported as numbers and percentages, and continuous measurements as mean and standard deviation (median and minimum-maximum where needed). Shapiro-Wilk test was used to determine whether the parameters in the study showed a normal distribution or not. The Kruskal Wallis test was used in the analysis of more than two groups. Bonferroni method, which is one of the Post Hoc analysis methods, was used to determine the source of the difference between the groups. Statistical significance level was taken as 0.05 in all tests.

RESULTS

The mean age of 100 patients who had HoLEP was 64.5 years. The mean prostate volume was 99.1 cc (45-281

Table 1. Patient demographics and perioperative results.

Mean age (years) P Mean PSA (ng/ml) P Mean prostate volume (ml) P Enucleation time (min) P Post hoc p Morcellation time (min) P Post hoc p Amount of removed tissue (gr) P Enucleation efficiency (g/min) P Post hoc p

Morcellation efficiency (g/min) P Post hoc p Loss of haematocrit P Length of hospitalization (day) P Length of removing (hour) P Post hoc p

< 80 G Group A Group B Group C Group D n n n n 12 10 12 11 68.1 63.5 61.6 65.2 .101 3.6 2.4 3 2.8 .851 64 63.1 59.7 65 .741 103.3 60.5 54.1 48.2 < .001 A-B; p < .001 A-C; p < .001 A-D; p < .001 14.3 13 11.6 11.8 < .001 A-C; p < .001 A-D; p < .001 B-D; p = .005 47.8 48.5 46.2 47.2 .874 .654 0.46 0.8 0.85 0.97 < .001 B-A; p < .001 C-A; p < .001 D-A; p < .001 D-B; p = .043 3.34 3.73 3.98 4 < .001 C-A; p = .003 D-A; p < .001 D-B; p = .003 4.2 3.7 3.5 2.5 .615 2.08 2.2 1.7 1.8 .275 34.8 30.2 27.8 25.6 .037 A-D; p = .044

Group A n 13 64.3

> 80 G Group B Group C n n 15 13 65.4 61.6

Group D n 14 66.4 .232 9.02 .977 125.7 .522 93.5 .001 A-B; p = .005 A-D; p < .001

9.8

8.35

7.8

131.3

116.5

143.8

156.9

108.6

125.7

26.7

26.3

28.6

23.9 .168

105

100.6

119

97.5

0.66

0.92

0.94

1.04 < .001 B-A; p = .003 C-A; p = .002 D-A; p < .001

3.93

3.82

4.25

4.07 0.040 C-B; p = .026

5.8

4.7

4.1

3.5

2.7

2.61

62.6

45.3

43.6

3.5 .907 2.14 .333 31.8 .024 A-D; p = .012

P < 0.05; Kruskal Wallis test. Post Hoc Bonferroni analysis; PSA: prostate-specific antigen. The efficiency of each procedure was calculated as weight of removed tissue in g/min.

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Figure 1. The difference between Enucleation efficiency ve Morcellation efficiency in 4 Groups at < 80 g prostate volume.

* Enucleation efficiency [weight of enucleated tissue/lasing time (g/min)) and morcellation efficiency (weight of enucleated tissue/morcellation time (g/min)].

cc). Patients with prostate smaller than 80 g were 45% of all patients. When these patients were considered, it is seen that there was no significant difference (p > 0.05) between mean age (p = .101), PSA (p = .851), prostate volume (p = .741), hematocrit loss (p=.615), and hospital stay (p = .275) of the patients in four groups (A, B, C, D). Enucleation time and morcellation time were statistically different between the groups (p < .05). The two most important parameters of the learning curve, Enucleation efficiency and Morcellation efficiency were 0.76 g/min (0.46-0.97 g/min) and 3.07 g/min (3.34-4 g/min), respectively. These two parameters were statistically and significantly different in all 4 groups (p < .05). Catheter removal time was also statistically different between the groups (p < .05) (Table 1 and Figure 1). The patients with prostates larger than 80 g were 55% of all patients. When these patients were considered, it was seen that there was no significant difference (p > .05) with respect of mean age (p = .232), PSA (p = .977), prostate volume (p = .522), morcellation time (p = .168), amount

of tissue removed (p = 0.654), hematocrit loss (p = .907), and length of hospital stay (days) (p = .333) between patients of four groups (A, B, C, D). Enucleation efficiency was 0.89 g/min (0.66-1.04 g/min) and Morcellation efficiency was 4.01 g/min (3.93-4.25 g/min). There was a statistically significant difference between the groups in terms of enucleation time, enucleation efficiency and morcellation efficiency (p < .05). Therefore, when all groups were considered, it was seen that the Enucleation efficiency and Morcellation efficiency were the highest in cases from 25th to 50th, although there was a further improvement even in the cases from 75th to 100th (Table 1 and Figure 2). Clavien grade 1 and grade 2 complications were observed in 19 cases in group A, in 16 cases in group B, in 5 case in group C and in 4 cases in group D. The most common complication was capsular perforation and it was seen in 16 (16%) patients. In the first 25 cases, 10 capsule perforations occurred although they were usually minimal. Clavien Grade 3 complication was seen in 9 cases in Figure 2. The difference between Enucleation efficiency ve Morcellation efficiency in Group D at > 80 g prostate volume.

* Enucleation efficiency [weight of enucleated tissue/lasing time (g/min)) and morcellation efficiency (weight of

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Does Holmium laser enucleation of the prostate (HoLEP) still have a steep learning curve?

number of cases ranged between 20 and 60 (20-30 most commonly). In addition, it was determined < 80 g > 80 g that the number of cases was less Group A Group B Group C Group D than 20 in only 2 studies (17). < 80 g > 80 g < 80 g > 80 g < 80 g > 80 g < 80 g > 80 g Shah et al. found out in their Capsule perforation (Clavien 1) 3 7 1 4 1 prospective series that the operaReturning to TURP or OP (Clavien 3) 3 tor became a master at HoLEP Not being able to proceed to after an average of 20 cases. Morcellation due to bleeding (Clavien 3) 1 2 1 However, this study was limited Leaving the case into the second session (Clavien 3) 2 1 to small prostates. It was reported Bladder injury (Clavien 1) 1 1 1 that additional learning is Ureteral orifice injury (Clavien 1) 2 required to pass on to large Blood transfussion (Clavien 2) prostate volume from small Re-catheterization (Clavien 1) 2 prostate volume (10). Seki et al. Urinary system infection (Clavien 2) 1 1 found the mean enucleation effiEarly period stress incontinence ciency to be 0.29 and 0.75 gm/m (Clavien 1) 3 5 2 4 2 2 1 2 in the first 10 and the last 10 cases Late period urinary incontinence of a total of 70 cases, respectively (Clavien 2-3) (11). Similarly, Placer et al. dividUrethral stricture (Clavien 3) 1 1 1 ed their series of 125 cases into subgroups of 25 consecutive patients each, showing that the group A, two in group B, and two in group C, and none efficiency of enucleation and morcellation increased with in group D. No Clavien Grade 4 or 5 complications were the number of procedures (9). Brunckhurst et al. reported seen in any group. Complication rates were found to be a steep increase in performance in the first 20-30 cases very low and stable between 50th and 75th case, while and a plateau occurring following the first 50-60 cases Grade 3, 4 and 5 complications were not seen between but they added that there were improvements and vari75th and 100th case (Table 2). ability in efficiency even after 150 cases (18). Moreover, Du et al. showed that enucleation efficiency increases with years of experience and is most encountered in men with DISCUSSION a large prostate > 100 g (19). Bae J et al. showed in their When HoLEP technique is compared with TURP and OP, study with 161 cases, that the enucleation efficiency it can be observed that it has superior haemostatic charincreased significantly after a minimum of 30 cases (20). acteristics, lower morbidity and more efficiency. Jeong et al. found that enucleation efficiency increased in Furthermore, global costs of HoLEP are comparable to the first 50 cases and there was a strong linear correlation those of TURP and proved to be a strong competitor of with total prostate volume. OP. On the other hand, the most important disadvantage Perioperative clinical variables, including enucleation of the HoLEP technique is that it is difficult to learn it. time, morcellation time, enucleation ratio (enucleation A significantly longer adaptation time is required espeweight/transitional zone volume), enucleation efficacy cially for novice surgeons when compared to TURP. (enucleated weight/enucleation time), enucleation ratio It requires considerable experience to determine the surefficacy (enucleation ratio/enucleation time), and early gical border between prostate adenoma and prostate capcomplication rate were analysed. They evaluated the enusule particularly for HoLEP. It is assumed that such a cleation ratio efficacy by dividing the enucleation ratio good method is still not globally adopted as the gold stan(enucleation weight/transitional zone volume) by enucledard treatment and it is seen as an alternative to TURP ation time. They suggested that this new parameter might and open prostatectomy according to the guidelines, remove the confounding effect of prostate size resulting because it is difficult to learn and has complications from enucleation efficiency. This parameter became staoccurring during the learning curve (14-16). ble after 25 cases, and the authors interpreted that this Both intraoperative and postoperative data are important number was also consistent with the surgeon's confidence for evaluating the learning curve of HoLEP. The indicain performing HoLEP (21). Similarly, Kim et al. proposed tors of surgical activity are enucleation efficiency (weight the enucleation time-energy efficacy, defined as enucleatof enucleated tissue/lasing time) and morcellation effied weight/enucleation time/consumed energy. In their ciency (weight of enucleated tissue/morcellation time). studies, this parameter continued to improve after 30 These two indicators of operative efficiency have been cases and it become stable between 60th and 70th cases used in various previous learning curve studies as a pri(22). Elzayat et al. reported that best enucleation efficienmary outcome measure (10, 11). In a systematic review cy was reached after about 20-30 cases (8). In both two which went over 24 studies, it was reported that only 4 subgroups in our study, enucleation efficiency displayed Authors of these 24 studies did not provide any recoma statistically significant steep curve after the first 25 cases mendations about the number of cases which was and enucleation efficiency increased in parallel with case required to complete the learning curve of HoLEP. experience in line with the literature. Besides, it was recommended in the 20 studies that the Morcellation efficiency is also an important indicthator Table 2. Intraoperative and postoperative complications.

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for the learning curve. Learning morcellation is relatively easier than learning enucleation. However, it has been reported in some publications that morcellation causes serious morbidities such as bladder injury at a rate of 18% (23-10) although it seems easier (23-10). Brunckhurst et al. showed that morcellation increased its efficiency after 40-60 cases (18). Soto et al. reported that morcellation efficiency increased statistically after the 50th case without mentor (24). In our study, morcellation efficiency increased significantly especially after the first 25 cases. It was seen that morcellation performance developed as the case experience increased. However, enucleation efficiency and morcellation efficiency require similar number of cases although morcellation is easier to learn than enucleation (25 cases). We explain this situation as the fact that haematuria, which occurs as a result of poor enucleation in the first 25 cases, affects the image quality, and the surgeon wants to work slowly and in a controlled manner as he fears of bladder injury during morcellation. Perioperative complications can also be a reference for the learning curve. Capsular perforation and superficial bladder mucosal injury have been shown to be the most common complications in the intraoperative period. The most comprehensive study on this subject was conducted by Kendidra et al. The complications of 280 patients were evaluated and it was reported that the most common perioperative complication was capsular perforation with 9.6% and the second most common perioperative complication was superficial bladder mucosal injury and ureter orifice injury (10). Accordingly, it is important to recognize the capsule in this operation both in terms of facilitating enucleation and being able to control bleeding more easily. It should be kept in mind by the surgeon that the prostate capsule in small prostates is not clearly separated and the prostate capsule has too many vascular networks in large prostates. In our study, we did not experience any capsule perforation in 10 patients (40%) in group A, 5 patients (20%) in group B, 1 patient (4%) in group C and none in group D. Perforations were minimal except for 3 patients in the first group and the catheter was kept for one more day in these patients. It was returned to open surgery during the operation (Clavien 3) in 3 patients because of large perforation area and the catheter was kept longer. We assumed that having such high capsule perforation rate especially in the first cases resulted from the lack of a mentor during learning. One of the perioperative complications is returning to TURP or OP. In their series of 146 cases, Kobayashi et al. reported that it was returned to TURP in only 12 cases in their series of 146 cases, and the main reason for this was capsular perforation or uncontrolled bleeding (25). However, it was reported in the study of Bapat et al. that it was returned to standard TURP in the first 13 cases (26). On the contrary to these two studies, Jeong et al. reported that it was not returned to TURP in any of the cases despite having no mentoring (21). In our study, it was returned to TURP/OP during the operation in 3 cases which had prostate volume of > 80 g in the first 25 cases. Postoperative complications can also affect the learning curve. Especially stress urinary incontinence (SUI) is one of the postoperative complications that surgeons feel more

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anxious. Urologists feel serious stress and the learning curve is prolonged due to the fear of causing a sphincteric insufficiency to the patient, due to sphincteric injury in case of long duration procedure, as well as excessive stretching of the anterior of the external sphincter during enucleation of the prostate at 12 o’clock and thermal injury due to use of laser near the sphincter. Placer et al. found that transient urinary incontinence, persistent stress urinary incontinence (lasting longer than 6 months), and storage symptoms were observed more commonly in the first 50 cases (9). Lerner et al. evaluated stress urinary incontinence (SUI) at 3 months in the early postoperative period during a single surgeon's learning curve and found out that SUI was more common when time intervals between the cases were longer (27). Shigemura et al. found that the experience with at least 20 cases significantly affected urinary incontinence (28). In another study, patients with enucleated prostate volume > 50 g and blood loss > 2.5 g/dL were associated with SUI (26). Kim et al. found that 11% of the patients had urge incontinence after the urethral catheters were removed after surgery (22). In our study, 8 (32%) of the first 25 cases had SUI in the first 3 months, and trend continued at a diminishing pace after 25 cases. None of SUI stayed permanent and all the cases returned to normal within 3 months. In this study, we compared the results of 100 consecutive cases of a single surgeon without a mentor with the literature. Our results were comparable with the literature in terms of learning curve, perioperative and postoperative outcomes, as well as functional outcomes and continence status. Our study has also some limitations. It reflects the results of only one centre and includes a limited number of patients. Another limitation is that it presents the experience of a single surgeon, so the results could be not reproducible by another surgeon with similar experience. In conclusion, this is the first study which focused on the learning curve in Turkey, to the best of our knowledge. The HoLEP technique still has a steep learning curve, and we predict that a surgeon should perform between 25-50 cases to reach the necessary experience. In addition, we believe a surgeon could cope with HoLEP technique without a mentor or simulation-based training.

CONCLUSIONS

HoLEP still has a steep learning curve. It is necessary to reach a number of cases of 25-50 to reach fundamental experience. Moreover, it can be coped with HoLEP without having a mentor.

REFERENCES

1. Gilling PJ, Kennett K, Das AK, et al. Holmium laser enucleation of the prostate (HoLEP) combined with transurethral tissue morcellation: an update on the early clinical experience. J Endourol. 1998; 12:457-9. 2. McVary KT, Roehrborn CG, Avins AL, et al. Update on AUA guideline on the management of benign prostatic hyperplasia. J Urol. 2011; 185:1793-803. 3. Cornu JN, Ahyai S, Bachmann A, et al. A systematic review and

Does Holmium laser enucleation of the prostate (HoLEP) still have a steep learning curve?

meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic obstruction: an update. Eur Urol. 2015; 67:1066-1096. 4. Ahyai SA, Gilling P, Kaplan SA, et al. Metaanalysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic enlargement. European urology. 2010; 58:384-97. 5. Foster HE, Barry MJ, Dahm P, et al. Surgical management of lower urinary tract symptoms attributed to benign prostatic hyperplasia: AUA Guideline. J Urol. 2018; 200:612-9. 6. Oelke M, Bachmann A, Descazeaud A, et al. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol. 2013; 64:118-40.

prostatectomy in a tertiary Italian center: A prospective cost analysis in comparison with bipolar TURP and open prostatectomy. Arch Ital Urol Androl. 2020; 92:82-88. 17. Kampantais S, Dimopoulos P, Tasleem A, et al. Assessing the learning curve of holmium laser enucleation of prostate (HoLEP). A systematic review. Urology. 2018; 120: 9-22. 18. Brunckhorst O, Ahmed K, Nehikhare O, et al. Evaluation of the learning curve for holmium laser enucleation of the prostate using multiple outcome measures. Urology. 2015; 86:824-829. 19. Du C, Jin X, Bai F, Qiu Y. Holmium laser enucleation of the prostate: the safety, efficacy, and learning experience in China. J Endourol. 2008; 22:1031-1036. 20. Bae J, Oh SJ, Paick JS. The learning curve for holmium laser enucleation of the prostate: a single-center experience. Korean J Urol. 2010; 51:688-693.

7. Van Rij S, Gilling PJ. In 2013, holmium laser enucleation of the prostate (HoLEP) may be the new 'gold standard'. Curr Urol Rep. 2012; 13:427-32.

21. Jeong CW, Oh JK, Cho MC, et al. Enucleation ratio efficacy might be a better predictor to assess learning curve of holmium laser enucleation of the prostate. Int Braz J Urol. 2012; 38:362-371.

8. Elzayat EA, Elhilali MM. Holmium laser enucleation of the prostate (HoLEP): long term results, reoperation rate, and possible impact of the learning curve. Eur Urol. 2007; 52:1465-71.

22. Kim KH, Kim KT, Oh JK, et al. Enucleated weight/enucleation time, is it appropriate for estimating enucleation skills for holmium laser enucleation of the prostate? A consideration of energy consumption. World J Mens Health. 2018; 36:79-86.

9. Placer J, Gelabert-Mas A, Vallmanya F, et al. Holmium laser enucleation of prostate: outcome and complications of self-taught learning curve. Urology. 2009; 73:1042-8. 10. Shah HN, Mahajan AP, Sodha HS, et al. Prospective evaluation of the learning curve for holmium laser enucleation of the prostate. J Urol. 2007; 177:1468-1474. 11. Seki N, Mochida O, Kinukawa N, et al. Holmium laser enucleation for prostatic adenoma: analysis of learning curve over the course of 70 consecutive cases. J Urol. 2003; 170:1847-1850. 12. Morgan M, Smith N, Thomas K, Murphy DG. Is Clavien the new standard for reporting urological complications? BJU Int. 2009; 104:434-6. 13. Donovan JL, Peters TJ, Abrams P, et al. Scoring the short form ICS male SF questionnaire. International Continence Society. J Urol. 2000; 164:1948-55. 14. Gravas S, Bachmann A, Reich O, et al. Critical review of lasers in benign prostatic hyperplasia (BPH). BJU Int. 2011; 107:10301043. 15. Khan N, Abboudi H, Khan MS, et al. Measuring the surgical 'learning curve': methods, variables and competency. BJU Int. 2014; 113:504-508. 16. Schiavina R, Bianchi L, Giampaoli M, et al. Holmium laser

23. Montorsi F, Naspro R, Salonia A, et al. Holmium laser enucleation versus transurethral resection of the prostate: results from a 2center prospective randomized trial in patients with obstructive benign prostatic hyperplasia. J Urol. 2008; 179(5 Suppl):S87-90. 24. Soto-Mesa D, Amorin-Diaz M, Perez-Arviza L, et al. Holmium laser enucleation of the prostate and retropubic prostatic adenomectomy: morbidity analysis and anesthesia considerations. Actas Urol Esp. 2015; 39:535-545. 25. Kobayashi S, Yano M, Nakayama T, Kitahara S. Predictive risk factors of postoperative urinary incontinence following holmium laser enucleation of the prostate during the initial learning period. Int Braz J Urol. 2016; 42:740-746. 26. Bapat S, Pai K, Purnapatre S, et al. Holmium laser assisted 'anatomical' enucleation of adenoma of benign hyperplasia of prostate. Indian J Urol. 2006; 22:49-52. 27. Lerner LB, Tyson MD, Mendoza PJ. Stress incontinence during the learning curve of holmium laser enucleation of the prostate. J Endourol. 2010; 24:1655-1658. 28. Shigemura K, Yamamichi F, Kitagawa K, et al. Does surgeon experience affect operative time, adverse events and continence outcomes in holmium laser enucleation of the prostate? A review of more than 1,000 cases. J Urol. 2017; 198:663-670.

Correspondence Kadir Karkin, MD kadir_karkin@msn.com Güçlü Gürlen, MD guclugurlen@hotmail.com Health Sciences University, Adana City Training and Research Hospital, Department of Urology, 01330, Adana, Turkey

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ORIGINAL PAPER

DOI: 10.4081/aiua.2021.4.418

The use and applicability of machine learning algorithms in predicting the surgical outcome for patients with benign prostatic enlargement. Which model to use? Panagiotis Mourmouris 1, Lazaros Tzelves , Georgios Feretzakis 2, 3, Dimitris Kalles 2, Ioannis Manolitsis 1, Marinos Berdempes 1, Ioannis Varkarakis 1, Andreas Skolarikos 1 1 2nd

Department of Urology, National and Kapodistrian University of Athens, Sismanogleio General Hospital, Athens, Greece; of Science and Technology, Hellenic Open University, 26335 Patras, Greece; 3 Department of Quality Control, Research and Continuing Education, Sismanogleio General Hospital, 15126 Marousi, Greece. 2 School

Summary

Objectives: Artificial intelligence (AI) is increasingly used in medicine, but data on benign prostatic enlargement (BPE) management are lacking. This study aims to test the performance of several machine learning algorithms, in predicting clinical outcomes during BPE surgical management. Methods: Clinical data were extracted from a prospectively collected database for 153 men with BPE, treated with transurethral resection (monopolar or bipolar) or vaporization of the prostate. Due to small sample size, we applied a method for increasing our dataset, Synthetic Minority Oversampling Technique (SMOTE). The new dataset created with SMOTE has been expanded by 453 synthetic instances, in addition to the original 153. The WEKA Data Mining Software was used for constructing predictive models, while several appropriate statistical measures, like Correlation coefficient (R), Mean Absolute Error (MAE), Root Mean-Squared Error (RMSE), were calculated with several supervised regression algorithms - techniques (Linear Regression, Multilayer Perceptron, SMOreg, k-Nearest Neighbors, Bagging, M5Rules, M5P - Pruned Model Tree, and Random forest). Results: The baseline characteristics of patients were extracted, with age, prostate volume, method of operation, baseline Qmax and baseline IPSS being used as independent variables. Using the Random Forest algorithm resulted in values of R, MAE, RMSE that indicate the ability of these models to better predict % Qmax increase. The Random Forest model also demonstrated the best results in R, MAE, RMSE for predicting % IPSS reduction. Conclusions: Machine Learning techniques can be used for making predictions regarding clinical outcomes of surgical BPRE management. Wider-scale validation studies are necessary to strengthen our results in choosing the best model.

KEY WORDS: Artificial intelligence; Benign prostatic enlargement; Machine learning; Transurethral resection; Transurethral vaporization. Submitted 8 August 2021; Accepted 22 September 2021

INTRODUCTION

The holy grail of surgery, in every surgical field, is the ability to make accurate predictions of magnitude and

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direction of possible outcomes, after performing each treatment-procedure for every individual patient. The best method to accomplish the aforementioned goal, especially in urology, was the development of nomograms, which are based on conventional statistical methods (1). Such statistical methods are performed on a specific dataset with the main purpose to identify potential relationships (2). These techniques are usually applied on local datasets, but to be valid, a set of assumptions should be met, which commonly are underestimated in medical literature (3). With the increase in volume and availability of data, a novel tool has emerged and has the potential to surpass all others, setting new standards in the management of patients. This novel tool is machine learning, a major artificial intelligence (AI) field, which develops models based on large volumes of data in order to detect relationships or make predictions (3). The strict assumptions, which determine statistics applicability, do not pose a limit for AI and machine learning (ML) techniques, offering the advantage of greater flexibility and access to more healthcare-related data, which commonly do not comply with these rules (3). In the past two decades, AI has been increasingly applied in everyday urological clinical practice and has shown promising results (1, 4). Most of available data of AI applications in urology, deal mainly with oncologic patients and associated health issues. In benign prostatic enlargement (BPE), AI has been recently used for predicting the severity of obstruction using diagnostic tests (5, 6). Torshizi et al. (6) attempted to infer symptom score and also provide a treatment suggestion for BPE, using a fuzzy-ontology system, which relies on a logic of imprecise information or variables used to make inferences (6, 7). A reported accuracy of 90%, when compared to expert opinion for making this decision, implies that AI can be helpful in benign urological conditions. Back in 2001, Megherbi et al. (8), evaluated four AI algorithms regarding their predictive ability of surgical treatment success for BPE, using either transurethral resection or visual laser ablation of the prostate (VLAP) (8). The small number of patients, along with the vague definition of outcome, limit the applicability of these findings. No conflict of interest declared.

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Machine learning in BPE surgery

Several techniques exist for the surgical management of BPE, including transurethral vaporization using normal saline and bipolar energy (TUVis), transurethral resection using normal saline and bipolar energy (TURis) and transurethral resection using monopolar energy (TURP), with results showing similar efficacy in most trials at a short-term follow-up of 12 months, using conventional statistical analysis (9). The aim of this study is to test and compare several machine learning algorithms, regarding their predictive ability for assessing treatment outcomes for BPE (IPSS score and Qmax changes), using baseline patient characteristics and one of the treatment methods (TUVis, TURis, TURP).

METHODS Patients Patients suffering from BPE, who were admitted at our tertiary care Urology Department between September 2017 and March 2019, were operated with one of three available methods (transurethral vaporization-TUVis, transurethral resection using bipolar energy-TURis, transurethral resection using monopolar energy-TURP), according to patient choice, physician surgical competence and equipment availability. Data were extracted retrospectively, using a prospectively collected database, and the study protocol was duly approved by the institutional review board of the hospital (19836/07.10.2020). All patients signed informed consent before being treated for their condition and were treated according to the principles of the Helsinki Declaration (10). Patients were included in the study if they had prostate volume > 30 ml, indication for surgical management (urinary retention, failure of medical management, recurrent hematuria or urinary tract infections), absence of diagnosed prostatic adenocarcinoma and/or pathologic digital rectal examination, IPSS> 7, and Qmax < 15 ml/sec. Data collected Baseline demographic data (age, medical history, use of antiplatelets, indication for surgery, ASA score) and BPEspecific data (IPSS/Qmax/post-voiding residual (PVR) preand postoperatively, prostate volume, PSA, procedural time, haemoglobin, and sodium changes and complication rates) were collected. Functional outcomes were assessed based on follow-up visits at 12 months after surgery. Operative technique Surgery was performed under spinal anesthesia in all cases, using a 26 Fr continuous flow resectoscope (Olympus TURis 2.0, Iglesias type) for bipolar resection and vaporization and a 28 Fr non-rotating continuous flow resectoscope (Karl Storz) for monopolar resection. Glycine 1.5% solution was used as irrigation flow for monopolar TUR-P and N/S 0.9% for bipolar TUR-P and vaporization. During vaporization of the prostate, an electrode with a mushroom-like shape was used, and energy settings were set at 270-290 watt for vaporization and 120-140 watt for coagulation. For transurethral resection, the method of Mauermayer or Nesbit was followed (11),

while for vaporization, the hovering technique was used during which the electrode comes in direct contact with the prostatic tissue. Data analysis Basic descriptive statistics (mean, standard deviation, range) for the numerical variables (age, prostate volume, baseline Qmax, baseline IPSS, % Qmax Increase, % IPSS reduction) have been used. Several independent variables and outcome measures have been tested, but we present only those predictors resulting in significant outcomes. The WEKA Data Mining Software was used for this study. This comprises an open-source machine learning toolkit containing a wide range of learning algorithms (12). Since no credible validation can be made to assess the performance of the final model (13), if the total dataset is used to train a model and then reused for testing, we set aside some data which must not be used during training. The dataset set aside makes up the test set, which allows us to compare actual values of the test data to the values predicted from the WEKA-based models. The most widely used method to take advantage of the dataset is cross-validation, where we can use all of the data in test sets, but not simultaneously. Therefore, our data were divided into a number of equal-sized subsets, called folds. If we have k folds, then this is called k-fold cross-validation. Each fold is used once for testing on the model built using the remaining k-1 folds. Cross-validation is widely regarded as a reliable way to assess the quality of results from machine learning techniques; in our analysis, we have used 10-fold cross-validation (14). While k-fold cross-validation is a standard method for making good use of available data, there are still various statistical measures which can be computed, and which reveal different interpretations/aspects. In order to find the best regression model for numeric prediction, we consider the performance measures of Correlation coefficient (R), Mean Absolute Error (MAE), Root Mean-Squared Error (RMSE), as reported by WEKA software (13) as described in Appendix A (Supplementary Materials). The supervised regression algorithms - techniques that are used in this research are: Linear Regression, Multilayer Perceptron, SMOreg, k-Nearest Neighbors, Bagging, M5Rules, M5P - Pruned Model Tree, and Random forests. Although the technical details of these techniques are beyond the scope of this article, a summary of them can be found in Appendix B (Supplementary Materials). Due to the small size of the initial data set, we examined the performance of aforementioned algorithms by applying a method for increasing our sample size, the Synthetic Minority Oversampling Technique (SMOTE), which is a statistical method for uniformly increasing the number of cases in a data set to render it more balanced. However, in our case, we just used SMOTE to increase our dataset by generating extra artificial instances in a statistically sound way. The new (artificial) instances that were generated by the SMOTE are not just duplicates of existing minority instances. Instead, this method takes feature space samples for each target class and its nearest neighbours. After that, new instances are produced that combine features of the target case with those from its neighbours (15). Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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Total Variable Age (years) Prostate volume(ml) Baseline Qmax (ml/sec) Baseline IPSS Percentage Qmax increase(%) Percentage IPSS reduction(%)

Range Mean/SD 47-91 70.39/8.67 20-175 59.48/24.44 3.40-11.90 7.24/1.75 16-29 21.81/2.97 60-394 160.39/62.98 29.4-76.5 59.5/7.1

Mean/SD 69.87/9.41 59.88/20.51 6.52/1.53 22.85/3.05 181.27/60.0 57.3/7.6

Per system TURis Range Mean/SD 47-89 70.87/8.73 20-175 63.48/29.20 3.40-11.90 7.83/1.90 17-29 21/2.60 60-394 149.60/72.4 44.0-75.0 63.2/7.1

TUVis Range Mean/SD 47-91 70.75/8.78 31-98 61.24/20.66 3.40-9.30 6.67/1.24 16-28 22.79/2.83 89.00-388.00173.62/47.96 29.4-75.0 57.46/6.5

Per system TURis Range Mean/SD 47-89 71.41/8.77 20-175 62.56/25.83 3.4-11.9 7.68/1.69 17-29 20.76/2.49 60.00-394.00 152.78/63.82 44-75 63.07/6.15

TUVis Range 47-91 31-98 3.40-9.30 16-28 89-388 29.4-75

Total Variable Age (years) Prostate volume (ml) Baseline Qmax (ml/sec) Baseline IPSS Percentage Qmax increase (%) Percentage IPSS reduction (%)

Range 47-91 20-175 3.40-11.90 16-29 60.00-394.00 29.4-76.5

Mean/SD 70.44/8.46 58.94/22.94 7.16/1.50 21.90/2.81 162.10/53.12 59.28/6.28

TURP Range 51-88 20-105 4.50-9.90 17-28 69-296 50-76.5

Mean/SD 70.43/7.68 54.81/21.78 7.38/1.51 21.57/2.90 149.67/47.89 58.07/4.55

TURP Range Mean/SD 51-88 69.09/7.57 20-105 52.74/20.64 4.50-9.90 7.13/1.37 17-28 22.06/2.71 59.00-296.00 159.81/42.71 50.0-76.5 57.30/4.02

Table 1. Baseline patient characteristics.

Table 2. Augmented dataset statistics after applying SMOTE *.

* SMOTE: Synthetic Minority Oversampling Technique.

RESULTS

A total of 153 patients with BPE were included (52 in TUVis group, 52 in bipolar-TURis group and 49 in monopolar TURP group). Baseline patient characteristics and % Qmax Increase, % IPSS reduction, are shown in Table 1. Machine learning techniques were applied in all outcomes gathered from chart review (functional outcomes-IPSS/PVR/Qmax change after surgery, haemoglobin drop postoperatively, sodium drop postoperatively, procedural time) using method of operation, age, prostate volume, ASA score, indication for surgery, use of antiplatelets, baseline Qmax and baseline IPSS as predictors, but in this study, only metrics of significant findings are reported. In order to better depict the increase in Qmax and reduction in IPSS, we use percentages rather than absolute differences. After applying the SMOTE, the new dataset contains an extra 453 synthetic instances,in addition to the original 153 patients’ data. The new allocation of the 606 instances is: 205 in TUVis group, 205 in bipolar-TURis group and 196 in monopolar TURP group. Baseline patient characteristics and % Qmax increase, % IPSS reduction, are shown in Table 2. According to Table 3, considering all three metrics (R, MAE, RMSE) for % Qmax increase, Random Forest algorithm outperforms other models, with values of correlation coefficient (R) 0.9697, MAE 7.78 and RMSE 13.26. The values of MAE and RMSE are percentage points since the target variable % Qmax increase denotes the corresponding percentage increase of Qmax after applying the corresponding system approach on a specific patient. As shown in Table 4, considering all three metrics (R, MAE, RMSE) for % IPSS reduction, the Random Forest model again outperforms other models, with values of

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Table 3. Percentage Qmax increase prediction using various machine learning methods. Method Linear regression Multilayer perceptron SMO reg lazy.IBk meta.Bagging M5Rules Trees.M5P trees.RandomForest

R 0.9004 0.9088 0.895 0.935 0.9526 0.9274 0.9253 0.9697 *

MAE 17.8 16.7 17.7 9.24 11.13 14.95 14.9 7.78 *

RMSE 23.12 22.2 23.85 18.80 16.25 19.88 20.15 13.26 *

R: Correlation coefficient; MAE: Mean Absolute Error; RMSE: Root Mean-Squared Error. Best results are marked by * in each column.

Table 4. Percentage IPSS reduction prediction using various machine learning methodslearning methods. Method Linear regression Multi layer perceptron SMOreg lazy.IBk meta.Bagging M5Rules

R 0.4493 0.5751 0.4199 0.8793 0.7906 0.678

MAE 4.14 3.95 4.17 1.53* 2.73 3.35

RMSE 5.61 5.36 5.7 3.07 3.91 4.62

trees.M5P trees.RandomForest

0.7231 0.8989 *

3.17 1.63

4.36 2.80 *

R: Correlation coefficient; MAE: Mean Absolute Error; RMSE: Root Mean-Squared Error. Best results are marked by * in each column.

Machine learning in BPE surgery

Figure 1. Development of a random forest from decision trees.

correlation coefficient 0.8989, MAE 1.63, and RMSE 2.80, with the only exception that k-Nearest Neighbors model has smaller but very close value of MAE. The values of MAE and RMSE are percentage points since the target variable % IPSS reduction denotes the corresponding percentage decrease of IPSS after applying the corresponding system approach. A Decision Tree algorithm is easily understood and ideal for obtaining non-linear relationships between independent and dependent variables. Random forest is a collection of decision trees constructed in a specific random manner. Random Forest usually performs better than a single Decision Tree in terms of accuracy and reduced overfitting. The major advantages of Random Forests are that they can handle both linear and non-linear relationships as well, they are not significantly impacted by outliers and they effectively balance the bias-variance tradeoff. Figure 1 shows an example of how a Random Forest is constructed from Decision Trees. Correlation coefficient (R) is used to measure the strength of a linear relationship between two variables, in our case the predicted and the actual values of the target variables % Qmax increase and % IPSS reduction. The closer the value of the correlation coefficient is to 1, the better the regression model is. Mean Absolute Error (MAE) is the average error between the absolute value of the predicted and actual value for each pair. Root Mean-Squared Error (RMSE) It shows how far predicted values fall from measured actual values using Euclidean distance. Concerning the values of the MAE and RMSE, the closer

their values to zero, the better the model's performance, since both metrics are proportional to the difference between the actual and predicted values. Readers can find on the website (16) two WEKA data set sample files (.arff) for experimental purposes to create their own models based on their local facility data. Furthermore, we have uploaded the two experimental models for % Qmax increase and % IPSS reduction prediction with considered independent variables the method of operation, age, prostate volume, baseline Qmax and IPSS.

DISCUSSION

The ultimate goal of AI is to create systems which are able to perform intellectually challenging tasks, similar to those performed by humans. Today, the closest we get to such systems, is usually aided by non-linear mathematic and statistical models (17) and mostly drawn from the machine-learning sub-field of AI, though significant developments also occur in other sub-fields too, such as natural language processing and visual perception with deep learning (7). A substantial number of such models attempt to assist medical practitioners, using a variety of sources for data and feedback, such as handwritten notes and books, medical imaging scanning and tissues grading. So, it is the impact on everyday clinical practice that will likely guide the training of these models and also decide the success of these AI technologies. In our study, we tested several machine learning algorithms, in order to find the Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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one with the least error in predicting IPSS reduction and Qmax increase, taking into consideration patient parameters that are widely available and easily assessed during daily urological practice in a usual clinical setting. Physicians could use these algorithms preoperatively and in conjunction with clinical judgement and discussion with patients, decide whether to perform surgery or not. There are, so far, some, but sparse, data about the implementation of this technological advance in urology, with the majority of existing studies in urological literature, focusing on the effect of these systems in improving prediction accuracy in prostate cancer diagnosis and management. There is still an unmet need for better prostate cancer detection in order to avoid unnecessary biopsies. A recent paper investigated different prostate-specific antigen (PSA) assays and developed a novel predictive tool based on artificial neural networks (ANN), concluding that AI technology can aid in minimizing variability of each PSA assay but only if a separate ANN system is utilized for every PSA assay and not one for all (18). As for the mpMRI diagnostic optimization, alongside their fusion biopsy implications, there is an increasing body of literature that reports on system development to integrate pre-processing, segmentation, and registration in order to fully automate the procedure, with promising outcomes so far (19-21). Besides cancer-related research, AI systems have also been utilized in other aspects of urological pathology. In urinary stone disease, there are reports that AI systems have been implemented in order to predict stone composition (22), surgical outcomes of percutaneous nephrolithotomy (PNL) (23), and shock wave lithotripsy (SWL) (24), with excellent accuracy. Similarly in patients with vesicoureteral reflux, as reported by Seckiner et al. (25), the ANN reported 98.5% sensitivity, 92.5% specificity, 97% positive predictive value, and 96% negative predictive value, which can definitely be considered very promising. Contradictive results were published for the role of AI systems in predicting surgical outcomes, mainly in robotic surgery (4, 26). The necessity to personalize treatment in patients with cancer and the high heterogeneity of neoplastic diseases is a potential reason that led scientists to focus mainly on this field of medicine and less on benign conditions like BPE. Notably, the implementation of AI techniques in BPE diagnosis and, especially, treatment is at its early stages, with currently scarce reports about the utilization of AI systems in BPE patients. Torshizi et al. presented a hybrid fuzzy- ontology intelligent system with multiple layers that consisted of two modules: the first was evaluating symptoms severity, whereas the second was evaluating the management options. Nevertheless, this system did not evaluate the outcomes of different surgical entities according to individual patient characteristics (6). Furthermore, the evaluation of bladder outlet obstruction symptoms has been the topic of another relatively recent study, where the detection rate of BPE in these patients using an ANN was 72%, and where the authors concluded that the pressure-flow study could not be omitted and replaced with the intelligent system.

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The management of BPE depends on disease stage, symptom intensity, patient preference and health status. Common indications for surgical management include failure of medical treatment for moderate- severe lower urinary tract symptoms (LUTS), recurrent urinary retention or infections, hematuria, bladder stones, kidney damage. A common perception is that prostate volume correlates with symptom severity and with health-related quality of life, but this is not backed up by the relevant literature (27). A clinical dilemma occurs in patients who do not fulfill criteria and absolute indications for surgery, while both physicians and patients need to know an estimation of functional outcomes post-operatively. Diagnostic tests are not highly specific for attributing LUTS to BPE, except for urodynamic testing, which is an invasive, costly and time-consuming examination. Choo et al developed a nomogram, which permits prediction of benign outlet obstruction-related surgery, with satisfactory metrics (28) based on clinical and urodynamic parameters. Since urodynamics is not available at every clinical setting, these nomograms may not be applicable for a substantial percentage of patients. According to Pielke (1984), a model can be considered predictive if two conditions are satisfied: (a) the standard deviations of the predictions and observations are approximately the same, and (b) RMSE is less than the standard deviation of the observations (29). Our results indicate that the Root Mean Squared Error (13.26) for the model % Qmax increase Random Forest is much smaller than the value of the standard deviation (53.12) of the actual values of the dependent variable % Qmax increase. Furthermore, the standard deviation of the predicted values is 57.53 percentage points (p.p.), which is close to the corresponding standard deviation of the actual values (62.79 p.p.). The results for the second model (% IPSS reduction Random Forest), indicate that the Root Mean Squared Error (2.80) for the best model is also much smaller than the value of the standard deviation (6.28) of the actual values of the dependent variable % IPSS reduction, and the standard deviation of the predicted values is 5.13 percentage points (p.p.) is very close to the corresponding standard deviation of the actual values (5.31 p.p.). Therefore, our proposed model meets the two conditions to be considered predictive, both regarding % Qmax increase and % IPSS reduction. Personalized medicine is touted as the future in healthcare settings, especially after the development of largescale databases with patient –omic characteristics (proteomics, genomics, metabolomics etc). Predictive analytics on data of such volume and complexity seems to be feasible using AI techniques with the ability to adapt and ‘’learn’’ from data during the whole process, giving endless opportunities both for patient outcomes improvement and cost savings for healthcare systems (30). A limitation of our study is that, due to the limited sample size, our models may not be immediately applicable to all urology departments. For that reason, it will be preferable that our methodology is implemented in the data of each local facility, or ideally, on a larger pool of data collected from multiple sites, so as to have a greater potential for learning and test whether the mean absolute

Machine learning in BPE surgery

error can be reduced. Another drawback of this study is that laser methods for prostate resection were not studied due to the lack of appropriate equipment during the period of data collection. Moreover, using more clinical-related data in the future, such asomic data, could pave the way for producing better predictive models. The retrospective collection of data is also a limitation, but since this was performed through a prospectively collected database, confounding is partially alleviated.

9. Gravas S CJ, Gacci M, Gratzke C, et al. Management of nonneurogenic male LUTS. EAU guidelines. ISBN 978-94-92671-07-3. 2020.

CONCLUSIONS

13. Ian H. Witten EF, Mark A. Hall, Christopher J. Pal. Data Mining, Fourth Edition: Practical Machine Learning Tools and Techniques (4th. ed.): Morgan Kaufmann Publishers Inc., San Francisco, CA, USA; 2016.

BPE is a very common clinical condition, with various treatment modalities available for patients. At the same time, AI models increasingly provide surgeons with accurate decision-making tools. As health information system (HIS) use is expanded in a healthcare facility, it will be easier to utilize data collected for the HIS using artificial intelligence techniques to benefit patients. This study presents a methodology for predicting clinical outcomes in BPE management, according to pre-operative characteristics and a variety of relatively standard and widely available AI techniques. Results are promising to regard IPSS and Qmax improvement, but more validation studies are needed before a wider scale application of these findings.

REFERENCES

1. Drouin SJ, Yates DR, Hupertan V, et al. A systematic review of the tools available for predicting survival and managing patients with urothelial carcinomas of the bladder and of the upper tract in a curative setting. World J Urol. 2013; 31:109-16. 2. Azzolina D, Baldi I, Barbati G, et al. Machine learning in clinical and epidemiological research: Isn’t it time for biostatisticians to work on it? Epidemiol. Biostat. Public Heal. 2019; 16:e13245-1-3. 3. Rajula HSRV G, Manchia M, Antonucci N, Fanos V. Comparison of conventional statistical methods with machine learning in medicine: diagnosis, drug development, and treatment. Medicina 2020; 56:455. 4. Hung AJ, Chen J, Gill IS. Automated performance metrics and machine learning algorithms to measure surgeon performance and anticipate clinical outcomes in robotic surgery. JAMA Surg. 2018; 153:770-1. 5. Sonke GS, Heskes T, Verbeek AL, et al. Prediction of bladder outlet obstruction in men with lower urinary tract symptoms using artificial neural networks. J Urol. 2000; 163:300-5. 6. Torshizi AD, Zarandi MH, Torshizi GD, Eghbali K. A hybrid fuzzy-ontology based intelligent system to determine level of severity and treatment recommendation for Benign Prostatic Hyperplasia. Comput Methods Programs Biomed. 2014; 113:301-13. 7. Zadeh LA. Fuzzy sets. Information and Control. 1965; 8:338-53. 8. Megherbi D, Boulenouar A, Kaula N, et al. Comparison of artificial intelligence and machine learning algorithms as a predictor of surgical outcomes in benign prostatic hyperlasia cases (BPH). Proc. SPIE 4389, Component and Systems Diagnostics, Prognosis, and Health Management, (20 July 2001).

10. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. Jama. 2013; 310:2191-4. 11. Mauermayer W. Transurethral surgery: Springer-Verlag Berlin Heidelberg; 1983. 12. Hall M, Frank E, Holmes G, et al. The WEKA data mining software: An update. SIGKDD Explor Newsl. 2008; 11:10-8.

14. Bengio Y, Grandvalet Y. No unbiased estimator of the variance of K-fold cross-validation.J Mach Learn Res. 2004; 5:1089-1105. 15. Microsoft Azure, SMOTE [Internet]. Cited at 03 July 2021. Available from: https://docs.microsoft.com/en-us/azure/machinelearning/algorithm-module-reference/smote 16. The use and applicability of machine learning algorithms in predicting the surgical outcome for patients with benign prostatic enlargement. Which model to use? Available online: http://www.learningalgorithm.eu/datafiles_Urol.html (accessed on 4July 2021). 17. Chen J, Remulla D, Nguyen JH, et al. Current status of artificial intelligence applications in urology and their potential to influence clinical practice. BJU Int. 2019; doi: 10.1111/bju.14852. 18. Stephan C, Cammann H, Meyer HA, et al. An artificial neural network for five different assay systems of prostate-specific antigen in prostate cancer diagnostics. BJU International. 2008; 102:799-805. 19. Song Y, Zhang YD, Yan X, et al. Computer-aided diagnosis of prostate cancer using a deep convolutional neural network from multiparametric MRI. J Magn Reson Imaging. 2018; 48:1570-7. 20. Wildeboer RR, van Sloun RJG, Wijkstra H, Mischi M. Artificial intelligence in multiparametric prostate cancer imaging with focus on deep-learning methods. Computer methods and programs in biomedicine. 2020; 189:105316. 21. van Sloun RJG, Wildeboer RR, Mannaerts CK, et al. Deep learning for real-time, automatic, and scanner-adapted prostate (zone) segmentation of transrectal ultrasound, for example, magnetic resonance imaging-transrectal ultrasound fusion prostate biopsy. Eur Urol Focus. 2021; 7:78-85. 22. Kriegshauser JS, Paden RG, He M, et al. Rapid kV-switching single-source dual-energy CT ex vivo renal calculi characterization using a multiparametric approach: refining parameters on an expanded dataset. Abdom Radiol (NY). 2018; 43:1439-45. 23. Aminsharifi A, Irani D, Pooyesh S, et al. Artificial neural network system to predict the postoperative outcome of percutaneous nephrolithotomy. J Endourol. 2017; 31:461-7. 24. Seckiner I, Seckiner S, Sen H, et al. A neural network - based algorithm for predicting stone - free status after ESWL therapy. Int Braz J Urol. 2017; 43:1110-4. 25. Seckiner I, Seckiner SU, Erturhan S, et al. The use of artificial neural networks in decision support in vesicoureteral reflux treatment. Urol Int. 2008; 80:283-6. 26. Hung AJ, Chen J, Che Z, et al. Utilizing machine learning and Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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automated performance metrics to evaluate robot-assisted radical prostatectomy performance and predict outcomes. J Endourol. 2018; 32:438-44. 27. Lepor H. Evaluating men with benign prostatic hyperplasia. Reviews in urology. 2004; 6 Suppl 1(Suppl 1):S8-s15. 28. Choo MS, Yoo C, Cho SY, et al. Development of decision support formulas for the prediction of bladder outlet obstruction and prostatic surgery in patients with lower urinary tract symptom/benign pro-

Correspondence Mourmouris Panagiotis, MD thodoros13@yahoo.com Manolitsis Ioannis, MD giannismanolit@gmail.com Berdempes Marinos, MD marinosberdebes@hotmail.com Varkarakis Ioannis, MD medvark3@yahoo.com Skolarikos Andreas, MD andskol@yahoo.com 2nd Department of Urology, National and Kapodistrian University of Athens, Sismanogleio General Hospital, Athens (Greece) Tzelves Lazaros, MD (Corresponding Author) lazarostzelves@gmail.com 2nd Department of Urology, National and Kapodistrian University of Athens, Sismanogleio General Hospital, Athens Sismanogleiou 1, 15126, Marousi (Greece) Feretzakis Georgios, MD georgios.feretzakis@ac.eap.gr Kalles Dimitris, MD Greece kalles@eap.gr School of Science and Technology, Hellenic Open University, 26335 Patras

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static hyperplasia: part I, development of the formula and its internal validation. 2017; 21(Suppl 1):S55-65. 29. Pielke RA. Mesoscale Meteorological Modelling. Academic Press, Orlando, 612pp. 30. Stanfill MH, Marc DT. Health information management: implications of artificial intelligence on healthcare data and information management. Yearb Med Inform. 2019; 28:56-64.

DOI: 10.4081/aiua.2021.4.425

ORIGINAL PAPER

Outcomes of fluoroscopy-free retrograde intrarenal surgery and predictive factors of stone-free Huseyin Kocakgol 1, Hasan Riza Aydin 2, Ahmet Ozgur Guctas 3, Cagri Akin Sekerci 4, Deniz Ozturk Kocakgol 5, Hamit Zafer Aksoy 2, Yiloren Tanidir 6, Huseyin Kocakgol 1 1 Department

of Urology, University of Health Sciences, Erzurum Regional Training and Research Hospital, Erzurum, Turkey; of Urology, University of Health Sciences, Kanuni Training and Research Hospital, Trabzon, Turkey; 3 Department of Urology, Marmara University Training and Research Hospital, Istanbul, Turkey; 4 Department of Urology, Division of Pediatric Urology, School of Medicine, Marmara University, Istanbul, Turkey; 5 Department of Radiology, Maresal Cakmak State Hospital, Erzurum, Turkey; 6 Department of Urology, School of Medicine, Marmara University, Istanbul, Turkey. 2 Department

Summary

Objective: To evaluate the outcomes of flouroscopy-free retrograde intrarenal surgery (ffRIRS) and to investigate the factors that may affect stone-free rate. Materials and methods: The charts of patients who underwent ffRIRS between January 2017 and August 2019 were reviewed retrospectively. Patients with missing preoperative imaging and patients with kidney anomalies were excluded from the study. Age, gender, stone size, stone localization, stone density, laterality, operation time, stone-free rate, complications and auxiliary procedures were recorded and analyzed. Results: Study group involved 44 (43.1%) female and 58 (56.8%) male patients. Stone-free rate in a single-session ffRIRS were found to be correlated with stone localization (p = 0.003), stone volume (p = 0.004), and stone density (p = 0.009) but not with age (p = 0.950). Patients with multiple calyceal stones and a stone burden over 520 mm3 were found to be less stone-free. The complication rate in female gender (n = 7) was significantly higher compared to male (n = 1) (p = 0.011). No major complications such as ureteral injury or avulsion were observed. Overall, 13 patients (12.7%) needed auxiliary procedures. The operation time seemed to be affected by stone size and gender (p = 0.005; p = 0.044, respectively). Conclusions: Stone-free rate in ffRIRS were found to be affected by stone density, size, and localization. Patients with multiple caliceal stones and high stone burden (< 520 mm3) have been found to have low stone-free rate, so one can speculate that having fluoroscopy assistance in RIRS might help us to improve surgical success.

KEY WORDS: Kidney stones; RIRS; Fluoroscopy free; Stone free; Stone density. Submitted 12 August 2021; Accepted 28 October 2021

INTRODUCTION

In recent years, technological advances have provided us with important facilities in the surgical treatment of urinary tract stone diseases (UTSD). Open surgery has been largely replaced by minimally invasive urological procedures. Retrograde intrarenal surgery (RIRS), which is one of the minimally invasive techniques, differs from open sur-

gery and percutaneous nephrolithotomy (PCNL) especially for avoidance of accessing to the renal cavities through the kidney cortex. Therefore, RIRS stands out as a better treatment option especially in avoiding some important complications such as bleeding and risk of injury of adjacent organs. However, minimally invasive stone surgery has potential problems, such as radiation exposure, for both the patient and the surgical team (1). Krup et al. reported their radiation exposure hypotheses according to a linear ‘‘non-threshold’’ model and estimated that one of every 1000 adult patients undergoing endoscopic stone surgery using fluoroscopy could experience secondary skin malignancy due to radiation exposure (2). The present study, aimed to investigate the factors affecting the outcome of RIRS and stone-free rate in fluoroscopy-free technique setting.

MATERIALS

AND METHODS

After obtaining local ethics committee approval (ethics committee decision no: 1050), the charts of patients at the University of Health Sciences Trabzon Kanuni Training and Research Hospital, who underwent flouroscopy-free retrograde intrarenal surgery (ffRIRC) between January 2017 and August 2019 were reviewed retrospectively. Patients with missing preoperative non-contrast computed tomography (NCCT) and/or congenital kidney anomalies were excluded from the study. Computed Tomography (CT) scans of the patients were performed with a Siemens Somatom Emotion 16 detector device. Shooting protocol was in 1.5 mm axial sections with 110 kV and 90 mAs energy and images obtained in coronal and sagittal planes. The CT sections were evaluated in the window settings L300/W1120 and maximum stone length was measured in axial, coronal and sagittal axis. The stone burden was calculated with formula of the ellipsoid volume (π/6 × D1xD2xD3) (3). A stone burden of 520 mm3 (when stone diameter was taken as 10 mm in all three planes) was used for comparison. Stone density was measured three times by taking more than 50% of the stone size from the center of the stone. The average

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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Hounsfield Unit of three measurements was recorded as stone density (4). Stone density above and below 1000 HU was compared (5). The “stone-free” condition was defined as absence of residual stones or presence of stone fragments less than 2 mm. Stone features, demographic features, and surgical findings of patients like age, gender, stone size, stone localization, stone density, residual stone size and number, complications, operation time, stone-free rate, number and type of auxiliary procedures were analyzed and compared. Surgical technique All patients were evaluated preoperatively with physical examination, routine blood tests, urine test and culture, kidney-ureter-bladder x-ray, and NCCT. The operation was performed when the urine culture was sterile and parenteral antibiotic prophylaxis was administered to all patients before the procedure. No medical expulsive treatment was given after the procedure. All patients were operated with the following standard equipment: 6/7.5 Fr Wolf® semirigid ureterorenoscope (URS), Storz® Flex-x 2S flexible ureterorenoscope (f-URS), Wolf® Mega Pulse Tower 30+ laser device and Cooks Medical® 10.7 Fr ureteral access sheath (UAS). All operations were done under the general anesthesia. Initially a ureteroscopy was done in the dorsal lithotomy position with a semi-rigid URS with the aid of a guidewire. Semi-rigid ureteroscopy helped the passive dilation of the ureteral orifice and assessed the calibration and patency of the ureter. A 10.7 Fr hydrophilic ureteral access sheath was gently advanced over the guidewire through the urethra into the ureters that look convenient for the UAS insertion. Fluoroscopyfree advancement of the UAS continue until any resistance was felt. In such cases, the guidewire was left on the patient and the UAS was taken out, and the lumen of the ureter was investigated with semi-rigid URS to assess the cause of resistance and possible ureter injury. In cases where UAS could not be placed, a double J stent was placed, and the procedure was terminated and postponed to another session. After placing the UAS, the collecting system of the kidney was inspected with the f-URS and laser lithotripsy was performed. Laser settings were modified according to the efficiency of lithotripsy. Following lithotripsy, collecting system of the kidney was inspected for residual stones. FURS was carefully taken out of the body with the access sheath simultaneously and the guidewire was left within the ureter, so that the ureter was re-observed against any risk of injury. A double J stent was routinely placed into the renal pelvis in each patient. On the first postoperative day, a KUB X-ray was obtained, and the uneventful patients were discharged. Patients were re-evaluated by either ultrasonography (US) (n: 64) or NCCT (n:38) in the first postoperative month. Patients with significant residual stones or hydronephrosis were scheduled for auxiliary interventions. Statistical analysis Statistical analysis was done using International Business Machines (IBM) Statistical Package for Social Sciences (SPSS) Statistics for Windows (IBM Corp. Released 2017, Version

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25.0. Armonk, NY: IBM Corp). Shapiro-Wilk test was used to evaluate the distribution of variables. Categorical variables were presented as numbers and percentages, and continuous variables as means and standard deviations. Categorical variables were analyzed using Chi-square test. Statistical analyses of the means of continuous variables were performed using Student’s T-test and analysis of variance. A P-value of less than 0.05 was considered statistically significant.

RESULTS

A total of 102 patients, 44 female (43.1%) and 58 male (56.9%), were included in our study. The mean age of the study group was 48.4 ± 14.4 years. In the primary procedure, RIRS was performed by placing a urethral sheath in 57 (55.8%) patients. A double J stent was placed in the remaining 45 patients and RIRS was performed in the next session. Almost half of the patients had stones in renal pelvis (n = 55, (53.9%) (Table 1). Mean stone volume of patients were found to be 428 ± 405 mm3. Of all patients treated with ffRIRS, stone-free status was achieved in 69 (67.6%). The mean age of these patients was similar to patients with residual stones (48.3 ± 14.4 years vs 48.5 ± 14.7 years; p = 0.950). Interestingly, stone free patients had a shorter operative time (62.8 ± 23.1 minutes vs 80.5 ± 24.5 minutes; p = 0.001). Also, some stone characters were found to be significantly different in stone-free patients like stone localization (p = 0.003), size (p = 0.004) and density (p = 0.009) (Table 1). No perioperative complications were found but eight patients (7 female, 1 male) suffered from postoperative complications. Majority of these patients (n = 4) had febrile urinary tract infection. Only one patient, required double J stent replacement in the postoperative early period. Three patients need a second look with URS/RIRS during stent removal due to high volume residual stones. Overall, a total of 13 patients underwent URS or RIRS as Table 1. Demographic features and parameters of stones (p values are for comparison of patients with and without residual stones).

Age (years) Gender Female Male Side Right Left Stone localization Upper pole Middle pole Pelvis Lower pole Multiple Stone volume < 520 mm3 > 520 mm3 Stone density < 1000 HU > 1000 HU

All patients (n = 102) 48.4 ± 14.4

Stone-free Patients with residual P value patients (n = 69) stones (n = 33) 48.3 ± 14.4 48.5 ± 14.7 0.950

44 (43.1%) 58 (56.8%)

33 (47.8%) 36 (52.1%)

11 (33.3%) 22 (66.7%)

0.167

58 (56.8%) 44 (43.1%)

42 (60.9%) 27 (39.1%)

16 (48.5%) 17 (51.5%)

0.237

7 (0.68%) 19 (18.6%) 55 (53.9%) 13 (12.7%) 8 (0.78%)

3 (4.3%) 14 (20.3%) 43 (62.3%) 8 (11.6%) 1 (1.4%)

4 (12.1%) 5 (15.2%) 12 (36.4) 5 (15.2%) 7 (21.2%)

0.003

77 (75.4%) 25 (24.6%)

58 (84.1%) 11 (15.9%)

19 (57.6%) 14 (42.4%)

0.004

53 (%51.9) 49(%48)

42 (60.9%) 27(39.1%)

11 (33.3%) 22 (66.7%)

0.009

Outcomes of ff RIRS

an auxiliary intervention. There was no statistically significant difference between the demographic or stone parameters of the patient who needed additional surgery (p > 0.05).

DISCUSSION

The main goal of the treatment of UTSD is to provide stone-free with minimum harm and maximum benefit. Therefore, predictive factors are important in the selection of the treatment procedure. In this study, we investigated the need for fluoroscopy and predictive factors of RIRS. It is a fact that fluoroscopy at many stages in the treatment of UTSD provides us with a roadmap function. However, ionizing radioactivity emitted from the X-ray device carries a potential risk for both the patient and the surgical team. Unfortunately, exposure to radioactivity does not have an exact threshold because the radioactive effect occurs in two ways with deterministic and stochastic effects. The detrimental effect occurs at radioactive exposure on the threshold dose. The stochastic effect is the mutations caused by the effect of radiation on DNA and it is thought that there is no threshold value for this effect (6). Today, technological developments enable us to work with tools that provide smaller diameter and higher quality images in endourological interventions. In addition, ureteral injuries are more rare complications due to high-quality guide wires and ureteral access sheaths and expertise gained by urologists in endourological interventions. Placing UAS during ffRIRS is one of the critical stages of the process. UAS provides direct access to the kidney during RIRS. However, it has been reported that it increases the susceptibility to urinary infection as well as ureteral injury (7). During UAS insertion, ureter damage may occur. Various techniques have been developed for the UAS placement procedure to prevent ureteral injury. Some authors recommend performing the procedure without UAS insertion, and others suggested placing UAS in pre-stented patients (8-10). Boulalas et al. evaluated ureteral compliance with a 9.5 Fr semi-rigid ureterorenoscopy routinely prior to 12/14 Fr UAS insertion in their prospective study. In patients with unsuitable small-diameter ureters, they continued the procedure with smaller-diameter instruments. In this series of 100 patients, UAS were successfully placed in the first session with this technique in 77 patients (77%), but ureteral complications were reported in 10%. Eight of these were reported as grade I secondary to 3 Fr guide wire induction, and the remaining two as Grade I and Grade III ureteral injuries secondary to UAS procedure (11). In our study, UAS could be placed in 57 (55.8%) patients at the first session in primary cases. We did not observe any complications related to ureteral injury. Routinely use of hydrophilic guidewire and a smaller diameter of 10.7 Fr UAS could explain this result. In addition, some Authors described the technique of wearing UAS on semi-rigid or flexible URS (12-13). The benefits of performing sheath placement under fluoroscopy are controversial, because fluoroscopy without the administration of opaque material has no ability to

show strictures, kinks, or non-opaque stones in the ureter. Wearing a UAS on the URS allows direct visualization of the ureter during the procedure. However, using the ureteroscope instead of the access sheath mandrel may cause the loss of the protection of the ureteral wall due to the mandrel that is a "non-traumatic, round structure that completely covers the sheath mouth". In our study, ffRIRS was applied to eligible patients in the first session, whereas non eligible patients were treated in a second session after double J stent. Various studies have been conducted on the treatment of ffRIRS. In a series of 100 patients, 33 patients underwent the procedure with fluoroscopy, while in 67 patients the procedure was done without fluoroscopy and no statistically significant difference was reported between the two groups in terms of perioperative complications. In the same study, there were no major complications such as ureter perforation, and no statistically significant difference was reported between stone-free rates (14). In another study in which RIRS was performed without using fluoroscopy a total of 5 complications (5 fever, 1 hematuria) in 140 patients were reported and a high stone-free rate of 95.7% was reported (6). When we searched the literature about RIRS, we did not find a study in which age, gender and side factor were found to be significant in providing stone free. In the study of Resorlu et al., patients were evaluated in four different age groups as ≤ 7, 8-17, 18-60, and > 60 years old and there was no statistically significant difference in stone-free rates between patient groups (15). Similarly, Soo Hyun Lim et al. did not report age and gender as a predictive factor in their study (16). In our study, the mean age of patients without residual stones was 48.3 ± 14.4 years, and the mean age of patients with residual was 48.5 ± 14.7 years (p = 0.950). Although our stone free rate was 75% in females and 62.1% in males, there was no statistically significant difference (p = 0.121). In many studies, stone size has been reported as an important predictive factor of success of RIRS (15, 16). However, the fact that the stone-free ratio tend to be lower with the increase in stone size does not mean that RIRS can be completely avoided in these patient groups. In EAU guidelines, total stone-free rates of 91% have been reported with 1.45 procedures in patients with stones over 2 cm (1719). We calculated stone size as mm³ aiming to have a more accurate evaluation of stone size. In our study, the rate of stone-free after one session was 75.2% in the patient group with a stone size < 520 mm³, while it was 44% in the group > 520 mm³ (p = 0.005). Stone localization and infundibulo-pelvic angle have been reported as important predictive factors in the RIRS procedure. Resorlu et al. reported that stone-free ratio was statistically decreased in lower pole stones, multi-calyceal stones and in patients with infundibulo-pelvic angle < 45° (15). Sung Yong Cho et al. reported that stone-free rates in multiple stones were statistically lower than in single stone in their study (p = 0.005) (20). The results of our study were compatible with the literature. Our stone-free rates were 73.7% and 78.2% in the middle pole and pelvis stones and were 61.5%, 42.9% and 12.5% in the lower pole, upper pole and multiple stones, respectively (p = 0.003). Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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Table 2. The comparison of studies with fluoroscopy assisted retrograde intrarenal surgery and present study Author/year Study design Number of patients (n) Stone free rate (%) Stone localization

Lim S.H. et al. 2010 (16) Retrospective 66 72.7% (46/66) Upper-middle pole or pelvis: SFR: 94.2% (17/18) Lower pole: SFR: 60.4% (29/48) (P: 0.007)

Resorlu et al. 2012 (15) Retrospective 207 %86 (178/207) Upper-middle pole: SFR: 92.7% (51/55) Pelvis: SFR: 90.6% (58/64)

Ito H. et al. 2014 (27) Retrospective 310 59.6% (185/310) Lower pole stone presence: SF Group: 53.5% (99/185) Non-SF group: 85.6% (107/125) (P < 0.001)

Lower pole: SFR: 78.4% (69/88) (P: 0.025)

Erbin A. et al. 2016 (28) Retrospective 339 70.1% (238/339) Upper calyx: SFR: 72.2% (26/36) Middle calyx: SFR: 92.9% (13/14) Pelvis: SFR: 73.1% (76/104) Lower calyx: SFR: 65.5% (91/139) Multiple calyces: SFR: 69.6% (32/46) (P: 0.247) Lower pole infindibulopelvic angle: SF Group: 49.5°± 12.3° Non-SF Group: 44.1°± 11.3° (P: 0.004) SF group: 13.6 ± 4.7 mm Non-SF group: 16.4 ± 6.5 mm (P: 0.000)

0-10 mm SFR: 88.9% (8/9) 11-20 mm SFR: 93.3% (153/164) > 20 mm SFR: 50% (17/50) (P < 0.001)

SF group: 15.88 mm Non-SF group: 32.79 mm P < 0.001

Stone density (HU)

≤ 150 mm2 SFR: 83.7% (41/49) > 150 mm2 SFR: 29.4% (5/17) (P < 0.001) SF group: 12 mm (9-17) NA

Operation time (min)

52 (15-95)

SF group: 944.49 (373.52) HU Non-SF group: 1099.73 (335.46) HU (P < 0.001) NA

Complication rate (%) Type of complication cases (n)

4 (6%) Intraoperative minor ureter injury (1) Febrile urinary tract infection (2) Postoperative paralytic ileus (1)

20 (9.66%) Ureteral perforation (1) Abdominal pain (4) Voiding disturbances (4) Hematuria (4) Postoperative fever or infection (5) Urosepsis (1)

18 (5.8%) High-grade postoperative fever (16) Postoperative ureteric stricture (2)

18 (5%) Clavien grade I or II complication (12) Clavien grade IIIA complication (urosepsis) (7)

Stone size

Xiao et al. 2017 (25) Retrospective 382 73.6% (281/382) Inferior pole stone group: SF Group: 47.6% (69/145) Non-Inferior pole stone free group: 89.5% (212/237) (P < 0.001) Single stone group: SFR: 85.8% (200/233) Multiple calyces stone group: SFR: 54.4% (81/149) (P < 0.001)

Present study Retrospective 102 67.6% (69/102) Upper pole SFR: 42.8% (3/7) Middle pole SFR: 73.6% (14/19) Pelvis: SFR: 78.1% (43/55) Lower pole: SFR: 61.5% (8/13) Multiple: SFR: 12.5% (1/8) (P: 0.003)

Mean stone size: 14 mm SF group: 12 mm (9-17) Non-SF group: 25 mm (18-29) (P < 0.001)

< 520 mm3 SFR: 75.3% (58/77) > 520 mm3 SFR: 44% (11/25) (P: 0.004)

SF group: 1022.59 ± 342.97 HU Non-SF group: 1193.43 ± 285.44 HU (P < 0.001) SF group: 50 (60–40; 20) min. Non-SF group: 60 (85–50; 35) min. (P < 0.001) 27 (7.1%) NA

< 1000 HU SFR: 79.2% (42/53) > 1000 HU SFR: 55.1% (27/49) (P: 0.009) 64.7 ± 23.2

8 (7.8%) Clavien grade I: Febrile urinary tract infection (4) Clavien grade IIIB: URS was performed due to a residual ureter stone that could not pass (4)

CRIRS: Retrograde Intrarenal Surgery; URS: Ureterorenoscopy; SF: Stone Free; SFR: Stone Free Rate; HU: Hounsfield Unit; min: minute; mm: millimeter; NA: Not available.

Stone density was another important parameter in treatment of renal stones. This parameter has found its place in many studies especially on extracorporeal lithotripsy (21, 22). Kim et al. reported that stone density did not affect the endoscopic treatment of ureteral stones (23). In the treatment of ureteral stones, it should be considered that a thicker laser probe can be used with the semirigid URS and that it can be easily manipulated. Predictive effect of the stone density in RIRS is controversial and there are a limited number of studies in the literature. Gucuk et al. found stone density to be insignificant as a predictive factor in RIRS treatment (p = 0.22). In this article, unlike the present study, the stones were

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divided as below and above 677 HU (24). In another study, stone density was evaluated in groups of patients with and without stone free and it was found to be higher in patients with residual stone (p < 0.001) but a density limit was not specified (25). In our study, stone density was found to be a predictive factor in stone-free when patients who underwent RIRS were evaluated according to two different categories of stone density (< 1000 HU and > 1000 HU): stone-free rate was 55.1% in patients with stone density above 1000 HU and 79.2% in the group below 1000 HU (p = 0.009). In our study, the gender was found to be a significant factor in the development of complications. No statistically

Outcomes of ff RIRS

significant difference was observed in other parameters. Seven of our 8 patients who developed complications were women (p = 0.04). Febrile urinary tract infection developed in 4 patients (Clavien grade I) and they were treated with appropriate antibiotics and antipyretic therapy. All the patients with febrile urinary infection were female. We think that this finding may be related to the fact that women are more prone to urinary tract infection (26). Complications requiring surgical intervention (Clavien grade 3B) developed in 4 patients and URS was performed due to a residual ureter stone that could not pass. A total of 13 patients underwent URS/RIRS as an additional intervention. 4 of them were secondary to complications, and the remaining 9 patients received RIRS treatment as second session. The 18 of the remaining patients who were not stone free were included in the follow-up protocol. In 11 of 13 patients who needed additional treatment, stone density was > 1000 HU (p = 0.08). In our study, the operation time was found to be significantly longer in high stone volume and men. While mean operation time was 64.7 ± 23.2 minutes in the patient group with stone burden < 520 mm³, it was 80.4 ± 26.6 minutes in the patient group with > 520 mm³ (p = 0.005). Similarly, the operation time was found to be longer in the non-stone free group (p = 0.001). Operation time in females was 62.8 ± 19.6 minutes and 72.8 ± 27.6 minutes in males (p = 0.044). It is not surprising that the operation time is longer in high stone volume. However, it is noteworthy that the duration of the operation in women is shorter. In our study, we think that the short female urethra and the low number of female patients with a stone size > 520 mm³ (n: 8) are an explanation of this result. The operation time was found to be 64.3 ± 25.5 minutes in patients with < 1000 HU, 73.1 ± 23.6 minutes in patients with > 1000 HU (p = 0.07). We summarized the results of some fluoroscopy assisted RIRS studies and our findings in Table 2. We choose these studies as the stone burden seemed to be similar to ours. Our stone-free rates are lower than those observed in these studies although complication rates were similar or lower. As an exception, Ito et al. reported worse stone free rates and almost similar complication rates, but in this series the majority of stones were in the lower pole (15, 16, 25, 27, 28). A randomized comparison should be necessary to confirm that fluoroscopy-free RIRS can obtain the same results of conventional RIRS with the use of fluoroscopy. The study has some limitations. This was a retrospective study, and all controls were not performed with CT. Our study has no control group, so it lacks the comparison with data of fluoroscopy assisted RIRS. We tried to get rid of this limitation by comparing our study with historical fluoroscopy assisted RIRS studies as shown in Table 2.

CONCLUSIONS

Although fluoroscopy is not protective against major complications such as ureteral injury, it may increase success in multiple calyx and large stones. Stone density, size, and localization were observed to affect the success of treatment. Particularly, stone density occurred as an important predictive factor for RIRS in this study. We hope that our

study will make an important contribution to the literature, evaluating ffRIRS and stone density as predictive factor.

REFERENCES

1. Olgin G, Smith D, Alsyouf M, et al. Ureteroscopy without fluoroscopy: a feasibility study and comparison with conventional ureteroscopy. J Endourol. 2015; 29:625-9. 2. Krupp N, Bowman R, Tenggardjaja C, et al. Fluoroscopic organ and tissue-specific radiation exposure by sex and body mass index during ureteroscopy. J Endourol. 2010; 24:1067-73. 3. Park J, Kang M, Jeong CW, et al. External validation and evaluation of reliability and validity of the modified seoul national university renal stone complexity scoring system to predict stone-free status after retrograde intrarenal surgery. J Endourol. 2015; 29:888-93. 4. Foda K, Abdeldaeim H, Youssif M, Assem A. Calculating the number of shock waves, expulsion time, and optimum stone parameters based on noncontrast computerized tomography characteristics. Urology. 2013; 82:1026-31. 5. Cakiroglu B, Eyyupoglu SE, Tas T, et al. Are Hounsfield densities of ureteral stones a predictive factor for effectiveness of extracorporeal shock wave lithotripsy? Int J Clin Exp Med. 2014; 7:1276. 6. Peng Y, Xu B, Zhang W, et al. Retrograde intrarenal surgery for the treatment of renal stones: is fluoroscopy-free technique achievable? Urolithiasis. 2015; 43:265-70. 7. Karaaslan M, Tonyali S, Yilmaz M, et al. Ureteral access sheath use in retrograde intrarenal surgery. Arch Ital Urol Androl. 2019; 91:112-114 8. Emiliani E, Motta G, Llorens E, et al. Totally fluoroless retrograde intrarenal surgery technique in prestented patients: tips and tricks. J Pediatr Urol. 2019; 15:570-3. 9. Tepeler A, Armagan A, Akman T, et al. Is fluoroscopic imaging mandatory for endoscopic treatment of ureteral stones? Urology. 2012; 80:1002-6. 10. Hein S, Schoenthaler M, Wilhelm K, et al. Ultralow radiation exposure during flexible ureteroscopy in patients with nephrolithiasis—How far can we go? Urology. 2017; 108:34-9. 11. Boulalas I, De Dominicis M, Defidio L. Semirigid ureteroscopy prior retrograde intrarenal surgery (RIRS) helps to select the right ureteral access sheath. Arch Ital Urol Androl. 2018; 90:20-4. 12. Ekici M, Özgür BC, S¸entürk AB, et al. All-seeing-access sheath: A novel fluoroscopy-free placement technique in retrograde intrarenal surgery. J Coll Physicians Surg Pak. 2019; 29:263-267. 13. Sönmez MG, Kara C. A new approach in ureteral access sheath locating in retrograde intrarenal surgery (RIRS) by endovisional technique. Arch Ital Urol Androl. 2015; 87:286-90. 14. Manzo BO, Lozada E, Manzo G, et al. Radiation-free flexible ureteroscopy for kidney stone treatment. Arab J Urol. 2019; 17:200205. 15. Resorlu B, Unsal A, Gulec H, Oztuna D. A new scoring system for predicting stone-free rate after retrograde intrarenal surgery: the “resorlu-unsal stone score”. Urology. 2012; 80:512-8. 16. Lim SH, Jeong BC, Seo SI, et al. Treatment outcomes of retrograde intrarenal surgery for renal stones and predictive factors of stonefree. Korean J Urol. 2010; 51:777-82. 17. Wendt-Nordahl G, Mut T, Krombach P, et al. Do new generation flexible ureterorenoscopes offer a higher treatment success than their predecessors? Urol Res. 2011; 39:185-8. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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18. Geraghty R, Abourmarzouk O, Rai B, et al. Evidence for ureterorenoscopy and laser fragmentation (URSL) for large renal stones in the modern era. Curr Urol Rep. 2015; 16:54. 19. Binbay M, Yuruk E, Akman T, et al. Is there a difference in outcomes between digital and fiberoptic flexible ureterorenoscopy procedures? J Endourol. 2010; 24:1929-34. 20. Cho SY, Choo MS, Jung JH, et al. Cumulative sum analysis for experiences of a single-session retrograde intrarenal stone surgery and analysis of predictors for stone-free status. PloS one. 2014; 9:e84878. 21. Wang L-J, Wong Y-C, Chuang C-K, et al. Predictions of outcomes of renal stones after extracorporeal shock wave lithotripsy from stone characteristics determined by unenhanced helical computed tomography: a multivariate analysis. Eur Radiol. 2005; 15:2238-43. 22. El-Nahas AR, El-Assmy AM, et al. A prospective multivariate analysis of factors predicting stone disintegration by extracorporeal shock wave lithotripsy: the value of high-resolution noncontrast computed tomography. Eur Urol. 2007; 51:1688-94. 23. Kim JW, Chae JY, Kim JW, et al. Computed tomography-based

novel prediction model for the stone-free rate of ureteroscopic lithotripsy. Urolithiasis. 2014; 42:75–79. 24. Gucuk A, Yilmaz B, Gucuk S, Uyeturk U. Are stone density and location useful parameters that can determine the endourological surgical technique for kidney stones that are smaller than 2 cm? A prospective randomized controlled trial. Urol J. 2019; 16:236-41. 25. Xiao Y, Li D, Chen L, et al. The R.I.R.S. scoring system: An innovative scoring system for predicting stone-free rate following retrograde intrarenal surgery. BMC Urology. 2017; 17:105. 26. Harrington RD, Hooton TM. Urinary tract infection risk factors and gender. The journal of gender-specific medicine: JGSM: the official journal of the Partnership for Women's Health at Columbia. 2000; 3:27-34. 27. Ito, H, Sakamaki K, Kawahara T, et. al. Development and internal validation of a nomogram for predicting stone-free status after flexible ureteroscopy for renal stones. BJU International. 2015; 115: 446-451. 28. Erbin A, Tepeler A, Buldu I, et al. External comparison of recent predictive nomograms for stone-free rate using retrograde flexible ureteroscopy with laser lithotripsy. J Endourol. 2016, 30: 1180-1184.

Correspondence Huseyin Kocakgol, MD (Corresponding Author) hsynkocakgl@gmail.com Department of Urology, University of Health Sciences, Erzurum Regional Training and Research Hospital, Adnan Menderes Mahallesi S¸ehit Burak Karakuş Sokak Al-Furkan Sitesi A Blok Kat:1 No:8 Palandöken/Erzurum (Turkey) Hasan Riza Aydin, MD hasanriza.aydin.61@gmail.com Hamit Zafer Aksoy, MD hamitzaferaksoy@hotmail.com Department of Urology, University of Health Sciences, Kanuni Training and Research Hospital, Trabzon (Turkey) Ahmet Ozgur Guctas, MD aoguctas@gmail.com Department of Urology, Marmara University Training and Research Hospital, Istanbul (Turkey) Cagri Akin Sekerci, MD cagri_sekerci@hotmail.com Department of Urology, Division of Pediatric Urology, School of Medicine, Marmara University, Istanbul (Turkey) Deniz Ozturk Kocakgol, MD dr.denizz@hotmail.com Department of Radiology, Maresal Cakmak State Hospital, Erzurum (Turkey) Yiloren Tanidir, MD yiloren@yahoo.com Department of Urology, School of Medicine, Marmara University, Istanbul (Turkey)

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DOI: 10.4081/aiua.2021.4.431

ORIGINAL PAPER

The active guidewire technique versus standard technique as different way to approach ureteral endoscopic stone treatment Alessandro Calarco 1, Marco Frisenda 1, 3, Emilio Molinaro 1, 3, Niccolò Lenci 2 1 Department

of Urology, “Cristo Re” Hospital Fondation, Rome, Italy; of Urology, “A. Gemelli” Academic Hospital, Catholic University of Sacred Heart, Rome, Italy; 3 Department of Urology, Policlinico Umberto I, “La Sapienza” University, Rome, Italy. 2 Department

Summary

Background: One of the greatest challenges in semi-rigid ureteroscopies, for both stones and tumors, is the control of endoscopic vision and the maintenance of low intracavitary liquid pressure. We present a comparison between two operative techniques: in the first method an ordinary guide wire (diameter 0.032'') is used for the procedure; in the second one a 5 Fr ureteral catheter replaces the guidewire (we called it “Active guidewire”) Methods We compared 50 semirigid ureteroscopies (sURS) performed using the active guidewire with another 50 procedures conducted with a classic guidewire. We evaluated the difference in operating times, quality of endoscopic vision, periprocedural infections rate and stone-free rate. Results: The use of active guidewire has considerably reduced the standardized operating times per unit stone-volume by about 39%. Vision quality has improved considerably thanks to the continuous flow in-and-out. Consequently, periprocedural infections decreased (3% vs 30%) and the stone-free rate rose from 86% to 92%. Discussion and conclusions: Employing an “active guidewire” instead of the standard guidewire, the risk of complications related to high pressures and operating time is considerably lower, as well as better treatment quality thanks to the cleaner vision. This technique has proven to be safe as well as easy to apply, and in our belief is to be preferred whenever the ureter accepts without forcing, both the presence of the catheter and the semi-rigid 7 F ureteroscope.

KEY WORDS: Ureteroscopy; Ureter; Guidewire; Ureteral stones; Retrograde intrarenal surgery; Lithotripsy. Submitted 12 July 2021; Accepted 25 August 2021

INTRODUCTION

AND BACKGROUND

In ureteral pathologies where indication is endoscopic treatment such as stones or urothelial tumors, the growing technological progress has led to a more frequent use of minimally invasive operative techniques including semi-rigid ureteroscopy and RIRS (Retrograde IntraRenal Surgery). All of these operating techniques use irrigation to permit the best possible endoscopic vision and simple safety maneuvers to minimize the risk of complications. Advances in technology have also generated ureterorenoscopes with increasingly smaller diameters, but the price

to pay for this reduction in diameter is one common channel for both irrigation and accessories, resulting in decreased irrigation flow. Good irrigation means good vision (1), poor irrigation means poor vision. It is clear that the key factor determining the best outcome of the intervention is based on the quality of the vision with containment of complications in association with reasonable operating times. In our belief, the most important safety maneuvers are the positioning of a safety guidewire, the use of low pressures and avoiding to force the advancement of the instrument. During semirigid ureteroscopy, whether it is for stones or for cancer, one of the essential conditions is certainly the quality of vision that can be implemented by better tools like digital cameras but remains very conditioned by the quality of the medium in which the camera is immersed. Moreover, there are concerns about the changes in the intra-pelvic pressure (IPP) that might reach critical levels, resulting in pyelovenous, pyelolymphatic, and pyelointerstitial backflow with subsequent systemic inflammatory response syndrome and sepsis. The association between surgery time and post-operative infectious complications was discussed in several studies in literature involving > 7.000 patients. According to the primary overall meta-analysis result, patients with longer operation time (min) are more vulnerable for infectious complication (OR = 1.03, 95% CI:1.01-1.04, I2 = 70.6%, p = 0.001). According to the subgroup analysis, patients with longer operation time (min) are vulnerable or postoperative fever/urinary tract infections (OR = 1.02, 95% CI:1.01-1.03, p < 0.001, I2 = 15.2%, p = 0.308) and also vulnerable for post-operative systemic inflammatory response syndrome/urosepsis (OR:1.08, 95% CI 1.021.14, p = 0.009, I2 = 69.4%, p = 0.0017) (2, 3). The rationale of our study is to make a comparison between endoscopic procedures performed with the use of a standard guidewire and a ureteral catheter, which allow to create a continuous flow, so that the intake liquid is given by the instrument and the outflow by the ureteral catheter. That variation generates a potentially nonstop laser procedure with reduced operating-time, better vision, and a decreased risk of high Intra Pelvic Pressure. This procedure can be called “active guidewire” technique, because of the active role of the ureteral catheter.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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METHODS

To overcome the problems of the current technique, such as poor vision and interruption of the flow at high intrarenal pressures, we describe the differences between the two techniques and in particular the advantages seen in the population treated with the active guidewire. In this technique the safety guidewire is replaced by a Pollack ureteral catheter (COOK Medical®) thus becoming an active, and no longer passive, element during the procedure. The “active guidewire” has a diameter of 5 F, with a soft tip at its head, and it is positioned in place of the safety guidewire, thus connecting the renal pelvis with the outside. The Pollack catheter has an internal size of 4 Fr. A 6,5/7 F Storz® semirigid ureteroscope is used and it has a 4 F irrigation channel. The two 4 F channels give us a perfect balance with in and out irrigation flow. A polytetrafluoroethylene (PTFE)-coated guidewire was used as standard guidewire. A PTFE-Nitinol guidewire with hydrophilic tip was used when the stone was impacted. For statistical evaluation IBM© SPSS Statistics program (Illinois, Chicago, v. 24) was used. Pearson's Chi-Square, Pearson correlation analysis and Student's test were used. Statistical significance was evaluated at p < 0.05. We took in consideration 100 patients undergoing semirigid ureterorenoscopy (sURS) for ureteral stones. Hydronephrosis was present in 60% of the patients. No double J (JJ) stent was inserted before the surgery, in any case (Table 1). All patients had a clinical evaluation, urine dipstick analysis with additional culture and sensitivity testing if a urinary tract infection (UTI) was suspected, a measurement of serum creatinine level, abdominal ultrasonography (US) and a plain abdominal X-ray. Patients with positive pre-operative urine culture (n. 4) were treated with specific antibiotics until complete remission (verified performing new urine culture and blood test). Preoperative additional computed tomography (CT) was used, according to the level of serum creatinine and stone radiolucency, in that patients in which US and X-ray were not adequate for the diagnosis. Patients were placed in the lithotomy position and received prophylactic parenteral antibiotics before the procedure, which was performed under spinal or general anesthesia. A retrograde pyelogram was performed to define the anatomy and visualize any filling defect. We created two groups. Group A: 50 patients underwent “active guidewire” technique and 50 underwent standard technique. The ureteral catheter was used until the end of the procedure in all patients of group A instead of the standard guidewire. Group B: 50 patients underwent standard procedure with the aid of traditional guidewire. The initial phases of both the surgical procedures were similar, up to the step of replacing the standard guidewire with the active one. Firstly, using a cystoscope, a urethrocystoscopy was performed to exclude any other urethral or bladder pathologies. Then a PTFE standard guidewire was placed in the ureter and the cystoscope removed. A second guidewire through the operative channel of 7 F ureteroscope was used to reach the stone, passing the instrument between

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the two guidewire. If the ureter appeared compliant and the stone was not completely obstructing the lumen, we removed the ureteroscope and we replaced the standard guidewire with a 5 F Pollack catheter, left aside the stone until the end of the procedure. This step was performed with the help of the fluoroscopy and contrast enhancement. Finally, the ureteroscope was reintroduced to begin the lithotripsy. Holmium-YAG laser was used for stone dusting or fragmentation. Operating time was considered from the beginning of the procedure (operator introduced the guidewire in the ureteral meatus) to the end (operator placed the ureteral stent). We evaluated as endpoints: – reduction of operating times related to the volume of the stone. – quality of endoscopic view (expert operator opinion AC). – reduction of the number of procedure-related Urinary Tract Infections (UTIs) by monitoring the leukocytes blood values before and after surgery. – stone free rate (SFR) valuated by 30 days no-CE CT scan. All procedures were performed by the same operator in high volume center with the same type of semi-rigid ureteroscope. Patient’s data collected, including age, gender, side, stone location (proximal, intermediate or distal ureteral).

RESULTS

We observed a statistically significant reduction (p = 0.01) in operating times of the procedure performed with the “active guidewire” compared to the control group, standardizing the operating times and relating them to the volume of the stone. We calculated a coefficient given by the ratio between the operating time (min) and the volume of the stone (mm3). This coefficient was 39% lower in the procedures conducted with active guidewire (5.72 vs 9.40) (Table 2). Pearson correlation analisys was conducted, that demostrates a direct correlation in favour of the active guidewire technique (r = 0.208, p = 0.035) (Table 3). In 10 patients of group A we found a reduction in post-

Table 1. Patient demographics. Patient, n Mean age years (range, median) Men, n (%) Women, n (%) Proximal ureteral stone, n (%) Intermediate ureteral stone, n (%) Distal ureteral stone, n (%) Hydronephrosis, n (%) Side right/left (%) Previous RIRS (%) Indwelling double-J stent, (%)

100 54 (28-86, 56) 63 (63) 37 (37) 32 (32) 26 (26) 42 (42) 78 (78) 49/51 (49/51) 0 (0) 0 (0)

Ureteral stone treatment: 2 techniques comparison

Table 2. Data analysis. Completed procedures sURS (%) Average age Average ratio operating time\stone volume (min\mm3) Mean increased postoperative leukocytosis in percentage Mucosal injury (%) Postoperative fever (%) Stone-free rate (%)

“Active guidewire” Standard guidewire 50 (50) 50 (50) 55 53

P-value -

5.72

9.4

0.01

3 0 (0) 1 (2) 46 (92)

30 5 (10) 8 (16) 43 (86)

< 0.01 < 0.01 < 0.01 0.914

Table 3. Pearson correlation analysis. Variable Person coefficent Endoscopic technique – operating time -0.532 Endoscopic technique – postoperative leukocytosis -0.654 Endoscopic technique – mucosal slippage -0.246 Endoscopic technique – operating time\stone volume (min\mm3) 0.208

white blood cell count, with an average white blood cell growth of 30%. Statistical analysis demonstrates a significative difference in reduction of leukocytosis, number of mucosal slippage and post-operative fever (Table 2). In group B, 5 episodes of ureteral mucosal injury occurred, which led to an early conclusion of the procedure and the placing of a ureteral stent. Stone free rate (SFR) was 92% and 86% respectively in “active guidewire” and standard guidewire group. No significant differences occurred on this field (Table 2). Pearson correlation analysis demonstrated an indirect correlation between the endoscopic technique and operating time (r = -0.532, p < 0.001), mucosal slippages (r = -0.246, p = 0.012) and postoperative leukocytosis (r = -0.654, p < 0.001) (Table 3).

DISCUSSION

P-value < 0.001 < 0.001 0.012 0.035

operative leukocytosis, thanks to the resolution of hydronephrosis. In the remaining 40 patients of group A we witnessed a postprocedural increase of the white blood cell count (< 20%). The mean increase of white blood cell count across all procedures performed with active guidewire was 3% compared to pre-operative blood cell count. Two of these patients had postoperative fever and leukocytosis > 20.000 WBC/mm3, treated with antibiotic therapy. All patients in group B showed rising

Figure 1. Clear vision of operative area with the use of an active guidewire.

A compliant ureter is defined as a ureter ≥ 12 F and so it should allow the easy passage of a semirigid 7 F ureteroscope with a safety guidewire (3 F) aside or “active guidewire” (5 F) (4). The usage of a ureteral catheter instead of the standard guidewire has some remarkable advantages. First of all, the quality of vision, in particular during laser lithotripsy, is absolutely better than the standard technique because the generated powder is immediately expelled through the catheter, thanks to the constant antegrade flow. Stone powder is not in suspension in our working area. The second advantage, directly connected to the first, is represented by a lower risk of ureteral mucosal injury due to a better vision (Figure 1). In group B, we observed 5 episodes of ureteral mucosal injury, occurred during laser lithotripsy. The cause of these injuries was the imperfect vision of the operating field, due to the stone powder and the necessity of a reduced or discontinuous inflow, in order to not push-up the stone. In fact, no ureteral tears or damage occurred in group A, because of a perfect vision of the ureteral field. Finally, it allows to reduce intrarenal pressure peaks. During the semi-rigid ureteroscope progression in ureter, the IPPmax (intrapelvic pressure Max) reaches high levels in renal pelvis; the use of pumpes also induces critical levels of IPPmax. Excessive irrigation pressures can be detrimental, leading to pyelolymphatic and pyelovenous backflow and consequent development of sepsis (1, 5). The use of a Pollack ureteral catheter during ureteroscopy, allow an excape way for saline irrigation preventing high pressure peaks. We were not able to evaluate the real renal pelvis IPPmax in the two groups, but we suppose that the presence of the 5 F ureteral catheter in pelvis can create a useful way of outflow. We think that the lower number of post-operative leukocytosis and fevers in Group A could be due to this expedient. In summary, a better vision of the operative area, the reduction of operating time and the low rate of leukocytosis can traslate in better results for this kind of surgery. In addition, during semi-rigid ureteroscopy it is mandatory to interrupt the treatment every time the antegrade flow ceases, due to the filling of the excretory route, because of the absence of a continuous flow of the instrument. So the usage of the ureteral catheter reduces the IPPmax, post-operative UTIs and allows a faster hospital Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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discharge of the patient (6-8). It results in a decrease of hospitalization costs.

CONCLUSIONS

If we consider the kidney as a closed system, without a discharge for saline irrigation during semi-rigid ureteroscopy, we have to consider that the most part of time is actively used (antegrade flow, good vision and lithotripsy) but a really long period of time is spent passively (discharge of the kidney), so it leads to a temporary interruption of the procedure. In our experience the “active guidewire technique” has proven to be safe as well as easy to apply in selected cases. The use of a small semi-rigid ureteroscope (7 F) is mandatory, because of the 5 F diameter of the ureteral catheter. We believe that this technique, compared to the use of the traditional guide wire, is to be preferred whenever the ureter allows the presence of the catheter and the semirigid 7 F ureteroscope (for a total of 12 F) in its lumen, avoiding forcing the passage of the instrument. The size of the catheter is acceptable, in consideration of the frequent use of ureteral sheaths with even larger diameters (from 12 to 14 Fr) in endoscopic urological surgery (9). The decompression of the pelvic-caliceal system leads to avoid pressure spikes, which might decrease infectious complications. Furthermore, the risk of complications related to high pressures and operating time is lower, as well as better treatment quality thanks to cleaner vision (10-12). Many authors suggested that high intrarenal pressure during ureteroscopy and iatrogenic trauma of the pelvicalyceal system during instrumental manipulations are the most probable mechanisms that lead to other life-threatening complications such as urinomas, perirenal abscesses and subcapsular, perirenal and retroperitoneal hematoma, reported with an incidence up to 2,2% (13, 14, 16, 17). Nevertheless, the use of “active guidewire” can decrease the IPPmax and let URS safer by acting as a safeguard against the consequences of increased IPP, even under manual pumping and forced irrigation (15). It needs a laboratory study to assess the real value of the IPP and the differences in the two surgical approaches. The comparison also needs a larger cohort of study to be better statistically evaluated in order to standardize a different and often safer approach to ureteral and renal stone.

ETHICS

APPROVAL AND CONSENT TO PARTICIPATE

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Each patient agreed to allow the use of their clinical data for the study and signed an informed consent. This study doesn’t require the approval by the ethics committee for its conception.

AVAILABILITY

OF DATA AND MATERIALS

The data that support the findings of this study are available on request from the corresponding author AC.

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The data are not publicly available for containing personal information that could compromise research participant privacy.

FUNDING

This study was not funded by any institution. Author contributions (initials name and surname): (I) Conception and design: AC, NL (II) Administrative support: MF, EM (III) Provision of study materials or patients: AC (IV) Collection and assembly of data: AC. NL (V) Data analysis and interpretation: NL, MF, EM (VI) Manuscript writing: All authors (VII) Final approval of manuscript: All authors.

REFERENCES

1. Michel MS, Honeck P, Alken P. Conventional high pressure versus newly developed continuous-flow ureterorenoscope: urodynamic pressure evaluation of the renal pelvis and flow capacity. J Endourol. 2008; 22:1083-1085. 2. Ma YC, Jian ZY, Yuan C, et al. Risk factors of infectious complications after ureteroscopy: a systematic review and meta-analysis based on adjusted effect estimate, Surg Infect. 2020; 21:811-822. 3. Southern JB, Higgins AM, Young AJ, et al. Risk Factors for postoperative fever and systemic inflammatory response syndrome after ureteroscopy for stone disease. J Endourol. 2019; 33:516-522. 4. Fulla J, Prasanchaimontri P, Rizk A, Loftus C, et al. Ureteral diameter as predictor of ureteral injury during ureteral access sheath placement. J Urol. 2021; 205:159-164. 5. Li T, Sun XZ, Lai DH, et al. Fever and systemic inflammatory response syndrome after retrograde intrarenal surgery: Risk factors and predictive model. Kaohsiung. J Med Sci. 2018; 34:400-408. 6. Moses RA, Ghali FM, Pais VM, Jr, Hyams E. Unplanned hospital return for infection following ureteroscopy - Can we identify modifiable risk factors? J Urol. 2016; 195:931-936. 7. Mitsuzuka K, Nakano O, Takahashi N, Satoh M. Identification of factors associted with postoperative febrile urinary tract infection after ureteroscopy for urinary stones. Urolithiasis. 2016; 44:257262. 8. Blackmur JP, Maitra NU, Marri RR, et al. Analysis of factors association with risk of postoperative urosepsis in patients undergoing ureteroscopy for treatment of stone disease. J Endourol. 2016; 30:963-969. 9. Boulalas I, De Dominicis M, Defidio L. Semirigid ureteroscopy prior retrograde intrarenal surgery (RIRS) helps to select the right ureteral access sheath. Arch Ital Urol Androl. 2018; 90:20-24. 10. Ogreden E, Oguz U, Demirelli E, et al. Categorization of ureterooscopy complications and investigation of associated factors by using the modified Clavine classification system. Turk J Med Sci. 2016; 46:686-694. 11. Somani BK, Giusti G, Sun Y, et al. Complications associated with ureterorenoscopy (URS) related to treatment of urolithiasis: the clinical research Office of Endourological Society URS Global study. World J Urol. 2017; 166:538-540. 12. Proietti S, Dragos L, Somani BK, Buttice S, Talso M, Emliani E, et al. In vitro comparision of maximum pressure developed by irrigation systems in a kidney model. J Endourol. 2017;31:522-527.

Ureteral stone treatment: 2 techniques comparison

13. De Coninck V, Keller EX, Somani B, et al. Complications of ureteroscopy: a complete overview. World J Urol. 2020; 38:21472166. 14. Bai J, Li C, Wang S, et al. Subcapsular renal haematoma after holmium: yttrium-aluminium-garnet laser ureterolithotripsy. BJU Int. 2012; 109:1230-1234. 15. Hyams ES, Munver R, Bird VG, et al. Flexible ureterorenoscopy and holmium laser lithotripsy for the management of renal stone bur-

dens that measure 2 to 3 cm: a multi-institutional experience J Endourol. 2010; 24:1583-1588. 16. Xu L, LiG Life-threatening subcapsular renal hematoma after flexible ureteroscopic laser lithotripsy: treatment with superselective renal arterial embolization. Urolithiasis. 2013; 41:449-451. 17. Meng HZ, Chen SW, Chen GM, et al. Renal subcapsular Hemorrhage complicating ureterolithotripsy: an unknown complication of a know day-to-day procedure. Urol Int. 2013; 91:335-339.

Correspondence Alessandro Calarco, MD alecalarco@gmail.com Marco Frisenda, MD (Corresponding Author) marco.frisenda57hu@gmail.com Emilio Molinaro, MD emilio.molinaro89@gmail.com Department of Urology, “Cristo Re” Hospital Fondation, Rome (Italy) Niccolò Lenci, MD lenci.niccolo@live.com Department of Urology, “A. Gemelli” Academic Hospital, Catholic University of Sacred Hearth, Rome, Italy

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DOI: 10.4081/aiua.2021.4.436

ORIGINAL PAPER

Is there a relationship between renal scarring and neutrophil-to-lymphocyte ratio in patients with vesicoureteral reflux? Mehmet Demir, !smail Yağmur, Eyyup Sabri Pelit, Bülent Katı, Eser Ördek, Halil Çiftçi Department of Urology, Harran University, Sanliurfa, Turkey.

Summary

Objectives: Vesicoureteral reflux (VUR) exacerbates the risk of renal scarring by establishing a ground for pyelonephritis. It is known that the inflammatory process is more influential than the direct damage caused by bacterial infection in the development of renal scars after pyelonephritis. Therefore, the present study aims to investigate the relationship between renal scarring and systemic inflammatory markers in patients with VUR. Material and methods: Hundred and ninety-two patients (116 females, 76 males) diagnosed with VUR were divided into two groups based on the presence or absence of renal scarring and into three groups according to the grade of VUR (low, moderate and high). Neutrophil count, lymphocyte count, mean platelet volume (MPV) and neutrophil-to-lymphocyte ratio (NLR) were compared among the groups. Results: Of the 192 patients, 102 had renal scarring. The age and gender distribution did not differ significantly between the groups with and without renal scarring (p > 0.05). However, the grade of reflux and lymphocyte count were significantly higher in the group with renal scarring (p < 0.05), and the NLR was significantly lower in the group with renal scarring (p < 0.05). The lymphocyte count was significantly higher (p < 0.05) and NLR was significantly lower in the high-grade VUR group (p < 0.05). However, MPV values did not differ significantly (p > 0.05) between the groups. Conclusions: NLR can be used to predict renal scarring in patients with VUR, especially in the period of 3-6 months after the first attack of infection, and may even serve as a candidate marker for treatment selection. However, larger series and prospective studies are needed.

KEY WORDS: Vesicoureteral reflux; Neutrophil-to-lymphocyte ratio; Pyelonephritis; Renal scarring. Submitted 15 October 2021; Accepted 28 October 2021

INTRODUCTION

Vesicoureteral reflux (VUR) is a functional and anatomical disorder that can result in renal scarring, hypertension and end-stage renal failure (1). VUR predisposes the patients to urinary tract infection (UTI) and pyelonephritis and increases the risk of scarring in the kidney (2). Renal scarring is an important cause of hypertension and chronic renal failure (CRF) in children and young adults (3). The etiopathogenesis of renal scarring has not been clearly understood. However, lymphocytes play an important role in the initi-

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ation of renal fibrosis (4). The infiltrating lymphocytes, monocytes/macrophages and mast cells activate and produce reactive oxygen species (ROS) after infection and release fibrogenic cytokines and growth factors (5, 6). The resulting damage causes interstitial inflammation, collagen deposition and disruption of the normal tubular arrangement. As a result, permanent parenchymal damage and scar formation occur, which are accompanied by tubular atrophy and interstitial fibrosis (7). Even if the infection is treated and VUR is corrected, the inflammatory process continues and scars may, therefore, develop (1). It is known that the complete blood count parameters vary qualitatively and quantitatively in inflammatory processes (8) and that the neutrophil-to-lymphocyte ratio (NLR) is effective in predicting inflammation (9). Platelets also contribute to increased inflammation by enhancing the secretion of cytokines at the beginning of inflammation (10). Mean thrombocyte volume (MPV) level can be used as an indicator of platelet functions (11). Tc-99m dimercaptosuccinic acid (DMSA) scintigraphy is the gold standard in detecting the development of renal scars after pyelonephritis (12). Pyelonephritic inflammatory changes in the kidney occur immediately and can be detected with DMSA. While some of these acute changes resolve within 6 months, some lead to renal scarring (13). Currently, the development of scars in patients cannot be predicted as there is no easily accessible predictive marker for renal scar development. If such a marker is identified, improvements can be made in the follow-up and treatment algorithm of patients with VUR. The present study aims to compare the NLR and MPV values in patients having VUR with and without renal scarring. To the best of our knowledge, this is the first study on the topic.

MATERIALS

AND METHODS

The hospital records of patients diagnosed with VUR using voiding cystourethrography (VCUG) between January 2008 and August 2020 were retrospectively reviewed. Ethics committee approval was granted by our Faculty Ethics Committee (HRU/16.06.27). Patients' age, frequency of past UTI episodes, use of prophylactic antibiotics, physical examination findings, blood urea nitrogen and creatinine, complete blood count, complete urinalysis, No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2021; 93, 4

Renal scarring and neutrophil-to-lymphocyte ratio

urine culture, ultrasound (USG), VCUG and DMSA findings were examined. The VCUG findings of the patients were evaluated according to the standards of the International Reflux Study in Children (14). Most of the patients were admitted to our clinic with the pre-diagnosis of VUR after acute infection, for further investigation, some of them were diagnosed with VUR after acute infection and for follow-up and treatment, and some of them were directly admitted to our clinic because of recurrent UTI. No new VCUG was performed in patients diagnosed with VUR and referred to our clinic. Imaging was performed in our hospital for patients who were referred with a pre-diagnosis of VUR and did not have VCUG. DMSA scintigraphs, provided that they were performed 3-6 months after the occurrence of UTI, were examined. DMSA scintigraphies taken during the acute infection period were not included in the study. The renal parenchymal scar was defined as cortical thinning, volume loss, decreased DMSA uptake and renal contour irregularities. Neutrophil count, lymphocyte count and MPV values were recorded by examining the results of complete blood count at the time of DMSA acquisition, and it was established that the patients had no active infection by demonstrating a sterile urine culture. Patients with malignant diseases and those on chronic anti-inflammatory drug therapy were excluded from the study. Patients with secondary VUR caused by other factors, such as neurogenic bladder and posterior urethral valve, and those with voiding dysfunction were excluded from the study. Hundred and ninety-two patients with accessible data were included in the study. The patients were divided into two groups based on the presence or absence of renal scarring and into three groups according to the grade of VUR (mild: grades I-II, moderate: grade III; high: grades IV-V). Neutrophil count, lymphocyte count, MPV values and NLR were compared among the groups. Statistical methods Mean, standard deviation, median, minimum, maximum value frequency and percentage were used for descriptive statistics. Kolmogorov-Smirnov test was employed to check the distribution of the variables. Mann-Whitney U test was used for the comparison of the quantitative data. Chi-square test was used for the comparison of the qualitative data. SPSS 26.0 was used for the statistical analysis.

RESULTS

Of the 192 patients with VUR, 116 were females, and 76 were males. The mean age of the patients was 5.4 ± 5 years. Of the patients, 124 had unilateral and 68 had bilateral VUR (Table 1). The age and gender distribution did not differ significantly between patients with and without renal scarring (p > 0.05). The rates of renal scarring were 9%, 32.5%, 57.1%, 67.3% and 65.6% in patients with grade I, II, III, IV and V VUR, respectively. The VUR grade and lymphocyte counts were significantly higher (p < 0.05) and the neutrophil count and NLR were significantly lower (p < 0.05) in the group with renal scarring than in the group without renal scarring. The MPV values did not differ sig-

Table 1. Demographic data of the patients. Age Gender Side

Grade

Neutrophil Lymphocyte NLR MPV

Min-max 0.10 - 36.00

Median 4.00

Girl Boy Right Left Bilateral I II III IV V 1.10 1.30 0.20 4.20

10.80 9.90 4.06 10.70

4.70 3.70 1.22 6.20

Mean ± sd/n-% 5.40 ± 5.00 116 60.4% 76 39.6% 43 22.4% 81 42.2% 68 35.4% 11 5.7% 40 20.8% 63 32.8% 46 24.0% 32 16.7% 4.78 ± 1.89 4.07 ± 1.55 1.37 ± 0.79 6.36 ± 0.99

NLR: Neutrophil Lymphocyte Ratio; MPV: Mean Platelet Volume.

Table 2. Comparison of patients with and without renal scarring. Scar (-) Scar (+) Mean ± sd/n-% Median Mean ± sd/n-% Median Age 5.80 ± 6.36 4.00 5.04 ± 3.37 4.00 Gender Girl 54 60.0% 62 60.8% Boy 36 40.0% 40 39.2% Side Right 19 21.1% 24 23.5% Left 42 46.7% 39 38.2% Bilateral 29 32.2% 39 38.2% Grade I 10 11.1% 1 1.0% II 27 30.0% 13 12.7% III 27 30.0% 36 35.3% IV 15 16.7% 31 30.4% V 11 12.2% 21 20.6% Neutrophil 5.19 ± 1.70 4.90 4.42 ± 1.98 4.40 Lymphocyte 3.71 ± 1.25 3.60 4.39 ± 1.71 3.80 NLR 1.59 ± 0.83 1.38 1.16 ± 0.70 0.99 MPV 6.28 ± 0.92 6.10 6.43 ± 1.04 6.30

P 0.620 0.912 0.492

m X2 X2

0.000 X2

0.002 0.020 0.000 0.395

m m m m

m: Mann-whitney u test; X2: Chi-square test; Statistically significant results are in bold italics (p < 0.05).

NLR: Neutrophil Lymphocyte Ratio; MPV: Mean Platelet Volume.

nificantly (p > 0.05) between the groups with and without renal scarring (Table 2). According to the grade of reflux, the patients were divided into three groups, that is, low (grades I-II), intermediate (grade III) and high (grades IV-V) VUR groups. Lymphocyte count was significantly higher in the highgrade VUR group than in the low- and moderate-VUR groups (p < 0.05). NLR was significantly lower in the high-grade VUR group than in the low- and moderateVUR groups (p < 0.05). However, neutrophil count and MPV values did not differ significantly according to the grade of VUR (p > 0.05) (Table 3). In the sub-data analysis, the patients who were divided into three groups (low, moderate and high) according to the degree of reflux were further divided into two groups based on the presence or absence of renal scarring. The neutrophil count was significantly lower in scar-positive patients with low-grade (grades I-II) VUR (p < 0.05) than in scar-negative patients. However, lymphocyte count and NLR did not differ significantly (p > 0.05) (Table 4). Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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bined with antibiotic therapy have been observed in animal studies based on the hypothesis that the development of renal Grade I-II Grade III Grade IV-V P scarring can be reduced by preventing the Mean ± sd/n-% Median Mean ± sd/n-% Median Mean ± sd/n-% Median inflammatory process (19). In a recent douK Age 7.50 ± 7.14 7.00 5.14 ± 3.71 5.00 4.23 ± 3.67 4.00 0.005 ble-blind, placebo-controlled study conX2 Gender Girl 40 78.4% 39 61.9% 37 47.4% 0.002 ducted by Shaikh et al., patients who were Boy 11 21.6% 24 38.1% 41 52.6% treated for UTI were divided into two Side Right 12 23.5% 15 23.8% 16 20.5% 0.124 X2 Left 28 54.9% 25 39.7% 28 35.9% groups. One group received antibiotics and Bilateral 11 21.6% 23 36.5% 34 43.6% placebo, while the other group received Neutrophil 4.79 ± 1.93 4.50 5.05 ± 1.75 5.10 4.56 ± 1.95 4.45 0.146 K antibiotics and corticosteroids. The develLymphocyte 3.51 ± 1.13 3.10 3.95 ± 1.50 3.60 4.55 ± 1.69 4.20 0.001 K opment of the renal scar was found to be NLR 1.51 ± 0.78 1.28 1.51 ± 0.84 1.45 1.16 ± 0.72 1.01 0.004 K lower in the group in which corticosteroids MPV 6.23 ± 0.90 6.10 6.41 ± 0.99 6.30 6.40 ± 1.04 6.15 0.540 K were added to the treatment although the K: Kruskal-wallis (Mann-whitney u test); X2: Chi-square test; Statistically significant results are in bold italics (p < 0.05). difference was not statistically significant NLR: Neutrophil Lymphocyte Ratio; MPV: Mean Platelet Volume. (20). Based on the results of the study, it was argued that better results could be achieved by adding corticosteroids to the Table 4. treatment of patients predicted to develop pyelonephritis Comparison of patients with and without renal scarring and renal scarring. Urinary inflammatory biomarkers such according to the grade of reflux. as TGF-b1, VEGF, and MCP-1 (15), Interleukin-18 (IL-18) Scar (-) Scar (+) P are known to play a role in renal ischemia-reperfusion and Mean ± sd/n-% Median Mean ± sd/n-% Median acute kidney injury, and procalcitonin (PCT) and CRP m Grade I-II Neutrophil 4.95 ± 1.55 4.80 4.38 ± 2.73 3.30 0.038 serum inflammation markers have proven to be reliable in m Lymphocyte 3.59 ± 1.25 3.30 3.28 ± 0.71 3.10 0.619 VUR patients (21). However, an easy-to-reach biomarker m NLR 1.53 ± 0.66 1.41 1.45 ± 1.05 0.97 0.202 predicting renal scar is still not available. m MPV 6.19 ± 0.89 6.10 6.36 ± 0.94 6.40 0.398 The NLR is a simple, useful parameter that is used as a m Grade III Neutrophil 5.39 ± 1.49 5.20 4.79 ± 1.91 4.75 0.173 systemic inflammation marker. It has been widely Lymphocyte 3.78 ± 1.35 3.90 4.08 ± 1.61 3.50 0.835 m m employed to predict the outcomes of oncological, cardioNLR 1.71 ± 0.98 1.45 1.36 ± 0.71 1.45 0.285 vascular, gastrointestinal and hematogenous infections MPV 6.42 ± 1.04 6.40 6.40 ± 0.96 6.30 0.867 m (22). It has been proposed as a marker of infection in Grade IV-V Neutrophil 5.32 ± 2.08 4.90 4.18 ± 1.79 3.95 0.020 m patients with sepsis and has been reported to be associatLymphocyte 3.82 ± 1.18 3.60 4.91 ± 1.79 4.50 0.016 m ed with the severity of the disease (23). In the study perNLR 1.57 ± 0.89 1.31 0.96 ± 0.52 0.83 0.001 m MPV 6.26 ± 0.84 6.10 6.48 ± 1.13 6.25 0.652 m formed by Terradas et al., increased mortality was demonm: Mann-whitney u test; Statistically significant results are in bold italics (p < 0.05). strated in patients with bacteraemia who had an NLR of NLR: Neutrophil Lymphocyte Ratio; MPV: Mean Platelet Volume. > 7 (24). In another study, it has been reported that the risk of sepsis increased after percutaneous nephrolithotomy in patients with an NLR of ≥ 2.5 (25). Neutrophil count, lymphocyte count and NLR did not difBased on the data from literature, we hypothesised that fer significantly (p > 0.05) between scar-positive and scarthere might be a relationship between renal scarring and negative patients with moderate (grade III) VUR (Table 4). complete blood count parameters. Hence, we analysed The lymphocyte count was significantly higher (p < 0.05) the complete blood count parameters of patients diagand the neutrophil count and NLR were significantly lower nosed with VUR. The NLR was 0.99 (1.16 ± 0.7) in the (p < 0.05) in scar-positive patients with high-grade (grades group with renal scarring and 1.38 (1.59 ± 0.83) in the IV-V) VUR than in scar-negative patients (Table 4). Table 3. Comparison of patients according to the grade of reflux.

DISCUSSION

VUR increases the risk of renal scarring by establishing a ground for UTI and pyelonephritis. If the necessary precautions are not taken and the condition is not treated in a timely manner, VUR causes reflux nephropathy and CRF develops in 25%-60% of these patients (15). The reflux of the infected urine back to the kidney does not always cause parenchymal damage and renal scar in VUR (16). It has been shown that the inflammatory process is more influential than the direct damage caused by bacterial infection in renal scar development after pyelonephritis (17, 18). It has been suggested that even if the infection is treated and VUR is corrected, the inflammatory process that has already started continues and therefore scar may develop (1, 15). Partial benefits of the use of corticosteroids com-

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Figure 1. The relationship between NLR and renal scarring.

Renal scarring and neutrophil-to-lymphocyte ratio

Figure 2. Relationship between the grade of VUR and NLR.

Figure 3. The relationship between the grade of reflux and renal scarring.

group without renal scarring. We found that NLR was low in patients with renal scars (Figure 1), and a relationship was discerned between the grade of reflux and NLR (Figure 2). Therefore, we considered that NLR can be used to predict renal scarring. Risk factors precipitating the development of renal scarring have been identified in patients with VUR (26). One of these factors is the severity of the reflux. The risk of renal scar developing after pyelonephritis increases with the severity of VUR (27, 28). In a study involving 303 children with UTI who were under 2 years of age, Stokland et al. showed that the risk of renal scarring was elevated in Tc-99m DMSA scintigraphy in cases with high-grade VUR (29). In the carried out by Bandari et al., the rates of renal scarring were 33%, 33%, 40%, 50% and 80% in patients with grade I, II, III, IV and V VUR, respectively (30). Similarly, Jaukovic et al. found renal scars in 26% of the children with low-grade VUR and in 56% of the children with high-grade VUR (31). In our study, the renal scar rates were 9%, 32.5%, 57.1%, 67.3% and 65.6% in patients with grade I, II, III, IV and V VUR, respectively. As seen in VUR studies in the literature and in the present study, the rate of scarring increased as the grade of reflux increased (Figure 3). However, not all patients with high-grade reflux develop renal scarring and those with low-grade reflux can also develop renal scars

since the inflammatory process and immune response progress differently in each patient (17, 32). In the subdata analysis of our study, the lymphocyte count was significantly higher (p < 0.05) and the neutrophil count and NLR were significantly lower (p < 0.05) in patients with renal scarring who had high-grade (grades IV-V) reflux than in those without renal scarring. We identified a relationship between renal scarring and NLR in patients with high-grade (grades IV-V) VUR. Although our study did not establish this relationship in the low and moderate (grades I, II and III) reflux groups, we think that NLR could be the reason why some patients develop renal scarring while others with a similar grade of VUR do not. Currently, requesting DMSA scintigraphy and performing VCUG for those with DMSA uptake are recommended as a Top-Down approach in the first-line workup after febrile UTI (13). VUR occurs in 24%-39% of patients with acute pyelonephritis detected by DMSA scintigraphy (33). In a systematic review by Shaikh et al., DMSA changes were found in the acute phase in 57% of the patients after the first UTI episode and these changes were observed in 15% of the patients during follow-up (32). Therefore, repeat DMSA imaging 6-12 months later is recommended to determine the long-term outcomes in patients with signs of acute pyelonephritis (34). However, DMSA screening in children is impractical and expensive (20). In addition, DMSA between the ages of 1-3 has disadvantages such as the need for sedation during scintigraphy (35) and irradiation (36). Therefore, we think that NLR can be used as a parameter in predicting renal scarring and that DMSA scintigraphy can reduce the number of shots. Limitations Our study has some limitations. The first limitation is the retrospective study design. Since the number of febrile UTI episodes in the study patients and whether they received an effective therapy are unknown, these data were not included in the study. Similarly, because we are a tertiary health centre, patients are referred from external centres. Therefore, most of the patients do not have complete blood count data for the acute period. Therefore, infection parameters pertaining to the acute infection period were not included in the study. We think that the relationship between the complete blood parameters at the time of acute infection and renal scar formation should be examined with prospective studies.

CONCLUSIONS

We opine that NLR can be used as a parameter to predict renal scarring in patients with VUR and may even be a guiding marker candidate for treatment selection. In addition, we anticipate that the number of DMSA scans, which are costly and relatively difficult to implement, can be reduced in this manner. However, these findings need to be confirmed by well-designed prospective studies.

REFERENCES

1. Tekgül S, Riedmiller H, Hoebeke P, et al. European Association of Urology. EAU guidelines on vesicoureteral reflux in children. Eur Urol. 2012; 62:534-42. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

439

M. Demir, !. Yağmur, E. Sabri Pelit, B. Katı, E. Ördek, H. Çiftçi

2. Sirin A, Emre S, Alpay H, et al. Etiology of chronic renal failure in Turkish children. Pediatr Nephrol. 1995; 9:549-52.

simple parameter of systemic inflammation and stress in critically ill. Bratisl Lek Listy. 2001; 102:5-14.

3. Chertin B, Abu Arafeh W, Kocherov S. Endoscopic correction of complex cases of vesicoureteral reflux utilizing Vantris as a new nonbiodegradable tissue-augmenting substance. Pediatr Surg Int. 2014; 30:445-8.

24. Terradas R, Grau S, Blanch J, et al. Eosinophil count and neutrophil-lymphocyte count ratio as prognostic markers in patients with bacteremia: a retrospective cohort study. PLoS One. 2012; 7:e42860.

4. Anders HJ, Ryu M. Renal microenvironments and macrophage phenotypes determine progression or resolution of renal inflammation and fibrosis. Kidney Int. 2011; 80:915-925. 5. Nikolic-Paterson DJ. CD4+ T cells: a potential player in renal fibrosis. Kidney Int. 2010; 78:333-5. 6. Cendron M. Reflux nephropathy. J Pediatr Urol. 2008; 4:414-21. 7. Jahnukainen T, Chen M, Celsi G. Mechanisms of renal damage owing to infection. Pediatr Nephrol. 2005; 20:1043-53. 8. Kapci M, Turkdogan KA, Duman A, et al. Biomarkers in the diagnosis of acute appendicitis. J Clin Exp Invest. 2014; 5:250-255 9. Turkmen K, Erdur FM, Ozcicek F, et al. Platelet-to-lymphocyte ratio better predicts inflammation than neutrophil-to-lymphocyte ratio in end-stage renal disease patients. Hemodial Int. 2013; 17:391-6. 10. Mantovani A, Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol. 2011; 11:519-31. 11. Bath P, Algert C, Chapman N, Neal B. PROGRESS Collaborative Group. Association of mean platelet volume with risk of stroke among 3134 individuals with history of cerebrovascular disease. Stroke. 2004; 35:622-6. 12. Hains DS, Cohen HL, McCarville MB, et al. Elucidation of renal scars in children with vesicoureteral reflux using contrast-enhanced ultrasound: a pilot study. Kidney Int Rep. 2017; 2:420-4. 13. Blumenthal I. Vesicoureteric reflux and urinary tract infection in children. Postgrad Med J. 2006; 82:31-5.

26. Lee YJ, Lee JH, Park YS. Risk factors for renal scar formation in infants with first episode of acute pyelonephritis: a prospective clinical study. J Urol. 2012; 187:1032-6. 27. Goldman M, Bistritzer T, Horne T, et al. The etiology of renal scars in infants with pyelonephritis and vesicoureteral reflux. Pediatr Nephrol. 2000; 14:385-8. 28. Zaffanello M, Cataldi L, Brugnara M, et al. Hidden high-grade vesicoureteral reflux is the main risk factor for chronic renal damage in children under the age of two years with first urinary tract infection. Scand J Urol Nephrol. 2009; 43:494-500. 29. Stokland E, Hellström M, Jacobsson B, et al. Renal damage one year after first urinary tract infection: role of dimercaptosuccinic acid scintigraphy. J Pediatr. 1996; 129:815-20. 30. Bandari B, Sindgikar SP, Kumar SS, et al. Renal scarring following urinary tract infections in children. Sudan J Paediatr. 2019; 19:25-30. 31. Jaukovic L, Ajdinovic B, Dopudja M, Krstic Z. Renal scintigraphy in children with vesicoureteral reflux. Indian J Pediatr. 2009; 76:1023-6.

14. Duckett JW, Bellinger MF. A plea for standardized grading of vesicoureteral reflux. Eur Urol. 1982; 8:74-7.

32. Shaikh N, Ewing AL, Bhatnagar S, Hoberman A. Risk of renal scarring in children with a first urinary tract infection: a systematic review. Pediatrics. 2010; 126:1084-91.

15. Morozova O, Morozov D, Pervouchine D, et al. Urinary biomarkers of latent inflammation and fibrosis in children with vesicoureteral reflux. Int Urol Nephrol. 2020; 52:603-610.

33. Levtchenko E, Lahy C, Levy J, et al. Treatment of children with acute pyelonephritis: a prospective randomized study. Pediatr Nephrol. 2001; 16:878-84.

16. Gordon I, Barkovics M, Pindoria S, et al. Primary vesicoureteric reflux as a predictor of renal damage in children hospitalized with urinary tract infection: a systematic review and meta-analysis. J Am Soc Nephrol. 2003; 14:739-44.

34. Biassoni L, Chippington S. Imaging in urinary tract infections: current strategies and new trends. Semin Nucl Med. 2008; 38:56-66.

17. Bille J, Glauser MP. Protection against chronic pyelonephritis in rats by suppression of acute suppuration: effect of colchicine and neutropenia. J Infect Dis. 1982; 146:220-6. 18. Roberts JA, Roth JK Jr, Domingue G, et al. Immunology of pyelonephritis in the primate model. V. Effect of superoxide dismutase. J Urol. 1982; 128:1394-400. 19. Haraoka M, Matsumoto T, Takahashi K, et al. Suppression of renal scarring by prednisolone combined with ciprofloxacin in ascending pyelonephritis in rats. J Urol. 1994; 151:1078-80. 20. Shaikh N, Shope TR, Hoberman A, et al. Corticosteroids to prevent kidney scarring in children with a febrile urinary tract infection: a randomized trial. Pediatr Nephrol. 2020; 35:2113-2120. 21. Yavuz S, Anarat A, Bayazıt AK. Interleukin-18, CRP and procalcitonin levels in vesicoureteral reflux and reflux nephropathy. Ren Fail. 2013; 35:1319-22. 22. Bolat D, Topcu YK, Aydogdu O, et al. Neutrophil to Lymphocyte Ratio as a predictor of early penile prosthesis implant infection. Int Urol Nephrol. 2017; 49:947-953. 23. Zahorec R. Ratio of neutrophil to lymphocyte counts--rapid and

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25. Sen V, Bozkurt IH, Aydogdu O, et al. Significance of preoperative neutrophil-lymphocyte count ratio on predicting postoperative sepsis after percutaneous nephrolithotomy. Kaohsiung J Med Sci. 2016; 32:507-513.

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35. Gordon I. Issues surrounding preparation, information and handling the child and parent in nuclear medicine. J Nucl Med. 1998; 39:490-4. 36. Smith T, Gordon I, Kelly JP. Comparison of radiation dose from intravenous urography and 99Tcm DMSA scintigraphy in children. Br J Radiol. 1998; 71:314-9. Correspondence Mehmet Demir, MD (Corresponding Author) drdemir02@gmail.com Ismail Yagmur, MD dr_iyagmur@hotmail.com Eyyup Sabri Pelit, MD dreyyupsabri@hotmail.com Bülent Katı, MD bulentkati@yahoo.com Eser Ördek, MD dr_eseser@hotmail.com Halil Çiftçi, MD halilciftci63@hotmail.com Harran University. Faculty of Medicine Urology Department Sanliurfa (Turkey)

DOI: 10.4081/aiua.2021.4.441

ORIGINAL PAPER

In women with incontinence, the need for pressure-flow study before surgery and abnormalities in the voiding phase. An up-to-date comment on the available problem accompanied by literature Kutluhan Erdem, Alper Cos¸kun, Fatih Üstün, Fatih Tarhan Department of Urology, University of Health Sciences, Kartal Dr. Lutfi Kırdar City Hospital, Istanbul, Turkey.

Summary

Objective: To investigate the differences between urodynamic findings and history in women with urinary incontinence before surgery and clarify the need for preoperative pressure-flow studies. Materials and methods: The medical records of 1018 women who underwent urodynamic examination for urinary incontinence between 2010 and 2015 were evaluated retrospectively. Stress (n = 442), urge (n = 334) and mixed (n = 242) were classified as type urinary incontinence according to urodynamics. The voiding phase findings of the patients were examined. Results: The mean age of the patients was 47.85 ± 0.27 years. 18.4% of patients (n = 187) had voiding phase problems. Furthermore, this condition was seen in the most urge incontinence type urinary incontinence (35%). There was a statistically significant difference between the groups' voiding phase findings (p < 0.0001). The relationship between the patient's history and international consultation on incontinence questionnaire form scoring (ICIQ) and the urodynamics results showed no excellent correlation. Conclusions: Voiding phase abnormalities are not uncommon in patients with urinary incontinence. They should be considered in the evaluation of patients. Voiding phase findings may show significant differences between urodynamic data and history. Besides, the data obtained with the questionnaire forms were significantly different from the findings obtained by urodynamics. Consequently, urodynamics may change pre-operative clinical decision.

KEY WORDS: Urinary incontinence; Urodynamics; Voiding. Submitted 28 February 2021; Accepted 14 June 2021

INTRODUCTION

Urinary incontinence is a common health condition that can affect about 50% of adult women and decrease life quality (1). This condition increases with age. Ten to twenty percent of women and up to 77% of women residing in nursing homes have urinary incontinence, yet only 25% attempt or receive treatment (2). In the evaluation of incontinence patients, the history alone may be insufficient to diagnose and classification. Understanding lower urinary tract function and revealing the underlying pathophysiology is essential for the evalu-

ation of these patients. Hence the information gained from urodynamics may help us. Performing urodynamics is controversial before surgical treatment of stress urinary incontinence (SUI) (3). According to the Cochrane library, urodynamics can change the clinical decision (4). The NICE (National Institute for health and care excellence) guideline recommends urodynamic examination before stress urinary incontinence surgery (5). EAU guidelines do not recommend routinely carrying out urodynamics when offering treatment for uncomplicated urinary incontinence (6). Incontinence mostly develops as a result of urine storage dysfunction and the incidence of bladder outlet obstruction (BOO) is low. For this reason, in daily practice, the only cystometry is usually performed in addition to history and physical examination. Since pressure-flow studies (PFS) are generally not implemented, the diagnosis of urinary voiding dysfunctions can be overlooked. Thus redundant surgical procedures and improper treatments can be applied to these patients. To clarify whether SUI patients are always pure SUI and if these patients should be submitted to urodynamic before surgery to prevent incorrect surgical approach, we aimed to retrospectively investigate the abnormalities in the voiding phase of female patients who have undergone PFS for incontinence.

MATERIALS

AND METHODS

Between January 2010 and June 2015, 1329 female patients aged 18-60 who had incontinence for at least six months and underwent urodynamics were evaluated retrospectively. Neurogenic lower urinary system dysfunction, active urinary infection, bladder stone, urethral stricture, pelvic radiation, pelvic surgery history, and patients who could not perform micturition in PFS were excluded from the study (311 patients). Patients' demographic properties, urination diary, pad test, urine analysis and culture, urethral mobility (Q tip), urinary ultrasonography, post-voided residue, and urodynamic examination findings were retrieved. At filling cystometry, urinary incontinence triggered with Valsalva or coughing was accepted as stress type urinary inconti-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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nence, involuntary and inhibited detrusor contractions as urge urinary incontinence and the presence of both findings as mixed urinary incontinence. At PFS, the inability of contraction at sufficient force or continuity resulting in prolonged or insufficient bladder discharge was considered underactive detrusor, Qmax > 12 ml/sec and Pdet Qmax > 20 cm H2O was considered as BOO. Voiding characterized by an intermittent or staccato flow pattern due to involuntary and irregular pelvic floor contractions in neurologically healthful patients was evaluated as dysfunctional voiding (7, 8). The patients were grouped as stress, urge, and mixed type urinary incontinence. Whether the voiding phase findings of the patients were normal or abnormal was checked. Urodynamics was applied according to the International Continence Association (ICS) (4). Chi-square test was utilized to evaluate the results with Prism 5.0 (GraphPad, USA) program. P value < 0.05 was accepted as statistically significant.

RESULTS

The average age of the patients was 47.85 ± 0.27 years. Of the patients, 442 (43%) were evaluated as stress-type, 334 (32%) as urge-type, and 242 (25%) as mixed-type incontinence (Figure 1). Urethral stricture was diagnosed in 6% (n = 11) of those with excretory phase problems, dysfunctional voiding in 51% (n = 96) and underactive detrusor in 43% (n = 80). Urethral stricture and dysfunctional voiding and the rate of underactive detrusor were higher in patients with urge-type urinary incontinence. (47%) (Table 1). Another finding was lack of good correlation between history and urodynamic filling phase results (Table 2). Similarly, data from International Consultation on Incontinence Questionnaire form (ICIQ) and findings from urodynamics are not fully concordant. There are considerable differences, especially in mixed urinary incontinence (Table 3).

Figure 1. Incontinence types and percentages.

Table 1. The voiding phase findings detected in the PFS. Groups Stress urinary incontinence (n = 442)

Urge type urinary incontinence (n = 334)

Mixed type urinary incontinence (n = 242)

Voiding phase findings Normal Urethral stricture Dysfunctional voiding Underactive detrusor Normal Uretral stricture Dysfunctional voiding Underactive detrusor Normal Uretral stricture Dysfunctional voiding Underactive detrusor

(n) 403 0 15 24 216 9 71 38 212 2 10 18

(%) 91 0 3 6 65 3 21 11 88 1 4 7

PFS: Pressure-flow study.

Table 2. Comparison of anamnesis and filling phase findings. Anamnesis SUI (n = 148) UUI (n = 120) MUI (n = 750)

Filling phase SUI UUI MUI SUI UUI MUI SUI UUI MUI

(n) (69) (37) (42) (46) (44) (30) (326) (266) (172)

(%) 47 25 28 38 37 25 43 35 22

SUI: Stress urinary incontinence; UUI: Urge urinary incontinence; MUI: Mixed urinary incontinence.

Table 3. Comparison of ICIQ and filling phase findings. Anamnesis SUI (n = 123 ) UUI (n = 116) MUI (n = 779)

Filling phase SUI UUI MUI SUI UUI MUI SUI UUI MUI

(n) (60) (31) (32) (50) (40) (26) (325) (271) (183)

(%) 49 25 26 43 35 22 42 35 23

SUI: Stress urinary incontinence; UUI: Urge urinary incontinence; MUI: Mixed urinary incontinence; ICIQ: International consultation on incontinence questionnaire form.

DISCUSSION

The bladder should be able to store urine at low pressure and at an appropriate volume, discharge the stored urine at once, and coordinate detrusor contraction and sphincter relaxation during voiding. The knowledge regarding the togetherness of urinary voiding dysfunctions in female patients with incontinence in the literature is unclear. In 18.4% (n = 187), we found that patients with incontinence also have voiding phase problems simultaneously. Additionally urethral stricture was found in 6% (n = 11), dysfunctional voiding in 51% (n = 96), and underactive detrusor in 43% (n = 80) of these patients. We established that our outcomes were consistent with the literature (7).

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Pressure-flow study in women with incontinence

If we come to underactive detrusor, we see that there are not enough studies and accepted objective criteria in female patients regarding underactive detrusor. The existing nomograms about underactive detrusor have been used to describe male voiding dysfunction (8). We defined that there were 7.9% (n = 80) underactive detrusor our patients. Estimating the prevalence of BOO in women with incontinence is problematic in light of the existing literature. A nomogram has been developed to diagnose BOO in women. However, due to the disparities in the pathophysiology of voiding problems compared to men, it has not been widely accepted, especially among urologists interested in this topic. Even so, it is possible to determine female bladder outlet obstruction with the support of pressure-flow studies and clinical symptoms simultaneously with video-urodynamics (8). It has been seen that even if in women with voiding difficulties and low urinary flow symptoms, the correlation between symptoms and urodynamics objective BUO is low, and it is not easy to reach a diagnosis in this way (9, 10). Another clinical entity that should be kept in mind is the possibility of the development of detrusor overactivity secondary to bladder outlet obstruction (7). As a matter of fact, in our study, the most common storage problem in patients with outflow obstruction was found to be urge type urinary incontinence. In addition, urethral stricture was found in 1.1% of the patients. Although dysfunctional voiding is primarily diagnosed in the pediatric age group, it is one of the most common urinary voiding dysfunctions in women with lower urinary tract symptoms. In the literature, dysfunctional voiding was established in women with lower urinary tract symptoms and urodynamic examination with a rate of 9.6-12% (11, 12). Similarly, we noticed dysfunctional voiding was at a rate of 9.4% in our study. It is a broad-spectrum non-neurogenic disorder involving dysfunction of the lower urinary tract and intestinal tract. Also, it is one of the most common urinary voiding dysfunctions in women with lower urinary tract symptoms. We presented treatment options such as behavioral therapy (pelvic floor physiotherapy, biofeedback), medical therapy, cognitive therapy and sacral neuromodulation to patients who were diagnosed with this dysfunctional voiding. Urodynamics after evaluation in the outpatient clinic changes the diagnosis by 57% and the choice of the treatment plan by 14%, and canalizes the surgical procedure (13-16). The best indicator for this is that 40% of overactive bladder patients are diverted for stress urinary surgery (8, 17). In another study, it has been indicated that the voiding phase is the most commonly used method to modify the surgical procedure in overactive bladder and intrinsic urinary sphincter deficiency (13). In our study, we found out that the diagnosis changed in 18.4% of patients after PFS. Thus, we think that unnecessary surgery in 69/684 (10%) patients and inappropriate medical treatment in 47/334 (14%) patients with urinary incontinence have been prevented. Limitations of our study are being a single-center study with retrospective design, lack of Overactive Bladder Questionnaire (OABQ) and ICIQ scoring in statistical data,

no follow-up of the patients after surgery. Another matter of criticism could be that evaluations were not made by a single physician. We also admit that our results do not support a new finding, but we believe that our study with a high number of patients may contribute to clarify the controversial topic of necessity to perform urodynamics before surgery.

CONCLUSIONS

Urodynamics can provide clinicians with detailed and useful information about lower urinary tract function that may affect medical and surgical decisions. We recommend performing pressure-flow studies together with cystometry not to overlook the diagnosis of possible urinary voiding dysfunction in female patients with incontinence undergoing urodynamic examination. We believe that supporting these data with multi-center and prospective studies will significantly contribute to the literature.

REFERENCES

1. Minassian VA, Stewart WF, Wood GC. Urinary incontinence in women: variation in prevalence estimates and risk factors. Obstet Gynecol. 2008; 111:324-331. 2. Tennstedt SL, Link CL, Steers WD, McKinlay JB. Prevalence of and risk factors for urine leakage in a racially and ethnically diverse population of adults: the Boston Area Community Health (BACH) Survey. Am J Epidemiol. 2008; 167:390-399. 3. Fletcher SG, Lemack GE. Clarifying the role of urodynamics in the preoperative evaluation of stress urinary incontinence. Scientific World Journal. 2008; 25:1259-1268. 4. Glazener CM, Lapitan MC. Urodynamic studies for management of urinary incontinence in children and adults. Cochrane Database Syst Rev. 2012; 18: CD003195. 5. Urinary Incontinence: The management of urinary incontinence in women. NICE Clinical Guideline 40. London, United Kingdom: National Institute for Health and Clinical Excellence, 2006. 6. Burkhard FC, Bosch JLHR, Cruz F, et al. EAU urinary incontinence guidelines 2018 ISBN 978-94-92671-07-3. 7. Yenilmez A, Turgut M, Dönmez T, Özyürek Y. Idrar kaçıran kadın hastalarda basınç-akım çalısmasının (BAÇ) Önemi. Turk J Urol. 2004; 30:451-456. 8. Onyishi SE, Twiss CO. Pressure flow studies in men and women. Urol Clin North Am. 2014; 41:453-67. 9. Groutz A, Blaivas JG, Chaikin DC. Bladder outlet obstruction in women: Definition and characteristics. Neurourol Urodyn 2000; 19:213-220. 10. Groutz A, Gordon D, Lessing JB, Wolman I, Jaffa A, David MP. Prevalence and characteristics of voiding difficulties in women: Are subjective symptoms substantiated by objective urodynamic data? Urology. 1999; 54: 268-272. 11. Carlson KV, Fiske J, Nitti VW. Value of routine evaluation of the voiding phase when performing urodynamic testing in women with lower urinary tract symptoms. J Urol. 2000; 164:1614-1618. 12. Nitti VW, Tu LM, Gitlin J. Diagnosing bladder outlet obstruction in women. J Urol. 1999; 161:1535-1540 13. Sirls LT, Richter HE, Litman HJ, et al. The effect of urodynamic testing on clinical diagnosis, treatment plan and outcomes in women Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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undergoing stress urinary incontinence surgery. J Urol. 2013; 189: 204-209. 14. Adelowo A, Dessie S, Rosenblatt L. The role of preoperative urodynamics in urogynecologic procedures. J Minim Invasive Gynecol. 2014; 21:217-222. 15. Serati M, Cattoni E, Siesto G, et al. Urodynamic evaluation: can it prevent the need for surgical intervention in women with apparent pure stress urinary incontinence? BJU Int. 2013; 112:344-350.

Correspondence Kutluhan Erdem, MD kutluhan1988@gmail.com Alper Coşkun, MD dr.alper05@gmail.com Fatih Üstün, MD drfatihustun@gmail.com Fatih Tarhan, MD tarhanf@yahoo.com Department of Urology, University of Health Sciences, Kartal Dr. Lutfi Kırdar City Hospital, Istanbul (Turkey)

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16. Rachaneni S, Latthe P. Does preoperative urodynamics improve outcomes for women undergoing surgery for stress urinary incontinence? A systematic review and meta-analysis. BJOG. 2015; 122:816. 17. van Leijsen SAL, Hoogstad-van Evert JS, J Mol BW, et al. The correlation between clinical and urodynamic diagnosis in classifying the type of urinary incontinence in women. A systematic review of the literature. Neurourol Urodyn. 2011; 30:495-502.

DOI: 10.4081/aiua.2021.4.445

ORIGINAL PAPER

Nocturnal polyuria in men performing uroflowmetry for lower urinary tract symptoms Emanuele Rubilotta 1, Daniele Castellani 2, Marilena Gubbiotti 3, Matteo Balzarro 1, Giacomo Maria Pirola 3, Rita Righetti 4, Pierpaolo Curti 4, Antonella Giannantoni 5, Maria Angela Cerruto 1, Alessandro Antonelli 1 1 Urology

Clinic, A.O.U.I of Verona, Verona, Italy; of Urology, IRCCS INRCA, Ancona, Italy; 3 Department of Urology, San Donato Hospital, Usl Toscana Sud-Est, Arezzo, Italy; 4 Department of Urology, AULSS 9, Ospedale Mater Salutis, Legnago, Italy; 5 Functional and Surgical Urology Unit, Department of Medical and Surgical Sciences and Neurosciences, University of Siena, Siena, Italy. 2 Department

Summary

Purpose: To assess the prevalence of nocturnal polyuria (NP) in males performing uroflowmetry (UF) for lower urinary tract symptoms (LUTS), the impact of NP on UF outcomes, and bladder emptying, the association between NP and LUTS. Materials and methods: Men scheduled for UF were recruited in two Centres. Data collected were medical history, IPSS, UF, post-void residual urine volume (PVR), 3-day frequency-volume charts (FVC). The NP index was used to assess NP with a threshold of ≥ 33%. The relationship between NP and patient’s aging was assessed. Results: 162 patients were included in the analysis. Mean age was 70.95 ± 8.04 years. The prevalence of NP was 54.9% (89/162). 110 (68%) patients reported nocturia, and among these, NP was documented in 76 (69%). Nocturia was found in 85% (76/89) of the population with NP. Total IPSS score, IPSS items #1, #2 and #7 showed a significant difference in men with NP compared with those without. Maximum flow rate and PVR did not significantly change comparing men with or without NP. Mean voiding volume (VV) of the night-time micturitions was significantly higher in men with NP compared to those without NP (532.1 ± 275.6 ml vs 175 ± 168.7 ml respectively, p < 0001), while mean VV day-time micturitions and mean VV at UF did not change between groups. Conclusions: NP had a high prevalence in men with LUTS performing UF. Aged males were more commonly affected by NP. Data demonstrated a strong relationship between NP and nocturia and increased urinary frequency while voiding symptoms were poorly related to NP.

KEY WORDS: Nocturnal polyuria; Nocturia; Uroflowmetry; Lower urinary tract symptoms; Male. Submitted 12 January 2021; Accepted 5 March 2021

INTRODUCTION

The complaining of lower urinary tract symptoms (LUTS) is one of the most common causes that lead men to seek urological attention. Among LUTS, nocturia is one of the most bothersome (1) and it is frequently caused by nocturnal polyuria (NP), even in neurological patients (2-6). NP is a multifactorial disorder (7), defined by the International

Continence Society (ICS) as “passing large volume of urine during the main sleep period” (8, 9). Among men complaining of nocturia, the prevalence rate of NP is quite high, ranging from 76 to 88%, and up to 93% in those aged ≥ 65 years old (3). In a large community study, the prevalence of NP was confirmed high, with a prevalence of 77.8% of the whole studied population (9); NP has been demonstrated more prevalent in men with nocturia (91.9%) compared to those without this condition (70.1%) (10). Thereby, a lot of males complaining of nocturia might be affected by an underlying condition of NP, which might remain unidentified and consequently not adequately treated whether a bladder diary or a frequency volume chart (FVC) has not been used. Males with LUTS including nocturia, usually perform uroflowmetry (UF) as a first step assessment, since these symptoms are commonly considered suggestive of bladder outlet obstruction (BOO)/benign prostatic hyperplasia (BPH). In these subjects, NP is rarely investigated before the UF and, consequently, the prevalence of nocturia remains unknown. Similarly, also most commonly LUTS associated with men with an underlying NP condition who are candidates for UF is undetermined. NP mainly influences the bladder storage phase, and therefore this disorder is not expected to play an essential role in the voiding phase. However, there is still no conclusive data showing, in real-life practice, the rate of men with an underlying NP condition performing UF for LUTS and studies excluding with certainly an impact of NP on UF results. This study aimed to assess the prevalence of NP in males performing UF for LUTS and the influence of NP on UF outcomes. We also evaluated whether NP was significantly associated with nocturia, with other urinary symptoms investigated by IPSS questionnaire, and with the bother due to LUTS in males scheduled for UF. Finally, an analysis of the relationship between NP and patient’s age was also performed.

MATERIALS

AND METHODS

Between September 2017 and January 2019, all consecutive men with LUTS scheduled for UF execution were

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screened in outpatient clinics of two Tertiary Hospitals for study inclusion. The experimental procedures were carried out in accordance with the Declaration of Helsinki. This research was registered in our Department clinical audit. All patients signed written informed consent. Data collected were a detailed medical history, selfadministered International Prostate Symptom Score (IPSS) questionnaire, UF, post-void residual urine volume (PVR) measured by ultrasound, and 3-day FVC, indicating “bedtime” and “waking time”. The 3-day FVC was delivered to patients at the time the UF was scheduled and was returned by patients on the day of UF execution. Increased urinary frequency, urinary urgency, voided volume (VV), and nocturnal urine production were assessed by 3-day FVC. Nocturia was defined as at least one episode of nocturnal voiding at 3-day FVC. The nocturnal polyuria index (NPi) was used to assess NP (8). NPi is calculated by dividing the amount of nocturnal urine production by 24-hour production, and the threshold of 33% is the most accepted cut-off (8). Therefore, we used a cut-off of NPi ≥ 33% of the total 24-h urine production to diagnose NP. Thus, patients were divided into two groups: Group A comprising males with NPi < 33% (no NP patients) and was the control group, and Group B including men with NPi ≥ 33% (NP patients). Inclusion criteria were age≥18 years, complete filling of both FVC and IPSS, UF with a voided volume higher than 150mL as suggested by ICS recommendation on Good Urodynamic Practices (11). Exclusion criteria were all conditions that could be confounding factors, as following: surgery of lower urinary tract (prostatectomy, radical prostatectomy, radical cystectomy, bladder, and urethral surgery), pelvic radiation, urolithiasis, double J stent, and urinary devices, and recurrent lower urinary tract infection. The relationship between NP and maximum flow rate (Qmax), VV at UF, and PVR after UF was evaluated. A comparison between the VV of the day-time and night-time micturitions was also assessed in each group. The VV of day-time and night-time micturitions and at UF were also compared between the two groups. The association between NP and urinary symptoms was evaluated through the IPSS questionnaire, analyzing the IPSS total score and all IPSS item scores. According to the last “ICS report on the terminology for adult male lower urinary tract and pelvic floor symptoms and dysfunction”, we divided the urinary symptoms reported by IPSS questionnaire as following: IPSS item #1 -feeling of incomplete bladder emptying- as a “Postvoiding symptom”; IPSS item #2 -increased urinary frequency, IPSS item #4 urgency, IPSS item #7 -nocturia- as “Storage symptoms”; IPSS item #3 -intermittency, IPSS item #5 -slow urinary stream, IPSS item #6 -straining to void- as “Voiding symptoms” (9). The sub-analysis, according to patients’ age, was also performed, distributing the patients into three groups according to age: 1) < 65 years, 2) between 65 and 74 years, and 3) ≥ 75 years. Statistical analysis Statistical analysis was performed with IBM-SPSS v.17 for Windows (IBM Corp, Armonk, NY, USA). Student’s t-test and the Mann- Whitney U test were performed to compare continuous parametric and nonparametric variables,

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as appropriate. Continuous variables were reported as mean ± SD. All values in the text and tables are expressed as mean ± SD. Statistically significant results were p < or equal to 0.05. Spearman correlations were used to test for the strength of linear association between variables along with the Wilcoxon and Mann-Whitney. X2 test was also used. Multiple linear regression analysis was performed evaluating NP and the following variables: NPi, total nocturnal diuresis, total daily (24 hours) diuresis, Qmax, PVR, age, cardiologic disease and diuretic drugs.

RESULTS

During the study period, 254 men met inclusion criteria and were enrolled in the study. Data on UF, PVR, and both IPSS and 3-day FVC were completed in 162/254 (63.8%) patients, who were included in the analysis. Table 1 shows the patients’ characteristics. Mean age was 70.95 ± 8.04 years. Among males aged lower than 65 years (Group i), one patient was 47 years old, and the remaining were older than 52 years. Eighty-eight (54.3%) patients were on urological therapy and 44 (27.1%) on cardiological treatment. Only 15 (9.2%) patients were on diuretics, and 7 (4.3%) were diabetic. The prevalence of NP was 54.9% (89/162 patients) with a mean NPi of 34.4 ± 11.2. Table 2 reports the rate of NP according to age, and Table 3 the comparison between the groups stratified by age. Younger males were the smaller group (n = 34), but with the highest NP rate (64.7%). 75% of the men affected by NP were aged ≥ 65 years old. Finally, we found a positive association between NP and age only in the group of men 65-74 years-old (p < 0.05). One-hundred-ten (68%) patients reported nocturia, and among these, NP was documented in 76 (69%). Nocturia was found in 85% (76/89) of the population with NP. Total IPSS score, IPSS items #1, IPSS items #2 and #7 showed a significant difference in men with NP compared with those without this disorder (Table 4). The maximum flow rate and PVR did not significantly change in the two groups of males (Table 4). Multiple regression analysis showed a significant correlation between NP and NPi, total nocturnal diuresis, total 24 h daily diuresis, age, cardiologic disease, and diuretic drugs (r = 0.96; p = 0.001), but not with Qmax and PVR (r = 2; p = 0.8). Table 1. Patients’ characteristics. Patients (n = 162) Patients in cardiological therapy - diuretic therapy - non diuretic therapy for hypertension - antiarrhythmics - antiplatelets/anticoagulants - diabetes therapy Patients in urological therapies - α1-blockers - 5α-reductase inhibitors - α1-blockers + 5α-reductase inhibitors - phytotherapy

n (%) 44 (27.1) 15 (9.2) 24 (14.8) 9 (5.5) 11 (6.7) 7 (4.3) 88 (54.3) 62 (38.3) 25 (15.4) 11 (6.8) 1 (0.6)

Nocturnal polyuria in men performing uroflowmetry

Table 2. Nocturnal polyuria prevalence according to patients’ age. Age (years)

NPi < 33% (n = 73) 12 (35.3) 34 (51.6%) 27 (43.6%) 73 (45.0%)

< 65 (n = 34) 65-74 (n = 66) ≥ 75 (n = 62) Tot n = 162

NPi ≥ 33% (n = 89) 22 (64.7%) 32 (48.4%) 35 (56,4%) 89 (55%)

NPi: nocturnal polyuria index.

Table 3. Comparison between patients with NPi > 33% stratified by age. NPi ≥ 33%

< 65 (n = 34) 22 (64.7%) 22 (64.7%)

65-74 (n = 66) 32 (48.4%) 32 (48.4%) -

≥ 75 (n = 62) 35 (56.4%) 35 (56.4%)

P 0.4 0.05 0.5

NPi: nocturnal polyuria index.

Table 4. Correlations between NP and IPSS scores, maximum flow rate, and post-void residual urine volume. IPSS score, mean ± SD Item # 1 Item # 2 Item # 3 Item # 4 Item # 5 Item # 6 Item # 7 Item # 8 Total Qmax (mean ± SD) PVR (mean ± SD)

NPi < 33% (n = 73) 1.0 ± 1.5 1.0 ± 1.1 0.9 ± 1.4 0.7 ± 1.2 1.3 ± 1.5 0.4 ± 0.8 1.5 ± 0.4 1.9 ± 0.8 6.5 ± 3.5 13.4 ± 2.5 40.05 ± 30.2

NPi ≥ 33% (n = 89) 1.2 ± 1.6 1.6 ± 0.9 1.4 ± 1.8 0.7 ± 1.4 1.6 ± 1.9 0.6 ± 1.3 2.5 ± 0.7 1.9 ± 1.1 9.8 ± 6.7 11.6 ± 2.6 37.8 ± 20.9

P 0.002 0.00 0.4 1 0.07 0.2 0.00 0.06 0.00 0.08 0.2

NPi: nocturnal polyuria index; IPSS: International Prostate Symptom Score; Qmax: maximnum flow rate; PVR: post-void residual.

Table 5. Comparison between voiding volume of day-time and nighttime micturition and voiding volume on uroflowmetry stratified according to Nocturnal polyuria index. VV of night-time micturition, mean ± SD VV of day-time micturition, mean ± SD VV at UF, mean ± SD

NPi < 33% (n = 73) NPi ≥ 33% (n = 89) 175.2 ± 168.7 532.1 ± 275.6 222.1 ± 83.1 213.7 ± 79.4 267.1 ± 136.3 246.7 ± 109.7

P 0.0001 0.5 0.2

NPi: nocturnal polyuria index; VV: voiding volume.

Table 5 reports data on the comparison of the mean VV of the micturitions at night-time, day-time, and at UF between the two groups. Mean VV of the night-time micturitions was significantly higher in men with the diagnosis of NP compared to those without NP recorded at FVC (p < 0001). Mean VV of the micturitions during the daytime and measured at UF was not statistically different between the two groups. However, volumes were slightly higher in Group A. In Group A, the mean VV of micturitions at day-time was 222.1 ± 83.1 ml, while at night-

time was 175.2 ± 168.7 (p = 0.03). Conversely, in Group B mean VV of micturitions at day-time was significantly lower than at night-time, 213.7 ± 79.4 ml, and 532.1 ± 275.6 ml respectively (p = 0.0001). Total daily (24-hours) diuresis was 757.8 ± 73.7 ml in Group A, and 1095.6 ± 103.8 ml in Group B (p < 0.0001). Total nocturnal diuresis was 223.8 ± 64.1 ml in Group A, and 587.1 ± 86.6 ml in Group B (p < 0.0001). The mean nocturnal number of voids was 0.8 ± 0.7 in Group A, and 1.9 ± 1 in Group B (p < 0.0001).

DISCUSSION

To date, the prevalence of NP in men candidates to UF for LUTS, and the impact of NP on bladder emptying, have been poorly investigated (12). Our study demonstrated a high NP prevalence (54.9%) in men performing UF for LUTS. In this cohort, NP was a common condition, identified by FVC in more than half of the cases. The rate of NP was lower than the data reported in community studies (10, 13). Nevertheless, it was comparable to the NP prevalence reported in the Caucasian population, and cohorts of men with LUTS (1416). The high rate of NP in this selected population of men performing UF for LUTS may be explained by the age and comorbidities of the patients, and by the coexistence of NP with other pathological conditions, such as BOO/BPH or overactive bladder (OAB) syndrome, which may cause LUTS. Another reason could be that NP, due to the related LUTS, in some cases could be confused with other clinical conditions needing an investigation with UF. In our series, NP had a relevant association with most of the storage symptoms, mainly nocturia, and with postvoiding symptoms, but not with voiding symptoms. At the same time, the parameters related to voiding and bladder emptying, such as Qmax and PVR, did not change significantly between the two groups of patients. Therefore, in our cohort, data on LUTS and UF demonstrated that NP had a significant impact on the bladder filling phase, but only a limited effect on the voiding phase. Men who referred mainly storage symptoms, complaining mostly of nocturia, and reported only a few voiding/postvoiding symptoms, were the most likely patients to be affected by NP. These males should be investigated with FVC in addition to symptomatic questionnaires, and to UF with PVR, to avoid misleading diagnosis, useless examinations, and treatments. Symptomatic questionnaires, as IPSS, are useful to define the patient’s LUTS, but they are not able to identify NP. These tools cannot assess whether nocturia was a symptom correlated to BOO/BPH or OAB, or, conversely, to the large amount of nocturnal urine which, continuously filling the bladder, leads the patient to awake. This latter pathophysiological mechanism was demonstrated by our data, showing that the mean VV of night-time micturitions was significantly higher in men with nocturia and NP. In males with unidentified NP, when nocturia is mistakenly evaluated as a BOO/BPH or OAB symptom, inappropriate therapies with alpha-blockers or anticholinergics agents may be offered to patients. The outcomes of these latter treatments have been reported as unsuccessful on NP and poorly effective on nocturia, and thus should be avoided (3, 12, 16). In men with BOO/BPH, usually voiding symptoms are Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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prevalent, and abnormal UF parameters are often associated with this condition (17). Conversely, our data showed that men with NP had no voiding symptoms, and both Qmax and PVR were not associated with NP, because the UF outcomes did not significantly differ between men affected by NP and males without NP. These results support the finding that NP is scarcely related to voiding dysfunctions, as was also supposed by a study on a small sample size of men with LUTS suggestive of BPH performing UF (12). In this small population, the rate of NP was 95%, and in 75% of these patients, NP did not significantly vary after alpha-blockers therapy, although an increase in Qmax was found in the treated men (12). Hence, males with NP may have concomitant BOO/BPH, but usually, the latter is not the leading cause of NP. For this reason, conventional BOO/BPH treatments often poorly influence NP conditions. The other pathological condition which should be distinguished from NP is represented by OAB syndrome, defined by “urinary urgency, usually accompanied by increased daytime frequency and nocturia, with or without urinary incontinence” (9). In our cohort, NP was significantly associated with increased urinary frequency and nocturia, but not with urinary urgency, which is one of the most characterizing symptoms of OAB (9). Furthermore, OAB syndrome is often accompanying by a reduced VV, which was not observed in NP patients of our study. Finally, the reporting of mainly storage symptoms, as frequency and nocturia, without urgency, and with no reduced VV at FVC, might be considered as a “red-flag” for differentiating between OAB and NP. An accurate assessment of LUTS and FVC, in addition to the other first-step office evaluations, may aid in the achievement of a correct differential diagnosis. Our study confirmed previous data on the very close relationship between nocturia and NP (2-4, 14, 15). The majority of the males with NP reported concomitant nocturia (85%), due to the increased nocturnal urine production, which led them to awake. On the other hand, patients reporting nocturia also demonstrated a high rate of NP (69%). Therefore, in males affected by nocturia, a concomitant NP should be supposed and should be investigated appropriately with FVC. Furthermore, our study confirmed that, also in men performing UF for LUTS, severe nocturia associated with VV significantly lower at day-time than at night-time might warn on a condition of NP (18). Feeling of incomplete bladder emptying, a postvoiding symptom, was significantly associated with NP. Patients affected by NP showed a higher severity of frequency and nocturia. Therefore, men with NP might be more concerned by the increased need to urinate, and consequently, they may have a greater sensation of not having completely emptied the bladder. Furthermore, in men with NP, the mean VV of the night-time micturitions was more than twice compared to the mean VV of the day-time, and significantly higher than the mean VV of micturitions at night of patients with no NP. The excessive night-time urine production may cause recurrent nocturnal overstretching of detrusor fibers, as the high nocturnal VV documented, leading patients to a worse bladder emptying and, as a consequence, to a greater feeling of incomplete bladder emp-

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tying. Moreover, the increased night-time bladder capacity may amplify the feeling of bladder filling even after micturition. These reasons may also explain the higher rate of increased urinary frequency in NP males. The quality of life (IPSS item #8) was not significantly associated with NP in our study. Patients enrolled during a UF, might have been more concerned by micturition and bladder emptying, which are poorly influenced by NP. This could be a possible explanation of this finding and could be a limit of our study. NP was more prevalent in younger males, but this result may be related to the low number of younger men included in our study. Indeed, we found that NP increased with age, showing that 75% of men with NP were aged ≥ 65 years old. Data also showed a significant association between NP rate and age in the older males, although not in the oldest (> 75 years). The relationship between NP and aging might be influenced by population selection, race, NPi criteria, and sample size. Most of the literature data on NP have been reported considering the general population or in community cohorts. Conversely, our cohort included only males with LUTS performing UF, with strict inclusion/exclusion criteria, and these parameters may have influenced our findings on aging. The strength of our study was the finding of the relevant prevalence of NP on a large sample size of males performing UF for LUTS. Our data also demonstrated that NP has a limited impact on micturition and bladder emptying. These latter data could only have been hypothesized, but not documented, before our study. Another strong point of our research was the identification, among the main storage symptoms, of those significantly associated with men with NP who perform UF for LUTS, and the uncovering of the voiding/postvoiding symptoms most commonly reported by these patients. Hence, the value of our study was to recognize the "warning symptoms" of men with NP, among the males scheduled for the UF for LUTS. A limit of our study was the lack of repeated UFs, due to the real-practice design of the present research. Another limit was the low sample size of the younger people, which was smaller than the other age groups. The choice of the NPi threshold of 33% might be a further limitation of the study. However, we have used this cut-off because it is one of the most accepted. Furthermore, there were only a few younger males in our study, and a lower threshold could have been useful in cohorts comprising younger patients than those enrolled in our study. A further limitation of the research is that NP has been correlated only with the urinary symptoms reported by the IPSS questionnaire, and not with all the LUTS. However, these symptoms are the most commonly complained by the males and assessed by clinicians. The strict inclusion/exclusion criteria led to reducing the number of males recruited in the study. The choice of these stringent parameters may have been a limit of this research, but allowed us to reduce potential biases and achieve more reliable data on the prevalence and impact of NP in men with LUTS performing UF.

CONCLUSIONS

In conclusion, our study highlighted that urologists should always look for NP among men who report noc-

Nocturnal polyuria in men performing uroflowmetry

turia and mainly storage symptoms, and only mild emptying/postvoiding symptoms. Both IPSS and FVC are needed to diagnose NP accurately, while UF with PVR assessment is useful for excluding potential associated pathological conditions.

REFERENCES

1. Agarwal A, Eryuzlu LN, Cartwright R, et al. What is the most bothersome lower urinary tract symptom? Individual- and population-level perspectives for both men and women. Eur Urol 2014; 65:1211-17. 2. Fujimura T, Yamada Y, Sugihara T, et al. Nocturia in men is a chaotic condition dominated by nocturnal polyuria. Int J Urol 2015; 22:496-501. 3. Weiss JP, Van Kerrebroeck PEV, Klein BM, Nørgaard JP. Excessive nocturnal urine production is a major contributing factor to the etiology of nocturia. J Urol 2011; 186:1358-63. 4. Chang SC, Lin ATL, Chen KK, Chang LS. Multifactorial nature of male nocturia. Urology 2006; 67:541-4. 5. Haddad R, Denys P, Arlandis S, et al. Nocturia and nocturnal polyuria in neurological patients: from epidemiology to treatment. A systematic review of the literature. Eur Urol Focus 2020; 6:922-34. 6. Birder LA, Van Kerrebroeck PEV. Pathophysiological mechanisms of nocturia and nocturnal polyuria: the contribution of cellular function, the urinary bladder urothelium, and circadian rhythm. Urology 2019; 133:14-23. 7. Cornu JN, Abrams P, Chapple CR, et al. A contemporary assessment of nocturia: Definition, epidemiology, pathophysiology, and management - A systematic review and meta-analysis. Eur Urol. 2012; 62:877-90. 8. Van Kerrebroeck P, Abrams P, Chaikin D, et al. The standardisation of terminology in nocturia: Report from the standardisation sub-

committee of the international continence society. Neurourol Urodyn. 2002; 21:179-83. 9. D’Ancona C, Haylen B, Oelke M, et al. The International Continence Society (ICS) report on the terminology for adult male lower urinary tract and pelvic floor symptoms and dysfunction. Neurourol Urodyn. 2019; 38:433-77. 10. Van Doorn B, Blanker MH, Kok ET, et al. Prevalence, incidence, and resolution of nocturnal polyuria in a longitudinal community-based study in older men: The Krimpen study. Eur Urol. 2013; 63:542-7. 11. Gammie A, Drake MJ. The fundamentals of uroflowmetry practice, based on International Continence Society good urodynamic practices recommendations. Neurourol Urodyn. 2018; 37: S44-S49. 12. Koseoglu H, Aslan G, Ozdemir I, Esen A. Nocturnal polyuria in patients with lower urinary tract symptoms and response to alphablocker therapy. Urology 2006; 67:1188-92. 13. Swithinbank L V, Vestey S, Abrams P. Nocturnal polyuria in community-dwelling women. BJU Int 2004; 93:523-7. 14. Mariappan P, Turner KJ, Sothilingam S, et al. Nocturia, nocturia indices and variables from frequency-volume charts are significantly different in Asian and Caucasian men with lower urinary tract symptoms: A prospective comparison study. BJU Int. 2007; 100:332-6. 15. Klingler HC, Heidler H, Madersbacher H, Primus G. Nocturia: An Austrian study on the multifactorial etiology of this symptom. Neurourol Urodyn. 2009; 28:427-31. 16. Yoong HF, Sundaram MB, Aida Z. Prevalence of nocturnal polyuria in patients with benign prostatic hyperplasia. Med J Malaysia. 2005; 60:294-6. 17. Thorner DA, Weiss JP. Benign prostatic hyperplasia: symptoms, symptom scores, and outcome measures. Urol Clin North Am. 2009; 36:417-29. 18. Presicce F, Puccini F, De Nunzio C, et al. Variations of night-time and daytime bladder capacity in patients with nocturia: implication for diagnosis and treatment. J Urol. 2019; 201:962-6.

Correspondence Emanuele Rubilotta, MD emanuele.rubilotta@aovr.veneto.it Matteo Balzarro, MD matteo.balzarro@aovr.veneto.it Maria Angela Cerruto, MD (Corresponding Author) mariaangela.cerruto@univr.it Alessandro Antonelli, MD alessandro.antonelli@univr.it Urology Clinic, A.O.U.I of Verona, Verona (Italy) Daniele Castellani, MD d.castellani@inrca.it Department of Urology, IRCCS INRCA, Ancona (Italy) Marilena Gubbiotti, MD marilena.gubbiotti@gmail.com Giacomo Maria Pirola, MD giacomomaria.pirola@uslsudest.toscana.it Department of Urology, San Donato Hospital, Usl Toscana Sud Est, Arezzo (Italy) Rita Righetti, MD rita.righetti@aulsslegnago.it Pierpaolo Curti, MD pierpaolo.curti@aulss9.veneto.it Department of Urology, AULSS 9, Ospedale Mater Salutis, Legnago (Italy) Antonella Giannantoni, MD antonella.giannantoni@unisi.it Functional and Surgical Urology Unit, Department of Medical and Surgical Sciences and Neurosciences, University of Siena, Siena (Italy) Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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DOI: 10.4081/aiua.2021.4.450

ORIGINAL PAPER

Telementoring for communication between residents and faculty physicians: Results from a survey on attitudes and perceptions in an Academic Tertiary Urology Referral Department in Italy Vincenzo Mirone 1, Massimiliano Creta 1, Marco Capece 1, Giuseppe Celentano 1, Gianluigi Califano 1, Claudia Collà Ruvolo 1, Lorenzo Spirito 1, Giovanni Maria Fusco 1, Luigi Cirillo 1, Nicola Longo 1, Ferdinando Fusco 2, Claudia Mirone 3, Roberto La Rocca 1, Luigi Napolitano 1 1 Department

of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples "Federico II", Naples, Italy; of Woman, Child and General and Specialized Surgery, Urology Unit, University of Campania “Luigi Vanvitelli'” Naples, Italy; 3 Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy. 2 Department

Summary

Introduction: Telemedicine has been adopted successfully in various urological scenarios. The aim of the present study was to explore attitudes and perceptions by urology residents toward the use of telementoring in the context of residents-faculty physicians communication for patient-related care. Methods: An online survey consisting of 19 multiple choice questions was designed including three sections: respondents’ demographics, attitudes and perceptions towards the use of telementoring. Invitations to participate in this anonymous survey were e-mailed to urology residents at University of Naples Federico II. Results: In total 60 responses were received (participation rate 86%). The frequency of telementoring use was described as occasional, frequent, very frequent, and rare by 51,3%, 41.0%, 5,1%, and 2,6% of respondents, respectively. WhatsApp messenger was used by 89.5% of respondents and photos were the most common type of media content shared (73.7%). Most of respondents declared a moderate and a strong agreement with respect to the utility of telementoring in improving the communication in relation to the interpretation of clinical, radiological, endoscopic, and functional findings. Overall, 78% of participants individuated risks of information flow distortions and misinterpretations as the major limit of telementoring. Conclusions: The use of telementoring is widespread and perceived as useful by urology residents in the context of residentsfaculty physicians communication in multiple settings of patientrelated care.

KEY WORDS: Telementoring; Telemedicine; Urology; Bladder cancer; Patient-related care; Survey; Pandemic; COVID-19: Medical informatics.

sidered to be under the umbrella of telehealth and refers specifically to remote clinical services (2). Remote care provides the advantage of reducing the use of resources in health centers, improving access to care, and minimizing the risk of direct transmission of the infectious agent (3). The adoption of telemedicine was first described in the 1950’s when a Nebraska psychiatrist connected to a prison over 150 miles through a closed-circuit television to provide mental health services (4). In recent years, with the advancement of mobile technologies, telemedicine is more accessible than ever before. In the USA the percentage of US hospitals that connect with patients through the use of video and other technology has increased from 35% in 2010 to 76% in 2017 (1). Available literature indicates that telemedicine has been adopted successfully in patients with common clinical urological conditions, including prostate cancer, uncomplicated urinary stones, uncomplicated urinary infections, urinary incontinence, or pelvic organ prolapse and hematuria (5). Moreover, literature on the use of telemedicine in medical education, called telementoring, is increasing and results underline the facilitation of the learning process while increasing motivation and enabling instant communication and discussion at a distance due to the possibility of sharing multimedia contents (6). The aim of the present study was to explore attitudes and perceptions by urology residents toward the use of telementoring in the context of residentsfaculty physicians communication for patient-related care in a large academic tertiary urology referral department in Italy.

Submitted 15 July 2021; Accepted 2 August 2021

INTRODUCTION

Telehealth, defined as the use of information technology and telecommunications to provide access to health assessment, consultation, diagnosis, intervention, supervision and information across distance, represents a rapidly evolving field of medicine (1). Telemedicine is con-

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METHODS Questionnaire An online survey consisting of 19 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 No conflict of interest declared.

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Telementoring in urology residency

(Google LLC). The questionnaire was composed of three Data analysis sections: a first one to assess respondents’ demographics Data were expressed as mean (Standard Deviation) and (age, sex, year of residency) a second one to evaluate their raw numbers and percentages of survey answers. attitudes, and a third to evaluate perceptions. Statistical analyses were two-sided using a significance Questions about attitudes toward use of telementoring level of 0.05. All statistical analyses were performed with during the residency program and in the context of resiSPSS version 17.0 (SPSS, Inc., Chicago, IL) software. dent to faculty physicians communication for patientrelated care investigated the following settings: frequency, duration, and temporal trend of telementoring adoption, RESULTS tools adopted (telephone call, e-mails, WhatsApp, others) In total 60 responses were received (participation rate clinical context in which telementoring was used (ward, 86%). Fifty-seven residents (95%) were male and 3 (5%) ambulatory care, referral activities), type of findings whose were female. Mean age was 31.36 (3.16). Overall, 23.33% interpretation made use of telementoring (findings from were 1st years residents, 16.6 2nd year, 10 % 3rd year, 15% physical examination, findings from radiological imaging, 4th year, 23.3% 5th year and 11.67% were specialist less findings from endoscopy, findings from functional investhan two year. The frequency of telementoring use in the tigations), type of shared data (text, video, audio, photos), context of resident to faculty physicians communication content of multimedia data shared (reports, radiological for patient-related care was described as occasional, freimages, drainages, findings from physical examination, quent, very frequent, and rare by 51.3%, 41.0%, 5.1%, endoscopic findings, intraoperative findings). and 2.6%, respectively. Questions about perceptions investigated the perceived Figure 1 shows the setting of utilization of telementoring usefulness of telementoring in improving resident to facuse by urology residents. ulty physicians communication for patient-related care in Figure 2 describes the percentage of utilization by resivarious clinical settings (ward, ambulatory care, referral dents of the different tools of telementoring in the context activities) and in relation to various clinical and instruof resident to faculty physicians communication for mental findings (findings from physical examination, patient-related care. endoscopy, radiological imaging, functional investigations). Respondents were invited to Figure 1. "strongly agree", "moderately agree", "slightly Setting of telementoring use in the context of resident to faculty physicians agree", "strongly disagree", "moderately disagree", communication for patient-related care and relative percentage of use "slightly disagree" with a series of statements in the various settings. about perceptions. A question was designed to investigate how often the use of telementoring was able to change the diagnostic and/or therapeutic decision-making process. Question about the perceived limits of telementoring investigated: medico-legal issues, risk of distortion of the information flow, risk of receiving incomplete data, risk of providing incomplete data. Some questions required a single answer while others gave the respondents the choice to select as many answers as they felt appropriate. Data collection Invitations to participate in this anonymous survey were e-mailed on 1 February 2021 to current urology residents and to urology residents who attended the urology residence program in the last three years at University of Naples Federico II and who gave the approval to the use of their e-mail address. 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 2021. 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.

Figure 2. Percentage of residents using different tools of telementoring in the context of resident to faculty physicians communication for patient-related care.

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Figure 3 shows the percentage of residents sharing different types of media contents in the context of resident to faculty physicians communication for patient-related care. Figure 4 shows the percentage of residents sharing different types of information as media contents in the context of resident to faculty physicians communication for patient-related care. Table 1 describes the perceptions about the usefulness of telementoring in improving resident to faculty physicians communication for patient-related care in various clinical settings and in relation to various clinical and instrumental findings. Finally, regarding perception of telementoring limitation, 78% of participants individuated risks of information flow distortions and misinterpretations, 56.4%found limits for a complete information collection, 35.9% risks of flow distortions to give information, and 28.2% legal risk.

Figure 3. Percentage of residents sharing different types of media contents in the context of resident to faculty physicians communication for patient-related care.

Figure 4. Percentage of residents sharing different types of information as media contents in the context of resident to faculty physicians communication for patient-related care.

DISCUSSION

Remote communication between members of a medical staff has always been the key element in any part of patients’ care (7). Of note, poor communication was considered by the 2011 Joint Commission sentinel event report as the main root cause of delays in patient treatment and the second leading cause of operative and post-operative complications (8). Interprofessional communication has a critical role mainly in university hospitals, where residents are involved in the management of patients. Indeed, ineffective communication between residents and attending surgeons has been reported to be a significant contributor to Table 1. Perceptions about the usefulness of telementoring in improving resident to faculty physicians communication for patient-related care in various clinical settings and in relation to various clinical and instrumental findings.

Telementoring is useful in improving resident to faculty physicians communication for patient-related care in the ward setting Telementoring is useful in improving resident to faculty physicians communication for patient-related care in the ambulatory setting Telementoring is useful in improving resident to faculty physicians communication for patient-related care in the referral activity setting Telementoring is useful in improving resident to faculty physicians communication for patient-related care thanks to the improvement of radiological imaging interpretation Telementoring is useful in improving resident to faculty physicians communication for patient-related care thanks to the improvement of endoscopic findings interpretation Telementoring is useful in improving resident to faculty physicians communication for patient-related care thanks to the improvement of interpretation of findings from physical examination Telementoring is useful in improving resident to faculty physicians communication for patient-related care thanks to the improvement of functional findings interpretation

452

Agree strongly n (%)

Agree moderately n (%)

Agree slightly n (%)

Disagree slightly n (%)

Disagree moderately n (%)

Disagree strongly n (%)

14 (23.3)

35 (58.3)

11 (18.3)

0 (0)

14 (23.3)

36 (60.0)

8 (13.3)

0 (0)

2 (3.3)

0 (0)

17 (28.3)

32 (53.3)

9 (15.0)

2 (3.3)

0 (0)

17 (28.3)

32 (53.3)

8 (13.3)

3 (5.0)

0 (0)

14 (23.3)

27 (45.0)

17 (28.3)

2 (3.3)

0 (0)

14 (23.3)

35 (58.3)

11 (18.3)

0 (0)

6 (10.0)

30 (50.0)

14 (23.3)

10 (16.6)

0 (0)

Archivio Italiano di Urologia e Andrologia 2021; 93, 4

Telementoring in urology residency

medical errors, patient injury, and malpractice claims (9). Verbal report via telephones has represented the traditional method of communication for years (10). However, although rapid, this method of communication can be inadequately objective and precise (10). Since the late 1990’s telemedicine gained popularity and clinical photographs taken by digital cameras were transmitted as downloadable files between computers having modem and telephone link to improve communication flow (10). Initially, several technological limitations including the lack of digitalization of medical records, the inability to send images quickly, and limited Internet lines strongly limited the use of telemedicine. In recent years, advances in information technology have driven dramatic changes in several aspects of human behavior and communication. Audiovisual communication in health care supported by smartphone apps is a novel concept that is rapidly gaining interest in all areas of medicine and surgery (11). Implementation of telemedicine is currently encouraged and supported by both states and multiple medical associations worldwide (12). To the best of our knowledge, we investigated for the first-time attitudes and perceptions about the use of telementoring in the context of resident to faculty physicians communication for patient-related care in an academic tertiary urology referral department in Italy. Most urology residents participating in the present survey declared to utilize telementoring for patient-related care and that the use of telementoring increased over time. This finding is in line with available evidence demonstrating the expanding role of telehealth (1). WhatsApp messenger was reported as the most commonly used tool for communication. WhatsApp is a method of sending and receiving messages to and from individuals or groups with additional features of sending images, videos, and links (13). WhatsApp has been evaluated in numerous subspecialties in both undergraduate and postgraduate settings and current available literature suggests it is an effective tool for medical learning (14). Some authors also consider WhatsApp as an effective telemedicine tool in many different fields of health care (11). Photos followed by text messages were the most common type of data shared by the respondents in present survey. In details, the main contents of photos were medical reports followed by radiological images and pictures of drainages. Accordingly, Sener et al. suggest that WhatsApp can be used to share photos of cases of hematuria to determine the severity of cases, and thereby discriminate whether active treatment is required (15). Urology residents are commonly involved in multiple activities characterized by increasing complexity. Most of respondents in the present survey perceived telementoring e as a useful communication tool in several aspects of patient care. Indeed, the majority of them declared a moderate and a strong agreement towards the utility of telementoring in improving resident to faculty physicians communication for patient-related care in the context of ambulatory care, ward, and urology referral consultation. In details, most declared a moderate and a strong agreement with respect to the utility of telementoring in improving the communication in relation to the interpretation of clinical, radiological, endoscopic, and function-

al findings. Interestingly, a high percentage of residents declared that the use of telementoring in the context of resident to faculty physicians communication for patientrelated care contributed to change the diagnostic and/or therapeutic decision making process. Taken together, results from the present survey underline the increasing and relevant role of telementoring as an additional tool in the context of resident to faculty physicians communication in several settings of patient-related care. However, telementoring is still in its infancy and a number of potential drawbacks still exist. These include mainly limitations with performing comprehensive medical history and physical examination and security breaches (2). Distortion of the medical information and limits in acquiring complete information were perceived by the participants in the present survey as the major drawbacks of telementoring in the context of resident to faculty physicians communication for patient-related care. The major limitation of this survey includes the small number of participants. Although respondents are not fully representative of the overall community of Italian urology residents, currently the School of Urology of the University of Naples Federico II represents the largest of the Southern Italy in terms of number of residents and one of the largest in Italy. Moreover, like any survey, participant responses were limited to the available choices. A further limit of the study is the lack of data about the feedback of faculty physicians. Further studies are needed to investigate the usefulness of telementoring by residents in relation to specific diseases (16).

CONCLUSIONS

Results from the present survey demonstrate that the use of telementoring is widespread and perceived as useful by urology residents in the context of resident to faculty physicians communication in multiple settings of patientrelated care and its use has increased over time. WhatsApp messenger is the most common tool adopted for remote communication with text and photos of reports and drainages being the most common data shared.

REFERENCES

1. Kichloo A, Albosta M, Dettloff K, et al. Telemedicine, the current COVID-19 pandemic and the future: a narrative review and perspectives moving forward in the USA. Fam Med Community Health. 2020; 8:e000530. 2. Gajarawala SN, Pelkowski JN. Telehealth benefits and barriers. J Nurse Pract JNP. 2021; 17:218-221. 3. Wittson CL, Affleck DC, Johnson V. Two-way television in group therapy. Ment Hosp. 1961; 12:22-3. 4. Monaghesh E, Hajizadeh A. The role of telehealth during COVID19 outbreak: a systematic review based on current evidence. BMC Public Health. 2020; 20:1193. 5. Novara G, Checcucci E, Crestani A, et al. Telehealth in Urology: a systematic review of the literature. How much can telemedicine be useful during and after the COVID-19 pandemic? Eur Urol. 2020; 78:786-811. 6. Mazzuoccolo LD, Esposito MN, Luna PC, et al. WhatsApp: A realtime tool to reduce the knowledge gap and share the best clinical Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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practices in psoriasis. Telemed J E-Health Off J Am Telemed Assoc. 2019; 25:294-300.

ger as an adjunctive tool for telemedicine: an overview. Interact J Med Res. 2017; 6:e11.

7. Haykal T, Al-Dulaimi R, Sidahmed S, et al. Understanding the means of communication between nurses and resident physicians in the modern world: A community-based university hospital survey results. J Community Hosp Intern Med Perspect. 2020; 10:107-110.

12. Becker CD, Dandy K, Gaujean M, et al. Legal perspectives on telemedicine Part 1: legal and regulatory issues. Perm J. 2019; 23:18-293.

8. Commission TJ. TJ Commission. Sentinel event data root causes by event type 2004-Third Quarter 2011. Washington, DC: The Joint Commission; 2011. 9. Senders ZJ, Aeder M, Semrau S, et al. Improving resident-toattending communication: implementing a tool to facilitate attending notification of critical patient events at a single academic institution. Am Surg. 2019; 85:663-670. 10. Wani SA, Rabah SM, AlFadil S, et al. Efficacy of communication amongst staffcmembers at plastic and reconstructive surgery section using smartphone and mobile WhatsApp. Indian J Plast Surg Off Publ Assoc Plast Surg India. 2013; 46:502-5. 11. Giordano V, Koch H, Godoy-Santos A, et al. WhatsApp messen-

Correspondence Vincenzo Mirone, MD mirone@unina.it Massimiliano Creta, MD, PhD (Corresponding Author) max.creta@gmail.com Marco Capece, MD drmarcocapece@gmail.com Giuseppe Celentano, MD dr.giuseppecelentano@gmail.com Gianluigi Califano, MD gianl.califano2@gmail.com Claudia Collà Ruvolo, MD c.collaruvolo@gmail.com Lorenzo Spirito, MD lorenzospirito@msn.com Giovanni Maria Fusco, MD giom.fusco@gmail.com Luigi Cirillo, MD cirilloluigi22@gmail.com Nicola Longo, MD nicola.longo@unina.it Roberto La Rocca, MD robertolarocca87@gmail.com Luigi Napolitano, MD luiginap89@gmail.com Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples "Federico II", 80131 Naples (Italy) Ferdinando Fusco, MD ferdinando-fusco@libero.it Department of Woman, Child and General and Specialized Surgery, Urology Unit, University of Campania “Luigi Vanvitelli'” 80131 Naples (Italy) Claudia Mirone, MD claudiamirone@outlook.it Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania “Luigi Vanvitelli”, 80131 Naples (Italy)

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13. Bakshi SG, Bhawalkar P. Role of WhatsApp-based discussions in improving residents’ knowledge of post-operative pain management: a pilot study. Korean J Anesthesiol. 2017; 70:542-549. 14. Coleman E, O’Connor E. The role of WhatsApp® in medical education; a scoping review and instructional design model. BMC Med Educ. 2019; 19:279. 15. Sener TE, Butticè S, Sahin B, et al. WhatsApp Use in the evaluation of hematuria. Int J Med Inf. 2018; 111:17-23. 16. Ambrosini F, Di Stasio A, Mantica G, Cavallone B, Serao A. 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..

DOI: 10.4081/aiua.2021.4.455

ORIGINAL PAPER

Professional roles of female urologists: A webinar-based survey of perceptions and obstacles to career development Sufyan Ibrahim 1, 2, Amelia Pietropaolo 2, 3, Nithesh Naik 2, 4, Anita Patel 5, Milap J. Shah 2, 6, Patricia Zondervan 7, Jean McDonald 8, 9, BM Zeeshan Hameed 2, 6, Bhavan Prasad Rai 2, 10, Hadis Karimi 11, Bhaskar K. Somani 2, 3, Joanne Cresswell 12 1 Kasturba

Medical College Manipal, Manipal Academy of Higher Education, Manipal, India; (International Training and Research in Uro-oncology and Endourology) Group; 3 Department of Urology, University Hospital Southampton NHS Trust, Southampton, UK; 4 Faculty of Engineering, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, India; 5 Global Hospitals, Maharashtra, India; 6 Department of Urology, Kasturba Medical College Manipal, Manipal Academy of Higher Education, Manipal, India; 7 Academic Medical Center, University of Amsterdam, Netherlands; 8 North Middlesex University Hospital, Sterling Way, London, United Kingdom; 9 Weymouth Street Hospital, Marylebone, London, United Kingdom; 10 Department of Urology, Freeman Hospital, Newcastle upon Tyne NE7 7DN, United Kingdom; 11 Manipal College of Pharmacy, Manipal Academy of Higher Education, Manipal, India; 12 The James Cook University Hospital, South Tees Trust, Middlesbrough, United Kingdom. 2 i-TRUE

Summary

Background: Urology, traditionally a maledominated specialty, keeping pace with the quickly changing gender landscape, has been characterized by waves of feminization. This study aims to understand the perspectives of women urologists on the obstacles to their career development, and the impact of such hurdles on their professional roles in urological education, practice, and leadership. Methods: 119 female urology residents/consultants were surveyed via a webinar-based platform, covering relevant questions on domains of Academia, Mentorship, Leadership, Parenting, and Charity. Statistical analysis was done using frequency distribution based on the responses. Results: 46.8% of the respondents felt that there is an under-representation of women in academia. ‘Having a good mentor’ was the most important factor for a novice to succeed in academia (68%). The most important trait in becoming a good leader was ‘good communication skills’ (35%), followed by ‘visionary’ (20%). The greatest challenge faced by leaders in the medical field was considered as ‘time management’ (31.9%). Only 21.2% of the participants felt difficulty in having a work-personal life balance, whereas 63.8% of them found it difficult only ‘sometimes’. As a working parent, ‘the guilt that they are not available all the time’ was considered the most difficult aspect (59.5%), and ‘more flexible schedule’ was needed to make their lives as a working parent easier (46.8%). 34% of the respondents were affiliated with some charitable organizations. The biggest drive to do charity was their satisfaction with a noble cause (72.3%). Conclusions: Need for increased encouragement and recruitment of females into urology, and to support and nurture them in their career aspirations.

KEY WORDS: Leadership; Mentorship; Academia; Parenting; Charity; Women in Urology; Gender disparity. Submitted 17 October 2021; Accepted 26 October 2021

INTRODUCTION

The year 1962 recognized the first woman as a board-certified urologist in the United States (1). Urology, like most other surgical disciplines of medicine, has traditionally been a male-dominated specialty. However, keeping pace with the quickly changing gender landscape, medical professions are also characterized by waves of feminization, with a steady and significant increase in the number of women working in urological practice and research over the recent years (2). Although still a minority, female urologists tend to perform more gender-neutral index surgical procedures on female patients relative to their male counterparts (3). Despite more women being attracted towards medicine, and qualifying as doctors, their career progression can be hindered by organizational barriers with rigid career structures that may favor their male counterparts (4). Continued advancement of women in academic surgery is dependent on addressing these concerns including the lack of gender equality, effective mentorship, and work-life balance facilitating family responsibilities (5). The rising trends of invited female speakers at academic conferences present an opportunity for increased representation within urology leadership (6). We aimed to understand the perspectives of women urologists on the obstacles to their career development, and the impact of such hurdles on their professional roles in urological education, practice, and leadership, through a webinar-based survey. Our objective was to understand the different barriers to career development experienced by female urologists, the gender disparity in urology, and the common factors affecting them. We also aimed to acknowledge the interest and involvement of female urologists in mentorship, leadership, and charity-based services.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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METHODS

A webinar titled “Today’s Women - Tomorrow’s Leaders: Urology Leading The Way” was conducted through an online platform with leading female urologists from India, United Kingdom, and the Netherlands as expert panelists. The target study population and potential respondents were female residents (urology trainees, registrars, and fellows) and urologists (consultants and practicing urologists). The webinar was attended by a total of 659 participants. A total of 43 different countries were represented by one or more participants in the webinar. Out of the total number of participants attending the webinar, 65% (n = 428) identified themselves as female participants, of which 28% (n = 119) were female consultants or resident urologists, the responses of whom are included in this study. It is of interest that 35% of participants were male, and this may reflect increasing interest to make Urology a more inclusive specialty. A structured poll-based survey to investigate the female-related obstacles was conducted simultaneously with the webinar in progress. The five cornerstone topics that were discussed by the eminent speakers in the webinar were under the aegis of (a) Academia, (b) Mentorship, (c) Leadership, (d) Parenting, and (e) Charity in Urology. The surveying content was initially drafted by the investigating team, which was then circulated and reviewed by the i-TRUE working group. The study was approved by the Survey and Behavioural Institutional Ethics Committee (IEC) of Kasturba Medical College, Manipal (Reference No: 628-2020). This methodology is a relatively unique way of receiving responses and has not been widely used in previous surveys. The introduction specifying the objectives and target audience of the study were informed by the moderators of the session. Implied consent was assumed when the respondent proceeded to the registration and completion of the webinar. The survey was anonymous. Internet Protocol (IP) restrictions were implemented, so one IP address could only complete the survey once. All the data were collected and were accessible only by the study investigators. Statistical data analysis was done using SPSS (version-26) software. Categorical data were presented with counts and percentages. Graphs and charts were appropriately plotted.

RESULTS

A total of 11 different questions related to the five domains were asked during the webinar. A single best response was considered for every question by every poll-

respondent. Following are the results of responses from female urologists as mentioned in our inclusion criteria (n = 119) with their graphical representation in Figure 1 and Figure 2. The respondents felt that there is an under-representation of women in academia (46.8%), while 38.3% felt otherwise and 14.89% chose rather not to comment. According to the respondents, the most important factor for a novice to understand and succeed in academia was a good mentor’ (68%). The other traits that were considered important by others were ‘a natural flair for research’ (19.1%), ‘good project’ (8.5%) and ‘being good at statistics’ (4.2%); surprisingly ‘being a good writer’ (0%) was totally out of contention by respondents. A large fraction of our audience (44.6%) had a fixed or structured training module/program at their hospital/institute, but 27.6% did not have it and the other 27.6% had unstructured training modules. According to poll-respondents, the most important trait in becoming a good leader was ‘good communication skills’ (35%), followed by ‘visionary’ (20%). Remarkably, an equal number of respondents (15%) considered the ‘ability to prioritize and focus’, ‘influencer/empowering’, and ‘patience or good listener’ as the most important qualities. The greatest challenge faced by leaders in the medical field was answered by a majority as ‘time management’ (31.9%), followed by ‘lack of resources’ and ‘coordination of work amongst members’ (25.5% each), ‘assigning a task as per the ability of the worker or resident’ (10.6%) and ‘patient mistrust’ (6.3%). An important and very pertinent issue highlighted during our webinar was that of a working parent. When polled if they have difficulty having a workpersonal life balance, 21.2% responded as ‘yes’ and 14.8% checked ‘no’. However, most of the respondents (63.8%) found it difficult to balance their work and family only ‘sometimes’. According to the respondents, the most difficult aspect that they consider as a working parent is that of ‘the guilt that they are not available all the time’ (59.5%), while others thought ‘lack of time with kids’ (19.1%), ‘lack of time with spouse’ (14.8%) and ‘unsupportive work colleagues’ (2.1%) as their important hurdles. Positively, a small (4.2%) number of them believed that parenting and working are easy. ‘More flexible schedule’ was felt to be the most important factor that could make their lives as a working parent easier or better, by almost half of the respondents (46.8%). Others considered ‘more supportive boss or co-worker’ (19.1%), ‘more meaningful work’ (14.8%), ‘telecommuting’ (12.7%), and ‘more help with chores or kids’ (6.3%) as the important factors for the same question. A total of 34% of the respondents were affiliated with some charitable organizations, a minor fraction (14.8%) were dubious with their response, and 51% were not associated with any. Of all the promoting factors, the biggest drive and

Figure 1. The responses for trichotomous questions of the survey.

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Perceptions and obstacles to career development of female urologists

Figure 2. Representation of the responses by the participants (n = 119) to the questions on (a) Leadership (b) Parenting (c) Academia, Mentorship and Charity.

The people involved with the charity or cause in question was also a factor considered by many (10.6%). The desire to mix socially with other attendees (6.3%), no specified reason (6.3%), and for maintaining a social status (4.2%) were the lowly rated attributes for the given question.

DISCUSSION

important source of motivation for our respondents to do charity or be involved as a part of a charitable organization, was their satisfaction with a noble cause (72.3%).

While the discordant representation of women in urology is well-established, only a few studies have attempted to delineate the cause of this disparity and the confounding effects it has on their personal lives (7). To our knowledge, there are no studies available in the current literature which address the perception of women urologists spanning across a full circle of academia, mentorship, leadership, parenting, and charity simultaneously. Although the majority of our poll-respondents agree to the existence of under-representation of females in urology, 38.3% however, felt that this was not so significant. This may be partly explained due to an increasing prevalence of female urologists in the recent past accounting for about 9.2% of the total workforce and about 21% of the under-45-year-olds in countries like the USA (6). Such demographic trends have greatly improved the visibility of female urologists in developed countries, who are also at a greater likelihood of pursuing sub-specializations, and positively increasing their identification with leadership roles (8). However, a recent study has shown that despite specialization or seniority, female surgeons perform less complex cases than their male peers, hence more needs to be done to recruit and retain all under-represented minorities, as greater diversity helps improve the outcomes of the general population (9). There is no single ‘best approach’ involved in Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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training and navigating across academia, but the presence of mentors can foster a sense of professional identity and facilitate a novice experience through guidance, support, and encouragement (10). Most of our participants (68%) felt that having a mentor, as a wise and trusted counselor, followed by a natural flair towards research are the keys to academic excellence. A healthy and strong mentormentee relationship stems based on consideration, great camaraderie, existing features of commonality, and virtues of confidentiality (11). Leaders are people with the capability to explicitly articulate protocols, augment productivity, motivate team members to achieve the desired goal to create a sustainable change in any profession (12). The core traits of becoming a good leader-talent, drive, willpower, practical wisdom, loyalty, ethical behavior, emotional intelligence, integrity, self-awareness, and resilience are all very essential (13). Our participants felt that exquisite communication skills are the most important attribute and a clear favorite prerequisite for charismatic leadership. This is in line with the expectations as interpersonal communication is the binding factor to show a leader’s assuredness, decision-making skills, and the ability to convey the strategies and outcomes of the vision and the mission to the team (14). The circumstances are no different for leaders in medicine who aim to improve the quality of healthcare (15). The main challenges, according to our poll-respondents, were the effective management of time, lack of resources, and coordination of work amongst members. This is indeed in conjunction with the other studies on leadership where proactive and focused personal time management was identified to be necessary for optimizing organizational productivity (16). This also highlights the persistent issue of imbalance in the allocation of resources for utilization despite being the central function of healthcare delivery systems (14). Appropriate delegation of duties matching the amount of responsibility with capability and authority, with regular feedback, will help in empowering colleagues to reach their potential (17). Work-personal life harmony is particular to every individual and thus attainment of a ‘balance’, if it exists, is a very subjective feeling, explaining the reluctance of poll-respondents in answering the question (18). It continues to be a very challenging issue, as according to the National Physician Burnout and Suicide Report 2020, urology topped the chart with 54% of practicing urologists reporting that they are victims of physician burnout (19). The prime reason for this was due to the administrative burden with too many bureaucratic tasks to fulfill, as driven by workplace and organizational culture. Spending too many hours at work and lack of respect from colleagues were the other important reasons cited by many (19). This is in concordance with our results as participants felt that the guilt of not being available at all times was their biggest concern. Parenting as female physicians may have additional challenges to address as they generally remain responsible for childcare and domestic activities compared to male counterparts, thus limiting their career advancement, while also feeling inadequate in performing the dual role (20). Strategies need to be implemented while structuring the programs to help strike a synergy in their personal and professional lives (19). Greater flexi-

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bility in the schedules, with allowance for dedicated maternity leaves for a longer duration, and support from employers and co-workers are the important contributors in this regard, as also evident from our survey (20).

CONCLUSIONS

Women play a vital role in all aspects of charity, leadership, academia, mentoring, and parenting. While urology is leading the way with more females taking up the specialty, gender disparity and traditional dogma is still a hindrance to it. Although urological societies recognize this, more needs to be done to encourage female recruitment into urology and to support and nurture them in their career pathways.

FUNDING

The authors report no involvement in the research by the sponsor that could have influenced the outcome of this work.

AUTHORS’

CONTRIBUTIONS

Sufyan Ibrahim and BM Zeeshan Hameed have given substantial contributions to the conception or the design of the manuscript. Nithesh Naik, Amelia Pietropaolo, Milap Shah, Patricia Zondervan and Anita Patel to acquisition, analysis and interpretation of the data. All authors have participated to drafting the manuscript, Bhaskar K Somani, Bhavan Prasad Rai and Joanne Cresswell revised it critically. All authors read and approved the final version of the manuscript.

ACKNOWLEDGEMENTS

The authors acknowledge Kasturba Manipal College, Manipal for permitting to carry out the study.

REFERENCES

1. Rickey LM, Yang CC, Lamb DJ. Women in urology 2014. Urol Pract. 2014; 1:104-6. 2. Amir H, Beri A, Yechiely R, et al. Do urology male patients prefer same-gender urologist? Am J Mens Health 2018; 12:1379-83. 3. Oberlin DT, Vo AX, Bachrach L, Flury SC. The gender divide: the impact of surgeon gender on surgical practice patterns in urology. J Urol. 2016; 196:1522-6. 4. Hirayama M, Fernando S. Organisational barriers to and facilitators for female surgeons’ career progression: a systematic review. J R Soc Med. 2018; 111:324-34. 5. Seemann NM, Webster F, Holden HA, et al. Women in academic surgery: Why is the playing field still not level? Am J Surg. 2016; 211:343-9. 6. Capella C, Schlegel L, Shenot P, Murphy A. Female representation at high-profile urology conferences, 2014-2019: a leadership metric. Urology. 2021; 150:72-76. 7. Carr PL, Gunn CM, Kaplan SA, et al. Inadequate progress for women in academic medicine: findings from the National Faculty study. J Womens Health (Larchmt). 2015; 24:190-9. 8. Nettey OS, Fuchs JS, Kielb SJ, Schaeffer EM. Gender Representation in Urologic Subspecialties. Urology. 2018; 114:66-70. 9. Dai JC, Agochukwu-Mmonu N, Hittelman AB. Strategies for

Perceptions and obstacles to career development of female urologists

attracting women and underrepresented minorities in Urology. Curr Urol Rep. 2019; 20:61.

CGJM. Medical leaders or masters? - A systematic review of medical leadership in hospital settings. PLoS One. 2017; 12:e0184522.

10. Kotsis SV, Chung KC. Application of the "see one, do one, teach one" concept in surgical training. Plast Reconstr Surg. 2013; 131:1194-1201.

16. Kumar S, Adhish VS, Chauhan A. Managing self for leadership. Indian J Community Med. 2014; 39:138-42.

11. Eby LT, Allen TD, Evans SC, et al. Does mentoring matter? A multidisciplinary meta-analysis comparing mentored and non-mentored individuals. J Vocat Behav. 2008; 72:254-267. 12. Vender RJ. Leadership: an overview. Am J Gastroenterol. 2015; 110:362-7. 13. Chan Z, Bruxer A, Lee J, et al. What makes a leader: Identifying the strengths of Canadian physical therapists. Physiother Canada. 2015; 67:341-8. 14. de Vries RE, Bakker-Pieper A, Oostenveld W. Leadership = communication? The relations of leaders’ communication styles with leadership styles, knowledge sharing and leadership outcomes. J Bus Psychol. 2010; 25:367-80. 15. Berghout MA, Fabbricotti IN, Buljac-Samardžic M, Hilders

17. Zhang X, Qian J, Wang B, et al. Leaders’ behaviors matter: The role of delegation in promoting employees’ feedback-seeking behavior. Front Psychol. 2017; 8:920. 18. Dyrbye LN, Freischlag J, Kaups KL, et al. Work-home conflicts have a substantial impact on career decisions that affect the adequacy of the surgical workforce. Arch Surg. 2012; 147:933-9. 19. Medscape National Physician Burnout & Suicide Report 2020: The Generational Divide (Internet). (cited 2020 Sep 11). Available from: https://www.medscape.com/slideshow/2020-lifestyle-burnout6012460#1 20. Parsons WL, Duke PS, Snow P, Edwards A. Physicians as parents: Parenting experiences of physicians in Newfoundland and Labrador. Can Fam Physician. 2009; 55:808.

Correspondence Sufyan Ibrahim, MD Kasturba Medical College Manipal, Manipal Academy of Higher Education, Manipal (India) Amelia Pietropaolo, MD Bhaskar K Somani, MD Department of Urology, University Hospital Southampton NHS Trust, Southampton (UK) Nithesh Naik, MD Faculty of Engineering, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal (India) Anita Patel, MD Global Hospitals, Maharashtra (India) Milap J Shah, MD BM Zeeshan Hameed, MD zeeshanhameedbm@gmail.com Department of Urology, Kasturba Medical College Manipal, Manipal Academy of Higher Education, Manipal (India) Patricia Zondervan, MD Academic Medical Center, University of Amsterdam, Netherlands Jean McDonald, MD North Middlesex University Hospital, Sterling Way, London (UK) Bhavan Prasad Rai, MD Department of Urology, Freeman Hospital, Newcastle upon Tyne NE7 7DN (UK) Hadis Karimi, MD Manipal College of Pharmacy, Manipal Academy of Higher Education, Manipal, India Joanne Cresswell, MD The James Cook University Hospital, South Tees Trust, Middlesbrough, United Kingdom BM Zeeshan Hameed, Professor (Corresponding Author) zeeshanhameedbm@gmail.com Department of Urology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India - 576104

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DOI: 10.4081/aiua.2021.4.460

ORIGINAL PAPER

Erectile dysfunction and testosterone levels prior to COVID-19 disease: What is the relationship? Kadir Karkin, Ergün Alma Department of Urology, Health Sciences University, Adana City Training and Research Hospital, Adana, Turkey.

Summary

Objective: We aimed to investigate the relationship between COVID-19 and Erectile Dysfunction (ED) and the effect of serum testosterone level on the disease prognosis. Methods: Between April-December 2020, 70 patients who were admitted with a complaint of ED after having COVID-19 and whose serum testosterone level was checked for varicocele, premature ejaculation, and infertility reasons before COVID-19. The patients filled the International Index of Erectile Function (IIEF-5) and their testosterone level was checked. The questionnaire was arranged to assess the first month before COVID-19 and after COVID-19. Testosterone levels of the patients before and after COVID-19 were compared. The relationship between testosterone levels and hospitalization in the intensive care was evaluated. Results: It was revealed that testosterone levels and IIEF-5 scores after COVID-19 in all patients were statisticaly and significantly different compared to the period before COVID-19 (p < 0.05). Testosterone levels of patients in need of intensive care were significantly higher than those without any need of intensive care (p < 0.05). Conclusions: Our study has presented that COVID-19 may cause ED and high testosterone levels increase the rate of hospitalization in the intensive care by intensifying the disease.

KEY WORDS: COVID-19; Erectile dysfunction; Testosterone. Submitted 18 September 2021; Accepted 9 October 2021

INTRODUCTION

The global coronavirus disease (COVID-19) results in a cytokine storm that leads to the development of microthrombosis and diffuse intravascular coagulation (DIC) (1). Despite the fact that lungs are the organs which are primarily targeted in cytokine storm, the cardiovascular system is also affected. The autopsies which were performed showed that there were signs of endothelial damage, pulmonary embolism, bleeding at multiple levels including alveolar, microangiopathy, and vascular dysfunctions in the form of vasculitis (2). The relationship between Erectile Dysfunction (ED) and COVID-19 develops due to vasculogenic and hormonal causes which were caused by the primary disease. The vasculogenic damage and ED are also seen as predictors of a cardiovascular pathology which may be observed in patients in the future (3). Testosterone, which is the most important hormone in male erection, modulates almost every component involved in erectile function, from the

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pelvic ganglia to smooth muscles and the endothelial cells of the corpora cavernosa (4). Low testosterone levels are associated with decreased libido, ED, decreased energy, depressive symptoms, and fatigue (5). Changes in testosterone levels after COVID-19 may not only increase the severity of ED but also cause ED alone (6). The relationship between COVID-19 and testosterone is based on contracting the disease, the severity of the disease and progression of the disease. COVID-19 makes use of Transmembrane protease serine 2 (TMPRSS2) to penetrate into the host cell and androgen receptors are transcription supportive for TMPRSS2. The higher the testosterone level, the easier it is for COVID-19 to penetrate into the host via this mechanism (7). Besides, TMPRSS2 is up-regulated in prostate cancer where it supports tumor progression, thus these patients may have a higher risk of SARS-CoV-2 infection. TMPRSS2 inhibitors may be useful for the treatment or prevention of COVID-19 (8). On the contrary, some other studies have reported that low testosterone levels are associated with acute respiratory distress syndrome (ARDS) by increasing proinflammatory cytokines and they intensify COVID-19 infection in elderly men (9). ED which is caused by COVID-19 appears to be associated with both vascular endothelial damage and reduction in testosterone level. Even though the studies in the last year mostly focused on primary disease due to the pandemic, In some studies, COVID-19 and its effects on sexual life have begun to be revealed and suggestions are made in terms of sexual health, especially through andrology associations (10), but the results on effects of COVID-19 infection on the male reproductive system are currently insufficient as they are based on a small number of patients and therefore are often contradictory (11). Our study aimed to figure out the factors which may play a role in the development of ED in our patients with COVID-19 and the effect of testosterone level on the prognosis of COVID-19.

MATERIALS

AND METHODS

Study design and patients Our study has been designed after being approved by the Republic of Turkey Ministry of Health and the local ethics committee (Ethical committe approval number: 1303/27.01.2021) and 210 patients who were admitted No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2021; 93, 4

Erectile dysfunction and testosterone in COVID-19

to our clinic with a complaint of ED between AprilDecember 2020 were evaluated prospectively. Written consent forms were obtained from all patients who participated in the study. In order to figure out the erectile conditions of the patients, the IIEF-5 questionnaire, fiveitem short version of the international index of erectile function (IIEF-EF), was used. This questionnaire was designed in a form assessing the first month before COVID-19 infection and the period after COVID-19. According to this form, scores between 5-7 were considered as severe, 8-17 as moderate, 17-21 as mild and 22-25 as no ED. Male patients with an elapsed time at least six months after COVID-19 and who did not have ED according to the IIEF-5 score before COVID-19 infection, and whose testosterone level was measured for varicocele, premature ejaculation, infertility reasons in the last year were included in our study. Furthermore, Beck depression scale was used to determine the current depressive states of the patients. Patients with minimal depression (0-9) according to this scale were included in the study. The patients who had comorbidities before COVID-19 such as obesity, hypertension, diabetes or heart disease, the patients who have used drugs (such as beta blocker) that can cause ED during and after COVID-19, the patients with who had an increase in smoking and alcohol use after COVID-19, the patients with an elapsed time of less than 6 months after COVID-19, the patients whose testosterone levels were not known before COVID-19, the patients who did not have a minimal depression level according to the Beck depression scale, the patients with an IIEF-5 score of 21 and below, the patients who had treatment for ED before COVID-19, whose detailed medical history could not be taken and who did not have education level enough to fill in IIEF-5 form were not included in the study. After being evaluated according to the exclusion criteria, our study was carried on with 70 patients. The ages of the patients, their results of COVID-19 polymerase chain reaction (PCR) test, testosterone level, reports consistent with COVID-19 observed in thoracic computed tomography (CT) and the presence of hospitalization in intensive care unit were recorded. The patients were evaluated after being classified under three different groups according to their ages. The patients aged between 20-40 were recorded in group 1, the ones aged between 40-60 were recorded in group 2 and the ones aged 60 or over were recorded in group 3. The levels of serum testosterone before and after COVID-19 were compared among the groups. The relationship between the levels of testosterone and the hospitalization in the intensive care unit and ED states of the patients hospitalized in the intensive care unit were evaluated. Data collection The electronic hospital information system was used to get epidemiological data, including demographic, clinical and laboratory findings. Considering the circadian rhythm of testosterone release, the total testosterone which were measured in the venous blood sample between 7 and 11 in the morning were recorded. Peripheral venous blood samples were evaluated in the Central Laboratory of Adana City Training and Research Hospital by using the standard pro-

cedures. Biochemical hormonal parameters were measured by Siemens ADVIA 1800 automatic biochemistry analyser (Siemens Healthcare Diagnostics Inc, Laboratory Diagnostics, Advia Centaur XPT, Erlangen, Germany, manufactured in Ireland). Statistical analysis SPSS 23.0 package program (IBM, Armonk, NY) was used in the statistical analysis of data. Categorical measurements were summarized as numbers and percentages, continuous measurements were summarized as mean, standard deviation and minimum-maximum. The appropriateness of the variables to normal distribution was investigated by using Kolmogorov-Smirnov/Shapiro-Wilk Tests. Mann-Whitney U test and Wilcoxon test were used in the groups which do not agree with normal distribution. Spearman correlation analysis was benefited from in the comparison of the relationship between the numerical variables. Statistical significance level was taken as 0.05 in all tests.

RESULTS

The mean age in our study was 52.3 ± 13.5 years. When the groups were considered, it was seen that 22.9% (n = 16) of the patients were in group 1, 47.1% (n = 33) were in group 2 and 30% (n = 21) were in group 3. The mean IIEF score of the patients was 23 before COVID-19 and 11.03 after COVID-19 (Table 1). No statistical difference was observed between the patient’s age and the rate of hospitalization in the intensive care unit (p > 0.05). A statistically significant difference was observed between the IIEF scores of the patients with and without intensive care need in the period after COVID-19 (p < 0.05). Testosterone levels of patients with intensive care need were significantly higher than those of the patients without intensive care need (p < 0.05) (Table 2). Testosterone levels after COVID-19 were found significantly lower than the testosterone levels before COVID19 (p < 0.001). In all three groups, it was seen that testosterone levels and IIEF scores after COVID-19 were statistically and significantly different compared to the ones before COVID-19 (p < 0.05). As the age of the patients increased, IIEF scores after COVID-19 and testosterone levels before and after COVID-19 were found to be significantly lower (p < 0.05). Also, there was a statistically significant relationship between IIEF scores and testosterone levels (p < 0.05). While there was a positive correTable 1. Demographic data and mean IIEF according to the patient groups. Age 20-40 40-60 60 and over Age IIEF Score before COVID IIEF Score after COVID

Frequency (n) 16 33 21 Mean ± SD 52.33 ± 13.51 23.5 ± 1.57 11.03 ± 3.76

Percentage (%) 22.9 47.1 30 Mediann (min-max) 56 (22-74) 23 (22-25) 11 (5-18)

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Table 2. Rates of hospitalization in the intensive care according to groups, evaluation of hospitalization in the intensive care and IIEF score before and after COVID-19 and correlation between the hospitalization in the intensive care and testosterone level.

Hospitalization in the intensive care Yes No

Hospitalization in the intensive care No Yes p

Hospitalization in the Intensive care No Yes

20-40 40-60 60 and over (n = 16) (n = 33) (n = 21) n (%) n (%) n (%) 5 (31.2) 11 (33.3) 6 (28.6) 11 (68.8) 22 (66.7) 15 (71.4) IIEF score before COVID IIEF score after COVID Median (min-max) Median (min-max) 24 (22-25) 13 (5-18) 23 (22-24) 8 (5-13) .95 Testosterone level Median (min-max) 291 (112-531) 390 (180-680)

.93 P < .001 < .001 < .001 P < .001

Table 3. Comparison of the IIEF scores and testosterone levels before and after COVID-19, evaluation of the IIEF scores and testosterone levels before and after COVID-19 according to groups and correlation between testosterone level, age and IIEF score. IIEF Score before COVID IIEF Score after COVID Testosterone level before COVID Testosterone level after COVID According to groups IIEF score before COVID IIEF score after COVID Testosterone before COVID Testosterone after COVID

IIEF score before COVID IIEF score after COVID

Mean ± SD 23.5 ± 1.57 11.03 ± 3.76 345.67 ± 109.48 297.31 ± 96.04 20-40 40-60 60 and over (n = 16) (n = 33) (n = 21) Median (min-max) Median (min-max) Median (min-max) 24(23-25) 23 ( 22-25) 22 (22-23) 14(6-18) 11 (5-18) 8 (5-17) 400 (213-531) 390 (122-680) 225 (112-423) 300 (230-449) 300 (100-600) 200 (100-400) Testosterone level Age r p r 0.383 .001 -0.675 0.423 < .001 -0.557

P < .001 < .001 P .9 < .001 < .001 < .001 p < .001 < .001

lation between the testosterone level findings, the IIEF scores before COVID-19 (r = 0.383) and the IIEF scores after COVID-19 (r = 0.423) of the patients who participated in the study, there was a negative correlation between the ages of the patients and the IIEF scores before COVID-19 (r = -0.675) and the IIEF scores after COVID-19 (r = -0.557) (p < 0.05) (Table 3).

DISCUSSION

We showed with this study that COVID-19 causes ED in all age groups, reducing testosterone levels seriously. Moreover, we also oberved that the higher the testosterone levels during COVID-19, the more severe the disease progresses. To the best of our knowledge, a similar study suggesting that COVID-19 causes ED has not been published before in the related literature.

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ED is multidimensional and commonly male sexual dysfunction involves a change in any component of the erectile response, including organic, relational, and psychological. Non-endocrine (neurogenic, vasculogenic, and iatrogenic) and endocrine pathways may cause ED (12, 13). Endothelial dysfunction equals erectile dysfunction or vice versa (ED-ED). It is presented in the literature that the prevalence of ED can be up to 30% in young men and that the rare of ED is further increased in elderly due to diseases of coronary and penile arteries (14-16). In COVID-19 infection, the ACE enzyme, which provides access to host cells, is expressed by endothelial cells and the fragile vascular bed is affected preparing the ground for the development of ED (17-22). Testosterone deficiency is one of the most important hormonal causes of ED development. Testosterone modulates almost all components of the erectile mechanism, down to the endothelial cells in the corpus cavernosum. Current EAU guidelines recommend to measure baseline testosterone levels in all men who admit with a complaint of ED (7). Araujo et al. showed in their studies that the testosterone levels of 24% of men aged between 30-79 were below 300 and 5.6% of them had symptomatic androgen deficiency (23). Yassin et al. reported that testosterone replacement therapy (TRT) improved erectile function in hypogonadal men who previously received phosphodisterase-5 inhibitor (PDE5I) before (24). Rizk et al. suggested that the use of TRT as monotherapy in patients with mild ED was effective (25). Our present study shows that patients of all age groups are affected, although ED which develops after COVID-19 seems to affect more elderly patients. It was also revealed that testosterone levels of the patients were significantly lower in all age groups, especially in elderly patients. In COVID-19 infection, Leydig cells in the testicles are damaged and this testicular damage causes a decrease in serum testosterone levels (26). Ling Ma et al. reported that testosterone/luteinizing hormone (LH) ratios were significantly lower in patients with COVID-19 infection (27). Vanhorebeek et al. observed that there was a decrease in testosterone level in the acute phase of COVID-19 (28). Also Okçelik reported that testosterone levels decreased during acute COVID-19 infection and especially in patients with pulmonary involvement (29). It was also concluded in our study that the significant decrease in the testosterone levels of patients after COVID-19 is an indicator of a possible testicular damage and this finding supports the studies in the literature. Testosterone is a hormone which has an effect not only on the erection mechanism but also on many functions in the body. Inflammation is known to be suppressed as a result of the decrease in pro-inflammatory cytokines and the increase of anti-inflammatory cytokines while responding to infections. It was shown in the study of Mohamad et al. that testosterone suppresses inflammation by increasing anti-inflammatory cytokines and decreasing pro-inflammatory cytokines (30). Malkin et al. conducted a crossover study with 27 men with symptomatic androgen deficiency. They concluded that testosterone treatment decreased pro-inflammatory cytokine levels and increased the concentration of interleukins, which are some of the anti-inflammatory cytokines (31). Although

Erectile dysfunction and testosterone in COVID-19

our study did not focus on any evaluation in this direction, we assume that the low testosterone level in patients after COVID-19 may have contributed to inflammation. We also believe that the investigation of the effect of TRT on the clinical findings of the patients should be supported by prospective studies. During the cytokine storm caused by COVID-19, low testosterone can also affect the prognosis of the disease. Jiawei et al. have suggested in their study that testosterone may play a role in the chain of events leading to the progression of COVID-19 infection due to the cytokine storm. It was concluded with this study that there may be a negative correlation between ACE2 expression and COVID-19 mortality as a result of suppression of ACE2 expression by inflammatory cytokines accompanying the decrease in androgens and oestrogens in the elderly (32). Giagulli et al. has shown that testosterone can make men susceptible to a common COVID-19 infection compared to oestrogen, and low serum testosterone levels in severe patients make men, especially older, susceptible to poor prognosis or death (33). Papadopoulos et al. reported that low testosterone levels are associated with ARDS increasing the severity of COVID-19 infection in elderly men and they added that normal testosterone levels may also provide some slight protection against COVID-19 (13). Similar studies in the literature support a relationship between the need for intensive care and low testosterone levels in COVID-19 infection (34, 35). Studies have also been reported that testosterone affects by using a different mechanism apart from the cytokine mechanism during COVID-19 infection. It has been reported in the study of Lii et al. that the first biological step which is necessary for the potential infectivity of COVID-19 is to activate ACE2 as the entry receptor and to use cellular transmembrane protease serine 2 (TMPRSS2) to prepare spike protein (36). Hoffmann et al. showed in their study that viral spread and pathogenesis are provided in infected hosts by spike proteins becoming ready by TMPRSS2 (37). Heurich et al. presented in their study that TMPRSS2 can also break down ACE2 for viral entry and that androgen receptor activity is a requirement for the transcription of the TMPRSS2 gene (38). There are studies reporting that high testosterone levels are associated with poor prognosis in COVID-19 through this mechanism. Wambier et al. reported that the hyperandrogenic phenotype may be associated with increased viral load, increased viral spread, and severity of lung involvement for COVID-19 (39). It was reported by Rozhivanov et al. that both TMPRSS2 expression and a more severe course of coronavirus infection were observed in men with hyperandrogenism. In this context, some researchers suggested the creation of androgen deprivation with drug treatments for men at high risk of developing COVID-19 (40). There are some contrasting views in the literature on the effect of testosterone level on COVID-19 prognosis and further studies are required to support them. The results of our study showed that patients with high testosterone levels need intensive care more and this supports the studies in the literature claiming that high testosterone level is a poor prognostic factor for COVID-19. There are some limitations of our study. Our study reflects the results of one centre and includes a limited

number of patients. Besides, although we have excluded many factors that cause ED (such as obesity, hypertension, diabetes or heart disease), the ED mechanism is dependent on a lot of factors that our study may not have been able to evaluate adequately since a non-ED vital disease is discussed. Other limitations are that the psychological state of the patients may have affected the IIEF-5 score, and conditions such as varicocele and infertility may cause low testosterone levels, which may affect our results. However, to the best of our knowledge, our study is one of the first studies showing that COVID-19 causes erectile dysfunction and there are only a limited number of studies in the literature on this subject. We hope that our study will make a considerable contribution to the literature with this aspect.

CONCLUSIONS COVID-19 can cause erectile dysfunction in men of all age groups, and high testosterone increases the rate of hospitalization in the intensive care unit by intensifying the disease.

ACKNOWLEDGMENT

We would like to thank the Adana City Hospital Urology Clinic for their contribution.

REFERENCES

1. Jose RJ, Manuel A. COVID-19 cytokine storm: the interplay between inflammation and coagulation. Lancet Respir Med 2020; 8:e46-e47. 2. Menter T, Haslbauer JD, Nienhold R, et al. Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction. Histopathology. 2020; 77:198-209. 3. Jannini EA. SM = SM: The interface of systems medicine and sexual medicine for facing non-communicable diseases in a genderdependent manner. Sex Med Rev. 2017; 5:349-364. 4. Isidori AM, Buvat J, Corona G, et al. A critical analysis of the role of testosterone in erectile function: from pathophysiology to treatment-a systematic review. Eur Urol. 2014; 65:99-112. 5. Schubert M, Jockenhovel F. Late-onset hypogonadism in the aging male (LOH): definition, diagnostic and clinical aspects. J Endocrinol Invest. 2005; 28:23-27. 6. Blute M, Hakimian P, Kashanian J, et al. Erectile dysfunction and testosterone deficiency. Front Horm Res. 2009; 37:108-122. 7. Mohamed MS, Moulin TC, Schiöth HB. Sex differences in COVID19: the role of androgens in disease severity and progression. Endocrine. 2021; 71:3-8. 8. Rodriguez Bustos H, Bravo Maturana G, Cortés-Chau F, et al. Effects of COVID-19 on male sex function and its potential sexual transmission. Arch Ital Urol Androl. 2021; 93:48-52. 9. Papadopoulos V, Li L, Samplaski M. Why does COVID-19 kill more elderly men than women? Is there a role for testosterone? Andrology. 2021; 9:65-72. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

463

K. Karkin, E. Alma

10. Maretti C, Privitera S, Arcaniolo D, et al. COVID-19 pandemic and its implications on sexual life: Recommendations from the Italian Society of Andrology. Arch Ital Urol Androl. 2020; 92:73-77 11. Delle Fave RF, Polisini G, Giglioni G, et al. COVID-19 and male fertility: Taking stock of one year after the outbreak began. Arch Ital Urol Androl. 2021; 93:115-119. 12. Yafi FA, Jenkins L, Albersen M, et al. Erectile dysfunction. Nat Rev Dis Primers. 2016; 2:16003. 13. Irwin GM. Erectile dysfunction. Prim Care. 2019; 46:249-255. 14. Guay AT. ED2: erectile dysfunction = endothelial dysfunction. Endocrinol Metab Clin North Am. 2007; 36:453-463. 15. Mola JR. Erectile dysfunction in the older adult male. Urol Nurs. 2015; 35:87-93 16. Nguyen HMT, Gabrielson AT, Hellstrom WJG. Erectile dysfunction in young men-A review of the prevalence and risk factors. Sex Med Rev. 2017; 5:508-520. 17. Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020; 395:1417-1418. 18. Maiorino MI, Bellastella G, Giugliano D, et al. From inflammation to sexual dysfunctions: a journey through diabetes, obesity, and metabolic syndrome. J Endocrinol Invest. 2018; 41:1249-1258. 19. Zhang H, Penninger JM, Li Y, et al. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020; 46:586590. 20. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020; 579:270-273. 21. Hamming I, Timens W, Bulthuis ML, et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J. Pathol. 2004; 203:631-637. 22. Lovren F, Pan Y, Quan A, et al. Angiotensin converting enzyme2 confers endothelial protection and attenuates atherosclerosis. Am. J. Physiol. Circ. Physiol. 2008; 295: H1377-H1384. 23. Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab. 2007; 92:4241-7. 24. Aksam A Yassin, Farid Saad. Testosterone and erectile dysfunction. J Androl. 2008; 29:593-604. 25. Rizk PJ, Kohn TP, Pastuszak AW, Khera M. Testosterone therapy improves erectile function and libido in hypogonadal men. Curr Opin Urol. 2017; 27:511-515. 26. Douglas GC, O’Bryan MK, Hedger MP, et al. The novel angiotensin-converting enzyme (ACE) homolog, ACE2, is selectively

Correspondence Kadir Karkin, MD (Corresponding Author) kadir_karkin@msn.com Ergün Alma, MD Health Sciences University, Adana City Training and Research Hospital, Department of Urology, 01330, Adana (Turkey)

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expressed by adult Leydig cells of the testis. Endocrinology. 2004; 145:4703-4711. 27. Ma L, Xie W, Li D, et al. Effect of SARS-CoV-2 infection upon male gonadal function: A single center-based study. MedRxiv; 2020. 28. Vanhorebeek I, Langouche L, Van den Berghe G. Endocrine aspects of acute and prolonged critical illness. Nat Clin Pract Endocrinol Metab. 2006; 2:20-31. 29. Okçelik S. COVID-19 pneumonia causes lower testosterone levels. Andrologia. 2021; 53:e13909. 30. Mohamad NV, Wong SK, Wan Hasan WN. The relationship between circulating testosterone and inflammatory cytokines in men. Aging Male. 2019; 22:129-140. 31. Malkin CJ, Pugh PJ, Jones RD, et al. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men J Clin Endocrinol Metab. 2004; 89:3313-8. 32. Chen J, Jiang Q, Xia X, et al. Individual variation of the SARSCoV-2 receptor ACE2 gene expression and regulation. Aging Cell. 2020; 19:e13168. 33. Giagulli VA, Guastamacchia E, Magrone T, et al. Worse progression of COVID-19 in men: Is testosterone a key factor? Andrology. 2021; 9:53-64. 34. Çayan S, Ug˘uz M, Saylam B, Akbay E. Effect of serum total testosterone and its relationship with other laboratory parameters on the prognosis of coronavirus disease 2019 (COVID-19) in SARSCoV-2 infected male patients: a cohort study. Aging Male. 2020; 23:1493-1503. 35. Rastrelli G, Di Stasi V, Inglese F, et al. Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients. Andrology. 2021; 9:88-98. 36. Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003; 426:450-454. 37. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020; 181:271-280.e8. 38. Heurich A, Hofmann-Winkler H, Gierer S, et al. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J Virol. 2014; 88:1293-1307. 39. Wambier CG, Goren A. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is likely to be androgen mediated. J Am Acad Dermatol. 2020; 83:308-309. 40. Rozhivanov RV, Andreeva EN, Melnichenko GA, Mokrysheva NG. Androgens and Antiandrogens influence on COVID-19 disease in men. Probl Endokrinol (Mosk). 2020; 66:77-81.

DOI: 10.4081/aiua.2021.4.465

ORIGINAL PAPER

The effect of N-acetyl cysteine consumption on men with abnormal sperm parameters due to positive history of COVID-19 in the last three months Bahare Rafiee 1, Seyed Mohammad Bagher Tabei 2 1 PhD

Student of Reproductive Biology, Department of Reproductive Biology, School of Advanced medical Sciences and Applied Technologies, Shiraz, Iran; 2 Genetics Department, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.

Summary

Male infertility is an important factor accounting for 40-50% of infertility cases that may be due to disturbance in one of the parameters as concentration, motility and morphology observed in one or two semen analysis with an interval of 1 and 4 weeks. COVID-19 may affect male fertility through virus division, cytotoxic effects on testicular tissue and immunopathological effect. N-acetyl cysteine (NAC) improved sperm concentration and acrosome reaction while reducing reactive oxygen species (ROS) and oxidation of sperm DNA. This interventional study was conducted on 200 men who were referred to private infertility clinics for female factor (their previous semen analysis was normal) and got COVID-19 infection in the last 3 months showing an impairment of the latest semen analysis due to COVID. Men were placed in two groups of control (n = 100) and intervention (NAC consumption). Subjects who got COVID-19 infection had a significant impairment of sperm quality (sperm concentration, sperm motility, and normal sperm morphology) compared to their semen analysis evaluated before the COVID-19 infection. NAC consumption significantly improved sperm total motility, sperm morphology and sperm concentration. COVID-19 infection has a negative effect on sperm parameters. NAC supplementation may have positive effect on sperm parameters.

KEY WORDS: COVID-19; Sperm; Morphology; Infection. Submitted 25 September 2021; Accepted 12 October 2021

INTRODUCTION

According to the International Committee for Monitoring Assisted Reproductive Technology of World Health Organization (WHO), infertility is a reproductive disorder that prevents clinical pregnancy after 12 months or more of unprotected intercourse (1). Studies have shown that nearly 72.4 million couples worldwide are involved in infertility problems (2). Male infertility is an important factor accounting for 40-50% of infertility cases that may be due to disturbance in one of the parameters of concentration, motility and morphology in one or two semen analysis with an interval of 1 and 4 weeks (3). Normal sperm parameters are assessed based on WHO criteria (4). Semen analysis is still a powerful and essential tool with a sensitivity of 89.6% that can identify 9 out of 10 men with infertility problems (5). Normal semen volume is the total amount of fluid ejaculated that should

be ≥ 1.5 mL. The sperm concentration is reported as the number of sperm per mL of semen that should be ≥ 15 million per mL. Total sperm number (also known as ‘total sperm count’) is described as the total number of sperm in the ejaculate, calculated by multiplying the semen volume by the sperm that should be ≥ 39 million. Sperm progressive motility should be ≥ 32% motile within 60 minutes of ejaculation. Sperm vitality should be ≥ 58%. Sperm normal morphology is described as the percentage of the total number of sperms that should be ≥ 4% (4). COVID-19 may affect male fertility through virus division, cytotoxic effects on testicular tissue and immunopathological effect (6). Coronavirus can directly affect testicular tissue as well as some sperm parameters by altering the expression of the angiotensin-converting enzyme 2 gene pattern (ACE-2) (7) because seminiferous cells, spermatogonia, Leydig cells and Sertoli cells express this enzyme (8). Studies have shown that ACE-2 is present in the post-acrosomal region, neck and middle part of normal sperm (9). Sperm ACE binds to the glycosyl-phosphatidyl-Inositol (GPI) portion of the oocyte Zona Pellucida and is therefore involved in fertilization (10). N-acetylcysteine (NAC), a derivative of amino acid L-cysteine, is used mainly as an antioxidant (11). NAC has free radical scavenging activity (12). In addition, daily treatment with NAC results in a significant improvement in sperm motility in comparison to placebo (13). NAC improved sperm concentration and acrosome reaction while reducing ROS and oxidation of sperm DNA (14). This study investigates the effect of NAC on abnormal sperm parameters in men with COVID 19 infection.

MATERIALS

AND METHODS

Design This interventional study was conducted from March 2020 to July 2021. All couples whose infertility treatment cycle were canceled due to COVID-19 pandemic were included in this study. Male patients with abnormal sperm analysis before COVID-19 were excluded from the study. In total, 273 male patients were included in this study, 47 patients did not present to the infertility center to continue treatment during the time of this study and

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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26 patients presented to continue the treatment more than two months after positive PCR and were excluded from the study. Other exclusion criteria were diabetes, hypertension, mumps history, sexually transmitted diseases, varicocele, and chronic diseases history. All the 200 eligible COVID-19 patients were willing to participate in the study and were randomly allocated in two groups of controls and treated subjects. All the cases gave a semen sample after completing written informed consent. Subjects having a positive nasopharyngeal swab test for COVID-19 (ESwab collection kit, Copan diagnostics) or positive Immunoglobulin (Ig) M and IgG antibodies were considered positive for COVID-19 (15). Intervention and assessment The subjects took NAC 600 mg/day by oral route for 3 months (16). Variables including seminal parameters were measured before and after the intervention. Semen sampling method Semen samples were collected once, at the beginning of study and at the end of the intervention. Sperm samples were taken by masturbation after 3-5 days of sexual abstinence and kept in a plastic container. Then the samples were incubated at 37°C for 30 minutes and analyzed after one hour. The sperms were counted by light microscope with a magnification of 400. Different characteristics of semen including appearance, volume, pH, color, viscosity, liquefaction time, sperm concentration and sperm motility were investigated. Statistical analysis For statistical analysis was used the Statistical Package for Social Science (SPSS Inc, Chicago, Illinois, USA) version 16.0. P value significance was set at 0.05 and confidence interval was at 95%. Paired t-test was used to compare the results before and after interventions. Independent t test was used to compare between control and intervention group.

RESULTS

The average time between initial normal sperm analysis and COVID-19 infection was 2 months (range 1-5 months). Average time from COVID-19 infection and sperm analysis re-evaluation was 6 weeks (range 3-8 weeks). Patients who presented more than 2 months after COVID-19 infection were excluded. Subjects suffering from COVID-19 infection had a statistically significant impairment of sperm quality (sperm concentration, sperm motility, and normal sperm morphology) compared to their semen analysis before the COVID-19 infection (Table 1). In Table 2, results of sperm analysis after NAC treatment were not significantly different from initial results of sperm analysis (before COVID). In Table 3 the results of sperm analysis during the followup of controls are described. Results of the initial sperm analysis (before COVID) and the last sperm analysis at 3 month follow-up were significant different for sperm motility (p = 0.04) and sperm concentration (p = 0.03).

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Table 1. Age, body mass index and semen parameters for individuals before and after COVID-19 infection. Age BMI (kg/m2) Volume (ml) Sperm concentration (106) Total motility (%) Morphology

Before COVID 36.1 ± 4.1 23.12 ± 2.5 3.5 ± 0.9 115.1 ± 35.1 69.9 ± 32.7 4 ± 1.2

After COVID 36.1 ± 4.1 21 ± 3.1 2.9 ± 0.6 68.7 ± 53.6 30.1 ± 29.6 2 ± 0.9

P value 0.96 0.04* 0.05* 0.01* 0.01* 0.03*

Table 2. Comparison of semen parameters before and after COVID and after 3 months treatment with NAC. NAC consumption significantly improved sperm total motility, sperm morphology and sperm concentration. Sperm Before parameters COVID Volume (ml) 3.10 ± 0.56 Total motility (%) 81.1 ± 23.2 Sperm concentration (106/mL) 115 ± 32.5 Morphology (%) 4 ± 0.6

After COVID before NAC 2.3 ± 0.6 35.1 ± 29.6 61.7 ± 53.6 2 ± 0.9

After NAC 4.02 ± 0.18 71.6 ± 25.3 98.7 ± 44.5 4 ± 1.5

P value before vs after NAC 0.03* 0.01* 0.04* 0.03*

Table 3. Comparison of semen parameters before and immediately after COVID infection and after 3 months of follow-up in the control group. Sperm parameters

After 3 P value after 3 months COVID vs 3 of follow-up months follow-up Volume (ml) 4.13 ± 0.61 2.5 ± 0.3 4.44 ± 1.32 0.04* Total motility (%) 65.10 ± 19.63 37.5 ± 25.1 43.3 ± 21.43 0.06 Sperm concentration (106/mL) 110 ± 21.42 58.8 ± 25.1 63.54 ± 54.21 0.071 Morphology (%) 3 ± 0.71 2 ± 2.1 3 ± 0.9 0.06

DISCUSSION

Before COVID

After COVID

Coronavirus disease 2019 (COVID-19) is a highly transmissible infectious disease caused by the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), a singlestrand enveloped RNA virus belonging to the family of coronaviridae (17). This virus enters host cells mainly through ACE-2 and transmembrane protease serine 2 (TMPRSS2) (18). Recent advances suggest a possible infection of the endocrine system in COVID-19 patients (19-21). In the present study, we evaluated semen parameters after acute SARS-CoV-2 infection. Subjects suffering from COVID-19 infection had a statistically significant impairment of sperm quality (semen volume, sperm concentration, sperm motility, and normal sperm morphology) compared to their semen analysis before the covid infection. Our findings are in accordance with other studies which are available in the literature (22-24). It is recommended that men with positive history of SARS-CoV-2 who are interested in fertility should be evaluated by a fertility specialist. N-acetylcysteine (NAC) is a thiol-based antioxidant that plays an important role in the protection of cellular con-

N-acetyl cysteine and abnormal sperm parameters after COVID-19

stituents against oxidative damage. The hypothetical action of NAC comes from the ability to stimulate and sustain intracellular levels of reduced glutathione and to detoxify ROS. NAC is one of the oldest and most powerful antioxidants that treat various diseases, including respiratory disorders, heart disease, heavy metal poisoning, overdose with acetaminophen and epilepsy (25). Safarinejad et al. also reported significant improvements in all semen parameters in subjects receiving selenium or NAC (13). The results of this study showed that sperm parameters (volume, concentration, motility and normal morphology) significantly improved after NAC supplementation. NAC also improved sperm concentration and morphology.

CONCLUSIONS

COVID-19 infection has a negative influence on sperm parameters. NAC oral supplementation may improve sperm parameters.

REFERENCES

1. Zegers-Hochschild F, Adamson GD, de Mouzon J, et al. International committee for monitoring assisted reproductive technology (ICMART) and the world health organization (WHO) revised glossary of ART terminology. Fertil Steril. 2009; 92:1520-4. 2. Rutstein SO, Shah IH. 2004. Infecundity, Infertility, and Childlessness in Developing Countries. DHS Comparative Reports No. 9. Calverton, Maryland, USA: ORC Macro and the World Health Organization. 3. Lotti F, Maggi M. Ultrasound of the male genital tract in relation to male reproductive health. Hum Reprod Update. 2015; 21:56-83. 4. World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Semen-Cervical Mucus Interaction, 6th ed., Cambridge University Press, Cambridge 2021, pp. 1-86. 5. Butt F, Akram N. Semen analysis parameters: Experiences and insight into male infertility at a tertiary care hospital in Punjab. J Pak Med Assoc. 2013; 63:558-62. 6. Aitken RJ. COVID-19 and human spermatozoa-potential risks for infertility and sexual transmission? Andrology. 2021; 9:48-52. 7. Verma S, Saksena S, Sadri-Ardekani H. ACE2 receptor expression in testes: implications in coronavirus disease 2019 pathogenesis. Biol Reprod. 2020; 103:449-451. 8. Li LJ, Zhang FB, Liu SY, et al. Human sperm devoid of germinal angiotensin-converting enzyme is responsible for total fertilization failure and lower fertilization rates by conventional in vitro fertilization. Biol Reprod. 2014; 90:125. 9. Nikolaeva MA, Balyasnikova IV, Alexinskaya MA, et al. Testicular isoform of angiotensin I-converting enzyme (ACE, CD143) on the surface of human spermatozoa: revelation and quantification using monoclonal antibodies. Am J Reprod Immunol. 2006; 55:54-68.

10. Foresta C, Mioni R, Rossato M, et al. Evidence for the involvement of sperm angiotensin converting enzyme in fertilization. Int J Androl. 1991; 14:333-9. 11. Zafarullah M, Li W, Sylvester J, Ahmad M. Molecular mechanisms of N-acetylcysteine actions. Cell Mol Life Sci. 2003; 60:6-20. 12. Ciftci H, Verit A, Savas M, et al. Effects of N-acetylcysteine on semen parameters and oxidative/antioxidant status. Urology. 2009; 74:73-6. 13. Safarinejad MR, Safarinejad S. Efficacy of selenium and/or Nacetylcysteine for improving semen parameters in infertile men: a double-blind, placebo controlled, randomized study. J Urol. 2009; 181:741-51. 14. Comhaire F, Christophe A, Zalata A, et al. The effects of combined conventional treatment, oral antioxidants and essential fatty acids on sperm biology in subfertile men. Prostaglandins Leukot Essent Fatty Acids. 2000; 63:159-65. 15. Holtmann N, Edimiris P, Andree M, et al. Assessment of SARSCoV-2 in human semen-a cohort study. Fertil Steril. 2020; 114: 233-8. 16. Ciftci H, Verit A, Savas M, et al. Effects of N-acetylcysteine on semen parameters and oxidative/antioxidant status. Urology. 2009; 74:73-6. 17. Gorbalenya AE, Baker SC, Baric RS, et al. The species Severe acute respiratory syndrome-related coronavirus: Classifying 2019nCoV and naming it SARS-CoV-2. Nat. Microbiol. 2020; 5:536-544. 18. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020; 181:271-280.e8. 19. Puig-Domingo M, Marazuela M, Giustina A. COVID-19 and endocrine diseases. A statement from the European Society of Endocrinology. Endocrine. 2020; 68:2-5. 20. Delle Fave RF, Polisini G, Giglioni G, et al. COVID-19 and male fertility: Taking stock of one year after the outbreak began. Arch Ital Urol Androl. 2021; 93:115-119. 21. Rodriguez Bustos H, Bravo Maturana G, Cortés-Chau F, et al. Effects of COVID-19 on male sex function and its potential sexual transmission. Arch Ital Urol Androl. 2021; 93:48-52. 22. Paoli D, Pallotti F, Colangelo S, et al. Study of SARS-CoV-2 in semen and urine samples of a volunteer with positive naso-pharyngeal swab. J Endocrinol Invest. 2020; 43:1819-1822. 23. Pan F, Xiao X, Guo J, et al. No evidence of severe acute respiratory syndrome-coronavirus 2 in semen of males recovering from coronavirus disease 2019. Fertil Steril. 2020; 113:1135-1139. 24. Kayaaslan B, Korukluoglu G, Hasanoglu I, et al. Investigation of SARS-CoV-2 in semen of patients in the acute stage of COVID-19 infection. Urol Int. 2020; 104:678-683. 25. Ciftci H, Verit A, Savas M, et al. Effects of Nacetylcysteine on semen parameters and oxidative/antioxidant status. Urology. 2009; 74:73-76.

Correspondence Bahare Rafiee, PhD Student of Reproductive Biology (Corresponding Author) medicalarticle2020@yahoo.com Department of Reproductive Biology, School of Advanced medical Sciences and Applied Technologies, Shiraz (Iran) Seyed Mohammad Bagher Tabei Genetics Department, School of Medicine, Shiraz University of Medical Sciences, Shiraz (Iran)

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DOI: 10.4081/aiua.2021.4.468

ORIGINAL PAPER

Epidemiological, clinical and laboratory differences between male urethral infections due to Haemophilus spp. and those due to Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium and Ureaplasma urealyticum: A descriptive study Alvaro Vives, Marco Cosentino, Lluis Bassas, Carles Alonso, Felix Millan Sexually Transmitted Infection Department, Andrology Service, Fundació Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain.

Summary

Objective: To describe the epidemiological, clinical and laboratory characteristics of male patients diagnosed with Haemophilus spp. urethral infection and to compare them with the characteristics of male patients diagnosed with N. gonorrhoeae, C. trachomatis, M. genitalium and U. urealyticum urethral infection. Over the past 2 years, an increase in urethral infections due to Haemophilus spp. was observed. Materials and methods: All male patients who attended our Department of Sexually Transmitted Infections between January 2018 and February 2019 were retrospectively studied; they underwent conventional bacteriological and multiplex PCR studies in the urethra at the same time. Results: Of the 86 patients studied, a unique microorganism was detected in 76 cases, N. gonorrhoeae in 24, Haemophilus spp. in 21 (16 H. parainfluenzae and 5 H. influenzae), C. trachomatis in 19, M. genitalium in 8 and U. urealyticum in 4; 10 cases presented more than one microorganism. In case of multiple aetiological agents, sexual partnership was multiple. In the Haemophilus group, 81% reported only unprotected oral insertive sex; symptoms lasted for more than one week in 62% of the patients. Conclusions: Haemophilus is an aetiological agent of non-gonococcal urethritis whose incidence is clearly increasing; the main route of transmission is oral sex. The most common reason for consultation is dysuria and testicular pain, while urethral discharge was predominant for the other causes of urethral infection. Due to the high frequency of antibiotic resistance in the Haemophilus group, it is necessary to confirm eradication by performing a test of cure.

KEY WORDS: Haemophilus spp.; Neisseria gonorrhoeae; Chlamydia trachomatis; Mycoplasma genitalium; Ureaplasma urealyticum; Urethral infections; Males; Sexually transmitted infections. Submitted 15 August 2021; Accepted 7 October 2021

INTRODUCTION

One of the most common presentations of sexually transmitted infections (STI) among men is acute urethritis. Classically, cases of sexually transmitted urethritis have been classified according to their aetiology, as either gono-

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coccal urethritis (GU), caused by Neisseria gonorrhoeae, or non-gonococcal urethritis (NGU), caused by other aetiological agents, such as Chlamydia trachomatis, Mycoplasma genitalium or Ureaplasma urealyticum (1). However, it is estimated that the aetiology remains unknown in up to 30%-40% of cases of NGU (2). In recent years, new microorganisms have been described as aetiological agents for NGU, with bacteria of the genus Haemophilus taking on special importance (3, 4). Sexual transmission to the urethra via insertive oral sex is recognized as a potential mode of transmission (5). However, this mechanism has not been fully proven. We conducted a retrospective study to describe the epidemiological, clinical and laboratory characteristics of male patients diagnosed with urethral infections due to Haemophilus spp. and to compare these characteristics with those observed in male patients diagnosed with urethral infections due to N. gonorrhoeae, C. trachomatis, M. genitalium and U. urealyticum.

MATERIALS

AND METHODS

Inclusion criteria The study population comprised all male patients who attended our Department of Sexually Transmitted Infections (STI) between January 2018 and February 2019 and underwent conventional bacteriological and multiplex PCR studies in the urethra at the same time. The study was approved by our institutional medical and research ethics committee. Demographic, behavioural, clinical and laboratory data were obtained by reviewing medical charts. The different parameters under study were defined as follows: • Sexual orientation. • Type of sexual partner. • Number of sexual partners during the 90 days prior to the infection. • Type of unprotected sex during the 90 days prior to the infection. • History of STIs: all patients were asked about their STI history. No conflict of interest declared.

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• • • • • • •

HIV status. Recreational drugs during the past year. Main reason for consultation. Duration of symptoms. Presence of leukocytes. Types of treatment Test of cure: This consists in the performance of a conventional bacteriological and/or multiplex PCR study 3 weeks after the end of the treatment. • Clinical cure: in our STI Department patient is seen again 3 weeks after the end of the treatment. All patients without signs and symptoms at that time are considered clinically cured. • Partner notification and treatment: We considered a positive result for partner notification when at least one of the sexual partners from the last 90 days had been advised and treated correctly.

Statistical analysis Statistical analysis was conducted using Statistical Product and Service Solutions Version 18.0 (SPSS). Descriptive statistics were used to evaluate the study outcomes. Mean values and ranges are presented for continuous measurements. Frequencies and percentages were reported for dichotomous and ordinal variables. Differences of discrete variables were analysed with unpaired two-tailed Student’s t test. Comparisons of proportions were performed with Fisher’s exact test. Statistical significance was set at p < 0.05. Multivariate binary logistic regressions were used to search for the better combination of variables to predict the aetiology of Haemophilus spp, and the accuracy of the model was measured as the area under the ROC curve (AUC).

According to the CDC STI guidelines, urethritis can be documented on the basis of any of the following signs or laboratory tests: 1) Mucoid, mucopurulent, or purulent discharge on examination. 2) Gram stain of urethral secretions exist that demonstrate ≥ 2 WBCs per oil immersion field. 3) Positive leukocyte esterase test on first-void urine or microscopic examination of sediment from a spun first-void urine demonstrating ≥ 10 WBCs/HPF.

In total, 158 patients met the inclusion criteria, all had symptoms except for 5 who attended for screening. The screening cases were men to whom a sexual partner of the last 90 days had warned a positive result for: N. gonorrhoeae, C. trachomatis, M. genitalium, U. urealyticum. We obtained 86 (54%) positive results for the microor-

Men evaluated in settings in which Gram stain or MB or GV smear is unavailable who meet at least one criterion for urethritis (i.e., urethral discharge, positive leukocyte esterase test on first void urine, or microscopic examination of first-void urine sediment with ≥ 10 WBCs/HPF) should be tested for C. trachomatis and N. gonorrhoeae by NAATs. Laboratory studies Only urethral samples were obtained: the first sample for culture and leukocyte counting while the second for multiple PCR. Conventional bacteriological study included direct examination by Gram stain of the sample smear under 100× and 1000× magnification, and culture. Petri dishes of chocolate agar (BD), Martin-Lewis agar (BD), Gardnerella agar (BD) and Sabouraud with gentamicin and chloramphenicol (BD) were used. Chocolate agar, Martin-Lewis agar and Gardnerella agar were incubated at 35°C with enriched 7% CO2 atmosphere for 3 days (chocolate and Martin-Lewis agar) or 2 days (Gardnerella agar). Sabouraud was incubated at 35°C for 2 days at room air. N. gonorrhoeae and Haemophilus strains were identified by API NH test (bioMérieux). Multiplex PCR was performed by AnyplexTM II STI-7 assay (Seegene), which detects five microorganisms in a single reaction: Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, Mycoplasma genitalium, Ureaplasma urealyticum. Leukocytes and other elements were looked for in LPF microscopy (100x). Then, leukocytes in 20 fields of these areas were observed at 1000x and the average was calculated. The antimicrobial susceptibility of N. gonorrhoeae and Haemophilus spp. strains was analyzed according to 2015 CLSI guidelines (6).

RESULTS

Table 1. Reasons for consultation. Reason for consultation Urethral secretion Dysuria Testicular pain Balanitis Meatitis Screening Hematospermia Urethrorrhagia Total

Positive cases * 55 (86.2%) 20 (42.5%) 6 (66.7%) 0 (0%) 2 (22.2%) 2 (40%) 1 (16.7%) 0 (0%) 86 (54.4%)

Total 69 47 9 12 9 5 6 1 158

* Positive results for any of the following microorganisms: Haemophilus, Neisseria gonorrhoeae,

Chlamydia trachomatis, Mycoplasma genitalium or Ureaplasma urealyticum.

Table 2. Classification of the isolated microorganisms. Microorganism Haemophilus spp.

Haemophilus parainfluenzae Haemophilus influenzae

Neisseria gonorrhoeae Chlamydia trachomatis Mycoplasma genitalium Ureaplasma urealyticum C. trachomatis + M. genitalium C. trachomatis + N. gonorrhoeae C. trachomatis + H. parainfluenzae C. trachomatis + H. influenzae U. urealyticum + H. parainfluenzae U. urealyticum + Gardnerella vaginalis N. gonorrhoeae + M. genitalium + U. urealyticum

16 5

Number 21 24 19 8 4 1 1 3 2 1 1 1

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ganisms under study however, when we focused the main reason for consultation. In patients with urethral discharge the percentage of positives increased to 86.2% (55 cases) (Table 1). Regarding the 86 positive results, a single microorganism was detected in 76 cases; 24 cases of N. gonorrhoeae, 21 cases of Haemophilus spp. (16 H. parainfluenzae and 5 H. influenzae), 19 cases of C. trachomatis, 8 cases of M. genitalium and 4 cases of U. urealyticum. Ten cases presented with more than one microorganism, being C. trachomatis the most frequent, followed by Haemophilus spp. (Table 2). In Table 3 we described the

demographic, behavioural, clinical and laboratory data according to the germ obtained or multiple infection. Demographic and behavioural differences Age: The mean age of the patients included in the study was 31.6 years (range 16-74). The lowest mean age (24.5 years) was observed in patients with infection by U. urealyticum while the highest was seen in those with N. gonorrhoeae infection (37.5 years); Haemophilus cases displayed the second highest mean age. Sexual orientation: For all microorganisms, including multiple infections, most cases occurred in males having sex

Table 3. Reasons for consultation. Aetiology Number of cases Mean age (years) Sexual orientation

Type of sexual partner Number of sexual partners Type of unprotected sex durings the past 90 day Previous history of STI HIV status

Recreational drugs

Main reason for consultation

Duration of symptoms

Presence of leukocytes Treatments

Clinical cure

MSW MSM BSM Single Multiple UOIS UVS UAIS Positive Negative Not available Alcohol Tobacco Other drugs Discharge Dysuria Testicular pain Meatitis Haematospermia Screening < 1 week > 1 week Not available Ceftriaxone (Ceft.) Ceft. + doxycycline Ceft. + azithromycin Doxycycline Azithromycin, single 1 g oral dose Azithromycin 5-day course Moxifloxacin Other Yes Not known

Haemophilus spp 21 35.6 (20–52) 13 (62%) 7 (33%) 1 (5%) 5 (24%) 16 (76%) 3.5 (1–20) 21 (100%) 4 (19%) 1 (5%) 9 (43%) 2 (10%) 14 (66%) 5 (24%) 18 (86%) 14 (66%) 3 (14%) 7 (33%) 8 (38%) 4 (19%) 1 (5%) 1 (5%) – 8 (38%) 13 (62%) – 5 (24%) – 2 1 2 – 3 – 13 19 (90%) 2 (10%)

Neisseria gonorrhoeae 24 37.5 (21–74) 14 (58%) 10 (42%) – 8 (33%) 16 (67%) 2.5 (1–10) 24 (100%) 9 (38%) 4 (17%) 7 (29%) – 21 (87%) 3 (13%) 22 (92%) 11 (46%) 3 (13%) 23 (96%) 1 (4%) – – – – 22 (92%) 2 (8%) – 18 (75%) 4 16 4 – – – – – 23 (96%) 1 (4%)

Chlamydia trachomatis 19 29.8 (16–57) 16 (84%) 3 (16%) – 9 (47%) 10 (53%) 2.4 (1–10) 18 (95%) 14 (74%) – 8 (42%) 2 (11%) 16 (84%) 1 (5%) 18 (95%) 12 (63%) 3 (16%) 13 (68%) 4 (21%) 2 (11%) – – – 11 (58%) 8 (42%) – 8 (42%) – 8 2 4 5 – – – 17 (89%) 2 (11%)

Mycoplasma genitalium 8 32.6 (21–47) 7 (88%) – 1 (12%) 4 (50%) 4 (50%) 3.,6 (1–20) 8 (100%) 7 (88%) 1 (12%) 2 (22%) – 8 (100%) – 8 (100%) 5 (63%) – 4 (50%) 3 (38%) – – – 1 (12%) 6 (75%) 1 (12%) 1 (12%) – – – – – – 4 4 – 8 (100%) –

Ureaplasma urealyticum 4 24.5 (16–38) 4 (100%) – – – 4 (100%) 2.2 (1–4) 4 (100%) 3 (75%) – – – 3 (75%) 1 (25%) 4 (100%) 2 (50%) 1 (25%) 1 (25%) 2 (50%) – – – 1 (25%) 2 (50%) 1 (25%) 1 (25%) – – 2 – 2 – – – – 3 (75%) 1 (25%)

Multiple infection 10 30.1 (18–46) 7 (70%) 1 (10%) 2 (20%) 2 (20%) 8 (80%) 8.4 (1–20) 10 (100%) 7 (70%) 1 (10%) 5 (50%) 1 (10%) 9 (90%) – 8 (80%) 6 (60%) 4 (40%) 8 (80%) 1 (10%) – 1 (10%) – – 8 (80%) 2 (20%) – 4 (40%) – 4 1 4 – 1 – – 10 (100%) –

19 (90%) –

– 23 (96%)

– 18 (95%)

8 (100%) 8 (100%)

– 3 (75%)

10 (100%) 10 (100%)

Culture/PCR control Partner notification and treatment

UOIS: unprotected oral insertive sex; UVS: unprotected vaginal sex; UAIS: unprotected anal insertive sex. HIV STATUS: at the time of the consultation or during the 3 months preceding the consultation. Treatments: Ceftriaxone 500 mg single intramuscular dose. Ceftriaxone 500 mg single intramuscular dose + doxycycline 100 mg every 12 h, orally, for 7 days. Ceftriaxone 500 mg single intramuscular dose + azithromycin 1 g single dose, orally. Doxycycline 100 mg every 12 h, orally, for 7 days. Azithromycin 1 g orally, single dose. Azithromycin 5-day course: 500 mg–250 mg–250 mg–250 mg–250 mg orally. Moxifloxacin 400 mg oral single dose daily for 7 days. Other treatments: ciprofloxacin, levofloxacin, amoxicillin and clavulanic acid. * P: Comparison of the most important aspects between single infections by Haemophilus spp and the other single infections combined (excluding multiple infections). Fisher test for comparison of proportions.

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P* p = 0.315 p = 0.459 p = 0.616 p = 0.560 p = 0.381 p = 0.381 p = 0.336 p = 0.676 p = 0.004 p = 0.922 p = 0.477 p = 0.651 p = 0.081 p = 0.182 p = 0.398 p = 0.546 p = 0.794 p = 0.003 p = 0.132 p = 0.096

p = 0.006 p = 0.002 p = 0.124 p = 0.968 p = 0.968 -

Differences between male urethral infections

with women (MSW). Of the cases of Haemophilus spp. and N. gonorrhoeae, 33% and 42% respectively occurred in males having sex with males (MSM). No cases of infection by U. urealyticum or M. genitalium were found in MSM. Type of sexual partner: For most aetiological agents, the type of sexual partner was multiple; an exception was M. genitalium infection, for which 50% of patients reported a single partner and 50% multiple partners. Number of sexual partners: The highest mean number of sexual partners in the last 90 days was observed in the multiple infection group (8.4), followed by M. genitalium (3.6) and Haemophilus spp. (3.5), with a range from 1 to 20. Type of unprotected sex: between 95 and 100% of all patients had unprotected oral insertive sex, being the most frequent risk sexual practice, without differences between the different germs. On the other hand, only 19% of the Haemophilus spp reported unprotected vaginal sex, which is statistically significant in relation to the other germs (p = 0.004) (Table 3). History of STIs: Between 22% and 50% of the patients had a history of STIs, without significant differences according to the microorganism, with the exception of patients with U. urealyticum infection, who had no history of STIs. HIV status: In 76 of the 86 cases (88%) the HIV status was known; only 5 patients were HIV+, and all of them were under treatment with negative viral load. Recreational drugs: Between 80% and 100% of the patients consumed alcohol on a regular basis and between 46% and 66% used tobacco, without significant differences between the various groups. Use of other drugs ranged between 13% and 40%, being higher in patients with multiple infections. Clinical differences Main reason for consultation: Of the 158 cases analysed, all were symptomatic except for 5 who consulted for screening. Among patients with single infections other than Haemophilus spp., urethral discharge was the main reason for consultation with a statistically significant difference observed in relation to the Haemophilus spp. group (p = 0.003); dysuria was the main reason for consultation in 38%, urethral discharge in 33%, testicular pain in 19%, Table 4. Antibiotic resistance in patients with H. parainfluenzae and H. influenzae infections. Antibiotic Ampicillin Amoxicillin + clavulanic ac Cefuroxime Cefotaxime Meropenem Cipro/Levoflox Cotrimoxazole Azithromycin Tetracyclines Rifampicin

H. parainfluenzae * Cases Sensitive Resistant 20 13 (65%) 7 (35%) 20 18 (90%) 2 (10%) 20 16 (80%) 4 (20%) 20 20 (100%) – 20 20 (100%) – 20 16 (80%) 4 (20%) 20 6 (30%) 14 (70%) 20 12 (60%) 8 (40%) 20 8 (40%) 12 (60%) 20 17 (85%) 3 (15%)

* H. parainfluenzae: 16 cases of single and 4 of multiple infections. ** H. influenzae: 5 cases of single and 2 of multiple infections.

H. influenzae ** Cases Sensitive Resistant 7 7 (100%) – 7 7 (100%) – 7 7 (100%) – 7 7 (100%) – 7 7 (100%) – 7 7 (100%) – 7 4 (57%) 3 (43%) 7 6 (86%) 1 (14%) 7 5 (71%) 2 (29%) 7 5 (71%) 2 (29%)

meatitis and haematospermia in 5%. The Haemophilus spp. group showed greater variability in the reasons for consultation. Of the 5 asymptomatic patients who consulted for screening, in one case we found M. genitalium and in another, U. urealyticum. Duration of symptoms: The duration of the symptoms was less than 1 week for the majority of infections (N. gonorrhoeae, M. genitalium, U. urealyticum and multiple infections). For C. trachomatis, the distribution was more homogeneous. In case of Haemophilus spp. infection, the duration was more than 1 week in the majority of cases, with statistically significant differences compared with the other infections (p = 0.002). Type of treatment: The type of treatment was empirical, before cultures or PCR results (46 of 86 cases, 53%), or based on the antibiogram for the isolated microorganism which usually became available after 4 days (40 of 86 cases, 47%). Clinical cure: Globally we achieved a high percentage of clinical cures, without significant differences between the microorganisms. In 6 cases (2 Haemophilus spp., 2 C. trachomatis, 1 N. gonorrhoeae and 1 U. urealyticum) patients went lost at follow up. Test of cure: PCR was done in all M. genitalium infections, as stated in the guidelines (7), and in all the results were negative. Bacteriological study (Gram stain and culture) was done in 90% of the cases of Haemophilus spp. infection cases, and in all the results were negative. We also performed a PCR test in all cases of multiple infections, and they were also all negative. Partner notification and treatment: We carried out the notification and treatment of sexual partners between 75 and 100% of the cases (7). Laboratory differences Presence of leukocytes: We observed the presence of leukocytes in 75% of N. gonorrhoeae infections, in 42% of C. trachomatis infections and in 40% of multiple infections, but in only 24% of Haemophilus spp. infections; the differences were not statistically significant. We did not observe leukocytes in any M. genitalium or U. urealyticum infections. Antibiotic resistance Antibiotic resistance was analysed only in cases in which the cultures were positive for N. gonorrhoeae or Haemophilus spp. Of the 26 cases positive for N. gonorrhoeae (24 single infections plus 2 multiple infections), we did not observe any case of resistance to ceftriaxone. Of the 27 cases positive for Haemophilus spp. (including those with multiple infections), 20 were positive for H. parainfluenzae, of which 70% were resistant to cotrimoxazole, 60% resistant to tetracyclines and 40% resistant to azithromycin. By comparison, among the 7 cases positive for Haemophilus influenzae we found 43% resistance to cotrimoxazole, 29% to tetracyclines and rifampicin and 14% to azithromycin. We observed a 20% resistance to quinolones in cases of Haemophilus parainfluenzae, without such resistance in Haemophilus influenzae (Table 4). Multivariate analysis Multivariate logistic regression was used to build a predictive model of assignment to the Haemophilus group, Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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using a combination of clinical variables. A backward stepwise (conditional) method was used to drop insignificant terms. The final model included as significant predictors the type of unprotected sex being exclusively oral, the main reasons for consultation (testicular pain, no urethral discharge), the duration of symptoms more than one week, and the lack of leukocytes in the urethral sample. The accuracy of the logistic function, measured as the calculated AUC on a ROC curve was 0.834 (0.7170.951), and OR of 8.076 (3.391-19.234), showing a sensitivity of 76% and a specificity of 90%.

DISCUSSION

To our knowledge this is the first study to compare the characteristics of Haemophilus infections with those of the other sexually transmitted urethral infections. Limitations of this study can be the small sample size and the lack of a representative control group. Over the past 2 years we have observed an increase in urethral infections due to Haemophilus spp. in our STI department for men, in keeping with other published reviews (8). Motivated by this, we decided to perform a retrospective study to identify the epidemiological, clinical and laboratory characteristics of these infections and to compare them with urethral infections by N. gonorrhoeae, C. trachomatis, M. genitalium and U. urealyticum. All male patients who underwent conventional bacteriological and multiplex PCR studies in the urethra at the same time between January 2018 and February 2019 were selected for inclusion in the study, yielding a total of 158 cases. Of these, 86 tested positive for one or more of these microorganisms, including 76 (88%) with infections by a single microorganism and 10 (12%) with multiple infections. This is consistent with the literature, where dual infections have been identified in up to 10% of men in some studies, expecially among C. trachomatis and M. genitalium (9, 10). Taking into account that (a) all 27 Haemophilus infections were symptomatic; (b) in 21 of the 27 cases a single microorganism was identified and; (c) all of these patients (except for 2 lost at follow up) had remission of symptoms and negative cultures at control, our first conclusion is that Haemophilus spp. are a sexually transmitted source of symptomatic urethral infection in men. Supporting this, we did not find any cases of Haemophilus infection in the 5 asymptomatic patients who attended for screening. Füzi was the first to report, in 1980, that Haemophilus could be a cause of sexually transmitted urethritis (11). The 2016 European Guideline on the management of NGU also refers to the fact that Haemophilus spp. are responsible for a small proportion of cases of NGU (7). In our study, Haemophilus spp. were responsible for at least 24.4% (21/86) of the cases and were the second most frequent microorganism to be isolated alone, behind N. gonorrhoeae but ahead of C. trachomatis and M. genitalium. This result does not match previous reports, where C. trachomatis was the most frequent microorganism, followed by N. gonorrhoeae and, thirdly, by M. genitalium (1, 12). In a cross-sectional study conducted by Orellana et al. (13), in which they analyzed 1248 male urethral samples over 3 years, H. parainfluenzae was isolated in 1.76% and

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H. influenzae in 1.12% of the samples. Probably the frequency of infection by Haemophilus spp. must be related to the sexual habits of the population, and the increasing practice of unprotected oral sex potentially explains these differences in incidence. In our series, H. parainfluenzae was more frequent than H. influenzae (74% vs 26%), which is in concordance with the literature review (4, 8, 14). Another discrepant finding in comparison to previously published studies, such as Rane’s review in 2014, which showed a higher prevalence of Haemophilus urethritis in MSM, is that in our series most infections were in MSW (62%), with only 33% in MSM (15). This may be because in our city MSM have access to regular screening and treatment in specific community settings. In our series, C. trachomatis, M. genitalium and U. urealyticum were less common in MSM than MSW with NGU, which is consistent with the literature (15). All of the Haemophilus group reported unprotected oral insertive sex and 81% of them denied having had another kind of unprotected sex, which was statistically significantly different compared with the other causes of urethritis. These results were similar to the findings of Deza et al. (2015), who reported that all cases in their series had practiced unprotected insertive oral sex (4). Therefore, it seems clear that the main route of transmission of Haemophilus is via this route (16). These data support the contribution of oropharyngeal exposure to this syndrome. Colonization of the oral cavity by H. parainfluenzae and H. influenzae in different amounts in healthy individuals is very frequent (17). One aspect that we did not evaluate in men with recurrences, was the need to study partner’s oral flora in order to establish a direct relation with oral sex and, also, to determine whether it is necessary to treat sexual partners. In cases of Haemophilus infection the main reason for consultation varied being the most common dysuria; the difference was statistically significant compared with the other causes of urethritis, for which urethral discharge was the main reason for consultation. In comparison, in the study by Deza et al. the most common clinical presentation among cases of Haemophilus infection was mucopurulent urethral discharge, suggesting potential difficulty in distinguishing causes of urethritis based on symptomatology (4). We did not find any cases of Haemophilus infection in the 5 asymptomatic patients who consulted for screening. Regarding the duration of the symptoms, it was longer than one week in the Haemophilus group but usually less than one week in the other groups, the statistical difference being significant. Leukocytes were frequently present in infections due to N. gonorrhoeae and C. trachomatis as well as multiple infections, but less frequent in infections due to Haemophilus and absent in infections due to U. urealyticum and M. genitalium. In this regard it should be noted that there is significant inter- and intra-observer error in counting polymorphonuclear leukocytes, especially in samples with low-grade inflammation (18). An interesting finding was the multiple resistances to antibiotics in the Haemophilus group, which suggests a need to reconsider which is the best empirical treatment as adjuvant to intramuscular ceftriaxone in patients consulting for urethritis. The most striking finding was that

Differences between male urethral infections

60% of H. parainfluenzae and 29% of H. influenzae infections were resistant to doxycycline and 40% of H. parainfluenzae and 19% of H. influenzae infections were resistant to azithromycin, both of which are recommended firstline drugs for the treatment of NGU (19). These percentages are similar to those described in other areas of the world such as East Asia (20). Among the H. parainfluenzae cases there was also a 20% rate of resistance to quinolones, which exclude them as a therapeutic option. Another drug that may be of special interest in usual practice is amoxicillin in combination with clavulanic acid, since we observed resistance to this combination in only 10% of H. parainfluenzae and none of H. influenzae infections. In view of these findings and the high prevalence of resistance either present prior to treatment or developing during treatment, it is important to perform a test of cure to confirm microbiological healing, as recommended in all guidelines for M. genitalium (21). We performed a test of cure in 100% of cases of M. genitalium and multiple infection, with clinical and microbiological cure confirmed in all cases. We also performed a test of cure in 90% (19/21) of the cases of single Haemophilus infection and in all of them we were able to confirm clinical and microbiological cure. An explanation for this high percentage of clinical cures could be that not all the positive cases were treated empirically; in 40 of the 86 cases, we waited for the results, which normally took about 4 days, and then adjusted the antibiotic depending on the antibiogram of the microorganism isolated. There is good evidence that U. urealyticum causes urethritis in some but not all men, the problem being that even the PCR test cannot distinguish between asymptomatic carriers and possible causality (22-24). On the other hand, there are reports of patients with persistent or recurrent Ureaplasma-positive urethritis who have been cured only after their sexual partner received appropriate treatment (23). There is some controversy over the timing of treatment of U. urealyticum, especially in asymptomatic patients. In our series, of the 7 positive patients, 6 had symptoms; in addition, all were MSW, with the exception of a single patient with multiple infections who was BSM, and their mean age of 24.5 years was lower than for all other microorganisms. Taking all of this into account, as well as the fact that there is clear evidence that U. urealyticum can affect seminal parameters (25-27), we decided to treat all patients with U. urealyticum immediately. To break the chain of transmission, we undertook partner notification and treatment in a large majority of cases, including 75% of U. urealyticum, 100% of M. genitalium and multiple infection and 95% of N. gonorrhoeae and C. trachomatis. Multivariate logistic regression model confirmed that patients having mainly oral sex, showing testicular pain but not no urethral discharge neither leukocytes in the urethra, and displaying symptoms for more than one week, were up to eight times more likely to have an Haemophilus as the cause of their urethritis. Finally, in relation to patients with multiple infections, it is of note that they had the highest mean number of sexual partners, the highest rate of drug use other than alcohol and tobacco and the highest rate of a history of STI.

Main limitation of the study is represented by the retrospective nature of the paper and the absence of a control group; another is the number of patients of our study that, even if it is high for a single Centre in one year, could be implemented to increase statistical significance. Finally, our diagnostic work out was focused on the diagnosis of urethritis not including a screening for concomitant prostatic infections.

CONCLUSIONS

To our knowledge, this is the first study to compare the characteristics of Haemophilus infections with those of the other sexually transmitted urethral infections. Haemophilus seems to be an aetiological agent of nongonococcal urethritis whose incidence is clearly increasing. Oral insertive sex is the main route of acquisition of Haemophilus urethral infection. In the Haemophilus group the main reason for consultation varied; this could make diagnosis difficult and the duration of symptoms was clearly longer than for other microorganisms. It is necessary to confirm eradication of infection due to the high rate of antibiotic resistance, for this reason, in the future we should update the guidelines for empirical treatment of urethritis. Finally, it would be interesting, in cases of recurrence, to detect Haemophilus spp. in the couple’s oral cavity and to compare whether the strain coincides with that of the urethra, in order to ascertain whether it is necessary to treat sexual partners.

REFERENCES

1. Ito S, Hanaoka N, Shimuta K, et al. Male non-gonococcal urethritis: from microbiological etiologies to demographic and clinical features. Int J Urol. 2016; 23: 325-331. 2. Janier M, Lassau F, Casin I, et al. Male urethritis with and without discharge: a clinical and microbiological study. Sex Transm Dis. 1995; 22:244-52. 3. Bradshaw CS, Tabrizi SN, Read TRH, et al. Etiologies of nongonococcal urethritis: bacteria, viruses, and the association with orogenital exposure. J Infect Dis. 2006; 193: 336-345. 4. Deza G, Martin-Ezquerra G, Gómez J, et al. Isolation of Haemophilus influenzae and Haemophilus parainfluenzae in urethral exudates from men with acute urethritis: a descriptive study of 52 cases. Sex Transm Infect. 2015; 92: 29-31. 5. Hsu MS, Wu MY, Lin TH, et al. Haemophilus parainfluenzae urethritis among homosexual men. J Microbiol Immunol Infect. 2012; 48: 450-452. 6. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fifth Informational Supplement. CLSI document M100-S25 (ISBN 156238-990-4). Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087. USA, 2015. 7. Horner PJ, Blee K, Falk L, et al. European guideline on the management of non-gonococcal urethritis. Int J STD AIDS. 2016; 27:928-37. 8. Vázquez F, Andrés MT, Palacio V. Isolation of Haemophilus influenzae and Haemophilus parainfluenzae in genitourinary infections: a 4year review. Enferm Infec Microbiol Clin. 1996; 14:181-185. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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9. Wetmore CMP, Manhart LEP, Lowens MSP, et al. Demographic, behavioral, and clinical characteristics of men with nongonococcal urethritis differ by etiology: a case comparison study. Sex Transm Dis. 2011; 38:180-6. 10. Gaydos C, Maldeis NE, Hardick A, et al. Mycoplasma genitalium compared to chlamydia, gonorrhoea and trichomonas as an aetiological agent of urethritis in men attending STD clinics. Sex Transm Infect. 2009; 85:438-40. 11. Füzi M. Haemophili in sexually transmitted diseases. Lancet. 1980; 2:476. 12. Manhart LE, Holmes KK, Hughes JP, et al. Mycoplasma genitalium among young adults in the United States: an emerging sexually transmitted infection. Am J Public Health. 2007; 97:1118-25. 13. Orellana MA, Gómez ML, Teresa Sánchez M, FernándezChacón T. Microbiological diagnosis of urethritis in men. 3 years Review. Rev Esp Quimioter. 2009; 22:83. 14. Sturm AW. Haemophilus influenzae and Haemophilus parainfluenzae in nongonococcal urethritis. J Infect Dis. 1986; 153:165-7. 15. Rane VS, Fairley CK, Weerakoon A, et al. Characteristics of acute nongonococcal urethritis in men differ by sexual preference. J Clin Microbiol. 2014; 52:2971-2976. 16. Bradshaw CS, Tabrizi SN, Read TRH, et al. Etiologies of nongonococcal urethritis: bacteria, viruses, and the association with orogenital exposure. J Infect Dis. 2006; 193:336-45. 17. Gonzalez MD, Ledeboer NA Haemophilus. Chapter 38. Manual of Clinical Microbiology, 12th Edition. 18. Smith R, Copas AJ, Prince M, et al. Poor sensitivity and consistency of microscopy in the diagnosis of low grade non-gonococcal urethritis. Sex Transm Infect. 2003; 79:487-90.

Correspondence Alvaro Vives, MD avives@fundacio-puigvert.es Marco Cosentino, MD (Corresponding Author) doccosentino@gmail.com Lluis Bassas, MD lbassas@fundacio-puigvert.es Carles Alonso, MD calonso@fundacio-puigvert.es Felix Millan fmillan@fundacio-puigvert.es Fundacio Puigvert, Barcelona, Spain

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19. CDC Sexually Transmitted Diseases Treatment Guidelines. 2021. 20. Deguchi T, Ito S, Hatazaki K, et al. Antimicrobial susceptibility of Haemophilus influenza strains isolated from the urthra of men with acute urethritis and/or epididymitis. J Infect Chemother. 2017; 23:804-7. 21. Horner P, Blee K, O'Mahony C, et al. Clinical Effectiveness Group of the British Association for Sexual Health and HIV. 2015 UK National Guideline on the management of non-gonococcal urethritis. Int J STD AIDS. 2016; 27:85-96. 22. Zhang N, Wang R, Li X, Liu X, Tang Z, Liu Y. Are Ureaplasma spp. a cause of nongonococcal urethritis? A systematic review and meta-analysis. PLoS One. 2014; 9: e113771. 23. Magri V, Boltri M, Cai T, et al. Multidisciplinary approach to prostatitis. Arch Ital Urol Androl. 2019; 90:227-248. 24. 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. 25. Ford DK,Henderson E. Non-gonococcal urethritis due to Tmycoplasma (Ureaplasma urealyticum) serotype 2 in a conjugal sexual partnership. Br J Venereal Dis. 1976; 52:341-342. 26. Lee JS, Kim KT, Lee HS, et al. Concordance of Ureaplasma urealyticum and Mycoplasma hominis in infertile couples: impact on semen parameters. Urology. 2013; 81:1219-24. 27. Ma XP, Gao XQ. The effect of Ureaplasma urealyticum on the level of P34H expression, the activity of hyaluronidase, and DNA fragmentation in human spermatozoa. Am J Reprod Immunol. 2017; 77. doi: 10.1111/aji.12600.

DOI: 10.4081/aiua.2021.4.475

ORIGINAL PAPER

Serenoa repens and its effects on male sexual function. A systematic review and meta-analysis of clinical trials Gianni Paulis 1, Andrea Paulis 2, Gianpaolo Perletti 3, 4 1 Department

of Uro-Andrology, Castelfidardo Medical Team, Rome, Italy; Center for applied Psychology and Neuroscience, Janet Clinical Centre, Rome, Italy; 3 Department of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, University of Insubria, Varese, Italy; 4 Faculty of Medicine and Medical Sciences, Ghent University, Belgium. 2 Neurosystem

Summary

Background: Serenoa repens (SR) is a plant used to treat benign prostatic hyperplasia and prostatitis. We know that SR act as a 5α-reductase inhibitor, moreover, several studies have proved that SR has anti-inflammatory and antioxidant properties. There is some belief among patients that SR may negatively impact male sexual function. Such belief is circulating in non-medical social networks and is perhaps maintained by patients as a result of incorrect web surfing. However, it is also possible that SR may exert a “nocebo” effect thus negatively impacting on the general well-being of patients. Objective: The aim of this study is to investigate whether SR is causing negative effects on male sexual function. Methods: To ascertain the effect of SR on male sexual function, we conducted a systematic review and meta-analysis, by performing an electronic database search in accordance with the PRISMA guidelines. Results: Out of 20 included papers, 8 papers reported comparisons of SR with placebo, and 7 studies reported comparisons of SR with tamsulosin. The standardized mean difference of changes from baseline scores of sexual function was not significantly different between SR and placebo (SMD: 0.43, 95% CI: 0.18 to 1.05; I^2 = 95%). Similarly, no significant mean differences in the Male Sexual Function-4 (MSF-4) test scores were found between SR and tamsulosin (SMD: -0.31, 95% CI: -0.82 to 0.19; I^2 = 90%). Conclusions: We found no statistically significant differences between negative effects on sexual function in patients treated with SR compared to patients who received placebo. The results of our meta-analysis are similar to those of other systematic reviews. Studies are warranted to ascertain whether any such effects might occur as a result of a nocebo effect.

KEY WORDS: Serenoa repens; Adverse effects; Nocebo effect; Male sexual health. Submitted 30 November 2021; Accepted 3 December 2021

INTRODUCTION

Serenoa repens (SR), also known as Saw palmetto, Sabal serrulata, and American dwarf palm tree, is a plant originally used by Native Americans (Seminole and Miccosukee tribes) both as food and to cure urogenital ailments (1). The plant belongs to the Arecaceae family and mainly

grows in the southern United States, particularly in Florida and South Carolina (2). SR is commonly used throughout the world to treat benign prostatic hyperplasia (BPH) and prostatitis. Although its mechanism of action has not fully been demonstrated yet, it is mainly used on the assumption that SR is a 5a-reductase inhibitor, consequently blocking the conversion of testosterone to dihydrotestosterone (DHT) a biologically more active hormone (2, 3). In the literature, however, several studies have proved that SR, besides being very selective for the prostate gland, has, above all, pro-apoptotic, anti-inflammatory, and antioxidant properties (4-21). Normally used SR doses vary between 320 and 450 mg/day. The aim of this study is to clarify whether SR is able to cause negative effects on male sexual function. Such belief is circulating in non-medical social networks and is maintained by patients as a result of web surfing. Not infrequently, even in our clinics, we encounter patients suffering from BPH or prostatitis who underwent treatment of varying length with SR, who claim to have noticed a significant reduction in their erectile potency, and in some cases even in their libido. Many web forums in the world discuss the alleged negative effects of SR, equating them directly to the post-finasteride syndrome; unfortunately, once pseudo-confirmation is found by surfing the net, a belief quickly and easily goes viral. Is it possible that SR may have a nocebo effect and therefore negatively impact the health of patients, regardless of any real pharmacological adverse effect (22)? The aim of this work was to assess whether SR can cause negative effects on male sexual function. We therefore carried out an in-depth systematic review and metaanalysis in accordance with the PRISMA guidelines (23).

MATERIALS

AND METHODS

This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) guidelines (23). The review protocol was submitted for registration on the PROSPERO platform (ID 287140). Two electronic databases (PubMed and EMBASE) were searched for articles published up to 30 September 2021. The search was performed using the following terms: (Serenoa repens OR Saw palmetto OR Sabal

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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serrulata) AND (Orgasm OR Ejaculation OR Erectile dysfunction OR sexual dysfunction, physiological). Relevant data were also hand-searched through other sources. We considered randomized controlled trials (RCTs) with an open-label or single/double blinded design published in English without time constraints. We included studies involving male subjects taking Serenoa repens extracts to treat a prostatic condition, compared with placebo, or with various drugs prescribed for benign prostatic hyperplasia (BPH) (e.g., alpha adrenoceptor blockers, alpha-reductase inhibitors). The following outcomes were considered: (i) the rate of sexual dysfunction (erectile dysfunction, ejaculatory dysfunction, dysorgasmia, loss of libido), and/or the changes of scores of questionnaires measuring sexual function. The Brief Male Sexual Function Inventory (BMSFI) is a questionnaire to measure male sexual function covering sexual drive (two items), erection (three items), ejaculation (two items), perceptions of problems in each area (three items), and overall satisfaction (one item) (24). The International Index of Erectile Function (IIEF) is a 15item questionnaire addressing five relevant domains of male sexual function (erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction) (25). An abridged, five-item version of the IIEF-5 can also be administered for the evaluation of erectile dysfunction (26). Increasing severity of sexual function is associated with lower scores of BMSFI and IIEF. The Male Sexual Function-

4 item (MSF-4) questionnaire is a concise survey evaluating four items (interest in sex, quality of erection, achievement of ejaculation, and achievement of orgasm). Lower scores of this instrument are associated with better preserved sexual function (27). Two independent authors performed title and abstract screening of all retrieved records to delete duplicates and to exclude reports that did not meet the inclusion criteria. A second round of full-text screening to confirm/exclude the inclusion of retrieved studies and to extract relevant information was performed by 2 authors using a standardized form. The publication bias was assessed in the presence of at least 5 trials. It was analyzed by visually inspecting funnel plots and by performing the Egger’s and Begg’s tests using the MetaEssentials 1 software (Rotterdam School of Management, Erasmus University, The Netherlands). Statistical analysis was performed using the RevMan5 software. Meta-analysis was performed using a random effects model. Dichotomous data (presence/absence of sexual dysfunction) or continuous data reporting changes of mean values of sexual function scores and number of per-protocol or intent-to-treat patients were extracted. For dichotomous data we calculated odds ratios (OR), for continuous data presented as pre-vs. post-therapy mean differences, we calculated inverse variance weighted standardized mean differences. For all analyses we calculated 95% confidence intervals (CI). Heterogeneity was assessed by calculating the I^2 value with 95% CIs, and interpreted as follows: 0% to 40%: might not be important; 30% to 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; 75% to 100%: considerable heterogeneity. A summary of findings table was generated, and the quality of the evidence emerging from meta-analyses including at least 3 studies was rated according to GRADE criteria.

RESULTS

A PRISMA flow diagram illustrates the results of the study selection process (see Figure 1). We retrieved 29 papers: 7 papers from PubMed, 17 papers from EMBASE and 5 from other sources (handsearching). Four duplicate papers were removed, and 5 papers were excluded as they were found to be not related to this review.

Figure 1. A PRISMA flow diagram.

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Serenoa repens and sexual function

Figure 2. Statistical analysis: differences in sexual dysfunction between treatment with Serenoa repens and placebo.

Figure 3. Statistical analysis: differences in the MSF-4 test scores between treatment with Serenoa repens and Tamsulosin.

Figure 4. Statistical analysis: ejaculatory disorders after treatment with Serenoa repens and Tamsulosin.

Out of the 20 remaining papers, we selected 8 papers reporting comparisons of SR with placebo. Three records were discarded after full-text reading (two were lacking information on sexual outcomes and one reported only information on sexual hormones). Other 7 studies reported comparisons of SR with tamsulosin. Two studies were excluded because Serenoa repens was administered in association with other herbal products and one because SR was administered in combination with tamsulosin versus tamsulosin alone. Two studies compared SR with finasteride; one was excluded because SR was administered in combination with other herbal products. Three studies compared a SR extract with other herbal products. Two were discarded because of lack of information on sexual function and one because SR was administered in a formulation containing other herbal products. The characteristics of the 10 studies finally included in this systematic review, and the evaluation of risk of bias are presented in the “Supplementary Materials”. Quantitative analysis was limited to five studies comparing therapy with a SR extract with placebo, and to four studies comparing a SR extract with tamsulosin (28-36). A study comparing a SR extract with finasteride was only qualitatively evaluated (37). To evaluate differences in sexual dysfunction between treatment arms we calculated standardized mean differ-

ences, as included trials used different sexual function scales. The standardized mean difference of changes from baseline scores was not significantly different between SR and placebo (SMD: 0.43, 95% CI: -0.18 to 1.05; 5 trials, 922 patients; Z = 1.37, P = 0.17; Egger’s P = 0.16; Begg’s P = 0.32). This analysis was characterized by considerable heterogeneity (I^2 = 95%) (Figure 2). No significant mean differences in the MSF-4 test scores were found between SR and tamsulosin (SMD: -0.31, 95% CI: -0.82 to 0.19; 3 trials, 826 patients; Z = 1.21, P = 0.22; I^2 = 90%) (Figure 3). However, random-effects meta-analysis revealed that treatment with SR is associated with significantly lower odds of ejaculatory disorders compared to tamsulosin (odds ratio = 0.10, 95% CI: 0.01 to 0.92; 2 trials, 164 participants, Z = 2.03, P = 0.04, I^2 = 0%), compared to placebo (see Figure 4) (34,35). Final results are reported in Table 1.

DISCUSSION

Although the quality of evidence grade of our meta-analysis is low (see Table 1), we found no statistically significant differences between negative effects on sexual function in patients treated with SR compared to patients who received placebo or tamsulosin. This suggests that SR does not appear produce negative Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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Table 1. Summary of findings. Serenoa repens compared with placebo or active drug (Tamsulosin) Patient or population: Patients with Benign Prostatic Hyperplasia Settings: Outpatient Intervention: Serenoa repens extract Comparators: Placebo or active comparator (alpha adrenoceptor blocker) Outcomes Intervention vs. comparator results Sexual (dys)function, SD units The sexual function score in the Serenoa repens [assessed using different sexual function scales] groups was on average 0.43 SDs (95% CI: -0.18 to 1.05) higher than in the placebo groups.

Sexual (dys)function, SD units [assessed using the Male Sexual Function 4-items test]

Number of participants (studies) 922 (5)

The score of the MSF-4 test in the tamsulosin groups was on average 0.31 SDs (95% CI: -0.82 to 0.19) lower than in the Serenoa repens groups.

826 (3)

Quality of the evidence (grade) ⊕⊕⊝⊝ low Reasons for downgrading: – Inconsistency (considerable heterogeneity) – Indirectness (subjectiveness) of evidences ⊕⊕⊝⊝ low Reasons for downgrading: – Inconsistency (considerable heterogeneity) – Indirectness (subjectiveness) of evidence

SD: Standard deviation; CI: Confidence interval; MSF-4: Male Sexual Function 4-items test. GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

effects on male sexual function. Such view is supported by two studies (Marks et al., 2000; Pytel et al., 2002) which did not detect a reduction in the serum levels of male sex hormones (testosterone, dihydrotestosterone) after treatment with SR (38, 39). The results of our meta-analysis are similar to those of other authoritative systematic reviews, where SR was proved to have no negative impact on male sexual function (40-42). It should furthermore be evaluated whether the negative effect of SR on male sexuality reported by a number of patients both in our clinics and on Internet forums may be generated by neuropsychological mechanisms. This is where the concept of nocebo comes in. A nocebo effect is generated when a patient’s beliefs and negative expectations cause a worsening of the individual’s health status (22). The psychological mechanisms underlying this pesky effect seem to include negative expectations concerning treatment, high levels of anxiety, and classic conditioning (43). A study by Mondaini et al. (2007) provides a very interesting analysis of the causal role of “negative expectations” on the nocebo effect, after patient have been informed of the possible side effects of a therapeutic substance (44). In this study, which included 107 patients suffering from BPH, two treatment groups were created, with finasteride 5 mg/day and a treatment length of 12 months. Patients of Group 1 (52 patients) were also not informed of the risk of side effects on their sexuality; patients of Group 2, instead, were told of the possible – albeit rare – onset of sexual problems such as erectile dysfunction (ED), decreased libido, and ejaculation disorders. The results, after treatment with finasteride 5 mg/day for 12 months, were the following: Group 1, adverse sexual side effects 15.3 % (ED 9.6%, decreased libido 7.7%, ejaculation disorders 5.7%); Group 2, adverse sexual side effects 43.6% (ED 30.9%, decreased libido 23.6%, ejaculation disorders 16.3%). The signifi-

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cantly higher rate of sexual dysfunctions in Group 2 compared to Group 1 clearly proves that the nocebo effect had a significant impact on the greater number of occurrences of sexual problems in the patients of Group 2 (44). It is possible that SR may also have a "nocebo" effect and therefore negatively impact the health of patients.

CONCLUSIONS

Based on the results of our review, SR does not appear to cause negative effects on male sexuality; should any such effects occur, they may be ascribed to a nocebo effect. Adequately powered studies are needed to confirm this hypothesis. In such a case to reduce the likelihood of a nocebo effect, when mentioning possible side effects during the informed consent process prior to treatment, it may be necessary to structure the information to patients by avoiding the classic “negative” narrative frame (percentage of possibility of having a specific side effect), employing instead a “positive” approach, providing information about the percentage of patients who are likely not to experience any side effects. A more in-depth knowledge of the mechanisms that cause the nocebo effect, will help to minimize its impact in the clinical activity of general practitioners and specialists alike.

ACKNOWLEDGMENTS

We thank dr. Pasquale Del Vecchio for bibliometric and data management analysis.

REFERENCES

1. Bennet BC, Hicklin JR. Uses of saw palmetto (Serenoa repens, Arecaceae) in Florida. Economic Botany. 1998; 52:381-393. 2. Duborija-Kovacevic N, Jakovljevic V, Sabo A, et al. Tolerability

Serenoa repens and sexual function

and toxicity of lipidosterolic extract of American dwarf palm Serenoa repens in Wistar rats: well-known extract, new insight. Eur Rev Med Pharmacol Sci. 2011; 15:1311-1317. 3. Bayne CW, Donnelly F, Ross M, et al. Serenoa repens (Permixon®): A 5areductase types I and II inhibitor—new evidence in a coculture model of BPH. Prostate. 1999; 40:232-241. 4. Habib FK. Serenoa repens: the scientific basis for the treatment of benign prostatic hyperplasia. Eur Urol Suppl. 2009; 8:887-893. 5. McNicholas TA, Kirby RS, Lepor H. Evaluation and nonsurgical management of benign prostatic hyperplasia. In: Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA, editors. Campbell-Walsh Urology.

18. Ren J, Chung SH. Anti-inflammatory effect of a-linolenic acid and its mode of action through the inhibition of nitric oxide production and inducible nitric oxide synthase gene expression via NF-kB and mitogen-activated protein kinase pathways. J Agric Food Chem. 2007; 55:5073-5080. 19. Olennikov DN, Zilfikarov IN, Khodakova SE. Phenolic compounds from Serenoa repens fruit. Chem Nat Compd. 2013; 49:526529. 20. Cristoni A, Di Pierro F, Bombardelli E. Botanical derivatives for the prostate. Fitoterapia. 2000; 71:S21-S28. 21. Nickel JC. Shoskes D, Roehrborn CG, et al. Nutraceuticals in prostate disease: the urologist’s role. Rev Urol. 2008; 10:192-206.

6. Paubert-Braquet M, Mencia Huerta JMM, Cousse H, et al. Effect of the lipidic lipidosterolic extract of Serenoa repens (Permixon®) on the ionophore A23187-stimulated production of leukotriene B4 (LTB4) from human polymorphonuclear neutrophils. Prostaglandins Leukot Essent Fatty Acids. 1997; 57:299-304.

22. Požgain I, Požgain Z, Degmecic D. Placebo and nocebo effect: a mini-review. Psychiatr Danub. 2014; 26:0-107.

7. Colado-Velázquez J, Mailloux-Salinas P, Medina-Contreras JML, et al. Effect of Serenoa repens on oxidative stress, inflammatory and growth factors in obese wistar rats with benign prostatic hyperplasia. Phytother Res. 2015;29:1525-1531.

24. O'Leary MP, Fowler FJ, Lenderking WR, et al. A brief male sexual function inventory for urology. Urology. 1995; 46:697-706.

8. Latil A, Pétrissans MT, Rouquet J, et al. Effects of hexanic extract of Serenoa repens (Permixon® 160 mg) on inflammation biomarkers in the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia. Prostate. 2015; 75:1857-1867. 9. Vela Navarrete R, Garcia Cardoso JG, Barat A, et al. BPH and inflammation: pharmacological effects of permixon on histological and molecular inflammatory markers. Results of a double blind pilot clinical assay. Eur Urol. 2003; 44:549-555. 10. Morgia G, Cimino S, Favilla V, et al. Effects of Serenoa repens, selenium and lycopene (Profluss®) on chronic inflammation associated with benign prostatic hyperplasia: results of FLOG (Flogosis and Profluss in Prostatic and Genital Disease), a Multicentre Italian Study. Int Braz J Urol. 2013; 39:214-221. 11. Park EJ, Kim SA, Choi YM, et al. Capric acid inhibits NO production and STAT3 activation during LPS-induced osteoclastogenesis. PLoS One. 2011; 6:e27739. 12. Kim HJ, Yoon HJ, Kim SY, et al. A medium-chain fatty acid, capric acid, inhibits RANKL-induced osteoclast differentiation via the suppression of NF-kB signaling and blocks cytoskeletal organization and survival in mature osteoclasts. Mol Cells. 2014; 37:598-604. 13. Henry GE, Momin RA, Nair MG, et al. Antioxidant and cyclooxygenase activities of fatty acids found in food. J Agric Food Chem. 2002; 50:2231-2234. 14. Hoshimoto A, Suzuki Y, Katsuno T, et al. Caprylic acid and medium-chain triglycerides inhibit IL-8 gene transcription in Caco-2 cells: comparison with the potent histone deacetylase inhibitor trichostatin A. Br J Pharmacol. 2002; 136:280-286.

23. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred Reporting Items for Systematic Reviews and MetaAnalyses: The PRISMA Statement. PLoS Med. 2009: 6:e1000097.

25. 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; 49:822-830. 26. Rosen RC, Cappelleri JC, Smith MD, et al. Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res. 1999; 11:319-326. 27. Marquis P, Marrel, A. Reproducibility and clinical and concurrent validity of the MSF-4: a four-item male sexual function questionnaire for patients with benign prostatic hyperplasia. Value Health. 2001; 4:335-343. 28. Avins AL, Bent S, Staccone S, et al. A detailed safety assessment of a saw palmetto extract. Complement Ther Med. 2008; 16:147154. 29. Gerber GS, Kuznetsov D, Johnson BC, et al. Randomized, double-blind, placebo-controlled trial of saw palmetto in men with lower urinary tract symptoms. Urology. 2001; 58:960-963. 30. Willetts KE, Clements MS, Champion S, et al. Serenoa repens extract for benign prostate hyperplasia: a randomized controlled trial. BJU Int. 2003; 92:267-70. 31. Ye Z, Huang J, Zhou L, et al. Efficacy and safety of Serenoa repens extract among patients with benign prostatic hyperplasia in China: a multicenter, randomized, double-blind, placebo-controlled trial. Urology. 2019; 129:172-179. 32. Zhang K, Guo RQ, Chen SW, et al. The efficacy and safety of Serenoa repens extract for the treatment of patients with chronic prostatitis/chronic pelvic pain syndrome: a multicenter, randomized, double-blind, placebo-controlled trial. World J Urol. 2021; 1-7.

15. Srivastava A, Rao LJM, Shivanandappa T. 14-Aminotetradecanoic acid exhibits antioxidant activity and ameliorates xenobiotics-induced cytotoxicity. Mol Cell Biochem. 2012; 364:1-9.

33. Debruyne F, Koch G, Boyle P, et al. Comparison of a phytotherapeutic agent (Permixon) with an a-blocker (tamsulosin) in the treatment of benign prostatic hyperplasia: a 1-year randomized international study. Eur Urol. 2002; 41:497-506.

16. Oh YT, Lee JY, Lee J, et al. Oleic acid reduces lipopolysaccharideinduced expression of iNOS and COX-2 in BV2 murine microglial cells: possible involvement of reactive oxygen species, p38 MAPK, and IKK/NF-kappaB signaling pathways. Neurosci Lett. 2009; 464:93-97.

34. Debruyne F, Boyle P, Calais Da Silva F, et al. Evaluation of the clinical benefit of permixon and tamsulosin in severe BPH patients PERMAL study subset analysis Eur Urol. 2004; 45:773-780.

17. Ambrozova G, Pekarova M, Lojek A. Effect of polyunsaturated fatty acids on the reactive oxygen and nitrogen species production by raw 264.7 macrophages. Eur J Nutr. 2010; 49:133-139.

35. Hizli F, Uygur MC. A prospective study of the efficacy of Serenoa repens, tamsulosin, and Serenoa repens plus tamsulosin treatment for patients with benign prostate hyperplasia. Int Urol Nephrol. 2007; 39:879-886. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

479

G. Paulis, A. Paulis, G. Perletti

36. Latil A, Pétrissans MT, Rouquet J, et al. Effects of hexanic extract of Serenoa repens (Permixon® 160 mg) on inflammation biomarkers in the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia. Prostate. 2015; 75:1857-1867. 37. Carraro JC, Raynaud JP, Koch G, et al. Comparison of phytotherapy (Permixon®) with finasteride in the treatment of benign prostate hyperplasia: a randomized international study of 1,098 patients. Prostate. 1996; 29:231-240. 38. Marks LS, Partin AW, Epstein JI, et al. Effects of a saw palmetto herbal blend in men with symptomatic benign prostatic hyperplasia. J Urol. 2000; 163:1451-1456.

41. Novara G, Giannarini G, Alcaraz A, et al. Efficacy and safety of hexanic lipidosterolic extract of Serenoa repens (Permixon) in the treatment of lower urinary tract symptoms due to benign prostatic hyperplasia: systematic review and meta-analysis of randomized controlled trials. Euro Urol Focus. 2016; 2:553-561. 42. Cai T, Cui Y, Yu S, et al. Comparison of Serenoa repens With Tamsulosin in the Treatment of Benign Prostatic Hyperplasia: A Systematic Review and Meta-Analysis. Am J Mens Health. 2020; 14: 1557988320905407.

39. Pytel YA, Vinarov A, Lopatkin N. et al. Long-term clinical and biologic effects of the lipidosterolic extract of Serenoa repens in patients with symptomatic benign prostatic hyperplasia. Adv Ther. 2002; 19:297-306.

43. Colloca L, Barsky AJ. Placebo and nocebo effects. N Engl J Med. 2020; 382:554-561.

40. Vela-Navarrete R, Alcaraz A, Rodríguez-Antolín A, et al. Efficacy and safety of a hexanic extract of Serenoa repens (Permixon®) for the treatment of lower urinary tract symptoms asso-

44. Mondaini N, Gontero P, Giubilei G, et al. Finasteride 5 mg and sexual side effects: how many of these are related to a nocebo phenomenon?. J Sex Med, 2007; 4:1708-1712.

Correspondence Gianni Paulis, MD (Corresponding Author) paulisg@libero.it Department of Uro-Andrology, Castelfidardo Medical Team, Rome (Italy) Andrea Paulis, Clinical Psychologist andrea.fx.94@gmail.com Neurosystem Center for applied Psychology and Neuroscience, Janet Clinical Centre, Rome (Italy) Gianpaolo Perletti, PhD gianpaolo.perletti@uninsubria.it Department of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, University of Insubria, Varese (Italy)

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ciated with benign prostatic hyperplasia (LUTS/BPH): systematic review and meta-analysis of randomised controlled trials and observational studies. BJU Int. 2018; 122:1049-1065.

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DOI: 10.4081/aiua.2021.4.481

ORIGINAL PAPER

Ectopic adrenal tissue in the kidney: A systematic review Davide De Marchi 1*, Alessandro Tafuri 2-4*, Guglielmo Mantica 5, Aliasger Shakir 6, Federico Scarfò 7, Giovanni Passaretti 1, Salvatore Smelzo 1, Silvia Proietti 1, Lorenzo Rigatti 1, Roberta Luciano 7, Alessandro Antonelli 3, Vincenzo Pagliarulo 2, Rosario Leonardi 1, Guido Giusti 1, Franco Gaboardi 1 1 Department

of Urology, San Raffaele Hospital, Milan, Italy; of Urology, “Vito Fazzi” Hospital, Lecce, Italy; 3 Department of Urology, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy; 4 Department of Neuroscience, Imaging and Clinical Sciences, University "G. d'Annunzio" of Chieti-Pescara, Chieti, Italy; 5 Department of Urology, University of Genova, Ospedale San Martino, Genova, Italy; 6 USC Institute of Urology, Catherine and Joseph Aresty Department of Urology, Keck School of Medicine, University of Southern California (USC), Los Angeles, CA, USA; 7 Department of Pathology, San Raffaele Hospital, Milan, Italy. * Equal contribution. 2 Department

Summary

Introduction: Ectopic adrenal tissue in the kidney, including “Ectopic adrenal tissue” and “Adrenal-renal fusion”, is a rare event with a specific behavior which may be difficult to distinguish clinically from renal neoplasms. We performed a systematic review on ectopic adrenal tissue variants reported in the literature underlining its clinical aspects. Methods: Manuscripts which presented a case report or case series of ectopic adrenal tissue in the kidney were included even if published in original articles, reviews, or letters to the editor. A specific search on SCOPUS®, PubMed®, and Web of Science® database was performed. Only English language papers published in a period ranging between August 1991 and April 2020 were considered. Additionally, a case we had at our institution is described, and its characteristics are included. Data on clinical presentation, type of adrenal anomaly, location, anatomopathological and immune-histotype characteristics were collected. Results: We identified 888 manuscripts. Among these 29 were included in this systematic review. Overall, 39 patients with renal adrenal fusion or adrenal ectopia were considered. In most cases, the diagnosis was made incidentally, or following investigation for flank pain, abdominal pain, or endocrinological disorders. CT scan frequently identified a solid vascularized lesion that was difficult to distinguish from renal neoplasm. Adrenal fusion was mostly located at the level of the upper pole. Adrenal rest was found in the renal parenchyma, renal hilum, or retroperitoneum in close proximity to the renal peduncle. Often these ectopic adrenal tissue lesions follow a benign behavior and can be classified as functioning or non-functioning adenomas. Rarely, they may experience neoplastic degeneration. The most frequently positive markers were inhibin, vimentin, melan-A, synaptophysin and anti-p450 scc. Conclusions: Ectopic adrenal tissue in the kidney is a rare event with specific clinical characteristics that need to be identified in order to arrive at a correct diagnosis and carry out appropriate treatment management.

KEY WORDS: Intrarenal adrenal tissue; Ectopic adrenal tissue; Renal-adrenal fusion; Adrenal rest; Incidental renal masses; Renal cancer; Small renal mass. Submitted 19 September 2021; Accepted 23 September 2021

INTRODUCTION

Renal cancer represents 3% of all neoplasms in western Countries. During the last few years, its incidence increased by 2% due to an increased amount of incidental radiological diagnosis, especially for small renal masses (< 4 cm of diameter) (1, 2), for which nephron sparing surgery is the treatment of choice (3). However, these small lesions can behave biologically different from other renal masses. It is estimated that 20-30% of small renal masses are benign and active surveillance is an acceptable tool that can be used to avoid the surgery and its related risks in this cohort of patients (2-4). The presence of ectopic adrenal tissue in the kidney, while benign, is a rare event that needs to be identified and distinguished from renal cancer. This condition can be divided into two entities based on the pathophysiological origin. First, “Ectopic adrenal tissue” or “adrenal rest”, initially described by Morgagni in 1740, is a congenital anomaly due to the migration, to other organs, of fragments of the primitive adrenal gland, and can be classified as “true” or “accessory” ectopy depending on the migration of the whole or part of the gland, respectively (5, 6). Second, “Adrenal-renal fusion”, first described by Rokitansky in 1855 (7), could be divided into a “congenital” form when it is caused by failure of the retroperitoneal mesenchymal cells to stimulate adrenal capsule formation, or “acquired” form when it is a consequence of inflammation of the perirenal fat. Consequently the adrenal gland becoming fused with the renal parenchyma, and become anatomically indivisible from the kidney (8). Most ectopic adrenal tissue is located along the migration path of the urogenital system but it could be present also at the level of celiac axis, broad ligament, spinal cord and other retroperitoneal parenchymatous organs (9). Ectopic adrenal tissue can be present in 50% of newborns, usually regressing and persisting in only 1% of the adult population (10). It is not a rare condition and can manifest clinically as endocrine abnormalities due to secretory activity, mass effect or neoplastic transformations. Additionally, due to the location where these lesions can arise, adrenal rest becomes part of the differential diagno-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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sis along with renal cell carcinoma and for this reason it must be correctly diagnosed (11). Here, we report a systematic review of the literature on ectopic adrenal tissue while underlining its main clinical aspects.

METHODS

We performed a systematic review limited to case reports, case series and all formats reporting a case description on

our specific topic. The purpose of this literature review is to describe the salient features of adrenal ectopia in order to assist the differential diagnosis process with renal neoplasms. For this reason, we considered only adrenal ectopias located at the renal level or in the retroperitoneum in close proximity to the renal pelvis in the study. A specific search on SCOPUS®, PubMed®, and WEB OF SCIENCE® database was performed including “[(intrarenal adrenal tissue) OR (ectopic adrenal tissue)] OR [(renal -

Figure 1. PRISMA flowchart. In November 2017, a 66 year-old man with a previous history of diabetes mellitus, hypertension, and benign prostatic hyperplasia came to our Institution. Due a single episode of hyperpyrexia associated with left flank pain, he performed an abdomen ultrasound with incidental finding of a left renal mass, and a following abdomen CT scan which confirmed the presence of an exophytic solid lesion of 10 x 14 mm, in the middle lateral margin of the left kidney (R.E.N.A.L. score 6A; P.A.D.U.A. 7 A), (Figure 2 A-B-C-D). Both adrenal glands had regular morphology, size and location. Complete blood count, creatinine, urine analysis values were all within normal limits. Given the small size of the neoformation, active surveillance of the neoformation was proposed to the patient but he preferred to remove the mass, and robot assisted left partial nephrectomy was performed in January 2018. A clampless enucleoresection was performed with a continuous suture on the resection bed by sliding suture technique with Hem-O-Lok. The post-operative period was regular and uncomplicated. The patient was discharged after three days. The definitive anatomopathological report reports “ectopic adrenal gland with renal tissue where occasional tubular thyroidization and minimal interstitial chromic nephritis” (Figure 3 A-B). The follow up was negative. Ultrasound of the abdomen and blood test with kidney function evaluation was negative.

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Box 1. Case report.

Ectopic adrenal tissue in the kidney

Table 1. Clinical and pathological characteristics of adrenal ectopias findings in the included studies. Author Goren et al. 1991 (14) Chin et al. 1994 (6) Colberg et al. 1998 (15) Ayala et al. 2000 (16) Souverijns et al. 2000 (17) Szumera et al. 2003 (11)

Type of article Case report Case report Case report Case report Case report Case report

N° of case 1 case 1 case 1 case 1 case 1 case 1 case

Clinical Presentations Left lumbar pain Incidental finding in patient with kidney neoplasia abdominal pain and weight loss Cushing’s syndrome Hypertension NS

Adrenal abnormalities Adrenal rest True heterotopia Adrenal renal fusion Adrenal rest Adrenal rest Adrenal rest

Fan et al. 2004 (18) Hsu et al. 2005 (19) Claahsen-van der Grinten et al. 2008 (20)

Case report Case report Case report

1 case 1 case 1 case

Incidental findings in patients with metabolic syndrome Incidental findings in Patient with kidney neoplasia Abdominal pain in patient with congenital adrenal hyperplasia

Adrenal renal fusion Adrenal rest Adrenal rest

Baydar et al. 2008 (32)

Case series

2 cases

Abdominal pain

Adrenal rest

LInder et al. 2009 (21)

Case report

1 case

Incidental finding

Renal adrenal fusion

Mahadevia et al. 2009 (22) Ye et al. 2009 (12)

1 case 9 cases

Abdominal pain -

Louiset et al. 2010 (23)

Case report Retrospective cases series Case report

1 case

ACTH-independent Cushing’s syndrome due to PPNAD

Brčić et al. 2011 (15)

Case report

1 case

Incidental finding

Cardinalli et al. 2012 (24) Wang et al. 2012 (9) Yokoyama et al. 2013 (25)

Case report Case report Case report

1 case 1 case 1 case

Incidental finding in Beckwith–Wiedemann syndrome Cushing’s syndrome Incidental finding

Adrenal rest Adrenal rest Adrenal rest

Tong et al. 2014 (26) Godin et al. 2014 (27) Griffin et al. 2015 (28) Clair et al. 2015 (29) Liu et al. 2016 (33)

Case report Case report Case report Case report Case report and review

1 case 1 case 1 case 1 case 1 case

Cushing’s syndrome Incidental finding Hypertension Abdominal pain Endocrinological Disorders: Amenorrhea and virilization and obstruction urinary output

Adrenal rest Adrenal rest Adrenal renal fusion Adrenal renal fusion Adrenal rest

Zhang et al. 2016 (10)

Case report and review

1 case

Hypertension and bilateral limb weakness

Adrenal rest

Sappal et al. 2016 (34) Zhao et al. 2018 (30)

Case report and review Case report

1 case 1 case

Incidental finding Cushing’s syndrome

Adrenal rest Adrenal rest

Case report

1 case

Back pain

Adrenal rest

Case report Case report and review

1 case 1 case

Incidental finding in patient with bladder neoplasia ACTH-independent Cushing’s syndrome

Adrenal renal fusion Adrenal rest

Incidental finding

Adrenal rest

Lee et al. 2018 (31) Bamford et al. 2018 (8) Lu et al. 2018 (35)

Current case

Case report and systematic review 1 case

adrenal fusion) OR (adrenal rest)] AND [(kidney cancer) OR (renal cancer) OR (renal cell carcinoma)]” MeSh terms. Only manuscripts in English language published in a period ranging between August 1991 and April 2020 were considered (Figure 1). All the manuscripts which presented a case report or case series were included even if published in original articles, reviews, or letters to the editor. Two authors (D.D.M.) and (G.M.) independently reviewed

AP report Ectopic adrenocortical adenoma ectopic adrenocortical adenoma Adrenocortical adenoma Ectopic adrenocortical adenoma Ectopic adrenocortical adenoma Ectopic adrenocortical adenoma

Markers NS Anti-P450 scc+ Pan cytokeratin - cytokeratin 7NS Vimentin + Vimentin + synaptophysin + cytokeratin- EMA Atrophic adrenal gland and renal cyst NS Ectopic adrenocortical adenoma NS Adrenal rest tumour cytokeratins 8/18 + inhibin + AE1/AE3 - epithelial membrane antigen - CD68 - CD10 - placental-like alkaline phosphatase Ectopic adrenocortical adenoma melan-A + inhibin + calretinin + EMA- pancytokeratin Eterotopic adrenal cortical tissue melan-A + synaptophysin + calretinin + EMA- CD68Adrenocortical adenoma MART-1 + MAK-6 + inhibin + CD10 - hmb-45 – AE1/3 - SMA Adrenocortical adenoma NS Ectopic adrenocortical adenoma NS

Adrenal renal fusion 7 adrenal rest 2 adrenal renal fusion Bilateral adrenocortical micronodular Bilateral adrenocortical hyperplasia and adrenal rest micronodular hyperplasia and ectopic adrenocortical adenoma Adrenal rest Ectopic adrenocortical adenoma

17-α hydroxylase+ 21-α hydroxylase+

HMB-45 + SMA + melan-A + inhibin + Calretinin+ AE1/3 - CD10 - EMA ectopic adrenocortical adenoma NS ectopic adrenocortical adenoma NS adrenocortical carcinoma P450c17 + SF-1 + DHEA-ST + 3β-HSD + Ectopic adrenocortical adenoma Melan-A+ HSD3B2+ CYP17A1+ Oncocytic adrenocortical adenoma NS Multinodular adrenal cortical hyperplasia NS Adrenocortical adenoma NS Ectopic adrenocortical adenoma Vimentin + Inhibin α+ Melan-A + Synaptophysin + NSE + CD56 + AE1/AE3 +/PAX 8 – S100 – Chromogranin A Ectopic adrenocortical adenoma Synaptophysin + CD56 + Vimentin + Ki-67 +(2%) Inhibin α+ Calretinin + chromogranin A - CD117CD10 - CK7 - EMA - CK-pan - melan-A Ectopic adrenocortical adenoma Melan-A + PAX 8 Adrenocortical adenoma with NS myelolipoma metaplasia Adrenocortical carcinoma Inhibin α+ Vimentin + Synaptophysin + Melan A focal + Ectopic adrenocortical adenoma Inhibition + Melan-A + Synaptophysin + Vimentin + AE1/AE3 + HMB45 +/- CD34 + Heterotopic adrenocortical adenoma NS

the literature using inclusion and exclusion criteria. All disagreements about eligibility were resolved by discussion with a third reviewer (A.T.) until consensus was reached. This study was performed using guidelines set out by Preferred Reporting Items for Systematic Reviews and metaanalysis (PRISMA) statement (12). Additionally, a case at our institution is described, and its characteristics are included in the following evidence synthesis (Box 1, Tables 1-2). Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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Table 2. CT characteristics characteristics of adrenal ectopias findings in the included studies. Author Goren et al. 1991 (14) Chin et al. 1994 (6) Colberg et al. 1998 (15) Ayala et al. 2000 (16) Souverijns et al. 2000 (17) Szumera et al. 2003 (11) Fan et al. 2004 (18) Hsu et al. 2005 (19) Claahsen-van der Grinten et al. 2008 (20) Baydar et al. 2008 (32) LInder et al. 2009 (21) Mahadevia et al. 2009 (22) Ye et al. 2009 (12) Louiset et al. 2010 (23) Brčić et al. 2011 (15) Cardinalli et al. 2012 (24) Wang et al. 2012 (9) Yokoyama et al. 2013 (25)

Location Left renal hilum Right upper pole Right upper pole Left renal hilum Retroperitoneal mass close to left renal vein Left upper pole Right upper pole Retroperitoneal paracaval mass Retroperitoneal mass beside Rx left kidney Right upper pole Left upper pole Right upper pole Left upper pole

CT-presentation 8 cm solid mass with contrast enhancement NS 2.9 cm solid mass 3.5 cm mass 5.5 cm mass with inhomogeneous peripheral contrast enhancement cystic lesion of 7 cm Cystic renal mass (Bosniak II) 5 cm contrast enhancing paracaval mass 5 cm retroperitoneal mass with multinodular aspect 1.5 cm solid mass 2 mm mass at upper pole 4.5 cm solid mass with minimal amount of fat 2 cm mass with low attenuation and heterogeneity 1 Mid pole left kidney, 6 superior pole NS 2 superior pole NS Right pararenal adrenal rest close 3.8 cm pararenal mass to the renal hilum Right upper pole 2 cm cystic and solid mass with contrast enhancement Left renal hilum NS Left upper pole NS

Tong et al. 2014 (26) Godin et al. 2014 (27)

Retroperitoneal mass between inferior vena cava and right kidney Left renal hilum Left upper pole

Griffin et al. 2015 (28) Clair et al. 2015 (29)

Right superior pole Left upper pole

Liu et al. 2016 (33)

Left renal hilum

Zhang et al. 2016 (10) Sappal et al. 2016 (34)

Right renal hilum Right upper pole

Zhao et al. 2018 (30)

Right renal hilum

Lee et al. 2018 (31) Bamford et al. 2018 (8)

Mid pole right kidney Bilateral superior pole

Lu et al. 2018 (35) Current case

Left renal hilum Mid pole of the left kidney

HU NS NS NS NS

MRI NS NS NS NS

Differential diagnosis Oncocytoma, RCC NS NS Ureteral tumor

NS NS WISP-like and thin NS

NS NS 9-10 NS

NS NS NS NS

Lymph node metastasis RCC Cystic RCC Lymph node metastasis

NS Normal NS NS Normal

NS NS NS NS Basal: -19A. Phase: +58V. Phase: +22 NS NS 28

NS NS NS NS

NS RCC RCC AML, RCC

NS NS NS NS

AML, RCC RCC RCC NS

NS NS 3 cm mass with fatty component and plentiful vascular supply NS

AML, RCC NS NS

NS NS Previous bilateral adrenalectomy

NS NS NS

6,5 cm retroperitoneal mass

NS NS Bilateral adrenal atrophy Normal

2.7 mass in the left renal hilum NS

Atrophic NS

NS NS

NS 2.5 cm heterogeneous mass with contrast enhancing 2.7 cm well-circumscribed soft-tissue mass with contrast enhancement with atrophic bilateral adrenals 3*3 cm mass with contrast enhancement 2.7 cm mass with contrast enhancement

NS NS

Atrophic

35 to 161

NS 4,8 cm heterogeneously enhancing mass NS Hypointense on T2 than renal cortex NS

Normal Lesions appeared inseparable from the right adrenal gland Normal

NS NS

NS RCC, pheocromocytoma Cystic RCC Papillary RCC, AML, RCC AML, oncocytoma, paraganglioma and RCC NS RCC

NS No demonstrable fat plan between renal lesions and adrenals Atrophic

NS 55

NS NS

RCC NS

Basal: - 5A. Phase: +90 V. Phase: +60

RCC, AML

3.6 cm solid mass with contrast enhancement. Adrenal gland were normal 13 cm heterogeneous mass Symmetrical well-defined low-attenuation subcapsular lesions each measuring 2.3 cm 3 cm well-circumscribed mass with athrophic bilateral adrenal glands 10 x 14 mm, in the middle lateral margin of the left kidney

RESULTS

Our online search identified 888 publications. Sixty-five had all the inclusion criteria, and 29 were included in this systematic review. Among these, 22 were single case reports (6, 8, 9, 13-31), 2 articles reported more than one case (11, 32), 4 were literature reviews with case report (10, 33-35), and 1 article was a letter to the publisher including a case reports (5). We therefore compared the cases present in the literature with one that happened in our center in January 2018 (Box 1), evaluating the main characteristics. Overall, 39 patients with renal adrenal fusion or adrenal ectopia were considered.

484

Native adrenals NS Normal NS Normal

Archivio Italiano di Urologia e Andrologia 2021; 93, 4

Normal

The main aspects examined in this review of the literature were the clinical presentation, the type of adrenal anomaly found, the location of this anomaly, the definitive anatomopathological report and the presence of immunehistotypic markers (Table 1). Type of adrenal anomalies “Adrenal rest” were present in 29 patients, “adrenal renal fusion” was present in 9 patients (Table 1). All cases had adrenal cortex tissue, in the absence of heterotopia with regard to the medullary portion. We found 1 case of “true heterotopia” as published by Chin

Ectopic adrenal tissue in the kidney

et al. in 1994 (6). In this case, the absence of an adrenal gland on the right side and the presence of normal left gland on the preoperative CT scan suggests a true heterotopia. From our review, it emerged, that the most frequent form of adrenal heterotopia is the adrenal rest, and in alignment with these findings, our clinical case also had this form of adrenal abnormality. Clinical presentation In 11 patients the diagnosis was incidental, in 8 patients the mass was found after clinical investigation was performed for flank or abdominal pain, in 7 patients presented with manifestations of endocrinological disorders, and in 3 patients, it was diagnosed during imaging evaluations which were performed for arterial hypertension refractory to therapy or metabolic syndrome. The onset of symptomatology was not reported in 9 patients derived from a retrospective case series (11). Most of the clinical cases in the literature have been accidentally diagnosed during clinical investigations for abdominal or lower back pain, high blood pressure, or during diagnostic routines for concomitant neoplasms. Seven cases showed endocrinological disorders such as Cushing syndrome, primary hyperaldosteronism or were present in the context of congenital anomalies such as BeckwithWiedemann syndrome (9, 16, 20, 23, 24, 26, 30, 33, 35). Abdominal pain may be due to an ureteropelvic obstruction due to the mass effect of the neoplasm, as in the case presented by Goren et al. (14) and Lee et al. (31). In another five cases the abdominal pain was not motivated by the size or the location of the adrenal abnormalities (15, 20, 22, 29, 32). Cushing syndrome was the most frequent clinical presentation when a secreting ectopic adrenal adenoma was reported (9, 16, 23, 26, 30, 35). The clinical presentation included moon facies, hirsutism, easy bruising and weakness, polydipsia and polyuria. Elevated blood pressure refractory to anti-hypertensive drugs was also present. In these patients, surgical removal of the adrenal adenoma led to a regression of symptoms except for the case published by Suverijns et al. in which the pressure remained high (10, 17, 28). In one case described by Cardinalli et al. in 2012 the adrenal rest was diagnosed during complementary radiological studies in a patient with Beckwith-Wiedemann Syndrome (BWS) (24). BWS is a growth disorder characterized by macrosomia, macroglossia, organomegaly, abnormalities of the ears, an increased risk for development of embryonal tumors and disorders of the adrenal gland. In this particular case the presence of ectopic adrenal tissue at the level of left renal hilum was associated with a myelolipoma but the authors concluded that a clear relationship between BWS, adrenal adenoma and myelolipoma is unclear (24). In our case, the diagnosis was incidental during routine investigation. In fact, the patient did not report abdominal pain, and did not manifest any endocrinological abnormalities or elevated blood pressure. Location and CT-presentation CT is considered the gold standard for the characterization of renal cancers. Multiphase CT has a sensitivity of

90% to 99% and a specificity of 99% to 100%. In our review, MRI was the method of choice for the study of renal mass only in two cases (9, 27). However, small kidney masses can exhibit similar behaviors making the differential diagnosis process difficult. Renal adrenal fusion as described by Rokitansky is due to the absence of adipose tissue that normally separates the adrenal gland and the upper pole of the kidney. In our review we identified 9 cases of renal adrenal fusion all located at the upper renal pole (Table 2). Among the 29 patients with adrenal rest, 17 had a localization at the kidney, 7 at the level of the renal hilum and 5 at the level of the retroperitoneum in close proximity to the renal peduncle (Table 2). In patients with localization at the kidney, the lesion most commonly occurred in the upper pole, while only 3 patients, including our case, had a lesion located in the middle third of the kidney (11, 31). In this subgroup of patients, the differential diagnosis included clear cell renal cell carcinoma (ccRCC), angiomyolipoma (AML), oncocytoma, papillary renal cell carcinoma (pRCC) and cystic RCC. In the remaining case reports with extra renal localization the differential diagnosis included lymph node metastases and ureteral tumors (Table. 2). Only 3 case reports present in our review reported the Hounsfield Units (HU) of the neoplasms. Fan et al. found that the lesion had a HU of 9-10. In this case, given the radiographic characteristics of the lesion, the differential diagnosis included a cystic renal neoplasm (18). Mahadevia et al. found a variation in HU depending on the phase of the study from -19 to +58 and +22. In this case the differential diagnosis was between AML and RCC (22). Liu et al., reported a change in HU from 35 to 161. In this case the differential diagnosis included AML, Oncocytoma, Paraganglioma and RCC (33). In our case, the neoplasm showed a behavior similar to that described by Mahadevia. In fact, the neoplasm had different HU -5, +90 and +60 according to the different phases of the CT study. Also, in our case, the main differential diagnoses were AML and RCC. Anatomopathological report More frequently these adrenal changes have a benign behavior and can be classified as functioning or nonfunctioning adenomas. However, in some cases, they may experience neoplastic degeneration as published by Yokoyama et al. and Lee et al. (25, 31). Godin et al. in 2014 published the first case of adrenocortical heterotopic oncocytoma of the kidney. As reported, the additional cases present in the literature had extrarenal locations being localized at the spinal or retroperitoneum level (27). Our case, according with the literature is one with a non-functioning adrenocortical adenoma (Box 1 Table 1). Additionally, the absence or poor presence of fibrous tissue between the kidney and heterotopic tissue was commonly reported, and a contact between the adrenal tissue and the renal parenchyma is frequently described. This feature is also present in our case (Figure 2). Immune-histotypic markers The immunohistochemistry has a pivotal role in the final Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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therefore, was not investigated with immunohistochemistry (Figure 2). Adrenal heterotopia is a rare condition, present in about 1% of the adult population. The main locations are celiac axis, broad ligament, spinal cord and other retroperitoneal parenchymatous organs and this is due to the embryological development of the adrenal gland. Adrenal heterotopia is a benign and asymptomatic condition; however, it can become evident clinically when endocrinological disorders manifest, neoplastic transformation occurs, or mass effect arises. In most cases it presents itself as an incidental finding during routine examinations performed for other causes and can mimic a solid lesion affecting parenchymatous organs, a retroperitoneal lesion compatible with a neoplasm or a metastasis if diagnosed during diagnostic investigations for other malignancies. Having a heightened clinical suspicion for these neoplasms in the setting of small renal masses will improve detection and diagnosis. In our review, 17 studies investigated the use allow more appropriate therapeutic planning with imporof immunohistochemistry in the diagnostic phase. tant clinical implications. In this review, we considered the Chin et al. in 1994, first used immunohistochemistry to clinical characteristics of a subgroup of adrenal heterotopias establish the steroidogenic potential of the sample under such as those located at the renal, perirenal and retroperiexamination (6). The kidney was incubated with adrenal toneal level in order to identify the main differences that can ectopic tissue and specific antibodies for cytochrome guide clinicians towards to a correct preoperative diagnosis. p 450 scc (a mitochondrial enzyme implicated in the synAs we reported, clinical presentation can be very varied. In thesis of steroid hormones), and a high response to the most cases, it is silent and diagnosed during routine exams. adrenal ectopic tissue was found. Subsequently, further In other cases, if the adenoma is secreting hormones, it markers were used in the differential diagnosis. The most manifests itself with endocrinological disorders, hypertenfrequently positive markers were inhibin, vimentin, sion refractory to medical therapy or abdominal pain. melan-A, synaptophysin and anti-p450 scc (Table 1). The most frequently occurring location of this lesion is at Our case report did not pose a diagnostic doubt and the level of the upper pole of the kidney with a typical morphology of solid lesion with fat content, and a hyper-vascularized pattern Figure 3. which includes differential diagnoses Histopathological findings of an ectopic adrenal gland. Normal kidney parenchyma of AML or ccRCC (Table 2). with glomeruli and tubules can be seen (BLUE SQUARE). The right side is occupied by normal tissue of the adrenal gland, where cells belonging In these, an attenuation of -10 HU or to the fasciculata and the reticularis can be spotted (YELLOW STAR). less is similar to AML. A strong conWhile the orthotopic adrenal gland is embedded and separated by the renal trast during CMP with HU values parenchyma by a fibrous capsule most of the time, in this case the glandular tissue greater than 100 with subsequent appears to be embedded directly in the renal parenchyma, since it is directly adjacent wash-out during the nephrogenic to it without any visible capsule or connective tissue. phase is similar to ccRCC. Also, pRCC has a more subtle enhancement pattern than ccRCC, further complicating the list of differentials (36). Finally, it can also present itself as a complex cyst as published by Fan et al. and, in this case the differential diagnosis is with cystic RCC (18). More frequently the anatomopathological report is a benign adenoma, however an adrenocortical neoplasm or other histological subtypes may be Figure 2. “A-B”: renal neoformation localized to the middle third of the left kidney; “C-D”: adrenal glands with regular size, morphology and localization.

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Ectopic adrenal tissue in the kidney

present sporadically as published by Godin et al. in 2014 (27). In many of the cases present in this review, immunohistochemical markers were used, in fact the histological structure was not always correctly reported. This is especially true for cases of adrenocortical carcinoma and rarer histological subtypes. The characteristics that our clinical case carried, correspond to clinical characteristics presented in the literature. The diagnosis was incidental during routine investigation, no painful or endocrinological symptoms were present. When the definitive anatomopathological report showed a well differentiated adrenal adenoma, further immunohistochemical investigations could have been avoided. The main feature that distinguishes our clinical case is the localization at the level of the middle third of the kidney on the lateral margin which is present only in two other clinical cases (11, 31). In our case, we proposed active surveillance, given the size of the mass, however the patient chose surgery to relieve the anxiety of carrying a cancer diagnosis. We had not proposed a renal biopsy and the EAU guidelines do not recommend a renal biopsy on a mass with contrast enhancement, given the high diagnostic accuracy of radiographic imaging. Furthermore, biopsy is not currently a requirement for initiating active surveillance (3). In a recent systematic review, Mir et al. found that less than 30% of patients included in retrospective active surveillance studies had a confirmatory biopsy (4). The diagnostic accuracy and safety of the method, previously controversial, are currently supported by a recent metaanalysis (37). In the absence of a definitive histology, active surveillance is based on initial dimensions and on its growth estimated as linear grow rate (cm/yr) but unfortunately growth is not an indicative parameter of the biology of a lesion, as even benign lesions can have a volumetric increase (4). On the contrary, a retrospective study done at Columbia University showed that low growth rate lesions do not progress to metastatic disease (38). Although it is a rare condition, adrenal heterotopia at the renal level presents itself as a contrast-enhancing neoplasm and therefore worthy of biopsy to avoid unnecessary surgery. Certainly, in the presence of a lesion suspected of renal neoplasia, it is difficult to include within the differential diagnosis a condition with such a low incidence, but,the presence of endocrinological disorders, hypertension refractory to medical therapy can guide the differential diagnosis process. Other symptoms such as abdominal pain, appear to be of lesser help in the diagnostic phase as it is linked to the localization of the neoplasm and to its size and not to a peculiar characteristic of the adrenal anomaly. The main location of the adrenal fusion is at the level of the superior pole, and adrenal rest can also be present in the retroperitoneum adjacenct to the renal pelvis. However, in some cases, such as ours, the adrenal ecotopia can also be localized at the level of the lateral margin of the kidney. This systematic review has intrinsic limitations such as the fact that it examines case series and case reports and the non-homogeneity of the cases taken into consideration. However, it underlines the main characteristics of

the types of adrenal ectopic tissue in the kidney. The astute clinician should be cognizant of this condition in the evaluation of small renal masses due to its benign behavior, and its differentiation by renal cancer could require a renal biopsy because active surveillance is indicated in these patients.

CONCLUSIONS The increase in the incidence of small renal masses due to the diffusion of radiological imaging has led to a better understanding of the behavior of these neoformations. Ectopic adrenal tissue in the kidney is a rare event with specific clinical characteristics which can clinically mimic a renal neoplasia and needs to be known in order to arrive at a correct diagnosis and carry out appropriate treatment management.

REFERENCES

1. Ferlay J, Colombet M, Soerjomataram I, et al. Cancer incidence and mortality patterns in Europe: Estimates for 40 countries and 25 major cancers in 2018. Eur J Cancer. 2018; 103:356-387. 2. Akdogan B, Gudeloglu A, Inci K, et al. Prevalence and predictors of benign lesions in renal masses smaller than 7 cm presumed to be renal cell carcinoma. Clin Genitourin Cancer. 2012; 10:121-5. 3. Ljungberg B, Albiges L, Abu-Ghanem Y, et al. European Association of Urology Guidelines on Renal Cell Carcinoma: The 2019 Update. Eur Urol. 2019; 75:799-810. 4. Mir MC, Capitanio U, Bertolo R, et al. Young Academic Urologists Kidney Cancer working group of the European Urological Association. Role of active surveillance for localized small renal masses. Eur Urol Oncol. 2018; 1:177-187. 5. Brčic´ I, Leniček T, Ulamec M, et al. Intrarenal ectopic adrenal tissue associated with renal angiomyolipoma. Pathol Int. 2011; 61:778-80. 6. Chin L, Brody RI, Morales P, Black VH. Immunocytochemical characterization of intrarenal adrenal tissue. Urology. 1994; 44:429-32. 7. von Rokitansky, KF. A manual of pathological anatomy. Vol. 3. 1855: Blanchard & Lea. 8. Bamford R, Bretherton J, Rosenfelder N, Bell J. Bilateral adrenalrenal fusion: A radiological diagnosis. BJR Case Rep. 2018; 5:20180108. 9. Wang XL, Dou JT, Gao JP, et al. Laparoscope resection of ectopic corticosteroid-secreting adrenal adenoma. Neuro Endocrinol Lett. 2012; 33:265-7. 10. Zhang J, Liu B, Song N, et al. An ectopic adreocortical adenoma of the renal sinus: a case report and literature review. BMC Urol. 2016; 16:3. 11. Ye H, Yoon GS, Epstein JI. Intrarenal ectopic adrenal tissue and renal-adrenal fusion: a report of nine cases. Mod Pathol. 2009; 22:175-81. 12. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS med. 2009; 6:e1000097. 13. Szumera A, Okoń K, Dobrowolska B, Dobrowolski Z. Adrenal rest presenting as a renal cyst. A case report. Pol J Pathol. 2003; 54:273-6. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

487

D. De Marchi, A. Tafuri, G. Mantica, et al.

14. Goren E, Engelberg IS, Eidelman A. Adrenal rest carcinoma in hilum of kidney. Urology. 1991; 38:187-90. 15. Colberg JW, Cai X, Humphrey PA. Unilateral adrenal heterotopia with renal-adrenal fusion. J Urol. 1998; 160:116. 16. Ayala AR, Basaria S, Udelsman R, et al. Corticotropin-independent Cushing's syndrome caused by an ectopic adrenal adenoma. J Clin Endocrinol Metab. 2000; 85:2903-6. 17. Souverijns G, Peene P, Keuleers H, Vanbockrijck M. Ectopic localisation of adrenal cortex. Eur Radiol. 2000; 10:1165-8. 18. Fan F, Pietrow P, Wilson LA, et al. Adrenal pseudocyst: a unique case with adrenal renal fusion, mimicking a cystic renal mass. Ann Diagn Pathol. 2004; 8:87-90 19. Hsu TH, Kessler R. Ectopic adrenal tissue as radiographic lymphadenopathy in renal cell carcinoma. Int Urol Nephrol. 2005; 37:25-6.

34. Sappal S, Sulek J, Smith SC, Hampton LJ. Intrarenal adrenocortical adenoma treated by robotic partial nephrectomy with adrenalectomy. J Endourol Case Rep. 2016; 2:41-3. 35. Lu D, Yu N, Ma X, et al. An ectopic adrenocortical adenoma in renal hilum presenting with Cushing's syndrome: A case report and literature review. Medicine (Baltimore). 2018; 97:e13322. 36. van Oostenbrugge TJ, Fütterer JJ, Mulders PFA. Diagnostic imaging for solid renal tumors: a pictorial review. Kidney Cancer. 2018; 2:79-93. 37. Marconi L, Dabestani S, Lam TB, et al. Systematic review and meta-analysis of diagnostic accuracy of percutaneous renal tumour biopsy. Eur Urol. 2016; 69:660-673. 38. Haramis G, Mues AC, Rosales JC, et al. Natural history of renal cortical neoplasms during active surveillance with follow-up longer than 5 years. Urology. 2011; 77:787-91.

20. Claahsen-van der Grinten HL, Duthoi K, Otten BJ, et al. An adrenal rest tumour in the perirenal region in a patient with congenital adrenal hyperplasia due to congenital 3beta-hydroxysteroid dehydrogenase deficiency. Eur J Endocrinol. 2008; 159:489-91 21. Linder B, Hong Y, Jarrett T. Intra-renal adrenal adenoma: a compelling addition to the differential diagnosis of renal mass. Int J Urol. 2009; 16:912-4. 22. Mahadevia S, Rozenblit A, Milikow D, Marinovich A. Renaladrenal fusion: instance of an adrenal adenoma mimicking a solid renal mass at CT--case report. Radiology. 2009; 251:808-12. 23. Louiset E, Gobet F, Libé R, et al. ACTH-independent Cushing's syndrome with bilateral micronodular adrenal hyperplasia and ectopic adrenocortical adenoma. J Clin Endocrinol Metab. 2010; 95:18-24. 24. Cardinalli IA, de Oliveira-Filho AG, Mastellaro MJ, et al. A unique case of synchronous functional adrenocortical adenoma and myelolipoma within the ectopic adrenal cortex in a child with BeckwithWiedemann syndrome. Pathol Res Pract. 2012; 208:189-94 25. Yokoyama H, Adachi T, Tsubouchi K, et al. Non-functioning adrenocortical carcinoma arising in an adrenal rest: immunohistochemical study of an adult patient. Tohoku J Exp Med. 2013; 229:267-70. 26. Tong A, Jia A, Yan S, et al. Ectopic cortisol-producing adrenocortical adenoma in the renal hilum: histopathological features and steroidogenic enzyme profile. Int J Clin Exp Pathol. 2014; 7:4415-21 27. Godin K, Bang N, Tolkach Y. Case report: Heterotopic intrarenally located adrenocortical oncocytoma. F1000Res. 2014; 3:73. 28. Boll G, Rattan R, Yilmaz O, Tarnoff ME. Intraoperative identification of adrenal-renal fusion. J Minim Access Surg. 2015; 11:205-6. 29. St Clair S, Machnicki S, Yurovitsky A. Adrenal renal fusion confusion: a case report of an adrenal cortical adenoma with adrenalrenal fusion. Clin Imaging. 2015; 39:695-8

Davide De Marchi, MD Federico Scarfò, MD Giovanni Passaretti, MD Salvatore Smelzo, MD Silvia Proietti, MD Lorenzo Rigatti, MD Leonardi Rosario, MD Guido Giusti, MD Franco Gaboardi, MD Department of Urology, San Raffaele Hospital, Milan (Italy) Alessandro Tafuri, MD (Corresponding Author) tafuri.alessandro@gmail.com Department of Urology, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Piazzale Stefani 1, 37126, Verona (Italy) Guglielmo Mantica, MD Department of Urology, University of Genova, Ospedale San Martino, Genova (Italy)

30. Zhao Y, Guo H, Zhao Y, Shi B. Secreting ectopic adrenal adenoma: A rare condition to be aware of. Ann Endocrinol (Paris). 2018; 79:75-81.

Aliasger Shakir, MD USC Institute of Urology, Catherine and Joseph Aresty Department of Urology, Keck School of Medicine, University of Southern California (USC), Los Angeles, CA (USA)

31. Lee JH, Choi YD, Cho NH. An Intrarenal adrenocortical carcinoma arising in an adrenal rest. J Pathol Transl Med. 2018; 52:416-419.

Roberta Luciano, MD Department of Pathology, San Raffaele Hospital, Milan (Italy)

32. Baydar D, Aydin O. Confusing cases: clear cell but not renal cell lesions in kidney. Pathol Int. 2008; 58:713-7.

Alessandro Antonelli, MD Department of Urology, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Verona (Italy)

33. Liu Y, Jiang YF, Wang YL, et al. Ectopic adrenocortical adenoma in the renal hilum: a case report and literature review. Diagn Pathol. 2016; 11:40.

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Correspondence

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Vincenzo Pagliarulo, MD Urology and Andrology Unit - Azienda Ospedaliera 'Vito Fazzi', Lecce, Italy

DOI: 10.4081/aiua.2021.4.489

ORIGINAL PAPER

Drug-induced gynecomastia: A systematic review and meta-analysis of randomized clinical trials Alberto Trinchieri 1, Gianpaolo Perletti 2, 3, Vittorio Magri 4, Konstantinos Stamatiou 5, Margherita Trinchieri 6, Emanuele Montanari 7 1 School

of Urology, University of Milan, Milan, Italy; of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, University of Insubria, Varese, Italy; 3 Faculty of Medicine and Medical Sciences, Ghent University, Belgium; 4 Urology Secondary Care Clinic, ASST-Nord, Milan, Italy; 5 Department of Urology, Tzaneio Hospital, Pireus, Greece; 6 Department of Neuroscience, Psychiatric Unit, University of Parma, Parma, Italy; 7 Department of Urology, IRCCS Ca’ Granda Ospedale Maggiore Policlinico - University of Milan, Milan, Italy. 2 Department

Summary

Objective: To review the evidence concerning treatment-related gynecomastia in patients taking spironolactone, antiandrogens, 5 alpha-reductase inhibitors, lipid-lowering and psychotropic drugs. Material and methods: A search of Medline and EMBASE was performed up to 30 June 2021. We included randomized controlled trials comparing the effects of a drug belonging to these classes versus placebo or versus a drug of the same class. Results: A total of 32 randomized controlled trials were included in the final review. There was an increased odds of gynecomastia in men receiving antiandrogens (OR = 17.38, 95% CI: 11.26 to 26.82; 6 trials, 9599 participants) and 5 alpha-reductase inhibitors compared to controls (OR = 1.77, 95% CI: 1.53 to 2.06; 7 series out of 6 trials, 34860 participants). The use of spironolactone in mixed gender populations was characterized by significantly higher odds of having gynecomastia compared to controls (OR = 8.39, 95% CI: 5.03 to 13.99; 14 trials, 3745 participants). No placebo-controlled trials focusing on the risk of gynecomastia in patients taking antipsychotic drugs was available, although there was a significant difference in the odds of having gynecomastia in a comparison between risperidone and quetiapine (OR = 4.32, 95% CI: 1.31 to 14.27; 3 trials, 343 participants). Limited evidence about the effects of statins on mammary glands was found. Conclusions: Antiandrogens and to a lesser extent 5 alphareductase inhibitors and spironolactone are associated with an increased risk of developing gynecomastia. Such effect can be explained by a modification of the testosterone to estradiol ratio. Gynecomastia (and galactorrhea) associated to the use of conventional and certain atypical antipsychotics can be related to high prolactin levels.

mammary ducts embedded in a fibroconnective tissue stroma. Gynecomastia is associated with medical conditions such as extreme obesity, hypogonadism, liver, and kidney failure. In addition, the administration of certain drugs is a known risk factor for gynecomastia. According to Food and Drug Administration (FDA) Adverse Event Reporting System, gynecomastia is most frequently reported after administration of inhibitors of 5alpha-reductase (dutasteride, finasteride), spironolactone, antipsychotics, lipid-lowering agents (rosuvastatin, atorvastatin, and simvastatin) and antiandrogens (1). Other drugs causing gynecomastia include antiretrovirals (protease inhibitors and nucleoside reverse transcriptase inhibitors), histamine2-receptor blockers (cimetidine), antimycotics (long-term use of ketoconazole), calcium channel blockers, and chemotherapeutic agents. Gynecomastia was also reported after intake of exogenous hormones (estrogens) or steroids (in adolescent boys), and after environmental exposure to phenothrin or intake of phytoestrogens (e.g., large quantities of phytoestrogencontaining soy products). There are numerous reports on the association between the intake of certain drugs and gynecomastia, but no meta-analysis has so far assessed the extent of the risk of gynecomastia linked to specific classes of drugs. The aim of this work was to review the scientific evidence on the risk of gynecomastia after administration of the drugs that are most frequently associated with the occurrence of this side effect.

KEY WORDS: Gynecomastia; Breast enlargement; Spironolactone; Antiandrogens; 5 alpha-reductase inhibitors; Psychotropic drugs; Statins.

MATERIALS

Submitted 20 September 2021; Accepted 1 November 2021

INTRODUCTION

Gynecomastia is a condition in which the male breast is enlarged due to an increase in ductal tissue, stroma, or fat. Histological observation shows a proliferation of the

AND METHODS

Electronic databases (e.g., PubMed and EMBASE) were searched for articles published up to 30 June 2021. Five separate searches were performed using the following MESH terms: “spironolactone AND gynecomastia”, “antiandrogens AND gynecomastia”, “(finasteride OR dutasteride) AND gynecomastia”, “psychotropic agents AND gynecomastia”, “statins AND gynecomastia”. Title and abstract and full-text screening were performed independently by two authors. We included randomized controlled trials (RCTs),

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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with an open-label or single/double blinded design, which enrolled patients treated for at least 6 weeks with antiandrogens, 5 alpha-reductase inhibitors, spironolactone, psychotropic drugs, and statins. Included studies should include a primary or secondary safety endpoint focusing on the side effects of treatment. The following information was extracted from each study: author(s), publication year; study design; population; intervention; rate of gynecomastia (or breast enlargement or breast tenderness or pain or galacthorrea). Two authors independently performed the quality assessment by identifying potential biases using the Cochrane risk of bias tool (2), focusing on the following items: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcomes, selective reporting and other biases. The risk of bias (ROB) was graded as high, low or unclear. Publication bias was assessed by visual inspection of funnel plots and by the Egger's regression test. Dichotomous data (presence/absence of gynecomastia) and number of per-protocol or intent-to-treat patients were extracted to calculate odds ratios (OR), confidence intervals (CI) to odds-ratios, and Z statistics according to the Mantel-Haenszel method. Meta-analysis was performed using a random-effects model. Heterogeneity was assessed

by I2 statistics, reported with 95% CIs, and interpreted as of lesser importance (≤ 40%), moderate (30%-60%), substantial (50%-90%) or considerable (≥ 75%), according to Cochrane criteria. The review (PROSPERO registration number: CRD42021276781) was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines (3). Statistical analysis was performed using the RevMan5 software. The Egger’s test was performed using the MetaEssentials software (Rotterdam School of Management, Erasmus University, The Netherlands).

RESULTS

Database search for the association between gynecomastia and treatment with spironolactone, antiandrogens, alphareductase inhibitors, and antipsychotics retrieved 74, 215, 42 and 74 papers respectively. A total of 68 papers was screened by title/abstract. After full-text screening with removal of duplicates or of articles describing series reported in other reports we included 32 papers in this systematic review (4-35). Out of them 30 reports were included in the quantitative analysis (4-33). A PRISMA flow-chart of the study selection process is shown in Figure 1. The supplementary appendix provides

Figure 1. PRISMA flow chart summary of the study selection procedure.

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Table 1. Drugs compared with placebo or active comparators - endpoint: gynecomastia. Patient or population: various. Settings: outpatient. Intervention: antiandrogens, 5-alpha reductase inhibitors, spironolactone, risperidone, quetiapine. Comparison: placebo or active comparator. Comparisons

Antiandrogens vs. placebo

Illustrative comparative risks (95% CI) Assumed Corresponding control risk intervention risk Placebo/active drug Intervention 81.24 per 1000 605.8 per 1000 (498.91 to 703.40)

Relative effect (95% CI)

No of participants (studies or comparisons)

Quality of the evidence (GRADE)

OR 17.38 (11.26 to 26.82)

9599 (6)

⊕⊕⊕⊝ Moderate

5-alpha reductase inhibitors vs. placebo

19.54 per 1000

34.07 per 1000 (29.59 to 39.44)

OR 1.77 (1.53 to 2.06)

34860 (7)

⊕⊕⊝⊝ Low

Spironolactone vs. placebo

6.5 per 1000

52.09 per 1000 (31.89 to 83.94)

OR 8.39 (5.03 to 13.99)

3745 (14)

⊕⊕⊕⊝ Moderate

Risperidone vs. quetiapine

19.35 per 1000

78.56 per 1000 (25.20 to 219.75)

OR 4.32 (1.31 to 14.27)

343 (3)

⊕⊕⊕⊝ Moderate

Comments

Reasons for upgrading: - large magnitude of effect Reasons for downgrading: - indirectness of evidence - risk of bias Reasons for upgrading: none Reasons for downgrading: - risk of bias - indirectness of evidence Reasons for upgrading: - large magnitude of effect Reasons for downgrading: - risk of bias - indirectness of evidence Reasons for upgrading: - large magnitude of effect Reasons for downgrading: - imprecision (small sample size, wide 95%CI) - risk of bias - indirectness of evidence

The corresponding intervention risk (and its 95% confidence interval) is based on the assumed control risk in the comparison group and the relative effect of the intervention (and its 95% CI). It is calculated from the odds ratio using the formula: OR/[1-ACR x (1-OR)]. CI: Confidence Interval. OR: Odds Ratio. ACR: Assumed Control Risk. GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

a list of included studies (Supplementary Materials), characteristics of the included trials and the risk-of-bias assessment. We included the most recent paper reporting the cumulative results at 10-year follow-up of three studies of the administration of bicalutamide in the frame of the Early Prostate Cancer (EPC) program which includes three large, randomized trials conducted in the United States, Europe, Mexico and Australia (4). Random-effects meta-analysis revealed that antiandrogen therapy is associated with significantly higher odds of gynecomastia (odds ratio, OR = 17.38, 95% CI: 11.26 to 26.82; 6 trials, 9599 participants) compared with placebo (4, 5, 7-9) or no treatment (6) (Figure 2A). Similarly, alpha-5-reductase inhibitors (OR = 1.77, 95% CI: 1.53 to 2.06; 6 trials, 34860 participants) and spironolactone (OR = 8.39, 95% CI: 5.03 to 13.99; 14 trials, 3745 participants) were significantly associated with gynecomastia (10-16) (Figures 2B-2C). It is known that dutasteride can inhibit the activity of both type I and II reductases, whereas finasteride is not active on isoform II. This might suggest an increased risk of gynecomastia in patients taking dutasteride. However, the comparison between dutasteride and finasteride resulted in non-significantly different (p = 0.31) odds of gynecomastia (OR = 0.66, 95% CI 0.30-1.48; 2 trials; 1697 participants) (Forest plot not shown). Risperidone

was significantly (p = 0.02) associated with higher odds of gynecomastia compared to quetiapine (OR = 4.32, 95% CI: 1.31 to 14.27; 3 trials, 343 participants) (Figure 2D), but not olanzapine (Forest plot not shown). Figure 3 shows the funnel plots for publication bias. No significant bias was identified by visual inspection and statistical analysis of funnel plots. Accordingly, the Egger’s test (antiandrogens/placebo, p = 0.43; 5-alpha reductase inhibitors/placebo, p = 0.37; spironolattone/placebo, p = 0.53; risperidone/quetiapine, p = 0.17). Between-study heterogeneity was moderate for the antiandrogens vs. controls comparison (I2 = 49%), and of lesser importance for all other analyses. Table 1 presents the summary of the findings of our pooled analyses, also including an evaluation of the quality of the evidence, performed according to GRADE criteria.

DISCUSSION

Mechanisms regulating the growth of the breast tissue are complex and not fully elucidated (36, 37). The breast tissue expresses receptors for both estrogens and androgens, which can induce the proliferation or inhibition of the growth and differentiation of the mammary gland, respectively. Gynecomastia can be caused either by overt reduction of circulating estrogen levels or Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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Figure 2. Pooled analysis of the comparisons between antiandrogens and placebo (panel A), 5-alpha-reductase inhibitors and placebo (panel B), spironolactone and placebo (panel C) and Risperidone and Quetiapine (panel D). The diamonds show the position of the pooled odds-ratios, extending to the 95% confidence interval limits. Values to the right of the no-effect vertical axis show increased odds for gynecomastia.

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Figure 3. Funnel plots for publication bias analysis. Top-left, antiandrogens vs. placebo; top-right, 5-alpha-reductase inhibitors vs. placebo; bottom-left, spironolactone vs. placebo; bottom-right, risperidone vs. quetiapine.

by an increase of androgen serum levels. In addition, imbalances between estrogen and androgen levels, which may retain serum concentrations within the normal ranges, may cause such effects. Furthermore, activity of estrogens and androgens can be locally modulated in the breast tissue (i) by increased local production of estrogens or decreased inactivation of estrogens, (ii) by decreased local production of androgens, or (iii) by changes in the number and/or activity of androgen or estrogen receptors. Besides androgens and estrogens, other hormones can interfere with the growth of men’s breast tissue, which presents receptors for prolactin, progesterone, insulin-like growth factor (IGF)-1, IGF-2, luteinizing hormone (LH) and/or human chorionic gonadotropin (hCG). Our metaanalysis confirmed that antiandrogens are associated with the highest risk of gynecomastia. Antiandrogens are used for the treatment of prostate cancer as monotherapy or in combination with LHRH inhibitors. Bicalutamide is the most used antiandrogen, though other agents, either steroidal like cyproterone acetate or non-steroidal like flutamide, have also been used for the treatment of prostate cancer. These agents bind to androgen receptors competitively, thus inhibiting testosterone or dihydrotestosterone receptor binding and activity. The administration of non-steroidal antiandrogens, as bicalutamide, causes an increase in the synthesis of testos-

terone due to the inhibition of the negative feedback of the hypothalamic-pituitary-gonadal axis. Increased availability of testosterone causes an increase in estradiol levels due to aromatization of testosterone. These hormonal changes explain the high risk of gynecomastia, which tends to occur in the first year of administration. The evaluation at different time intervals of the rates of gynecomastia in patients taking bicalutamide included in the same series of Early Prostate Cancer program showed rates of gynecomastia and breast pain of 64.9% and 65.1% after a median follow up of 2.6 years (38), 66.3% and 67.9% at 5.1 years (39) and 66.8 and 73.7% at 9.7 years (40). Cyproterone acetate is expected to involve a lower risk of gynecomastia because, in contrast to nonsteroidal antiandrogens, it can decrease estrogen levels via inhibition of the secretion of gonadotropins. However, a comparative study by EORTC described similar gynecomastia rates in patients treated with cyproterone or flutamide, though the latter was more frequently associated with painful gynecomastia (35). Inhibitors of 5-alpha-reductase are widely used for the treatment of benign prostatic hyperplasia. These agents inhibit the conversion of testosterone to dihydrotestosterone through inhibition of the 5-alpha-reductase enzyme, thus reducing prostate cell proliferation. They also cause an increase in the synthesis of testosterone and, consequently, of estrogen through aromatization of Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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testosterone. Spironolactone may induce gynecomastia by several mechanisms: (i) increased peripheral conversion of testosterone to estradiol, (ii) displacement of testosterone from SHBG, or (iii) binding to peripheral androgen receptors to competitively inhibit testosterone and dihydrotestosterone. Our meta-analysis confirms that spironolactone and 5-alpha-reductase inhibitors are associated with an increased risk of gynecomastia, although to a lesser extent than antiandrogens. Although an increased risk of gynecomastia could be expected in patients taking dutasteride, which inhibits the activity of both type 1 and 2 reductases, our metaanalysis could not demonstrate a different risk of gynecomastia between finasteride and dutasteride (16). Statins are inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme that lowers the serum levels of lipids by blocking the pathways of cholesterol synthesis. Inhibition of adrenal and gonadal steroid synthesis may entail to an increased estradiol: testosterone ratio. A meta-analysis showed that a reduction in circulating testosterone levels in patients receiving statin (41). Our search did not retrieve randomized controlled studies that evaluated the possible occurrence of gynecomastia after treatment with statins. It was therefore not possible to investigate the potential risk of gynecomastia associated with the use of these drugs, which was observed following treatment with statins in a case-control cohort study (42). On the other hand, some case reports have suggested that pravastatin, atorvastatin, and rosuvastatin may cause gynecomastia that can be reverted by withdrawal or substitution with a less potent statin. In addition, pharmacovigilance studies include HMG-CoA reductase inhibitors among the most frequent causes of drug-induced gynecomastia (43, 44). Some antipsychotics are correlated with the risk of gynecomastia because of their effect on prolactin secretion. Antipsychotics block pituitary dopamine D2 receptors and prevent their inhibitory effect on prolactin secretion. Hyperprolactinemia may in turn decrease the secretion of GnRH by hypothalamus feedback causing hypogonadism. Nonetheless, prolactin receptors have also been found in male breast tissue, and this may also contribute to the development of gynecomastia (45, 46). Most first-generation antipsychotics and some secondgeneration antipsychotics, particularly risperidone and paliperidone, have been found to increase prolactin levels, with accompanying gynecomastia. The onset of gynecomastia after administration of risperidone is more frequently associated with the use of high doses of the drug and can be triggered by the simultaneous administration of fluoxetine which can interfere in the metabolism of risperidone by inhibition of cytochrome P450.Our meta-analysis confirmed a greater risk of gynecomastia associated with the use of risperidone compared to another atypical antipsychotics. A limitation of the meta-analysis evidence presented in this review is the possible under-reporting of breast enlargement or gynecomastia in the female population taking spironolactone or antipsychotics because this effect may be unnoticed or even considered a beneficial effect by female patients, while in the male population it may have been reported with more attention, as it modifies the body image

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more heavily. Unfortunately, no study has provided a separate assessment of the appearance of this side effect in relation to gender. In populations of adult women who took spironolactone for the treatment of acne, the appearance of breast tenderness and breast enlargement was estimated at 2.5% and 2.1% respectively (47, 48). The prevalence of gynecomastia could therefore be underestimated in mixed gender populations taking spironolactone or antipsychotics compared to male populations receiving antiandrogens or alpha-reductase inhibitors. In conclusion, our study confirmed the high risk of gynecomastia in patients taking antiandrogens for the treatment of prostate cancer. The frequent occurrence of gynecomastia is a limiting factor of this treatment and ablation of the breast tissue by ionizing radiation is sometimes used to prevent this effect. The risk of gynecomastia is lower but significantly higher than placebo in patients receiving spironolactone, 5-alpha-reductase inhibitors, and atypical antipsychotics (risperidone vs. quetiapine). The potential risk of gynecomastia associated with the use of statins should be better assessed with studies evaluating the long-term side effects of these drugs. In the clinical practice, the possible additive or synergic interaction of several drugs predisposing to the onset of gynecomastia must be cautiously considered.

REFERENCES

1. Bowman JD, Hyunah Kim H, Bustamante JJ. Drug-induced gynecomastia. Pharmacotherapy. 2012; 32:1123-1140 2. Higgins JP, Altman DG, Gøtzsche P, Cet al.Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011; 343:d5928. 3. Moher D, Liberati A, Tetzlaff J, Altman DG. The PRISMA Group (2009) Preferred Reporting Items for Systematic Reviews and MetaAnalyses: The PRISMA Statement. PLoS Med 6: e1000097. 4. Iversen P, McLeod DG, See WA, et al. Casodex Early Prostate Cancer Trialists' Group. Antiandrogen monotherapy in patients with localized or locally advanced prostate cancer: final results from the bicalutamide Early Prostate Cancer programme at a median followup of 9.7 years. BJU Int. 2010; 105:1074-81. 5. Shipley WU, Seiferheld W, Lukka HR, et al. NRG Oncology RTOG. Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer. N Engl J Med. 2017; 376:417-428. 6. Zanardi S, Puntoni M, Maffezzini M, et al. Phase I-II trial of weekly bicalutamide in men with elevated prostate-specific antigen and negative prostate biopsies. Cancer Prev Res (Phila). 2009; 2:377-84. 7. Alberts SR, Novotny PJ, Sloan JA, et al. Flutamide in men with prostatic intraepithelial neoplasia: A randomized, placebo-controlled chemoprevention trial American Journal of Therapeutics. 2006; 13:4(291-297). 8. Narayan P, Trachtenberg J, Lepor H, et al. A dose-response study of the effect of flutamide on benign prostatic hyperplasia: results of a multicenter study. Urology. 1996; 47:497-504. 9. Berger BM, Naadimuthu A, Boddy A, et al. The effect of zanoterone, a steroidal androgen receptor antagonist, in men with benign prostatic hyperplasia. The Zanoterone Study Group. J Urol. 1995; 154:1060-4.

Drug-induced gynecomastia

10. Andriole GL, Bostwick DG, Brawley OW, et al. REDUCE Study Group Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 2010; 362:1192-202 11. Na Y, Ye Z, Zhang S. Efficacy and Safety of Dutasteride in Chinese Adults with Symptomatic Benign Prostatic Hyperplasia : A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study with an Open-Label Extension. Clin Drug Investig. 2012; 32:29-39. 12. Roehrborn CG, Boyle P, Nickel J, et al. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia Urology. 2002; 60:3(434-441). 13. McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety Study Group. N Engl J Med. 1998; 338:557-63. 14. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer.N Engl J Med. 2003; 349:215-24. 15. Amory JK, Wang C, Swerdloff RS, et al. The effect of 5a-reductase inhibition with dutasteride and finasteride on semen parameters and serum hormones in healthy men Journal of Clinical Endocrinology and Metabolism. 2007; 92:5(1659-1665). 16. Nickel JC, Gilling P, Tammela TL, et al. Comparison of dutasteride and finasteride for treating benign prostatic hyperplasia: the Enlarged Prostate International Comparator Study (EPICS). BJU Int. 2011; 108:388-94. 17. Bianchi S, Bigazzi R, Campese VM. Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease Kidney International 2006; 70:2116-2123. 18. Charytan DM, Himmelfarb J, Ikizler TA, et al. Hemodialysis Novel Therapies Consortium. Safety and cardiovascular efficacy of spironolactone in dialysis-dependent ESRD (SPin-D): a randomized, placebocontrolled, multiple dosage trial. Kidney Int. 2019; 95:973-982. 19. Edelmann F, Wachter R, Schmidt AG, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: The Aldo-DHF randomized controlled trial JAMA - Journal of the American Medical Association 2013; 309:781-791. 20. Gao X, Peng L, Adhikari CM, et al. Spironolactone Reduced Arrhythmia and Maintained Magnesium Homeostasis in Patients With Congestive Heart Failure Journal of Cardiac Failure 2007; 13:170-177. 21. Ito Y, Mizuno M, Suzuki Y, et al. Long-term effects of spironolactone in peritoneal dialysis patients Journal of the American Society of Nephrology. 2014; 25:1094-1102. 22. Kayrak M, Bacaksiz A, Vatankulu MA, et al. The effects of spironolactone on atrial remodeling in patients with preserved left ventricular function after an acute myocardial infarction: A randomized follow-up study Coronary Artery Disease. 2010; 21:477-485. 23. Matsumoto Y, Mori Y, Kageyama S, et al. Spironolactone reduces cardiovascular and cerebrovascular morbidity and mortality in hemodialysis patients. J Am Coll Cardiol. 2014; 63:528-36. 24. Ni X, Zhang J, Zhang P, et al. Effects of spironolactone on dialysis patients with refractory hypertension: A randomized controlled study Journal of Clinical Hypertension. 2014; 16:658-663. 25. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999; 341:709-17.

26. Skvortsov AA, Mareev VY, Chelmakina SM, et al. Efficacy and safety of long-term application of spironolactone in patients with moderate and severe chronic heart failure receiving optimal therapy. Kardiologiia. 2007; 47:12-23. 27. Tofte N, Lindhardt M, Adamova K, et al. PRIORITY investigators. Early detection of diabetic kidney disease by urinary proteomics and subsequent intervention with spironolactone to delay progression (PRIORITY): a prospective observational study and embedded randomised placebo-controlled trial. Lancet Diabetes Endocrinol. 2020; 8:301-312. 28. Vatankulu MA, Bacaksiz A, Sonmez O, et al. Does spironolactone have a dose-dependent effect on left ventricular remodeling in patients with preserved left ventricular function after an acute myocardial infarction? Cardiovascular Therapeutics. 2013; 31:224-229. 29. Vizzardi E, Pina PD, Caretta G, et al. The effect of aldosteroneantagonist therapy on aortic elastic properties in patients with nonischemic dilated cardiomyopathy Journal of Cardiovascular Medicine. 2015; 16:597-602. 30. Zarraga IGE, Dougherty CM, MacMurdy KS, Raitt MH. Tachyarrhythmias the effect of spironolactone on ventricular tachyarrhythmias in patients with implantable cardioverter-defibrillators Circulation: Arrhythmia and Electrophysiology. 2012; 5:739-747. 31. Kelly DL., Conley RR. A randomized double-blind 12-week study of quetiapine, risperidone or fluphenazine on sexual functioning in people with schizophrenia Psychoneuroendocrinology. 2006; 31:340346. 32. McEvoy JP, Lieberman JA, Stroup TS, et al. CATIE Investigators. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006; 163:600-10. 33. McEvoy JP, Lieberman JA, Perkins DO, et al. Efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: A randomized, double-blind 52-week comparison American Journal of Psychiatry. 2007; 164:1050-1060. 34. McEvoy JP, Byerly M, Hamer RM, et al. Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial. JAMA. 2014; 311:1978-87. 35. Schröder FH, Whelan P, de Reijke TM, et al. Members of the EORTC Genito-Urinary Group. Metastatic prostate cancer treated by flutamide versus cyproterone acetate. Final analysis of the "European Organization for Research and Treatment of Cancer" (EORTC) Protocol 30892. Eur Urol. 2004; 45:457-64. 36. Narula HS, Carlson HE. Gynaecomastia-pathophysiology, diagnosis and treatment. Nat Rev Endocrinol. 2014; 10:684-698. 37. Kanakis GA, Nordkap L, Bang AK, et al. EAA clinical practice guidelines-gynecomastia evaluation and management. Andrology. 2019; 7:778-793. 38. Wirth M, Tyrrell C, Wallace M, et al. Bicalutamide (Casodex) 150 mg as immediate therapy in patients with localized or locally advanced prostate cancer significantly reduces the risk of disease progression Urology. 2001; 58:146-150. 39. Wirth M, Tyrrell C, Delaere K, et al. Bicalutamide ('Casodex') 150mg in addition to standard care in patients with nonmetastatic prostate cancer: Updated results from a randomised double-blind phase III study (median follow-up 5.1y) in the early prostate cancer programme Prostate Cancer and Prostatic Diseases 2005; 8:194200. 40. Iversen P, McLeod DG, See WA, et al. Casodex Early Prostate Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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A. Trinchieri, G. Perletti, V. Magri, K. Stamatiou, M. Trinchieri, E. Montanari

Cancer Trialists' Group. Antiandrogen monotherapy in patients with localized or locally advanced prostate cancer: final results from the bicalutamide Early Prostate Cancer programme at a median followup of 9.7 years.BJU Int. 2010; 105:1074-81. 41. Skeldon SC, Carleton B, Brophy JM, et al. Statin medications and the risk of gynecomastia. Clin Endocrinol (Oxf). 2018; 89:470-473. 42. Schooling CM, Au Yeung SL, Freeman G, Cowling BJ. The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials. BMC Med. 2013; 11:57. 43. Roberto G, Biagi C, Montanaro N, et al. Statin-associated gynecomastia: evidence coming from the Italian spontaneous ADR reporting database and literature. Eur J Clin Pharmacol. 2012; 68:1007-11. 44. Batteux B, Llopis B, Muller C, et al. French National Network of Pharmacovigilance Centres. The drugs that mostly frequently induce

gynecomastia: A national case - noncase study. Therapie. 2020; 75:225-238. 45. Grigg J, Worsley R, Thew C, et al. Antipsychotic-induced hyperprolactinemia: synthesis of world-wide guidelines and integrated recommendations for assessment, management and future research. Psychopharmacology. 2017; 234:3279-3297. 46. Ferreira M, Mesquita M, Quaresma M & André S. Prolactin receptor expression in gynaecomastia and male breast carcinoma. Histopathology. 2008; 53:56-61. 47. Layton AM, Eady EA, Whitehouse H, et al. Oral Spironolactone for Acne Vulgaris in Adult Females: A Hybrid Systematic Review. Am J Clin Dermatol. 2017; 18:169-191. 48. Muhlemann MF, Carter GD, Cream JJ, Wise P. Oral spironolactone: an effective treatment for acne vulgaris in women. Br J Dermatol. 1986; 115:227-32.

Correspondence Alberto Trinchieri, MD (Corresponding Author) alberto.trinchieri@gmail.com School of Urology, University of Milan Via Commenda 15, 20100 Milano (Italy) Gianpaolo Perletti, PhD gianpaolo.perletti@uninsubria.it Department of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, University of Insubria, Varese (Italy) Vittorio Magri, MD vittorio.magri@yahoo.it Urology Secondary Care Clinic, ASST-Nord, Milan (Italy) Konstantinos Stamatiou, MD stamatiouk@gmail.com Department of Urology, Tzaneio Hospital, Pireus (Greece) Margherita Trinchieri, MD margherita.trinchieri11@gmail.com Department of Neuroscience, Psychiatric Unit, University of Parma, Parma (Italy) Emanuele Montanari, MD emanuele.montanari@unimi.it Department of Urology, IRCCS Ca’ Granda Ospedale Maggiore Policlinico University of Milan, Milan (Italy)

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LETTER TO EDITOR

DOI: 10.4081/aiua.2021.4.497

Comment on renal autotransplantation: A final option to preserve the kidney after an iatrogenic ureteral injury Christos Damaskos 1, 2*, Nikolaos Garmpis 2, 3*, Konstantinos Nikolettos 4, Alexandros Patsouras 2, Dimitrios Schizas 5, Anna Garmpi 6, Vasiliki E. Georgakopoulou 7, Athanasios Syllaios 5, Dimitrios Dimitroulis 3 1 Renal

Transplantation Unit, Laiko General Hospital, Athens, Greece; Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 3 Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 4 Obstetric and Gynecologic Clinic, Medical School, Democritus University of Thrace, Alexandroupolis, Greece; 5 First Department of Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 6 First Department of Propedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 7 Department of Pulmonology, Laiko General Hospital, Athens, Greece. 2 N.S.

*Equal contribution. Submitted 26 May 2021; Accepted 12 July 2021

To the Editor, Autologous Renal Transplantation (ART) since firstly described in 1963 by Hardy, has been used in various cases (1). There are various reasons for the transplantation such as iatrogenic ureteral damage, chronic kidney pain, unresectable renal tumors or renovascular diseases (2, 3). Indications concerning the suitable patients for this kind of procedure are gradually increasing. Nevertheless, each case is unique, and the treatment must be personalized. ART is a procedure with various complications. These include infections, graft failure, urine leak and renal vein thrombosis (2). However, the kidney preservation is of great clinical significance for the patient. In response to the case of Moulavasilis et al., kidney preservation was a decision made by both the patient and the multidisciplinary medical team (4). The patient was 41 years old, still capable of getting pregnant. However, she was in an advanced but not prohibitive age for reproduction with increased possibility of complications. Why to operate since there is one more functional kidney? During the second half of pregnancy, the glomerular infiltration is increased more than 40% normally (5). Chronic kidney disease or even small renal impairment can facilitate the appearance of pregnancy complications such as preeclampsia, in which albuminuria and arterial hypertension are included (6). Furthermore, arterial preeclampsia can accelerate renal damage, by causing podocyte loss, endothelial damage, and acute kidney injury (5). As a result, the preference of the patient for renal preservation, the possible desire for pregnancy as well as her good clinical state rendered surgery the final choice. All the aforementioned complications can also occur in pregnancy after renal transplantation (7). Risk factors for complications are immunosuppressive treatment (donor transplantation), maternal proteinuria and hypertension (8). These pregnancies are associated with higher risk of both maternal and fetal complications. Acute graft rejection, preeclampsia, cesarian sections and low birth weight of fetus are common problems. It should be noticed that the possibility of graft loss is slightly higher the first 2 years postpartum, and no difference is noticed 10 years postpartum compared to nulliparous controls (7-9). Except for renal autotransplantation, other choices also exist in patients with ureteral avulsion. Anastomosis between pelvis of the kidney and ileum constitutes the ileal ureter. It is recommended in cases with extensive ureter injuries. However, urinary infections and pain can occur in the post-surgical period (10). Furthermore, metabolic and intestinal complications are also a frequent medical entity after this type of surgery (11). Even appendix interposition has been reported in the literature (12). Buccal mucosa onlay constitutes another choice for management of ureteral injuries. The oral mucosa is easily accessible and wet. Grafts are taken from either the inner chick or lip. It is an innovative technique, which is used the last years. It can be performed as an open surgery, laparoscopic or robot assisted. Even though the reported success of this surgery is very high, this technique should be used in larger series for final assessment (13). However, no information about the success of this surgery exists in patients who need reconstruction of the ureter more than 11 cm (14). Restenosis or stricture recurrence have also occurred in some cases (13, 15). Nephrostomy is another alternative for cases of ureteral damage. It is a minimally invasive technique which is easily performed. It is usually conducted in patients, in order to stabilize them, and does not usually constitute a permanent solution. The morbidity is very low, less than 0.04% and comNo conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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C. Damaskos, N. Garmpis, K. Nikolettos, A. Patsouras, D. Schizas, A. Garmpi, V.E. Georgakopoulou, A. Syllaios, D. Dimitroulis

plications include colon perforation or bleeding. Antibiotic usage before the implementation of the nephrostomy should be initiated (16). Finally, nephrectomy is another choice in patients with extensive ureteral damage. The decision of the patient and the difficulty of a possible ureter reconstruction render laparoscopic nephrectomy a possible choice (17). In addition, this procedure is safer, with less complication especially in patients with other comorbidities. On the other hand, the patient has only one functional kidney. Various surgical techniques exist for the management of ureteral avulsion. ART is a medical intervention, which can be both beneficial and harmful. Medical expertise is required, and its use should be implemented when conventional therapeutic methods have already been considered. The reason, time and type of surgery are very important for the clinical outcome of the patient. Thus, all types of management can be considered both right and wrong, depending on the final clinical outcome. ART is a challenge.

REFERENCES

1. Hardy JD, Eraslan S. Autotransplantation of the kidney for high ureteral injury. J Urol. 1963; 90:563-574. 2. Vrakas G, Sullivan M. Current review of renal autotransplantation in the UK. Curr Urol Rep. 2020; 21:33. 3. Liu LH, Chen Z, Xiong YY, et al. Clinical application of renal autotransplantation in complex urological disease]. Zhonghua Yi Xue Za Zhi. 2019; 99:907-911. 4. Moulavasilis N, Katafigiotis I, Staios D, et al. Renal autotransplantation: A final option to preserve the kidney after an iatrogenic ureteral injury. Arch Ital Urol Androl. 2020; 91:263-264. 5. Cornelis T, Odutayo A, Keunen J, Hladunewich M. The kidney in normal pregnancy and preeclampsia. Semin Nephrol. 2011; 31:4-14. 6. Kattah A. Preeclampsia and kidney disease: Deciphering cause and effect. Curr Hypertens Rep. 2020; 22:91. 7. Deshpande NA, James NT, Kucirka LM, et al. Pregnancy outcomes in kidney transplant recipients: A systematic review and meta-analysis. Am J Transplant. 2011; 11:2388-2404. 8. van Buren MC, Schellekens A, Groenhof TKJ, et al. Long-term graft survival and graft function following pregnancy in kidney transplant recipients: A systematic review and meta-analysis. Transplantation. 2020; 104:1675-1685. 9. Sibanda N, Briggs JD, Davison JM, et al. Pregnancy after organ transplantation: A report from the UK Transplant pregnancy registry. Transplantation. 2007; 83:1301-1307. 10. Sevinc C, Balaban M, Ozkaptan O, et al. The management of total avulsion of the ureter from both ends: Our experience and literature review. Arch Ital Urol Androl. 2016; 88:97-100. 11. Kocot A, Kalogirou C, Vergho D, Riedmiller H. Long-term results of ileal ureteric replacement: A 25-year single-centre experience. BJU Int. 2017; 120:273-279. 12. Dagash H, Sen S, Chacko J, et al. The appendix as ureteral substitute: A report of 10 cases. J Pediatr Urol. 2008; 4:14-19. 13. Xiong S, Wang J, Zhu W, et al. Onlay repair technique for the management of ureteral strictures: A comprehensive review. Biomed Res Int. 2020; 2020:6178286. 14. Zhao LC, Yamaguchi Y, Bryk DJ, et al. Robot-assisted ureteral reconstruction using buccal mucosa. Urology. 2015; 86:634-638. 15. Arora S, Campbell L, Tourojman M, et al. Robotic buccal mucosal graft ureteroplasty for complex ureteral stricture. Urology. 2017; 110:257-258. 16. Zagoria RJ, Dyer RB. Do's and don't's of percutaneous nephrostomy. Acad Radiol. 1999; 6:370-377. 17. Ordon M, Schuler TD, Honey RJ. Ureteral avulsion during contemporary ureteroscopic stone management: "The scabbard avulsion". J Endourol. 2011; 25:1259-1262. Correspondence Christos Damaskos, MD, MSc, PhD (Corresponding Author) x_damaskos@yahoo.gr Renal Transplantation Unit, Laiko General Hospital & N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens; 17 Agiou Thoma Street, Athens, 11527 (Greece) Nikolaos Garmpis, MD, MSc, PhD N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens & Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, (Greece)

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Dimitrios Schizas, MD, PhD, Assistant Professor of Surgery First Department of Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, Athens (Greece) Anna Garmpi, MD First Department of Propedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, Athens (Greece) Vasiliki E. Georgakopoulou, MD Department of Pulmonology, Laiko General Hospital, Athens (Greece)

Konstantinos Nikolettos, MD Obstetric and Gynecologic Clinic, Medical School, Democritus University of Thrace, Alexandroupolis, (Greece)

Athanasios Syllaios, MD First Department of Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, Athens (Greece)

Alexandros Patsouras, MD N.S. Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, Athens (Greece)

Dimitrios Dimitroulis, MD, MSc, PhD, Professor of Surgery Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, Athens (Greece)

Archivio Italiano di Urologia e Andrologia 2021; 93, 4

DOI: 10.4081/aiua.2021.4.499

LETTER TO EDITOR

Varicocele and varicocelectomy: Which news from the past? Nicola Zampieri Woman & Child Hospital, Department of Surgery, Dentistry, Paediatrics and Gynecology; Division of Pediatric Surgery, University of Verona, Italy.

KEY WORDS: Varicocele; Treatment; Option; Fertility. Submitted 12 October 2021; Accepted 12 October 2021

To the Editor, In 1952, after many centuries, the varicocele was treated to resolve infertility. From Celsus to modern surgical techniques, over the centuries, many surgeons have proposed numerous treatment options, some very traumatic others more "physiological" (1-14). Cases of varicocele have been treated because they were associated with "melancholic blood" or were associated with pain or were associated with infertility. However, since the latest clinical research, varicoceles have been treated mainly because they are associated with infertility, although recently the treatment of varicoceles, in the era of medical assisted procreation, has been questioned (15-17). Therefore, there are some fundamental points to clarify. Why do patients with varicoceles become infertile? Patients with subclinical varicoceles are now surgically treated if there is alteration of the semen, why do we have to operate a patient with varicocele if we can use assisted reproduction? A fundamental point is to clarify the role of varicocelectomy on the pregnancy rate; does it make sense to perform expensive (robotic varicocelectomy), or potentially harmful (x-ray embolization) surgical treatments if we then have to resort to assisted reproduction? What treatment can we offer to adolescents or what therapeutic procedure should we do for adolescents? Finally, are we therefore returning to treat varicocele only if associated with pain, because for infertility we will have assisted reproduction? With respect to the history of surgical procedures proposed to treat varicocele, “innovative” were Osborn and Ogston who, between 1880 and 1886, proposed a trans-scrotal treatment using a hairpin (without closing the artery) and a glowing needle. Was this perhaps the first "bipolar cautery" varicocelectomy? (9, 13) However, it is interesting to note that from the earliest treatment in history, Corner, Skillen, O'Conor, and Robson reported numerous complications and raised doubts on the real benefit of the procedure (4-6, 11). Tait in 1904 was the first to introduce clear guidelines about clinical indications for varicocelectomy: one should operate large varicocele (or painful varicocele) including cases with testicular atrophy or marked endo-phlebitis and varicocele causing the rejection of candidates for certain positions (Army and Navy). In his "guidelines" he also added more information about who should be treated: voluminous and painful varicocele equivalent to an appreciable deformity and smaller varicocele at the patient's repeated request to be rid on an infirmity. Finally, he added a last important chapter: one should never operate varicocele in genitourinary hypochondriacs or in neurasthenics and in case of simple dilatation of the veins inducing no symptoms (the most common form of varicocele) (7). In comparison to the, more or less invasive, treatments proposed from Celsus onwards, to the surgical indications proposed in the past, to the results of the first cases treated in history and to the related post-operative complications, what have we learned or modified with respect to the past? Perhaps the only answer we can give is that we still know very little about varicocele and its treatment.

REFERENCES

1. Marmar JL. The evolution and refinements of varicocele surgery. Asian J Androl 2016; 18:171-8. 2. Coutts WE. Orchidopexy for varicocele. A method for treating varicocele by means of living tissue. Ann Surg. 1928; 88:1093-5. 3. Porrit AE. The injection treatment of hydrocele, varicocele, burse and nevy. Proc R Soc Med 1931; 24: 971-975. No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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4. O’Connor J. The radical cure of varicocele. Br Med J. 1921; 1:783-789. 5. Skillen PG. A consideration of the varicocele operation and avoidance of post-operative induration. Ann Surg. 1920; 72:508-510. 6. Corner EM, Nitch CAR. The immediate and remote results of the high operation for varicocele. Br Med J 1906; 27:191-193. 7. Tait D. Contribution to the study of varicocele. Cal State J Med. 1904; 2:363-367. 8. Curling TB. Varicocele treated by pressure. Med Chir Trans. 1846; 29:259-268. 9. Osborn S. The treatment of varicocele by acu-pressure of spermatic vein. Br Med J. 1880; 1:52. 10. Duncan J. Clinical observations of the subcutaneous ligature of varix and varicocele. Br Med J. 1881; 2:37-38. 11. Robson AWM. Treatment of varicocele by excision. Br Med J. 1886; 27:389-390. 12. Ogston A. The operation for varicocele. Ann Surg. 1886; 4:120-123. 13. Noske HD, Weidmer W. Varicocele a historical perspective. World J Urol. 1999; 17: 151-157. 14. Keetly CB. The cure of varicocele. Ann Surg. 1888; 8: 205-207. 15. Turgut H. The effect of varicocelectomy on the pregnancy rate in patients with severe oligospermia. Niger J Clin Pract. 2020; 23:1744-1747. 16. Schlegel PN, Sigman M, Collura B, et al. Diagnosis and treatment of infertility in men: AUA/ASRM Guideline Part II. J Urol. 2021; 20:44-45. 17. Kimura M, Nagao K. Role of varicocele repair for male infertility in the era of assisted reproductive technologies. Reprod Med Biol. 2014; 13:185-192.

Correspondence Nicola Zampieri, Prof., MD, PhD nicola.zampieri@aovr.veneto.it Pediatric Fertility Lab Woman & Child Hospital, Department of Surgery, Dentistry, Paediatrics and Gynecology; Division of Pediatric Surgery, University of Verona, Italy Piazzale Aristide Stefani 1, 37100 Verona (Italy)

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LETTER TO EDITOR

DOI: 10.4081/aiua.2021.4.501

Unit, S. Donato Hospital, Arezzo, Italy; Unit, S. Maria della Gruccia Hospital, Montevarchi, Italy; 3 Department of Medical Biotechnologies, University of Siena, Italy. 2 Urology

KEY WORDS: Benign prostatic hyperplasia; Pulsed electromagnetic fields, Alpha-bocker agents; Randomized crossover clinical trial. Submitted 27 August 2021; Accepted 19 September 2021

To the Editor, Benign Prostatic Hyperplasia (BPH) is one of the main causes of patients seeking urological counselling in Western countries. It has been estimated that nearly 70 percent of United States men between the ages of 60 and 69 years, and nearly 80 percent of men ≥ 70 years, have some degree of BPH (1). BPH is a histologic diagnosis defined as an increase in the total number of stromal and glandular epithelial cells within the transition zone of the prostate gland. BPH results in Benign Prostatic Enlargement (BPE) that can, in turn, lead to Bladder Outlet Obstruction (BOO). BPE and mostly BOO is often associated with Lower Urinary Tract Symptoms (LUTS), which can be subdivided into symptoms of urinary storage (eg, urgency, daytime frequency, nocturia, incontinence, etc.), symptoms of urinary voiding (eg, slow stream, intermittent stream or intermittency, hesitancy, straining to void, terminal dribble, dysuria, etc.) and post-voiding symptoms (eg, sensation of incomplete bladder emptying, post-void urinary dribbling, etc.). All above-mentioned symptoms reported by patients with BPH contribute to a significantly reduced quality of life (2, 3). The initial treatment for Bladder Outlet Obstruction (BOO) secondary to Benign Prostatic Hyperplasia (BPH) is generally pharmacologic, especially in patients with mild to moderate symptoms and no clear indication for surgical intervention. Medical therapy consists of alpha-blockers, 5-alpha reductase inhibitors, or a combination of these agents (4). Alphablockers are first-line agents used for the treatment of symptomatic BPH. These drugs relax the smooth muscle tone at the bladder neck. If associated with 5-alpha reductase inhibitor drugs the use of alpha-blockers agents may result more effective than monotherapy with either drug alone (5). Given the above, several data in the literature reported that electromagnetic fields (EMF) have many biological activities capable of interfering with the ability to reproduce and differentiate cells, modulating the inflammatory system through the increase of oxide-reductive potential, and increasing microvascular motility, ATP production, hormonal secretion, antioxidant enzyme activity, and cellular metabolism (6); moreover EMF at high frequency and low intensity allows to obtain significant therapeutic results without unwanted side effects, allowing their use also in a wide spectrum of chronic diseases characterized by functional disorders and pain, such as chronic inflammatory diseases (7). The antiphlogistic and stimulating effects of the tissue repair produced by magnetic fields in humans allows to achieve favorable therapeutic results especially in diseases affecting the osteoskeletal system, such as the fractures and the arthropathies (8). The vibrating systems are equipment capable of generating sinusoidal oscillations at various frequencies and transfer them to the body of the subject to be treated through pressure waves, with specially designed platforms just capable of vibrating at variable frequencies (Hertz/sec) (9). The treatment with vibrations exerts a safe myo-relaxant effect with consequent reduction of muscle spasticity and is widely used in the field of neuro-rehabilitation (10). With vibratory frequencies varying between 5 and 30 Hz, an increase in cerebral cortisone and serotonin has been demonstrated in the rat; in humans, mono or polysynaptic connections are activated in order to generate reflex contractions (11). The STIM-PLAVIM®, a device which is capable of simultaneously generating an intense variable electromagnetic field and vibratory stimulation, was object of an observational perspective study in patients affected by voiding symptoms attributed to bladder outlet obstruction secondary to benign prostatic hyperplasia and already treated by alpha-blocker agents. These No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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patients without stopping the pharmacologic therapy added the application of the STIM-PLAVIM® device at the perineal level every day for 30 minutes for a period of 60 days. The application of the above mentioned device resulted in a rapid improvement of voiding symptoms as confirmed by the statistically significant reduction in the mean score of the International Prostatic Symptoms Score (IPPS) (12). However, the above mentioned study was performed in an uncontrolled design hence the need to compare the STIM-PLAVIM® with the use of alpha-blocker agents which today represent the cornerstone of the current standard therapy for bladder outlet obstruction secondary to BPH (4). We hypothesized that, in the above-mentioned patients the use of STIM-PLAVIM® device would be more effective than alpha-blockers in reducing the mean volume of bladder residue after voiding. We further hypothesized that the use of STIM-PLAVIM® device would improve secondary parameters tied to BPH such as the prostatic volume, the total PSA value and the IPSS more than conventional alpha-blockers agents therapy.

MATERIAL

AND METHODS

This study was performed in a monocentric, controlled, randomized, two-periods crossover design. Each period included 45 daily applications of STIM-PLAVIM® device at the perineal level each lasting 30 minutes without the intake of any alpha- blocker agent (although 5-alpha reductase inhibitors, mainly dutasteride and secondarily finasteride, were used in 60% of cases) or the daily oral intake of an alpha-blocker agent (60% alfuzosin and tamsulosin for the rest) for a same length of 45 days. When already in use the 5-alpha reductase inhibitors were associated with the alpha-blocker agents too and therefore the use of 5-alpha reductase inhibitors remained unchanged in both periods. At crossover and at the end of the study assessment were done. Patients were randomly assigned to start the study with a period of daily STIM-PLAVIM® device application or a period of daily oral intake of an alpha-blocker agent using a computer-generated list. Masking the treatment allocation for physician and patients was not feasible. Ten ambulatory patients (mean age 65 ± 7 years) affected by bladder outlet obstruction secondary to BPH were enrolled. All patients provided written informed consent before participating. The inclusion criteria were a clinical, laboratory and ultrasound diagnosis of benign prostatic hyperplasia at least 6 months prior and age between 50 and 80 years. Exclusion criteria were a proven diagnosis of prostatic cancer, urinary infections, the permanent or temporary use of bladder catheter, neurological voiding disturbances, alpha-blockers agents intolerance or the presence of medical electrical devices incompatible with the use of electromagnetic fields. The volume of bladder residue after voiding was estimated with a suprapubic ultrasound method as well as the prostatic volume was assessed by a transrectal ultrasound method in both cases using the same ultrasound device Logiq S7 (GE Medical Systems Italy S.P.A. Milan, Italy) sonographic system equipped with 3 to 5 Mhz convex transducers for the suprapubic ultrasound and a BE9CS (GE Medical Systems Italy S.P.A. Milan, Italy) Biplane intracavity probe with a bandwidth of 4-11 Mhz for the transrectal ultrasound. All ultrasonography examinations were carried out by the same nephrologist experienced in ultrasound examination. To characterize the subjective evaluation of the urological symptoms, the International Prostatic Symptoms Score (IPSS) was assessed and finally was tested the total PSA value. The STIM-PLAVIM® device used in our study is a Medical Device consisting of a polyethylene/erthalite container hand piece, washable and sterilizable, consisting of two cylinders: the larger one contains a low voltage electric motor inside, which is connected by a joint to a shaft in aluminum/stainless steel with a modulating speed motor. The shaft containing the motor has the shape of a cradle able to house the high-quality neodymium magnet which exerts an intense magnetic force between 1000 and 1500 Gauss. The housing of the magnet in the cradle is assembled asymmetrically so that the rotation of the motor, with adjustable speed by means of a special dedicated electronic program, allows to simultaneously generate an intense permanent and rotating magnetic field and a vibratory trend with specific frequency (between 80 and 140 Hertz). The handpiece, with an ergonomic cylindrical shape, is closed at the two lower and upper ends with two caps with screw closure; the upper part of the Device also contains a rechargeable electric accumulator (with a common 220 Volt electric socket) (Figures 1, 2). Statistical analysis Quantitative variables, pre- and post-treatment with STIM-PLAVIM® device, were tested for their mean reduction using Student's t-test for paired data, before testing for normality with the Kolmogorov-Smirnov test. A significance level of 95% (p < 0.05) was chosen for all statistical analyses performed with SPSS software, version 10. Figure 2. STIM-PLAVIM® device application modality.

Figure 1. STIM-PLAVIM® device.

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RESULTS

Statistically significant reductions in prostate volume, postvoid residual bladder volume and suprapubic prostatic transverse diameter between pre- and post-treatment with STIM-PLAVIM® device were found while there was no statistically significant reduction in PSA and IPSS. Prostatic volume, postvoid residual bladder volume, suprapubic prostatic transverse diameter, total PSA and IPSS before and after application of STIM-PLAVIM® device are shown in Table 1. The statistical results of the comparison between pre- and post-treatment data with STIM-PLAVIM® device are instead shown in Table 2. Reductions in prostate volume (mean difference of 6.35 ml, p = 0.003), postvoid residual bladder volume (mean difference of 28.8 ml, p = 0.032) and suprapubic prostatic transverse diameter (mean difference of 4 mm, p = 0.001) were significant at 95%, while there was no statistically significant reduction in PSA and IPSS. No problems related to adverse reactions or intolerance neither with the oral intake of alpha-blocker agents neither with application of STIMPLAVIM® device were reported. All patients completed the planned two-periods of the study, and none was excluded because of intolerance or lack of compliance.

DISCUSSION

Table 1. Prostatic volume, postvoid residual bladder volume, suprapubic prostatic transverse diameter, total PSA and IPSS before and after application of STIM-PLAVIM® device.

Prostatic volume (ml) Postvoid residual bladder volume (ml) Suprapubic prostatic transverse diameter (mm) Total PSA (ng/ml) IPSS (International Prostatic Symptoms Score)

After the daily oral intake of an alpha‐blocker agent for 45 days and before any application of STIM‐PLAVIM® device 44 ± 14 56 ± 70

After 45 daily application of STIM‐PLAVIM® device and without any alpha‐blocker agent 37 ± 11 28 ± 45

47 ± 5 2±2

43 ± 6 2±2

15 ± 6

13 ± 7

Table 2. Statistical results of the comparison between pre- and post-treatment data with STIM-PLAVIM® device. Variable

Prostatic volume (ml) Postvoid residual bladder volume (ml) Total PSA (ng/ml) IPSS Suprapubic prostatic transverse diameter (mm)

p-value

3.95 2.54 1.03 0.77

0.003 0.032 0.328 0.459

Mean 95% reduction confidence interval Lower bound Upper bound 6.35 2.72 9.98 28.8 3.14 54.5 0.479 -0.57 1.53 1.90 -3.66 7.46

The main finding of this study is that STIM-PLAVIM® device significantly reduced, in BPH patients, prostate volume and postvoid bladder volume more than the intake of 4.90 0.001 4.00 2.15 5.85 any alpha-blocker agent as well as the suprapubic prostatic transverse diameter. Instead, there was no statistically significant reduction in total PSA and IPSS. These results are partially consistent with the results of previous studies such as that one of Elgohary et al. (13) which demonstrated the effectiveness of pulsed electromagnetic fields alone or in association to exercise therapy in the treatment of benign prostatic hypertrophy in terms of IPSS improvement and reduction of bladder residue after voiding and that of Tenuta et al. (14) which likewise demonstrated the effectiveness of pulsed electromagnetic fields in terms of prostate volume reduction and IPSS enhancement. In neither of the two studies however the pulsed electromagnetic fields were compared with the standard drug therapy for benign prostatic hypertrophy. In the study of Giannakopoulos et al. (15) the exposure of BPH patients to a pulsed electromagnetic field or an alpha blocker therapy resulted in a statistically significant decrease of prostate volume and bladder residue after voiding, in the pulsed electromagnetic fields group, while the IPSS showed a statistically significant decrease before and after treatment both with pulsed electromagnetic fields and with the use of alpha-blockers. All above studies however used pulsed electromagnetic fields devices without the vibratory stimulus that is present in the STIM-PLAVIM® device. About lack of improvement in IPSS with STIM-PLAVIM® device it is necessary to point out that are well known the changes in the IPSS obtained with dutasteride, tamsulosin, and combination therapy in men with symptomatic benign prostatic hyperplasia and an enlarged prostate because the combination therapy with tamsulosin and dutasteride affords the greatest and the most rapid symptomatic benefit among those men and is effective regardless of previous BPH medical therapy (16). Given the above, the performance of STIM-PLAVIM® device about IPSS, similarly to what found in the work of Giannakopoulos (15), represents an invariance result rather than a failure since this result was obtained in comparison with alpha blockers that are very effective in ameliorating the IPSS. Besides, the failure to reduce IPSS remained within clinically insignificant limits and may be certainly compensated by the advantages in terms of greater safety, since all the adverse effects usually associated with alpha-blockers were excluded and there was no notable adverse effect with the use of STIM-PLAVIM® device nor significant contraindications to its use which resulted always well tolerated. Furthermore STIM-PLAVIM® device proved to be safe and more effective than alpha-blockers with respect to quantitative and objective parameters such as prostate volume and bladder residue after voiding. About the invariance of total PSA we must point out that in the our study the daily oral intake of an alpha-blocker agent or the use of STIM-PLAVIM® device were associated with a wide use of 5-alpha reductase inhibitors whose use remained therefore unchanged throughout the all duration of the study, so that we believe that the use of 5-alpha reductase inhibitors may be cause of the invariance of the total PSA values since those drugs have a deep impact over the total PSA values (16). Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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CONCLUSIONS

The our study, despite the small scale of the sample examined, it is the first pulsed electromagnetic fields study provided in a controlled, randomized and crossover design in patients affected by bladder outlet obstruction secondary to BPH where the pulsed electromagnetic fields (with the vibratory stimulus that is present in the STIM-PLAVIM® device) were compared with the standard BPH drug therapy obtaining a statistically significant decrease of two objective and quantitative parameters as the prostate volume and the postvoid residual bladder volume. This study therefore may open to a clinical use on a larger scale of this device in the same patients affected by bladder outlet obstruction secondary to BPH.

REFERENCES

1. McVary KT. Epidemiology and pathophysiology of benign prostatic hyperplasia. In: UpToDate, post TW (Ed), UpToDate, Waltham, MA. 2020. 2. McVary KT. Lower urinary tract symptoms in men. In: UpToDate, post TW (Ed), UpToDate, Waltham, MA. 2020. 3. Fourcade RO, Lacoin F, Rouprêt M, et al. Outcomes and general health-related quality of life among patients medically treated in general daily practice for lower urinary tract symptoms due to benign prostatic hyperplasia. World J Urol. 2012; 30:419-426. 4. Gratzke C, Bachmann A, Descazeaud A, et al. EAU Guidelines on the assessment of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol. 2015; 67:1099-1109. 5. Roehrborn CG, Siami P, Barkin J, et al. For the CombAT Study Group. The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the CombAT study. J Urol. 2008; 179:616-621. 6. BinhiV, Savin A. Effects of weak magnetic fields on biological systems: physical aspects, Phys Us pekhi. 2003; 46:259-291. 7. McFarlane JP, Foley SJ, de Winter P, et al. Acute suppression of idiopathic detrusor instability with magnetic stimulation of the sacral nerve roots. Br J Urol. 1997; 80:734-741. 8. Haddad JB, Obolensky AG, Shinnick P. The biologic effects and the therapeutic mechanism of action of electric and electromagnetic field stimulation on bone and cartilage: New findings and a review of earlier work. J Altern Complement Med. 2007; 13:485-490. 9. Bosco C, Cardinale M. Nuove frontiere dell’allenamento sportivo: le vibrazioni. Effetti sul comportamento meccanico del muscolo scheletrico. Coaching and Sport Science Journal. 1998; 3:53-59. 10. Flieger J, Karachalios T, Khaldi L, et al. Mechanical stimulation in the form of vibration prevents postmenopausal bone loss in ovariectomized rats. Calcif Tissue Int. 1998; 63:510-514. 11. Rodrigues MP, Paiva LL, Ramos JGL, Ferla L. Vibratory perineal stimulationfor the treatment of female stress urinary incontinence: A systematic review. Int Urogynecol J. 2018; 4:555-562. 12. Brardi S, Biandolino P, Giovannelli V, et al. Possible applications of electromagnetic fields in the treatment of symptoms related to benign prostatic hyperplasia. Am J Urol Res. 2020; 5:006-010. 13. ElgoharyHM, Tantawy SA. Pulsed electromagnetic field with or without exercise theraphy in the treatment of benign prostatic hyperplasia. J Phys Ther Sci. 2017; 29:1305-1310. 14. Tenuta M, Tarsitano MG, Mazzotta P, et al. Therapeutic use of pulsed electromagnetic field therapy reduces prostate volume and lower urinary tract symptoms in benign prostatic hyperplasia. Andrology. 2020; 8:1076-1085. 15. Giannakopoulos XK, Giotis C, karkabounas S Ch, et al. Effects of pulsed electromagnetic fields on benign prostate hyperplasia. Int Urol Nephrol. 2011; 43:955-60. 16. Roehrborn CG, Siami P, Barkin J, et al. The influence of baseline parameters on changes in international prostate symptom score with dutasteride, tamsulosin, and combination therapy among men with symptomatic benign prostatic hyperplasia and an enlarged prostate: 2-year data from the combat study. Eur Urol. 2009; 55:461-471.

Correspondence Simone Brardi, MD (Corresponding Author) sibrardi@gmail.com Hemodialysis Unit, S. Donato Hospital, Arezzo (Italy) Giuseppe Romano, MD giuseppe.romano@uslsudest.toscana.it Urology Unit, S. Maria della Gruccia Hospital, Montevarchi (Italy) Gabriele Cevenini, MD gabriele.cevenini@unisi.it Department of Medical Biotechnologies, University of Siena (Italy)

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ORIGINAL PAPER - SUPPLEMENTARY MATERIAL

The use and applicability of machine learning algorithms in predicting the surgical outcome for patients with benign prostatic enlargement. Which model to use? Panagiotis Mourmouris 1, Lazaros Tzelves , Georgios Feretzakis 2, 3, Dimitris Kalles 2, Ioannis Manolitsis 1, Marinos Berdempes 1, Ioannis Varkarakis 1, Andreas Skolarikos 1 1 2nd

APPENDIX A In what follows, assume𝑦1, 𝑦2, …𝑦𝑛to be the predicted values on test instances and 𝑦1, 𝑦2,..,𝑦𝑛to be the actual values. a) The correlation coefficient measures the correlation and dependence between observed values. The values range between -1 and 1, where 0 indicates no correlation, 1 a very strong positive correlation, and -1 a very strong negative correlation. The correlation coefficient measures the statistical correlation between 𝑦’s and 𝑦’s. 𝑟𝑦𝑦=𝑖=1𝑛(𝑦𝑖−𝑦)(𝑦𝑖−𝑦)𝑖=1𝑛(𝑦𝑖−𝑦)2𝑖=1𝑛(𝑦𝑖−𝑦)2 where𝑦=1𝑛𝑖=1𝑛𝑦𝑖 and 𝑦=𝑖=1𝑛𝑦𝑖 b) Mean Absolute Error (MAE) – this is an alternative calculated by the average of the individual errors without taking account of their sign. The mean-squared error tends to exaggerate the effect of outliers – instances whose prediction error is larger than the others – but the absolute error does not have this effect: all sizes of error are treated evenly according to their magnitude. 𝑀𝐴𝐸=𝑖=1𝑛𝑦𝑖−𝑦𝑖𝑛 c) Root Mean-Squared Error (RMSE) is the standard deviation of the prediction errors. The sensitivity of the RMSE to outliers is the most common concern with the use of this metric since the RMSE penalizes large errors while the MAE gives the same weight to all errors (1). 𝑅𝑀𝑆𝐸=𝑖=1𝑛𝑦𝑖−𝑦𝑖2𝑛 Concerning the values of the MAE and RMSE, the smaller their values, the better the model's performance, since both metrics are proportional to the difference between the actual and predicted values.

APPENDIX B 1) Linear Regression is a common statistical approach for constructing a linear model (function) predicting a value of the variable while knowing the values of the other variables. It uses the least mean square method to adjust the parameters of the linear model. 2) Multilayer Perceptron is performed on multi-layered neural networks, usually interconnected in a feed-forward manner, where each neuron on all layers, except the output one, feeds into the subsequent layer's neurons. The network parameters can also be monitored and modified during training time. Such networks are usually trained using an error back-propagation mechanism where the observed differences between actual and expected outputs help drive the adjustment of the weights (the connections between neurons). 3) SMOreg implements the support vector machine for regression (2). The parameters can be learned using various algorithms. The default algorithm (RegOptimizer) is the RegSMOImproved (3). 4) Instance-Based Learning (k-Nearest Neighbors) (lazy.IBk) Instance-based learning approaches (4), such as the k-nearest neighbors (kNN) algorithm, adopt a straightforward approach to estimate real or discrete-valued target functions (5). Predicting the output of a new input vector involves collecting and aggregating outputs from similar instances No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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(called “neighbors”) from the saved training data. Unlike many other techniques that create only one local approximation to the target function, an important advantage of instance-based algorithms is that the model can build a new approximation to the target function for each new query instance. This gives instance-based algorithms the ability to capture very complicated relationships between attributes and outputs. If the target variable depends only on a few of the attributes, this can cause very similar instances to be predicted at a large distance (6). In our experiments, the value of k was set to 4. 5) Meta-learning method ‘’Bagging’’ consists of aggregating results of n models generated on the basis of n bootstrap sets. The bootstrap sets are generated using feature selection or random drawing with substitution from the original dataset. The final result is calculated by averaging the outputs of individual models built over each bootstrap set (7-9). 6) M5Rules.This algorithm generates a decision list for regression problems using separate-and-conquer. In each iteration, it builds a model tree and then generates a rule out of the "best" leaf. The algorithm divides the space of the parameters into subspaces and builds in each of them a linear regression model. It is based on the M5 algorithm. Once all the examples are covered, the algorithm terminates (7, 9). 7) M5P – Pruned Model Tree. The algorithm is based on decision trees; however, instead of having values at the tree's nodes, it contains a multivariate linear regression model at each node. The input space is divided into cells using training data and their outcomes; then, a regression model is constructed as a tree leaf in each cell (7, 10, 11). 8) Random forests (12) is a substantial modification of bagging that creates a large number of de-correlated trees and then averages them. On many problems, the performance of random forests is very similar to boosting, and they are simpler to train and tune.

REFERENCES 1. Chai T. DRR. Root mean square error (RMSE) or mean absolute error (MAE)? – Arguments against avoiding RMSE in the literature. Geoscientific Model Development. 2. Smola AJ, Schölkopf B. A tutorial on support vector regression. Statistics and Computing. 2004; 14:199-222. 3. Shevade SK, Keerthi SS, Bhattacharyya C, Murthy KRK. Improvements to the SMO algorithm for SVM regression. IEEE Transactions on Neural Networks. 2000; 11:1188-93. 4. Ramyaa R, Hosseini O, Krishnan GP, Krishnan S. Phenotyping women based on dietary macronutrients, physical activity, and body weight using machine learning tools. Nutrients. 2019; 11. 5. Mitchell TM. 1997: McGraw-Hill Inc.: New York, NY, USA. 6. Wildeboer RR, van Sloun RJG, Wijkstra H, Mischi M. Artificial intelligence in multiparametric prostate cancer imaging with focus on deep-learning methods. Comput Methods Programs Biomed. 2020; 189:105316.

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7. Graczyk M, Lasota T, Trawi´nski B, Trawi´nski K, editors. Comparison of bagging, boosting and stacking ensembles applied to real estate appraisal. Intelligent Information and Database Systems; 2010 2010//; Berlin, Heidelberg: Springer Berlin Heidelberg. 8. Breiman L. Bagging predictors. Machine learning 1996; 24:123140. 9. Holmes G, Hall M, Prank E. Generating rule sets from model trees. Advanced topics in artificial intelligence. In: Foo N. (eds) Advanced Topics in Artificial Intelligence. AI 1999. Lecture Notes in Computer Science, vol 1747. Springer, Berlin, Heidelberg. 10. Quinlan RJ. Learning with Continuous Classes. In: 5th Australian Joint Conference on Artificial Intelligence, Singapore. 1992; 343348. 11. Wang Y, Witten IH. Induction of model trees for predicting continuous classes. Working Paper. 1996 Contract No.: 96/23. 12. Breiman L. Random Forests. Machine Learning. 2001; 45:5-32.

ORIGINAL PAPER - SUPPLEMENTARY MATERIAL

Serenoa repens and its effects on male sexual function. A systematic review and meta-analysis of clinical trials Gianni Paulis 1, Andrea Paulis 2, Gianpaolo Perletti 3, 4 1 Department

Characteristics of included studies COMPARISON TO PLACEBO Author, year Population Gerber 2001 Symptomatic BPH > 45 years

Intervention 160 mg twice daily, Nutraceutical, Ogden, Utah 136-152 mg fatty acids and sterols

Willetts 2003

Symptomatic BPH < 80 years 74 men sexually active

Zhang 2021

Ye 2019

CP/CPPS 18-50 years

354 patients with LUTS/BPH from 19 institutions

Control Serenoa 39

Follow up 6 months

Placebo 40

Serenoa repens extract 160 mg of CO2 extract; Blackmores Ltd, Sydney, Australia BID

Serenoa 46

Serenoa 160 mg soft capsule BID; supercritical carbon dioxide extract, provided by TAD Pharma GmbH

Serenoa 148

Serenoa repens extract (320 mg) or placebo groups for 24 weeks

Serenoa 150

12 weeks

Placebo 47

12 weeks

Placebo 73

Placebo 154

24 weeks

Outcome O’Leary Sexual function questionnaire Serenoa Pre 20.7 (11.3) Post 20.6 (11.2) Delta - 0.1 (8.0) Placebo Pre 21.7 10.1 Post 21.6 10.7 Delta - 0.1 (6.8) P = 0.75 IIEF score Serenoa 51.5 (43.9–59.1) 55.11 (48.4–61.8) Delta 3.6 ± 1.49 Placebo 49.4 (43.3-55.4) 48.7 (41.9–55.4) Delta 0.7 ± 1.33 IIEF-5 Serenoa Pre 18.82 ± 4.47 Delta + 1.32 ± 2.95 Placebo Pre 17.89 ± 5.50 Delta + 1.01 ± 3.07 P = 0.4778 MSF-4 Serenoa Pre 12.01 +/- 3.98 Delta + 1.15+/-3.47 Placebo Pre 11.70 +/-3.66 Delta + 0.23 +/- 2.69 0.0096 IIEF Serenoa Pre 32.06 +/- 16.47 Delta - 2.61 +/-11.22 Placebo Pre 34.69 +/-15.63 Delta + 0.88 +/- 9.72 0.0068

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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Avins 2009

Symptomatic BPH > 50 years

Saw palmetto berry extract, 160 mg twice daily

Serenoa 112

12 months

O’Leary Brief Sexual Function Inventory Serenoa 22.34 ± 0.471 22.45 ± 0.477 Delta 0.11 ± 0.063 Placebo 22.27 ± 0.471 22.19 ± 0.475 Delta 0.08 ± 0.063

3 months

MSF4 score Serenoa 7.4 (4.5) 7.7 (4.8) Delta 0.36 (0.35) Tamsulosin 6.9 (4.5) 7.7 (4.7) Delta 0.64 (0.35) MSF4 Serenoa 8.3 (5.5) 8.8 (5.4) Delta 0.5 (3.3) Placebo 7.7 (5.0) 8.2 (5.0) Delta 0.4 (3.5) 0.69 Ejaculation disorderd 0/65 1/59

Placebo 113

COMPARISON WITH TAMSULOSIN Latil 2015 Symptomatic BPH 45-85 years

Debruyne 2002

Symptomatic BPH 50-85 years

Serenoa repens 320 mg

Serenoa 83

Hexanic extract

Tamsulosin 0.4 mg 86

Serenoa

Serenoa 267

12 months

Hexanic extract Tamsulosin 266

Debruyne 2004

Severe symptomatic BPH

Serenoa

The mean (S.D.) patient age was 65.2 (7.5) years

Hizli 2007

43 years and 73 years, with symptomatic BPH were included in the study. This open-label

COMPARISON WITH FINASTERIDE Carraro 1996 Patients with symptomatic BPH > 50 years

MSF4 Serenoa 8.9 (5.70) Delta + 0.2 (3.7) Placebo 8.0 (5.55) Delta + 1.0 (4.0) P = 0.46

Serenoa Open label

Serenoa hexane extract 160 mg bid Finasteride 5 mg

475 B

Serenoa 65 Tamsulosin 59

Archivio Italiano di Urologia e Andrologia 2021; 93, 4

Serenoa 20 Tamsulosin 20 Association 20

6 months

467

26 weeks

484

‘‘achieving ejaculation’’ rather worsened in the tamsulosin group p = 0.087 Ejaculation disorders Serenoa 0 Tamsulosin 7 Association 3

Sexual function score Serenoa 8.4 (5.5) 7.9 (5.4) (NS) Finasteride 8.6 (5.5) 9.3 (5.7) P < 0.001

Serenoa repens and sexual function

Incomplete outcome data

Selective reporting

Other biases

L L L L L

Serenoa extract compared to tamsulosin Debruyne ? L L

2002 Debruyne 2004 Hizli 2007 Latil 2015

Blinding of participants and personnel

? L ? ? ?

Allocation concealment

Serenoa extract compared to placebo Avins 2009 ? L ? Gerber 2001 L L L Willetts 2003 L L L Ye 2019 ? L L Zhang 2021 L L L

Random sequence generation

Blinding of outcome assessment

Risk of Bias

? ?

H H

L L

Serenoa extract compared to finasteride Carraro 1996 L L L

Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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ORIGINAL PAPER - SUPPLEMENTARY MATERIAL

List of papers included in the metanalysis 1. Schröder FH, Whelan P, de Reijke TM, Kurth KH, PavoneMacaluso M, Mattelaer J, van Velthoven RF, Debois M, Collette L; Members of the EORTC Genito-Urinary Group. Metastatic prostate cancer treated by flutamide versus cyproterone acetate. Final analysis of the "European Organization for Research and Treatment of Cancer" (EORTC) Protocol 30892. Eur Urol. 2004; 45:457-64. 2. Iversen P, McLeod DG, See WA, Morris T, Armstrong J, Wirth MP; Casodex Early Prostate Cancer Trialists' Group. Antiandrogen monotherapy in patients with localized or locally advanced prostate cancer: final results from the bicalutamide Early Prostate Cancer programme at a median follow-up of 9.7 years. BJU Int. 2010; 105:1074-81. 3. Shipley WU, Seiferheld W, Lukka HR, Major PP, Heney NM, Grignon DJ, Sartor O, Patel MP, Bahary JP, Zietman AL, Pisansky TM, Zeitzer KL, Lawton CA, Feng FY, Lovett RD, Balogh AG, Souhami L, Rosenthal SA, Kerlin KJ, Dignam JJ, Pugh SL, Sandler HM; NRG Oncology RTOG. Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer. N Engl J Med. 2017; 376:417-428. 4. Zanardi S, Puntoni M, Maffezzini M, Bandelloni R, Mori M, Argusti A, Campodonico F, Turbino L, Branchi D, Montironi R, Decensi A. Phase I-II trial of weekly bicalutamide in men with elevated prostate-specific antigen and negative prostate biopsies. Cancer Prev Res (Phila). 2009; 2:377-84. 5. Alberts SR, Novotny PJ, Sloan JA, Danella J, Bostwick DG, Sebo TJ, Blute ML, Fitch TR, Levitt R, Lieberman R, Loprinzi CL. Flutamide in men with prostatic intraepithelial neoplasia: A randomized, placebo-controlled chemoprevention trial. American Journal of Therapeutics 2006; 13: 291-297. 6. Narayan P, Trachtenberg J, Lepor H, Debruyne FM, Tewari A, Stone N, Das S, Jimenez-Cruz JF, Shearer R, Klimberg I, Schellhammer PF, Costello AJ. A dose-response study of the effect of flutamide on benign prostatic hyperplasia: results of a multicenter study. Urology. 1996; 47:497-504. 7. Berger BM, Naadimuthu A, Boddy A, Fisher HA, McConnell JD, Milam D, Mobley D, Rajfer J. The effect of zanoterone, a steroidal

androgen receptor antagonist, in men with benign prostatic hyperplasia. The Zanoterone Study Group. J Urol. 1995; 154:1060-4. 8. Andriole GL, Bostwick DG, Brawley OW et al. REDUCE Study Group Effect of dutasteride on the risk of prostate cancer. N Engl J Med 2010; 362:1192-202. 9. Na Y, Ye Z, Zhang S. Efficacy and Safety of Dutasteride in Chinese Adults with Symptomatic Benign Prostatic Hyperplasia: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study with an Open-Label Extension. Clin Drug Investig. 2012; 32:29-39. 10. Roehrborn CG, Boyle P, Nickel J.Curtis, Hoefner K, Andriole G. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia Urology 2002; 60:34-441. 11. McConnell JD, Bruskewitz R, Walsh P, Andriole G, Lieber M, Holtgrewe HL, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety Study Group. N Engl J Med. 1998; 338:557-63. https://doi.org/10.1056/NEJM199802263380901 PMID: 9475762. 12. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, Coltman CA Jr. The influence of finasteride on the development of prostate cancer.N Engl J Med. 2003; 349:215-24. 13. Amory JK, Wang C, Swerdloff RS, Anawalt BD, Matsumoto AM, Bremner WJ, Walker SE, Haberer LJ, Clark RV. The effect of 5areductase inhibition with dutasteride and finasteride on semen parameters and serum hormones in healthy men Journal of Clinical Endocrinology and Metabolism 2007; 92:1659-1665. 14. Nickel JC, Gilling P, Tammela TL, Morrill B, Wilson TH, Rittmaster RS. Comparison of dutasteride and finasteride for treating benign prostatic hyperplasia: the Enlarged Prostate International Comparator Study (EPICS). BJU Int. 2011; 108:388-94. 15. Bianchi S., Bigazzi R., Campese VM. Long-term effects of

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 4

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A. Trinchieri, G. Perletti, V. Magri, K. Stamatiou, M. Trinchieri, E. Montanari

spironolactone on proteinuria and kidney function in patients with chronic kidney disease Kidney International 2006; 70:2116-2123. 16. Charytan DM, Himmelfarb J, Ikizler TA, Raj DS, Hsu JY, Landis JR, Anderson AH, Hung AM, Mehrotra R, Sharma S, Weiner DE, Williams M, DiCarli M, Skali H, Kimmel PL, Kliger AS, Dember LM; Hemodialysis Novel Therapies Consortium. Safety and cardiovascular efficacy of spironolactone in dialysis-dependent ESRD (SPin-D): a randomized, placebo-controlled, multiple dosage trial. Kidney Int. 2019; 95:973-982. 17. Edelmann F, Wachter R, Schmidt AG, Kraigher-Krainer E, Colantonio C, Kamke W, Duvinage A, Stahrenberg R, Durstewitz K, Löffler M, Düngen H-D, Tschöpe C, Herrmann-Lingen C, Halle M, Hasenfuss G, Gelbrich G, Pieske B. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: The Aldo-DHF randomized controlled trial JAMA - Journal of the American Medical Association. 2013; 309:781791. 18. Gao X, Peng L, Adhikari CM, Lin J, Zuo Z. Spironolactone Reduced Arrhythmia and Maintained Magnesium Homeostasis in Patients With Congestive Heart Failure Journal of Cardiac Failure, 2007; 13:170-177 19. Ito Y, Mizuno M, Suzuki Y, Tamai H, Hiramatsu T, Ohashi H, Ito I, Kasuga H, Horie M, Maruyama S, Yuzawa Y, Matsubara T, Matsuo S, Watanabe M, Nishimura H, Mizutani M, Kinashi H, Dambara A, Saka Y, Toda S, Kimu S, Minoshima K, Yamaha M, Takahashi R, Kimura K, Naruse T, Matsuoka T, Inaguma D, Kurata K. Long-term effects of spironolactone in peritoneal dialysis patients Journal of the American Society of Nephrology 2014; 25:1094-1102. 20. Kayrak M, Bacaksiz A, Vatankulu MA, Ayhan SS, Ari H, Kaya Z, Ozdemir K. The effects of spironolactone on atrial remodeling in patients with preserved left ventricular function after an acute myocardial infarction: A randomized follow-up study Coronary Artery Disease 2010; 21:477-485. 21. Matsumoto Y, Mori Y, Kageyama S, Arihara K, Sugiyama T, Ohmura H, Yakushigawa T, Sugiyama H, Shimada Y, Nojima Y, Shio N. Spironolactone reduces cardiovascular and cerebrovascular morbidity and mortality in hemodialysis patients. J Am Coll Cardiol. 2014; 63:528-36. 22. Ni X, Zhang J, Zhang P, Wu F, Xia M, Ying G, Chen J.Effects of spironolactone on dialysis patients with refractory hypertension: A randomized controlled study Journal of Clinical Hypertension 2014; 16:658-663. 23. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999; 341:709-17. 24. Skvortsov AA, Mareev VY, Chelmakina SM, Baklanova NA,

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Belenkov IuN. [Efficacy and safety of long-term application of spironolactone in patients with moderate and severe chronic heart failure receiving optimal therapy]. Kardiologiia. 2007; 47:12-23. 25. Tofte N, Lindhardt M, Adamova K, Bakker SJL, Beige J, Beulens JWJ, Birkenfeld AL, Currie G, Delles C, Dimos I, Francová L, Frimodt-Møller M, Girman P, Göke R, Havrdova T, Heerspink HJL, Kooy A, Laverman GD, Mischak H, Navis G, Nijpels G, Noutsou M, Ortiz A, Parvanova A, Persson F, Petrie JR, Ruggenenti PL, Rutters F, Rychlík I, Siwy J, Spasovski G, Speeckaert M, Trillini M, Zürbig P, von der Leyen H, Rossing P; PRIORITY investigators. Early detection of diabetic kidney disease by urinary proteomics and subsequent intervention with spironolactone to delay progression (PRIORITY): a prospective observational study and embedded randomised placebocontrolled trial. Lancet Diabetes Endocrinol. 2020; 8:301-312. 26. Vatankulu MA, Bacaksiz A, Sonmez O, Alihanoglu Y, Koc F, Demir K, Gul EE, Turfan M, Tasal A, Kayrak M, Yazici M, Ozdemir K. Does spironolactone have a dose-dependent effect on left ventricular remodeling in patients with preserved left ventricular function after an acute myocardial infarction? Cardiovascular Therapeutics 2013; 31:224-229. 27. Vizzardi E, Pina PD, Caretta G, Bonadei I, Sciatti E, Lombardi C, D'Aloia A, Curnis A, Metra M. The effect of aldosterone-antagonist therapy on aortic elastic properties in patients with nonischemic dilated cardiomyopathy Journal of Cardiovascular Medicine. 2015; 16:597-602. 28. Zarraga IGE, Dougherty CM, MacMurdy KS, Raitt MH. Tachyarrhythmias the effect of spironolactone on ventricular tachyarrhythmias in patients with implantable cardioverter-defibrillators Circulation: Arrhythmia and Electrophysiology. 2012; 5:739-747. 29. Kelly DL, Conley RR. A randomized double-blind 12-week study of quetiapine, risperidone or fluphenazine on sexual functioning in people with schizophrenia Psychoneuroendocrinology. 2006; 31:340-346. 30. McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA, Swartz MS, Perkins DO, Keefe RS, Davis CE, Severe J, Hsiao JK; CATIE Investigators. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006; 163:600-10. 31. McEvoy JP, Lieberman JA, Perkins DO, Hamer RM, Gu H, Lazarus A, Sweitzer D, Olexy C, Weiden P, Strakowski SD. Efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: A randomized, double-blind 52-week comparison American Journal of Psychiatry. 2007; 164:1050-1060. 32. McEvoy JP, Byerly M, Hamer RM, Dominik R, Swartz MS, Rosenheck RA, Ray N, Lamberti JS, Buckley PF, Wilkins TM, Stroup TS. Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial. JAMA. 2014; 311:1978-87.

Drug-induced gynecomastia

ANTIANDROGENS

Author/Year

Population

Intervention

Follow-up

Gynecomastia/ Painful gynecomastia

Flutamide (250 mg t.i.d. p.o.) Cyproterone (100 mg t.i.d. p.o.)

8.6 yrs

Without pain 34 (22.5) 35 (23.0) Painful 65 (43.0) 11 (7.2)

Localized (T1-2, N0/Nx) or locally advanced (T3-4, any N; or any T, N+) prostate cancer (all M0) Prostate-cancer recurrence after radical prostatectomy (elevated PSA)

Bicalutamide 150 mg daily vs placebo three double-blind, placebo-controlled trials 8113 pts 4052+4061 Radiation therapy Plus Bicalutamide 150 mg daily Vs Radiation therapy alone Plus placebo 258+258

9.7 yrs

Phase I-II trial men with PSA > 4 ng/mL and negative biopsies

Nonrandomly assigned three-arm trial bicalutamide 50 mg/wk (n = 26) 100 mg/wk (n = 28) no treatment (n = 26)

6 months

Breast pain Gynaecomastia Bicalutamide 2766 (68.8) 2963 (73.7) Placebo 334 (8.3) 308 (7.6) Gynecomastia Bicalutamide Grade 1 42.4% Grade 2 23.6% Grade 3 3.7% Total 69.7% Placebo 8.8% 2.1% 0% 10.9% Gynaecomastia Grade 2 6 (23%) 50 mg/wk 12 (43%) 100 mg/wk 0 (0%)

Men with biopsy proven HGPIN

Flutamide 250 mg/d = 30 placebo = 30 randomized in a double-blind Flutamide 125 mg twice daily = 75 Flutamide 250 mg once daily = 69 Flutamide 250 mg twice daily = 74 Flutamide 250 mg three times daily = 75 Placebo = 74

1 yr

Cyproterone vs Flutamide Schröder 2004 Metastatic prostate cancer and favourable prognostic factors

Bicalutamide Iversen 2010

Shipley 2017

Zanardi 2009

Flutamide Alberts 2006

Narayan 1996

benign prostatic hyperplasia 372 patients

24 months

24 weeks

Slight/moderate Flutamide 11/4 Placebo 1/0 Breast tenderness (42% to 52%) 38 36 31 32 4 gynecomastia (14% to 19%) 12 10 14 11 2

Archivio Italiano di Urologia e Andrologia 2021; 93, 4

489 C

A. Trinchieri, G. Perletti, V. Magri, K. Stamatiou, M. Trinchieri, E. Montanari

Zanoterone Berger 1995

Benign prostatic hyperplasia 463 patients

Zanoterone 100 mg. = 89 200 mg. = 92 400 mg. = 95 800 mg. = 94 Placebo = 93

6 months

Breast pain 36 (40) 51 (55) 52 (55) 70 (74) 4 (4) Gynecomastia 16 (18) 16 (17) 19 (20) 32 (34) 1 (1)

double-blind randomized treatment

5-ALPHA-REDUCTASE INHIBITORS 5-ALPHA-REDUCTASE INHIBITORS

Author/Year Dutasteride Andriole 2010

Na 2012

Roehrborn 2004

Population

Intervention

Follow-up

Gynecomastia Intervention/Control

REDUCE 50 to 75 years PSA 2.5-10.0 negative prostate biopsy 253

Dutasteride = 4105 Placebo = 4126

4 yrs

76 43

Dutasteride 126 PBO 127 Dutasteride PBO

12 mo

1/126 0/127

1 yr 1397+1405 2 yr 1128+1123

1.1 vs 0.5%

Finasteride = 1524 Placebo = 1516 Finasteride = 9423 Placebo = 9457

2-4 yrs

1.8% 1.1% 426 261

Finasteride = 34 Dutasteride = 33 Placebo = 32

8/34 3/33 2/32

ARIA 3001 ARIA 3002 2802

Finasteride McConnell 1998

3040

Thompson 2003

PCPT

Durasteride vs Finasteride Amory 2007 99 healthy men

Nickel 2011

489 D

BPH patients = 1630

double-blinded, placebocontrolled trial Dutasteride 813 Finasteride 817

Archivio Italiano di Urologia e Andrologia 2021; 93, 4

7 yrs

Notes

1.6 vs 0.2%

1 yr

D and F significantly (P < 0.001) suppressed serum DHT transiently increased serum T.

48 wks

9/813 10/817

Drug-induced gynecomastia

SPIRONOLACTONE

Author/Year

Population

Intervention

Follow-up

Bianchi 2006

Patients with chronic kidney disease Hemodialysis patients

Spironolactone 25 mg/day randomized open-label study Spironolactone 12.5-50 mg/day placebo

1 yr

Charytan 2019

Edelmann 2013

Chronic heart failure

Gao 2007

Congestive heart failure (CHF)

Ito 2014

ESRD undergoing peritoneal dialysis Revascularized with percutaneous coronary intervention

Kayrak 2010

a double-blind, placebo-controlled Spironolactone 25 mg placebo Spironolactone 20 mg placebo Spironolactone control group Spironolactone 25 mg/day

Oligoanuric hemodialysis patients

standard conventional therapy Spironolactone controls

Ni 2014

Dialysis patients with refractory hypertension

randomized, controlled, open-label trial Spironolactone 25!mg/day placebo

Pitt 1999

Severe heart failure left ventricular ejection fraction < 35% Chronic heart failure (CHF)

Matsumoto 2014

Skvortsov 2013

Tofte 2020

25 - 75 mg Type 2 diabetes

Vatankulu 2013

Revascularized patients with acute ST elevation MI (STEMI)

Vizzardi 2015

Nonischemic dilated cardiomyopathy

Zarraga 2012

Patients with implantable cardioverterdefibrillators (ICDs)

Spironolactone 25 mg placebo Group 1 - 19 patients receiving spironolactone in a 24 hour dose 25 - 75 mg, group 2 - control group 30 patients Spironolactone 25 mg placebo 102 vs 107 Spironolactone 12.5 25 mg none Spironolactone 25!mg/day (up to 100!mg/day) placebo Spironolactone 25 mg placebo

36 wks

Gynecomastia Intervention/Control 6/83 0/82 3/76 2/51

12 mo

9/213 0/209

6 mo

3/58 0/58

2 yrs

11/78 2/80 3/55 0/55

6 mo

36 wks

16/157 0/152

12 wks

1/40 0/36

24 mo

61 of 614 men 9 of 604 men

12 mo

Gynecomastia or pain in the region of mammary glands were fixed in 26,3% of patients in 12 months of treatment Gynecomastisa

2·51 years

3/102 vs 0/107 6 mo

0/50 4/54 0/56

6 mo

1/51 0/51

35 mo

4/44 0/46

double-blind fashion

Archivio Italiano di Urologia e Andrologia 2021; 93, 4

489 E

A. Trinchieri, G. Perletti, V. Magri, K. Stamatiou, M. Trinchieri, E. Montanari

ANTIPSYCHOTICS

489 F

Author/Year

Population

Intervention

Follow-up

Kelly 2006

Schizophrenia (males)

Risperidone (4 mg/day), quetiapine (400 mg/day) fluphenazine (12.5 mg/day)

12-week

Mc Evoy 2006

Schizophrenia with inadequate response to treatment

Mc Evoy 2007

Early psychotic illness

McEvoy 2014

Schizophrenia or schizoaffective disorder

randomized double-blind Clozapine (N=49) olanzapine (N=19) quetiapine (N=15) risperidone (N=16) randomly assigned to open-label treatment Olanzapine quetiapine risperidone randomized, double-blind Paliperidone Palmitate 39 to 234 mg Haloperidol Decanoate 25 to 200 mg Intramuscular monthly double-blind, randomized clinical trial

Archivio Italiano di Urologia e Andrologia 2021; 93, 4

3 mo

Gynecomastia/galactorrhea Intervention/Control risperidone 1/9 males (11%) fluphenazine 0/8 quetiapine 0/6 1/49 1/19 0/15 0/16

52-week

9/133 3/134 13/133

24 months

4 /147 (2.7%) 5/ 147 (3.4%)

Drug-induced gynecomastia

Blinding of participants and personnel

Blinding of outcome assessment

Incomplete outcome data

Selective reporting

Other biases

Antiandrogens Cyproterone vs flutamide Schroder 2000-2004 ? Bicalutamide vs placebo Iversen 2010 L Bicalutamide Shipley 2017 ? Bicalutamide Zanardi 2009 ? Bicalutamide Flutamide vs placebo Alberts 2006 L Flutamide Narayan 1996 ? Flutamide Zanoterone vs placebo Berger 1995 ? Zanoterone 5-alpha-reductase Dutasteride Andriole 2010 ? Na 2012 L Roehrborn 2002 ? Finasteride McConnell 1998 ? Thompson 2004 L Dutasteride vs finasteride Amory 2007 L Nickel 2011 ? Spironolactone Bianchi 2006 L Charytan 2019 L Edelmann 2013 L Gao 2007 ? Ito 2014 ? Kayrak 2010 ? Matsumoto 2014 ? Ni 2014 ? Pitt 1999 ? Skvortsov 2013 ? Tofte 2020 L Vatankulu 2013 ? Vizzardi 2015 ? Zarraga 2012 L Antipsychotics Kelly 2006 ? Mc Evoy 2006 ? Mc Evoy 2007 ? Mc Evoy 2014 ?

Allocation concealment

Random sequence generation

Risk of Bias assessment

? ? ?

L ? ?

? ? ?

L L ?

L L L

L ?

? ?

? L

L L

L ?

? ?

L L

H L L ? H H H ? ? H L H ? L

H ? L L L H H ? L H L L ? L

? L L L ? ? H ? ? ? ? ? ? L

L L L L L L L L L L L L L L

? ? ? ? ? ? ? ? L ? ? ? ? L

? ? ? ?

? ? L L

? ? ? L

H L L L

L L L L

Archivio Italiano di Urologia e Andrologia 2021; 93, 4

489 G

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