Archivio Italiano di Urologia e Andrologia - Vol. 94 - n. 2 - 2022 by Edizioni Scripta Manent

ISSN 1124-3562

Vol. 94; n. 2, June 2022

ORIGINAL PAPERS 129

Outcomes of nephrectomy for renal cell carcinoma: An ecologic retrospective study in a middle-income country Alexandre Dib Partezani, Hugo Octaviano Duarte-Santos, Breno Santos Amaral, Alan Roger Gomes Barbosa, Marcelo Apezzato, João Brunhara, Bianca Bianco, Gustavo Caserta Lemos, Arie Carneiro

134

Endoscopic laser en bloc removal of bladder tumor. Surgical radicality and improvement of the pathological diagnostic accuracy Rosario Leonardi, Alessandro Calarco, Lorenzo Falcone, Vincenzo Grasso, Marco Frisenda, Antonio Tufano, Pietro Viscuso, Antonio Rossi, Lorenzo Memeo

138

Variant histologies of urothelial carcinoma: Does it change the survival outcomes in patients managed with radical cystectomy? João Nuno Pereira, João Duarte Reis, Isaac Braga, Rui Freitas, Vitor Moreira da Silva, Sanches Magalhães, Francisco Lobo, António Morais

144

Extraperitoneal cystectomy with ureterocutaneostomy derivation in fragile patients - should it be performed more often? Rafaela Malinaric, Guglielmo Mantica, Federica Balzarini, Carlo Terrone, Massimo Maffezzini

150

The effect of retroperitonealization of ureteroileal anastomosis on perioperative complications of radical cystectomy with ileal conduit urinary diversion Ali Ariafar, Mehdi Salehipour, Shahriar Zeyghami, Mehran Rezaei

155

Morbidity following transperineal prostate biopsy: Our experience in 8.500 men Pietro Pepe, Michele Pennisi

160

Cost-effectiveness analysis of short biparametric magnetic resonance imaging protocol in men at risk of prostate cancer Niccolò Faccioli, Elena Santi, Giovanni Foti, Pierpaolo Curti, Mirko D’Onofrio

166

Erectile dysfunction following hydrogel injection and hypofractionated radiotherapy for prostate cancer: Our experience in 56 cases Pietro Pepe, Maria Tamburo, Paolo Panella, Ludovica Pepe, Giulia Marletta, Michele Pennisi, Francesco Marletta

169

Prostate resection weight matters in severely obstructed men undergoing transurethral resection of the prostate Filipe Lopes, Ricardo Pereira e Silva, Miguel Fernandes, Tito Palmela Leitão, José Palma dos Reis

174

Is Holmium Laser Enucleation of Prostate equally effective in management of benign prostatic hyperplasia patients with either voiding or storage lower urinary tract symptoms? A comparative study Mostafa M. Mostafa, Nilesh Patil, Mahmoud Khalil, Mohammed A. Elgammal, Ayman Mahdy

180

Comparative analysis of MOSESTM technology versus novel thulium fiber laser (TFL) for transurethral enucleation of the prostate: A single-institutional study Hazem Elmansy, Amr Hodhod, Ahmed Elshafei, Yasser A Noureldin, Vahid Mehrnoush, Ahmed S. Zakaria, Ruba Abdul Hadi, Moustafa Fathy, Loay Abbas, Ahmed Kotb, Walid Shahrour

186

Sheathed flexible retrograde intrarenal surgery without safety guide wire for upper urinary tract stones Murad Asali

190

Retrograde Intrarenal Surgery (RIRS) for upper urinary tract stones in children below 12 years of age: A single centre experience Mohanarangam Thangavelu, Ajit Sawant, Ali Abbas Sayed, Praksah Pawar, Mohamed Hamid, Sunil Patil, Vikas Bhise, Jeni Mathews, Raunak Shewale, Mohan Gadodia

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

- NOVITÀ Questo Trattato nasce dall’esigenza di offrire evidenze scientifiche della letteratura in diversi àmbiti clinici, riguardo alla Nutraceutica in Pediatria, in un contesto attuale dove è molto forte da parte della società la propensione a ricorrere a “prodotti naturali”. I temi trattati sono a sostegno di scelte mirate da parte del Pediatra, che possono essere di supporto dal punto di vista preventivo e terapeutico, per la salute di bambini e adolescenti.

25 Capitoli 64 Autori 480 Pagine a cura di Gianvincenzo Zuccotti Enza D’Auria Elvira Verduci

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ORIGINAL PAPERS 195

Spinal versus general anesthesia in retrograde intrarenal surgery Mehmet Yoldas, Tuba Kuvvet Yoldas

199

Molecular analysis of microorganisms in the semen and their impact on semen parameters Jenniffer Puerta Suárez, Juan Carlos Hernandez, Walter Dario Cardona Maya

206

Role of tunica vaginalis flap and dartos flap in tubularized incisional plate for primary hypospadias repair: A retrospective monocentric study Faisal Ahmed, Hossein-Ali Nikbakht, Khalil Al-Naggar, Saleh Al-Wageeh, Qasem Alyhari, Saif Ghabisha, Ebrahim Al-Shami, Menawar Dajenah, Waleed Aljbri, Fawaz Mohammed, Abdu Al-Hajri

211

Erectile dysfunction and mobile phone applications: Quality, content and adherence to European Association guidelines on male sexual dysfunction Luigi Napolitano, Giovanni Maria Fusco, Luigi Cirillo, Marco Abate, Claudia Mirone, Biagio Barone, Giuseppe Celentano, Roberto La Rocca, Vincenzo Mirone, Massimiliano Creta, Marco Capece

217

Platelet volume parameters as a tool in the evaluation of acute ischemic priapism in patients with sickle cell anemia Essa A. Adawi, Mazen A. Ghanem

222

The distribution of the clinical variables in a population of adult males circumcised for phimosis: A contribution to the clinical classification of phimosis Giuseppe La Pera, Stefano Lauretti

228

Cyber pornography use and masturbation outburst. Considerations on 150 italian patients complaining erectile dysfunction and trying to solve it Diego Pozza, Mariangela Pozza, Augusto Mosca, Carlotta Pozza

232

Erectile function in amateur cyclists

Duarte Vieira e Brito, Mário Pereira-Lourenço, Jose Alberto Pereira, Miguel Eliseu, Carlos Rabaça

REVIEWS 237

An update on the management algorithms of priapism during the last decade Mohamad Moussa, Mohamad Abou Chakra, Athanasios Papatsoris, Athanasios Dellis, Michael Peyromaure, Nicolas Barry Delongchamps, Hugo Bailly, Sabine Roux, Ahmad Abou Yassine, Igor Duquesne

248

The association of bladder cancer and Cannabis: A systematic review Vahid Mehrnoush, Stacy Grace de Lima, Ahmed Kotb, Matthew Eric Hyndman

252

Effect of alpha-adrenoceptor antagonists on sexual function. A systematic review and meta-analysis Rawa Bapir, Kamran Hassan Bhatti, Ahmed Eliwa, Herney Andrés García-Perdomo, Nazim Gherabi, Derek Hennessey, Vittorio Magri, Panagiotis Mourmouris, Adama Ouattara, Gianpaolo Perletti, Joseph Philipraj, Alberto Trinchieri, Noor Buchholz

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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 2022, 94, 2

III

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DOI: 10.4081/aiua.2022.2.129

ORIGINAL PAPER

Summary

Objective: The aim of this study was to describe and compare the outcomes and indirect costs of oncological radical (RN) and partial nephrectomies (PN) in hospitals from the São Paulo public health system, Brazil. Materials and methods: An ecologic retrospective study was performed from 2008 to 2019, using the TabNet Platform of the Brazilian Unified Health System Department of Informatics. Hospitals were classified according to volume of surgeries (low and high-volume, and also into four quartiles according to volume of surgeries), and with or without medical residency program in urology. The results were compared between groups. Results: In the period analyzed were performed 2.606 RN in 16 hospitals. Data available for PN ranged only from 2013-2019 and included 1.223 surgeries comprising 15 hospitals. Overall mortality rates were 0.41% for PN and 2.87% for RN. The length of hospital stay was significantly higher in low-volume hospitals for both RN and PN (8.97 vs. 5.62 days, p = 0.001, and 7.75 vs. 4.37 days, p = 0.001, respectively), and also for the RN in hospitals without residency program in Urology (9.37 vs. 6.54 days, p = 0.03). When the volume of surgeries was divided into four quartiles, the length of hospital stay and ICU hospitalization days were significantly higher in the first quartile hospitals for RN (p = 0.016) and PN (p = 0.009), respectively. The mortality rates and indirect costs were not different considering PN and RN in the different types of hospitals. Conclusions: The length of hospital stay was significantly lower for both PN and RN in high-volume hospitals, and also for RN in hospitals with residency program in Urology.

KEY WORDS: Nephrectomy; Renal cell carcinoma; Mortality rates; Teaching Hospital. Submitted 25 March 2022; Accepted 31 May 2022

INTRODUCTION

Renal cell carcinoma (RCC) derives from the renal cortex, comprising approximately 85% of all primary renal neoplasms. It mostly affects older adults, presenting between 50 years and 70 years along with known risk factors, such as smoking, obesity and hypertension. It represents 2-3% of all cancers, its incidence has been increasing worldwide, being 5.8 per 100.000, and it is the most lethal of common urological cancers, although the five-year survival rate has doubled over the last 60 years from 34% in 1954 to 75% between 2009 and 2015 (1-5).

These better outcomes in survival rate have been achieved because of the widespread use of cross-sectional imaging in recent years, leading to an increase in incidental detection (6, 7), that contribute to better prognostic factors and TNM staging, therefore leading to the best treatment approach (8). The gold standard treatment is surgical management: radical nephrectomy (RN) and partial nephrectomy (PN). RN can be performed open or laparoscopically (robotassisted or not). PN has been widely used in the last few years because of improvements in surgical techniques, surgical apparatus and increased diagnosis of small RCC, and should be prioritized in the setting of solitary kidneys, bilateral renal tumors and advanced chronic kidney disease (CKD) (9, 10). Due to the preservation of renal function with PN, some studies suggest better overall survival in comparison with RN (11, 12). Although a randomized controlled trial (EORTC 30904) (13) did not confirm this finding for tumors < 5 cm. Each of these procedures has specific complications which should be considered before the surgery is indicated. In terms of hemorrhage, urine leak/fistula and reoperation for complications, RN versus PN were 1.2% vs. 3.1%, 0% vs. 4.4%, and 2.4% vs. 4.4%, respectively (13). RN increases the risk for CKD (11, 14, 15) and has an increased cardiovascular-specific mortality in comparison with PN (12, 16). From the 210 million Brazilian inhabitants, about 80% of patients rely on public health services, also known as Sistema Único de Saude (SUS) for medical treatment. São Paulo city has one of the largest populations worldwide, and in 2018, it had about 34 million medical appointments relying on SUS (17, 18). Hospitals of the public health system charge the procedures according to the codes and receive a predetermined fixed amount of reimbursement for each code. We hypothesize that high volume centers with experienced staff and standardized protocols may provide lower morbidity and costs related to RCC treatment, hence providing a higher standard of care for such patients. The outcomes of such investigation may lead to referral recommendations to concentrate procedures in such institutions. The aim of this study was to describe and compare the outcomes and costs of oncological radical and partial nephrectomies in the Sao Paulo Public Health System, Brazil, from 2008 to 2019, and to compare data

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 2

129

A. Dib Partezani, H. Octaviano Duarte-Santos, B. Santos Amaral

among hospitals volume, and with or without medical residency program in urology.

METHODS

An ecologic retrospective study was performed from 2008 to 2019 using the TabNet Platform of the Department of Information Technology of the Brazilian public health system (DATASUS). This database consists of an open data source, containing information about procedures performed in the Brazilian public health system (Sistema Único de Saúde SUS), available at https://datasus.saude.gov.br/. Procedure codes used for this study were total nephrectomy in Oncology (code 0416010075) and Partial Nephrectomy in Oncology (code 0416010210). The study was approved by the Research Ethics Committee of the “Hospital Israelita Albert Einstein” (approve code CAAE: 17208019.0.0000.0071 and date of approval 07/10/2019) and was performed in accordance with relevant guidelines and regulations. Participants' informed consent is not applicable. Outcomes analyzed included number of surgeries, mortality rate during hospital stay, length of hospital stay, length of intensive care unit (ICU) stay, and indirect costs. Since data related to cost for each hospitalization were not available, indirect cost was calculated as the total amount paid per year for each institution according to each procedure divided by the total number of hospitalizations related to the same procedure. Hospitals were classified as low- and high-volume surgery centers, and were divided into two groups using a cut-off of 10 surgeries per year for PN (19) from 2013 to 2019, and 20 surgeries per year for RN (20) from 2008 to 2019, to consider it as a high-volume center. We also divided the hospital volume of surgeries in four quartiles according to the caseload per year. Besides, we classified the centers with and without a medical residency program in Urology. Comparisons were then made among groups.

Table 1. Overall mean length of hospital stay, ICU hospitalization, intrahospital mortality and indirect costs of partial nephrectomy and radical nephrectomy between 2008 and 2019 in São Paulo. Variables Hospitals (n) Total of surgeries (n) Hospitals with Residency in Urology a Hospitals volume (n) Low-volume High-volume Length of hospital stay b (days) ICU hospitalization b (days) Intrahospital mortality b Indirect costs b (R$)

Radical nephrectomies 16 2606 7 (43.7%)

Partial nephrectomies 15 1223 7 (46.7%)

12 4 8.13 (2.78) 1.87 (2.48) 75 (2.87%) 2614.17 (358.89)

11 4 6.85 (5.93) 1.09 (0.50) 5 (0.41%) 28782.16 (52632.61)

a These variables are presented as total number and percentage (%). b These variables are presented as mean

and standard deviation (SD). ICU: Intensive care unit. R$: Brazilian Real.

the low volume group consisted of 12 hospitals and the high volume group consisted of four hospitals. Overall mortality rate was 2.87%. Data available for PN ranged only from 2013 to 2019 and included 1.223 surgeries. The procedures were performed in 15 institutions, of which seven (46.7%) presented medical residency program in Urology. Considering the volume of surgeries, the low volume group consisted of 11 hospitals and the high volume group consisted of four hospitals. Overall mortality rate was 0.41%. Table 2 summarizes the length of hospital stay, ICU hospitalization days, intrahospital mortality and indirect costs for RN and PN according to the volume of surgeries. The length of hospital stay was significantly higher in low-volume than in high-volume hospitals in both types of surgeries, PN and RN (7.75 days vs. 4.37 days, p = 0.001; and 8.97 days vs. 5.62 days, p = 0.001, respectively). The average ICU hospitalization days was also higher in low-volume hospitals; however, there was no statistical significance difference for both PN and RN (1.22 days vs. 0.77 days, p = 0.142; and 2.09 days vs.

Statistical analysis Statistical analysis was performed using SPSS 13.0 (SPSS for Mac OS X, SPSS, Inc., Chicago, IL, USA). Data normality was verified using the Shapiro-Wilk test. The MannWhitney and Kruskal-Wallis tests were used to compare non-normal Table 2. variables and T-test or ANOVA for Length of hospital stay, intensive care unit hospitalization days, intrahospital mortality variables with normal distribution. and indirect costs of partial nephrectomy and radical nephrectomy analyzed according Proportions were analyzed using the to low- and high-volume hospitals from 2008 to 2019 in São Paulo. chi-square test (mortality rate). Statistical significance was considVariables Radical nephrectomy Partial nephrectomy ered when p < 0.05. Low-volume High-volume p-value Low-volume High-volume P-value Length of hospital staya (days)

RESULTS

Table 1 summarizes data for overall RN and PN. A total of 2.606 RN were performed from 2008 to 2019. The procedures were performed in 16 institutions, of which seven (43.7%) presented medical residency program in Urology. Regarding the volume of surgeries,

130

ICU hospitalizationa (days) Intrahopitalar mortalityb Indirect costsa (R$)

8.97 (2.73) 2.09 (2.87) 27/931 (2.90%) 2612.08 (405.18)

5.62 (0.41) 1.22 (0.08) 48/1675 (2.86%) 2620.43 (204.89)

0.001 c 0.808 d 0.959 e

0.969 c

7.75 (6.76) 1.22 (0.52) 1/323 (0.3%) 37970.19 (59357.94)

4.37 (0.63) 0.77 (0.30) 4/900 (0.44%) 3515.08 (4715.69)

a These variables are presented as mean and standard deviation (SD). b This variable is presented as number/total of surgeries and percentage (%). c T-test. d Mann-Whitney test. e Chi-square test. ICU: Intensive care unit, R$: Brazilian Real.

Archivio Italiano di Urologia e Andrologia 2022; 94, 2

0.001 d 0.142 c 0.741 e

0.151 d

Outcomes of nephrectomy in brazilian public health

Table 3. Length of hospital stay, Intensive care unit hospitalization days, intrahospital mortality and indirect costs of partial nephrectomy and radical nephrectomy according to hospitals volume (quartiles) from 2008 to 2019 in São Paulo.

ed into four quartiles. The length of hospital stay was also significantly different considering RN: in the first quartile hospitals was observed a higher length of hospital stay comVariables Radical nephrectomy Partial nephrectomy pared to fourth quartile hospitals Quartile p-value Quartile P-value (p = 0.015). No difference was 1 2 3 4 1 2 3 4 observed regarding PN. Number of hospitals 4 4 4 4 --4 3 4 4 --The ICU hospitalization days were Range of cases 1-16 17-107 136-218 248-788 --1-7 8-42 50-59 79-506 --higher in the first quartile hospitals; a c* d Length of hospital stay (days) 11.16 8.50 7.26 5.62 0.016 7.55 10.49 5.15 4.37 0.570 however, there was no statistical (2.11) (3.02) (1.76) (0.41) (3.35) (11.16) (1.19) (0.63) difference considering RN. ICU hospitalization a (days) 3.58 1.49 1.20 1.22 0.945 d 1.75 1.43 0.74 0.77 0.009 c ** Regarding PN, hospitals in the first (4.98) (0.80) (0.49) (0.08) (0.35) (0.34) (0.32) (0.30) quartile presented statistically highb e e Intrahopitalar mortality 1/31 4/191 22/709 48/1675 0.900 0/13 0/85 1/225 4/900 0.930 er ICU hospitalization days when (0.032%) (0.020%) (0.031%) (0.028%) (0%) (0%) (0.004%) (0.004%) compared to hospitals in the third Costs a (R$) 2843.95 2501.48 2490.81 2620.43 0.803 c 86293.02 25543.88 14154.38 4715.69 0.147 d (p = 0.032) and fourth (p = 0.039) (580.88) (194.45) (345.12) (204.89) (99667.48) (40322.65) (14106.48) (2357.84) quartiles. Mortality rates were not a These variables are presented as mean and standard deviation (SD). b This variable is presented as number/total of surgeries and percentage (%). c ANOVA test. d Kruskal wallis test. e Chi-square test. ICU: Intensive care unit. R$: Brazilian Real. * Post hoc analysis showed difference between hospitals in the first quartile different among quartiles for both and fourth quartile (p = 0.015). ** Post hoc analysis showed difference among hospital in the first quartile and third (p = 0.032) and fourth (p = 0.039) quartile. PN and RN. Indirect costs were higher in first quartile hospitals for both PN and RN, however, no sta1.22 days, p = 0.808, respectively). Mortality rates were tistical difference was observed among the quartiles. similar for both low- and high-volume hospitals. When Table 4 summarizes the length of hospital stay, ICU hosconsidering PN, there was one death out of 323 surgeries pitalization days, intrahospital mortality and indirect performed in low-volume hospitals and four deaths out costs for RN and PN according to the hospitals with and of 900 surgeries performed in high-volume hospitals without medical residency program in Urology. A total of (0.3% mortality rate vs. 0.44% mortality rate, p = 0.741). 2.232 RN were performed in hospitals with medical resiThis can also be observed in RN, with 27 deaths out of dency program in Urology (85.6%) and 374 (14.4%) in 931 surgeries performed in low-volume hospitals and 48 hospitals without medical residency program in Urology. deaths out of 1675 surgeries performed in high-volume Regarding RN, the length of hospital stay was significanthospitals (2.9% mortality rate vs. 2.86% mortality rate, ly shorter in hospitals with medical residency in Urology p = 0.959). Indirect costs were higher in low-volume hos(6.54 days vs. 9.37 days; p = 0.03). Considering PN, none pitals when considering PN, with an average of R$ of the outcomes were statistically difference between hos37970.19 per patient when compared to high-volume pitals with and without medical residency program in hospitals, which had an average of R$ 3,515.08 per Urology, although indirect costs were 4.5 times higher in patient. However, this difference was not statistically sighospital without medical residency program in Urology nificant (p = 0.151). In the RN group, average indirect (R$ 45298.93 vs. R$ 9905.85; p = 0.205). costs were very similar between low- and high-volume hospitals (R$ 2,612.08 vs. R$ 2,620.43; p = 0.969). Table 3 summarizes the length of hospital stay, ICU hosDISCUSSION pitalization days, intrahospital mortality and indirect costs In this study, we described and compared the outcomes for RN and PN according to the volume of surgeries dividand indirect costs of RN and PN in the Sao Paulo Public Health System, Brazil, from 2008 to 2019, and compared data considerTable 4. ing the hospitals volume of surgerLength of hospital stay, intensive care unit hospitalization days, intrahospital mortality ies, and with or without medical and indirect costs of partial and radical nephrectomies performed in hospital with residency program in urology. and without medical residency program in Urology from 2008 to 2019 in São Paulo. From the perspective of the Brazilian public healthcare system, Variables Radical nephrectomy Partial nephrectomy our findings showed that, both for With residency Without residence p-value With residency Without residence P-value in Urology in Urology in Urology in Urology RN and PN, length of hospital stay Length of hospital stay a (days) 6.54 9.37 0.03 c 5.26 8.24 0.350 d was significantly lower in high-vol(1.56) (2.95) (1.08) (8.03) ume hospitals, while indirect costs ICU hospitalization a (days) 1.24 2.36 0.390 d 0.87 1.31 0.099 c and ICU stay also trended favor(0.34) (3.30) (0.30) (0.58) ably for high-volume hospitals, b e e Intrahopitalar mortality 67/2232 8/374 0.357 4/979 1/244 1 although no statistical difference (3.00%) (2.13%) (0.40%) (0.40%) was found between low- and highIndirect costs a (R$) 2536.48 2674.59 0.464 d 9905.85 45298.93 0.205 d volume hospitals. (287.62) (412.39) (11713.02) (68954.31) The volume of surgeries divided a These variables are presented as mean and standard deviation (SD). b This variable is presented as number/total of surgeries and percentage (%). into four quartiles disclosed that c T-test. d Mann-Whitney test. e Chi-square test. ICU: Intensive care unit. R$: Brazilian Real. for RN, in the first quartile hospiArchivio Italiano di Urologia e Andrologia 2022; 94, 2

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tals was observed a higher length of hospital stay compared to fourth quartile hospitals, whereas the mean ICU hospitalization days were higher in the first quartile hospitals when compared to hospitals in the third and fourth quartiles for PN. Mortality rates and indirect costs were not different among quartiles for both PN and RN. Regarding the hospitals with and without medical residency program in Urology, the length of hospital stay was significantly lower in hospitals with residency program in Urology for RN. These data underscore the importance of concentrating complex procedures in specialized centers, so as to pursue optimized results. RN and, especially PN, are procedures that have a significant learning curve. The competence acquisition results in a composite outcome including a combination of operative time, complications, and surgical success. In 2004, Gaston et al. (21) demonstrated the learning curve of residents for hand-assisted laparoscopic nephrectomy, according to difficulty scores and procedure duration, stabilized after the 6th nephrectomy. On the other hand, Rouach et al. (22) demonstrated that at least 10 partial nephrectomies are necessary to gain domain regarding the steps of the surgery. When performed by more experienced doctors, the length of surgery and outcomes may be optimized. BaezSuarez et al. (23) demonstrated that a cutoff of 50 nephrectomies performed by the same surgeon decreased perioperative outcomes, including hospital stay length. This might explain why our analysis demonstrated no statistical difference in the length of stay when comparing PN in hospitals with and without medical residency program in Urology, but there was a significantly lower length of stay when comparing RN in these groups of hospitals. Following RN and PN, specific care needs to be taken in the postoperative setting. Therefore, it is expected that hospitals with a greater volume of procedures already have postoperative protocols established with ICUs and wards, favoring a rapid discharge from hospitals. This may also explain why the length of stay was significantly lower for both RN and PN in high-volume than in low-volume hospitals. Gozen et al. (24) observed that the learning curve for retroperitoneal laparoscopic radical nephrectomy was shorter for the surgeons who had no or limited experience in open surgery, and that were trained by surgeons who had previous experience in open surgery but no laparoscopic training, although these surgeons operated on a significantly higher number of patients with more advanced diseases. Recently, Spampinato et al. (25) concluded that assuming an adequate case volume and a proper exposure to surgical techniques, junior surgeons can readily achieve comparable levels of expertise compared with senior practitioners, and urological surgical outcomes is not only directly influenced by the individual surgical experience but also by the experience of the surgical team. A possible explanation for the longer hospital stay in patients undergoing RN (8.13 days) when compared to those for PN (6.85 days), found in our analysis may be that patients submitted for RN hypothetically had larger tumor volumes, were more fragile and required longer/larger surgeries, leading to an important metabolic and inflammatory response. These patients also had a longer ICU length of stay (1.87 days vs. 1.09 days for RN and PN, respectively)

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and higher intrahospital mortality rates (2.87% vs. 0.41% for RN and PN, respectively), probably for the same reasons as hypothesized above. PN is known to be a more complex surgery, in most cases, when compared to RN. To perform PN, there is a need for a wide range of materials available in the operating room, especially if performed laparoscopically. This includes, among others, disposable polymer clips, laparoscopic bulldogs, absorbable sutures and eventually hemostatic agents. For this reason, an increase in costs is expected for the health system when PNs are performed. This was visible in our analysis, where the average cost of hospitalization for PN was R$ 28,782.16 compared to R$ 2,614.17 for RN hospitalization. There was no statistical difference in costs when comparing hospital volume and with or without medical residency in Urology, but this may be explained by the fact that Brazilian Health System (SUS) reimburse the same value to every hospital for each procedure, and the individual cost for each patient is not accounted for. Values of total hospitalization may vary if the patient has been submitted for different procedures during the same hospitalization, and this is one of the limitations of the analysis of costs presented here. Considering the available details, a discussion can be commenced regarding the possibility of referring patients for the treatment of RCC to high-volume centers with the objective of shortening the length of hospital stay by focusing on a higher bed turnover; a scenario in which elective surgeries are sometimes cancelled due to the lack of hospital beds. The centralization of the treatment of RCC could be made the part of a public health policy to establish RCC-treatment reference hospitals and improve RCC surgical outcomes. Per the data, it is noted that one single institution inflated the values paid (reimbursements) for partial nephrectomies in hospital without medical residency in Urology and in low-volume hospital groups. This institution is a hospital specializing in the treatment of pediatric urological pathologies and received R$ 401,162.11 for performing two PN in the period analyzed. There is no plausible explanation for this amount due to limitations of publicly available data. This study also has other limitations. The data available in the online health system database considers only the details of one single hospitalization per patient, so mortality data and costs involving following hospitalizations after discharges are not considered in this study. The costs are indirect costs represented by modality of reimbursement of Brazilian health system. For an appropriate comparison of costs, it should be necessary to estimate direct costs in each hospital considering cost for personnel, disposables, time of use of operatory theatre and hospitalization. What can be stated is that National Health Service does not reimburse higher fares to high-volume hospitals. Moreover, the data were restricted to inform only the major types of surgery performed, and details such as time of procedure, patient age, specific complications and technique (open or laparoscopic) were not available. Also, the data were collected from a secondary source that is fueled by health professionals, who often do not fill out the forms correctly, therefore interfering in statistical analysis and results. In addition, our findings may not be representative of the entire

Outcomes of nephrectomy in brazilian public health

Brazilian population, since we analyzed data only from the São Paulo city, although this is the most populous city in the country. A final limitation is that hospitals with residency are the hospitals with the higher number of beds, so it is difficult to establish if better outcome is related to residency program or to high-volume.

CONCLUSIONS

In summary, the length of hospital stay was significantly lower for patients who underwent PN and RN in highvolume hospitals, and also in hospitals with medical residency in Urology for RN.

REFERENCES

1. Atkins, MB; Choueiri, TK. Epidemiology, pathology, and pathogenesis of renal cell carcinoma. Waltaham, MA: Wolters Kluwer, 2020. 2. Campbell SL. Malignant Renal Tumors. In: Wein A, Kavoussi L, Partin A, Peters C. Ed. Campbell-Walsh Urology. 11th. Philadelphia, PA: Elselvier, 2016, chapter 57, p.1314-1364. 3. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013; 63:11-30. 4. 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. 5. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011; 61:69-90. 6. Parsons JK, Schoenberg MS, Carter HB. Incidental renal tumors: casting doubt on the efficacy of early intervention. Urol. 2001; 57:1013-5. 7. Decastro GJ, McKiernan JM. Epidemiology, clinical staging, and presentation of renal cell carcinoma. Urol Clin North Am. 2008; 35:581-92. 8. Brierley JD. TNM Classification of Malignant Tumors. UICC international Union Against Cancer. In: Sobin LH, Gospodarowicz MK, Wittekind C. TNM Classification of Malignant Tumors. 7th. Chichester, West Sussex: Wiley-Blackwell, 2009. 9. Huang WC, Levey AS, Serio AM, et al. Chronic kidney disease after nephrectomy in patients with renal cortical tumours: a retrospective cohort study. Lancet Oncol. 2006; 7:735-40. 10. Sciorio C, Prontera PP, Scuzzarella S, et al. Predictors of surgical outcomes of retroperitoneal laparoscopic partial nephrectomy. Arch Ital Urol Androl. 2020; 92:165-168. 11. Kim SP, Murad MH, Thompson RH, et al. Comparative effectiveness for survival and renal function of partial and radical nephrectomy for localized renal tumors: a systematic review and meta-analysis. J Urol. 2012; S0022-5347(12)05254-8. 12. Huang WC, Elkin EB, Levey AS, et al. Partial nephrectomy versus radical nephrectomy in patients with small renal tumors--is there a difference in mortality and cardiovascular outcomes? J Urol. 2009; 181:55-61. 13. Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol. 2011; 59:543-52. 14. Adams KF, Leitzmann MF, Albanes D, et al. Body size and renal cell cancer incidence in a large US cohort study. Am J Epidemiol. 2008; 168:268-77.

15. Scosyrev E, Messing EM, Sylvester R, et al. Renal function after nephron-sparing surgery versus radical nephrectomy: results from EORTC randomized trial 30904. Eur Urol. 2014; 65:372-7. 16. Kates M, Badalato GM, Pitman M, McKiernan JM. Increased risk of overall and cardiovascular mortality after radical nephrectomy for renal cell carcinoma 2 cm or less. J Urol. 2011; 186:1247-53. 17. IBGE. Estimativas da População Residente para os Municípios e para as Unidades da Federação Brasileiros com data de Referência de 1o de Julho de 2019. SAÚDE, M. D. Rio de Janeiro, RJ, Brasil: IBGE 2019. Available at https://www.ibge.gov.br/estatisticas/sociais/populacao/9103-estimativas-de-populacao.html?=&t=o-que-e. 18. Boletim CEInfo Saúde em Dados. Ano XVIII. São Paulo, SP, Brasil: Secretaria Municipal de Saúde 2019. Available at https://www.prefeitura.sp.gov.br/cidade/secretarias/saude/epidemiologia_e_informacao/index.php?p=258529. 19. Couapel JP, Bensalah K, Bernhard JC, et al. Is there a volumeoutcome relationship for partial nephrectomy? World J Urol. 2014; 32:1323-9. 20. Birkmeyer JD, Siewers AE, Finlayson EV, et al. Hospital volume and surgical mortality in the United States. N Engl J Med. 2002; 346:1128-37. 21. Gaston KE, Moore DT, Pruthi RS. Hand-assisted laparoscopic nephrectomy: prospective evaluation of the learning curve. J Urol. 2004; 171:63-7. 22. Rouach Y, Timsit MO, Delongchamps NB, et al. Néphrectomie partielle laparoscopique: courbe d'apprentissage d'un interne en urologie sur un modèle porcin [Laparoscopic partial nephrectomy: urology resident learning curve on a porcine model]. Prog Urol. 2008; 18:344-50. 23. Baez-Suarez Y, Amaya-Nieto J, Garcia-Lopez A, Giron-Luque F. Hand-assisted laparoscopic nephrectomy:evaluation of the learning curve. Transplant Proc. 2020; 52:67-72. 24. Gozen AS, Gherman V, Akin Y, et al. Evaluation of the complications in laparoscopic retroperitoneal radical nephrectomy; An experience of high volume centre. Arch Ital Urol Androl. 20171; 89:266-271. 25. Spampinato G, Binet A, Fourcade L, et al. Comparison of the learning curve for robot-assisted laparoscopic pyeloplasty between senior and junior surgeons. J Laparoendosc Adv Surg Tech A. 2021; 31:478-483.

Correspondence Alexandre Partezani ale.partezani@gmail.com Hugo Octaviano Duarte-Santos, MD hugosantos90@gmail.com Breno Amaral, MD drbrenoamaral@gmail.com Alan Roger Gomes Barbosa, MD alan_roger@hotmail.com Marcelo Apezzato, MD mapezzato@uol.com.br João Brunhara, MD jbrunhara@gmail.com Bianca Bianco, MD (Corresponding Author) bianca.bianco@einstein.br Gustavo Lemos, MD gustavo.lemos@einstein.br Arie Carneiro, MD arie.carneiro@einstein.br Department of Urology, Hospital Israelita Albert Einstein Av Albert Einstein 627, São Paulo, SP, CEP 05652-900 (Brazil) Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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ORIGINAL PAPER

DOI: 10.4081/aiua.2022.2.134

Endoscopic laser en bloc removal of bladder tumor. Surgical radicality and improvement of the pathological diagnostic accuracy Rosario Leonardi 1, Alessandro Calarco 2, Lorenzo Falcone 1, Vincenzo Grasso 1, Marco Frisenda 3, Antonio Tufano 3, Pietro Viscuso 3, Antonio Rossi 2, Lorenzo Memeo 4 1 Casa

di Cura Musumeci GECAS, Gravina di Catania (CT), Italy; Re” Hospital, Rome, Italy; 3 Department of Maternal-Infant and Urological Sciences, "Sapienza" Rome University, Policlinico Umberto I Hospital, Rome, Italy; 4 IOM (Istituto Oncologico del Mediterraneo), Viagrande (CT), Italy. 2 “Cristo

Summary

Introduction: Bladder cancer is one of the most common tumors among the general population. The first surgical approach to the tumor is often the transurethral resection with monopolar or bipolar loop. Recently, laser energy has become an alternative for resection of small bladder tumor, because it allows to obtain high quality samples with the “en bloc” technique. Our study aims to show the results of endoscopic diode laser treatment of bladder tumor up to three centimeters in maximum diameter. Materials and methods: 189 patients underwent “en bloc” resection with diode dual length laser (980 nm-1470 nm). Follow up was over 12 months. Patients age range was from 45 to 75 years. Maximum diameter of the lesions was 3.0 cm. For each patient, a cold forceps biopsy sample was performed. Results: All samples collected presented detrusorial layer. Pathological exam showed: 28 (14.8%) Ta, G1-G2; 7 (3.7%) T3, G2-G3; 14 (7.4%) T1, G2-G3 and 140 ( 74.1%) Ta, G2-G3. No complications occurred during or after surgery. At a median follow-up period of 6 months, we had no recurrence in the previous site of tumor. In the follow up at 3/6/12 months in 4 cases we had recurrence in different sites of bladder wall. Conclusions: Laser “en bloc” resection is an effective, feasible, and safe treatment for bladder tumor. It could be a valid alternative to monopolar and bipolar resection in small bladder cancer treatment.

KEY WORDS: Laser; Bladder tumor; Endoscopic resection; En-bloc; Diode. Submitted 8 June 2022; Accepted 15 June 2022

INTRODUCTION

Bladder cancer is one of the most common tumors of the genitourinary system. More than 81.000 new cases resulting in 17.100 deaths have been estimated in 2022 in the United States (1). Moreover, bladder cancer confers the largest financial burden per patient of all types of malignant tumors. This is because of its high recurrence and progression rate, which requires lifelong monitoring and repeated treatment (2). Most cases (75%) are non muscleinvasive bladder cancer (NMIBC), and transurethral resection of bladder tumor (TURBT) is regarded as the standard diag-

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nostic and therapeutic method even if, this technique, has been associated with significant complications (bleeding, bladder perforation, obturator nerve reflex, and even bladder explosion) (3). Another problem is incomplete primary endoscopic resection with absence of muscle tissue in the samples and uncertainty of the margins, which often leads to reprogramming, especially in T1, a second look TUR after forty days from the first intervention, with an increase in costs for public health and discomfort for patients, especially in this period of pandemic not yet fully resolved (4). We know that TURBT “incising and scattering” procedure contradicts the basic surgical oncologic principles of take out the tumor “en bloc” with sure margins of resection and histopathology evaluation of wall invasion. Another problem is the possible seeding of exfoliated cancer cells (5). Each urologist has his/her own experience in endoscopic treatment of bladder tumors, which refers, in particular, to the type of energy used during the surgical procedure. Monopolar energy in cutting loop is the most used current for the treatment of NMIBC although it is correlated with some adverse events including blood loss or disorder of electrolyte balance for mannitol absorption. Recently, use of bipolar energy has spread due to reduced risk of metabolic alterations and improved precision of resections (6-8). In 1984, Food and Drug Administration (FDA) approved the use of laser in bladder resection. In the last 10 years, various types of laser energy have been used for the endoscopic treatment of bladder cancer, due to their efficient tissue vaporization and hemostatic effect as well as high safety (Holmium and Thullium, in particular). The use of laser surgery helps in “en bloc” resection and can provide an intact tissue specimen for a more accurate pathological evaluation; it also reduce the risk of dissemination of malignant cells (9-11). Our study, therefore, aims to verify if diode laser “en-bloc” surgery of bladder tumors could be able to improve the diagnostic rate and to reduce the risk of positive margins and incomplete resection of the bladder base implant of the neoplasm. We want also to evaluate safety and reduction of catheterization and hospitalization time. No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2022; 94, 2

Diode laser en bloc removal of bladder tumor

MATERIALS

AND METHODS

From January 2015 to February 2022, 189 patients underwent “en bloc” resection with the laser. Random cold forceps biopsy samples were also taken. The total operation time, pathologic result, and intraoperative and postoperative complications were recorded. Each patient was followed up for ≥ 12 month. Patients age range was from 45 to 75 years, and 20% of patients were females. We used a diode dual length laser (980 nm-1470 nm). The two waves length can be freely mixed. A power of 15/20 watts with a mix of 85% of 980 and 15% of 1470 was used. The conical front emitting laser fiber of 1000 micron was used. We treated bladder tumor of a diameter up to 3.0 cm of maximum diameter. Maximum number of lesions was 2. The time of the operation depended on the size of the neoplasm, from a minimum of 20 min, for neoplasms smaller than one centimeter up, to 45 min for neoplasms with a maximum diameter of 3.0 cm

The specimens were extracted from the bladder cavity from the outer channel of the resectoscope that was used like e trocar. Morcellator was not used. All patients were able to return home the day after operation without catheter. After patients dismission, we observed 2 events of late hematuria, resolved with the recommendation of high hydration. At a median follow-up period of 6 months, we had no recurrence in the previous site of tumor. In the follow up at 3/6/12 months the recurrence in other sites of bladder was of 28 cases without any case of progression.

DISCUSSION

The evolution of technology, over the last few years, has made possible to significantly improve the endoscopic treatment of bladder tumors, especially for NMIBCs. Nowadays, in particular, great attention is given to the use of lasers for the “en-bloc” treatment of small bladder tumors. The Holmium and Thulium lasers are of certain efficacy and safety, despite the limited differences in terms of operRESULTS ating time compared to monopolar and bipolar energy (12). The “en bloc” resection of tumors was successful in all On the other hand, improvements have been made in term cases. The resected tumors were intact with detectable of obturator nerve reflex, transient hematuria, postoperamargins and the detrusor muscle architecture was always tive bladder irritation and catheterization and hospitalizaavailable for pathologic evaluation. Definitive pathologition time (13). Further advantages of “en bloc” resection are cal analysis resulted in: 28 (14.8%) cases of Ta,G1-G2; 7 samples of better quality and less residual tumor (14). (3.7%) T2,G2-G3, 14 (7.4%) T1,G2-G3 and 140 (74.1%) The diode laser has recently been widely used in the treatTa,G2-G3 (Figure 1). No complications occurred during ment of benign prostatic hyperplasia and showing high or after surgery. efficacy and tolerability (15, 16). The main advantage of No bladder wall perforation was observed. the diode laser is its high hemostatic capacity, which makes it more effective especially in patients on antiplatelet Figure 1. A. Low power image of the “en bloc” resection of a pTa urothelial papillary carcinoma low and anticoagulant therapy (17). grade with intense lymphocytic infiltrate of the suburothelial connective tissue. There are currently not many The tumor is totally resected and the deep resection margin is on normal tissue. studies regarding the use of B. A case of MIBC diagnosed by “en bloc” surgery. It was possible to highlight, in a precise diode lasers in the treatment of way, the depth of invasion of the tumor in the muscular strates of the detrusor bladder tumors. Our prelimi(pT2 urothelial carcinoma). nary data, therefore, appear to be of particular interest as they allow us to observe how this type of laser can also be safely used on bladder wall. The absence of complications and the precision of the treatment made it possible to obtain samples of excellent quality. In all cases the detrusor layer was A. B. included in the sample (Figure 2), avoiding the patient to perFigure 2. form second look TUR. The “en A. Anatomic operative specimen obtained by “en bloc” removed bladder neoplasia. bloc” resection, if compared B. A detail of the “en bloc” sample showing the deep resection margin on normal tissue (4X). with traditional TURB, allows the histological evaluation of a larger and anatomically oriented portion of the bladder wall. This could increase the detection of small foci of neoplastic cells in the sub-urothelial tissue or in the tonaca muscolaris and have an impact in the correct A. B. staging of the tumor. Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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Figure 3. Bladder tumor that laps the upper border of the left ureteral orifice.

Figure 4. The use of NBI allows us to better identify the limits of the tumor.

Figure 5. A. Perfectly spared ureteral orifice with millimeter incision of the neoplasm. B. Ureteral orifice preserved during urination. C The tumor resected by en bloc technique floating inside the bladder cavity. D. Tumor extracted ready to be sent for histopathological examination.

Figure 6. The tumor with the muscle tissue of the implant base is above the right section of the picture. The laser fiber is used to tension the muscle fibers and better define the incision line.

The limit of “en-bloc” method are obviously large tumors, as they cannot be extracted from the resectoscope without causing injury to the sample or having to use a morcellator, which would make the sample not evaluable by the pathologist. According to our experience, the most common sites in which the “en bloc” laser surgery of invasive non-muscle bladder neoplasms becomes unsurpassable is when they are located close to the ureteral meatus (Figure 3). We usually use the narrow band imaging (NBI) system to better define the margins of the neoplasm that are marked before starting the “en bloc” removal procedure (Figure 4). In doing so, we have never had positive margins. In these cases, it is possible to remove the neoplasm without having to resect the meatus as often happens with traditional surgery (Figure 5). The most difficult site for tumor removal is the posterior wall. In these cases, an accurate section plane must be achieved by proceeding lateromedially from both sides and subsequently, from bottom to top, to completely eradicate the neoplasm with its implant base. The upper locations, often difficult for traditional surgery, does not present any problem for “en bloc” laser surgery. In these cases, we proceed in a proximal distal direction after having identified the right section plane. The neoplasm is gradually pulled from the wall with its implant base until it is completely removed by cutting the flap of mucosa that holds it adhering to the wall. The use of 1000 micron fiber to move or lift the neoplastic tissue adhering to the muscular wall is of great help. The muscle fibers are put in tension and in doing so it becomes easy to proceed quickly in dissecting the muscular plane (Figure 6). An important trick to have a bloodless field is to gradually photo-coagulate the small vessels that are encountered in the dissection, and which often are identified by transparency, before engraving the tissue. It should be noted that, based on the reduced thickness of the bladder wall of the woman, when we implement an “en bloc” in a female subject, we always operate with a medium-low bladder filling in order not to thin the bladder wall.

CONCLUSIONS

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The results of our study have shown that laser “en-bloc” resection is an effective, feasible, and safe alternative to monopolar and bipolar loop energy for bladder tumor resection. It is able to reduce the second-look TURB in

Diode laser en bloc removal of bladder tumor

case of T1 or for absence of the muscular tissue in the sample of first resection. It was associated with no complications and allows accurate oncological pathologic evaluation. It is associated to a reduced hospitalization and catheterization time. The laser “en bloc” surgery of NMIBC can be considered, in our preliminary experience, an evolution of endoscopic surgery of bladder cancer.

tion in saline (TURis): outcome and complication rates after the first 1000 cases. J Endourol. 2009; 23:1145-9.

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3. Rozanec JJ, Secin FP. Epidemiología, etiología, prevención del cáncer vesical (Epidemiology, etiology and prevention of bladder cancer.). Arch Esp Urol. 2020; 73:872-878. 4. Cumberbatch MGK, Foerster B, Catto JWF, et al. Repeat transurethral resection in non-muscle-invasive bladder cancer: a systematic review. Eur Urol. 2018; 73:925-933. 5. Territo A, Bevilacqua G, Meneghetti I, et al. En bloc resection of bladder tumors: indications, techniques, and future directions. Curr Opin Urol. 2020; 30:421-427. 6. Mao X, Zhou Z, Cui Y, et al. Outcomes and complications of bipolar vs. monopolar energy for transurethral resection of bladder tumors: a systematic review and meta-analysis of randomized controlled trials. Front Surg. 2021; 8:583806. 7. Burke N, Whelan JP, Goeree L, et al.. Systematic review and metaanalysis of transurethral resection of the prostate versus minimally invasive procedures for the treatment of benign prostatic obstruction. Urology. 2010; 75:1015-22. 8. Puppo P, Bertolotto F, Introini C, et al. Bipolar transurethral resec-

9. Xu J, Wang C, Ouyang J, et al. Efficacy and safety of transurethral laser surgery versus transurethral resection for non-muscle-invasive bladder cancer: a meta-analysis and systematic review. Urol Int. 2020; 104:810-823. 10. Korn SM, Hübner NA, Seitz C, et al. Role of lasers in urology. Photochem Photobiol Sci. 2019; 18:295-303.

13. Razzaghi MR, Mazloomfard MM, Yavar M, et al. Holmium LASER in comparison with transurethral resection of the bladder tumor for non-muscle invasive bladder cancer: randomized clinical trial with 18-month follow-up. Urol J. 2021; 18:460-465. 14. Hashem A, Mosbah A, El-Tabey NA, et al. Holmium Laser Enbloc resection versus conventional transurethral resection of bladder tumors for treatment of non-muscle-invasive bladder cancer: a randomized clinical trial. Eur Urol Focus. 2021; 7:1035-1043. 15. Mithani MH, Khalid SE, Khan SA, et al. Outcome of 980 nm diode laser vaporization for benign prostatic hyperplasia: A prospective study. Investig Clin Urol. 2018; 59:392-398. 16. Leonardi R. The LEST technique: Treatment of prostatic obstruction preserving antegrade ejaculation in patients with benign prostatic hyperplasia. Arch Ital Urol Androl. 2019; 91:35-42. 17. Zhang J, Li J, Wang X, et al. Efficacy and safety of 1470-nm diode laser enucleation of the prostate in individuals with benign prostatic hyperplasia continuously administered oral anticoagulants or antiplatelet drugs. Urology. 2020; 138:129-133.

Correspondence Rosario Leonardi, MD (Corresponding Author) urologialeonardi@gmail.com Lorenzo Falcone, MD lorenzo.falcone@gmail.com Vincenzo Grasso, MD vincenzo.grasso@gmail.com Casa di Cura Musumeci GECAS, Gravina di Catania (CT) (Italy) Alessandro Calarco, MD alecalarco@gmail.com Antonio Rossi, MD antonio.rossi@uniroma1.it “Cristo Re” Hospital, Rome (Italy) Marco Frisenda, MD marco.frisenda57hu@gmail.com Pietro Viscuso, MD pietro.viscuso@uniroma1.it Antonio Tufano, MD antonio.tufano@uniroma1.it Department of Maternal-Infant and Urological Sciences, "Sapienza" Rome University, Policlinico Umberto I Hospital, Rome (Italy) Lorenzo Memeo, MD lorenzo.memeo@gmail.com IOM (Istituto Oncologico del Mediterraneo), Viagrande (CT) (Italy)

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DOI: 10.4081/aiua.2022.2.138

ORIGINAL PAPER

Variant histologies of urothelial carcinoma: Does it change the survival outcomes in patients managed with radical cystectomy? João Nuno Pereira 1, João Duarte Reis 2, Isaac Braga 1, Rui Freitas 1, Vitor Moreira da Silva 1, Sanches Magalhães 1, Francisco Lobo 1, António Morais 1 1 Department

of Urology, Portuguese Institute of Oncology, Oporto, Portugal; Department, University of Aveiro, Portugal.

2 Mathematics

Summary

Objective: To investigate the impact of variant histologies (VH) of urothelial carcinoma (UC) on survival outcomes after radical cystectomy (RC). Materials and methods: Data from 181 patients with UC treated with RC between January 2013 and December 2019 at a single tertiary care referral center were retrospectively accessed. All RC specimens were assigned by genitourinary dedicated pathologists. Overall survival (OS), disease-specific survival (DSS) and recurrence-free survival (RFS) were evaluated using the Kaplan-Meier methodology and the Cox proportional hazards regression. Results: Of 181 patients, 43.1% (n = 78) had VH, with the most common being squamous differentiation (n = 29), followed by mixed variants (n = 18), micropapillary variant (n = 10) and other subtypes (n = 21). The median (range) follow-up was 35 (18-59) months. Kaplan-Meier survival analysis shows that median OS and DS were significantly worse for VH patients (78 vs 31 months, p = 0.038; not reached vs 42 months; p = 0.016). At 5 years, VH was associated with a 12% and 14% decrease in OS and DSS, respectively. No significant statistical difference between the two groups was reached regarding RFS. However, after adjusting for confounders, such as, demographics characteristics, comorbidities and pathological features, VH were not associated with any survival outcomes. Conclusions: Our study evidenced the high incidence of bladder cancers with VH. Although clearly associated with features of more aggressive behavior, VH had not any significant impact in survival expectancies when all confounders are adjusted in multivariate analyses.

KEY WORDS: Urothelial carcinoma; Variant histology; Radical cystectomy. Submitted 2 April 2022; Accepted 16 April 2022

INTRODUCTION

Bladder cancer is the tenth most common cancer worldwide, accounting for 3% of all new cases worldwide (1). Urothelial carcinoma (UC) is the commonest histology of bladder cancer. However, due to its known propensity for divergent differentiation, the 2004 World Health Organization (WHO) classification of tumors of the urinary system recognized a wider spectrum of variant histologies (VH) (2). One of its aims was increase the aware-

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ness for the identification of those variants on pathology specimens and, in that way, better understand its clinical and therapeutic impact. VH have been reported in 7-81% (3) and, although the presence of VH has been associated with a more aggressive behavior, conclusive data on their effect on survival outcomes are currently not well stablished. The optimal therapeutic management of this patients is based in expert opinion and so, no strong recommendations in this respect can be done. Therefore, this is the first Portuguese-based cohort to report the oncological and survival outcomes after radical cystectomy (RC) in patients with VH, comparing against patients with pure urothelial carcinoma (PUC).

MATERIALS

AND METHODS

A retrospective review was done using an electronic data search of all patients submitted to radical cystectomy (RC) between January 2013 and December 2019 in our Institution. The procedures were approved by the Institutional Internal Review Board. Overall, 240 consecutive patients were identified. Exclusion criteria were: lymph node or distant metastasis on initial staging (n = 43), pure non-urothelial carcinomas (n = 8), no transurethral resection of bladder tumor prior to RC (n = 5) and lost in follow-up or insufficient data (n = 3). A multidisciplinary team reviewed all patients preoperatively with chest, abdominal and pelvic computed tomography (CT) or magnetic resonance imaging (MRI) if TC was contraindicated. Open RC with pelvic node dissection was performed by a team of urologists using standard techniques. All RC specimens were assigned by genitourinary dedicated pathologists and histological type was classified according to the 2004 WHO classification of tumors of the urinary system (2). Pathological stages were classified according to 2010 American Joint Committee on Cancer (AJCC)/Union International Contre le Cancer (UICC) Tumor, Node, Metastasis (TNM) staging classification (7th edition) (4). Only VH on RC specimens were included. For the purpose of this study, we didn’t discriminate the amount of VH on the specimen and assumed that any component of VH would drive outcomes. VH with less than 10 cases were classified as other variants and more than one VH on the RC specimen as mixed variants. No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2022; 94, 2

Variant histologies and survival after radical cystectomy

Patients were followed-up, at least, every 6 months for the first 2 years and then yearly with a clinical review, complete blood count and serum chemistry evaluation and CT or abdominal and pelvic ultrasonography plus chest x-ray. Additional investigation (e.g., bone scan, PETCT, urine cytology, neocystoscopy) was performed when clinically indicated. We aimed to prove that patients with VH had worst survival outcomes, defined as overall survival (OS), diseasespecific survival (DSS) and recurrence-free survival (RFS), in comparison with patients with PUC. Recurrence was defined as the evidence of any locoregional or distant metastasis on imaging follow-up. Evidence of disease progression in patients with positive surgical margins was not consider as recurrence, rather persistence of disease. Descriptive statistical analysis was performed using Pearson chi-square test to compare categorical variables and Mann-Whitney-U (2 categories) or Kruskal-Wallis (3 or more categories) tests to compare continuous variables. The Kaplan-Meier method was used to estimate OS, DFS and RFS and differences between groups were assessed using log-rank test. Multivariable Cox proportional hazards regression analysis tested the effect of VH on recurrence, disease specific (DSM) and overall (OM) mortality after adjustment for age, gender, body mass index (BMI), estimated 10-year survival according to Charlson comorbidity index (CCI), time to RC, neoadjuvant chemotherapy (NAC), pathological T and N stage, positive surgical margins (PSM) and lymph vascular invasion (LVI). All models were tested for concordance probability using Wald and Score tests. Schoenfield residual plots were used to test the proportional hazards assumption. Statistical significance was considered as p < 0.05. Statistical analyses were conducted using SPSS Statistics® v. 24.0 (IBM Corp., Armonk, New York, United States of America) and RStudio v. 1.4.1 (Integrated Development for R. RStudio, PBC, Boston, United States of America).

Table 1. Clinicopathological characteristics of cohort.

Age. median. range (years) Male gender BMI ≥ 25 Estimated 10-year survival according CCI TURBT muscle invasive NAC Time to RC. median. range (weeks) Pathological stage T0 pTa-T1-cis T2 T3-T4 pN+ PSM LVI

PUC (n = 103; 57%) 69 (62-74) 88 (85%) 58 (56%) 21% (2-53) 79 (76.7%) 44 (42.7%) 19 (10-27)

VH (n = 78; 43%) 69 (62-75) 67(86%) 38 (49%) 21% (2-53) 65 (83.3%) 20 (25.3%) 16 (10-22)

P-value

22 (21.3%) 31 (30.1%) 15 (14.6%) 35 (34.0%) 24 (23.3%) 7 (6.8%) 34 (33.0%)

5 (6.4%) 4 (5.1%) 11 (14.1%) 58 (74.4%) 29 (37.2%) 14 (17.9%) 47 (60.3%)

< 0.0001

RESULTS

In total, 181 patients were included after meeting inclusion/exclusion criteria. Median age was 69 years [interquartile range (IQR): 62-75)] and 86% (n = 155) were male. Figure 1. The Kaplan Meier analysis assessing overall survival (A), disease-specific survival (B) and recurrence-free survival (C). NR – Not reached; PUC – Pure urothelial carcinoma; VH: Variant histology.

PUC VH

0.659 0.930 0.311 0.220 0.542 0.017 0.094

PUC VH

2-years OS 0.72 0.63

5-years OS 0.54 0.42

Disease-specific survival

Median (months) NR 42

0.042 0.020 < 0.0001

BMI: Body mass index; CCI: Charlson comorbidity index; LVI: Lymphvascular invasion; NAC: Neoadjuvant chemotherapy; PSM: Positive surgical margins; PUC: Pure urothelial carcinoma; RC: Radical cystectomy; VH: Variant histology.

Median (months) 78 31 B

PUC VH

Overall ssurvival

2-years DSS 0.76 0.64

5-years DSS 0.63 0.49

Recurrence-free survival

Median (months) NR NR

2-years RFS 0.70 0.70

5-years RFS 0.63 0.63

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Table 2. Multivariable Cox regression analyses predicting de risk of overall mortality (OM), disease-specific mortality (DSM) and recurrence.

higher pathological stage, regional lymph node metastasis, PSM and LVI, comparing to PUC patients. OM DSM Recurrence The median follow-up was 35 HR [95% CI] P-value HR [95% CI] P-value HR [95% CI] P-value (IQR: 18-59) months for all Age 0.99 [0.95; 1.03] 0.55 0.99 [0.95; 1.04] 0.76 0.98 [0.93; 1.02] 0.34 cases. Over that period, 50.3% Gender (male ref.) 0.74 [0.37; 1.50] 0.41 0.86 [0.41; 1.79] 0.68 0.92 [0.39; 2.16] 0.85 (n = 91) of patients died and canBMI ≥ 25 (< 25.0 ref.) 0.65 [0.42; 1.02] 0.06 0.63 [0.38; 1.04] 0.07 0.71 [0.42; 1.24] 0.23 cer related mortality was 40.3% Time to RC 1.00 [0.99; 1.01] 0.18 1.00 [0.99; 1.01] 0.65 1.00 [0.99; 1.01] 0.79 (n = 73). Disease recurrence NAC 0.76 [0.45; 1.30] 0.32 0.80 [0.44; 1.46] 0.47 0.95 [0.51; 1.80] 0.88 occurred in 35.4% (n = 64) of all Estimated 10-y survival CCI 0.99 [0.98; 1.01] 0.27 0.99 [0.98; 1.01] 0.69 0.99 [0.98; 1.01] 0.26 patients. Kaplan-Meier survival ≥ pT3 (pT0-T2 ref) 3.30 [1.81; 6.01] < 0.001 4.67 [2.24; 9.78] < 0.001 3.51 [1.77; 6.93] < 0.001 analysis shows that median OS pN+ 1.97 [1.16; 3.34] 0.01 1.93 [1.07; 3.47] 0.03 32.54 [1.41; 4.60] < 0.001 (Figure 1A) and DSS (Figure 1B) PSM 1.99 [1.10; 3.61] 0.02 2.35 [1.26; 4.39] 0.007 0.08 [0.01; 0.61] 0.01 were significantly worse for VH patients (78 vs 31 months, LVI 1.54 [0.88; 2.68] 0.13 2.03 [1.17; 3.71] 0.02 1.93 [1.05; 3.55] 0.03 p = 0.038; Not Reached vs 42 PUC (ref) months; p = 0.016). At 5 years, VH 0.83 [0.52; 1.33] 0.44 0.91 [0.54; 1.53] 0.72 0.75 [0.42; 1.35] 0.33 VH was associated with a 12% Squamous 0.68 [0.36; 1.31] 0.25 0.77 [0.38; 1.56] 0.47 0.72 [0.32; 1.59] 0.41 and 14% decrease in OS and Micropapillary 0.58 [0.24; 1.42] 0.23 0.63 [0.25; 1.58] 0.32 0.78 [0.28; 2.18] 0.64 DSS, respectively. No significant Mixed 0.86 [0.41; 1.81] 0.69 1.01 [0.46; 2.24] 0.97 0.66 [0.35; 2.14] 0.38 statistical difference between the Others 1.24 [0.64; 2.41] 0.52 1.40 [0.46; 2.24] 0.39 0.66 [0.26; 1.69] 0.75 two groups was reached regardConcordance (SE): 0.761 (0.026) Concordance (SE): 0.795 (0.026) Concordance (SE): 0.779 (0.031) ing RFS (Figure 1C). Likelihood ratio test: p < 0.001 Likelihood ratio test: p < 0.001 Likelihood ratio test: p < 0.001 Multivariable Cox regression Wald test: p < 0.001 Wald test: p < 0.001 Wald test: p < 0.001 analyses predicting the risk of Score test: p < 0.001 Score test: p < 0.001 Score test: p < 0.001 OM, DSM and recurrence are BMI: Body mass index; CCI: Charlson comorbidity index; LVI: Lymphvascular invasion; NAC: Neoadjuvant chemotherapy; PSM: Positive surgical margins; represented in Table 2. No differPUC: Pure urothelial carcinoma; RC: Radical cystectomy; VH: Variant histology. ences were seen in these endpoints between PUC and VH patients. On the other hand, Regarding histology, 57% (n = 103) patients had PUC, higher pathological stage, regional lymph node metastasis whereas 43% (n = 78) patients had VH. Squamous cell difand PSM were all independent predictors for OM, DSM ferentiation (SQD; n = 29, 16.0%) was the commonest VH, and recurrence. A significant higher proportion of patients followed by mixed VH (n = 18; 9.9%), micropapillary VH with PUC were submitted to NAC as opposite to patients (MPV; n = 10, 5.5%) and others VH (n = 21; 11.6%), which with VH (42.7% vs 25.3%, p = 0.017). comprise nested VH (n = 7; 3.9%), glandular VH (n = 5; When we looked for the effects of NAC in survival out2.8%), sarcomatoid VH (n = 4; 2.2%), plasmacytoid (n = 3; comes, although no statistically significant difference was 1.7%), microcystic (n = 1; 0.5%) and poorly differentiated seen, patients submitted to NAC of both groups had bet(n = 1; 0.5%). Table 1 shows clinicopathological characterter OS, DSS and RFS compared to patients undergoing istics of the cohort. Patients with VH had a significantly RC only (Figure 2). Figure 2. The Kaplan Meier analysis assessing OS (A), DSS (B) and RFS (C) in patients with PUC and VH stratified for NAC. NR – Not reached; PUC – Pure urothelial carcinoma; VH: Variant histology.

RC only NAC prior to RC

140

Overall survival - PUC

Median (months) 49 NR

2-years OS 0.66 0.80

Archivio Italiano di Urologia e Andrologia 2022; 94, 2

5-years OS 0.49 0.61

RC only NAC prior to RC

Overall survival - VH

Median (months) 28 72

2-years OS 0.59 0.75

5-years OS 0.39 0.53

Variant histologies and survival after radical cystectomy

Median (months) NR NR

RC only NAC prior to RC

DISCUSSION

Disease-specific survival - PUC

2-years DSS 0.70 0.84

5-years DSS 0.57 0.72

Median (months) 65 NR

2-years RSS 0.66 0.75

Median (months) 42 72

RC only NAC prior to RC

Recurrence-specific survival - PUC

5-years RSS 0.57 0.72

Over the last decade, an increasing number of studies has been published about VH and its clinical significance. This trend is not the result of an increase in true prevalence of VH, but rather the result of a growing awareness and recognition of VH after the 2004 WHO classification of urothelial carcinomas, updated in 2016 (2, 5). As an example, Linder et al. re-reviewed all pathological specimens of patients submitted to RC between 1980 and 2005 and concluded that, of 1211 patients initially diagnosed with PUC, 33% were reclassified as VH (6). Similarly, Shah et al. reported that 44% of VH weren’t documented by referral institutions, being then recognized by central pathology rereview (7). We report that 43% of patients had VH, with SQD (16%), mixed VH (9.9%) and MPV (5.5%) being the most common variants. Although the frequency of VH reported in our cohort is superior of those reported in largest series published in the past few years, which have found prevalences of VH between 17-32%, VH subtypes proportions is in concordance, being SQD and MPV between the most common variants reported (8-11). In our study, VH were significantly associated with pre-

RC only NAC prior to RC

Disease-specific survival - VH

2-years DSS 0.61 0.75

5-years DSS 0.48 0.53

Recurrence-specific survival - VH

Median (months) NR 65

2-years RSS 0.67 0.70

5-years RSS 0.62 0.65

dictors of more aggressive disease comparing with PUC, such as, higher pathological stages, higher rates of regional nodal involvement, higher rates of LVI and PSM. The key question is to know if whether these VH pathological findings translate in worse survival outcomes. For the entire cohort, the 5-year OS and DSS were 49% and 57%, respectively, which were in line with a recent review, where the 5-year OS is between 36-48% for patients with non-metastatic muscle-invasive disease (12). When we looked for survival differences between VH and PUC patients, we found that patients with VH had significantly worst OS and DSS in comparison with PUC patients, with a decrease of 12 and 14% in 5 yearOS and DSS, respectively. However, after adjusting for cofounders, such as, demographics characteristics, comorbidities and pathological features, VH didn’t reach statistical significance to infer it as a predictor of survival, namely, OM and DSM. The same results in multivariate Cox analyses continued to be truth when we stratified VH into subgroups, such as, SQD, MPV, mixed VH and other VH. We also didn’t find any differences in uni- or multivariate analyses regarding recurrences when comparing both groups. Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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It probably contributes the fact that we didn’t consider as recurrence patients with PSM (significantly higher in VH group) that had disease progression over the follow-up period. To date, the evidence with regard to survival outcomes in this subset of patients is based in retrospective series, with heterogenous results in stablish if whether or not VH is a true predictor of worse survival outcomes. Xylinas et al. reported that VH were significantly associated with more advanced tumor stages, lymph node metastasis, LVI and PSM, which as a negative effect in univariate analyses of DSS and RFS of patients with non-PUC and non-SQD variants. However, no differences were seen in multivariate Cox regression analyses (8). Soave et al. stated identical results, with higher diseasespecific mortality in VH patients in univariate analyses, but no differences when adjusting for cofounders (13). Sefik et al. concluded, in a study with nearly the size of ours, that, although patients with variant histology (especially SQD variant) have proportionally higher T stage compared to non-VH, there weren’t significant differences for DSS and OS (14). In contrast, Stroman et al found that patients with VH had higher probability of death of all and disease-related causes, even after adjusting for cofounders, with HR 1.86 (95% CI: 1.21-2.85) and HR 1.89 (1.91-3.01), respectively. A recent meta-analysis, which include 20544 patients of 39 studies, has concluded that patients with VH have worse OS (pooled HR 1.44; 95% CI 1.26-1.65; significant heterogeneity), DSS (pooled HR 1.37; 95% CI 1.24-1.50; no significant heterogeneity) and RFS (pooled HR 1.32; 95% CI 1.20-1.45; no significant heterogeneity). Furthermore, the subgroup analyses showed that the variants with worst OS were small cell (pooled HR 3.32; 95% CI 1.98-5.59; no significant heterogeneity), plasmacytoid (pooled HR 2.03; 95% CI 1,17-3,52; significant heterogeneity) and micropapillary VH (pooled HR 1.20; 95% CI 1.02-1.41; no significant heterogeneity) (15). The 2020 European Urology Association Guidelines strongly recommends to offer neoadjuvant cisplatin-based combination therapy to patients with muscle-invasive BC prior to RC, based in a 8% improve on 5-year OS (16). However, this survival benefit of NAC was mostly seen in patients with UC histology. At the best of our knowledge, the available evidence regarding the added benefit of NAC for patients with VH is limited due to the lack of RCT. In a retrospective study, Vetterlein et al. evaluated the benefit of NAC in patients with muscle-invasive VH and concluded that NAC lowered the rates of non-organ-confined disease at the time of RC in patients with neuroendocrine, micropapillary, sarcomatoid and adenocarcinoma differentiation tumours. However, that pathological benefit only translates in better OS for neuroendocrine patients (HR 0.49; 95% CI 0.33-0.74; p = 0.01) (17). In our study, patients of both groups had better OS, DSS and RFS in univariate analyses when stratified for NAC, although no statistical difference was seen. Furthermore, the potential negative effect of delayed cystectomy due to NAC was not seen in multivariate Cox analyses, as time to cystectomy was not a predictor of worst survival outcomes. There are several limitations that worth mention. First and foremost, it was a retrospective single-center study

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and our findings should be interpreted in this context. Second, RC specimens weren’t re-review and so pathological findings are unified in two dedicated genitourinary pathologists. Third, the small proportions of VH limited the subanalyses and conclusions in this regard. Fourth, there were more RC specimens with pT0 and pTa-T1-cis in the PUC group (51.4%) comparing with VH group (11.5%). For this, probably contributes the higher rate of PUC patients submitted to NAC prior to cystectomy and although it was accounted for multivariate Cox analyses, this may contribute to worse survival outcomes for VH patients.

CONCLUSIONS

Our study evidenced the high incidence of bladder cancers with variants histologies. Although clearly associated with features of more aggressive behavior, there was not any significant impact in survival expectancies when all cofounders are adjusted in multivariate analyses. More than large prospective studies assessing outcomes of different morphology variants, we believed that the future directions are in treatment modalities targeting molecular subtypes of bladder cancer.

REFERENCES

1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71:209-49. 2. Montironi R, Lopez-Beltran A. The 2004 WHO Classification of bladder tumors: a summary and commentary. Int J Surg Pathol. 2005; 13:143-53. 3. Chalasani V, Chin JL, Izawa JI. Histologic variants of urothelial bladder cancer and nonurothelial histology in bladder cancer. Can Urol Assoc J. 2009; 3:193. 4. Edge S, Compton C. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. In Ann Surg Oncol; 2010. p. 1471-4. 5. Humphrey PA, Moch H, Cubilla AL, et al. The 2016 WHO classification of tumours of the urinary system and male genital organs— Part B: prostate and bladder tumours. Eur Urol. 2016; 70:106-19. 6. Linder BJ, Boorjian SA, Cheville JC, et al. The Impact of Histological Reclassification during Pathology Re-Review— Evidence of a Will Rogers Effect in Bladder Cancer? J Urol. 2013; 190:1692-7. 7. Shah RB, Montgomery JS, Montie JE, Kunju LP. Variant (divergent) histologic differentiation in urothelial carcinoma is under-recognized in community practice: Impact of mandatory central pathology review at a large referral hospital. Urol Oncol Semin Orig Investig. 2013; 31:1650-5. 8. Xylinas E, Rink M, Robinson BD, et al. Impact of histological variants on oncological outcomes of patients with urothelial carcinoma of the bladder treated with radical cystectomy. Eur J Cancer. 2013; 49:1889-97. 9. Monn MF, Kaimakliotis HZ, Pedrosa JA, et al. Contemporary bladder cancer: variant histology may be a significant driver of disease. Urol Oncol Semin Orig Investig. 2015; 33:18.e15-18.e20. 10. Moschini M, Dell’Oglio P, Luciano’ R, et al. Incidence and effect of variant histology on oncological outcomes in patients with bladder

Variant histologies and survival after radical cystectomy

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and squamous differentiation on oncological results and patient’s survival after radical cystectomy. Arch Ital Urol Androl. 2018; 90:172-5.

11. Stroman L, Nair R, Russell B, et al. The impact of non-urothelial variant histology on oncological outcomes following radical cystectomy. BJU Int. 2019; 124:418-23.

15. Mori K, Abufaraj M, Mostafaei H, et al. A systematic review and meta-analysis of variant histology in urothelial carcinoma of the bladder treated with radical cystectomy. J Urol. 2020; 204:1129-40.

12. Lenis AT, Lec PM, Chamie K, Mshs M. Bladder cancer: a review. JAMA. 2020; 324:1980.

16. Witjes JA, Bruins HM, Cathomas R, et al. European Association of Urology guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2020 guidelines. Eur Urol. 2021; 79:82-104.

13. Soave A, Schmidt S, Dahlem R, et al. Does the extent of variant histology affect oncological outcomes in patients with urothelial carcinoma of the bladder treated with radical cystectomy? Urol Oncol Semin Orig Investig. 2015; 33:21.e1-21.e9. 14. Sefik E, Celik S, Basmaci I, et al. Effect of variant histology presence

17. Vetterlein MW, Wankowicz SAM, Seisen T, et al. Neoadjuvant chemotherapy prior to radical cystectomy for muscle-invasive bladder cancer with variant histology: neoadjuvant CTX and bladder cancer variants. Cancer. 2017; 123:4346-55.

Correspondence João Nuno Pereira, MD (Corresponding Author) joao.pereira@ipoporto.min-saude.pt jnp.urologia@gmail.com Isaac Braga, MD isaac.braga@ipoporto.min-saude.pt Rui Freitas, MD antoniofreitas@ipoporto.min-saude.pt Vitor Moreira da Silva, MD i11074@ipoporto.min-saude.pt Sanches Magalhães, MD i10997@ipoporto.min-saude.pt Francisco Lobo, MD i2045@ipoporto.min-saude.pt António Morais, MD i1900@ipoporto.min-saude.pt Department of Urology, Portuguese Institute of Oncology, Oporto (Portugal) João Duarte Reis, MD jduarte.reis@ua.pt Mathematics Department, University of Aveiro (Portugal)

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DOI: 10.4081/aiua.2022.2.144

ORIGINAL PAPER

Extraperitoneal cystectomy with ureterocutaneostomy derivation in fragile patients - should it be performed more often? Rafaela Malinaric 1, Guglielmo Mantica 1, Federica Balzarini 1, Carlo Terrone 1, Massimo Maffezzini 2 1 Department 2 Department

of Urology, San Martino Hospital, University of Genoa, Genoa, Italy; of Urology, Hospitals of Legnano and Magenta, Milan, Italy.

Summary

Introduction and objectives: Radical cystectomy (RC) continues to be standard of care for muscle-invasive bladder cancer and recurrent or refractory nonmuscle invasive bladder cancer. Unfortunately, it has high rates of perioperative morbidity and mortality. One of the most important predictors of postoperative outcomes is frailty, while the majority of complications are diversion related. The aim of our study was to evaluate safety of extraperitoneal cystectomy with ureterocutaneostomy in patients considered as frail. Materials and methods: We retrospectively collected data of frail patients who underwent extraperitoneal cystectomy with ureterocutaneostomy from October 2018 to August 2020 in a single center. We evaluated frailty by assessing patients' age, body mass index (BMI), nutritional status by Malnutrition Universal Screening Tool, overall health by RAI (Risk Analysis Index) and ASA (American Society of Anaesthesiologists) score, and laboratory analyses. We observed intraoperative outcomes and rates of perioperative (within 30 days) and early postoperative (within 90 days) complications (Clavien-Dindo classification). We defined extraperitoneal cystectomy with ureterocutaneostomy as safe if patients did not develop Clavien Dindo IIIb, or worse, complication. Results: A total of 34 patients, 3 female and 31 male, were analyzed. The median age was 77, BMI 26, RAI 28, ASA 3 and the majority had preexisting renal insufficiency. Blood analyses revealed presence of severe preoperative hypoalbuminemia and anemia in half of our cohort. Intraoperative median blood loss was 250 cc, whilst operative time 245 min. During perioperative period 60% of our cohort developed Clavien Dindo II complication and during early postoperative period 32% of patients required readmission. One death occurred during early postoperative period (2.9%). After 12 months of follow-up, we observed stability of the renal function for most patients. Conclusions: We believe that extraperitoneal cystectomy with ureterocutaneostomy could be considered as a treatment option for elderly and/or frail patients.

KEY WORDS: Bladder cancer; Extraperitoneal cystectomy; Ureterocutaneostomy; Frailty; Feasibility. Submitted 14 January 2022; Accepted 16 April 2022

INTRODUCTION

When both sexes are considered, bladder cancer is one of the most common cancers worldwide, sitting at the 7th place (1). Although the majority of patients present with

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non-muscle invasive disease, bladder cancer can often recur or even progress (2). Currently, radical cystectomy (RC) is considered as the gold standard for treating muscle-invasive bladder cancer (1). Unfortunately, it continues to be one of the surgical procedures with the highest rates of morbidity and mortality to date (3). Although chronological age is an important risk factor for development of intra- and peri-operative complications, several concurrent losses in resources, should be considered in the estimation of surgical risk (4). Actually, frailty has been recognized as the most important predictor of poor postoperative outcomes. Although there is still no consensus on clinical definition of frailty (6), some authors refer to it as “a state of reduced physiologic reserve beyond that would be expected with normal aging”. It is thought to be the final product from the cumulative effect of multiple physiologic changes over time (5). Fried et al. designed a list that could help clinicians in assessing general physical state of patients and listed these components as a part of frail phenotype: a) self-reported weight loss; b) self-reported exhaustion; c) low energy expenditure; d) slow gait speed; e) weak grip strength (6). Frail patients have a compromised pulmonary function, decreased time to desaturation, higher hypoxia and hypercarbia. Altered renal and hepatic functions are also frequent, with consequent decreased drug metabolism, dehydration, electrolyte disbalance and increased haemorrhagic and drug toxicity risk. Lastly, because of the sarcopenia and generally reduced serum albumin, they are more prone to hypothermia and are more sensitive to effect of the anaesthetics (7). Consequently, a frail patient is more vulnerable to a stressor event and has a lower capacity of recovery after the stressor stimulation ceases. Furthermore, the prevalence of frailty increases with age. Considering that the life expectancy has increased by more than two years per decade since the 1960s (8), the proportion of elderly population diagnosed with bladder cancer undergoing cystectomy has been rising as well. Although not conducted on a frail population, Berger et al. published a retrospective, multicenter study comparing the rates of complications in ureterocutaneostomy (UCS) and urinary diversion using bowel. They observed reduced operative time, shorter stay in intensive care unit No conflict of interest declared.

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and significantly lower complication rates (graded as Clavien III-V) in UCS group (9). Moreover, a great part of data present in the literature reports that most perioperative and postoperative complications are diversion realted (10). When treating frail patients, the main goal is, when possible, to achieve radicality, or, when this is not achievable, to provide a patient a decent quality of life. In fact, by performing cystectomy, patients will not experience anymore recurrent hematuria, suprapubic pain, lumbar discomfort, dysuria or urinary retention. A lot of studies demonstrated successful outcomes after surgery performed on frail patients, but there is little evidence on patients undergoing radical cystectomy (11-13). Therefore, the aim of our study was to evaluate the safety of extraperitoneal cystectomy with UCS performed on frail and/or elderly patients.

MATERIALS

AND METHODS

Study design We retrospectively collected clinical and pathological data of frail patients who underwent extraperitoneal cystectomy with UCS from October 2018 to August 2020 in a single center. Patients were considered frail if they met 3 or more of the following criteria: advanced age (> 70), low or high body mass index (BMI) (< 18 and > 25), altered nutritional status [Malnutrition Universal Screening Tool (MUST) > 1] (14) and altered general physical health [Risk Analysis Index (RAI) > 25] (15), American Society of Anesthesiology (ASA) score > 3 (16), preoperative anemia (< 12 g/dL), renal insufficiency [serum creatinine (Crs) > 1.3 g/dL, eGFR < 60] and hypoalbuminemia (< 3 mg/dL). The MUST questionnaire considers three factors: BMI, unintentional weight loss and inability of the oral nutritional intake due to acute illness (> 5 days). After appropriate evaluation, risk of malnutrition can be appropriately designated as low risk (score 0), medium risk (score 1), high risk (score 2 or more) (14). Risk Analysis Index is a simplified Porock's 6-months mortality Index developed in 2015. It assesses age, sex, presence of malignancy, medical comorbidities, residence, cognition and daily activities. Once the questionnaire is filled, the score matches the risk of perioperative and postoperative complications development (15). Lastly, patients were assigned their ASA score (16). Evaluating patients in this, more holistic manner, we were able to identify the most fragile, sarcopenic, malnourished patients with highly catabolic disease that could benefit from extraperitoneal cystectomy with UCS. Preoperatively all patients underwent CT or MRI imaging in order to complete clinical staging. Consent form was obtained from all the patients prior to surgery. All patients were operated by one, same surgeon (M.M.) with more than 200 extraperitoneal cystectomies performed and 2 decades of experience in the field of open, uro-oncologic surgery. Female patients who were considered frail and with advanced disease underwent genital sparing extraperi-

toneal cystectomy, whilst frail male patients underwent standard extraperitoneal cystectomy. Lymph node dissection was performed only in significant, clinically evident lymphadenopathy (gross and palpable lymph nodes). Frail patients with non-metastatic disease underwent radical extraperitoneal cystectomy with standard lymph node dissection (up to the common iliac arteries). All patients received UCS as urinary diversion, and all the procedures were performed using the open approach. Intraoperatively 4.8 Ch "Bracci pattern" ureteral catheters were positioned. Two weeks postoperatively "Bracci" catheters were substituted with ureteral catheters in polyurethane (Wiruthan). ERAS protocol was implemented, when possible, with epidural catheter positioning, antithrombotic prophylaxis with heparin 100 units/kg/24h (fractioned in two doses) for 3-4 weeks, antibiotic prophylaxis with Clindamycin 1200 mg/24h and Metronidazole 1000 mg/24h (both fractioned in two doses) for 48 hours postoperatively. In case of allergies, they were substituted by Piperacillin/ Tazobactam 13.5 g/24h (fractioned in three doses). All drugs were adjusted based on cardiac, renal and hepatic function. Postoperatively patients entered our standard follow-up protocol, with CT scans repeated quarterly or biannually, complete blood panel, urinalysis and urine cytology, depending on the intent of cystectomy (curative or not) and their final pathology findings. Ureteral catheters were substituted in ambulatory setting every 3-4 weeks in absence of infections, calcifications and obstruction. Data collection and classification of complications Patients’ information was collected from hospital database. We assessed duration of the surgery, anaesthesia protocol and blood loss, whilst data regarding histopathological reports were recorded according the TNM classification approved by the Union International Contre le Cancer (UICC) (8th Edn.) (17). Subsequently, we observed duration of the hospital stay, hematologic and biochemical alterations, perioperative (within 30 days) and early postoperative (within 90 day) complications (Clavien Dindo classification) (18) and readmission rates. Outcomes We hypothesized that this surgical technique would be a safer approach when treating frail and elderly patients, decreasing the risk of perioperative morbidity and mortality. We considered extraperitoneal cystectomy with UCS a safe procedure if patients did not develop any Clavien Dindo > IIIb complication. Statistical analysis Descriptive statistics included frequencies and proportions for categorical variables. Means, medians, and interquartile ranges (IQR) were reported for continuously coded variables. We considered age, BMI, MUST score, ASA score, RAI score, preoperative and postoperative laboratory results, tumor pathological stage and postoperative outcomes. The Mann-Whitney and Fisher’s exact test examined the Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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statistical significance of mean and distribution differences among patients with or without complications. The characteristics of patients with and without complications were compared with the Mann-Whitney and Fisher’s exact tests, accordingly. All tests were two sided with a level of significance set at p < 0.05. R software environment for statistical computing and graphics (version 4.1.3) was used for all analyses (R Core Team 2021). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. Available at: URL https://www.R-project.org/.)

RESULTS Patient population and perioperative characteristics We collected data of 34 patients, 3 (8.8%) females and 31 (91.2%) males, that met the frailty criteria. The median follow-up was 12 (5.75-15.25) months. The majority of the patients (86%) were 70 years old or older, with median age of 77.5 (IQR 71.1-80.2), and were smokers (58.8%). Median BMI was 26 and most of them already had preexisting renal insufficiency (median Crs 1.33 mg/dL (IQR 1.17-1.62), with an eGFR 35.5). Seventeen (50%) patients reported unvoluntary weight loss three months prior to surgery, 12 (35%) were medium risk for malnutrition, while 5 (15%) were high risk. All the high-risk patients were referred to the specialized dietitian (Table 1). Median RAI score was 28 (IQR 25.0-31.0), in fact 30 (88%) patients scored over 25. Furthermore, most patients (23, 68%) were classified as ASA 3 (Tables 1-2). Thirty-three (97%) patients had a preoperative hypoalbuminemia (serum albumin ≤ 3 g/dL) and 22 (64.7%) anemia (hemoglobin ≤ 12.5 g/dL) (Table 2). Table 1. Descriptive characteristics of 34 patients treated with extraperitoneal cystectomy and ureterocutaneostomy from October 2018 to August 2020 Characteristics Age, (years) Female Male BMI, (kg/m2) Preoperative creatinine, (mg/dL) Preoperative albumin, (g/dL) Preoperative hemoglobin (g/dL) MUST score 0 1 2 ASA score 1 2 3 4 RAI

34 *

77.5 (71.1, 80.2) 3 (8.8%) 31 (91.2%) 26.0 (24.0, 30.0) 1.33 (1.17, 1.60) 3.20 (2.62, 3.77) 12.15 (10.7, 13.28) 17 (50%) 12 (35%) 5 (15%) 1 (2.9%) 9 (26%) 23 (68%) 1 (2.9%) 28.0 (25.0, 31.0)

* Median (IQR); n (%).

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Overall, 27 (79.4 %) patients presented with symptomatic disease including suprapubic pain, recurrent macrohematuria and urinary retention (Table 2). Seven patients (20.5%) presented with BCG refractory disease. None of the patients underwent neoadjuvant chemotherapy because of late stage of the disease, or because of the general health status and advanced age. One patient did, however, undergo pelvic radiotherapy that caused actinic hematuria and severe anemization (Table 2). Cystectomy was radical in 23 patients (68%) and palliative in 11 (34%) with no lymphadenectomy (Table 1). Median duration of surgery (skin-to-skin) was 245 (124420) minutes and registered blood loss was 250 (100800) mL. ERAS protocol was applied in all eligible patients (20 patients, 59%). On the contrary, 14 patients underwent general anesthesia with use of opioids for analgesia. On the final histopathological examination 4 (12%) patients had a pTa urothelial tumor, 5 (14%) pT1, 9 (27%) pT2, 7 (20%) pT3 and 9 (27%) pT4, respectively. A mean of 8 lymph nodes per patients was removed and 4 patients (12%) had lymph node metastases. The same number of patients (4, 12%) had a distant organ metastasis ab initio. Furthermore, in our cohort for 11 (32%) patients the surgery was not radical, and they did not undergo pelvic lymph node dissection. Finally, 5 (15%) patients had a positive surgical margin, all with pT4 tumor. Clinical outcome Median hospital stay was 13 (range 7-87) days. Postoperatively, renal function remained stable (median creatinine increase was 0.09 mg/dL) for the majority of patients. Two patients had a major drop [from 6.2 mg/dL to 5.0 mg/dL on 3rd postoperative day (POD) and from 6.0 mg/dL to 4.4 mg/dL on 3rd POD], one had a major increase (from 3.8 mg/dL to 7.2 mg/dL 3rd POD). Noticeably, the same patient who had an increase in Crs, Table 2. General patients' characteristics and number/percentage of patients divided by various subgroups. Characteristics Age ≥ 75 years History of smoking BMI ≤ 21 or ≥ 25 (kg/m2) Preoperative albumin < 3 g/dL Preoperative hemoglobin < 12.5 g/dL) ASA score ≥ 3 RAI score ≥ 25 BCG refractory disease Pathological Stage > cT3 cN+ cM+

N = 34 * 33 (97%) 20 (58.8%) 24 (70.6) 33 (97%) 22 (64.7%) 25 (73.5%) 30 (88.2%) 7 (20.5%) 16 (47%) 8 (23.5%) 4 (11.7%)

Clinical symptoms More than one variable combined

27 (79.4%) 34 (100%)

* n (%).

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had a pT4 bladder cancer at the final pathology and a severe preoperative and postoperative hypoalbuminemia. Subsequently, he developed surgical site infection (SSI) during hospital stay and later required readmission. Most patients passed gas in the 2nd POD (21 pts, 62%, range 1-3 POD) and one third of patients passed feces in 5th POD (10, 30%, range 3-15 POD). Perioperative complications During hospital stay 20 (58.8%) patients developed Clavien Dindo >/= II grade complication [12 SSI, 2 paralytic ileus, 1 acute kidney injury, 15 blood transfusions, 4 urinary tract infections (UTIs), 2 atrial fibrillations and 1 lymphocele]. Eight (24%) patients developed more than one complication requiring simultaneous administration of antibiotics and blood components. Only 2 (5.9%) patients developed Clavien Dindo III complication (two deep subfascial infections, of which one with simultaneous evisceration). Both patients were treated with Vacuum Assisted Closure Therapy (VAC) (19), and the patient with evisceration underwent surgical correction using Linberg flap technique. A strong association between perioperative hypoalbuminemia and SSI was noted. All the patients with SSI (12, 35.29%) had a marked hypoalbuminemia (≤ 3 g/dL) on the 3rd POD and the majority of them (10 patients) had it also preoperatively, being at medium/high risk of malnutrition. An association between BMI (> 25) and septicemia was observed in 6 patients of 8 (75%) who developed fever. Higher rates of complications and readmission rates were noted in patients that had ASA score > 3 and presented medium/high risk of malnutrition. During perioperative period there were no deaths observed due to the surgical complications. Postoperative complications During early postoperative period (within 90 days) 11 (32%) patients required a readmission. Most of complications were infectious, refractory to the antibiotic therapy administered by general medicine physician: 2 SSIs (5.9%) and 5 UTIs (14.7%). Less frequent complications were: 2 lymphoceles (5.9%), 1 pulmonary thromboembolism (2.9%) and 1 intestinal subocclusion (2.9%). All were classified as Clavien Dindo grade II (Table 3). Rates of readmission showed a similar trend. Patients with complications had a significantly higher RAI Table 3. Clavien-Dindo grading in relation to perioperative and early postoperative period. Complication (Clavien-Dindo) I II IIIa IIIb IV V * n (%).

N = 34 * Perioperative (within 30 days) 0 (0%) 20 (58.8%) 1 (2.9%) 1 (2.9%) 0 (0%) 0 (0%)

N = 34 * Early postoperative (within 90 days) 0 (0%) 11 (32.4%) 0 (0%) 0 (0%) 0 (0%) 1 (2.9%)

score if compared with patients without complications (p = 0.027) (Table 4). Lastly, one death occurred during early postoperative period (2.9%) due to recurrent UTIs and sepsis (Table 3). At median postoperative follow-up of 12 (5.75-15.25) months, 7 (20%) patients were dead, 4 due to the disease progression and 3 due to non-cancer specific causes. Sixteen (47%) patients were alive without evidence of the disease recurrence.

DISCUSSION

AND CONCLUSION REMARKS

Approximately 25% of newly diagnosed patients with bladder cancer presented as muscle invasive disease (1), and 2% as locally advanced (pT4) (20), with high probability of manifesting irritative lower urinary tract symptoms (LUTS), suprapubic pain and gross hematuria. Therefore, advanced bladder cancer can be significantly disabling and can worsen patients' quality of life. EAU guidelines recommend radical cystectomy as the first treatment option1, mainly because of its' superiority regarding overall survival (OS) and cancer specific survival (CSS) when compared to bladder sparing treatments such as radiotherapy, TURBT-T or chemotherapy alone (21). Moreover, these treatments could actually make patients' quality of life deteriorate by exacerbating the local symptoms or causing treatment-related symptoms (e.g. actinic colitis) (22). On the contrary, if left untreated, 38% of the patients will present metastasis within 6 months of initial diagnosis (21). Radical cystectomy was first described in 1940s and was associated with extremely elevated perioperative mortality, up to 33% (23), but few decades later mortality rates stabilized at 2-5% (3). Some authors described up to 13.7% mortality rates during early postoperative period for frail patients (24), whilst some tertiary centers report extremely low rates, as low as 0.5%, that could be explained by patient selection Table 4. Descriptive characteristics of 34 patients treated with extraperitoneal cystectomy and ureterocutaneostomy from October 2018 to August 2020, stratified by complications. Characteristics Age, (years) BMI, (kg/m2) Preoperative creatinine, (mg/dL) Preoperative albumin, (g/dL) MUST score 0 1 2 ASA score 1 2 3 4 RAI

Complication No, n = 14 * Yes, n = 19 * 76.7 (72.3, 80.0) 77.8 (71.8, 80.5) 25.0 (23.1, 26.8) 27.0 (25.0, 30.5) 1.27 (1.13, 1.48) 1.40 (1.19, 1.76) 3.11 (2.62, 3.79) 3.30 (2.80, 3.71) 7 (50%) 6 (43%) 1 (7.1%)

9 (47%) 6 (32%) 4 (21%)

1 (7.1%) 5 (36%) 7 (50%) 1 (7.1%) 26.5 (25.0, 28.8)

0 (0%) 3 (16%) 16 (84%) 0 (0%) 30.0 (27.5, 33.0)

P-value ** > 0.9 0.082 0.3 0.7 0.6

0.11

0.027

* Median (IQR); n (%). ** Wilcoxon rank sum exact test; Wilcoxon rank sum test; Fisher's exact test.

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bias, although it is a well-known fact that high-volume centers tend to have less peri- and postoperative complications (25). Furthermore, one study revealed that the probability of undergoing radical cystectomy for elderly patients is five-fold lower than for younger ones (26). Consequently we asked ourselves the following questions. Should we deny a surgical option to patients in our cohort who were considered frail? Could we instead treat those frail patients with extraperitoneal cystectomy followed by ureteral diversion to the abdomen wall that is reputed as the simplest form of urinary diversion with lower complication rates, morbidity and mortality (27)? Furthermore, when Longo et al. assessed the quality of life in patients treated with ileal conduit and UCS using the Bladder Cancer Index, patients reported the same level of discomfort equally in both groups (28). In our study we confirmed findings previously reported in the literature. In fact, in our cohort median blood loss and operative time were reduced, when compared to reports of intraperitoneal radical cystectomy with bowel diversion. De Nunzio et al. described even more reduction in operative time, but that could be due to different surgical technique or more experienced second surgeon (29). The association between some preoperative characteristics of the patients and rates of complications were previously reported in the literature (30, 31). The association between perioperative hypoalbuminemia and risk of wound infection was also reported by other authors (32). Similar observations were made for BMI and septicemia and for anemia, ASA > 3 and RAI score > 25 and development of deep subfascial wound infection with evisceration or needing readmission. Moreover, in our cohort, there were no complications such as anastomotic leakage, hematomas or mechanical bowel obstructions, and at the end of perioperative period we did not observe any death although we had one death in the early postoperative period. Due to this experience, we believe that performing an extraperitoneal cystectomy with UCS and implementation of the ERAS protocol, the risk of intestinal complications such as paralytic ileus, gastroparesis and electrolytic imbalance are significantly lowered, as well as likelihood of urinary fistulas. Where the surgery was only palliative, we avoided lymphadenectomy and, thus, lymphocele and all the related consequences. These are the main reasons why we consider extraperitoneal cystectomy with UCS a safer surgical technique when treating frail patients. However, our study is not without limits. Firstly, it is a retrospective study on a small cohort of patients. Secondly, some patients may have not undergone correct staging of disease as they did not undergo the lymphadenectomy. Furthermore, patients, although all considered frail, were not homogeneous. They, in fact, differed in age, clinical manifestation of disease, BMI, stage, laboratory findings, malnourishment risk and not all patients underwent ERAS protocol. Furthermore, there is no control group due to the fact that this surgery is reserved only for the patients that would otherwise be considered unfit for surgery. However, the aim of this study was to evaluate the safety

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of extraperitoneal cystectomy with UCS in frail patients, and it is also the main reason why having a more homogeneous cohort is difficult, if not impossible. Nevertheless, this technique should be evaluated on larger cohorts. We do believe it is our duty to evaluate patients in more holistic manner in order to choose the right surgical approach. We should inform patients about the risks we are taking and use all preoperative tools at our disposal in order to prepare patients for this battle (e.g. could we administer intravenous albumin?). And while for the 'fit-for-surgery' patients there is continuously more evidence for robotic-assisted radical cystectomy (33), we do believe that the 'frail patients' category is somehow forgotten. Open extraperitoneal cystectomy with UCS could be considered as a surgical option for those who are categorized as 'unfit', especially if it could be radical and ensure patients a disease-free residual life. We do, however, have to perform an accurate preoperative evaluation and the surgery should be performed by an experienced surgeon who is comfortable with extraperitoneal approach to the bladder.

REFERENCES

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13. Hirpara HD, Kidane B, Rogalla P, et al. Frailty assessment prior to thoracic surgery for lung or esophageal cancer: a feasibility study. Support Care Cancer. 2019; 27:1535-1540. 14. Cawood AL, Walters ER, Sharp SKE, et al. Self-screening' for malnutrition with an electronic version of the Malnutrition Universal Screening Tool ('MUST') in hospital outpatients: concurrent validity, preference and ease of use. Br J Nutr. 2018; 120:528-536. 15. Melin AA, Schmid KK, Lynch TG, et al. Preoperative frailty Risk Analysis Index to stratify patients undergoing carotid endarterectomy. J Vasc Surg. 2015; 61:683-9. 16. https://www.asahq.org/standards-and-guidelines/asa-physicalstatus-classification-system. 17. TNM classification of malignant tumors. UICC International Union Against Cancer. 8th edn., G.M. Brierley JD, Wittekind C., Editor. 2017, Wiley-Blackwell and UICC: New York, USA. 18. Clavien PA, Barkun J, de Oliveira ML, et al. 'The Clavien-Dindo classification of surgical complications: five year experience' Ann Surg. 2009; 250:187-96. 19. Yadav S, Rawal G, Baxi M. Vacuum assisted closure technique: a short review. Pan Afr Med. 2017; 28:246. 20. Maisch P, Lunger L, Duwel C, et al. Outcomes of palliative cystectomy in patients with locally advanced pT4 bladder cancer. Urol Oncol. 2021; 39:368.e11-368.e17. 21. Gild P, Nguyen DD, Fletcher SA, et al. Contemporary survival rates for muscle-invasive bladder cancer treated with definitive or nondefinitive therapy. Clin Genitourin Cancer. 2019; 17:e488-e493. 22. Ploussard G, Daneshmand S, Efstathiou JA, et al. Critical analysis of bladder sparing with trimodal therapy in muscle-invasive bladder cancer: a systematic review.Eur Urol 2014; 66:120-137. 23. Jewett HJ, Lewis EL. Infiltrating carcinoma of the bladder; curability by total cystectomy. J Urol. 1948; 60:107-118. 24. Llorente C, Guijarro A, Hernandez V, et al. Effect of hospital volume on 90-day mortality after radical cystectomy for bladder cancer in Spain. World J Urol. 2020; 38:1221-1228.

25. Afshar M, Goodfellow H, Jackson-Spence F, et al. Centralisation of radical cystectomies for bladder cancer in England, a decade on from the ‘Improving Outcomes Guidance’: the case for super centralisation. BJU Int. 2018; 121:217-224. 26. Williams SB, Huo J, Kosarek CD, et al. 'Population-based assessment of racial/ ethnic differences in utilization of radical cystectomy for patients diagnosed with bladder cancer' Cancer Causes Control. 2017; 28:755-66. 27. Nieuwenhuijzen JA, de Vries RR, Bex A, et al. Urinary diversions after cystectomy: the association of clinical factors, complications and functional results of four different diversions. Eur Urol. 2008; 53:834-44. 28. Longo N, Imbimbo C, Fusco F, et al. Complications and quality of life in elderly patients with several comorbidities undergoing cutaneous ureterostomy with single stoma or ileal conduit after radical cystectomy. BJU Int. 2016; 118:521-6. 29. De Nunzio C, Cicione A, Leonardo F, et al. Extraperitoneal radical cystectomy and ureterocutaneostomy in octogenarians. Int Urol Nephrol 2011; 43:663-667. 30. Kavukoglu Ö, Coskun A, Sabuncu K, et al. Is it possible to reduce the complications and mortality of patients undergoing radical cystectomy? Effectiveness of pre-operative parameters. A prospective study. Arch Ital Urol Androl. 2021; 93:379-384. 31. 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. 32. Mayr R, Gierth M, Zeman F, et al. Sarcopenia as a comorbidityindependent predictor of survival following radical cystectomy for bladder cancer. J Cachexia Sarcopenia Muscle 2018; 9:505-13. 33. Mantica G, Smelzo S, Ambrosini F, et al. Port-site metastasis and atypical recurrences after robotic-assisted radical cystectomy (RARC): an updated comprehensive and systematic review of current evidences. J Robot Surg. 2020; 14:805-812.

Correspondence Rafaela Malinaric, MD (Corresponding Author) rafaela.malinaric@gmail.com Guglielmo Mantica, MD gugliemo.mantica@gmail.com Federica Balzarini, MD balzarini.federica90@gmail.com Carlo Terrone, MD carlo.terrone@med.unipo.it San Martino Hospital, University of Genoa, Genoa (Italy) Massimo Maffezzini, MD massimo.maffezzini@gmail.com Department of Urology, Hospitals of Legnano and Magenta, Milan (Italy) Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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DOI: 10.4081/aiua.2022.2.150

ORIGINAL PAPER

Summary

Background: Radical cystectomy (RC) has been considered the standard management of muscle-invasive bladder cancer. Despite the improvements in surgical techniques and perioperative care, RC is still associated with high perioperative morbidity and mortality. Objective: This study aims to evaluate the effect of retroperitonealization of ureteroileal anastomosis on perioperative complications of RC with ileal conduit urinary diversion. Patients and methods: This is a retrospective cohort study. We reviewed medical charts of 876 patients who underwent RC between 2016 and 2021. Based on the inclusion and exclusion criteria, 748 patients entered the study. According to retroperitonealization of the ureteroileal anastomosis, patients were categorized into two groups (group I without retroperitonealization of the ureteroileal anastomosis and group II with retroperitonealization of the ureteroileal anastomosis). Patients’ characteristics and occurrences of any complications and high-grade complications were compared between these groups. Results: In comparing the complication categories between the two groups, fewer patients in group II suffered from gastrointestinal, urinary, and cardiac events (p values were 0.018, 0.021, and 0.013, respectively). Moreover, fewer patients in group II experienced any complications and high-grade complications (p values were < 0.001 and < 0.001, respectively). The length of hospital stay was also significantly shorter in group II (p < 0.001). Conclusions: RC is associated with comparatively high perioperative morbidity and mortality. In the present study, 61% of the patients experienced at least one complication postoperatively. Retroperitonealization of the ureterointestinal anastomosis may decrease perioperative adverse events of RC with ileal conduit urinary diversion.

KEY WORDS: Radical cystectomy; Complication; Retroperitonealization. Submitted 6 May 2022; Accepted 19 May 2022

INTRODUCTION

Bladder cancer is a global disease, with 573.278 incident cases and 212.536 deaths in 2020 worldwide (1). About 25% of patients with bladder cancer are diagnosed with muscle-invasive bladder cancer (2). Since the early 1960s, radical cystectomy (RC) and pelvic lymphadenectomy have been considered the standard management of

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muscle-invasive bladder cancer and a valid option for selected patients with high-grade non-muscle invasive bladder cancer (3, 4). Even with improvements in surgical techniques and perioperative care, RC is a technically challenging operation and is associated with comparatively high perioperative morbidity and mortality (5, 6). The incidence of complications after the surgery has been reported to be in the range of 11-70% and late morbidity in contemporary series has been 19 to 58% (6, 7). It has been shown that complications after RC and urinary diversion severely affect the patients’ quality of life (8). Therefore, improving surgical techniques to reduce postoperative complications is required. In this study, we investigated the effect of ureteroileal anastomosis retroperitonealization on perioperative complications of radical cystectomy with ileal conduit urinary diversion.

PATIENTS

AND METHODS

We retrospectively reviewed medical data of all patients who underwent RC between 2016 and 2021 at two highvolume referral urology centers. Three different expert surgeons had performed the operations. Our inclusion criteria were 1. RC was performed to manage bladder urothelial carcinoma; 2. The ileal conduit was performed as urinary diversion; 3. The ureteroileal anastomosis was performed according to Wallace 1 technique. Our exclusion criteria were 1. Patients with anatomical single kidney and ureter; 2. Those with incomplete medical charts which did not provide appropriate data about all of the variables that were investigated in this study. Patients who met all of the inclusion criteria and lacked the exclusion criteria were entered into the study. We collected data regarding patients’ characteristics and all of the postoperative complications within 90 days of surgery. Any deviations from the normal postoperative course were considered complications (9). Perioperative mortality was determined as death from any cause within 90 days of operation. Procedure Antiplatelet and anticoagulant medications were stopped at least 1 week before the operation. All patients received mechanical bowel preparation. We utilized elastic comNo conflict of interest declared.

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pressive stocking as mechanical prophylaxis for deep vein thrombosis. Ceftriaxone 1 gr, metronidazole 500 mg, and pantoprazole 40 mg were administered intravenously when anesthesia was initiated and maintained for the time of hospital admission postoperatively. The nasogastric tube was not inserted routinely. RCs were performed according to the procedure suggested by the International Consultation on Bladder Cancer (10). Lymph node dissection included the removal of all lymphatic tissues around the external iliac and internal iliac arteries and from the obturator region bilaterally. After completion of RC and lymph node dissection, a segment of 10-20 cm of ileum approximately 20 cm proximal to the ileocecal valve was isolated. The stapled ileoileal anastomosis was performed. The mesentery window was closed with interrupted sutures, and the conduit was flushed with saline and povidone-iodine until the irrigant is clear. Afterward, ureters were conjoined, with the left ureter transposed to the right side of the pelvis through a tunnel prepared at the base of the sigmoid mesentery in front of the common iliac vessels. Tension-free ureteroileal anastomosis was accomplished according to Wallace 1 technique (11) with 5-0 polydioxanone sutures and was stented intraoperatively for at least 30 days. In completing cutaneous rosebud stoma formation, in patients who were operated on from 2016 to mid-2018, we only brought the segment directly to the anterior abdominal wall (group I). In patients who were operated on from then to 2021, we placed a peritoneal flap over the ureteroileal anastomosis in that stage of surgery. The flap was sutured to the conduit and the lateral peritoneum so that the ureteroileal anastomosis was completely covered by the peritoneum and effectively retroperitonealized (group II). We performed this surgical technique with the purpose of separating the ureterointestinal anastomosis from the peritoneal cavity and decreasing intraperitoneal urine extravasation. Before wound closure, we placed an 18-24fr drain tube through the abdominal wall and a 24fr Foley catheter via the urethra into the pelvic cavity. Postoperatively, patients were managed in the intensive care unit. Subcutaneous daily administration of lowmolecular-weight heparin, or every 8 hours unfractionated heparin in patients with renal failure, was started 24 hours after surgery and maintained for at least 4 weeks postoperatively. Further postoperative management was continued in the urology ward according to our standardized clinical care pathways for cystectomy. A day after surgery, mobilization was initiated as soon as the patient could be ambulated. On the third postoperative day, if the patient had bowel movements, he/she was allowed to take sips of water. If the patient tolerated drinking water, the diet advanced gradually to a soft diet. We started a regular diet two weeks postoperatively. The amount of drained fluid out of the Foley catheter and the drain tube was measured continuously. If the creatinine concentration of drained fluid was 30% more than the concomitant serum creatinine concentration, the patient is presumed to have urine leakage. More diagnostic studies including abdominopelvic sonography, supine and upright abdominopelvic X-rays, and intravenous contrast-enhanced abdominopelvic CT scan were requested in case of persistent postoperative

azotemia, sepsis or symptoms and signs of peritonitis to rule out urinary extravasation or other possible intraabdominal complications. Statistical analysis Mean ± standard deviation and range of quantitative variables and frequencies of the qualitative variables are presented. According to the characteristics of the variables, the Mann-Whitney U test or chi-square test were used to compare the two groups. P-value < 0.05 was considered Table 1. Patients’ characteristics. Total Group I Group II P-value* n = 748 n = 362 (48.4%) n = 386 (51.6%) Age (years), mean ± SD (range) 64.97 ± 7.31 64.82 ± 6.88 65.11 ± 7.70 0.527 (44-84) (49-83) (44-84) ≥ 70 years old, n (%) 216 (28.9) 97 (26.8) 119 (30.8) 0.224 Sex 0.803 Male, n (%) 586 (78.3) 285 (78.7) 301 (78.0) Female, n (%) 162 (21.7) 77 (21.3) 85 (22.0) Body mass index (kg/m2), 24.37 ± 4.92 24.42 ± 4.61 24.33 ± 5.19 0.435 mean ± SD (range) (16.99-34.96) (17.09-34.96) (16.99-34.83) Current smoking, n (%) 470 (62.8) 222 (61.3) 240 (62.2) 0.493 DM, n (%) 246 (32.9) 124 (34.3) 122 (31.6) 0.574 Cerebrovascular comorbidities, n (%) 40 (5.3) 19 (5.2) 23 (6.0) 0.673 Cardiovascular comorbidities, n (%) 185 (24.7) 113 (31.2) 112 (29.0) 0.512 Pulmonary comorbidities, n (%) 26 (3.5) 11 (3.0) 15 (3.9) 0.527 Routine dialysis, n (%) 50 (6.7) 12 (3.3) 18 (4.7) 0.348 Previous abdominopelvic surgery, n (%) 137 (18.3) 72 (19.9) 65 (16.8) 0.281 Neoadjuvant chemotherapy, n (%) 245 (32.8) 113 (31.2) 132 (34.2) 0.385 Poor (< 4 MET) functional capacity, n (%) 154 (20.6) 82 (22.7) 72 (18.7) 0.176 ASA score 0.443 1, n (%) 78 (10.4) 36 (9.9) 42 (10.9) 2, n (%) 511 (68.3) 242 (66.9) 269 (69.7) 3, n (%) 159 (21.3) 84 (23.2) 75 (19.4) Serum creatinine (mg/dl), 1.86 ± 1.29 1.48 ± 1.00 1.57 ± 1.1 0.329 mean ± SD (range) (0.8-8.1) (0.8-8.0) (0.7-8.0) Hemoglobin concentration (g/dl), 13.11 ± 1.78 13.10 ± 1.71 13.12 ± 1.85 0.708 mean ± SD (range) (7.1-18.5) (10.0-16.0) (7.1-18.5) Preoperative anemia, n (%) 323 (43.2) 156 (43.1) 167 (43.3) 0.963 NLR, mean ± SD (range) 5.80 ± 1.52 5.71 ± 1.56 5.78 ± 1.54 0.436 (2.10-8.99) (2.34-8.98) (2.10-8.99) Hypoalbuminemia, n (%) 297 (39.7) 149 (41.2) 172 (44.6) 0.348 Clinical T stage 0.466 1, n (%) 18 (2.4) 10 (2.8) 8 (2.1) 2, n (%) 569 (76.1) 282 (77.9) 287 (74.4) 3, n (%) 135 (18) 60 (16.6) 75 (19.4) 4, n (%) 26 (3.5) 10 (2.8) 16 (4.1) Operative time (min), 351.31 ± 99.93 351.33 ± 98.23 351.30 ± 101.63 0.918 mean ± SD (range) (180-560) (180-540) (180-560) Blood Loss (cc), 803.93 ± 386.10 825.03 ± 395.90 784.15 ± 376.11 0.141 mean ± SD (range) (200-5100) (200-5100) (210-4000) Intraoperative Blood Transfusion, n (%) 394 (52.7) 202 (55.8) 192 (49.7) 0.097 Surgeons 0.666 I, n (%) 255 (34.1) 118 (32.6) 137 (35.5) II, n (%) 273 (36.5) 137 (37.8) 136 (35.2) III, n (%) 220 (29.4) 107 (29.6) 113 (29.3) Group I without retroperitonealization of the ureteroileal anastomosis; group II with retroperitonealization of the ureteroileal anastomosis. * Group I vs II. MET: Metabolic equivalent; ASA: American Society of Anesthesiology; NLR: Neutrophil to lymphocyte ratio; Hypoalbuminemia: serum albumin concentration < 3.5 g/dl.

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as a significant level. Statistical analyses were performed using the IBM SPSS Statistics for Windows, version 24 (IBM Corp., Armonk, N.Y., USA).

RESULTS

Out of 876 RCs that were performed in five years, 748 patients did not have the exclusion criteria and met all of the inclusion criteria; consequently, enrolled in the study. Table 1 shows the summary of the patients’ characteristics. Men accounted for 586 (78.3%) of patients. The mean age at RC was 64.97 ± 7.315 years, the mean body mass index (BMI) was 24.37 ± 4.92 kg/m2, the mean operative time was 351.31 ± 99.93 minutes, and the mean estimated blood loss was 803.93 ± 386.1 ml. The average length of stay after RC was 7.66 ± 4.26 days. Table 2. Summary of complication categories and types. Category

Complications

Total n (%) Group I n (%) Group II n (%) of patients of patients of patients Gastrointestinal 147 (19.7) 84 (23.2) 63 (16.3) Postoperative ileus 116 (15.5) 63 (17.4) 53 (13.7) Anastomotic bowel leakage 11 (1.5) 8 (2.2) 3 (0.8) Gastrointestinal bleeding 10 (1.3) 6 (1.7) 4 (1.0) Diarrhea 18 (2.4) 12 (3.3) 6 (1.6) Infectious 78 (10.4) 43 (11.9) 35 (9.1) FUO 16 (2.1) 7 (1.9) 9 (2.3) UTI 39 (5.2) 15 (4.1) 24 (6.2) Sepsis 28 (3.7) 22 (6.1) 6 (1.6) Wound 133 (17.8) 70 (19.3) 63 (16.3) SSI 112 (15.0) 53 (14.6) 59 (15.3) Wound dehiscence 23 (3.1) 19 (5.2) 4 (1.0) Genitourinary 81 (10.8) 49 (13.5) 32 (8.3) Hydronephrosis 54 (7.2) 29 (8.0) 25 (6.5) Renal failure 7 (0.9) 6 (1.7) 1 (0.3) Urine leakage 39 (5.2) 30 (8.3) 9 (2.3) Cardiac 15 (2.0) 12 (3.3) 3 (0.8) Arrhythmia 5 (0.7) 3 (0.8) 2 (0.5) Myocardial infarction 10 (1.3) 8 (2.2) 2 (0.5) Congestive heart failure 4 (0.5) 3 (0.8) 1 (0.3) Pulmonary 22 (2.9) 13 (3.6) 9 (2.3) Pneumonia 12 (1.6) 6 (1.7) 6 (1.6) Pleural effusion 7 (0.9) 4 (1.1) 3 (0.8) Lung edema 3 (0.4) 3 (0.8) 0 Bleeding 21 (2.8) 14 (3.9) 7 (1.8) Anemia requiring transfusion 21 (2.8) 14 (3.9) 7 (1.8) Thromboembolic 10 (1.3) 7 (1.9) 3 (0.8) Deep venous thrombosis 10 (1.3) 7 (1.9) 3 (0.8) Pulmonary embolism 3 (0.4) 2 (0.6) 1 (0.3) Neurologic 10 (1.3) 6 (1.7) 4 (1.0) Cerebrovascular event 5 (0.7) 4 (1.1) 1 (0.3) Delirium 6 (0.8) 3 (0.8) 3 (0.8) Surgical 7 (0.9) 5 (1.4) 2 (0.5) Rectal injury 6 (0.8) 3 (0.8) 2 (0.5) Obturator nerve injury 2 (0.3) 0 2 (0.5) Miscellaneous 7 (0.9) 3 (0.8) 4 (1.0) Death 11 (1.5) 6 (1.7) 5 (1.3) All complications 456 (61) 246 (68.0) 210 (54.4) High-grade complications 115 (15.4) 93 (25.7) 22 (5.7) Hospital stay, 7.66 ± 4.26 8.54 ± 5.71 6.84 ± 1.78 mean ± SD (range) (5-73) (5-73)

P-value* 0.018 0.166 0.104 0.460 0.116 0.209 0.707 0.202 0.001 0.281 0.805 0.001 0.021 0.418 0.047 < 0.001 0.013 0.602 0.044 0.286 0.308 0.911 0.642 0.073 0.089 0.089 0.169 0.169 0.526 0.460 0.156 0.937 0.221 0.602 0.170 0.768 0.681 < 0.001 < 0.001 < 0.001 (5-18)

Group I without retroperitonealization of the ureteroileal anastomosis; group II with retroperitonealization of the ureteroileal anastomosis. * Group I vs II. FUO: Fever of unknown origin; UTI: urinary tract infection; SSI: Surgical site infection.

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Table 3. Highest Clavien complication grade in each patient. Highest Clavien complication grade I II III IV V

Total n (%) 220 (29.4) 114 (15.2) 51 (6.8) 53 (7.1) 11 (1.5)

Group I n (%) 98 (27.1) 49 (13.5) 40 (11.0) 47 (13.0) 6 (1.7)

Group II n (%) 122 (31.6) 65 (16.8) 11 (2.8) 6 (1.6) 5 (1.3)

Five hundred ninety-nine complications were recorded in 456 (61%) patients within 90 days of surgery. To enhance the comparability among populations, we classified our complications using the modified Clavien grading system (9) and category grouping reported by Shabsigh et al. (12). In our study, the most common complication categories were gastrointestinal 147 (19.7%), wound-related 133 (17.8%), genitourinary 81 (10.8%), and infectious 78 (10.4%). Ileus 116 (15.5%), surgical site infection (SSI) 112 (15.0%), hydronephrosis 54 (7.2%), urine leakage 39 (5.2%), and urinary tract infections 39 (5.2%) were the most frequent complications. Table 2 represents a comprehensive breakdown of our complications. The highest complication grade in each patient was Clavien grade I in 220 (29.4%), grade II in 114 (15.2%), grade III in 51 (6.8%), grade IV in 53 (7.1%), and grade V in 11 (1.5%) patients (Table 3). Eleven (1.5%) deaths were recorded within 90 days of surgery. No patient died intraoperatively. Five patients died from gastrointestinal events, three from infectious events (sepsis), two from cardiovascular events, and one from a cerebrovascular event. Group I and II consisted of 362 and 386 patients, respectively. Patients’ characteristics were not significantly different between these groups. The number of patients who were operated on by each surgeon was not significantly different between the two groups (Table 1). Incidences of sepsis, wound dehiscence, renal failure, urine leakage, and myocardial infarction, were significantly lower in group II (p values were 0.001, 0.001, 0.047, < 0.001, and 0.044, respectively). In comparing the complication categories between the two groups, fewer patients in group II suffered from gastrointestinal, urinary, and cardiac events (p values were 0.018, 0.021, and 0.013, respectively). Moreover, fewer patients in group II experienced any complications and high-grade complications (p values were < 0.001 and < 0.001, respectively). The length of hospital stay was also significantly shorter in group II (p < 0.001) (Table 2).

DISCUSSION

Despite recent advances in surgical techniques, RC is still highly morbid with complications occurring in up to two-thirds of patients within 90 days (6, 7, 13-17). Various factors have been related to post-RC complications and prognosis. Maffezzini et al. have demonstrated that advanced age of more than 70 years and Charlson Comorbidity Index > 3 are associated with worse post-RC prognosis (18). It has been shown that in patients undergoing RC, low serum albumin concentration is a signifi-

Retroperitonealization of ureteroileal anastomosis

cant predictor of mortality and serious adverse events (19). Other factors that are associated with adverse outcomes after RC include sarcopenia, an increased BMI, female gender, prior abdominopelvic surgery, extravesical disease, and prior pelvic radiotherapy (20-22). Although the majority of the post-RC complications are minor, it has been reported that up to 20% of patients will experience a major complication (23, 24). Multiple studies reported that more common complication categories are gastrointestinal, infectious, wound-related, and genitourinary (12, 25). In our study, five hundred ninety-nine complications were recorded in 456 (61%) patients within 90 days of surgery. 15.4% of our patients experienced major (≥ grade III) complications. Our observation was comparable with the study by Shabsigh et al. (12) reporting that the overall complication rate was 64% and the major complication rate was 13%. Hautman et al. (25) also reported complications in RC and ileal neobladder cases using the same standards. In their study, 58% of the patients experienced at least one complication within 90 days of surgery. In our cohort, the most common complication categories were gastrointestinal, wound-related, genitourinary, and infectious. Ileus, SSI, hydronephrosis, urine leakage, and urinary tract infections were the most frequent complications. This distribution was similar to the results obtained from other studies (12, 25). Retroperitonealization of the ureteroileal anastomosis during RC is mainly performed to prevent the herniation of the small bowel lateral to the conduit and the effect of performing this maneuver on perioperative complications has not been thoroughly studied. In this concept, Soleimani et al. compared the postoperative complications of transperitoneal vs extraperitoneal RC. They reported that early gastrointestinal complications including oral intake intolerance, ileus, intestinal obstruction, and anastomosis leakage were lower in the extraperitoneal RC group. Also in this group, the rate of postoperative urine leakage and wound-related complications were lower (26). Kulkarni et al. investigated the transperitoneal and extraperitoneal RC complications and reported that the rates of gastrointestinal complications, reoperation, and intestinal obstruction were significantly lower in the extraperitoneal approach. They noted that extraperitonealization of the neobladder or conduit may make postoperative urinary leakages amenable to less invasive managements such as simple extraperitoneal drainage or transurethral catheterization alone (27). In our study, the incidences of sepsis, wound dehiscence, renal failure, urine leakage, and myocardial infarction, were significantly lower in group II (p values were 0.001, 0.001, 0.047, < 0.001, and 0.044, respectively). In comparing the complication categories between the two groups, fewer patients in group II suffered from gastrointestinal, genitourinary, and cardiac events (p values were 0.018, 0.021, and 0.013, respectively). Overall, fewer patients in group II experienced any complications (246 (68.0%) vs 210 (54.4%), p < 0.001) and high-grade complications (93 (25.7) vs 22 (5.7%), p < 0.001). The length of hospital stay was also significantly shorter in group II (8.54 ± 5.71 vs 6.84 ± 1.78, p < 0.001). One of the possible reasons for these findings, which

according to the nature of our intervention seems to be rational, might be a decrease in the rate of postoperative urine leakage from ureteroileal anastomosis. It has been reported that post-RC urinary extravasation may lead to a prolonged hospital stay, chemical peritonitis, and ureteroileal anastomosis stricture (28), which in turn may result in renal deterioration. Also, severe urinary leakage has been associated with perioperative mortality (29). In our investigation, hospital stay was significantly longer in patients with postoperative urine leakage than in those who did not suffer from this complication (12.38 ± 4.16 vs 7.22 ± 3.99, p < 0.001). Besides, the rate of urine leakage was significantly lower in group II (30 (8.3%) vs 9 (2.3%), p < 0.001). However, it must be stated that only a limited number of studies with controversial results investigated the effect of retroperitonealization of the ureterointestinal anastomosis on post-RC urine leakage. Kavaric et al., as a part of their modification of the Wallace technique, retroperitonealized the conduit by suturing the serosa of the conduit to the posterior peritoneum above the anastomosis, thus placing the ureterointestinal anastomosis in the retroperitoneum. They reported that their technique significantly decreased postoperative urine leakage (30). As mentioned earlier, Soleimani et al. reported that the rate of postoperative urine leakage was lower in the extraperitoneal than transperitoneal RC group (26). Contrary to these findings and our assumption, in Kulkarni et al.’s study, although the rate of post-RC urine extravasation was not significantly different in the extraperitoneal vs transperitoneal approach, the rates of gastrointestinal complications, reoperation, and intestinal obstruction were lower in the former group (27). This suggests that other causative factors might have a role in the decrease in perioperative adverse events. Due to our study design, we could not assess whether the decrease in the rate of urine leakage is a true cause of lower complications occurrence in the group with retroperitonealization of the ureteroileal anastomosis or not. Further investigations to clarify the pathophysiology of these findings are required. The present study is among the few investigations that have assessed the effect of retroperitonealization of ureteroileal anastomosis on the perioperative complications of RC. Albeit, the current study has several shortcomings including its retrospective design and the short duration of follow-up. In addition, it is possible that some minor adverse events were not recorded. However, major adverse events or deaths were probably not overlooked. Also in this study, we only enrolled patients with ileal conduit diversion and ureteroileal anastomosis that was performed according to the Wallace technique; other types of urinary diversions and ureterointestinal anastomoses were not covered. Finally, based on the study design, we were not able to factor out time and experience in the earlier group rather than the latter group. However, it must be noted that the operations were performed by surgeons with more than a decade of experience in radical cystectomy in high-volume urology centers and we have not changed our postoperative care during the five-year period of the study. Thus, it seems that these factors might have a negligible effect on our comparison and interpretation. Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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CONCLUSIONS

RC is associated with comparatively high perioperative morbidity and mortality. In the present study, 61% of the patients experienced at least one complication postoperatively. During RC with ileal conduit urinary diversion, retroperitonealization of the ureterointestinal anastomosis may decrease urine extravasation and some of the other adverse events and shorten the length of hospital stay.

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27. Kulkarni JN, Agarwal H. Transperitoneal vs. extraperitoneal radical cystectomy for bladder cancer: A retrospective study. Int Braz J Urol. 2018; 44:296-303. 28. Regan JB, Barrett DM. Stented versus nonstented ureteroileal anastomoses: is there a difference with regard to leak and stricture? J Urol. 1985; 134:1101-3. 29. Hensle TW, Bredin HC, Dretler SP. Diagnosis and treatment of a urinary leak after ureteroileal conduit for diversion. J Urol. 1976; 116:29-31. 30. Kavaric P, Eldin S, Nenad R, et al. Modified Wallace anastomotic technique reduces ureteroenteric stricture rates after ileal conduit urinary diversion. Int Braz J Urol. 2020; 46:446-55. Correspondence Ali Ariafar, MD Mster20012002@yahoo.com Mehdi Salehipour, MD salehipour@sums.ac.ir Shahriar Zeyghami, MD zeyghamishahryar@yahoo.com Mehran Rezaei, MD (Corresponding Author) mrezaei1986@gmail.com Department of Urology, Shiraz University of Medical Sciences, Shiraz (Iran)

DOI: 10.4081/aiua.2022.2.155

ORIGINAL PAPER

Morbidity following transperineal prostate biopsy: Our experience in 8.500 men Pietro Pepe, Michele Pennisi Urology Unit - Cannizzaro Hospital, Catania, Italy.

Summary

Introduction: To evaluate clinical complications following transperineal prostate biopsy

in 8.500 patients. Materials and methods: From January 2000 to January 2022, 8,500 men (median age: 62.8 years) underwent transperineal prostate biopsy; since 2011, 1,850 patients were submitted to mpMRI and in the presence of a PI-RADS score ≥ 3, a transperineal targeted biopsy was added to systematic prostate biopsy (4 cores). All patients underwent antibiotic prophylaxis (20002011: levoxacin 500 tablet; 2012-2022: 2 grams intravenous of cefazolin). Among 8.500 men 1.350 (15.8%) vs. 4.520 (53.3%) vs. 2.630 (30.9%) underwent 12 vs. 18 vs. > 24 needle cores, respectively. The prostate biopsy-related complications were evaluated within 20 days from prostate biopsy; the number of patients who needed hospital admission or emergency department visit (EDV) was recorded. Results: Prostate cancer was found in 3.150/8.500 (37.1%) patients; overall, hospital admission and EDV were equal to 1.5% and 8.9% and the side effects were directly correlated with the number of needle cores resulting equal to 17.4% (12 cores), 38.7% (18 cores) and 55.3% (> 24 cores) (p = 0.001). Hospital admission and EDV in men who underwent 12 vs. 18 vs. > 24 cores occurred in 1.5% and 7.4% vs. 1.4% and 8.7% vs. 1.7% and 10.6% (p > 0.05), respectively. Conclusions: Clinical complications following transperineal prostate biopsy involved 35.9% of the patients but only 1.5% of them required hospital admission; urinary tract infection with fever was the most frequent cause of hospital recovery (33.4% of the cases), but none of the patients developed sepsis.

KEY WORDS: Prostate cancer; Transperineal prostate biopsy; Prostate biopsy; Complications; Sepsis. Submitted 25 April 2022; Accepted 30 April 2022

INTRODUCTION

Prostate cancer (PCa) is the most frequent tumor diagnosed in men with about 2 million procedures carried out in the United States and Europe every year (1). Although it has an overlapping detection rate for PCa with respect to transrectal procedure, transperineal biopsy is recommended as the first-choice technique for diagnosis of prostate cancer owing to lower rates of post-procedural sepsis in comparison with transrectal approach (2-4). Although the use of targeted antibiotic therapy obtained by rectal swab culture and rectal preparation with povidone-iodine decrease the risk of infections and/or sepsis

after transrectal prostate biopsy, it remains higher than after transperineal approach because of bacterial resistance to antibiotics (5). In fact, in case of transrectal biopsy the risk of complications requiring hospital admission ranges from 0.1% to 2.5% (6) being in most of the cases secondary to urinary tract infection (UTI), fever or sepsis. In addition, transperineal prostate biopsy improves the detection of clinically significant prostate cancer (csPCa) located in the anterior zone of the gland especially in men submitted to repeated biopsies or enrolled in Active Surveillance (AS) protocols (7, 8). In this study, the clinical complications following prostate biopsy in 8.500 patients submitted to transperineal approach in more than twenty years of clinical practice have been retrospectively evaluated.

MATERIALS

AND METHODS

From January 2000 to January 2022, 8.500 men aged between 38 and 96 years (median age: 62.8 years) underwent prostate biopsy under the suspicion of PCa. The indications for biopsy were: abnormal digital rectal examination, PSA >10 ng/mL or PSA values between 4.1-10 ng/ml, and 2.6-4 ng/ml with Free/Total PSA < 25% and < 20%, respectively; moreover, 175 men enrolled in AS protocol underwent scheduled repeated biopsies. Since 2011, 1.850 patients were submitted to mpMRI for initial (1.100 cases) and repeated (750 cases) procedure; 5.550 (65.3%) vs. 2.950 (34.7%) men underwent initial vs. repeated prostate biopsy. After institutional review board and ethical committee approval were granted the informed consent was obtained from all individual partecipants included in the study. In the presence of a Prostate Imaging-Reporting and Data System-version 2 (PI-RADS) score ≥ 3, a transperineal mpMRI/TRUS fusion targeted biopsy (TPBx: 4 cores for each suspicious area) was added to systematic prostate biopsy (8, 9). All mpMRI examinations were performed using a 1.5 or 3.0 Tesla scanner (ACHIEVA 3T; Philips Healthcare Best, the Netherlands) equipped with: a 16-channel phased-array coil placed around the pelvic area with the patient in the supine position, a multi-planar turbo spin-echo T2-weighted, an axial diffusion weighted imaging and an axial dynamic contrast enhanced MRI. All the data were collected using the START criteria (10). In the case of initial or repeated procedure an extended (ePBx: 12-18 cores) vs. a saturation transperineal biopsy (SPBx: 24 cores) was done (9). From 2002 to 2009

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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prostate biopsy was performed under local anesthesia (2% lidocaine 10-20 mL) and from 2010 to 2022 under sedation; SPBx was always performed under sedation in surgery room. The patients underwent antibiotic prophylaxis assuming one tablet of levofloxacin (500 mg daily) for 3 days beginning the day before biopsy from 2000 to 2011; from 2012 to 2022 the patients underwent a single intravenous dose of 2 grams of cefazolin. In men with previous endocarditis or with artificial cardiac valve a single dose of penicillin plus aminoglycoside was administered before biopsy. Anticoagulant drugs (i.e., dicumarol) were stopped 5-7 days before biopsy and replaced with a daily dose of low molecular weight of heparin. Prostate biopsy was performed transperineally (8, 10) using a freehand technique, a tru-cut 18 gauge needle (Bard; Covington, GA) and a GE Logiq 500 PRO and P6 ecograph (General Electric; Milwaukee, WI) supplied with a biplanar transrectal probe (5-6.5 MHz); the TPBx was performed transperineally using using a Hitachi 70 Arietta ecograph, (Chiba, Japan) supplied with a bi-planar transrectal probe (8). The prostate biopsy scheme at 12, 18 or > 24 cores included 3 vs. 6 vs. 12 cores in the posterior zone of each lobe (apex, middle zone and base of the gland) beginning parasagittally to reach the outer edges of the gland (lateral margins); in case of repeated procedure the biopsy included 2-4 cores in the transition and anterior zone (9, 11, 12). Among 8.500 men 1.350 (15.8%) vs. 4.520 (53.3%) vs. 2.630 (30.9%) were submitted to 12 vs. 18 vs. 24 or more needle cores, respectively. In detail, 1.150/1.850 (62.1%) men submitted to mpMRI underwent TPBx combined with systematic biopsy for PI-RADS score 3 lesions (625 cases: 54.4%) vs. 4 (370 cases: 32.1%) vs. 5 (155 cases: 13.5%); over time, the use of mpMRI in clinical practice allowed to reduce the number of needle biopsy cores performed during prostate biopsy. Clinical (comorbidities, drug therapy, risk factors) and laboratory data were collected from each patient’s medical record; overall, 6.595/8.500 (77.5%) patients utilized alpha blockers. Overall prostate biopsy-related complications were evaluated within 20 days from prostate biopsy when the histological report was given; moreover, number of patients who needed hospital admission or emergency department visit (EDV) was recorded. The patients without clinical complications following prostate biopsy did not undergo additional clinical evaluation. Definition of urinary tract infection (UTI) was given by presence of fever, positive urine culture and/or leucocytosis without bacteremia; moreover, in case of fever greater than 38.5°C the presence of bacteremia was investigated by blood culture. All patients were prospectively evaluated with the 5-item version of the International Index of Erectile Function (IIEF-5) at time zero and at 1, 3 and 6 months from prostate biopsy (13). The Clavien-Dindo grading system for the classification of biopsy complications was used (14). For statistical analysis the t Student’s - test was used; a p value < 0.05 was considered statistically significant.

RESULTS

Overall, PCa was found in 3.150/8.500 (37.1%) patients, high grade prostatic intraepithelial neoplasia (HGPIN) in

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209 (2.4%), atypical small acinar proliferation (ASAP) in 102 (1.3%) and normal parenchyma in 5.039 (59.2%); 2.135 (67.8%) and 2.310 (73.3%) out 3,150 with PCa had a PSA < 10 ng/mL and a T1c clinical stage, respectively. Detection rate for csPCa (15) increased with the use of mpMRI (PI-RADS ≥ 3) reducing the risk of overdiagnosis in comparison with systematic prostate biopsy (17 vs. 28%). Overall, clinical parameters and histological findings in presence of PCa diagnosed at initial or repeat biopsy are listed in Table 1. Overall, hospital admission and EDV were equal to 1.5% (129/8.500) and 8.9% (755/8.500); moreover, clinical complications of men submitted to 12 vs. 18 vs. > 24 cores are listed in Table 2. Overall, side effects following prostate biopsy occurred in 40.5% (3,441/8,500) of the patients (5.8% of them had two or more symptoms); in detail, overall complications were directly correlated with number of needle cores resulting equal to 17.4% (235 cases), 38.7% (1.751 cases) and 55.3% (1.455 cases) in patients who underwent 12 vs. 18 vs. > 24 cores (p = 0.001), respectively. Hospital admission and EDV in men who underwent 12 vs. 18 vs. > 24 cores occurred in 1.5% (21/1.350) and 7.4% (100/1.350) vs. 1.4% (63/4.520) and 8.7% (395/4.520) vs. 1.7% (45/2.630) and 10.6% (280/2.630) (p > 0.05), respectively. Overall, the most frequent biopsy complication that needed hospital admission vs. EDV was UTI (73 cases: 0.8%) vs. acute urinary retention (435 cases: 5.1%), respectively (Table 2). UTI with fever greater than 38.5° C was the most frequent cause (43 men: 33.3%) of hospital recovery. In all the 43 men admitted to hospital for UTI the blood culture was negative and a double antibiotics therapy was administered (penicillin plus aminoglycoside for 5 days) acquiring a complete remission of Table 1. Clinical characteristics and results in 8.500 patients (pts) who underwent 12, 18 and ≥ 24 needle cores as an initial or repeat transperineal prostate biopsy. Scheme of biopsy

12 cores pts = 1.350 Number of biopsies 1st 2nd 3d Number of patients 1.350 Median number of cores (range) 12 (10-15) Median age (years; range) 68.2 (40-85) number of pts PSA ≤ 2.5 ng/mL (F/TPSA ≤ 15%) 71 PSA 2.6-4 ng/mL (F/TPSA ≤ 20%) 195 PSA 4.1-10 ng/mL (F/TPSA ≤ 25%) 599 PSA > 10 ng/mL 485 Abnormal DRE 190 Median prostate weight (grams) 47 (24-94) RESULTS % Prostate cancer (PCa) 39.8 Gleason score (median) 7.3 Clinically insignificant PCa 2 -

18 cores pts = 4.520 1st 2nd 3d 3510 870 140 18 (16-21) 61.8 (49-78) number of pts 84 - 185 55 2479 97 1462 158 150 58 58 (23-128) % 47.5 13.7 7.2 6.4 8.7 34.4 -

≥ 24 cores pts = 2.630 1st 2nd 3d 195 1978 457 28 (24-38) 63.2 (48-76) number of pts 5 - 35 90 65 1030 232 72 841 260 18 44 16 63 (20-209) % 48.6 28 9.3 6.75 6.3 6 18.3 36.8 38

PCa ≤ 10 ng/mL Clinical stage T1c

68.2 77.8 74.3 81.8 -

77.8 63 66.7 76 93 92

54. 53.4

DRE: digital rectal examination; F/T: percentage of free/total PSA; Clinically insignificant PCa: ≤ 2 positive cores with percentage of cancer ≤ 50% and Gleason score 6 (Grade group 1) .

Transperineal prostate biopsy complications

Table 2. Complications following transperineal prostate biopsy in 8.500 patients (pts) submitted to 12 vs. 18 vs. ≥ 24 needle cores. Complications Hematuria Urethrorrhagia Hemospermia Acute urinary retention Prostatitis Sepsis Orchiepidymitis Urinary tract infection Perineal hematoma Vagal syndrome Erectile dysfunction** (6 months from biopsy) Fever Systemic adverse events*** Hospital admission (within 20 days) Emergency department visit (within 20 days)

12 cores * 1.350 pts 101 (7.4%) 28 (2.1%) 105 (10.7%) 48 (3.5%) 7 (0.5%) 6 (0.4%) 16 (1.2%) 5 (0.3%) 9 (0.9%)

18 cores *° vs 4.520 pts 352 (8.4%) 75 (1.6%) 915 (20.2%) 285 (6.3%) 29 (0.6%) 18 (0.4%) 30 (0.6%) 20 (0.4%) -

≥ 24 cores ° 2.630 pts 235 (8.9%) 60 (2.2%) 785 (29.8%) 270 (10.2%) 21 (0.8%) 16 (0.6%) 16 (0.6%) 18 (0.7%) -

3 (0.2%) 7 1 (0.07%)

15 (0.3%) 12 -

10 (0.3%) 24 -

21 (1.5%)

63 (1.4%)

45 (1.7%)

100 (7.7%)

395 (8.7%)

280 (10.6%)

* Prostate biopsy performed under local anesthesia (*) or sedation (°); **Transient Erectile dysfunction resolved within 3-6 months from biopsy; ***Acute cardiac ischemia.

symptoms and fever within 3 days; moreover, 3/43 (7%) patients had a positive urine culture for gram negative bacteria after the double antibiotics administration. Only two patients with gross hematuria needed blood transfusion and all men with urinary retention had catheters removed within 7 days. Among each complication, only hemospermia significantly correlated with the number of needle cores resulting equal to 36.5% (960/2.630) vs. 11.8% (160/1.350) (p = 0.001) in patients submitted to more than 24 vs 12 cores, respectively; moreover, urinary retention was most frequent in patients with a higher prostate weight who underwent SPBx (Table 1). Biopsy complication rate that needed hospital admission vs EDV was superimposable in presence (1.2 vs. 8.9%) and absence of PCa (1.3% vs. 9.3%). Hospital recovery occurred a median of 2 days (range: 1-3) after prostate biopsy for a median duration of 3 days (range: 2-6), moreover, EDV was performed within 3 days (range: 1-7) from the procedure. Complication rate was superimposable in patients submitted to prostate biopsy under local anesthesia office performed (2.105 cases) vs. sedation in surgery room (6.495 cases); from 2000 to 2022 UTI resulted superimposable and equal to 0.6% (2002) vs 0.9% (2022), respectively, moreover, nobody had sepsis or needed recovery in intensive care unit. Finally, among the patients who needed hospital admission 69 (53.4%) and 60 (46.8%) were assigned a grade II and I of the Clavien-Dindo complications scale (14), respectively; moreover, all patients submitted to EDV had a grade I.

DISCUSSION

The latest EAU guidelines strongly recommend to perform transperineal approach to reduce the risk of sepsis (1) sug-

gesting a single dose of antibiotic (i.e., cefazolin) (2) for the antibacterial prophylaxis. Infections are well-established adverse events after transrectal prostate biopsy; asymptomatic bacteriuria, febrile UTI, acute bacterial prostatitis, orchitis, epididymitis, and urinary sepsis represent the broad spectrum of possible infectious complications. Medical comorbidities (particularly diabetes or metabolic syndrome) and older age are independent predictors increasing the risk of infections and sepsis; a previous history of prostatitis, antibiotics within 6 months before prostate biopsy, and non-adherence to antibiotic prophylaxis or resistence to antibiotics (i.e., quinolone) represent other risk factors (16, 17). Whether a repeated biopsy protocol, including those done in AS, could increase the risk of infection is unclear; Loeb et al. (18), reported a cumulative increase in the risk of having a complication where each additional biopsy was associated with a 1.7-fold increase in overall hospitalizations, and a 1.7-fold increase in serious infectious complications. Clinical complications and hospital admissions following transrectal prostate biopsy have increased during the last years primarily due to an increasing rate of infections (9); Carignan et al. (20) in 5.798 submitted to transrectal prostate biopsy demonstrated an increased incidence of infections from 0.52% in 2002-09 to 2.15% in 2010-11 secondary in the 52% of the cases to pathogens (Escherichia Coli in the 75% of the cases) resistant to ciprofloxacin especially in patients with diabetes, chronic obstructive pulmonary disease and in those hospitalized during the precedent month. Loeb et al. (21) in a random sample of Medicare participants in Surveillance, Epidemiology and End Results (SEER) regions from 1991 to 2007 found that prostate biopsy was associated with a 2.65-fold increased risk of hospitalization secondary to infections within 30 days compared to the control population; men who were hospitalized for infectious complications had a 12-fold higher 30-day mortality rate in comparison to those who were not. The use of targeted antibiotic therapy obtained from rectal swab culture combined with rectal preparation using povidone-iodine decrease the risk of infections and/or sepsis in men submitted to transrectal biopsy (22); recently, Dai et al. (23) reported clinically fewer infections (1.9% vs. 2.9%) in men managed with targeted antibiotic prophylaxis, although the difference was not statistically significant (p = 0.53). Transperineal prostate biopsy in comparison with transrectal approach reduce number of infections and reset sepsis rate (0-0.2%) (24), given the avoidance of bacterial contamination which is common during transrectal access (25). Miller et al. (26) compared side effects following transrectal and transperineal biopsy showing a superimposable incidence of clinical complications (19.8 vs. 22.2%) but a sepsis rate equal to 1.2 vs. 0%, respectively. In a recent meta-analysis including 90 randomized controlled trials (16.941 participants) Pradere et al. (27) showed that transperineal biopsy was associated with significantly reduced infectious complications as compared to transrectal biopsy; on the contrary, no difference in infectious complications/hospitalization was found for number of biopsy cores, periprostatic nerve block, number of injections for periprostatic nerve block, needle guide type, needle type and rectal preparation with enema. In addition, in Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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a systematic review and meta-analysis on 37.805 men submitted to transperineal biopsy Spyridon et al. (28) showed that incidence of sepsis was similar in the patients who received antibiotics or not (0.05 vs 0.08%; p = 0.2) underlining the safety of the procedure. In our series, to our knowledge the first that evaluated transperineal prostate biopsy complications in a so high number of patients of a single center (8.500 cases), overall hospital admission and EDV were equal to 1.5% (129/8.500) and 8.9% (755/8.500). Overall, side effects following prostate biopsy occurred in 40.5% (3.441/8.500) of the patients (5.8% of them had two or more symptoms); in detail, side effects were directly correlated with number of needle cores resulting equal to 17.4% (235 cases), 38.7% (1.751 cases) and 55.3% (1,455 cases) in patients who underwent 12 vs. 18 vs. > 24 cores (p = 0.001), respectively. Hospital admission and EDV in men who underwent 12 vs. 18 vs. > 24 cores occurred in 1.5% (21/1.350) and 7.4% (100/1.350) vs. 1.4% (63/4.520) and 8.7% (395/4.520) vs. 1.7% (45/2.630) and 10.6% (280/2.630) (p > 0.05), respectively. Overall, the most frequent biopsy complication that needed hospital admission vs. EDV was UTI (73 cases: 0.8%) vs. acute urinary retention (435 cases: 5.1%), respectively; 43/73 (59%) men with UTI had fever greater than 38.5°C, but nobody developed sepsis or needed recovery in resuscitation department. Erectile dysfunction following prostate biopsy was restored within 3-6 months irrespective of the number of needles cores obtained. Some limitations and considerations of the present study deserve mention. First, we don’t know if a greater percentage of patients developed complications after our evaluation performed 20 days from prostate biopsy. Second, some cases of UTI could be missed because no additional clinical evaluation were required in absence of urinary symptoms. Third, the reduction of needle cores following the introduction in clinical practice of mpMRI could reduce prostate biopsy complications. Finally, our data refer in the majority of the cases to procedures performed under sedation, but the same biopsy protocol could be office-performed under local anesthesia (29, 30).

CONCLUSIONS

Clinical complications following transperineal prostate biopsy involved 35.9% (3.050/8.500) of the patients but only 1.5% (129/8.500) of them required hospital admission; UTI with fever was the most frequent cause of hospital recovery (33.4% of the cases), but none of the patients developed sepsis. Finally, number of needle cores (12 vs. 18. vs. > 24) significantly correlated with increased onset of side effects, but did not significantly increased hospital admission or EDV.

REFERENCES

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3. Mehmood S, Alothman KI, Alwehaibi A, Alhashim SM. Diagnostic efficacy and safety of transperineal prostate targeted and systematic biopsy: The preliminary experience of first 100 cases. Arch Ital Urol Androl. 2021; 93:127-131. 4. Derin O, Fonseca L, Sanchez-Salas R, Roberts MJ. Infectious complications of prostate biopsy: winning battles but not war. World J Urol. 2020; 38:2743-2753. 5. He J, Guo Z, Huang Y, et al. Comparisons of efficacy and complications between transrectal and transperineal prostate biopsy with or without antibiotic prophylaxis Urol Oncol 2022; S10781439(22)00004-7. 6. Pinkhasov GI, Lin YK, Palmerola R, et al. Complications following prostate needle biopsy requiring or emergency department visitsexperience from 1000 consecutive cases. BJU Int. 2012; 110:369374. 7. Meyer AR, Mamawala M, Winoker JS, et al. Transperineal prostate biopsy improves the detection of clinically significant prostate cancer among men on active surveillance J Urol. 2021; 205:1069-1074. 8. Pepe P, Aragona F. Prostate biopsy: results and advantages of the transperineal approach--twenty-year experience of a single center. World J Urol. 2014; 32:373-377. 9. Pepe P, Garufi A, Priolo GD, et al. Is it time to perform only MRI targeted biopsy? Our experience in 1032 men submitted to prostate biopsy. J Urol. 2018; 200:774-778. 10. Pepe P, Aragona F. Saturation prostate needle biopsy and prostate cancer detection at initial and repeat evaluation. Urology. 2007; 70:1131-1135. 11. Moore CM, Kasivisvanathan V, Eggener S, et al. Standards of Reporting for MRI-targeted Biopsy Studies (START) of the Prostate: Recommendations from an International Working Group. Eur Urol. 2013; 64:544-552. 12. Pepe P, Pennisi M, Fraggetta F. How many cores should be obtained during saturation biopsy in the ra of multiparametric magnetic resonance? Experience in 875 patients submitted to repeat prostate biopsy. Urology. 2020; 137:133-137. 13. Pepe P, M Pennisi. Erectile dysfunction in 1050 men following extended (18 cores) vs saturation (28 cores) vs saturation plus MRItargeted prostate biopsy (32 cores). Int J Impot Res. 2016; 28:1-3. 14. Valerio M, Anele C, Bott SR, et al. The prevalence of clinically significant prostate cancer according to commonly used histological thresholds in men undergoing template prostate mapping bopsies. J Urol. 2016; 195:1403-1408. 15. Dindo D, Demartines N and Clavien PA. Classification of surgical complications. A new proposal with evaluation in a Cohort of 6336 patients and results of survey. Ann Surg. 2004; 2:205-213. 16. Tan WP, Papagiannopoulos D, Latchamsetty KC, et al. Predictors of fluoroquinolone-resistant bacteria in the rectal vault of men undergoing prostate biopsy. Prostate Cancer Prostatic Dis. 2019; 22:350. 17. Papagiannopoulos D, Abern M, Wilson N, et al. Predictors of Infectious Complications after Targeted Prophylaxis for Prostate Needle Biopsy. J Urol. 2018; 199:155-160. 18. Loeb S, Vellekoop A, Ahmed HU, et al. Systematic review of complications of prostate biopsy. Eur Urol. 2013; 64:876-892. 19. Carignan A, Roussy JF, Lapointe V, et al. Increasing risk of infectious complications after transrectal ultrasound-guided biopsies: time to reassess antimicrobial prophylaxis? Eur Urol. 2012; 62:453-459. 20. Nam RK, Saskin R, Lee Y, et al. Increasing hospital admission

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26. Miller J, Perumalla C, Heap G. Complications of transrectal versus transperineal prostate biopsy. ANZ J Surg. 2005; 75:48-50.

21. Loeb S, van den Heuvel S, Zhu X, et al. Infectious complications and hospital admissions after prostate biopsy in a European randomized trial. Eur Urol. 2012; 61:1110-1114.

27. Pradere B, Veeratterapillay R, Dimitropoulos K, et al. Nonantibiotic strategies for the prevention of infectious complications following prostate biopsy: a systematic review and meta-analysis. J Urol. 2021; 205:653-663.

22. Pilatz A, Veeratterapillay R, Köves B, et al. Update on strategies to reduce infectious complications after prostate biopsy. Eur Urol Focus. 2019; 5:20-28. 23. Dai J, Leone A, Mermel L, Hwang K, et al. Rectal swab culturedirected antimicrobial prophylaxis for prostate biopsy and risk of postprocedure infection: a cohort study. Urology. 2015; 85:8-14. 24. Pepe P, Aragona F. Morbidity after transperineal prostate biopsy in 3000 patients undergoing 12 vs 18 vs more than 24 needle cores. Urology. 2013; 81:1142-1146. 25. Berry B, Parry MG, Sujenthiran A, et al. Comparison of complications after transrectal and transperineal prostate biopsy: a national population-based study. BJU Int. 2020; 126:97-103.

28. Basourakos SP, Alshak MN, Lewicki PJ, et al. Role of prophylactic antibiotics in transperineal prostate biopsy: a systematic review and meta-analysis. Eur Urol Open Sci. 2022; 37:53-63. 29. Stefanova V, Buckley R, Flax S, et al. Transperineal prostate biopsies using local anesthesia: experience with 1,287 patients. Prostate cancer detection rate, complications and patient tolerability. J Urol. 2019; 201:1121-1126. 30. Cricco-Lizza E, Wilcox Vanden Berg RN, Laviana A, et al. Comparative effectiveness and tolerability of transperineal MRI-targeted prostate biopsy under local versus sedation. Urology. 2021; 155:33-38.

Correspondence Pietro Pepe, MD (Corresponding Author) piepepe@hotmail.com Michele Pennisi, MD michepennisi2@virgilio.it Urology Unit - Cannizzaro Hospital, Via Messina 829, Catania (Italy)

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DOI: 10.4081/aiua.2022.2.160

ORIGINAL PAPER

Cost-effectiveness analysis of short biparametric magnetic resonance imaging protocol in men at risk of prostate cancer Niccolò Faccioli 1, Elena Santi 2, Giovanni Foti 3, Pierpaolo Curti 2, Mirko D’Onofrio 1 1 Department

of Radiology, G.B. Rossi Hospital, Università di Verona, Verona, Italy; of Radiology, Mater Salutis Hospital, Legnago, Verona, Italy; 3 Department of Radiology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy. 2 Department

Summary

Objectives: To compare the cost-effectiveness of a short biparametric MRI (BP-MRI) with that of contrast-enhanced multiparametric MRI (MP-MRI) for the detection of prostate cancer in men with elevated prostatespecific antigen (PSA) levels. Materials and methods: We compared two diagnostic procedures for detection of prostate cancer (Pca), BP-MRI and MP-MRI, in terms of quality-adjusted life years (QALY), incremental costeffectiveness ratio (ICER) and net monetary benefit (NMB) for a hypothetical cohort of 10,000 patients. We compared two scenarios in which different protocols would be used for the early diagnosis of prostate cancer in relation to PSA values. Scenario 1. BP-MRI/MP-MRI yearly if > 3.0 ng/ml, every 2 years otherwise; Scenario 2. BP-MRI/MP-MRI yearly with age-dependent threshold 3.5 ng/ml (50-59 years), 4.5 ng/ml (60-69 years), 6.5 ng/ml (70-79 years). Results: BP-MRI was more effective than the comparator in terms of cost (160.10 € vs 249.99€) QALYs (a mean of 9.12 vs 8.46), ICER (a mean of 232.45) and NMB (a mean of 273.439 vs 251.863). BP-MRI was dominant, being more effective and less expensive, with a lower social cost. Scenario 2 was more cost-effective compared to scenario 1. Conclusions: Our results confirmed the hypothesis that a short bi-parametric MRI protocol represents a cost-efficient procedure, optimizing resources in a policy perspective.

KEY WORDS: Cost-effectiveness analysis; Magnetic Resonance Imaging; Multiparametric MRI; Bi-parametric MRI; Prostatic cancer. Submitted 14 March 2022; Accepted 25 April 2022

INTRODUCTION

Prostate cancer (Pca) is very common in men and is frequently associated with long-term survival in affected subjects (1). In most cases, it remains asymptomatic for a long time; about 29% of localized Pca is classified as very low or low risk with slow growth (1-2). Conventionally, suspicion of Pca is based on digital rectal examination (DRE) and/or elevated prostate specific antigen (PSA), and is then typically confirmed by prostate biopsy (1, 3). According to PI-RADS v2.1 guideline, multiparametric MRI (MP-MRI) proved to be valuable in the Pca diagnostic process in men with high levels of PSA (2, 3).

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According to recent studies, dynamic contrast enhancement (DCE) use has been resized in PI-RADS version 2.1, restricted to the interpretation of ambiguous findings in the peripheral zone (2, 4-6). Particularly, its role is limited to upgrading category PI-RADS score 3 to PI-RADS score 4 (2, 5). However, this upgrading could be unnecessary in decision-making (performing biopsy or not) (7). In addition, MP-MRI protocol has some disadvantages, including longer time and higher cost, and the use of gadolinium-based contrast agents that may be problematic for patients with a glomerular filtration rate < 30 ml/min; moreover, the risk of potential brain accumulation is well described (8). For these reasons some authors have proposed a short protocol, using the biparametric MRI (BP-MRI) (9-11). The diagnostic value of BP-MRI in detecting suspected lesions in the peripheral zone (PZ) and the transitional zone (TZ) has been validated (10-11) and is justified because: a) ensures lesion identification and localization in any prostatic area; b) avoids the use of gadolinium-DTPA; c) examination lasts about 15 minutes; d) allows money saving. With this paper, we tried to put together our experience with prostate MRI and that regarding the cost-analysis of imaging studies. This study investigates cost-effectiveness of patients with suspect Pca, tailoring an approach based on risk stratifications for a both safe and cost-effective management. The objective of this simulated cost-effectiveness study is therefore to determine the potential cost-effectiveness of BP-MRI protocol compared to MP-MRI for Pca diagnosis.

MATERIALS

AND METHODS

Target population Target population includes a hypothetical cohort of 10,000 men aged between 50-79 years of age, with PSA level > 3 ng/ml and no previous prostate biopsy. The base case was a 65-year-old man, performing prostatic MRI because of elevated PSA levels and/or clinically significant DRE. These demographic features are based on the median age of the Pca onset (1, 12). The model was tested by age groups in order to examine the cost-effectiveness, given varying levels of cancer prevalence and life expectancy. No conflict of interest declared.

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Biparametric MRI cost-effectiveness in prostate cancer detection

Since it was a simulated study, no patients or animals were involved, and ethical approval or informed consent were not necessary. Procedures compared The procedures assessed in the model are: Strategy 1. Detecting prostate cancer with non-contrast BP-MRI; Strategy 2. Detecting prostate cancer with MP-MRI. Using our base case, we first observed the optimal strategy. Then, we compared costs and QALYs among the two strategies. We evaluated the cost-effectiveness of each strategy for three age groups with a different Pca prevalence. Several economic-based models assessed some hypothetical screening strategies based on PSA thresholds, in relation to age categories (11-16). Our analysis, based on age and PSA stratification, try to better understand the potential impact of BP-MRI on QALY and costs. We weighted pros and cons of two hypothetical different scenarios, joining PSA values and BP-MRI/MP-MRI: Scenario 1. BP-MRI/MP-MRI yearly if > 3 ng/ml, every 2 years otherwise; Scenario 2. BP-MRI/MP-MRI yearly with age dependent threshold 3 ng/ml (50-59), 4.5 ng/ml (60-69), 6.5 ng/ml (70-79). Study design and decision analysis model We conducted a simulation study based on a model of decision analysis, according to the guidelines established by the Panel on Cost-Effectiveness in Health and Medicine (17). In this case study, two variables are considered: cost and clinical effectiveness. This study is performed from a health care perspective, and we consider only direct costs of diagnostic tests, assessing whether BP-MRI adds enough value to justify costs. In the first case, the tree will produce the expected survival rate, in the second the life expectancy in years, and finally, in the third case, the life expectancy in QALYs. Other variables are incremental cost-effectiveness ratio (ICER) and net monetary benefit (NMB) (Table 1). Using an analysis software (OpenMarkov; CISIAD, UNED, Madrid, Spain), we tried to assess prospectively whether BP-MRI is convenient compared to the current strategy (MP-MRI). In a cost-effectiveness analysis, we refer to an incremental cost threshold considered economically sustainable and therefore acceptable. We identify the optimal strategy with a WTP of € 30.000 per QALY earned, threshold calculated on average daily earnings based on Eurostat statistics for 2017 (18). We set the time horizon to 10 years.

The entire cohort is distributed in final health states, each associated with a volume of costs. Quality of life Our model (state-transition model) demands to define the "health states" and therefore to specify the "transition rules" linked to the corresponding health status. Like quality of life indicators, health utilities specify the patient’s experience of disease and are included in the model. To calculate the total QALYs for each diagnostic strategy, we based on previously published data (19-20) and quality of life scores obtained from health-related quality of life questionnaires. We used the Short Form health survey (SF-12) Memorial Anxiety Scale for Prostate Cancer (MAX-PC), the Decisional Conflict Scale (DCS), the Centre of Epidemiologic Studies Depression scale (CES-D) and the Eysenck Personality Questionnaire (EPQ) 11-16 as tools to measure general health-related quality of life and anxiety. Details of these questionnaires have been described in Literature (20-22). QALYs are calculated by multiplying the duration of time spent in a health state by this utility score associated with that health state. Sources of probabilities and cost estimates Table 2 lists all parameters of the model. At our institution, prostate MRI is performed on a 1.5T scanner (Philips Medical Systems, Healthcare, Eindhoven, the Netherlands). We suggest a BP-MRI protocol with axial T1W gradientecho sequence with fat-suppression technique (THRIVE) imaging, multiplanar T2W FSE imaging, axial DWI sequence and apparent diffusion coefficient (ADC) map calculation. Direct medical costs, analyzed from a health care perspective, included costs of diagnostic procedures, calculated considering the initial investment of equipment, additional costs during use, maintenance costs, years of use, personnel costs, materials used (provided by the Hospital Technical Department). Direct cost of MP-MRI was 249.44 €, direct cost of BP-MRI was 160.10 €. Performance characteristics and utility values of crosssectional imaging were derived from published information: prevalence of prostate cancer, probability of detecting clinically significant cancer (Table 2) (23). Sensitivity rates of BP-MRI and MP-MRI in the detection of Pca are 86.7% (80.8, 91.3%) and 93.9% (87.9-99.9%) respectively (4, 6, 11, 23-25). Specificity values of BP-MRI and MP-MRI in the detection of Pca are 90.9% (87.4-93.6) and 88.1% (84.3-91.3), respectively (Table 3) (4, 6.24-26). BP-MRI had a high accuracy (89.1%) and negative predictive value (92.7%) for clinically significant prostate cancer (Gleason score ≥ 3+4, and/or volume > 0.5cc, and/or

Table 1. Description of terms “QALY”, “ICER”, “NMB” and “WTP”, and how they are calculated. QALY

Quality-adjusted life years are a measure of longevity, in units of years of life, adjusted for the ‘quality’ of life during those years. It is the arithmetic product of life expectancy and a measure of the quality of the remaining life years (quality of life coefficient). A way of determining the quality of a particular health state is to use a standard descriptive systems questionnaire.

ICER

The incremental cost-effectiveness ratio is a statistic used in cost-effectiveness analysis to summarize the cost-effectiveness of a health care intervention. It is defined by the difference between two possible interventions: ICER = (C1 - C0) ÷ (E1 - E0), where C1 and E1 are the cost and effect in the intervention group and where C0 and E0 are the cost and effect in the control care group.

NMB

Net monetary benefit represents the value of an intervention in monetary terms when a willingness to pay threshold is known. NMB is calculated as: (incremental benefit x threshold) – incremental cost.

WTP

A willingness-to-pay threshold, according to the World Health Organization (WHO), represents “an estimate of what a consumer of health care might be prepared to pay for the health benefit”.

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Table 2. Model Inputs. Parameter

Value

Prevalence of cancer in men aged 51–60 years Prevalence of cancer in men aged 61–70 years Prevalence of cancer in men aged 71–80 years Probability cancer is clinically significant Prevalence of Pca in men with abnormal PSA Incidence of significant Pca in PSA ranges, mg/l, 1 to < 3.0 Incidence of significant Pca in PSA ranges, mg/l, 3.0–10.0 Incidence of significant Pca in PSA ranges, mg/l, > 10.0 DRE findings, Normal DRE findings, Abnormal Prostate volume, ml, 25-40 cm3 Prostate volume, ml, 40 - 60 cm3 Prostate volume, ml, > 60 cm3 Model duration

0.44 0.65 0.71 0.50 61%

Starting age Cost of mpMRI scan

50 249.44 €

Cost of bpMRI scan

160.10 €

PSA threshold

3.0 ng/ml

Sensitivity values 0.00–0.90 0.00–0.90 0.00–0.90 0.00–0.90 53%, 69%

Source 1, 31 1, 31 1, 31 1, 31 1, 31

1, 31

12%

1, 31

40% 6% 57% 8% 19% 27% 10 years

1, 31 1, 31 1, 31 1, 31 1, 31 1, 31 Long-term and short-term assessed 23 Hospital Technical Department Hospital Technical Department 14, 15

5, 10 years 55, 70

RESULTS

Pca = Prostate Cancer; PSA = Prostate Specific Antigen; DRE = Digital Rectal Examination; MP-MRI = Multi-Parametric Magnetic Resonance Imaging; BP-MRI = Bi-Parametric Magnetic Resonance Imaging.

Table 3. Comparison of diagnostic accuracy of the abbreviated biparametric versus the full multiparametric protocol. Parameter Sensitivity (%) * Specificity (%) * Positive predictive value * Negative predictive value * Overall diagnostic accuracy *

Abbreviated biparametric Full multiparametric protocol protocol 86.7 (80.8, 91.3) 93.9 (87.9, 99.9) 90.9 (87.4, 93.6) 88.1 (84.3, 91.3) 82.4 (76.1, 87.5) 78.4 (72.0, 83.90 92.7 (89.5, 95.2) 92.6 (89.8, 95.5) 89.1 (86.2, 91.6) 87.6 (84.6, 90.3)

Source 24-28 24-28 24-28 24-28 24-28

* Data in parentheses are 95% CIs.

extraprostatic extension) (10-11). Life expectancy was estimated from Eurostat Statistics Life Tables (18). Sensitivity analysis We performed univariate sensitivity analysis to calculate any variations of each single parameter. Its execution involves recalculating each value of the parameter of interest. It allows us to identify the threshold beyond which, for the variation of that parameter, the diagnostic strategy is no longer optimal. Then, we performed a probability sensitivity analysis by recompiling 10.000 times at ran-

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dom for each parameter. This approach simultaneously considers the uncertainty of each parameter using the Monte Carlo simulation. We assigned a beta distribution to utilities and a range distribution to costs. Table 1 shows the results of the univariate sensitivity analysis and the costs of our model. NMB is defined as the difference between the value of the benefits obtained and the cost of obtaining them and may be calculated as follows: NMB = ΔQALY • WTP - Δcost, where WTP (Willingness To Pay) is the cost-effectiveness acceptability threshold considered in the analysis.

Baseline analysis Using BP-MRI for diagnosis costed 160.10 €, yielded an average QALY of 9.12 and an average NMB of 273,439. Diagnosis of a Pca performed with MP-MRI costed 249.99€ per patient, yielded an average of 8.46 QALY and an average NMB of 251,863. ICER was 496.33 for 50-59 years’ group, 111.68 for 60-69 years’ group, and 89.34 for 70-79 years’ group (Table 4). For the base case, BP-MRI is identified as an optimal procedure at a willingness to pay 30.000 € per QALY gained. For scenario 1 (Table 5), mean costs per patient were respectively 3602.25€ for BP-MRI and 5612.4€ for MP-MRI. For BPMRI, corresponding mean QALY was 9, mean ICER was 395.79 and mean NMB 266.397. For MP-MRI mean QALY was 8.9, mean ICER was 630.16 and mean NMB was 261.387. In case of scenario 2 (Table 4), mean costs per patient were respectively 3191.32 € for BP-MRI and 4972.17€ for MP-MRI. For BP-MRI, corresponding mean Table 4. QALY, ICER and NMB among the 2 strategies (BP-MRI, MP-MRI). QALY BP-MRI QALY MP-MRI ICER NMB BP-MRI NMB MP-MRI

50-59 y 9.08 8.9 496.33 272.239 266.750 (dominated)

60-69 y 9.09 8.29 111.68 272.539 245.839 (dominated)

70-79 y 9.19 8.19 89.34 275.539 243.000 (dominated)

QALY = Quality Adjusted Life Years; ICER = Incremental Cost Effectiveness Ratio; NMB = Net Monetary Benefit; MP-MRI = Multi-Parametric Magnetic Resonance Imaging; BP-MRI = Bi-Parametric Magnetic Resonance Imaging.

Table 5. Costs, QALY, ICER and NMB among 2 scenarios. SCENARIO

Cost BP-MRI

SCENARIO 1 Screen yearly if PSA > 3.0 ng/ml, every 2 years otherwise

3602.25 €

SCENARIO 2 Screen yearly with age dependent threshold 3.5 (50–59), 4.5 (60–69), 6.5 (70–79)

3191.32 € (mean)

Archivio Italiano di Urologia e Andrologia 2022; 94, 2

QALY, ICER, NMB BP-MRI Mean QALY 9 Mean ICER 395.79 Mean NMB 266,397

Cost MP-MRI

Mean QALY 9.09 Mean ICER 342.58 Mean NMB 269,508

4972.17€ (mean)

5612.4€

QALY, ICER, NMB MP-MRI Mean QALY 8.9 Mean ICER 630.16 Mean NMB 261,387 Dominated Mean QALY 9 Mean ICER 554.65 Mean NMB 265,027 Dominated

Biparametric MRI cost-effectiveness in prostate cancer detection

Figure 1. A tornado diagram for 50-59 years’ group. The horizontal axis represents the variation in the expected utility for each parameter.

QALY was 9.09, mean ICER was 342.58 and mean NMB 269.508. For MP-MRI mean QALY was 9, mean ICER was 554.65, mean NMB 265,027. MP-MRI procedure was dominated. Using the ICER decision rule, we can see that the most cost-effective option is BP-MRI, and all other options are dominated. Probabilistic cost-effectiveness sensitivity analysis We built a cost-effectiveness acceptability curve representing the probability of a scenario to be cost-effective related to one or more comparators, related to threshold values of WTP. In case of Scenario 1, for a willingness to pay of € 30.000/QALY, there is 96% probability of BP-MRI being the optimal procedure; the probability of MP-MRI being optimal is 4%. The probabilistic sensitivity analysis indicates that BP-MRI is dominant and cost-effective in 96% when WTP is 30.000 €/QALY earned. In case of Scenario 2, for example in the 50-59 years group, when willingness to pay is above € 10.000/QALY, performing BP-MRI is always the most beneficial decision. Tornado analysis (Figure 1) identified only two parameters that significantly affected the NMB: cost of MP-MRI and cost of BP-MRI.

DISCUSSION

We performed a cost-effective evaluation of a short protocol BP-MRI for Pca detection. Then, we correlated its use in two hypothetical scenarios with introduction of PSA threshold and age stratification. BP-MRI was dominant (more effective and less expensive) over MP-MRI

with an ICER that was below the acceptability threshold values considered (30.000 €/QALY earned). Overall, both BP-MRI and MP-MRI proved to be highly effective diagnosing clinically significant cancer across age groups. BP-MRI has a slightly higher QALY value, probably due to the lack of contrast media and a shorter examination, which provide better patient comfort. We also considered two possible scenarios with PSA value introduction, the first with a PSA threshold > 3 ng/ml for all ages, the second based on the increasing value of PSA according to age (27). The best scenario in terms of costeffectiveness is the second, with an average cost of €3191.32 for BP-MRI and €4972.17 for MP-MRI. Our analysis also revealed that even a minimal improvement in BP-MRI sensitivity leads to a high cost-effectiveness ratio thanks to savings due to avoiding contrast media. Consequently, BP-MRI has a better ICER and NMB than MP-MRI. Sensitivity analyses indicated a cost-saving of €89.34 for each BP-MRI performed instead of MP-MRI, representing significant earnings for National Health System (NHS). Differences in QALY are small and fluctuate steadily from 0.1 to 1. Although MRI is an expensive procedure, this approach has brought the best NMB, with spending values within the WTP threshold, with appropriate use of public money. Our analysis, based on age and PSA stratification, suggests that it can be cost-effective in all age and PSA categories we studied (11-14, 2728). Use of contrast enhanced transrectal ultrasound (CETRUS) was also proposed but, unlike liver or pancreatic lesions, contrast enhanced ultrasound is less suitable in Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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Pca detection (29-31). The most common comparative diagnostic methods respect to MRI are TRUS, CE-TRUS and, more recently, micro-ultrasound; these methods can be better evaluated by a dedicated future study (32). Our study shows that BP-MRI effectively has a significant role detecting Pca; also, it could reasonably reduce the number of biopsies, thanks to its high sensitivity in identification and in localization of index lesions < 5 mm and < 7 mm (33). This approach leads to a reduction in biopsies amount, which represents a considerable spending, as well as a significant impact on the patient’s life. PSA screening may be useful to reduce mortality related to Pca (14, 16, 33). With a PSA cut off value of 3 ng/ml, the positive predictive value is 24%, compared to 10% in case of a threshold of 1.0 ng/ml (24, 27, 29, 33). A higher threshold leads to greater specificity and reduced sensitivity, minimizing the number of unnecessary negative biopsies. Diagnosis and management of Pca can be implemented by multivariate stratification based on patient risk (PSA, DRE, age), associated with BP-MRI (scenario 2). Some trials show that stratifying patients can be a winning strategy to maximize benefits and reduce costs for both diagnosis and therapy (14, 29-37). An important implication of BP-MRI, however, regards the PIRADS assessment categories, as already well explained in PIRADS guidelines v2.1 (2). The PIRADS 3 category for a finding in PZ will be not upgraded, as the DCE sequence is not performed; thus, the proportion of PIRADS 3 will increase, with a decrease in the amount of PIRADS 4 (611, 37, 38). This reallocation could lead to further investigations for the patient, with subsequently diagnostic pathway modifications and additional costs. Nevertheless, our hypothesis is validated by the recent changes of PI-RADS system, where DCE’s role is to distinguish PI-RADS 3 versus PI-RADS 4 lesions, in case of T2 - DWI/ADC mismatch (25-31, 34-37). It is important to note that our study is retrospective and based on hypothetical constructs with inherent limitations, as many economic models, and the results are based on findings of excellence centers. Real-life could be different. Some clinical hypotheses have been formulated about age ranges and age limits. In addition, patients were assumed not to have contraindications to the contrast agent. PSA presents some risks inherent in its low specificity: high rate of false-positives, biopsy complications, risk of overdiagnosis and overtreatment, with consequent sexual and urinary problems (17, 30). A short protocol may not be suitable for all patients and specific individual needs: for example, imaging of tumor extension and local recurrence may require additional sequences or the use of DCE. We agree with PIRADS V2.1 guideline, which recommends DCE use in following cases: previous negative biopsies and increase of PSA; suspicion of disease and no findings on prior BP-MRI; previous prostate surgery; hip orthopedic implants that could degrade DWI weighted imaging. Our results confirmed the hypothesis that a short MRI protocol represents a possible cost-effective strategy, optimizing resources in a policy perspective. This study investigates cost-effectiveness of patients with suspect Pca, tailoring an approach based on risk stratifications for a both safe and cost-effective management,

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keeping in mind medicolegal implications, as for other pathologies. Furthermore, we suggest the inclusion of BP-MRI as surveillance diagnostic test in patients with suspect Pca, putting this improvement into a prospective long-term evolution in health economics and without any presumption to replace the existing protocols. We believe that this paper could represent a starting point to rediscuss the importance of the MRI protocol according to the risk stratification of patients.

CONCLUSIONS

In an efficient multidisciplinary model that takes care of the patient with suspect Pca, from the beginning to the diagnosis, BP-MRI is valuable for its high sensitivity in lesions identification, with similar results with respect to MP-MRI. BP-MRI is cost-effective and economically sustainable in the perspective of NHS and therefore can represent a valid diagnostic option, being a potential viable alternative to MP-MRI.

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DOI: 10.4081/aiua.2022.2.166

ORIGINAL PAPER

Erectile dysfunction following hydrogel injection and hypofractionated radiotherapy for prostate cancer: Our experience in 56 cases Pietro Pepe 1, Maria Tamburo 2, Paolo Panella 1, Ludovica Pepe 1, Giulia Marletta 2, Michele Pennisi 1, Francesco Marletta 2 1 Urology

Unit, Cannizzaro Hospital, Catania, Italy; Unit, Cannizzaro Hospital, Catania, Italy.

2 Radiotherapy

Summary

Introduction: The incidence of erectile dysfunction (ED) in men with organ-confined prostate cancer (PCa) submitted to hypofractionated radiotherapy (HRT) has been prospectively evaluated. Materials and methods: From April 2018 to September 2020, 56 patients (median age 70 years) with cT1c PCa were treated by HRT directed to the prostate and seminal vesicle. Median PSA was 8.3 ng/ml; 20 patients (35.7%) vs. 28 (50%) vs. 8 (22.3%) had a PCa Grade Group 1 vs. 2 vs. 3, respectively. All patients underwent hydrogel injection of Space OAR and intraprostatic fiducials before HRT. The prescription dose was 60 Gy in 20 fractions 5 days/week over 4 weeks. During the follow up, PSA, genitourinary (GU) and gastrointestinal (GI) toxicities were evaluated. The sexual function was evaluated by International Index of Erectile Function - 5 (IIEF-5) before, 6 and 18 months from HRT; 32/56 (57.1%) men referred a normal sexual activity before HRT (median IIEF-5 score: 22). Results: Median PSA level at median follow up of 18 months was 0.92 ng/ml and none used adjuvant therapy. One man (1.8%) referred a tardive grade 1 GU complication. At a median follow up of 6 and 18 months, 20/32 (62.5%) kept pretreatment sexual potency (median IIEF-5 score: 21). The 12/32 men who worsened the sexual function following HRT had a median age higher than patients without ED (78 vs. 67 years). Conclusions: The use of hydrogel injection and intraprostatic fiducials followed by HRT allowed to kept pretreatment sexual potency in 62.5% of the cases.

KEY WORDS: Prostate cancer; Erectile dysfunction; Hypofractionated radiotherapy; Intraprostatic fiducials; Hydrogel injection. Submitted 10 April 2022; Accepted 23 April 2022

INTRODUCTION

Prostate cancer (PCa) is the most commonly diagnosed male malignancy and radical prostatectomy or external radiotherapy (RT) are currently recommended as definitive treatment alone or combination in men with a life expectancy greater than 10 years. Radiation damage to neural and vascular tissue, such as the neurovascular bundles (NVBs) and internal pudendal arteries (IPAs), during radiotherapy for PCa may cause erectile dysfunction (ED). The advances in physics, engineering and imaging have been channeled into the development of image-guided

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intensity-modulated radiotherapy that has shown that increasing dose improves biochemical disease-free survival with acceptable acute and long-term complications (1, 2). Recently, injection of a hydrogel spacer (Space OAR) between the rectum and the prostate and the use of intraprostatic fiducials have been suggested to reduce rectal toxicity and improve selective prostate radiation therapy (3-8) resulting particularly useful in men candidate to hypofractionated radiotherapy (HRT) (9-11). In this study, the incidence of ED in men with organ-confined PCa submitted to HRT has been prospectively evaluated.

MATERIALS

AND METHODS

From April 2018 to September 2020, 56 patients (median age 70 years; range = 58-82) with organ-confined PCa (cT1c stage) were treated by HRT directed to the prostate and seminal vesicle. All the patients were previously submitted to multiparametric magnetic resonance imaging (mpMRI) (13) and transperineal prostate biopsy (14-15). The median PSA was 8.3 ng/ml (range = 4.5-23.1); 20 patients (35.7%) were at low risk (Grade Group 1/Gleason score 6), 28 (50%) at favorable intermediate risk (Grade Group 2/Gleason score 3 + 4) and only 8 (22.3%) at unfavorable intermediate risk (Grade Group 3/Gleason score 4 + 3) (6); moreover, all patients were without evidence of disease spread to the lymph nodes or the bones. All patients were selected for a hydrogel injection Space OAR before HRT. The injection of hydrogel was performed under sedation by transrectal ultrasound guidance, furthermore, three gold fiducials were inserted transperineally at the prostate base and mid-gland (8). Patients were simulated 2 weeks after placement; CT simulation was obtained at 3 mm slice thickness using an immobilization device, extending from L1 to below the ischial tuberosities. CT-MRI image registration was accomplished using the MIM-software (Maestro, version 7.0.5, MIM Software Inc., Cleveland, OH, USA). The whole prostate and seminal vesicle were delineated as the clinical target volume (CTV). Non-uniform planning target volume (PTV) was defined by adding margins to CTV; the margin was 8 mm in the anterior, lateral, superior and inferior directions, while it was 4 mm in the posterior direction. The rectum, urinary bladder, bowel, femoral No conflict of interest declared.

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Erectile dysfunction and hypofractionated radiotherapy

heads and penile bulb were contoured as organs at risk. The rectum was delineated from the rectosigmoid flexure to the anus; the treatment planning system was MonacoElekta (Elekta AB, Stockholm, Sweden). The prescription dose was 60 Gy in 20 fractions 5 days/week over 4 weeks, the CTV was planned to receive at least 100% of the prescription dose and the PTV at least 95% with maximum dose at CTV < 110% of the prescription dose. Dose-volume constraints were: dose given to 30% of rectal volume < 46 Gy, dose given to 50% of rectal volume < 37 Gy, dose given to 30% urinary bladder volume < 46 Gy, dose given to 30% urinary bladder volume < 37 Gy, dose given to 5% left/right femoral head volume < 43 Gy. Patients were treated with volumetric modulated arc therapy (VMAT) using the LINAC Sinergy Elekta and pretreatment verification of the prostate was conducted using a kilovoltage cone-beam CT during each treatment session. Patients were followed every 3 months for 2 years, and thereafter every 6 months. PSA relapse was determined according to the Phoenix consensus definition (nadir PSA value plus 2 ng/ml). Genitourinary (GU) and gastrointestinal (GI) toxicities were evaluated following RTOG/EORT score. Acute toxicity was defined as that occurred within 3 months after the initiation of radiotherapy, while late toxicity was observed after 3 months. The sexual function was evaluated by International Index of Erectile Function-5 (IIEF-5) (12) before (baseline), 6 and 18 months from HRT. None of the patients used 5-phosphodiesterase inhibitors or prostaglandins to improve sexual activity. The median prostate volume was 69.4 cm2; clinical (comorbidities, drug therapy) and laboratory data collected before prostate biopsy are reported in Table 1. Thirtytwo (57.1%) men referred a normal sexual activity before HRT (median IIEF-5 score: 22; range 20-25) and among them 12 (37.5%) vs. 18 (56.2%) vs. 2 (6.3%) men had a PCA Grade Group equal to 1 vs. 2 vs. 3, respectively.

RESULTS

All patients tolerated well the injection of Space OAR plus intraprostatic fiducials and completed the HRT treatment. Median PSA level at median follow up of 18 months was 0.92 ng/ml (range: 0.01-3.6 ng/ml) and none used adjuvant therapy. Only one man (1.8%) referred a tardive grade 1 GU complication, the remain 55 (98.2%) had no tardive side effects. Among the 32/56 (57.1%) men who had a normal sexual activity before HRT (median IIEF-5 score: 22; range 2025), at a median follow up of 6 and 18 months, 20/32 (62.5%) kept pretreatment sexual potency (median IIEF-5 score: 21; range = 19-25) (Table 2). The 12/32 men who worsened the sexual function following HRT had a median age higher than patients without DE (78 vs. 67 years).

DISCUSSION

However the advent of modern technology using advanced prostate targeting and penile-bulb sparing techniques, ED is a prevalent side effect of PCa treatment; Hunt et al. (16) in a recent systematic review of the literature reported in 2,714 patients at 2-year follow-up a median increase of ED equal to 17%, 26%, 23%, and

Table 1. Clinical findings and drugs therapy in the 56 patients submitted to hypofractionated radiotherapy. Clinical findings Median age (years) PSA 4.1-10 ng/mL PSA > 10 ng/mL Abnormal DRE LUTS Qmax IPSS (median) Comorbidities: Diabetes mellitus Hypertension Gastritis Cardiovascular ischemic disease Other Drug therapy (overall): Oral hypoglycemic Antihypertensive Antiplatelet agents Diuretic Proton pomp inhibitor Alfa-blockers Other

No (%) of patients 70 (range: 58-82) 43 13 42 12 11 (4-29) 35 9 23 12 6 9 495 (88.3) 6 25 34 10 23 50 15

DRE: digital rectal examination; LUTS: lower urinary tract symptoms; IPSS: international prostate symptoms score.

Table 2. International Index Erectile Function (IIEF-5) in 56 patients before (baseline) and after 6 and 18 months from hypofractionated radiotherapy. IEFF-5 (score: 5-25) median age: 70 years Absence of erectile dysfunction (ED) (22-25) median age: 67 years Mild ED (17-21) median age: 72 years Mild-moderate ED (12-16) median age Moderate ED (8-11) median age: 76 years Severe ED (5-7) median age: 78 years

Baseline (%)

6 months (%)

18 months (%)

32 (57.1)

20 (62.5)

4 (7.1)

3 (5.3)

2 (3.5)

4 (7.1)

5 (8.9)

4 (7.1)

3 (5.3)

2 (3.5)

12 (21.5)

13 (23.2)

14 (25)

23%, in men who underwent three-dimensional conformal radiation therapy, intensity-modulated radiotherapy, low dose rate of brachytherapy, and stereotactic body radiation therapy, respectively. Goy et al. (17) reported in 1,503 men with intermediate risk PCa who underwent radical prostatectomy vs. external radiotherapy vs. brachytherapy a prevalence of ED at 10 years of follow up equal to 24.3%, 6.6%, 8.2%, respectively; in addition, ED was not significantly different in men submitted to standard dose radiation therapy (38.1%) vs. dose escalated radiation therapy (49.7%) (18). Recently, the introduction in clinical practice of the so-called precision medicin Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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decreased the risk of complications; in fact, neurovascular-sparing magnetic resonance-guided adaptive radiotherapy seems to reduce the risk of ED following external radiotherapy (19). At the same time, CT-MRI image registration using dedicated software, the use of intraprostatic fiducials and hydrogel spacer could help to better focalize radiation therapy into the prostate; therefore, these devices used before radiotherapy could better preserve neurovascular bundle reducing the risk of ED. In our series, to our knowledge the first that evaluated ED following HRT in men submitted hydrogel spacer and intraprostatic fiducials injection, we reported among 32/56 (57.1%) men who had a normal sexual activity before HRT, at a median follow up 18 months, a restored pretreatment sexual potency in 20/32 (62.5%) (median IIEF-5 score: 21; range = 19-25). In addition, the 12/32 men who worsened the sexual function following HRT had a median age higher than patients without DE (78 vs. 67 years). Regarding our results some considerations should be done. Firstly, the true sexual activity of the couple administering a sexual questionnaire to the partners was not investigated. Secondly, in the absence of a control group we don’t know if the onset of ED was really given by HRT; at the same time, the role of hydrogel injection in preventing ED in comparison with HRT alone can not be established. Finally, a greater number of patients should be evaluated. In conclusion, in our preliminary experience, the use of hydrogel injection and intraprostatic fiducials followed by HRT allowed to kept pretreatment sexual potency in 62.5% of the cases.

REFERENCES

1. Dearnaley DP, Jovic G, Syndikus I, et al. Escalated-dose versus control-dose conformal radiotherapy for prostate cancer: long-term results from the MRC RT01 randomised controlled trial. Lancet Oncol 2014; 15:464-473. 2. Aluwini S, Pos F, Schimmel E, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): late toxicity results from a randomised, non-inferiority, phase 3 trial. Lancet Oncol 2016; 17:464-474. 3. Hall WA, Tree AC, Dearnaley D, et al. Considering benefit and risk before routinely recommending SpaceOAR. Lancet Oncol 2021; 22:11-13. 4. Ung M, Bossi A, Abbassi L, et al. [Dosimetric impact of hydrogel spacer use for stereotactic body radiotherapy of localised prostate cancer]. Cancer Radiother 2021; 25:237-241. 5. Babar M, Katz A and Ciatto M. Dosimetric and clinical outcomes of SpaceOAR in men undergoing external beam radiation therapy for localized prostate cancer: A systematic review. J Med Imaging Radiat Oncol 2021; 65:384-397. 6. Butler WM, Kurko BS, Scholl WJ, et al. Effect of the timing of hydrogel spacer placement on prostate and rectal dosimetry of lowdose-rate brachytherapy implants. J Contemp Brachytherapy 2021; 13:145-151. 7. Aminsharifi A, Kotamarti S, Silver D, et al. Major Complications and adverse events related to the injection of the SpaceOAR hydrogel system before radiotherapy for prostate cancer: review of the manufacturer and user facility device experience database. J Endourol 2019; 33:868-871. 8. Pepe P, Tamburo M, Pennisi M, et al. Clinical Outcomes of Hydrogel

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Spacer Injection Space OAR in Men Submitted to Hypofractionated Radiotherapy for Prostate Cancer. In Vivo 2021; 35:3385-3389. 9. Dearnaley D, Syndikus I, Mossop H, and CHHiP Investigators: Conventional versus hypofractionated high-dose intensitymodulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol 2016; 17:10471060. 10. Lee WR, Dignam JJ, Amin MB, et al. Randomized Phase III noninferiority study comparing two radiotherapy fractionation schedules in patients with low-risk prostate cancer. J Clin Oncol 2016; 34:23252332. 11. Catton CN, Lukka H, Gu CS, et al. Randomized trial of a hypofractionated radiation regimen for the treatment of localized prostate cancer. J Clin Oncol 2017; 35:1884-1890. 12. Pepe P, Pennisi M: Erectyle dysfunction in 1,050 men submitted to extended (18 cores) vs saturation (28 cores) vs saturation plus MRI targeted prostate biopsy (32 cores). Int J Impot Res 2016; 28:1-3. 13. Pepe P, Garufi A, Priolo GD, et al. Is it time to perform only MRI targeted biopsy? Our experience in 1032 men submitted to prostate biopsy. J Urol 2018; 200:774-778. 14. Pepe P, Pennisi M, Fraggetta F. How many cores should be obtained during saturation biopsy in the era of multiparametric magnetic resonance? Experience in 875 patients submitted to repeat prostate biopsy. Urology 2020; 137:133-137. 15. Pepe P, Pepe L, Pennisi M, Fraggetta F. Which prostate biopsy in men enrolled in active surveillance? Experience in 110 men submitted to scheduled three-years transperineal saturation biopsy combined with fusion targeted cores. Clin Genitourin Cancer. 2021; 19:305-308. 16. Hunt AA, Choudhury KR, Nukala V, et al. Risk of erectile dysfunction after modern radiotherapy for intact prostate cancer. Prostate Cancer Prostatic Dis. 2021; 24: 128-134. 17. Goy BW, Burchette R: Ten-year treatment complication outcomes of radical prostatectomy vs external beam radiation vs brachytherapy for 1503 patients with intermediate risk prostate cancer. Brachytherapy 2021; 20:1083-1089. 18. Hall WA, Deshmukh S, Bruner DW, et al. Quality of Life Implications of Dose-Escalated External Beam Radiation for Localized Prostate Cancer: Results of a Prospective Randomized Phase 3 Clinical Trial, NRG/RTOG 0126. Int J Radiat Oncol Biol Phys. 2022; 112:83-92. 19. Teunissen FR, Wortel RC, Wessels FJ, et al. Interrater agreement of contouring of the neurovascular bundles and internal pudendal arteries in neurovascular-sparing magnetic resonance-guided radiotherapy for localized prostate cancer. Clin Transl Radiat Oncol. 2021; 32:29-34. Correspondence Pietro Pepe, MD (Corresponding Author) piepepe@hotmail.com Paolo Panella, MD ppanella5@gmail.com Ludovica Pepe, MD ludopepe97@gmail.com Michele Pennisi, MD michepennisi2@virgilio.it Urology Unit, Cannizzaro Hospital, Via Messina 829, Catania (Italy) Maria Tamburo, MD marinellatamburo@virgilio.it Giulia Marletta, MD marlettagiulia1@gmail.com Francesco Marletta, MD francescomarletta1@gmail.com Radiotherapy Unit, Cannizzaro Hospital, Catania (Italy)

DOI: 10.4081/aiua.2022.2.169

ORIGINAL PAPER

Prostate resection weight matters in severely obstructed men undergoing transurethral resection of the prostate Filipe Lopes 1, Ricardo Pereira e Silva 1, 2, Miguel Fernandes 1, Tito Palmela Leitão 1, 2, José Palma dos Reis 1, 2 1 Urology 2 Urology

Department, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal; University Clinic, Faculty of Medicine, University of Lisbon, Portugal.

Summary

Objectives: Transurethral resection of the prostate (TURP) remains one of the goldstandard surgical treatments for benign prostatic hyperplasia/lower urinary tract symptoms. The usefulness of a complete adenoma resection is questionable, with studies reporting no impact of the amount of resected tissue on surgical outcomes, irrespective of prostate volume. The aim of this study was to assess whether in less obstructed patients a less extensive TURP may be considered. Materials and methods: Retrospective analysis of 185 men undergoing TURP in one university hospital. Retrieved data included pre-operative prostate volume and Qmax, as well as resected prostate weight and post-operative Qmax. Patients were divided in two groups according to pre-operative Qmax < 10mL/s and ≥ 10 mL/s. Results: A correlation was found between absolute resected prostate weight and post-operative Qmax in the group of patients with pre-operative Qmax < 10 mL/s (r2 = 0.038, p = 0.032), independently of the pre-operative prostate volume. This association was neither observed in the group of patients with pre-operative Qmax ≥ 10 mL/s (r2 = -0.033, p = 0.796) nor in whole population analysis (r2 = 0.019, p = 0.064). Likewise, in the group of patients with pre-operative Qmax < 10 mL/s, the improvement in Qmax was correlated with absolute resected weight and percentage of prostate resected weight (r2 = 0.036, p = 0.037 and r2 = 0.040, p = 0.029, respectively). None of these correlations was found in the group of patients with pre-operative Qmax ≥ 10 mL/s (r2 = 0.009, p = 0.463 and r2 = -0.018, p = 0.294, respectively). Conclusions: Patients with pre-operative Qmax ≥ 10 mL/s may do well with less profound prostate resections, whereas patients with lower pre-operative Qmax seem to benefit from a complete adenoma resection.

KEY WORDS: Transurethral resection of prostate; Prostatic hyperplasia; Lower urinary tract symptoms; Adenoma; Urologic surgical procedures. Submitted 12 May 2022; Accepted 27 May 2022

INTRODUCTION

Benign prostatic hyperplasia (BPH) is one of the most common causes of lower urinary tract symptoms (LUTS) in men. Current international guidelines recommend a stepwise approach to the treatment of BPH/LUTS (1). However, surgery remains the gold-standard in severe or

refractory LUTS, and transurethral resection of the prostate (TURP) is the procedure of choice for the majority of men with BPH/LUTS, especially for prostate volumes between 30 and 80 mL (1). Despite all the technological and technical improvements since the initial TURP descriptions almost a century ago (3), there is still controversy regarding the need for a complete prostatic tissue resection. Although some literature recommends a total removal of the adenomatous tissue (4), a relevant body of research supports the thesis that a complete adenoma resection may not be essential, with similar post-operative results with or without it (6). Similarly, a relationship between the amount of resected prostate and the outcomes of the surgery has been pursued, yet no correlation has been found between these two variables, neither in smaller (< 40 g) nor in larger (> 40 g) prostates (6). TURP is especially effective when bladder outlet obstruction (BOO) due to Benign Prostatic Obstruction (BPO) is the main cause for the patient’s LUTS. A satisfactory surrogate marker for the severity of BOO may however be obtained with urinary flow rate studies, as stated by the SirokyLiverpool nomograms, in which maximum flow rate (Qmax) and bladder volume are used to predict BOO (7). Furthermore, a recent randomized controlled trial was not able to prove a benefit in performing urodynamic studies in men with LUTS, since surgical treatment was necessary in around 37% of patients irrespectively of performing urodynamic studies (8). Although considered a safe procedure, sexual side effects after TURP are still an important issue, with 60-70% of patients reporting retrograde ejaculation, and up to 6.5% complaining of erectile dysfunction (9). Other side effects include early urge-incontinence, even though late stress incontinence is rare (0.5%) (10). In recent years, new approaches to TURP have been developed, aiming at the reduction of morbidity while maintaining the benefits of the procedure. In that regard, ejaculation preserving techniques are a promising development, with reports of antegrade ejaculation at 3 months post-op in around 90% of patients undergoing ejaculation preserving TURP (epTURP), with symptomatic and functional outcomes similar to the classic technique (11, 12). A vaporization technique using laser (LEST) has also been described, with antegrade ejaculation maintained in up to 80% of

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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patients (13). To our knowledge, no diagnostic feature has been firmly established as a predictor for TURP outcomes. However, the results of this procedure are heterogenous, with studies reporting a failure in symptomatic relief in around 12% of patients (14), raising the possibility that such predictors exist, at least for some patients. These may nevertheless be statistically concealed in the published studies, due to the analysis of the studied populations as a whole, irrespective of important factors such as BOO severity (5). Therefore, the aim of this study is to analyze whether pre-operative BOO severity may affect a possible influence of prostate resected weight in TURP outcomes.

METHODS

We conducted a retrospective analysis of patients submitted to TURP in a university hospital between February 2011 and November 2015. Exclusion criteria were previous LUTS surgery, prostate cancer, urethral stricture or voided volumes < 125 mL in uroflowmetry. Pre-operative data was retrieved, including clinical history, comorbid conditions, medications, uroflowmetry and prostate volume (determined by transrectal ultrasound). Post-operatively, weight of the resected dry specimen and post-operative uroflowmetry values were considered. As a second measure of depth of resection, and in order to evaluate a possible influence of pre-operative prostate size, a ratio between the absolute resected prostate weight and prostate volume measured via ultrasound was calculated, henceforth referred to as “percentage of resected weight”. All patients were diagnosed with BPH/LUTS refractory to medical treatment with alfa-blockers and/or 5-alfa reductase inhibitors (5-ARI). Surgery was performed by 5 different urologists using monopolar or bipolar standard 26French resectoscopes (Karl Storz®), depending on surgeon preference. The resected tissue underwent fixation with Formalin 10% and was weighted using precision scales in the Pathology laboratory before routine histologic analysis. Bladder catheters were removed 2 to 3 days after the procedure and the patients discharged following spontaneous micturition. Post-operative uroflowmetry was performed 4-6 weeks after surgery. Patients were stratified in two groups according to preoperative Qmax, following the Siroky-Liverpool nomograms, which define a cut-off value of 10 mL/s as a very strong predictor of BOO (≤ 2 standard deviations of the mean for a voided volume ≥ 125 mL) (7, 15). The first group was comprised of patients with pre-operative Qmax < 10 mL/s, and the second included patients with preoperative Qmax ≥ 10 mL/s. Statistical analysis was performed using non-parametric tests as appropriate (given the non-normality of the distributions as determined by Kolmogorov-Smirnov tests) with IBM SPSS® 27.0. Since the present study was performed in a retrospective fashion, no informed consent was required. Complete anonymity of all patients was, however, ensured.

RESULTS

A total of 185 patients were included, with a mean age of 58.5 (± 7.2) years and a mean pre- and post-operative

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Qmax of 8.8 ± 3.6 and 14.9 ± 7.2 mL/s, respectively. The mean change in Qmax after surgery was 6.2 ± 7.1 mL/s. Other demographic and clinical characteristics are displayed in Table 1. In the whole sample analysis, no statistically significant correlations were found between absolute resected prostate weight or percentage of resected weight and post-operative Qmax (r2 = 0.019, p = 0.063 and r2 = 0.019, p = 0.064, respectively). Similarly, the pre/post-operative difference in Qmax showed no correlation with the resection weight (r2 = 0.006, p = 0.290) or the percentage of resected prostate weight (r2 = 0.006, p = 0.283). When stratifying patients into two groups according to pre-operative Qmax < 10 mL/s (n = 121) and ≥ 10 mL/s (n Table 1. Patient characteristics. Age (y) Prostate volume (mL) Uroflowmetry Qmax Pre-op (mL/s) Post-op (mL/s) Difference (mL/s) Resected weight (g) PRW (%) Frequency comorbid conditions Diabetes mellitus (n %) Neurologic disease (n %) Previous AUR (n %) Medications Anti-cholinergic (n %) Alfa-blocker (n %) 5-ARI (n %)

Mean ± SEM 58.5 ± 0.53

Median ± IQR 59 ± 9

Range 37-77

51.78 ± 1.13

50 ± 22.5

25.0-103.0

8.78 ± 0.26 14.9 ± 0.53 6.2 ± 0.52 7.7 ± 0.40 15.2 ± 0.74

8.3 ± 5 14 ± 10.3 5.6 ± 9 6 ± 5.5 13 ± 11.5

2.0-18.0 2.0-45.0 -7.2-34.8 0.4-28.0 1.0-54.0 16 (8.8) 8 (4.3) 14 (7.7) 8 (4.4) 170 (92.9) 115 (62.8)

SEM: Standard error of the mean; IQR: Interquartile range; PRW: percentage of resected weight; AUR: Acute urinary retention; 5-ARI: 5-alfa reductase inhibitor.

Table 2. Group characteristics comparison.

Age (y) mean (SEM) Prostate volume (ml) mean (SEM) Uroflowmetry Qmax Pre-op (ml/s) mean (SEM) Post-op (ml/s) mean (SEM) Difference (ml/s) mean (SEM) Resected weight. g. mean (SEM) PRW. %. mean (SEM) Comorbid conditions Diabetes mellitus (n %) Neurologic disease (n %) Previous AUR (n %) Medications Anti-cholinergic (n %) Alfa-blocker (n %) 5-ARI (n %)

Pre-operative Qmax N = 121 < 10 mL/s ≥ 10 mL/s (N = 121) (N = 64) 59.0 (2.7) 57.5 (2.6) 51.4 (4.0) 52.4 (3.8)

P-value 0.097† 0.540†

6.6 (1.4) 14.3 (2.7) 7.7 (2.5) 7.5 (2.4) 14.8 (3.2)

12.8 (1.5) 16.2 (2.6) 3.4 (2.3) 8.0 (2.1) 16.0 (3.1)

0.000† 0.028† < 0.001† 0.106† 0.109†

9 (7.4) 5 (4.1) 9 (7.4)

7 (10.9) 3 (4.7) 5 (7.8)

0.432‡ 0.860‡ 0.928‡

3 (2.5) 110 (90.9) 74 (61.2)

5 (7.8) 60 (93.8) 41 (64.1)

0.087‡ 0.372‡ 0.650‡

SEM: Standard error of the mean; PRW: percentage of resected weight; AUR: Acute urinary retention; 5-ARI: 5-alfa reductase inhibitor. †: Mann-Whitney test; ‡: Chi-square test; significant differences are highlighted in bold.

TURP resection weight matters

= 64), no differences in demographic or clinical characteristics were found, with the exception of post-operative Qmax and Pre/post-operative difference in Qmax (Table 2). Post-operative maximum flow was superior in patients with already higher pre-operative Qmax (16.2 mL/s vs 14.3 mL/s, p = 0.028). Both groups showed a significant increase in Qmax post-operatively when compared to baseline maximum flow, although this increase was higher in the group with pre-operative Qmax < 10 mL/s (7.7 mL/s vs 3.4 mL/s, p < 0.001). In the group of patients with pre-operative Qmax < 10 mL/s, post-operative Qmax was correlated with absolute resected prostate weight (r2 = 0.038, p = 0.032), as well as with percentage of resected prostate weight (r2 = 0.051, p = 0.013). In these patients, the difference in pre/postoperative Qmax was also strongly associated with absolute resected prostate weight (r2 = 0.036, p = 0.037) and percentage of resected prostate weight (r2 = 0.040, p = 0.029) (Figures 1, 2). Neither of the above-mentioned correlations were established in the group of patients with pre-operative Qmax

≥ 10 mL/s. Absolute resected prostate weight and percentage of resected prostate weight were not associated with post-operative Qmax (r2 = -0.033, p = 0.796 and r2 = -0.009, p = 0.458, respectively), nor with peri-operative change in Qmax (r2 = 0.009, p = 0.463 and r2 = -0.018, p = 0.294, respectively) (Figures 1, 2).

DISCUSSION

Although many new techniques have evolved in recent years regarding the surgical management of BPH/LUTS, TURP remains as the gold-standard surgical therapy in most men with prostatic volume between 30-80 mL (16). However, the extension of adenoma resection is under debate, since some studies reported similar outcomes between complete and partial adenoma resection (6). The outcome of surgical treatment of BPH depends on many factors, both related and unrelated to the surgical procedure itself. Recent studies analyzed the applicability of machine learning in predicting these outcomes (17). Symptomatic relief achieved following TURP is the pri-

Figure 1. Post-operative Qmax (mL/s) per absolute resected weight in patients with pre-operative Qmax < 10 mL/s and ≥ 10 mL/s.

Figure 2. Post-operative Qmax (mL/s) per Percentage of resected weight in patients with pre-operative Qmax < 10 mL/s and ≥ 10 mL/s.

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mary goal of this procedure and is best measured through symptom scores, such as the International Prostate Symptom Score (IPSS). IPSS was found to be correlated with other clinical parameters, such as Qmax (18). Preand post-operative improvement in uroflowmetry is therefore commonly used as an objective method for surgical effectiveness assessment (16). In agreement with previous studies, our analysis failed to find an association between the extension of adenoma resection and postoperative outcomes in the whole sample analysis. Similarly to the present study, other reports explored the influence of pre-operative prostate volume in this correlation, yet no differences were noted (6). These studies concluded that post-operative clinical and symptomatic improvement was not impacted by the resected volume. The same conclusion was obtained through a different line of investigation. With the intent of avoiding sexual sideeffects of TURP, recent surgical techniques have been developed, which include the epTURP, in which pre and paracollicular tissue is spared (11). Although not formally measured, the preservation of some prostatic tissue results in an expected decrease of resected weight. In the available literature, the outcomes (IPSS, Qmax, voided volume and post-void residual) of epTURP are reported as similar to the classic technique, implying that an incomplete adenoma resection may be a viable option (12). However, further studies are necessary to confirm these results, especially since long-term surgical outcomes of this procedure are scarcely reported, with only one available study reporting favorable results at a follow-up of 60 months (11). Although BOO diagnosis may only be obtained through pressure/flow studies, maximum flow rate obtained via uroflowmetry is much more frequently used, due to its availability, reduced invasiveness and cost, when compared to urodynamic studies (19). Furthermore, the recent UPSTREAM trial did not prove an advantage in performing urodynamic tests in men with BPH/LUTS, showing similar surgery rates, as well as clinical outcomes in both arms of the study (8). While of unquestionable usefulness in certain patient groups, pressure/flow studies seem not to add value in the diagnostic process of the majority of non-neurogenic male LUTS, in which cases uroflowmetry might be enough to diagnose BOO. In fact, SirokyLiverpool uroflowmetry nomograms predict this condition with great efficacy using bladder volume and maximum flow rate. As stated by the authors, a Qmax < 10 mL/s is a strong predictor of a clinically relevant BOO for bladder volumes of 125 mL or higher (7). More recent investigations reported that around 90% of men with a severe BOO (grade III-VI - Schäfer classification (20, 21) had a Qmax < 14 mL/s on uroflowmetry, whereas only 6% of all men with a low-grade BOO (Grade I-II) had a Qmax < 10 mL/s (22). Furthermore, a recent study reported that men with Qmax < 10 mL/s were more likely to develop an acute urinary retention episode (hazard ratio: 5.6) when compared to men with Qmax ≥ 10 mL/s (23). This cut-off value was thus used to dichotomize between patients considered as severely obstructed (Qmax < 10 mL/s) and patients with mild to moderate voiding dysfunction (Qmax ≥ 10 mL/s). The influence of the extent of prostatic resection in TURP outcomes has been the scope of some research. However, to our knowledge this is the first analysis of the influence

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of pre-operative Qmax in this relationship. In fact, none of the above-mentioned studies could certify the presence of BOO as a cause for LUTS, since none report urodynamic tests. Therefore, it is possible that some patients in these analyses were actually not suffering from true BOO. Our analysis suggests that in patients with pre-operative Qmax < 10 mL/s, a more thorough resection of the prostate is associated with better surgical outcomes. This association was not present in patients with pre-operative Qmax ≥ 10 mL/s, although surgery was beneficial in both groups. As suggested by other authors, prostate initial volume could play a role in this relationship, since a larger amount of tissue may need to be resected in order to treat BOO in larger rather than in smaller prostates. However, no such influence seems to exist, as the ratio between resected weight/prostate volume is similarly correlated with postoperative Qmax only in the group of patients with preoperative Qmax < 10 mL/s. Similar findings were previously reported by another study (6). These results suggest that severely obstructed patients may profit from a complete adenoma resection. Conversely, men with higher maximum flow rates may be good candidates for techniques with less morbidity, such as epTURP. If further studies confirm our results, surgeons should be encouraged to adapt their TURP technique to the patients’ pre-operative clinical details and expectations concerning surgical side effects, in a patient-tailored way. The present study has several limitations. First, the retrospective design may be a source of bias. Second, we did not consider symptom scales such as IPSS in our analysis, mainly due to a high level of missing data. Even though previous studies proved a high correlation between maximum flow rate and IPSS (18), LUTS grading and change after surgery would have been of great value in the analysis. Another source of relevant information would be urodynamic studies, which in our center are not routinely performed to all men with BPH/LUTS. Furthermore, in our study, the resected prostate weight was measured in the Pathology laboratory after fixation with formaldehyde, using precision scales. This fixation method results in a considerable reduction in specimen weight, and therefore this parameter, while valid for analysis within our studied group, is not directly comparable to previous studies (24). In conclusion, our analysis suggests that patients with preoperative Qmax < 10 mL/s undergoing TURP benefit from a complete adenoma resection, since resected prostate weight is directly correlated to post-operative Qmax and pre/post-operative difference in Qmax. The same does not apply for patients with pre-operative Qmax ≥ 10 mL/s, in which post-operative Qmax and Qmax improvement after surgery are independent of resected prostate weight. Our results suggest that men with higher pre-operative Qmax may do well with less thorough prostate resections, potentially avoiding important side-effects of TURP.

REFERENCES

1. Gravas S, Cornu JN, Gacci M, et al. Management of non-neurogenic male LUTS. In: EAU Guidelines. EAU Guidelines Office; 2020. 2. Parsons JK, Dahm P, Köhler TS, et al. Surgical management of lower urinary tract symptoms attributed to benign prostatic hyperplasia: AUA Guideline Amendment 2020. J Urol. 2020; 204:799-804.

TURP resection weight matters

3. Walker KM. Per-urethral operations for prostatic obstruction. Br Med J. 1925; 1:201-204. 4. Milonas D, Verikaite J, Jievaltas M. The effect of complete transurethral resection of the prostate on symptoms, quality of life, and voiding function improvement. Cent Eur J Urol. 2015; 68:169-174.

treatment of benign prostatic hyperplasia: A systematic review and meta-analysis of effectiveness and complications. Medicine (Baltimore). 2018; 97:e13360. 15. Siroky MB, Olsson CA, Krane RJ. The flow rate nomogram: I. Development. J Urol. 1979; 122:665-668.

5. Park HK, Paick SH, Lho YS, et al. Effect of the ratio of resected tissue in comparison with the prostate transitional zone volume on voiding function improvement after transurethral resection of prostate. Urology. 2012; 79:202-206.

16. Huang SW, Tsai CY, Tseng CS, et al. Comparative efficacy and safety of new surgical treatments for benign prostatic hyperplasia: Systematic review and network meta-analysis. BMJ. 2019; 367:l5919.

6. Hakenberg OW, Helke C, Manseck A, Wirth MP. Is there a relationship between the amount of tissue removed at transurethral resection of the prostate and clinical improvement in benign prostatic hyperplasia. Eur Urol. 2001; 39:412-417.

17. Mourmouris P, Tzelves L, Feretzakis G, et al. The use and applicability of machine learning algorithms in predicting the surgical outcome for patients with benign prostatic enlargement. Which model to use? Arch Ital di Urol e Androl. 2021; 93:418-424.

7. Siroky MB, Olsson CA, Krane RJ. The flow rate nomogram: II. Clinical correlation. J Urol. 1980; 123:208-210.

18. Itoh H, Kojima M, Okihara K, et al. Significant relationship of time-dependent uroflowmetric parameters to lower urinary tract symptoms as measured by the International Prostate Symptom Score. Int J Urol. 2006; 13:1058-1065.

8. Drake MJ, Lewis AL, Young GJ, et al. Diagnostic assessment of lower urinary tract symptoms in men considering prostate surgery: a noninferiority randomised controlled trial of urodynamics in 26 hospitals. Eur Urol. 2020; 78:701-710. 9. Chung A, Woo HH. Preservation of sexual function when relieving benign prostatic obstruction surgically: Can a trade-off be considered? Curr Opin Urol. 2016; 26:42-48.

19. Drake MJ, Doumouchtsis SK, Hashim H, Gammie A. Fundamentals of urodynamic practice, based on International Continence Society good urodynamic practices recommendations. Neurourol Urodyn. 2018; 37:S50-S60.

10. Rassweiler J, Teber D, Kuntz R, Hofmann R. Complications of transurethral resection of the prostate (TURP)-Incidence, management, and prevention. Eur Urol. 2006; 50:969-980.

20. Schäfer W. Analysis of bladder-outlet function with the linearized passive urethral resistance relation, linPURR, and a disease-specific approach for grading obstruction: from complex to simple. World J Urol. 1995; 13:47-58.

11. Alloussi SH, Lang C, Eichel R, Alloussi S. Ejaculation-preserving transurethral resection of prostate and bladder neck: Short- and longterm results of a new innovative resection technique. J Endourol. 2014; 28:84-89.

21. 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; 38:433-477.

12. Ben Rhouma S, Ben Chehida MA, Ahmed S, et al. MP42-18 Can we preserve ejaculation after transurethral resection of the prostate ? Comparative study between the conventional technique and a new technique about 70 cases. J Urol. 2016; 195:e577.

22. Boci R, Fall M, Waldén M, et al. Home uroflowmetry: Improved accuracy in outflow assessment. Neurourol Urodyn. 1999; 18:25-32.

13. Leonardi R. The LEST technique: Treatment of prostatic obstruction preserving antegrade ejaculation in patients with benign prostatic hyperplasia. Arch Ital di Urol Androl. 2019; 91:35-42. 14. S Sun F, Sun X, Shi Q, Zhai Y. Transurethral procedures in the

23. Chan CK, Yip SKH, Wu IPH, et al. Evaluation of the clinical value of a simple flowmeter in the management of male lower urinary tract symptoms. BJU Int. 2012; 109:1690-1696. 24. Lukacs S, Vale J, Mazaris E. Difference between actual vs. pathology prostate weight in TURP and radical robotic-assisted prostatectomy specimen. Int Braz J Urol. 2014; 4:823-827.

Correspondence Filipe Lopes, MD (Corresponding Author) filopes94@gmail.com Ricardo Pereira e Silva, MD ricardomanuelsilva7@gmail.com Miguel Fernandes, MD mivafer@gmail.com Tito Palmela Leitão, MD titopleitao@gmail.com José Palma dos Reis, MD jpalmareis@campus.ul.pt Serviço de Urologia, Hospital de Santa Maria Avenida Professor Egas Moniz 1649-035 Lisboa, Portugal Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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ORIGINAL PAPER

DOI: 10.4081/aiua.2022.2.174

Is Holmium Laser Enucleation of Prostate equally effective in management of benign prostatic hyperplasia patients with either voiding or storage lower urinary tract symptoms? A comparative study Mostafa M. Mostafa 1, 2, Nilesh Patil 1, Mahmoud Khalil 2, Mohammed A. Elgammal 2, Ayman Mahdy 1 1 Division 2 Asiut

of Urology, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati (US); University Hospitals, Asiut, Egypt.

Summary

Objective: To evaluate and compare the effectiveness and safety of holmium laser enucleation of prostate (HoLEP) in relieving either voiding or storage lower urinary tract symptoms (LUTS) in benign prostatic hyperplasia (BPH) patients. Materials and methods: The charts of patients with BPH who underwent HoLEP for either predominant voiding or predominant storage LUTS at University of Cincinnati hospitals in the period between February 2015 and December 2020 were retrospectively reviewed and analyzed for changes in voiding symptomatology, storage symptomatology, hematuria, International Prostate Symptom Score (IPSS), peak flow rates (Qmax), presence of detrusor overactivity (DO), and post-voiding residual urine (PVR) from baseline to up to 6 months postoperatively. Results: A total of 132 patients were included in the analysis. Patients were divided into two groups: Group 1 included BPH patients with predominant voiding LUTS (68 Patients) while group 2 involved those with predominant storage LUTS (64 Patients). HoLEP was equally effective in management of both groups with significant improvement in urodynamics study (UDS) parameters, patient voiding and storage symptomatology, and IPSS from preoperatively to up to 6 months postoperatively with relatively low procedure complication rate and postoperative need for medication or procedure. Conclusions: HoLEP is a safe, effective, and reliable minimally invasive surgical modality that can be relied on for BPH patients with either predominant voiding or predominant storage symptoms with relatively low procedure complication rate and postoperative need for medication or procedure.

KEY WORDS: Holmium Laser Enucleation of Prostate (HoLEP); Benign Prostatic Hyperplasia (BPH); Lower Urinary Tract Symptoms (LUTS). Submitted 28 March 2022; Accepted 14 May 2022

INTRODUCTION

Benign prostatic hyperplasia (BPH) is a common condition affecting a large number of men over the age of 50 years and is the major cause of the highly prevalent lower urinary tract symptoms (LUTS) in men of this age group that often necessitate surgical intervention (1, 2). The LUTS associated with BPH are generally divided into voiding

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symptoms (slow stream, splitting or spraying, intermittency, hesitancy, straining, terminal dribbling) and storage symptoms (day-time urinary frequency, nocturia, urgency, urinary incontinence) (3). These LUTS are among the most common clinical complaints in adult men with reported increasing prevalence with aging (4). The storage LUTS may also be termed overactive bladder (OAB) symptoms and are largely encompassed by the term overactive bladder syndrome (OABS) (5). While the voiding symptoms are usually more prevalent, the storage symptoms are almost always more bothersome (6). Associated with a significant burden on both patients and society, these LUTS also have a major impact on patients’ quality of life (QoL) (7). As such, the American Urological Association (AUA) has developed the International Prostate Symptom Score (IPSS) as one of the most reliable tools to evaluate the severity of LUTS associated with BPH which, in turn, plays a major role in determining the most appropriate treatment option for BPH (8-10). After being the preferred surgical treatment for BPH patients for more than 30 years, transurethral resection of prostate (TURP) has been replaced by holmium laser enucleation of prostate (HoLEP) as the gold standard surgical treatment for BPH (5, 11, 12). Introduced in 1995, HoLEP is a minimally invasive surgical procedure that has become the first line treatment of BPH as it provides both effective and safe surgical treatment option for BPH without any size limitation, although at the expense of occasional complications (11, 13, 14). HoLEP has the advantage of enucleating the enlarging BPH adenoma without destroying the bladder neck thus relieving bladder outflow obstruction (BOO) immediately, safely, and effectively (5). Although improvement in both storage and voiding LUTS has been demonstrated after either medical treatment with an alpha-blocker or a 5-alpha-reductase inhibitor or surgical treatment with TURP for BPH patients, few studies have been made to measure the outcomes of HoLEP in BPH-related voiding and/or storage LUTS (11). We performed our study with the aim to evaluate and compare the effectiveness and safety of HoLEP in relieving either voiding or storage LUTS in BPH patients. No conflict of interest declared.

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HoLEP for voiding or storage LUTS

MATERIALS

AND METHODS

After our study protocol approval by University of Cincinnati Institutional Review Board (IRB ID:2021-0666), we started reviewing the charts of all patients who underwent HoLEP at University of Cincinnati hospitals in the period between February 2015 and December 2020. All patients had routine initial evaluation with complete medical history, digital rectal examination (DRE), IPSS questionnaire, urinalysis, serum creatinine level, determination of serum prostate-specific antigen (PSA) when needed, transrectal ultrasonography (TRUS), peak flow rate (Qmax), postvoiding residual urine (PVR), and urodynamic study (UDS) before proceeding to any surgical intervention. Our inclusion criteria included patients with BPH who underwent HoLEP for either predominant voiding or predominant storage LUTS. We excluded patients who underwent the procedure for BPH with concomitant bladder stones and/or neurogenic bladder. We also excluded patients with predominant storage LUTS along with PVR of 150 ml or more, patients taking medications that may mimic or aggravate the LUTS such as antidepressants, diuretics, bronchodilators, anticholinergics, sympathomimetics, and antihistamines (15), and those having uncontrolled diabetes mellitus (DM) or recurrent urinary tract infections (UTIs). For proper allocation of patients to either of our two comparative groups (BPH patients with predominant voiding symptoms versus those with predominant storage symptoms), we used the principal indication for surgical intervention as determined by both subjective and objective parameters as the main allotment tool. Regarding the subjective parameters, we analyzed nine symptoms in all patients and categorized them into two main categories in order to determine the type of patient predominant symptomatology: storage symptoms (frequency, urgency, nocturia, and urinary incontinence) and voiding symptoms (hesitancy, intermittency, terminal dribbling, straining, and urinary retention) (3). We also analyzed hematuria, a relevant symptom that is not specific for either group. Analysis of symptoms was performed by the attending physician at the patient’s first presentation via asking the patient an open-ended question about the patient’s main complaint that urged him to seek medical care followed by closed-ended or binary questions to confirm the absence of the other relevant symptoms. Additionally, to both confirm the proper allocation of each patient to the pertinent group and avoid reporting bias, we used UDS as an objective parameter. As such, we identified patients with predominant voiding symptoms as those who reported their voiding symptoms as the more bothersome, whose voiding symptoms were the main drive for intervention, and whose UDS showed a predominant obstructive pattern with urodynamic evidence of BOO (BOO index > 40 using ICS nomogram (16). On the other hand, patients with predominant storage symptoms were defined as those who identified their storage symptoms as the more bothersome, who had no history of urinary retention, whose storage symptoms were the only indication for intervention, and whose UDS showed a predominant OAB pattern with volume to first contraction less than 350 mL and DO (involuntary detrusor contraction ≥ 10 cm H2O) (17).

All the cases included were performed by one highly skilled surgeon in the procedure (AM) to avoid the interference of below optimum surgical skills or learning curve complications in our results. Treatment efficacy, which was the primary outcome, was evaluated by comparing the preoperative UDS parameters, patient symptomatology, and IPSS with their postoperative counterparts. UDS parameters (Qmax, PVR, and demonstration of DO) were reported twice: at baseline and at the 6month follow-up visit. We collected and compared them between the two groups. Patient voiding symptomatology, storage symptomatology, hematuria, and IPSS were reported at baseline, 3-month, and 6-month postoperatively. We also collected, analyzed, and compared them between the two groups. For the secondary outcome (treatment safety), any reported complication within the first 6 postoperative months was collected and analyzed. We also collected, analyzed, and compared the postoperative need for medication (antimuscarinic alone or antimuscarinic+ beta-3 agonist) or procedure (Botox injection, urethral dilatation, or open prostatectomy) within the first 6 postoperative months between the two groups. Figure 1. Flowchart on inclusion and exclusion steps.

Table 1. Demographic and baseline characteristics of the studied groups. Variables Age (years) Mean ± SD BMI (kg/m2) Mean ± SD Ethnicity White Black/African American Hispanic Smoking Diabetes mellitus Heart failure Hypertension

Group 1 (n = 68)

Group 2 (n = 64)

P-value

75.2 ± 6.1

74.9 ± 5.5

0.767

25.6 ± 2.68

25.6 ± 1.2

0.916

26 (38.2%) 30 (44.1%) 12 (17.6%) 32 (47.1%) 26 (38.2%)

26 (40.0%) 20 (31.3%) 18 (28.1%) 30 (46.9%) 30 (46.9%)

0.214

25 (36.8%) 37 (54.4%)

21 (32.8%) 33 (51.6%)

0.634 0.743

0.983 0.315

SD: Standard deviation.

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Statistical analysis All statistical analyses were conducted using the IBM SPSS software package version 20.0 (Armonk, NY: IBM Corp). Quantitative variables are presented as means ± standard deviation, and qualitative variables are expressed as frequencies with percentages. Results were compared between two groups using Student’s t-test and MannWhitney U test for quantitative variables and chi-square test and McNemar’s test for qualitative variables. A P-value of < 0.05 was considered significant.

RESULTS

In total, 132 patients met the inclusion criteria, had complete follow-up data in their charts with preoperative and postoperative documentation of various voiding and storage symptomatology, IPSS, and UDS parameters and were included in our study. We allocated these patients into two groups: Group 1 (68 patients) included those with predominant voiding symptoms while group 2 (64 patients) involved those with predominant storage symptoms (Figure 1). Demographic and baseline characteristics of the studied groups The median age was 75.2 ± 6.1 and 74.9 ± 5.5 years for groups 1 and 2, respectively with no significant differences in demographic and baseline characteristics between the two groups (Table 1).

cantly higher decrease in DO after the procedure in group 2 (p-value = < 0.001) than in group 1 (p-value = 0.008). As to post-voiding residual urine (PVR), there was a significant decrease in PVR after HoLEP in both groups with p-value of improvement of < 0.001 for both groups (Table 2). Patient symptomatology of the studied groups There was a significant decrease in the frequency of the 4 studied storage symptoms and the 5 studied voiding symptoms in both groups from preoperatively to both 3and 6- month postoperatively. Eleven (16.2%) and Seven (10.9%) patients from groups 1 and 2, respectively had preoperative hematuria that was completely alleviated after HoLEP (Table 3). IPSS of the studied groups The mean preoperative IPSS was 28.4 ± 3.4 and 26.9 ± 3 for groups 1 and 2, respectively, and there was significant decrease in IPSS from preoperatively to both 3- and 6month postoperatively in both studied groups with pvalue of decrease of < 0.001. Interestingly, even though the preoperative IPSS was significantly higher in group 1 than in group 2 (p-value = 0.010), there was non-significant difference in the decrease in IPSS between both groups at both 3-month follow-up (p-value = 0.842) and 6-month follow-up (p-value = 0.483) (Table 4).

Procedure complication rate and postoperative need for medication or procedure in the studied groups UDS parameters of the studied groups There was no significant difference between the studied The mean preoperative peak flow rates (Qmax) were 8.6 ± groups as regarding procedure complication rate and 2 and 12.5 ± 1.9 for groups 1 and 2, respectively with a postoperative need for medication or procedure. significant increase in Qmax postoperatively with p-value The most encountered complication was urinary tract of increase of < 0.001 for both groups. infection occurring in 22 (32.4%) and 14 (21.9%) group With reference to DO, there was a remarkable decrease in 1 and 2 patients, respectively followed by urinary inconthe presence of DO after the procedure in both groups (4 tinence, bleeding, urethral stricture, and finally residual out of 16 patients and 12 out of 64 patients with preopprostatic tissue. Most patients didn’t require postoperaerative DO for groups 1 and 2, respectively) with signifitive medication or procedure with only 10.3% and 4.4% of group 1 patients and 23.4% and 4.7% group 2 patients Table 2. requiring postoperative medicaChanges in urodynamic study (UDS) parameters at 6-month postoperatively tion and procedure, respectively and comparison with preoperatively. (Table 5). Variables

Peak flow rate (Qmax) Preoperatively (Mean ± SD) (ml/s) 6-month Postoperatively (Mean ± SD) P-value from preoperatively to 6-month postoperatively Increase (Mean ± SD) Detrusor over activity (DO)

Post-voiding residual urine (PVR) (ml)

Group 2 (n = 64)

P-value

8.6 ± 2 14.2 ± 2.4 < 0.001 5.6 ± 2.2

12.5 ± 1.9 15.6 ± 1.7 < 0.001 3.1 ± 1.9

< 0.001 < 0.001 < 0.001

Preoperatively No Yes 6-month postoperatively No Yes P-value from preoperatively to 6-month postoperatively

52 (76.5%) 16 (23.5%)

0 (0%) 64 (100%)

< 0.001

64 (94.1%) 4 (5.9%) 0.008

52 (81.3%) 12 (18.8%) < 0.001

0.024

Preoperatively (Mean ± SD) 6-month Postoperatively (Mean ± SD) P-value from preoperatively to 6-month postoperatively Decrease (Mean ± SD)

239.4 ± 69.7 53.7 ± 26.9 < 0.001 185.7 ± 72.1

104.7 ± 22.6 48.3 ± 15.3 < 0.001 56.4 ± 24.86

< 0.001 0.156

SD: Standard deviation.

176

Group 1 (n = 68)

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< 0.001

DISCUSSION

To the best of our knowledge, we performed the first large study comparing the outcomes of HoLEP in BPH patients with predominant voiding symptoms and those with predominant storage symptoms in subjective outcomes (patient symptomatology and IPSS), objective outcomes (UDS parameters), procedure complication rate and postoperative need for medication or procedure. Our study confirms that HoLEP is associated with significant improvement in UDS

HoLEP for voiding or storage LUTS

Storage symptoms

Voiding symptoms

Variables Frequency Preoperatively 3-month postoperatively 6-month postoperatively P-value from preoperatively to 3-and 6-month postoperatively Urgency Preoperatively 3-month postoperatively 6-month postoperatively P-value from preoperatively to 3-and 6-month postoperatively Nocturia Preoperatively 3-month postoperatively 6-month postoperatively P-value from preoperatively to 3-and 6-month postoperatively Urinary incontinence Preoperatively 3-month postoperatively 6-month postoperatively P-value from preoperatively to 3-and 6-month postoperatively Hesitancy Preoperatively 3-month postoperatively 6-month postoperatively P-value from preoperatively to 3-and 6-month postoperatively Intermittency Preoperatively 3-month postoperatively 6-month postoperatively P-value from preoperatively to 3-and 6-month postoperatively Terminal dribbling Preoperatively 3-month postoperatively 6-month postoperatively P-value from preoperatively to 3-and 6-month postoperatively Straining Preoperatively 3-month postoperatively 6-month postoperatively P-value from preoperatively to 3-and 6-month postoperatively Urinary retention Preoperatively 3-month postoperatively 6-month postoperatively P-value from preoperatively to 3-and 6-month postoperatively Hematuria Preoperatively 3-month postoperatively 6-month postoperatively P-value from preoperatively to 3-and 6-month postoperatively

Group 1 (n = 68)

Group 2 (n = 64)

P-value

24 (35.3%) 9 (13.2%) 6 (8.8%) < 0.001

54 (84.4%) 24 (37.5%) 16 (25%) <0.001

< 0.001 0.001 0.013

19 (27.9%) 9 (13.2%) 3 (4.4%) < 0.001

53 (82.8%) 19 (29.7%) 8 (12.5%) < 0.001

< 0.001 0.021 0.093

30 (44.1%) 12 (17.6%) 6 (8.8%) < 0.001 8 (11.8%) 2 (2.9%) 0 (0%) 0.006 54 (79.4%) 16 (23.5%) 8 (11.8%) < 0.001 52 (76.5%) 16 (23.5%) 5 (7.4%) < 0.001 56 (82.4%) 22 (32.4%) 5 (7.4%) < 0.001 50 (73.5%) 34 (50%) 9 (13.2%) < 0.001 68 (100%) 1 (1.5%) 0 (0%) < 0.001 11 (16.2%) 2 (2.9%) 0 (0%) < 0.001

parameters, patient storage and voiding symptomatology, and IPSS from preoperatively to both 3- and 6- month postoperatively with remarkably low procedure complication rate and postoperative need for either medication or procedure and with similar efficacy in BPH patients with either predominant voiding or predominant storage symptoms. Vavassori et al. performed a study evaluating outcomes of HoLEP in 330 consecutive patients and reported significant improvement in Qmax, IPSS, and QoL after 3-year follow-up with 8.5% of their patients having postoperative transient irritative symptoms, 7.3% having transient postoperative urinary incontinence, and 2.7% having persistent BOO requiring reoperation (18). Our results confirm the reported improvement in Qmax and IPSS and the possibility of transient postoperative irritative symp-

Table 3. Changes in patient symptomatology at 3- and 6month postoperatively and comparison with preoperatively

toms or urinary incontinence after HoLEP. However, we also noted significant improvement in both PVR and DO and comparable efficacy in management of both voiding and storage 38 (59.4%) < 0.001 9 (14.1%) 0.021 LUTS after HoLEP. 3 (4.7%) 0.111 Pyun et al performed a study to < 0.001 compare the outcomes of HoLEP between 3 groups: BOO-only, 10 (15.6%) < 0.001 BOO with detrusor underactivity 5 (7.8%) 0.014 2 (3.1%) 0.098 (DU), and BOO with DO and 0.047 concluded that the improvement in the IPSS and Qmax was higher 8 (12.5%) < 0.001 in the BOO-only group than in 4 (6.3%) 0.006 the BOO with DO and BOO 0 (0%) 0.058 with DU groups (19). 0.018 In contrast to their results, our 10 (15.6%) < 0.001 results confirm that HoLEP has a 4 (6.3%) < 0.001 comparable efficacy in manage1 (1.6%) 0.209 ment of BPH patients with either 0.011 predominant voiding or predominant storage symptoms with sig24 (37.5%) < 0.001 15 (23.4%) 0.002 nificant improvement in UDS 6 (9.4%) 0.485 parameters, patient symptoma< 0.001 tology, and IPSS in both groups of patients, and we can assume 0 (0%) < 0.001 that the difference between our 0 (0%) 1.000 results can be attributed to the 0 (0%) – – fact that they had significantly higher number of patients in the 7 (10.9%) 0.381 BOO-only group (138 patients) 1 (1.6%) 1.000 compared to BOO with DO 0 (0%) – group (56 patients) and BOO 0.005 with DU group (33 patients) and that they included a group having DU in the comparison denoting including patients with late stage bladder dysfunction in their study. Besides, we would like to point that it is better to compare the preoperative with the postoperative Qmax for each of the studied groups rather than the degree of increase in Qmax between the studied groups because the lower the Qmax, the higher the room for increase. For example, in our study, the Qmax was preoperatively significantly lower in group 1 having recurrent attacks of urinary retention, and so, although there was a higher increase in Qmax after HoLEP in group 1, the postoperative Qmax was still higher in group 2. Jeong et al. conducted a study to evaluate the effect of the presence of preoperative detrusor overactivity on the functional outcomes of HoLEP and concluded that although the storage symptoms improved in patients who had preoperative DO and those who did not, a significant 52 (81.3%) 26 (40.6%) 6 (9.4%) < 0.001

< 0.001 0.004 0.912

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Table 4. Changes in International Prostate Symptom Score (IPSS) at 3- and 6- month postoperatively and comparison with preoperatively. IPSS Preoperatively (Mean ± SD) 3-month postoperatively (Mean ± SD) 6-month postoperatively (Mean ± SD) P-value from preoperatively to 3and 6-month postoperatively Decrease in IPSS From preoperatively to 3-month postoperatively (Mean ± SD) From preoperatively to 6-month postoperatively (Mean ± SD)

Group 1 (n = 68)

Group 2 (n = 64)

P-value

28.4 ± 3.4 19.9 ± 5.2 12.3 ± 5.7

26.9 ± 3 18.3 ± 4.3 10.3 ± 5.1

0.010 0.061 0.036

< 0.001

8.5 ± 3.8

8.6 ± 3.4

0.842

16 ± 4.6

16.6 ± 4.7

0.483

SD: Standard deviation.

Table 5. Comparison of procedure complication rate and postoperative need for medication or procedure within the first 6 postoperative months between the two groups. Variables Residual prostatic tissue Bleeding Urinary Tract Infection Urinary incontinence Urethral stricture Postoperative need for medication No Antimuscarinic alone Antimuscarinic + Beta-3 Agonist Postoperative need for procedure No Botox Urethral dilatation Open prostatectomy

Group 1 (n = 68) 1 (1.5%) 7 (10.3%) 22 (32.4%) 5 (7.4%) 2 (2.9%)

Group 2 (n = 64) 0 (0%) 4 (6.3%) 14 (21.9%) 7 (10.9%) 1 (1.6%)

61 (89.7%) 5 (7.4%) 2 (2.9%)

49 (76.6%) 11 (17.2%) 4 (6.2%)

P-value 1.000 0.401 0.177 0.474 1.000 0.128

0.466 65 (95.6%) 0 (0%) 2 (2.9%) 1 (1.5%)

61 (95.3%) 2 (3.1%) 1 (1.6%) 0 (0%)

number of those who had preoperative DO required postoperative anticholinergics (11). We agree with their results that patients with preoperative DO on UDS would require transient postoperative anticholinergic therapy and can add that there is significant improvement in both voiding and storage symptoms after HoLEP in patients with and without preoperative DO on UDS. Study limitations The retrospective nature of the study and the absence of comparative groups including patients who underwent other BPH procedures to compare the effectiveness and complication rate of HoLEP with those of other BPH procedures can affect the generalizability of our results. Although we would have preferred to use the IPSS voiding subscore (IPSS-V) and the IPSS storage subscore (IPSS-S) rather than the total IPSS (IPSS-T) to facilitate assignment of the patients to either of the two groups, we could not do so as we retrospectively reviewed the charts of patients after the IPSS-T rather than the IPSS-V and

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IPSS-S had already been calculated at the time of the patients’ visits. However, we used both subjective and objective parameters to compensate for the lack of data regarding the IPSS subscores and to ensure the proper allocation of patients to the relevant study groups.

CONCLUSIONS

HoLEP is a safe and reliable minimally invasive surgical modality with reported significant improvement in both subjective (measured by patients’ symptomatology and IPSS) and objective (measured by UDS parameters) aspects associated with BPH. It is highly efficient in alleviating both voiding and storage symptoms and can be resorted to whether the patient is suffering from predominant voiding or predominant storage symptoms. Moreover, the procedure complication rate and postoperative need for medication or procedure are relatively low.

REFERENCES

1. Porreca A, D'Agostino D, Vigo M, et al. "In-bore" MRI prostate biopsy is a safe preoperative clinical tool to exclude significant prostate cancer in symptomatic patients with benign prostatic obstruction before transurethral laser enucleation. Arch Ital Urol Androl. 2020; 91:224-9. 2. Lee YJ, Oh SA, Kim SH, Oh SJ. Patient satisfaction after holmium laser enucleation of the prostate (HoLEP): A prospective cohort study. PLoS One. 2017; 12:e0182230. 3. Gratzke C, Schlenker B, Seitz M, et al. Complications and early postoperative outcome after open prostatectomy in patients with benign prostatic enlargement: results of a prospective multicenter study. J Urol. 2007; 177:1419-22. 4. Martin SA, Haren MT, Marshall VR, et al. Prevalence and factors associated with uncomplicated storage and voiding lower urinary tract symptoms in community-dwelling Australian men. World J Urol. 2011; 29:179-84. 5. Saito K, Hisasue S, Ide H, et al. The impact of increased bladder blood flow on storage symptoms after Holmium laser enucleation of the prostate. PLoS One. 2015; 10:e0129111. 6. Peters TJ, Donovan JL, Kay HE, et al. The International Continence Society "Benign Prostatic Hyperplasia" Study: the botherosomeness of urinary symptoms. J Urol. 1997; 157:885-9. 7. 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; 67:1099109. 8. Rodrigues P, Meller A, Campagnari JC, et al. International Prostate Symptom Score--IPSS-AUA as discriminat scale in 400 male patients with lower urinary tract symptoms (LUTS). Int Braz J Urol. 2004; 30:135-41. 9. Barry MJ, Fowler FJ, Jr., O'Leary MP, et al. The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol. 1992; 148:1549-57; discussion 64. 10. O'Leary MP, Wei JT, Roehrborn CG, et al. Correlation of the International Prostate Symptom Score bother question with the Benign Prostatic Hyperplasia Impact Index in a clinical practice setting. BJU Int. 2008; 101:1531-5. 11. Jeong J, Lee HS, Cho WJ, et al. Effect of detrusor overactivity on

HoLEP for voiding or storage LUTS

functional outcomes after Holmium laser enucleation of the prostate in patients with benign prostatic obstruction. Urology. 2015; 86:133-8. 12. Schiavina R, Bianchi L, Giampaoli M, et al. Holmium laser 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. 13. Ryoo HS, Suh YS, Kim TH, et al. Efficacy of Holmium laser enucleation of the prostate based on patient preoperative characteristics. Int Neurourol J. 2015; 19:278-85. 14. Romagnoli D, Ghaemian M, D'Agostino D, et al. Not fatal venous air embolism after holmium laser enucleation of the prostate: Case report and review of literature. Arch Ital Urol Androl. 2020; 92:55-7. 15. Wuerstle MC, Van Den Eeden SK, Poon KT, et al. Contribution of common medications to lower urinary tract symptoms in men. Arch Intern Med. 2011; 171:1680-2. 16. Abrams P, Cardozo L, Fall M, et al. The standardisation of termi-

nology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Am J Obstet Gynecol. 2002; 187:116-26. 17. Allameh F, Basiri A, Razzaghi M, et al. Clinical efficacy of transurethral resection of the prostate combined with oral anticholinergics or botulinum toxin - A injection to treat benign prostatic hyperplasia with overactive bladder: a case-control study. Clin Pharmacol. 2020; 12:75-81. 18. Vavassori I, Valenti S, Naspro R, et al. Three-year outcome following holmium laser enucleation of the prostate combined with mechanical morcellation in 330 consecutive patients. Eur Urol. 2008; 53:599-604. 19. Pyun JH, Kang SG, Kang SH, et al. Efficacy of holmium laser enucleation of the prostate (HoLEP) in men with bladder outlet obstruction (BOO) and non-neurogenic bladder dysfunction. Kaohsiung J Med Sci. 2017; 33:458-63.

Correspondence Mostafa M. Mostafa, MD (Corresponding Author) mostafmm@ucmail.uc.edu Research Fellow of Urology, Division of Urology, Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267 Assistant Lecturer of Urology, Asiut University Hospitals, Asiut, Egypt Nilesh Patil, MD patilnh@ucmail.uc.edu Associate Professor of Urology, Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267 Mahmoud Khalil, MD mahmoud.magdy51@gmail.com Lecturer of Urology, Asiut University Hospitals, Asiut, Egypt Mohammed A. Elgammal, MD mohammedelgammal@aun.edu.eg Professor of Urology, Asiut University Hospitals, Asiut, Egypt Ayman Mahdy, MD, PhD, MBA mahdyan@uc.edu Chief of Urology, Professor of Urology, R. Bruce and Barbara Bracken Endowed Chair in Surgical Urology, Director of Voiding Dysfunction and Female Urology, Medical Director of Urology, the West Chester Hospital, Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0589, Cincinnati, OH 45267

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DOI: 10.4081/aiua.2022.2.180

ORIGINAL PAPER

Comparative analysis of MOSESTM technology versus novel thulium fiber laser (TFL) for transurethral enucleation of the prostate: A single-institutional study Hazem Elmansy 1, Amr Hodhod 1, Ahmed Elshafei 1, Yasser A Noureldin 1, 2, Vahid Mehrnoush 1, Ahmed S. Zakaria 1, Ruba Abdul Hadi 1, Moustafa Fathy 1, 3, Loay Abbas 1, Ahmed Kotb 1, Walid Shahrour 1 1 Urology

Department, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada; Department, Benha University, Benha, Egypt; 3 Urology Department, Menoufia University, Shebin Elkom, Egypt. 2 Urology

Summary

Introduction: Novel laser technologies have been developed for the minimally invasive surgical management of benign prostatic hyperplasia (BPH). The objective of this study was to assess the safety and efficacy of MOSESTM technology versus the thulium fiber laser (TFL) in patients with BPH undergoing transurethral enucleation of the prostate. Methods: We conducted a retrospective review of prospectively collected data of eighty-two patients who underwent transurethral enucleation of the prostate using MOSESTM or TFL technologies from August 2020 to September 2021. Preoperative and intraoperative parameters, in addition to postoperative outcomes, were collected and analyzed. Results: Twenty patients underwent transurethral enucleation of the prostate with TFL, while 62 had MOSESTM HoLEP. No statistically significant difference in preoperative characteristics was observed between the groups. Patients in the TFL group had longer median enucleation, hemostasis, and morcellation times (p < 0.001) than those in the MOSESTM cohort. The longer morcellation time of TFL is mostly related to less visibility. The postoperative outcomes IPSS, QoL, Qmax, and post void residual (PVR), were comparable between the groups at 1, 3 and 6 months. The incidence of urge urinary incontinence (p = 0.79), stress urinary incontinence (p = 0.97), and hospital readmission rates (p = 0.1) were comparable between the two groups. Conclusions: A satisfactory safety and efficacy profile with comparable postoperative outcomes was demonstrated for both techniques; though, MOSESTM technology was superior to TFL in terms of shorter overall operative time.

KEY WORDS: Benign Prostatic Hyperplasia; Laser; Enucleation. Submitted 23 March 2022; Accepted 25 April 2022

INTRODUCTION

A wide range of laser technologies have been developed for anatomical endoscopic enucleation of the prostate (AEEP), which adopts the principle of open prostatectomy (OP). The efficacy and safety of AEEP have been widely demonstrated, regardless of the energy source utilized (1). Holmium laser enucleation of the prostate (HoLEP) is a safe

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and effective treatment option for patients experiencing symptoms of an enlarged prostate. The HoLEP procedure has comparable results to transurethral resection of the prostate (TURP) and OP, with a low morbidity rate and shorter hospital stay (2-6). HoLEP also demonstrated an acceptable steep learning curve (7). Improvements in outcome parameters following HoLEP are durable, and the late complications and reoperation rates reported are very low, up to 18 years (8). Recent evidence suggests that MOSESTM technology has further revolutionized HoLEP with modulated pulsed energy transmission (9). Enhanced energy delivery is believed to increase efficiency during HoLEP and reduce the operative and catheterization times, as well as blood loss (10). HoLEP performed using MOSESTM technology has been shown to provide faster hemostasis than HoLEP with a standard 100-W holmium laser (9). Thulium fiber laser enucleation of the prostate (ThuFLEP) is an emerging technology for endoscopic prostate enucleation. One of the advantages of the thulium fiber laser (TFL) is its wavelength (1940 nm), which has a photothermal effect and a more shallow penetration depth. This allows for precise tissue cutting and reduces the carbonization effects associated with Thulium:YAG lasers (11-13). Recent data demonstrate that ThuFLEP is an effective minimally-invasive technique for the surgical management of benign prostatiec hyperplasia (BPH), with treatment outcomes comparable to TURP and OP (13, 14). The objective of this study was to assess the safety and efficacy of TFL in patients who underwent ThuFLEP compared to those that underwent MOSESTM HoLEP at our institution.

PATIENTS

AND METHODS

After obtaining Research Ethics Board approval, we conducted a retrospective review of prospectively collected data of eighty-two patients who underwent transurethral enucleation of the prostate at our institution from August 2020 to September 2021. Patients were dichotomized depending on whether they underwent enucleation of the prostate using a 120-W MOSESTM (Lumenis, Yoknaem, No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2022; 94, 2

MOSESTM vs. TFL enucleation of prostate

Israel) or TFL (Soltive Premium, Olympus, USA). A 550-μm laser fiber and a 28-F continuous flow resectoscope (Karl Storz SE & Co. KG, Tuttlingen, Germany) were used for both procedures. We included patients with a prostate size > 80 g that presented with severe lower urinary tract obstruction that did not respond to medical treatment, refractory urinary retention, refractory hematuria due to prostate enlargement, and bladder stones secondary to BPH. Preoperative evaluation included patient demographics, a complete medical history, physical examination including a digital rectal exam (DRE), the use of antiplatelets and anticoagulants, history of urinary retention, and previous prostate surgery. Symptom assessment was completed using the International Prostate Symptom Score (IPSS) and quality of life (QoL) questionnaires. Patients underwent prostate-specific antigen (PSA) testing, uroflowmetry, a post-void residual (PVR) bladder scan, and a transrectal ultrasound for prostate volume estimation. Patients with PSA values above normal or those with abnormal DRE findings underwent a preoperative biopsy to exclude prostate cancer. A preoperative cystoscopy was performed in individuals who previously underwent TURP to exclude urethral strictures and bladder neck (BN) contracture. Surgical parameters including enucleation time, enucleation efficiency, morcellation time, laser energy, resected weight, intraoperative complications, and the need for blood transfusion were recorded. Enucleation efficiency is defined as the weight of enucleated prostatic tissue (grams) divided by the enucleation time (minute). Early postoperative complications included clot retention, a failed trial of void (TOV) and hospital readmission. Preoperative and postoperative hemoglobin levels were measured. Late postoperative complications included urge urinary incontinence (UUI), stress urinary incontinence (SUI), urethral strictures, and BN contraction. SUI was evaluated with a detailed history regarding the involuntary passage of urine while coughing or sneezing or the use of pads to avoid wetting. Clinical evaluation of SUI was conducted by asking the patient, with a full bladder, to cough and by observing the passage of any urine. All patients had postoperative follow-ups at 1, 3, 6 and 12 months. Our evaluation included IPSS, QoL, Qmax, and PVR. PSA levels were measured at three months postoperative. Surgical technique Our top-down enucleation techniques using the holmium laser or TFL were reported in previous publications (15, 16). Postoperative care Until August 2020, we performed standard 100-W HoLEP, and our practice was an overnight hospital admission with a next-day TOV (< 24 hours). After acquiring MOSESTM technology in December 2020, we implemented same-day discharge and same-day TOV for patients that underwent MOSESTM HoLEP. The standard practice for TFL prostate enucleation was an overnight admission and next-day TOV (< 24 hours). Patients who met predetermined discharge criteria following an assess-

ment by the surgeon were offered same-day catheter removal 3 hours postoperatively. They were informed that our standard practice was an overnight admission or same-day discharge with outpatient catheter removal on postoperative day one (POD1). Patients with an unfit medical condition (e.g., uncontrolled cardiovascular disease, cognitive disorder, and anticoagulant or antiplatelet therapy) were excluded from early discharge. Those without a caregiver or residing beyond city limits were also excluded. Patients were not excluded based on PVR, the presence of an indwelling catheter or other subjective criteria. All patients were counselled regarding the option to decline same-day catheter removal and discharge if they felt uncomfortable. If medically feasible, patients were instructed to temporarily hold their antiplatelet and anticoagulant medications before surgery for 7 and 3 days, respectively. A same-day TOV was not offered to patients who could not withhold their antiplatelet or anticoagulant therapy. All patients had a three-way Foley catheter (22 F, with 75 ml of sterile water in the balloon) inserted postoperatively and were kept on mild traction with continuous bladder irrigation (CBI). The cases were postoperatively transferred to the Post Anesthesia Care Unit (PACU) for observation. For MOSESTM patients, CBI was continued for 2 hours and was then stopped for an additional hour to evaluate the degree of hematuria. While patients who underwent TFL were admitted overnight with CBI. Routine blood testing, including a complete blood count and basic metabolic profile, were conducted in the PACU. Voiding trials were performed 3 hours postoperatively for MOSESTM patients and next day for the TFL group. Following TOV, all patients were assessed by the urologist for suitability for discharge. A TOV was performed by filling the catheter with 300500 mL of saline or until the patient felt the urge to urinate. The urine colour, volume voided, and PVR were assessed to ensure there was no concern for hematuria or possible clot retention. Predetermined discharge criteria included: if the patient was deemed medically fit, was not on anticoagulants or antiplatelets, had a caregiver, and met discharge criteria (17). Patients with a minimum score of 9 on the modified Post Anaesthetic Discharge Scoring System were considered ready for discharge. A score of ≥ 2 was required for vital signs, pain and surgical bleeding criteria, whereas a minimum score of 1 was required for all other criteria. Before discharge, patients were also required to have acceptable laboratory results, hematuria scores (without CBI or the presence of clots) (18), tolerate diet, and ambulate independently. A TOV was considered successful if the patient had a PVR < 300 and if the residual volume was less than half the voided volume, and there was no concern for hematuria or possible clot retention. Statistical analyses Data collection and statistical analyses were performed using Statistical Package for the Social Sciences (SPSS®) version 26.0 (Chicago, IL, USA) and JMP® Pro16 software (SAS Institute Inc., Cary, NC). Continuous data were presented using medians and interquartile ranges (IQR) and compared with the Mann-Whitney U Test. Numbers and Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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percentages were used to describe categorical data, which was compared using the Chi-Square test. The p-value was considered statistically significant if p < 0.05.

RESULTS

Of the 82 patients included in the study, 62 underwent MOSESTM HoLEP, and 20 had transurethral enucleation of the prostate with TFL. The preoperative characteristics of the two groups are listed in Table 1. There was no difference between treatment modalities in terms of compared preoperative parameters. Patients who underwent TFL prostate enucleation had longer median enucleation, hemostasis, and morcellation times (p < 0.001) compared to MOSESTM (Table 2). Moreover, the enucleation efficiency was significantly higher using MOSESTM technology (p = 0.006). No intraoperative complications were recorded for both technologies. Two patients (10%) in the TFL cohort required hospital readmission compared to one (1.6%) in the MOSESTM group (p = 0.1). All three cases of hospital readmission were due to hematuria. All patients in our study had their catheters removed postoperatively and were discharged from the hospital within 24 hours; though, patients who underwent MOSESTM HoLEP had their catheters removed within 3 hours postoperatively with a hospital stay ≤ 6 hours. Table 1. Preoperative characteristics of both groups.

Age at surgery (median/IQR) yrs Indication Urine retention n (%) LUTS/hematuria n (%) Comorbidities n (%) Prostate volume (median/IQR) cc Preoperative IPSS (median/IQR) Preoperative QoL (median/IQR) Preoperative Qmax (median/IQR) ml/min Preoperative PVR (median/IQR) ml Preoperative PSA (median/IQR) ng/dl Preoperative hemoglobin (median/IQR) g/L

MOSESTM (62 patients) 71.4 (64.5-80.1) 12 (19.4) 50 (80.6) 51 (82.3) 109 (87-122) 25 (22-28) 5 (4-5.25) 7.7 (5.7-10.6) 223 (130-323) 4.8 (3.6-7.4) 145 (140-151)

TFL (20 patients) 73.8 (66.2-82.6) 7 (35) 13 (65) 13 (65) 102 (91.5-118.75) 25.5 (23.3-28.5) 5 (4.25-6) 7.95 (6.4-11) 234 (99.5-440) 4.8 (4.2-5.5) 139 (131.3-143)

P-value 0.2 0.15 0.1 0.97 0.55 0.34 0.74 0.82 0.89 0.052

Table 2. Operative parameters comparing MOSESTM to TFL technologies in prostate enucleation.

Enucleation time (median/IQR) min Hemostasis time (median/IQR) min Morcellation time (median/IQR) min Laser energy (median/IQR) KJ Prostate enucleated weight (median/IQR) g Hemoglobin drop (median/IQR) g/L Enucleation efficiency (median/IQR) g/min Readmissions n (%)

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MOSESTM (62 patients) 46.5 (40-54) 3 (2-4) 10 (6.7-12) 79.7 (65.4-99.7) 70 (60-90) 10 (7-14) 1.6 (1.3-2) 1 (1.6)

TFL (20 patients) 61.5 (55-68.7) 5 (5-6.7) 15 (10.2-22.7) 78.4 (67.8-95.3) 79 (58.5-90.8) 10.5 (7.3-14) 1.4 (1-1.6) 2 (10)

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P-value < 0.001 < 0.001 < 0.001 0.75 0.51 0.6 0.006 0.1

Patients who underwent TFL enucleation of the prostate had their catheters removed within 24 hours and had a hospital stay of ≤ 24 hours. None of the patients in our study required postoperative blood transfusion. Following catheter removal, one patient (5%) in the TFL group and 3 individuals (4.8%) in the MOSESTM group experienced SUI (p = 0.97). The incidence of UUI post-catheter removal was 10% (2 patients) and 8.1% (5 patients) in the TFL and MOSES TM groups, respectively (p = 0.79). All cases of SUI and UUI were resolved at 3-months follow-up. The postoperative functional outcomes were comparable between the two groups including median Qmax at 1, 3 and 6 months (p = 0.55, p = 0.32, p = 0.82), respectively and median PVR at 1, 3, and 6 months (p = 0.88, p = 0.92, p = 0.31), respectively. The median IPSS at 1, 3 and 6 months (p = 0.6, p = 0.26, p = 0.11), respectively and median QoL at 1, 3 and 6 months (p = 0.6, p = 0.32, p = 0.71), respectively were also comparable between the groups (Figure 1). At 6-months follow-up (Figure 2), there were no differences between the groups in terms of improvement in percentages of IPSS (p = 0.38), QoL (p = 0.77), Qmax (p = 0.84), and PVR (p = 0.33).

DISCUSSION

Over the last few years, emerging laser technologies have been introduced for BPH management. This study compared two well-known technologies: MOSESTM and the novel TFL. Both modalities demonstrated promising results in the management of primary and recurrent enucleation of BPH (19). Though MOSES TM and TFL were individually studied with other modalities in the literature, the two technologies were not previously compared. MOSESTM technology was associated with a shorter operative time compared to conventional HoLEP. This may be due to the enhanced hemostatic properties of MOSESTM (9, 10, 20). Compared to OP, TFL was associated with a shorter hospital stay and earlier return to normal activities (14). Moreover, TFL was comparable to conventional monopolar TURP in the management of moderate-sized prostates (< 80 cc). At 12-months follow-up, TFL was associated with a greater reduction in PSA levels, indicating enhanced removal of the prostatic adenoma (13). In the current study, MOSESTM HoLEP was associated with significantly less enucleation and hemostasis times than TFL. This could be explained by better hemostasis achieved with MOSESTM technology than TFL. Doizi and colleagues found incision depth and coagulation areas were greater with the holmium laser than TFL. Moreover, they noticed that the holmium laser had no carbonization zone while it was constant with the TFL (21). In this study, MOSESTM technology had better enucleation efficiency than TFL (1.6 vs 1.4 g/min, p = 0.006). Our reported TFL enucleation efficiency is comparable to other studies. Enikeev et al. had an enucleation efficiency of 1.04 g/min using TFL (14). Nevo and colleagues reported a mean enucleation efficiency of 1.7 g/min with MOSESTM 2.0 technology (10). We found that morcellation time was shorter in the

MOSESTM vs. TFL enucleation of prostate

Figure 1. Functional outcomes comparing MOSESTM to TFL technologies for prostate enucleation.

MOSESTM group compared to the TFL cohort, 10 vs 15 minutes, respectively (p < 0.001). We observed a higher clarity of vision with MOSESTM due to better hemostasis that facilitated faster morcellation of the adenoma. Our morcellation time is similar to that of Large and colleagues (mean time = 10.4 min) (9). The morcellation time following TFL prostate enucleation is not well documented in the literature.

We cannot compare TOV for MOSESTM and TFL because we adopted a same-day TOV for the MOSESTM cohort, whereas patients who underwent TFL were kept overnight. Similarly, the hospital stay cannot be compared as TFL patients were routinely admitted and discharged the following day. In the current study, same-day TOV following MOSESTM enucleation was successful in about 93.5% of patients. Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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Figure 2. Percentage of improvement in IPSS, QoL, Qmax, and PVR at 6-months follow-up.

This result seems promising if we compare it with the 88% successful same-day TOV rate, reported by Slade et al., following conventional HoLEP (22). Although the intraoperative enucleation parameters were better with MOSESTM technology, both TFL and MOSESTM had comparable postoperative outcomes at 6 months follow-up (Figures 1, 2). Other studies reported similar results for both laser technologies (9, 10, 13, 14). Our study has some limitations, including its retrospective nature, though it is a retrospective analysis of prospectively collected data. A second limitation is the small number of patients in the TFL group. A similar number of procedures were used to evaluate laser enucleation of the prostate in other studies (10). Moreover, the hospital stay and same-day TOV of both technologies could not be compared. Our study has a relatively short follow-up period; however, similar follow-up intervals were used in the literature (9, 14). Additional studies with larger sample sizes and more extended follow-up periods are warranted.

CONCLUSIONS

To the extent of our knowledge, this is the first study comparing MOSESTM and TFL technologies for transurethral prostate enucleation. A satisfactory safety and efficacy profile with comparable postoperative outcomes was demonstrated for both techniques; though, MOSESTM technology was superior to TFL in terms of shorter overall operative time.

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16. Elmansy H, Shabana W, Waugh M, Ahmad A, Hadi RA, Shahrour W. Top-down thulium fiber laser enucleation of the prostate: technical aspects. Cent European J Urol 2021; 74:271.

10. Nevo A, Faraj KS, Cheney SM, Moore JP, Stern KL, Borofsky M, et al. Holmium laser enucleation of the prostate using Moses 2.0 vs non-Moses: a randomised controlled trial. BJU Int 2021; 127:553-9. 11. Fried NM, Murray KE. High-power thulium fiber laser ablation of urinary tissues at 1.94 microm. J Endourol 2005; 19:25-31. 12. Enikeev D, Glybochko P, Rapoport L, Gahan J, Gazimiev M, Spivak L, et al. A randomized trial comparing the learning curve of 3 endoscopic enucleation techniques (HoLEP, ThuFLEP, and MEP) for BPH using mentoring approach-Initial results. Urology 2018; 121:51-7. 13. Enikeev D, Netsch C, Rapoport L, Gazimiev M, Laukhtina E, Snurnitsyna O, et al. Novel thulium fiber laser for endoscopic enucleation of the prostate: A prospective comparison with conventional transurethral resection of the prostate. Int J Urol 2019; 26:1138-43. 14. Enikeev D, Okhunov Z, Rapoport L, Taratkin M, Enikeev M, Snurnitsyna O, et al. Novel Thulium fiber laser for enucleation of prostate: a retrospective comparison with open simple prostatectomy. J Endourol 2019; 33:16-21. 15. Elmansy H, Hodhod A, Kotb A, Prowse O, Shahrour W. Top-

17. Palumbo P, Tellan G, Perotti B, Pacile MA, Vietri F, Illuminati G. Modified PADSS (Post Anaesthetic Discharge Scoring System) for monitoring outpatients discharge. Ann Ital Chir 2013; 84:661-5. 18. Abdul-Muhsin H, Critchlow W, Navaratnam A, Gnecco J, Tay K, Girardo M, et al. Feasibility of holmium laser enucleation of the prostate as a 1-day surgery. World J Urol 2020; 38:1017-25. 19. Becker B, Netsch C, Glybochko P, Rapoport L, Taratkin M, Enikeev D. A feasibility study utilizing the Thulium and Holmium laser in patients for the treatment of recurrent benign prostatic hyperplasia after previous prostatic surgery. Urol Int 2018; 101:212-8. 20. Nottingham CU, Large T, Agarwal DK, Rivera ME, Krambeck AE. Comparison of newly optimized Moses technology vs standard Holmium:YAG for endoscopic laser enucleation of the prostate. J Endourol 2021; 35:1393-9. 21. Doizi S, Germain T, Panthier F, Comperat E, Traxer O, Berthe L. Comparison of Holmium:YAG and Thulium fiber lasers on soft tissue: an ex vivo study. J Endourol. 2022; 36:251-258. 22. Slade A, Agarwal D, Large T, Sahm E, Schmidt J, Rivera ME. Expanded criteria same day catheter removal following Holmium laser enucleation of the prostate (HoLEP). J Endourol 2022. doi: 10.1089/end.2022.0007. Epub ahead of print.

Correspondence Hazem Elmansy, MD, MSc, FRCSC hazem.mansy@rocketmail.com Associate Professor & Program Director of the Minimally Invasive Urologic Surgery Fellowship Program, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada 146 Court Street South, Thunder Bay, ON, P7B 2X6 Amr Hodhod, MD Ahmed Elshafei, MD Yasser A Noureldin, MD Vahid Mehrnoush, MD Ahmed S Zakaria, MD Ruba Abdul Hadi, RD Moustafa Fathy, MD Loay Abbas, MD Ahmed Kotb, MD Walid Shahrour, MD Urology Department, Northern Ontario School of Medicine, Thunder Bay, Ontario (Canada)

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ORIGINAL PAPER

Sheathed flexible retrograde intrarenal surgery without safety guide wire for upper urinary tract stones Murad Asali Urology Department, Barzilai Medical Center, Ben Gurion University of the Negev, Beer Sheva, Israel; Assuta Medical Center, Beer Sheva, Ramat Hyal, Ben Gurion University of the Negev, Beer Sheva, Israel.

Summary

Objectives: To assess the success rate and intraoperative complications of flexible ureterorenoscopy (f-URS) in patients with upper urinary tract (UUT) stones using a ureteral access sheath (UAS) without a safety guide wire (SGW). Patients and methods: Between April 2010 and March 2022, 464 renal units in patients with renal stones with and without concomitant ureteral stones (UUT), underwent ureterorenoscopy by one surgeon, and UAS was used in all of them. The primary endpoint was the stone-free rate (SFR). SFR was defined as no residual fragments at all. The following characteristics were examined: age, sex, laterality, renal/ureteral stones, stone diameter, SFR, Hounsfield unit, auxiliary procedures, double-J stent insertion, and intraoperative complications. This study was retrospective, with all the data recorded prospectively. Patients with residual stones were scheduled for the 2nd RIRS. The Clavien-Dindo classification was used to report complications. Results: The mean patient age was 52.9 years. The mean stone size was 13.1 mm. Lower pole, upper and middle calyces, renal pelvis and ureteral stones were found in 51.5% (239), 34.9% (162), 18.3% (85) and 46.9% (218) of cases, respectively. The mean diameter was 8.1 mm, 8 mm, 12.5 mm and 8.1 mm for the lower pole, upper and middle calyces, renal pelvis and ureteral stones, respectively. The single- and second-session SFRs were 90% and 100%, respectively. The mean number of procedures per renal unit was 1.1. Ureteral double-J stents were inserted in 45.7% (212) of patients. In 96 cases, a stent was placed before surgery. Postoperative complications were minor, with no avulsion or perforation of the ureters; readmission and insertion of a DJ stent occurred in one patient. Ureteral stricture developed in one patient (0.2%) and needed treatment with laser ureterotomy. Conclusions: f-URS is a safe and effective mode of surgical management of renal and simultaneous renal and ureteral calculi using the ureteral access sheath without a safety guide wire. A guide wire should not be routinely used in these cases.

KEY WORDS: RIRS; Retrograde intrarenal surgery; Safety guide wire; Ureteral access sheath; Renal stones; Ureteroscopy. Submitted 5 May 2022; Accepted 27 May 2022

INTRODUCTION

Nephrolithiasis is a common disease in Asia with a rate of 1-5% (1). For decades, it was advised to have a safety guide wire

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(SGW) present during ureteroscopy to ease the management of possible complications (2, 3). With the development of small flexible ureteroscopes and the improvement of laser lithotripsy, ureteroscopy has become the standard of care for treating urolithiasis less than 2 cm (4, 5). Should we still use the SGW? Does the use of a ureteral access sheath (UAS) alter the results or increase the complications? The goal of this study was to assess the success rate of flexible ureterorenoscopy (f-URS) in patients with renal stones with or without ureteral stones using UAS without a safety guide wire. To our knowledge, there are no articles discussing the use of UASs without guide wires present in upper urinary tract (UUT) stones.

PATIENTS

AND METHODS

Between April 2010 and March 2022, 464 renal units in patients with renal stones with and without concomitant ureteral stones, underwent ureterorenoscopy by one surgeon, and UAS was used in all of them. A guide wire was used just to place the UAS and during insertion of ureteral double-J stent. No SGW was used inside or outside the UAS during the operation. The UAS was always placed below the ureteral stone and moved up to the middle or proximal ureter for renal stone treatment. All the patients were included in the study after they matched our inclusion criteria. The inclusion criteria were as follows: 1. Upper tract stones, renal stones with or without ureteral stones. 2. The same flexible ureteroscope (flexible uretero-renoscope FLEX- X2s (Karl Stortz & Co. KG, Tuttlingen, Germany) was used. 3. The Holmium YAG LASER energy was used (fibres 272 µ, 200 µ and 230 µ). 4. The LASER generator Sphinx Jr 30 watt (LISA Laser Products GmbH, Germany) or Mega Plus 15 Watt (Richard Wolf GmbH, Knittlingen, Germay) or Luminis 120 watt (Luminis, Yokneam, Israel) was used. 4. A ureteral access sheath (Flexor ureteral access sheath 12/14F, 28, 35, 45 cm; FUS- Cook Medical, Bloomington, IN, USA) was used. 5. All data recorded. 6. Adults aged 18 years and older. No conflict of interest declared.

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The exclusion criteria were as follows: 1. Using other flexible ureteroscopes. 2. Comorbidities that interfered with the completion of the study included severe. systemic disease, congestive heart failure, pregnancy, and severe chronic lung disease. 2. Missed data. 3. No or other access sheath used. 4. Patients with non-compliant ureters. 5. Using rigid ureteroscope. The primary endpoint was the stone-free rate (SFR). Stone-free status was defined as no residual fragments at all. At the end of the operation, a triple test was done for all the calyces, using a plain abdominal radiograph of the kidneys, ureter and bladder, using the scope and the Carm while injecting contrast intraoperatively as a retrograde pyelography and screening every calyx using the endoscope and simultaneously following the anatomy on the C-arm screen. We evaluated 464 consecutive renal units that underwent f-URS for UUT stones (Table 1). In all patients, the following characteristics were examined: age, sex, laterality, renal/ureteral stones, stone diameter, Hounsfield unit, stone-free rate, auxiliary procedures per renal unit, double-J stent insertion, length of hospital stay, and any perioperative complications. Stone-free status was defined as complete stone removal. This study was retrospective, and all the data (demographic data, stone characteristics, operative and postoperative data) were recorded prospectively. Postoperative follow-up was scheduled at one month later with renal scan DTPA, urine culture, and renal function. Patients with residual stones were scheduled for a 2nd RIRS (retrograde intrarenal surgery). The Clavien-Dindo classification was used to report complications (6).

RESULTS

The mean patient age was 52.9 years. The mean maximum stone diameter was 13.1 mm. Lower pole, upper and middle calyces, and renal pelvis stones were in 51.5% (239), 34.9% (162), and 18.3% (85), respectively. Ureteral stones were associated to renal stones in 46.9% (218) of cases. The mean diameter was 8.1 mm, 8 mm, 12.5 mm and 8.1 mm of the lower pole, upper and middle calyces, renal pelvis and ureteral stones, respectively.

Table 1. Patient demographics and stone characteristics. Patients Gender M/F Renal units (Kidney +/- Ureter) Male Age (years) Hounsfield unit Mean Maximum Stone Diameter (mm) Lateralization R/L

423 266/157 464 0.63 52.9 880.1 13.1 210/254

Table 2. Renal and Ureteral Stone Location and Diameter. No 464 239 159 85 98 46 74

Renal and ureter Lower pole Upper and middle calyx Renal pelvis Upper ureter Middle ureter Lower ureter

% 100 51.5 34.3 18.3 21.1 9.9 15.9

Total Stone Diameter (mm) 13.1 8.1 8 12.5 8.9 7.3 7.4

Table 3. Stone-free rate/auxiliary F-URS. No 464 418 464 46 31.3 0.54

Renal units SF- 1ST Session SF- 2nd Session Auxiliary F-URS Laser frequency (HZ) Energy (Joule)

% 100 90 100 9.9 ** **

SF = Stone Free; F-URS = Flexible Ureteroscopy; HZ = Hertz.

Table 4. Complications. Renal units Renal colic needs IM/IV* treatment Haematuria Insetion of stent due to pain Fever Ureteral stricture Ureteral avulsion Ureteral Perforation Clavien- Dindo classification I Clavien- Dindo classification III Clavien- Dindo classification II, IV, V

No 464 13 1 1 2 1 0 0 16 2 0

% 100 2.8 0.2 0.2 0.4 0.2 0 0 3.4 0.4 0

*IM = Intramuscular, IV = Intravenous.

The renal and ureteral stone characteristics are shown in Table 2. As shown in Table 3, the single-session SFR was 90% (418/464), and the two-stage procedure SFR was 100%. The mean number of procedures per renal unit was 1.1. Ureteral double-J stents were inserted 45.7% (212) postoperatively. In 96 cases, a stent was placed before surgery. The mean hospital stay was one day. Intra- and postoperative complications were minor, as shown in Table 4. There was no avulsion of the ureters, no need for conversion to open surgery, no ureteral perforation; there was readmission and insertion of an a-DJ stent in one patient (0.2%). In the follow up ureteral stricture developed in one patient that needed treatment with laser ureterotomy (0.2%). Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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M. Asali

DISCUSSION

RIRS is a safe and valuable alternative option for the management of renal stones. It is a well-established procedure under constant evolution with advances in technique and technology. It has gained worldwide popularity due to its minimal invasiveness and satisfactory outcomes (7). With the development of small flexible ureteroscopes and the improvement of laser lithotripsy, ureteroscopy has become the standard of care for treating urolithiasis less than 2 cm (4, 5). The stone-free rate (SFR) is higher in percutaneous nephrolithotomy-PCNL, but RIRS is also an option for large renal stones larger than 2.5 cm with low morbidity (8). Ho et al. published their review highlighting the expanding role of URS for the management of more complex stones and patients with good outcomes (9). Advances in flexible ureteroscope design and accessory instrumentation and new LASER generators have allowed for more challenging cases to be treated ureteroscopically. A safety guide wire is still used during ureteroscopy or RIRS to ease the management of possible complications (2, 3). There is a belief that the use of a safety guide wire could help when prompt stent placement is needed in the event of a major ureteral perforation or bleeding precluding continuing URS (3, 10). Patel et al. showed that the flexible ureteroscope itself could be used as a safe guide wire and that working without SGW facilitates access, scope manipulation and stone basketing. There is less friction passing the ureteroscope alongside a guide wire (11). In their retrospective study, Johnson et al. treated renal stones with wireless and sheathless flexible URS. There were no false passages or ureteral perforations secondary to ureteroscope placement (12). Eandi et al. also reported no intraoperative complications related to lack of a safety wire in semirigid and flexible URS for the treatment of urolithiasis (13). Using the UAS makes it easier to enter and exit the ureter, renal pelvis and calyces during the operation and even more so when handling large stones. Moran and Bratslavsky studied a single urologist’s experience with flexible ureteroscopic laser lithotripsy without the use of an SGW, and the stone-free rate was 96% (326/340) for those who did not use an SGW compared to a contemporary, large single-centre experience with eleven treating urologists (Table 5). There were no complications in the group without a safety wire secondary to loss of upper tract access (14). Table 5. Current study/other series.

Patel et al. (11) Eandi et al. (13)

SGW

No.

No No

268 322

Mean renal stone diameter (mm) 12 N/A

Mean ureteral stone diameter (mm) ** N/A

SFR (%) N/A N/A

N/A 8.8 7.9 ** 8.1

96 85.9 77.1 88.9 90

Moran & Bratslavsky (14) Ulvik et al. [15]

No 340 N/A No 500 N/A Yes 480 N/A Dickstein et al. (16) No 270 9.1 Current study No 464 8.8 SGW: safety guide wire; SFR: stone-free rate; UAS: ureteral access sheath.

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Ulvik et al. compared the results of URS for the treatment of ureteral stones at two different hospitals where the SGW was either routinely used or omitted. Both groups had 500 patients each. Pre-treatment stone status differed in many aspects between groups. There was no significant difference in the overall intraoperative complication rates at the two hospitals. The overall stone-free rates were 77.1% and 85.9% with and without the SGW, respectively (p = 0.001). A significant increase in the number of patients (14 patients, 3.4%) with post-endoscopic ureteral stenosis was found at the hospital where the SGW was routinely used compared to the hospital where an SGW was omitted (six patients, 1.2%), p = 0.039 (15). UAS was not routinely used in the different studies dealing with wireless f-URS, so it is hard to make a comparison between these series (11-13, 16-17). In the Moran and Bratslavsky comparative study, there was no information about the UAS (14). Molina et al., in their review, showed a lack of relevant data supporting the use of SGW during retrograde URS (18). Eandi et al. concluded that the presence of a safety guide wire adjacent to the endoscope inhibits passage of the ureteroscope in an in vitro animal model. Technologic advancements in ureteroscope design and use of the holmium laser lithotrite minimize ureteral trauma and obviate the need for routine use of a safety wire during ureteroscopy (13). Dutta et al., in their article titled "Death of the Safety Guide Wire", concluded that a safety guide wire served an important function in providing safer percutaneous and ureteroscopic procedures during the initial endourological history score. However, the decrease in the size of today’s ureteroscopes coupled with the advent of effective ureteral access sheaths and the evolution of endoscopic percutaneous renal access has largely eliminated the need for safety guide wires in both ureteroscopic and percutaneous procedures. They argued that what was once a “help” had become an inhibitor and a nuisance, as recent studies have shown that the safety guide wire increases the resistance to passage of the ureteroscope (19). To our knowledge, there are no articles dealing with the use of UAS without guide wires present in upper urinary tract stones. Table 5 summarizes some of the results of this study compared to other studies and shows that this study had the greatest number of cases with UAS and without SGW simultaneously, with success similar to other studies and no major complications. The uniqueness of the current study is that similar components were used in all the patients. In all patients we used UAS UAS Ureteral Ureteral (n) perforation avulsion without SGW, a holmium 40 0 0 LASER, fibres (200 µ, 230 µ 0 0 0 and 272 µ) with the same ureteroscope (Karl-Stortz N/A 0 0 flex-x2s), access sheaths 1 6 1 158 11 1 (12/14 28, 35, or 45 cm) from the same company, and 0 0 0 the same surgeon. 464 0 0 We showed that f-URS was successful in 90% of cases in

RIRS without safety guide wire

a single session and 100% in the second session. The mean number of procedures per renal unit was 1.1. According to the Clavien-Dindo classification, no major complications were observed. We achieved good results, although there were more lower pole stones (239/464).

rograde intrarenal surgery in the treatment of urolithiasis. Eur Urol Focus. 2017; 3:46-55.

CONCLUSIONS

10. Kumar PV, Keeley FX, Timoney AG. Safe flexible ureterorenoscopy with a dual lumen access catheter and a safety guide wire. BJU Int. 2001; 88:638-9.

f-URS is a safe and effective mode of surgical management of renal and simultaneous renal and ureteral calculi using the ureteral access sheath without a safety guide wire. A guide wire should not be routinely used in these cases.

ACKNOWLEDGEMENTS

Thanks to AJE for their editing services.

REFERENCES

1. Sorokin I, Mamoulakis C, Miyazawa K, et al. Epidemiology of stone disease across the world. World J Urol. 2017; 35:1301-1320. 2. Sprunger JK, Herrell SD 3rd. Techniques of ureteroscopy. Urol Clin North Am. 2004; 31:61-9. 3. Bagley DH, Kuo RL, Zeltser IS. An update on ureteroscopic instrumentation for the treatment of urolithiasis. Curr Opin Urol. 2004; 14:99-106. 4. de la Rosette J, Denstedt J, Geavlete P, et al. CROES URS Study Group. The clinical research office of the endourological society ureteroscopy global study: indications, complications, and outcomes in 11,885 patients. .J Endourol. 2014; 28:131-9. 5. Kılıç Ö, Akand M, Van Cleynenbreugel B. Retrograde intrarenal surgery for renal stones - Part 2. Turk J Urol. 2017; 43:252-260. 6. 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. 7. Sanguedolce F, Bozzini G, Chew B, et al. The evolving role of ret-

8. Breda A, Angerri O. Retrograde intrarenal surgery for kidney stones larger than 2.5 cm. Curr Opin Urol. 2014; 24:179-83. 9. Ho A, Sarmah P, Bres-Niewada E. Ureteroscopy for stone disease: expanding roles in the modern era. Cent European J Urol. 2017; 70:175-178.

11. Patel SR, McLaren ID, Nakada SY. The ureteroscope as a safety wire for ureteronephroscopy. J Endourol. 2012; 26:351-4. 12. Johnson GB, Portela D, Grasso M. Advanced ureteroscopy: wireless and sheathless. J Endourol. 2006; 20:552-5. 13. Eandi JA, Hu B, Low RK. Evaluation of the impact and need for use of a safety guide wire during ureteroscopy. J Endourol. 2008; 22:1653-8. 14. Moran ME, Bratslavsky G. Changing paradigm during routine flexible ureteroscopy and Holmium: YAG laser lithotripsy: need for safety wires? J Endourol. 2003; 17:A225. 15. Ulvik Ø, Rennesund K, Gjengstø P, et al. Ureteroscopy with and without safety guide wire: should the safety wire still be mandatory? J Endourol. 2013; 27:1197-202. 16. Dickstein RJ, Kreshover JE, Babayan RK, Wang DS. Is a safety wire necessary during routine flexible ureteroscopy? J Endourol. 2010; 24:1589-92. 17. Ulvik Ø, Wentzel-Larsen T, Ulvik NM. A safety guide wire influences the pushing and pulling forces needed to move the ureteroscope in the ureter: a clinical randomized, crossover study. J Endourol. 2013; 27:850-5. 18. Molina WR Junior, Pessoa RR, Silva RDD, et al. Is a safety guide wire needed for retrograde ureteroscopy? Rev Assoc Med Bras (1992). 2017; 63:717-721. 19. Dutta R, Vyas A, Landman J, Clayman RV. Death of the safety guide wire. J Endourol. 2016; 30:941-4.

Correspondence Murad Asali, MD (Correspnding Author) dr.muradasali@gmail.com Department of Urology, Barzilai Medical Center Ben Gurion University, Beer Sheva, Sokolov 26/99, 8430905

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DOI: 10.4081/aiua.2022.2.190

ORIGINAL PAPER

Retrograde Intrarenal Surgery (RIRS) for upper urinary tract stones in children below 12 years of age: A single centre experience Mohanarangam Thangavelu 1, Ajit Sawant 2, Ali Abbas Sayed 2, Praksah Pawar 2, Mohamed Hamid 2, Sunil Patil 2, Vikas Bhise 2, Jeni Mathews 2, Raunak Shewale 2, Mohan Gadodia 2 1 Department 2 Department

of Urology, Ysbyty Gwynedd, Bangor LL57 2PW, United Kingdom; of Urology, LTMC & General Hospital, Sion, Mumbai - 400022, India.

Summary

Objective: Retrograde Intra Renal Surgery (RIRS) is a minimally invasive surgical modality for the treatment of renal stones. We evaluated the efficacy of RIRS in children below aged 12 years of age in the form of stone-free rate (SFR), complications and the feasibility of the procedure. Materials & methods: This retrospective study included all children ≤ 12 years of age, with upper urinary tract stones single or multiple ≤ 15 mm in size who underwent RIRS between February 2019 to November 2021. RIRS was performed with 7.5 Fr flexible ureterorenoscope over the guidewire, the stones were dusted with Laser and the ureteral stent was left after RIRS. All patients had the post-procedure stent removed within 3 weeks after checking for residual stones with X-ray and ultrasonography of Kidney-Ureter-Bladder (USG-KUB). Follow-up USG KUB was done at 4 months. Results: 15 patients included in our study met the inclusion criteria. The mean age was 8.7 ± 2.8 years, the mean stone size was 11.26 ± 2.14 mm and 26.6 % had multiple stones. Retrograde access failure was noted in 36.3 % in non stented patients. The mean operative time was 72.6 ± 20 minutes, fluoroscopy time was 4.4 ± 0.9 minutes and the mean LASER time was 26 ± 3.9 minutes. The mean hospital stay was 2.8 ± 0.9 days. Ureteral access sheath (UAS) was used in one patient. Conversion to mini PCNL was done in one pre stented patient due to access failure and one patient had a second look RIRS for residual stone. No major complications were noted except onr patient who had sepsis. The stone-free rates were 93.3% after primary RIRS and 100% after second look RIRS. Conclusions: RIRS is a feasible, safe procedure for pediatric upper urinary stones with excellent stone-free rates and a low rate of complications.

KEY WORDS: RIRS; Laser lithotripsy; Flexible ureterorenoscopy; Pediatric upper urinary stones. Submitted 9 May 2022; Accepted 20 may 2022

INTRODUCTION

There is a global increase in the prevalence of urolithiasis in children attributed to lifestyle changes, dietary habits, climate changes, childhood obesity and the wider availability of ultrasonography (1). Underlying causes such as

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metabolic disorders, anatomical anomalies and infection should be investigated in pediatric stone disease and failure to evaluate these causes will lead to higher stone recurrence after treatment (2). The European guidelines on the management of pediatric stones recommend Extracorporeal Shockwave Lithotripsy (ESWL) or Percutaneous Nephrolithotomy (PCNL) for the treatment of renal and upper ureteric calculi in the pediatric age group based on stone location, volume and density but with increasing evidence on the outcome of Flexible ureterorenoscopy (FURS), it has been added to the armamentarium to treat upper urinary tract stones in children (3). With the miniaturization of endourological instruments, retrograde intrarenal surgery (RIRS) has advantages over ESWL and PCNL due to its high stonefree rate (SFR) which is usually achieved in a single sitting with acceptable efficacy and low morbidity in pediatric patients. There are very few studies done to evaluate the efficacy of this method in pediatric patients. Hence in our study, we evaluated the efficacy of RIRS among children up to 12 years of age. The primary objective of our study is to evaluate the SFR with RIRS for upper urinary tract stones in pediatric patients. The secondary objectives were the evaluation of post-procedure complications, radiation time, pain score, and duration of hospital stay.

MATERIALS

AND METHODS

This is an observational retrospective study done at a tertiary care centre. The study was conducted from February 2019 to November 2021 and the data was collected from the hospital records. All pediatric patients aged 12 years and below with renal and upper ureteric stones of size less than 1.5 cm treated with RIRS were included. Children with genetic disorders, medical renal disease and previous stone treatment on the same side were excluded. Fifteen children met the inclusion criteria and demographic data and laboratory investigations were collected from hospital records. All patients had Xray of KidneyUreter-Bladder (Xray-KUB) and Ultrasongraphy of KidneyUreter-Bladder (USG-KUB) and those with normal serum No conflict of interest declared.

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creatine underwent Computed Tomography (CT) urography. Those patients who already had non-contrast CT KUB underwent DTPA Renogram to assess the renal functional status. All procedures were performed under general anaesthesia after confirming a sterile urine culture. Patients have been given prophylactic antibiotic ceftriaxone 100 mg/kg IV at the time of induction of anaesthesia. Patients were positioned in lithotomy position and cystourethroscopy was performed using a 6.5 Fr Storz semirigid ureteroscope and a 0.032-inch guidewire was inserted into the ureter. Balloon dilatation of the ureteric orifice was done over the guidewire followed by semirigid ureteroscopy to assess the distensibility of the ureter. After this, under fluoroscopic and visual supervision, a 7.5 Fr FURS (Storz FLEX X2) was placed into the ureter over the guidewire without the use of an access sheath. If the FURS could not be negotiated, the ureteral stent was inserted for passive dilatation and RIRS was performed later in 2 weeks. The complete pelvicalyceal system was examined with the FURS. Stone dusting was done using 272 microns Holmium laser fibre with a power of 0.2-0.6 J and 10-20 Hz frequency. This ensured that the stone was dusted and not fragmented. Visual inspection of the pelvicalyceal system and fluoroscopy was done to look for any residual stone fragments after surgery and the ureter was evaluated while removal of FURS to detect any potential ureteral trauma. A 5 Fr ureteral stent was routinely placed at the end of the RIRS and was left in place between 1 to 3 weeks. Per urethral Foleys catheter was removed on the first post-operative day. We used the Visual Analog Scale for postoperative pain assessment. The children went home with prophylactic antibiotics for 5 days and oxybutynin till the stent removal. Xray and USG KUB were done before the stent removal between 1 to 3 weeks after RIRS to assess any residual calculi. The presence of any calculi ≥ 3 mm was considered treatment failure in calculating SFR. After confirming the absence of residual calculi, the ureteral stent was removed under general anesthesia. Follow-up USG KUB was performed at 4 months to assess the stone recurrence. The statistical investigation was performed using Microsoft Excel. The collected data was evaluated and presented as a range, mean, standard deviation, and percentages.

RESULTS

In our study, 15 children with upper urinary tract stones met the inclusion criteria. Four patients had multiple stones in the kidney. Demographics shown in Table 1. Out of 15 patients, four patients had elective ureteral stenting before the RIRS procedure and 11 patients were not pre-stented. Retrograde access failed in 36.3% of nonstented patients requiring a second attempt after a 2 week stenting period. Conversion to mini PCNL was necessary in one of the patients who had elective pre-stenting due to access failure. Ureteral access sheath (UAS) (9/11 Fr 25 cm) was used only in one patient due to higher stone volume and capa-

cious ureter. All patients were discharged on the second postoperative day, except one patient who had a postoperative fever – grade 2 on the Clavien Dindo scale – and required high dose antibiotics with a longer hospital stay of 6 days. One patient with 14 mm lower pole calculi was found to have residual calculi of 7 mm in the lower pole three weeks after RIRS due to migration of the fragment which was not identified during the initial procedure. Redo RIRS was done for this patient with complete clearance. The average fluoroscopy time was 4.4 ± 0.9 minutes. The stone-free rate was 93.3% after primary RIRS and 100% after a second look RIRS. The operative and post-operative are shown in Table 2.

Table 1. Demographic details. Variables Age-years 0-4 years 5-8 years 9-12 years Sex Male Female Side Right Left Stone location Upper ureter Renal pelvis Upper calyx Mid Calyx Lower Calyx Multiple stones Stone size - mm Hounsfield units (HU)

Number of patients (%)

Mean

Range

2 4 9

8.73 ± 2.81 years

3-12 years

11.26 ± 2.15 mm 1132 ± 234.37 HU

7 to 14 mm 720-1432 HU

7 8 9 6 2 (13.3 %) 6 (40 %) 3 (20 %) 2 (13.3 %) 2 (13.3 %) 4 (26.6 %)

Table 2. Operative and post operative details. Variables Elective ureteral stent Ureteral access sheath used Access failure during first RIRS in non stented patients Total number of access failure (with & without ureteral stent) Operative time (minutes) Laser time (minutes) Radiation time (minutes) Hospital stay (days) Conversion to mini PCNL Residual stone Redo RIRS for residual stone Post-operative complications Clavien Didno – grade 2 Pain score (Visual analog scale) Stone free rate After primary RIRS Final

Number of patients (%) 4 /15 (26.6%) 1 (6.6%)

Mean

Range

72.6 ± 20 26.07 ± 3.9 4.4 ± 0.9 2.8 ± 0.9

50 to 120 15 to 30 3 to 6 2 to 6

1.2 ± 0.9

0 to 2

4 /11 (36.3%) 1 / 15 (6.6%)

1 (6.6%) 1 (6.6%) 1 (6.6%) 1 (6.6%) 93.3% 100%

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DISCUSSION

Management of urolithiasis in children poses a challenge because of smaller size kidneys with a small collecting system, and a small-caliber ureter. Ferretti et al. (4) in their study noted that an high proportion of children with stones was associated with comorbidities like urologic malformations (42.8%), urinary infections (25%), metabolic disorders (17.8%) and non-urologic diseases (25%). This study demonstrates the need for thorough investigations in pediatric stone patients to reduce the chances of recurrent stone formation and to reduce the complications of the surgical treatment. ESWL has been one of the standard treatment methods for renal stones up to 2 cm however it has its own disadvantages. The stone-free rates depend upon the stone volume, density, location, caliceal anatomy, and renal function. The overall stone-free rates of 79.9%, clinically insignificant residual fragments in 13.2% at 3 months, retreatment rate of 53.9%, and complication rate of 9.69% were observed in a large retrospective study by Muslumangolu et al. (5) The need for general anesthesia, multiple sessions, pre ESWL stenting for larger stones, post-procedure steinstrasse, technical difficulties in stone localization and unknown long term effects on renal parenchyma are the drawbacks of ESWL. PCNL is a more invasive method reserved for larger and complex renal stones. Unsal et al. (6) in their study of PCNL in children below 18 years divided into 3 groups based on their age and reported overall average stone-free rates of 82.3% after the primary procedure and 93.1% after the adjunctive procedure. They noted more bleeding and a drop in hemoglobin in children between 8 to 16 years which also depended upon the size of the instruments. The most frequently reported complication is bleeding requiring blood transfusion in less than 10% and others are postoperative infection, pain, and fever. The average hospital stay was between 3 to 4 days for PCNL. With the miniaturization of FURS and the availability of efficient energy sources, RIRS for upper urinary tract stones has become a safe option. A systematic review of studies between 1990 to 2014 by Ishii et al. (7) on the safety and efficacy of flexible ureterorenoscopy and lasertripsy (FURSL) in children with a mean age of 7.3 years reported mean stone-free rates of 85.5% and complication rate of 12.4% for the size of the stone varied from 1 to 30 mm. Kim et al. (8) reported in their study of 170 FURS procedures in children with a mean age of 5.2 years, stone-free rates of 100% for stones burden < 10 mm and 97% for stones > 10 mm after a single RIRS procedure. A study by Unsal et al. (9) reported a series of RIRS in 16 children below 7 years of age with a stone-free rate of 100% for stones below 10 mm and 81.8% for stones > 10 mm in size with one complication of ureteral perforation occurring after balloon dilatation of ureteric orifice. Ferretti S et al. (4) reported in their study of 28 children with a mean age of 8 years with urinary tract stones achieved stone free rate of 76.6% after first procedure and 93.3% after redo surgery with no major complications. In their study the stone size ranged from 5 to 24 mm with a mean stone area of 1.15 cm2 and they used rigid URS, RIRS and combination of both procedures to treat the

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stone. In our study the stone-free rate observed was 93.3%, with no major complications for the mean stone size of 11.2 ± 2.15 mm after a single RIRS procedure. As RIRS procedure is done through a natural orifice (urethra) without any need for a puncture in the kidney which causes minimal post-procedure pain, low requirement of analgesics, faster recovery, and shorter hospital stay. Complications like bleeding, clot retention, and need for blood transfusion are rare with this procedure (9) We used balloon dilatation of the ureteric orifice in all cases but Kim et al. (8) did not use active ureteric dilatation with good stone-free rates and other studies mention hydrodistension is equally effective (3). We did not routinely perform pre-procedure ureteral stenting and our retrograde access failure rate was 36.3% for primary RIRS in non stented patients. Chandramohan et al. (10) in their study of RIRS of 67 preschool children aged < 5 years for pediatric renal stones reported routine pre-procedure stenting in all their patients and reported only a 5.98 % retrograde access failure rate. Corcoran et al. (11) mention that routine placement of a pre-procedure ureteral stent for passive ureteral dilatation is not required for successful ureteroscopic access to the renal pelvis in prepubertal age group children. If the initial attempt of ureteroscopy is unsuccessful then placement of a ureteral stent decreases the number of procedures while maintaining a low complication rate. In our experience, we did not routinely use UAS except in one patient due to larger stone volume and a capacious ureter. We did not use the basket for stone retrieval as the stone was dusted with laser energy and it was not necessary for the repeated passage of FURS to retrieve the stone fragments which increases the chance of ureteral trauma. In a study (10) of RIRS for renal stones in preschool children only in 63.5 % of the cases, UAS could be safely used even though all of the patients had undergone preRIRS stenting and in the study are reported 2 ureteral injuries of grade 1 and grade 2 according to the Traxer and Thomas classification (12) which were managed by post-procedure stenting for 4 weeks with no long term complications like ureteral stricture. They have also noted lower success rate of placing UAS in children less than 4 years old in spite of pre-RIRS ureteral stent insertion for passive ureteral dilatation. Anbarasan et al. (13) reported the results of RIRS using 9.5 Fr UAS in 21 pediatric patients with a mean age of 11.8 years with a mean follow-up of 26 months with no long-term complications. In their study, only 8 patients had pre-procedure stenting. Berrettini et al. (14) performed RIRS for stones in 13 preschool children with body weight < 20 kg, and all of them had pre-procedure stenting. They concluded that the use of UAS is safe and effective with no long term complications. Mosquera et al. (15) reported from the data collected from 48 patients with a mean age of 10.7 years mention that use of UAS was safe with excellent outcomes, especially for large and multiple stones. They noticed grade 1 ureteric injury in one patient and suggest to use the smallest size UAS. All our patients had post-procedure stenting and most of the studies advocate post-procedure stenting or ureteral catheter drainage with variable duration. Chen Y et al. (16) did a systematic review on the safety and

RIRS for upper urinary tract stones in children

efficacy of PCNL versus RIRS for pediatric upper urinary stones and noted significantly shorter hospital stay and fluoroscopy time for RIRS than PCNL. The overall minor and major complication rates were higher in PCNL but not statistically significant. RIRS benefits from the significantly lesser requirement of blood transfusion. They also found no significant differences in the stone-free rates and operative times. Bas O et al. (17) reported that for stones between 10-20 mm, RIRS has similar success and complication rates with shorter hospital stay and low radiation exposure when compared to micro-PCNL. For stones larger than 2 cm, Saad KS et al. (18) reported that RIRS monotherapy has lower stone-free rates than mini-PCNL but with the advantages of decreased radiation exposure, fewer complications, and shorter hospital stay. Mokhless et al. (19) in their prospective study compared ESWL versus RIRS for 10 to 20 mm stones and found that stone free rate after a single session was 70% and 86.6% and overall stone-free rate at 3 months was 93.3% and 96% with no major complications in both the groups. Ergin et al. (20) did a retrospective study that reported similar stonefree rates for ESWL and RIRS for pediatric renal stones between 10 to 20 mm with no complications seen in either modality. ESWL had longer fluoroscopy time and shorter hospital stay but RIRS had a higher cost per patient. The mean fluoroscopy time in our study was 4.4 ± 0.9 minutes and the lower radiation is beneficial for pediatric patients when additional procedures are required for stone clearance. He Qing et al. (21) in their systematic review of three modalities of treatment – ESWL, PCNL and RIRS – for pediatric upper urinary tract stones concluded that ESWL provides shorter hospital stay and operative time, lower SFR, higher auxiliary procedure rate with relatively lower effectiveness quotient (EQ). PCNL is associated with higher SFR than ESWL, but has longer fluoroscopy time, operative time, and highest EQ when compared to RIRS and ESWL. RIRS offers higher SFR after a single session, a lower retreatment rate than ESWL, a shorter hospital stay than PCNL, and lower EQ. Complication rates were comparable among the three modalities however higher complication rates were found in subgroups of PCNL. There was no major post-operative complication in our study, only one patient had sepsis requiring high dose antibiotics and a longer hospital stay. Mosquera et al. (22) reviewed the data of 57 children who underwent FURSL for lower pole stones from two large European tertiary endourology centers and reported initial and final stonefree rates of 82.4% and 98.2% respectively; 1.19 procedures per patient were required to be stone free. Despite the advantages of RIRS, there are certain drawbacks associated with this procedure. Pre-procedure ureteral stent under general anesthesia for passive ureteral dilatation may be required especially in children below 5 years of age. It has lower stone-free rates for stones sizes more than 2 cm and may require additional procedures. There are chances of ureteral injury during placement of UAS and sometimes the UAS could not be safely used in spite of pre-procedure stenting. Most of the patients require ureteral stent insertion after RIRS which requires another procedure under general anesthesia for stent removal. These additional procedures could influence the

EQ of RIRS. With increasing expertise, RIRS has become a good option over ESWL for upper urinary stones of 10 to 20 mm size in children as it has higher stone-free rates which are usually achieved in a single sitting, and also over PCNL as it has lower morbidity and low post-operative complications with faster recovery. Our study suggests that RIRS is a feasible and safe alternative to PCNL for pediatric patients with upper urinary stones in selected cases with lower complication rates and a faster recovery period.

CONCLUSIONS Pediatric RIRS requires expertise and to be carried out in tertiary centers. Routine pre-procedure ureteral stenting and use of ureteral access sheath are not required; however, a randomized prospective study with multivariate analysis would be helpful. RIRS is a safe endourological procedure with high stone-free rates, low complication rate for the treatment of pediatric upper urinary tract stones less than 2 cm in size.

REFERENCES

1. Clayton DB, Pope JC. The increasing pediatric stone disease problem. Ther Adv Urol 2011; 3:3-12. 2. Copelovitch L. Urolithiasis in children: medical approach. Pediatr Clin North Am 2012; 59:881-96. 3. EAU-Guidelines-on-Paediatric-Urology-2022.pdf. https://d56bo chluxqnz.cloudfront.net/documents/full-guideline/EAU-Guidelineson-Paediatric-Urology-2022.pdf 4. Ferretti S, Cuschera M, Campobasso D, et al. Rigid and flexible ureteroscopy (URS/RIRS) management of paediatric urolithiasis in a not endemic country. Arch Ital Urol Androl. 2021; 93:26-30. 5. Muslumanoglu AY, Tefekli A, Sarilar O, et al. Extracorporeal shock wave lithotripsy as first line treatment alternative for urinary tract stones in children: a large scale retrospective analysis. J Urol. 2003; 170:2405-8. 6. Unsal A, Resorlu B, Kara C, et al. Safety and efficacy of percutaneous nephrolithotomy in infants, preschool age, and older children with different sizes of instruments. Urology. 2010; 76:247-52. 7. Ishii H, Griffin S, Somani BK. Flexible ureteroscopy and lasertripsy (FURSL) for paediatric renal calculi: results from a systematic review. J Pediatr Urol. 2014; 10:1020-5. 8. Kim SS, Kolon TF, Canter D, et al. Pediatric flexible ureteroscopic lithotripsy: the children's hospital of Philadelphia experience. J Urol. 2008; 180:2616-9. 9. Unsal A, Resorlu B. Retrograde intrarenal surgery in infants and preschool-age children. J Pediatr Surg. 2011; 46:2195-9. 10. Chandramohan V, Siddalingaswamy PM, Ramakrishna P, et al. Retrograde intrarenal surgery for renal stones in children < 5 years of age. Indian J Urol 2021; 37:48-53. 11. Corcoran AT, Smaldone MC, Mally D, et al. When is prior ureteral stent placement necessary to access the upper urinary tract in prepubertal children? J Urol. 2008; 180(4 Suppl):1861-3. 12. Traxer O, Thomas A. Prospective evaluation and classification of ureteral wall injuries resulting from insertion of a ureteral access sheath during retrograde intrarenal surgery. J Urol. 2013; 189:580-4. Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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13. Anbarasan R, Griffin SJ, Somani BK. Outcomes and long-term follow-up with the use of ureteral access sheath for pediatric ureteroscopy and stone treatment: results from a tertiary endourology center. J Endourol. 2019; 33:79-83.

18. Saad KS, Youssif ME, Al Islam Nafis Hamdy S, et al. Percutaneous nephrolithotomy vs retrograde intrarenal surgery for large renal stones in pediatric patients: a randomized controlled trial. J Urol. 2015; 194:1716-20.

14. Berrettini A, Boeri L, Montanari E, et al. Retrograde intrarenal surgery using ureteral access sheaths is a safe and effective treatment for renal stones in children weighing < 20 kg. J Pediatr Urol. 2018; 14:59.e1-59.e6.

19. Mokhless IA, Abdeldaeim HM, Saad A, Zahran AR. Retrograde intrarenal surgery monotherapy versus shock wave lithotripsy for stones 10 to 20 mm in preschool children: a prospective, randomized study. J Urol. 2014; 191(5 Suppl):1496-9.

15. Mosquera L, Pietropaolo A, Brewin A, et al. Safety and Outcomes of using ureteric access sheath (UAS) for treatment of Pediatric renal stones: Outcomes from 2 tertiary endourology centers. Urology. 2021; 157:222-226.

20. Ergin G, Kirac M, Kopru B, et al. Shock wave lithotripsy or retrograde intrarenal surgery: which one is more effective for 10-20-mm renal stones in children. Ir J Med Sci. 2018; 187:1121-1126.

16. Chen Y, Deng T, Duan X, et al. Percutaneous nephrolithotomy versus retrograde intrarenal surgery for pediatric patients with upper urinary stones: a systematic review and meta-analysis. Urolithiasis. 2019; 47:189-199. 17. Baş O, Dede O, Aydogmus Y, et al. Comparison of retrograde intrarenal surgery and micro-percutaneous nephrolithotomy in moderately sized pediatric kidney stones. J Endourol. 2016; 30:765-70.

Correspondence Mohanarangam Thangavelu, MBBS, FEBU, FRCS (Urology) (Corresponding Author) drtmohan@hotmail.com Consultant Urology, Ysbyty Gwynedd, Bangor, LL57 2PW, United Kingdom Ajit Sawant, MBBS, MS, MCh (Urology) drajitsawant@gmail.com Ali Abbas Sayed, MBBS, MS, MCh (Urology) draliabbas09@gmail.com Prakash Pawar, MBBS, MS, MCh (Urology) praxpawar@gmail.com Mohamed Hamid, MBBS, MS, MCh (Urology) khanmohdhamid@gmail.com Sunil Patil, MBBS, MS, MCh (Urology) sunil7887@gmail.com Vikas Bhise, MBBS, MS, MCh (Urology) drvikasbhisegsmc@gmail.com Jeni Mathews, MBBS, MS, MCh (Urology) mathewjeni25@gmail.com Raunak Shewale, MBBS, MS, MCh (Urology) raunakshewale91@gmail.com Department of Urology, Room number 219, College Building, Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai 400022 (India)

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21. He Qing, Xiao K, Chen Y, et al. Which is the best treatment of pediatric upper urinary tract stones among extracorporeal shockwave lithotripsy, percutaneous nephrolithotomy and retrograde intrarenal surgery: a systematic review. BMC Urol. 2019; 19:98. 22. Mosquera L, Pietropaolo A, Madarriaga YQ, et al. Is flexible ureteroscopy and laser lithotripsy the new gold standard for pediatric lower pole stones? Outcomes from two large European tertiary pediatric endourology centers. J Endourol. 2021; 35:1479-1482.

DOI: 10.4081/aiua.2022.2.195

ORIGINAL PAPER

Spinal versus general anesthesia in retrograde intrarenal surgery Mehmet Yoldas 1, Tuba Kuvvet Yoldas 2 1 Tepecik 2 Ege

Training and Research Hospital Urology Clinic, Izmir, Turkey; University Faculty of Medicine Anesthesiology and Reanimation Department, Izmir, Turkey.

Summary

Aim: The indications for retrograde intrarenal surgery (RIRS) have greatly increased, however, there is still no consensus on the use of spinal anesthesia (SA) during this procedure. The aim of this study was to evaluate the comparability of surgical outcomes of RIRS performed under SA versus general GA for renal stones. Materials and methods: This was a retrospective, observational study in patients scheduled for RIRS in a single teaching hospital in Turkey. Inclusion criteria were age > 18 years and the presence of single or multiple renal stones. We recorded information concerning the site of lithiasis, the number of calculi, total stone burden, and the presence of concomitant ureteral stones or hydronephrosis. Results were evaluated in terms of surgical outcome, intraoperative and postoperative complications. Patients were followed-up until day 90 from discharge. Results: The data of 502 patients, 252 in GA group and 250 in SA group, were evaluated. The stone-free rate was 81% in the GA group and 85% in the SA group (p = 0.12). No cases of conversion from SA to GA were recorded. Complication rates were similar in the 2 groups (19% vs 14.5%, p = 0.15). Conclusions: In our cohort, RIRS performed under SA and GA was equivalent in terms of surgical results and complications.

KEY WORDS: Spinal Anesthesia; Retrograde intra-renal surgery; Urolithiasis. Submitted 21 April 2022; Accepted 20 May 2022

INTRODUCTION

With the evolution of instruments and techniques, retrograde intrarenal surgery (RIRS) gained an established role as a minimally invasive procedure with fast recovery, short hospitalization, and low rates of complications (1-3). However, high-grade complications are still possible (4-5), and linked to the use of general anesthesia (GA). In this scenario, the use of spinal anesthesia (SA) could move toward the reduction of invasiveness, costs, and hospitalization (6-7). Endoscopic procedure of renal stones has increased in the last decade in accordance with minimally invasive principles. Ureteral stone treatment has been described and widely accepted under SA (8-9), however, GA is usually offered during RIRS because it has some advantages: in case of a large stone burden the lithotripsy is easier with reduced renal movement caused by respiration, the comfort for the patient is expected to be better, and there is no risk for the anesthesia duration to be exceeded.

SA also has advantages: it avoids some GA related complications, allows an early mobilization, and is cost effective. Few studies compared different anesthesia modality during RIRS for renal stones and the only randomized controlled trial (9) compared RIRS performed under combined spinal-epidural anesthesia with GA (10). The aim of this study was to compare surgical results, intraoperative and postoperative complications, and analgesia demand of RIRS performed under SA versus GA.

MATERIALS

AND METHODS

The data of the patient who underwent RIRS due to kidney stones between January 2013 and January 2022 were reviewed retrospectively. Those with missing data, bilateral RIRS, additional procedure with RIRS (percutaneous nephrolithotomy, rigid ureterorenoscopy, etc.), urinary system anomaly (double collecting system, horseshoe kidney, pelvic kidney, urinary diversion, etc.), previous stone surgery, extracorporeal shock wave lithotripsy (ESWL) history, patients with nephrostomy or double J stent were excluded from the study. A total of 502 patients were evaluated after exclusion criteria. The ethics committee of the study was obtained from the local Tepecik training and research hospital local ethics committee. Informed consent was obtained from all patients. Stones and urinary systems of all patients were evaluated with computed tomography (CT) in the preoperative lowdose stone protocol, urinalysis and urine culture, and biochemistry including urea, creatinine, and hemogram. All patients underwent the procedure with a clean urine culture or under antibiotic. All patients received preoperative antibiotic prophylaxis. Stone protocol CT was performed for stone-free rate assessment at 4 week post operative in all patients, and patients with residual stone less than 4 mm were considered as stone-free. We divided the patients in 2 groups, according to the anesthesia regimen chosen by the anesthesiologist: SA and GA. Patients in both groups were compared in terms of demographic data such as age and gender, stone size, stone side, stone localization, number of stones, and stone density as Hounsfield Unit. The complications that developed within both groups were grouped according to the modified Clavien-Dindo classification and compared one by one.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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RIRS procedure Under spinal or general anesthesia, ureter and renal pelvis were evaluated under direct vision with a 7 F semi rigid ureteroscope. The distance between the ureteropelvic junction and the external meatus was marked on the rigid scope and a 0.038 inch guide wire was placed in the collecting system, 9.5 F ureteral access sheet was placed in the collecting system on the guide as long as the measured distance. After the guide was taken out, a 7-8 F flexible scope was entered. The stone was broken with a 272 or 360 micron laser probe. At the end of the procedure, the ureter was evaluated with a semi-rigid scope. When necessary, a double J stent stent was placed in the ureter. Anesthesia In all patients, a peripheral vein was cannulated and a single dose of antibiotic prophylaxis was administered and normothermia maintained with warm air devices. Perioperative heart rate, peripheral oxygen saturation, and blood pressure values were monitored until transfer to the urological ward, when the Aldrete score was ≥ 8. In the SA group, anesthesia was administered using a 25 gauge atraumatic Sprotte type needle with 10-20 mg hyperbaric 1% or 0.05% bupivacaine at L2-3 level to provide a sensitive block up to T8-10. We administered an intranasal oxygen supply only if SpO2 was below 92%. Additional sedation was based on 2 mg midazolam boluses or low-dose propofol infusion according to the Schneider model effect-site target-controlled infusion 1 mg/mL, plus additional low-dose remifentanil (Minto model effectsite target-controlled infusion 0.5-2 ng/mL) if analgesia was inadequate. Target controlled infusion was titrated based on the clinical response in the SA group. In the GA group, anesthesia was induced with propofol 2 mg/kg and fentanyl 1 mg/kg and maintained with either propofol Schneider model effect-site target-controlled infusion, sevoflurane or desflurane plus remifentanil with the Minto model effect-site target-controlled infusion according to the anesthesiologist’s choice. In all cases in the GA group, anesthesia depth was monitored with the entropy index, targeting values between 40 and 60. After induction, a laryngeal mask was placed avoiding the use of neuromuscular blockade when clinically feasible. We administered ranitidine plus ondansetron intraoperatively as prevention of postoperative nausea and vomiting. An opioid-free postoperative analgesia regimen was preferred, based on acetaminophen 1000 mg plus ketorolac 30 mg. Rescue doses were administered if the pain numeric rating scale was above 4. Statistical analysis Continuous variables are reported as a mean ± SD and compared with the Student’s t-test. Categorical variables are presented as the absolute frequency (percentage) and compared with the chisquare or Fisher’s test, as appropriate. All the statistical analyses were performed using SPSS v.23 (IBM Corp., Armonk, NY), and significance considered for two-tailed p < 0.05.

RESULTS

The data of 502 patients, 252 in GA group and 250 in SA group, were evaluated retrospectively.

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The mean age of GA group was 47.31(16-83) years and the mean age of SA group was 46.16 (20-75) years; GA group included 156 (62%) men and 96 (38%) women, SA group 176 (71%) males and 74 (29%) females. The mean stone size was 13.57(+-2,6) mm2 in GA group and 12.43(+-2,8) mm2 in SA group. There was no statistically significant difference between the two groups for stone size (p = 0.21). In GA group, 124 patients had a stone in the right side and 128 in the left side, in SA group 128 patients had a stone in the right side and 122 patients in the left side (p = 0.25). In GA group the stone was in the lower calyx, which was the most difficult to reach, in 71 (28.4%) patients, whereas in SA it was in the lower calyx in 71 (28.7%) patients (p = 0.13). The demographic and stone data of the patients are shown in Table 1 and intraoperative and post-operative data of the patients in Table 2. The operation time of the patients in GA group was 57.65 (+-11.56) min, in SA group 54.3 (+-12.1) min. The duration of scopy in the GA group was 24.29 (+-2.3) sec, in the SA group. 26.32 (+-3.2) sec. Operation time and duration of scopy was equal between the two groups (p = 0.29 and p = 0.35, respectively). Mean hospital stay was 1.06 (+-0.25) days in GA group, and 1.37 (+-0.22) days in SA group. Although in SA group hospital stay was longer, there was no statistically significant difference between groups (p = 0.12). Complications developed in 48 (19%) patients in the GA group and in 36 (14.5%) patients in SA group. No difference was observed for grade 1 (p = 0.18) and grade 2 (p = 0.11) complication rate between the two groups. None of our patients needed blood transfusion. Due to stenosis in the distal ureter in 3 of our patients in GA group, access to the renal pelvis was achieved by using baloon dilatation. High post-operative fever was detected in 20 patients of GA group: two of them received parenteral antibiotic in hospital, 2 of them were treated with oral antibiotic as outpatients, 16 patients were treated with antipiretic as outpatients; 16 patients in SA group developed fever and were treated with antipiretic as outpatients; 5 were treated with oral antibiotic as outpatients. Table 1. The demographic and stone data of the patients. Age Stono size cm2 Gender Laterality

F M Right Left

GA group (252) 47.31+-3.5 13.57(+-2.6) 96(38%) 156 (62%) 124 128

SA group (250) 46.16+-3.8 12.43(+-2.8) 74 (29%) 176 (71%) 128 122

Lower calix Middle calix Upper calix Pelvis More than one calix

71 (28.4%) 11 (4.4%) 9 (3.7%) 118 (46.4%) 43 (16.9%)

71 (28.3%) 21 (8.3%) 5 (2%) 117 (46.2%) 36 (14.5%)

Localization

P-value 0.39 0.25 0.22 0.52 0.19 0.16 0.08 0.08 0.15 0.15

Spinal versus general anesthesia in retrograde intrarenal surgery

Table 2. Intraoperative and post-operative data of the patients. Operation time (min) Scopy time (sc) Postoperative hospitalization (days) Complications Degree 1 Use of antiemetics, antipyretics, analgesics etc. Degree 1 Headache (cerebrospinal fluid leak after spinal anesthesia) Degree 2 Fever requiring antibiotics Degree 3a Hematoma, urinoma Degree 3a Low grade ureteral injury Degree 3a Nephrostomy insertion Degree 3a Installing post op djs Degree 3b Urs again (due to ureteral stone) Degree 3b Foreign body in the ureter (djs guide wire basket ureteral sheed etc.) Degree 4 Intensive care follow-up due to sepsis Degree 5 Ex Stone free rate (SFR)

GA group 57.65 (+/-11.56) 24.29 (+/-2.3) 1.06 (+-0.25) 48 (19%)

SA group 54.3 (+/-12.1) 26.32 (+/-3.2) 1.37 (+/- 0.22) 36 (14.5%)

P-value 0.29

16 (6.2%)

11 (4.4%)

0.18

4 (1.7%) 1 (0.4%) 4 (1.7%) 3 (1.3%) 2 (0.1%) 8 (1.7%)

4 (1.6%) 5 (2%) 1 (0.4%) 5 (2%) 5 (2%) 0 0

0.11 0.25 0.09 0.08 1.00 1.00

3 (1.3%) 6 (1.2%) 1 (0.2%) 202 (81%)

0 5 (2%) 0 214 (85%)

1.00 0.19 1.00 0.12

0.35 0.12 0.15

Subcapsular hematoma and then urinoma developed in GA group in 2 patients who were treated with double J stent and percutaneous drainage. Low-grade ureteral injury occurred in 8 patients in GA group and 1 patient in SA group, and they were followed up with double J stent. No avulsion occurred in any of our patients. Nephrostomy or double J stents were placed in 8 patients in GA group and 1 patient in SA group due to renal colic and hydronephrosis. Stents were removed 2 weeks later due to regression of hydronephrosis and colic. Re-URS was performed in 8 of our patients in GA group because of the steinstrasse; this complication was not observed in any of our patients in SA group. In GA group, the laser probe tip or the hydrophilic tip of the Sensor guide remained in the renal pelvis in 3 patients as a result of a fracture of the device. Six patients in GA group and one patient in SA group were followed up in the post-operative intensive care unit. In GA group, one patient died due to post-operative multi-organ failure and sepsis.

DISCUSSION

The first treatment choice for intrarenal stones < 2 cm in size and hard stones is RIRS (11). In this study, we report similar SFR, intraoperative and postoperative outcomes and complications in patients treated with RIRS under GA versus SA. Our results concord with the previous published studies and added value to the use of SA for RIRS, particularly when a fast recovery and a short hospitalization are intended to be achieved. Kidney stone surgeries are developing towards to non-invasive methods. Endoscope miniaturization, improved deflection mechanism, improved optical quality, and advancement in

laser technology have led to the increased use of URS for kidney and ureteral stones (12). The 2022 EAU Urolithiasis Guidelines states that for retrograde stone removal both local and SA is feasible, however, the majority of patient still undergo GA (13). SA reduces anesthesiologic costs and hospital stay when compared with GA. Generally, the anesthesiologist for rapid endoscopic procedures proposes SA because it has lower risks of anaphylaxis, vascular, pulmonary, and neurological complications and compared with GA it does not present the risk of intubation-related problems (14). The overall complication rate was found to be 3.5% in a series of 11.885 prospectively studied RIRS published by CROES. According to the modified Clavien classification, 2.8% of these complications are grade 1 and 2 (15). In our study, general complications were 48 (19%) in GA group, 36 (14.5%) in SA group; grade 1-2 complications 20 (7.9%) in GA group and 20 (8%) in SA group. This may have been caused by the high density of difficult cases (lower pole, more than 1 stone and large stone size) because we are a third-level hospital. For grade 1-2 complications, no significant difference was found between the two groups. Urinoma and hematoma have been reported in the literature to be more likely in patients over 70 years of age, using anticoagulants and having chronic kidney disease; the probability of this complication is less than 1%. In our study, 2 (0.4%) patients in GA group had supcapsular hematoma cured with nephrostomy and double J stent insertion. Bleeding is seen at a rate of 0.3-2.1% after URS, due to the introduction of the scope, stone breakage procedure or damage caused by the guide wire in the calyceal structures. Bleeding often stops spontaneously, but the hematoma caused by it may cause colic pain and hydronephrosis in the postoperative period. Six patients in GA group, and one patient in SA group had nephrostomy due to clot hydronephrosis and renal colic. Two patients in GA group had double J stent for the same reasons and the catheters were removed 2 weeks later in their follow-up. Stone tract (Clavien 3b), which is an important complication, was seen in 9 (0.6%) patients in a study conducted with 1571 patients (16). This complication is the only that was found associated to stone size. In fact, SFR after RIRS was found significantly correlated with the stone size (17). In our study, Steinstrasse was observed in 8 (1.7%) patients in GA group who had stones larger than 3 cm according with the literature. The fragments were endoscopically extracted and the stones cured. This complication was not observed in any patient in SA group. Loss of the integrity of the stents is also an important problem. Zisman et al. (18) evaluated ureteral stents with spontaneous multiple fragmentations observing that the fracture resistance was decreased dramatically. Fractured stents were removed after 4 weeks. Due to cost problems, some materials were used longer than the recommended time. We may have encountered this complication due to the high stone load in our cases and the long duration of the cases. In the prospective study of CROES, it was reported death in 5 cases due to sepsis, pulmonary embolism, multiple organ dysfunction, and cardiac causes (15). Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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In our series, 6 patients were followed up with post-operative sepsis: 2 with hydronephrosis due to ureteral stone, 1 with hemorrhage and clot-related hydronephrosis without stones, and 3 patients with sepsis without any stone or hydronephrosis. All the patients had pre-operative hydronephrosis. These results are comparable to most previous report of the literature. One of our patients died due to post-operative sepsis and multiorgan failure in GA group. This 76-year-old patient had a stone size of 0.9 cm2 and 2 stones in the lower calyx and pelvis. The urine culture was clean preoperatively but preoperative hydronephrosis was present. The stone size was small but the stone was difficult to reach and the operation time was long (108 min). Furthermore, ureteral access sheath (UAS) could not be used due to ureteral stenosis. In the literature, it is emphasized that sepsis is generally related with high intrapelvic pressure (15, 17). Consequently, UAS should be used during RIRS and high pressure should be avoided. In the literature the success rate of RIRS is reported to be between 73.6% and 94.1%. In the study of 207 patients conducted by Reşorlu et al. (19) in 2012, it was described a new scoring system (Reşorlu-Ünsal Taş score) that can help us predict postoperative stone-free rates (18). In the study, the factors affecting success were examined and parameters such as age, gender, body mass index, stone size, stone side, location, composition, number of stones, lower pole infundibulopelvic angle, use of anticoagulant therapy, skeletal and renal anomalies were evaluated. They reported that stone size, number, location, composition, renal malformations, and lower pole infundibulopelvic angle significantly affected success. In our cases, the success rate of 81% in GA group and 85% in SA group were lower than in the literature, because of high frequency of lower pole stones and multiple stones. According to the literature, in our study we did not find any statistically significant differences in terms of intraoperative and postoperative complications, analgesia demand, and SFR in patients with single or multiple renal stones with a stone burden up to 30 mm treated with flexible ureteroscopy in GA versus SA (SFR rate p = 0.12).

cations of spinal anaesthesia in percutaneous nephrolithotomy: our experience. J Clin Diagn Res. 2017; 11:UC08. 8. Cybulski PA, Joo H, Honey RJ. Ureteroscopy: anesthetic considerations. Urol Clin North Am. 2004; 31:43. 9. Zeng G, Zhao Z, Yang F, et al. Retrograde intrarenal surgery with combined spinal-epidural vs general anesthesia: a prospective randomized controlled trial. J Endourol. 2015; 29:401. 10. Bosio A, Dalmasso E, Alessandria E, et al. Retrograde intra-renal surgery under spinal anesthesia: the first large series. Minerva Urol Nefrol. 2018; 70:333. 11. Wendt-Nordahl G, et al. Do new generation flexible ureterorenoscopes offer a higher treatment success than their predecessors? Urol Res. 2011; 39:185. 12. 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; 16:1-6. 13. Skolarikos A, Neisius A, Petr̆ík A, et al. EAU Guidelines on Urolithiasis. Edn. presented at the EAU Annual Congress Amsterdam 2022. 14. Breen P, Park KW. General anesthesia versus regional anesthesia. Int Anesthesiol Clin. 2002; 40:61-71. 15. de la Rosette J, Denstedt J, Geavlete P, et al. CROES URS Study Group. The clinical Research Office of the Endourological Society ureteroscopy global study: Indications, complications, and outcomes in 11885 patiens. J Endourol. 2014; 28:131-9. 16. Okan Baş, Can Tuygun, Onur Dede, et al. Factors affecting complication rates of retrograde flexible ureterorenoscopy: analysis of 1571 procedures-a single-center experience World J Urol. 2017; 35:819-826. 17. Maugeri O, Dalmasso E, Peretti D, et al. Stone free rate and clinical complications in patients submitted to retrograde intrarenal surgery (RIRS): Our experience in 571 consecutive cases.Arch Ital Urol Androl. 2021; 93:313-317. 18. Zisman A, Siegel YI, Siegmann A, Lindner A. Spontaneous ureteral stent fragmentation. J Urol. 1995; 153:718-21. 19. Resorlu B, Unsal A, Gulec H, et al. A new scoring system for predicting stonefree rate after retrograde intrarenal surgery: the "resorlu-unsal stone score". Urology. 2012; 80:512-518.

REFERENCES

1. Doizi S, Traxer O. Flexible ureteroscopy: technique, tips and tricks. Urolithiasis. 2018; 46:47. 2. Giusti G, Proietti S, Villa L, et al. Current standard technique for modern flexible ureteroscopy: tips and tricks. Eur Urol. 2016; 70:188. 3. Osther PJS. Risks of flexible ureterorenoscopy: pathophysiology and prevention. Urolithiasis. 2018; 46:59. 4. Reis Santos JM. Ureteroscopy from the recent past to the near future. Urolithiasis. 2018; 46:31.

Mehmet Yoldas, MD (Corresponding Author) yoldas_2297@hotmail.com Tepecik Training and Research Hospital Urology Clinic, Izmir (Turkey)

6. Cindolo L, Castellan P, Scoffone CM, et al. Mortality and flexible ureteroscopy: analysis of six cases. World J Urol. 2016; 34:305.

Tuba Kuvvet Yoldas, MD drtuba2004@hotmail.com Ege University Faculty of Medicine, Anesthesiology and Reanimation Department, Izmir (Turkey)

7. Kamal M, Sharma P, Singariya G, Jain R. Feasibility and compli-

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5. Xu Y, Min Z, Wan SP, et al. Complications of retrograde intrarenal surgery classified by the modified Clavien grading system. Urolithiasis. 2018; 46:197.

Archivio Italiano di Urologia e Andrologia 2022; 94, 2

DOI: 10.4081/aiua.2022.2.199

ORIGINAL PAPER

Molecular analysis of microorganisms in the semen and their impact on semen parameters Jenniffer Puerta Suárez 1, Juan Carlos Hernandez 2, Walter Dario Cardona Maya 1 1 Grupo

Reproducción, Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad de Antioquia - UdeA, Medellín, Colombia; 2 Infettare, Facultad de Medicina, Universidad Cooperativa de Colombia, Medellín, Colombia.

Summary

Objective: Chronic genitourinary infections can alter male fertility and even promote carcinogenic processes. This study aimed to evaluate the effect of the presence in the semen of microorganisms on semen quality. Materials and methods: Clinical symptoms and conventional and functional seminal parameters of eleven fertile donors and ten volunteers with prostatitis-like symptoms were evaluated. Nitric oxide, antioxidant capacity, and pro-inflammatory cytokines in semen and seminal plasma samples were also quantified. Finally, the expression of the ROR-γT, FoxP3, and T-bet genes in semen and the presence of DNA of microorganisms associated with prostatitis in urine and semen were evaluated. Results: When compared with fertile donors, volunteers with chronic prostatitis-like symptoms reported erectile dysfunction (0% vs. 10%, p = 0.2825) and premature ejaculation (0% vs. 40%; p = 0.0190). No statistically significant differences were observed in seminal parameters, cytokine measurement, antioxidant capacity, nitric oxide concentration and ROR-γT, FoxP3, T-bet. Microorganisms responsible for sexually transmitted infections and some bacteria associated with the microbiota and infections in the prostate gland were detected. In the semen from the subjects with prostatitis-like symptoms T. vaginalis DNA was detected; in addition, N. gonorrhoeae DNA was also detected in semen and urine samples. S. pyogenes was detected in the urine samples from the control group. Conclusions: Prostatitis-like symptoms are a common finding in young men that affect sexual and reproductive health, but not always the seminal parameters or fertility. The presence of prostatitis-like symptoms does not affect seminal quality. However, it appears to be associated with an increased likelihood of erectile dysfunction and premature ejaculation. Thus, affecting the quality of life and sexual and reproductive health.

KEY WORDS: Prostatitis; Fertility; Infection; Inflammation; Seminal quality; Sexual health. Submitted 17 February 2022; Accepted 7 April 2022

INTRODUCTION

Frequent exposure of the prostate to infectious processes can promote chronic inflammation (1), alter fertility (24), and even promote cancer (5-7). The role of infection, microbiota and inflammation on male fertility is still controversial (8). In vitro studies have shown how microorganisms can affect sperm function by altering motility, inducing apoptosis, increasing reactive oxygen species,

altering DNA and the acrosomal reaction, and other factors (8-14). However, these results should be interpreted cautiously because the semen of both fertile and infertile men contains microbiota, mainly bacterial (8). Urogenital infections in men are less frequent than in women, although they can trigger chronic inflammatory processes such as prostatitis (15). Clinically, prostatitis is classified into four types: i) acute bacterial prostatitis; ii) chronic bacterial prostatitis; iii) chronic pelvic pain syndrome; and iv) asymptomatic inflammatory prostatitis (16-18). Chronic bacterial prostatitis is responsible for 5 to 10% of total prostatitis cases, and at least 30% of those involve recurrent urinary infections (18). It is estimated that 5 to 10% of acute genitourinary infectious and inflammatory processes end in chronic prostatitis (16). Therefore, this work aimed to evaluate the effect of the presence of microorganisms in the semen on seminal quality and inflammatory markers.

MATERIALS

AND METHODS

Study participants This project was approved by the Bioethics Committee for research in humans at the Institute of Medical Research, Medical School, University of Antioquia (Act number 006, April/2018). Ten subjects with chronic prostatitis-like symptoms and eleven fertile donors asymptomatic for urogenital infections volunteered to participate to the study. The National Institute of Health of chronic prostatitis symptoms index (NIH-CPSI) (19) translated and validated into Spanish (20) was employed to select the volunteers according to the criteria reported by Nickel et al. (21). The questionnaire contains 13 items that are scored in three discrete domains: pain, urinary symptoms, and the impact on quality of life. We considered as fertile donors those who had children under two years or their partner in pregnancy at study recruitment. To be included in the study they should have no history of any genitourinary symptoms, instrumentation, or surgery, and NIH-CPSI total score lesser than 3. On the other hand, the inclusion criteria for the chronic prostatitis-like group were aged > 18 years and presence of prostatitis-like syndrome longer than three months (pain and/or discomfort in the perineum or on ejaculation) with a score in the pain domain of the NIH-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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CPSI greater than 4. After agreeing with their participation in the study, all individuals were required to sign an informed consent. Each volunteer gave a semen sample and a urine mid-stream sample. A blood sample was also taken by qualified personnel in a red Vacutainer tube (Becton Dickinson, NJ, USA) to obtain the serum. Finally, participants also filled out a survey including information on sociodemographic factors, lifestyle, urinary symptoms, and relevant other aspects of sexual and reproductive health that allowed us to identify factors associated with prostatitis symptoms. Semen collection and analysis Semen samples were collected into a sterile sample cup through masturbation after sexual abstinence for 2 to 5 days. Conventional seminal parameters Volume, progressive motility, concentration, and sperm morphology were evaluated according to parameters established by the World Health Organization in the fifth edition of its Human Semen Processing Manual (22, 23). The sperm concentration was evaluated using the Makler chamber (22, 23). Functional seminal parameters Sperm mitochondrial membrane potential (24), sperm membrane integrity (25), chromatin structure assay (26), sperm membrane lipoperoxidation (27), and intracellular levels of reactive oxygen species (ROS) (24) were evaluated by flow cytometry (Fortessa-Becton Dickinson, NJ, USA), according to previously established protocols in our lab (24, 28, 29), and analyzing between 5,000 and 10,000 sperm cells. Data were plotted and processed using the FlowJo 7.6 (Tree Star, Inc. Oregon, USA). Seminal plasma total antioxidant capacity evaluation Three mL of DPPH (2,2-diphenyl-1-picrylhydracil) were mixed with 200μL of the sample. After one hour of incubation, the sample was read in a spectrophotometer (Spectronic 20 Spectrophotometer®; Genesys, Rochester, NY, USA) at 515 nm, used ascorbic acid as a positive control (28, 29). Nitric oxide determination Nitric oxide quantification was performed using the commercial Griess Reagent Kit for nitrite determination (Molecular probes, Oregon, USA) according to the manufacturer's instructions and after deproteinization of the semen and serum samples according to the Serafini method (30) as previously reported (29). Cytokine quantification Quantification of IL-12p70, IL-10, IL-1a, IL-6, IL-8, TNF, IL-2, IL-4, IL-17, and IFN-a was performed by BD Cytometric Bead Array (CBA) in semen samples (Human Inflammatory Cytokines Kit, and Human Th1/Th2/Th17 Cytokine Kit, Becton Dickinson, NJ, USA), and the analysis was carried out in the FlowJo 7.6 as previously reported (29). Forkhead box P3 transcription factor (FoxP3), T-box 2 (T-bet), and retinoid-related orphan receptor gt (RORgT) mRNA expression. Total RNA extraction was performed from 200 µL of semen sample using a commercial kit

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(Qiagen RNeasy Mini Kit, QIAGEN, Hilden, Germany). The RNA was used to synthesize cDNA using the commercial RevertAid H Minus First Strand cDNA Synthesis kit (Thermo Fisher Scientific, Waltham, Massachusetts, USA). With the cDNA obtained, polymerase chain reactions were performed in real-time for the FoxP3 (Forward: 5-CAGCACATTCCCAGAGTTCCTC-3; Reverse: 5-GCGTGTGAACCAGTGGTAGATC-3); ROR-gt (Forward: 5-TTTTCCGAGGATGAGATTGC-3; Reverse: 5- CTTTCCACATGCTGGCTACA-3), and T-bet (Forward: 5-GCCTACAGAATGCCGAGATTACT-3; Reverse: 5-GGATGC TGGTGTCAACAGATG-3) genes. The gene expression levels were normalized using LCt with b-actin (31). Bacterial detection in semen specimens by PCR assays DNA extraction DNA extraction was performed using the phenol-chloroform technique using 500 µL of the semen sample and the 10 mL urine pellet. Briefly, the semen samples were centrifuged at 200g for 10 minutes, and the urine samples were centrifuged at 22000 g for 10 minutes. For each urine or semen sample, 0.5 mL of lysis solution (1M Tris, 0.5M EDTA, 5M NaCl, 10% SDS, and 0.1% triton x-100) and 5 μL of proteinase K were added for 12 hours at 54°C. Subsequently, 1 mL of phenol-chloroform-isoamyl was added, and it was centrifuged at 5000 g for 10 min. Then, 1mL of absolute ethanol (-20°C), 50 µL of 3M sodium acetate was added to the recovered supernatant, and it was left at -20°C overnight to precipitate the DNA. Finally, it was washed with 1 mL of 70% ethanol; the ethanol was allowed to dry, the DNA was diluted in 100 µL of DNAse/RNAse-free water and quantified in a Nanodrop 2000 Spectrophotometer (Thermo Scientific, Massachusetts, USA). Polymerase chain reaction The final 25μL reaction volume contained 12.5μL of Master Mix (Thermo-Scientific, Massachusetts, USA), a solution containing 0.025 U/L of Taq DNA polymerase, 2 mM of MgCl2, and 0.2 mM of each dNTP (dATP, dCTP, dGTP, and dTTP), 0.2M of each primer, 2 µL of DNA (200 ng), and 9.3 µL of water were added to each reaction. The PCR was carried out in a T3000 thermal cycler (Whatman, Biometra, Goettingen, Germany); cycling conditions consisted of an initial denaturation step at 94-95ºC for 5 min, followed by 35-40 cycles of specific conditions as previously, and a final elongation of 5-10 min at 72°C, using primers and following PCR conditions previously described (32) for b-actin (33), Chlamydia trachomatis (34), Escherichia coli (35), Klebsiella pneumnoniae (36), Lactobacillus spp (37), Mycoplasma genitalium (34), Neisseria gonorrhoeae (34), Ochrobatrum atrophy (38), Pseudomonas aeruginosa (36), Staphylococcus aureus (36), Staphylococcus epidermidis (39), Streptococcus agalactiae (40), Streptococcus pneumoniae (41), Streptococcus pyogenes (42), Treponema pallidum (34), Trichomonas vaginalis (34), Universal bacteria 27F y 1942R (43), Ureaplasma urealyticum (44), Herpes simplex virus I (34) and II (34), and Human papillomavirus (34). DNA extracted from each bacterial strain or clinical isolates obtained from patients was a positive reaction control. Lactobacillus spp. DNA

Prostatitis, semen parameters, and microorganisms

was obtained from a woman's vaginal smear on day 14 of her menstrual cycle. Serum prostate-specific antigen (PSA) quantification According to the manufacturer's instructions, total serum PSA quantification was performed using the commercial total PSA kit (DiaMetra, Perugia, Italy). PSA values greater than 4 ng/mL were considered positive, as previously reported (29). Statistical analysis A chi-square and a Mann Whitney test were used to compare both groups' dichotomous and numerical variables. The data were analyzed using the statistical program Graph Pad Prism 6.0 (GraphPad, San Diego, CA, USA), and a value of p < 0.05 was considered significant.

RESULTS

Eleven fertile donors (median age of 32 years) and ten chronic volunteers with prostatitis-like symptoms (median age of 39.5 years) (p = 0.5219) were included in the study (Table 1). Mean body mass index was similar in the two groups (fertile donors 25.7 vs. prostatitis-like subjects 23.4, p = 0.2299). Only 40% of the prostatitis-like group were married or living with a partner, compared to 100% of the control group (p = 0.0099). Erectile dysfunction (10%) and premature ejaculation (40%) were self-reported by the subjects with prostatitis-like symptoms (p = 0.2825 and p = 0.0190, respectively). In addition, 50% of subjects with prostatitis-like symptoms reported a history of chronic diseases and stress (p = 0.0072 and p = 0.0382), and 70% reported feeling anxiTable 1. Sociodemographic characteristics. Characteristics Children Education level High school Technician University Postgraduate Marital status Unmarried Married Divorced Number of sexual partners None One to three More than three Type of sex Masturbation Vaginal Oral Anal Insertive Receptive Condom use Always Frequently Rarely Never

Control group n = 11 100

Prostatitis group n = 10 40

9.1 0 18.2 72.7

0 10 60 30

Chi-square. Data indicate percentage.

0 100 0

50 40 10

0 36.4 63.6

10 40 50

63.6 100 63.6

70 60 60

36.4 0

40 20

0 18.2 64.6 18.2

10 20 30 40

P-value 0.0034 0.1005

0.0099

ety (p = 0.0166) associated with their symptoms. Three subjects with prostatitis-like symptoms were excluded from the seminal quality analysis because they reported being vasectomized. No statistically significant differences were found on other sexual health and reproductive aspects evaluated, nor on conventional or functional seminal parameters evaluation. No differences were found between groups in seminal plasma antioxidant capacity, plasma/serum nitrites concentration, or PSA determinations (Table 2). The IL-12p70, IL-10, IL-1b, IL-6, IL-8, TNF, IL-2, IL-4, IL17, IFN-g cytokines concentrations were evaluated in serum and seminal plasma samples without finding differences (Table 3). Table 2. Seminal parameters, nitric oxide concentration and serum PSA. Parameters Volume (mL) Progressive motility (%) Concentration/mL Viability (%) Normal morphology (%) Teratozoospermia index High mitochondrial membrane potential (%) Plasma membrane integrity (%) ROS production (%) DNA fragmentation index (%) Membrane lipoperoxidation (%) Total antioxidant seminal plasma capacity (%) Seminal plasma nitric oxide concentration (Nitritos µM) Serum nitric oxide concentration (Nitritos µM) Serum PSA (ng/mL)

Prostatitis group 3.5 (1.5-11.8) 49.0 (6.0-67.0) 182.0 (7.0-254.0) 82.0 (49.0 -85.0) 4.6 (4.2-7.0) 1.18 (1.12-1.37)

P-value 0.4556 0.7414 0.3269 0.8485 0.3874 0.4091

61.3 (33.5-73.5) 63.9 (37.8-84.4) 63.0 (34.8-86.2) 10.9 (10.4-14.9) 66.8 (9.1-93.3)

66.6 (12.3-75.5) 63.1 (12.1-70.0) 56.9 (17.7-66.8) 10.6 (10.3-14.3) 71.1 (44.9-96.9)

0.3167 0.8095 0.3612 0.5795 0.3269

61.0 (22.1-81.4)

62.3 (9.5-69.7)

> 0.9999

1.25 (0.55-11.7)

0.55 (0.23-2.16)

0.1384

4.6 (1.6-13.0) 0.0 (0.0-18.1)

2.8 (1.2-7.4) 0.45 (0.0-120.0)

0.1728 0.3292

Mann Whitney test. Data presented as median and range. ROS: Reactive oxygen species; PSA: Prostatic-specific antigen.

Table 3. Detection of cytokines in seminal plasma and serum.

Seminal plasma

0.5250

0.7574 0.0197 0.8639 0.2568 0.5366 0.1189 0.3580

Control group 2.0 (1.5-4.7) 49.0 (19.0-81.0) 100.0 (40.5-270.0) 79.0 (76.0-91.0) 5.2 (4.2-8.7) 1.25 (1.10-1.52)

Serum

Cytokine pg/mL IL-12p70 IL-1β IL-6 IL-8 TNF IL-2 IL-4 IL-10 IL-17 IFN-γ IL-12p70 IL-1β IL-6 IL-8 TNF IL-2 IL-4 IL-10 IL-17 IFN-γ

Control 0 (0-68.9) 0 (0-36.8) 8.9 (0-86.9) 1808 (0-4202) 0 (0-83.8) 3.9 (0-23.5) 0 (0-13.7) 0 (0-26.7) 9.3 (0-73.1) 0 (0-5.9) 0 (0-304.3) 0 (0-54.3) 0 (0-15.6) 23.6 (0-301.3) 0 (0-92.7) 4.9 (2.1-36.0) 0 (0-19.4) 0 (0-10.5) 0 (0-182.7) 0.3 (0-12.8)

Prostatitis-like symptoms 8.5 (0-107.5) 2.7 (0-31.53) 7.1 (0-101.9) 1692 (680.4-4334) 24.7 (0-127.5) 11.4 (4.3-45.7) 0 (0-19.3) 1.3 (0-19.3) 6.6 (0-429.9) 0 (0-33.5) 0 (0-95.1) 0 (0-2.7) 0 (0-14.9) 9.6 (0-66.1) 0 (0-30.4) 8.2 (4.1-47.3) 0 (0-27.0) 0 (0-13.1) 9.9 (0-85.6) 1.3 (0-6.3)

P-value 0.5907 0.7260 0.9159 > 0.999 0.1553 0.2940 0.1454 0.9113 0.8749 0.6084 > 0.9999 0.3246 0.2479 0.6668 0.3128 0.2439 0.3128 0.5573 0.2757 0.6476

Mann Whitney. Data presented as median and range.

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Figure 1. ROR-gT, FoxP3 and T-bet genes expression.

Figure 2. STIs DNA detection.

Figure 3. DNA detection from other bacteria associated.

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Prostatitis, semen parameters, and microorganisms

We also found no statistical difference in the expression of ROR-gT, FoxP3, and T-bet genes in semen samples (Figure 1). Finally, we detected microorganisms responsible for STIs (Figure 2) and some bacteria associated with the microbiota and infections of the prostate gland (Figure 3). T. vaginalis DNA was detected in 40% of the semen samples of the subjects with prostatitis-like symptoms (p = 0.0197). Furthermore, N. gonorrhoeae DNA was detected in in 50% and 40% of semen and urine samples of this group (p = 0.0072 and p = 0.0197). S. pyogenes was detected in 45.5% of the urine samples from the control group volunteers (p = 0.0146).

DISCUSSION

Male factor is responsible in 50% of infertility cases, highlighting urogenital infections as the leading causes (8, 45). Urinary tract infections are the most common type of infection in humans, with an estimated annual prevalence of 150 million, representing a high financial impact (46). In men, urogenital infections are a risk factor for prostatitis development, a disease that dramatically impacts mental and sexual health and quality of life (19, 47). Chronic prostatitis is a common but poorly understood disease that affects men of any age regardless of their geographical origin (15, 21). Prostatitis has been associated with detriments in seminal quality and affects male fertility (4). In the present study, the seminal quality of fertile donors asymptomatic for urogenital infections was compared with that of men with symptoms of chronic prostatitis without finding significant differences in the conventional or functional parameters. Volunteers with prostatitis-like symptoms had 75 and 82% greater semen volume and concentration than the control group of fertile donors, although the difference did not reach statistical relevance. Similar findings were obtained by Shang et al. (18). N. gonorrhoeae and T. vaginalis were detected more frequently in volunteers with prostatitis-like symptoms. Both were also observed in the semen of infertile men being globally prevalent although easily treatable (48). In addition, the genome of other microorganisms, as Propionibacterium acnes, was frequently observed in the semen and urine of patients with recurrent urinary tract infections (49), and the presence of T. vaginalis in the urogenital tract was also associated with an increase of the risk of prostate cancer (50). In fact, there is a close relationship between urogenital infections and prostate cancer. It is estimated that one in five neoplasms could be attributed to microorganisms (1), and prostatitis was considered as a risk factor for cancer development (7, 51). However, microorganisms are not a synonymous of disease, because it has been described that the microbiota modulates the immune system; for example, Lactobacillus spp. is a protective factor in prostatitis (52). On the other hand, in chronic pelvic pain syndrome animal models, infiltration of macrophages and CD4+ T cells has been observed, which according to the local microenvironment, can differentiate into Th1, Th2, Th17, or Treg (regulatory) cells (7). Chronic prostatitis patients show specific Th1 and Th17 immune responses to prostate anti-

gen associated with chronic inflammation of the male genital tract, which may be the basis for the induction and development of chronic pelvic pain (53). Among the T cell subpopulations are Treg cells that secrete transforming growth factor b (TGF-b) and IL-10 and express the FoxP3 transcription factor. Th17 lymphocytes secrete IL-17 and IL-22 and express the transcription factor ROR-gT with a critical role in infections and tumors. Th1 cells secreting IFN-g cytokines, IL-2 and TNF-a express the transcription factor T-bet and are essential in developing autoimmune prostatitis (7). Activation of Th1 and Th17 profiles inhibits Treg cells' action, promoting the appearance of chronic pelvic pain (7). Therefore, we assessed in semen samples the mRNA expression of lineage-specifying transcription factors FoxP3, T-bet, and RORg-T. Furthermore, although we evaluated several essential aspects of sexual and reproductive health and lifestyle, other variables not evaluated in this study including the impact of ejaculation delayed and intercourse interruptions, were described as risk factors for chronic prostatitis (54). Even urinary retention and anxiety are risk factors for chronic prostatitis (7). However, this is an excellent approach to evaluating prostatitis's effect on male fertility and understanding the relationship between the urogenital microbiota, infection, and inflammation. The present study is an interesting approach, as a baseline, to understand the impact on the fertility of chronic prostatitis. Although prostatitis does not seem to alter the seminal quality, it seems to impact on fertility by promoting the appearance of other diseases such as erectile dysfunction and premature ejaculation. However, a limitation of the present study is the limited number of subjects included in the study could explain the lack of difference observed in the comparison of microbiology and immune response between controls and subjects with prostatitis-like symptoms.

CONCLUSIONS

Although chronic prostatitis is a disease that affects the quality of life, it does not appear to affect seminal parameters. However, chronic prostatitis seems to be related to alterations in sexual function, such as premature ejaculation and erectile dysfunction.

ACKNOWLEDGMENTS

The authors acknowledge the valuable contributions of the volunteers. Puerta-Suárez J was supported by a fellowship from MINCIENCIAS (785-2017).

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Correspondence Jenniffer Puerta Suárez jenniffer.puerta@udea.edu.co Grupo Reproducción, Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad de Antioquia, Medellín (Colombia) Juan Carlos Hernandez juankhernandez@gmail.com Infettare, Facultad de Medicina, Universidad Cooperativa de Colombia, Medellín (Colombia) Walter Dario Cardona Maya (Corresponding Author) wdario.cardona@udea.edu.co Grupo Reproducción, Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad de Antioquia, Medellín (Colombia)

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DOI: 10.4081/aiua.2022.2.206

ORIGINAL PAPER

Role of tunica vaginalis flap and dartos flap in tubularized incisional plate for primary hypospadias repair: A retrospective monocentric study Faisal Ahmed 1, Hossein-Ali Nikbakht 2, Khalil Al-Naggar 1, Saleh Al-Wageeh 3, Qasem Alyhari 3, Saif Ghabisha 3, Ebrahim Al-Shami 1, Menawar Dajenah 3, Waleed Aljbri 4, Fawaz Mohammed 5, Abdu Al-Hajri 3 1 Urology

Research Center, Al-Thora General Hospital, Department of Urology, School of Medicine, Ibb University of Medical Science, Ibb, Yemen; 2 Social Determinants of Health Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; 3 Department of General Surgery, School of Medicine, Ibb University of Medical Science, Ibb, Yemen; 4 Department of Urology, School of Medicine, 21 September University, Sana'a, Yemen; 5 Department of Orthopedy, School of Medicine, Ibb University of Medical Science, Ibb, Yemen.

Background: In the tubularized incised plate (TIP) procedure, flap interposition between the skin and neourethra is highly recommended to decrease the postoperative fistula rate. However, there is no consensus regarding the ideal flap for this procedure. This study aimed to report our experiences in the one-stage TIP hypospadias surgery utilizing dartos flap (DF) (penile skin subcutaneous tissue) and tunica vaginalis flap (TVF) (parietal layer of the testis) as a tissue coverage of neourethra. Methods: In a retrospective study from Sep 2018 to May 2021, 16 cases of hypospadias with different types, ranging from midpenile to penoscrotal types, were managed with TIP urethroplasty using DF or TVF as a tissue coverage of neourethra were enrolled. The demographic characteristics of the participants, type of hypospadias, outcome, and complications were analyzed and compared. Result: We used TVF and DF as soft tissue coverage in 11 (68.8%) and 5 (31.3%) patients, respectively. The mean age was 56.38 ± 47.83 months. Mid-penile, proximal, and penoscrotal hypospadias were presented in 3 (18.8%), 8 (50.0%), and 5(31.2%) patients, respectively. The total success rate was 14 (87.5%), while 2 (12.5%) patients developed a urethrocutaneous fistula, which required delayed closure later. In comparison between TVF and DF groups: the TVF was applied in all patients with moderate and severe chordee and all patients with penoscrotal hypospadias, and six patients with proximal hypospadias, while only three patients with mild chordee and two patients with proximal hypospadias used the DF and showed statistical significance between groups (p < 0.001 and 0.012) respectively. The success rate was 90.9% vs. 80.0% in TVF and DF groups, respectively, with no statistical significance between groups (p = 1.000). Conclusions: In the primary TIP repair, the TVF is a practical option as a DF for the interposition cover of a neourethra, especially in penoscrotal and proximal hypospadias with severe chordee.

INTRODUCTION

KEY WORDS: Hypospadias; Dartos fascia; Tunica vaginalis; Tubularized incised plate.

Study design We retrospectively reviewed the medical records of 16 consecutive children with hypospadias repairs from Sep

Summary

Submitted 1 April 2022; Accepted 23 April 2022

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Hypospadias, one of the most common congenital malformations, affects one in every 200 to 300 live births. It is typically accompanied by a band of fibrotic tissue arising from the abnormal meatal opening to the glans. It causes the shortens of the penile shafts in the ventral aspect, causing downward deformity of the penis (chordee) (1). Hypospadias is classified into penoscrotal, proximal, midpenile, distal, and coronal hypospadias (2). The techniques used to repair hypospadias are heavily influenced by the anomaly's components, including the size of the urethral plate and penis, the presence of penile chordee, the location of the meatal opening, and the experience of the surgeon (3). The main aim of hypospadias surgery is to correct the penile chordee and move the meatus opening to the glandular area (4). With over a hundred techniques published, the tabularized incisional plate (TIP) is presently the most fantastic procedure for primary hypospadias surgery (5). Urethrocutaneous fistula is the most complication observed in TIP urethroplasty, with a range of incidence between 0 to 28%. To reduce the risk of urethrocutaneous fistula, most surgeons now perform tissue interposition between the neourethra and the skin of the penis as a standard step during TIP surgeries (3). The Dartos flap (DF) and tunica vaginalis fascia (TVF) are the most commonly used urethral interposition with good postoperative outcomes, though different research findings reported the results (6-8). There is no agreement on which DF or TVF flap techniques are superior (3). Our goal was to share our experiences of hypospadias surgery with TIP repair using TVF and DF, outcome, and complications.

MATERIALS

AND METHODS

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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2018 to May 2021. Patients' and operations' characteristics, such as type of hypospadias, degree of chordee, flap usage, success rate, and complications, were collected, analyzed, and compared. The ethics committees of Ibb University of Medical Sciences approved this thesis, which was carried out in compliance with the Helsinki Declaration. Additionally, informed consent was obtained from the patients' families to participate in our research. Surgical procedure We illustrate a case of penoscrotal hypospadias (Figure 1). All procedures were carried out while the patients were anesthetized. A stay suture was placed in the dorsal aspect of the glans to aid in traction of the phallus and fix the urethral catheter later. The penile skin was degloved. Then, if the penile chordee was greater than 30 degrees, the chordee was intraoperatively corrected. The urethral plate was incised from the hypospadias meatus to the penial glans. Then, the tabularization was made over a Nelaton catheter (6 to 10 French) depending on the patients' age. Then, subcuticular continuous suturing was made with a 6.0 Vicryl (1). The neourethra suture was completed to the subcoronal level (Figure 2). Dartos flap A dartos layer from penile skin subcutaneous tissue was dissected to cover the neourethral suture line and fixed Figure 1. Show the penoscrotal hypospadias with meatus opening (yellow arrow).

with PDS 5/0. Then by creating the buttonhole in the midshaft skin of the penis, the penis was delivered through it and sutured with vicryl 5/0. A thin dressing was used to keep the penis in place. A suprapubic catheter was inserted into the bladder and fixed with silk 2/0. On the second postoperative day, an open dressing was applied. The patient was discharged on the fourth day following the operation with the proper antibiotic. The suprapubic and urethral catheters were removed on the 10th and 14th postoperative days. Tunica vaginalis flap Harvesting for additional TVF coverage was done (left or right side testicular vaginalis). Using micro-scissors, an adequate TVF was harvested from the dorsal part of the vaginalis. The flap was at least 5 mm in width and long enough to cover the neourethra. To avoid glans dehiscence, the distal end of the TVF was fixed in the subcoronal area. An interrupted suture was used to place the graft over the neourethra. The remainder of the procedure was similar to that described in the DF procedure. Statistical analysis The variables' descriptive statistics were calculated as mean, standard deviation, maximum, and minimum, and qualitative variables with frequency (percentage) were presented. An independent sample T-test or MannWhitney test compared the qualitative variables. The Chisquare test or Fisher's exact test compared the qualitative variables. Data were analyzed using statistical software (SPSS Inc., Chicago, IL, USA) version 22. A P value < 0.01 was considered a significant level.

RESULTS

Figure 2. A. Show the postoperative meatal opening (yellow arrow) and the skin covered with the pineal midshaft buttonhole (green arrow). B. Show the postoperative meatal opening after dartos flap (yellow arrow).

Out of 16 hypospadias patients who underwent primary TIP repair, in 11 (68.8%) of patients, we used TVF as a soft tissue coverage. In 5 (31.3%) patients, the DF was utilized for coverage. The mean age was 56.38 ± 47.83 (22.50-94.50) months. Mild, moderate, and severe degree of chordee was presented in 3 (18.8%), 2 (12.5%), and 9 (56.2%), respectively, and it was corrected successfully in both groups. The chordee was repaired by complete degloving of the penis and release of dysplastic dartos tissues in most patients, and only two cases with penoscrotal hypospadias required multiple transverse incisions of the ventral aspect of the corpus cavernosum. The total success rate was 14 (87.5%), while 2 (12.5%) patients developed fistula, which required delayed closure later. After surgery, urinary tract infection (UTI) was presented in 3 (18.8%) patients and was treated with a proper antibiotic. Pain during micturition after surgery was presented in 3 (18.8%) patients and was treated with oxybutynin. After 24 months of follow-up, there was no incidence of new fistula, meatal stricture, or other complications. Comparison between using TVF and DF The mean age of patients who underwent TVF was 72.36 ± 49.77 months, and the mean age of patients who underwent DF was 21.20 ± 11.69 months, and their age was significantly different (p = 0.007). The TVF was applied in all patients with moderate and severe chordee, Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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while only in three patients with mild chordee the DF was used showing statistical significance between groups (p < 0.001). For all the patients with penoscrotal hypospadias and six patients with proximal hypospadias, the TVF was applied. Only in two patients with proximal hypospadias the DF was used with statistical significance between groups (p = 0.012). The time of operation for both groups was similar at 2 hours. In the TVF group, the success rate was 90.9%, while the success rate in the DF group was 80.0%, with no statistical significance between groups (p = 1.000) (Table 1).

can be harvested via a penile incision degloving up to the basis of the penis or via an additional scrotal incision reaching and covering the neourethra via a subcutaneous scrotal tunnel (6). Snow and associations were the first to document the use of TVF as an interposition graft in 1995, with a postoperative fistula rate of about 9% (12). Similar findings were reported by Shankar et al. (13). Our study used the TVF for all patients with penoscrotal hypospadias and six patients with proximal hypospadias, while the DF was used in only two patients with proximal hypospadias. We find that TVF is a good interposition flap in proximal and penoscrotal hypospadias. A similar result was reported by Radhakrishnan et al. and DISCUSSION Braga et al. (14, 15). Hypospadias surgery is continually changing, suggesting Regarding the age of surgery, the mean age of patients that no single technique is thought to be ideal. The use of who underwent TVF and DF were 72.36 ± 49.77 months interposition flaps in the research is well demonstrated, vs. 21.20 ± 11.69 months, respectively, and their age was such as triangular soft tissue flaps and Belman flaps harsignificantly different (p = 0.007). Delayed presentations vested from the prepuce. Smith D flap is derived from the in our patients were due to misinterpreting hypospadias penile skin, whereas Buck's fascial flap is derived from the as a normal variation (Paribor or cut by angels), being penile, shaft, and DF from penile skin subcutaneous tistold by general physicians that repair is futile, and fear of sue. The TVF is derived from the testis, and the scrotal future surgery complications. Similar reasons were DF is derived from the scrotum (3). reported by Zargooshi et al. (16). Additionally, age is not Snodgrass presented use of a flap that was dissected from a predisposing factor for postoperative complications. the dorsal preputial and shaft skin to provid additional Bush and Snodgrass obtained a similar result in 186 coverage of the ventral aspect of the neourethra. This dispatients operated on for hypospadias. They find that of section requires experience, and there is a risk of dermal preoperative factors, including meatal location, urethral necrosis (3, 9). However, there are many choices for soft plate width, glans width, and age, only glans width less tissue covers, and the suitable one has yet to be discovthan 14 mm was associated with increased urethroplasty ered (10). complications (17). DF is easily obtainable, easy to mobilize, provides excelThe American Academy of Pediatrics chordee survey claslent coverage for repeat proximal hypospadias surgery, sifies penile curvature as mild, moderate, and severe. The and does not require an additional extra incision (3). mild curvature is less than 30 degrees, moderate is 30 to In contrast, TVF is a good choice for re-do hypospadias 43 degrees, and severe is more than 43 degrees (18). cases and proximal and penoscrotal hypospadias where In our study, mild, moderate, and severe degree of dissection is extended to the root of the penis (11). TVF chordee was presented in 3 (18.8%), 2 (12.5%), and 9 (56.2%) patients, respectively. Additionally, the TVF was applied Table 1. in all patients with moderate and Comparison between tunica vaginalis flap (TVF) and dartos flap (DF). severe chordee, while only two patients with mild chordee used the Variable * Subgroups Total n (%) Type of surgery P-value** DF and showed statistical signifiTVF (11, 68.8%) DF (5, 31.3%) cance between groups (p < 0.001). Outcome Success 14 (87.5) 10 (90.9) 4 (80.0) 1.000 TVF was used to correct chordees Failure 2 (12.5) 1 (9.1) 1 (20.0) in children with severe hypospadias Type of hypospadias Middle 3 (18.8) 0 (0.0) 3 (60.0) 0.012 (19). However, the reported findProximal 8 (50.0) 6 (54.5) 2 (40.0) ings of this technique have been Penoscrotal 5 (31.3) 5 (45.5) 0 (0.0) contradictory. Ritchey reported Age (year) <3 7 (43.8) 3 (27.3) 4 (80.0) 0.077 excellent results with TVF (21). At a ≥3 9 (56.3) 8 (72.7) 1 (20.0) median follow-up of 9 months durComplication No 8 (50.0) 5 (45.5) 3 (60.0) 0.769 ing second stage repair, only 1 of Fistula 2 (12.5) 1 (9.1) 1 (20.0) their 25 patients with scrotal or UTI 3 (18.8) 3 (27.3) 0 (0.0) perineal hypospadias had evidence Pain in micturition 3 (18.8) 2 (18.2) 1 (20.0) of recurrent ventral chordee (20). Type of chordee No 2 (12.5) 0 (0.0) 2 (40.0) < 0.001 In 25 patients with scrotal or perMild (less than 30) 3 (18.8) 0 (0.0) 3 (60.0) ineal hypospadias associated with Moderate (30-43) 2 (12.5) 2 (18.2) 0 (0.0) Severe (more than 43 degree) 9 (56.3) 9 (81.8) 0 (0.0) severe ventral chordee, Ritchey and associations et al. reported excellent Associated anomaly No 14 (87.5) 9 (81.8) 5 (100) 1.000 UDT 1 (6.3) 1 (9.1) 0 (0.0) results with TVF of the corpora Cleft plate 1 (6.3) 1 (9.1) 0 (0.0) without chordee recurrence (21). UTI: urinary tract infection, UDT: Undescended testicle. Note: * Data was presented as n (%). ** P-values of < 0.01 were considered significant. A recent study by Braga et al. mentioned that in the short-term out-

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come of ventral penile lengthening, TVF alone to correct severe chordee is favorable, with a 95% success rate (15). Our result was similar to those reports. On the other hand, Caesar reported that 60% of TVF patients had recurrent ventral chordees (22). Vandersteen and Husmann also discovered late-onset recurrent chordee after successful hypospadias repair with TVF (23). Correction of penile chordee begins with complete degloving of the penial skin, the release of the dysplastic dartos tissues, and induction of an artificial erection (21). When the chordee is severe, the urethral plate is mobilized from the underlying corpus cavernosum, accompanied by movements of the normal proximal urethra up to the bulbar urethra (19). In our cases, the chordee was repaired by complete degloving of the penis and release of the dysplastic dartos tissues, and only two patients with penoscrotal hypospadias required multiple transverse incisions in the penile ventral aspect that had a maximum curvature; our result in chordee correction was similar to the experience reported by Snodgrass et al. (24). The final step in hypospadias repair is skin covering, and it is critical to resurface the penis after the TIP procedure. Numerous procedures have been used to accomplish skin covering. Some techniques involve suturing the lateral skin edges together in the ventral aspect of the penis. However, this technique may cause skin tension, and a dorsal skin incision for avoiding tension may be required. In some other method, as in our cases, creating a buttonhole incision in the midshaft skin of the penis, delivering the penis through it, and suturing was made (2, 25). Complications of TIP hypospadias procedure include urethrocutaneous fistula formation, stenosis of the new meatus, diverticulum formation, and TVF complications such as scrotal hematoma in the 2% to 4% range. Fistula formation is the most frequent complication, with reported incidences ranging from 3 % to 50% (26). We report a similar result in fistula rate of 9.1% and 20% for TVF and DF, respectively, without statistically significant (p = 0.769). In a prospective study comparing the DF vs. TVF as flap coverage for primary TIP procedure, Chatterjee et al. found that the fistula rate was 0% and up to 20% for TVF and DF, respectively (11). Dhua and the association reported that TVF had an optimal tissue coverage of the neourethra than the DF (3 fistulae in the DF group) (3). In contrast, Zheng et al. reported similar fistula rates of DF and TVF (27). A systematic review recommended a double DF for distal hypospadias and TVF for proximal hypospadias during TIP surgery (28). The reasons for a different incidence rate of fistula in our study with previously published articles were that all the patients with penoscrotal and proximal hypospadias were repaired using TVF. In contrast, the DF was used in two patients with proximal hypospadias. Additional reasons are older age at operation in the TVF group, and a small number of patients explain this different fistula rate in both groups. A similar reason was mentioned by Dhua et al. (3). In our study, we insert suprapubic catheter drainage at the end of the procedure to improve the healing of the new urethra and minimize the risk of urethrocutaneous fistula. According to Duarsa et al., the suprapubic cystotomy insertion could reduce the risk of urethrocutaneous

fistula following hypospadias surgery (29). Most of our patients achieved the external meatal orifice up to the subcoronal level, particularly those with proximal or penoscrotal hypospadias. A subcoronal meatus was appropriate by patients' families in cases where local anatomy was not allowed to prefer spreading the neourethra up to the glanular area. Counseling before operation with family is essential. Furthermore, it is well documented that the meatal orifice location at the subcoronal area is functional with acceptable cosmetic outcomes (26, 30). There were several limitations to the current study. First and foremost, the small number of patients (only 16) and TVF and DF groups do not have similar cases. Secondly, the TVF was used in all cases of penoscrotal hypospadias and most proximal hypospadias cases, while the DF was used only in two cases of proximal hypospadias. Finally, a retrospective analysis could have resulted in selection bias. Additional prospective studies with strict follow-up and large sample size are required to evaluate the outcome and complication rate after primary TIP with TVF vs. DF as tissue coverage.

CONCLUSIONS

In the primary TIP repair, the TVF is a practical option as a DF for the interposition cover of a neourethra. This finding needs to be confirmed in a large cohort study with long-term post-procedural follow-up to demonstrate the superiority of TVF over DF.

ACKNOWLEDGMENTS

The authors would like to thank the General Manager of Althora General Hospital, Ibb, Yemen, Dr. Abdulghani Ghabisha, for editorial assistance.

REFERENCES

1. Snodgrass WT, Nguyen MT. Current technique of tubularized incised plate hypospadias repair. Urology. 2002; 60:157-62. 2. Omar RG, Khalil MM, Sherif H, et al. Pedicled preputial island flap for double functions in hypospadias surgery. Turk J Urol. 2018; 44:423-7. 3. Dhua AK, Aggarwal SK, Sinha S, et al. Soft tissue covers in hypospadias surgery: Is tunica vaginalis better than dartos flap? J Indian Assoc Pediatr Surg. 2012; 17:16-9. 4. Subramaniam R, Spinoit AF, Hoebeke P. Hypospadias repair: an overview of the actual techniques. Semin Plast Surg. 2011; 25:206-12. 5. Satjakoesoemah AI, Situmorang GR, Wahyudi I, et al. Single-stage urethroplasty: An eight-year single-centre experience and its associated factors for urethrocutaneous fistula. J Clin Uro. 2021; 14:190-5. 6. Yang H, Xuan X-x, Hu D-l, et al. Comparison of effect between dartos fascia and tunica vaginalis fascia in TIP urethroplasty: a meta-analysis of comparative studies. BMC Urology. 2020; 20:161. 7. Cheng EY, Vemulapalli SN, Kropp BP, et al. Snodgrass hypospadias repair with vascularized dartos flap: the perfect repair for virgin cases of hypospadias? J Urol. 2002; 168:1723-6; discussion 6. 8. Landau EH, Gofrit ON, Meretyk S, et al. Outcome analysis of Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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tunica vaginalis flap for the correction of recurrent urethrocutaneous fistula in children. J Urol. 2003; 170:1596-9; discussion 9. 9. Snodgrass W. Tubularized, incised plate urethroplasty for distal hypospadias. J Urol. 1994; 151:464-5. 10. Bilici S, Sekmenli T, Gunes M, et al. Comparison of dartos flap and dartos flap plus spongioplasty to prevent the formation of fistulae in the Snodgrass technique. Int Urol Nephrol. 2011; 43:943-8. 11. Chatterjee US, Mandal MK, Basu S, et al. Comparative study of dartos fascia and tunica vaginalis pedicle wrap for the tubularized incised plate in primary hypospadias repair. BJU Int. 2004; 94:1102-4.

28. Fahmy O, Khairul-Asri MG, Schwentner C, et al. Algorithm for Optimal Urethral Coverage in Hypospadias and Fistula Repair: A Systematic Review. Eur Urol. 2016; 70:293-8. 29. Duarsa GWK, Tirtayasa PMW, Daryanto B, et al. Risk factors for urethrocutaneous fistula following hypospadias repair surgery in Indonesia. J Pediatr Urol. 2020; 16:317.e1-.e6. 30. Fichtner J, Filipas D, Mottrie AM, et al. Analysis of meatal location in 500 men: wide variation questions need for meatal advancement in all pediatric anterior hypospadias cases. J Urol. 1995; 154:833-4.

12. Snow BW, Cartwright PC, Unger K. Tunica vaginalis blanket wrap to prevent urethrocutaneous fistula: an 8-year experience. J Urol. 1995; 153:472-3. 13. Shankar KR, Losty PD, Hopper M, et al. Outcome of hypospadias fistula repair. BJU Int. 2002; 89:103-5. 14. Radhakrishnan CN, Radhakrishna V. The tunica-vaginalis flap to prevent postoperative fistula following severe hypospadias repair: Has the search for Holy Grail ended? Actas Urol Esp (Engl Ed). 2021; 45:552-6. 15. Braga LH, Pippi Salle JL, Dave S, et al. Outcome analysis of severe chordee correction using tunica vaginalis as a flap in boys with proximal hypospadias. J Urol. 2007; 178:1693-7; discussion 7. 16. Zargooshi J. Tube-onlay-tube tunica vaginalis flap for proximal primary and reoperative adult hypospadias. J Urol. 2004; 171:224-8. 17. Bush NC, Snodgrass W. Pre-incision urethral plate width does not impact short-term Tubularized Incised Plate urethroplasty outcomes. J Pediatr Urol. 2017; 13:625.e1-.e6. 18. Braga LH, Lorenzo AJ, Bägli DJ, et al. Ventral penile lengthening versus dorsal plication for severe ventral curvature in children with proximal hypospadias. J Urol. 2008; 180:1743-7; discussion 7-8. 19. Perlmutter AD, Montgomery BT, Steinhardt GF. Tunica vaginalis free graft for the correction of chordee. J Urol. 1985; 134:311-3. 20. Lindgren BW, Reda EF, Levitt SB, et al. Single and multiple dermal grafts for the management of severe penile curvature. J Urol. 1998; 160:1128-30. 21. Ritchey ML, Ribbeck M. Successful use of tunica vaginalis grafts for treatment of severe penile chordee in children. J Urol. 2003; 170:1574-6; discussion 6. 22. Caesar RE, Caldamone AA. The use of free grafts for correcting penile chordee. J Urol. 2000; 164:1691-3. 23. Vandersteen DR, Husmann DA. Late onset recurrent penile chordee after successful correction at hypospadias repair. J Urol. 1998; 160:1131-3; discussion 7. 24. Snodgrass W, Prieto J. Straightening ventral curvature while preserving the urethral plate in proximal hypospadias repair. J Urol. 2009; 182:1720-5. 25. Bakal Ü, Abes M, Sarac M. Necrosis of the ventral penile skin flap: a complication of hypospadias surgery in children. Adv Urol. 2015; 2015:452870. 26. Kadian YS, Singh M, Rattan KN. The role of tunica vaginalis flap in staged repair of hypospadias. Asian J Urol. 2017; 4:107-10. 27. Zheng D, Fu S, Li W, et al. The hypospadias classification affected the surgical outcomes of staged oral mucosa graft urethroplasty in hypospadias reoperation: An observational study. Medicine (Baltimore). 2017; 96:e8238.

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Correspondence Faisal Ahmed, MD (Corresponding Author) fmaaa2006@yahoo.com Khalil Al-Naggar, MD alnajjarkh1234@gmail.com Saleh Al-Wageeh, MD Alwajihsa78@gmail.com Qasem Alyhari, MD qalyhary@hotmail.com Saif Ghabisha, MD saifalighabisha@yahoo.com Ebrahim Al-Shami, MD alshami_ebrahim@yahoo.com Menawar Dajenah, MD dajenahmenawar@gmail.com Abdu Al-Hajri, MD abdulhagri@gmail.com Urology Office, Althora General Hospital, Alodine street, Ibb (Yemen) Hossein-Ali Nikbakht, MD Ep.nikbakht@gmail.com Social Determinants of Health Research Center, Health Research Institute, Babol University of Medical Sciences, Babol (Iran) Waleed Aljbri, MD Dr.Waleed112@gmail.com Urology Office, School of Medicine, 21 September University, Sana'a (Yemen) Fawaz Mohammed, MD falnehari@gmail.com Orthopedy Office, Althora General Hospital, Alodine street, Ibb (Yemen)

DOI: 10.4081/aiua.2022.2.211

ORIGINAL PAPER

Erectile dysfunction and mobile phone applications: Quality, content and adherence to European Association guidelines on male sexual dysfunction Luigi Napolitano 1, Giovanni Maria Fusco 1, Luigi Cirillo 1, Marco Abate 1, Claudia Mirone 2, Biagio Barone 1, Giuseppe Celentano 1, Roberto La Rocca 1, Vincenzo Mirone 1, Massimiliano Creta 1, Marco Capece 1 1 Department

of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples "Federico II", Naples, Italy; Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli", Naples.

2 Multidisciplinary

Summary

Introduction: Nowadays numerous mobile health applications (MHA) have been developed to assist and simplify the life of patients affected by erectile dysfunction (ED), however the scientific quality and the adherence to guidelines are not yet addressed and solved. Materials and methods: On 17 January 2022, we conducted a search in the Apple App Store and Google Play Store.We reviewed all mobile apps from iTunes App Store and Google Play Store for ED and evaluated different aspects as well as their usage in screening, prevention, management, and their adherence to EAU guidelines. Results: A total of 18 apps were reviewed. All apps are geared towards the patient and provide information about diagnoses and treatment of ED. Conclusions: MHA represent an integral part of patients’ lives, and apps providing services for male sexual dysfunction are constantly increasing. Despite this the overall quality is still low. Although many of these devices are useful in ED, the problems of scientific validation, content, and quality are not yet solved. Further work is needed to improve the quality of apps and developing new accessible, user designed, and high-quality apps.

KEY WORDS: App; e-health; Mobile phone; Erectile dysfunction; MARS. Submitted 17 May 2022; Accepted 20 May 2022

INTRODUCTION

Erectile Dysfunction (ED) is defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance with high impact on the quality of life (QoL) (1). The prevalence ranges from 3% to 76.5%, and increases with age, affecting over 50% of men aged 40-70 years, with a negative effect on QoL of affected men and their sexual partners (2). ED is generally related to cardiovascular disease, diabetes mellitus, hyperlipidemia, and hypertension, among other disorders (3-9). Many options are currently available for ED treatment: lifestyle changes, medical and surgical treatments or their combination (10). Mobile applications (apps) have grown expo-

nentially in recent years and become a more popular tool to support health behavior and to access health information for patients (11). In the last years numerous mobile health applications (MHA) have been developed, including in urological and andrological fields, aimed to simplify and assist the lives of patients (12, 13). Nowadays more than thousands MHA are available for mobile devices, but assessment of their quality is still a problem (14). Instruments for the assessment of the quality and content of MHA are highly needed, and one of the most used tools is Mobile Application Rating Scale (MARS). MARS has been used in the evaluation of a variety of health apps including depression, urinary incontinence, menstrual cycle and other (16, 17). Several apps have been developed for assessing and management of ED. These represent an important tool for patients. However, despite their potential utility, much effort must be made regarding the quality, the validation, and the adherence to guidelines. To the best of our knowledge, there are no studies reporting the quality of apps for ED and their adherence to guidelines. The aim of this study is to give an overview of apps for ED, currently available on the market to evaluate the quality and the adherence to guidelines.

MATERIAL

AND METHODS

Search strategy On 17 January 2022 we conducted a search in Google Play Store for Android phones and Apple App Store for iPhones with the keywords ‘erectile dysfunction’ and ‘impotence’ using the search tab. We used a wide array of keywords because Google Play Store and Apple App Store search strategy is based on finding keywords in the title, app descriptions and tags. Other searches of information provided in books or other formats were excluded. Two authors (GMF, LC) screened separately in App Store and Google Play Store apps during the search by reading the title and description in the app store. A third author (MA)

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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Table 1. App characteristics. Name of application E.D. Therapy Meditation IIEF-5 Erectile Dysfunction iDi - Erectile dysfunction myED - impotence IIEF-5 test SMART SAA Morning Glory Tracker Men Sexual Health Erectile dysfunction self-test Erectile dysfunction cure yoga Erectile dysfunction treatment Erectile dysfunction treatment Erectile dysfunction remedy 2021 Erectile dysfunction remedies Home remedies Erectile dysfunction questionnaire Erection test IIEF-5 for erectile dysfunction Herbal cure

Android/Apple/Both Apple Apple Apple Apple Apple Apple Android Android Android Android Android Android Android Android Android Android Android Android

Download n.a. n.a. n.a. n.a. n.a. n.a. > 10000 1000 10000 1000 5000 100 5000 100000 1000 1000 500 100000

resolved any discrepancies. At the beginning all apps were reported in Excel form and after they were screened according to the exclusion criteria. A total of 493 apps were found by our search, 467 of them were from the Google Play Store (Android) and 26 of them were from the Apple App Store (iOS). Of the total, 409 apps were screened after removing duplicates Figure 1. and paid apps. Of the total screened PRISMA. apps, 343 apps met excluding criteria and were removed. In total, 66 apps were eligible for the final evaluation and were downloaded. Finally, 18 apps were included in the final review after removing 48 apps that met exclusion criteria after download. A flow diagram based on the PRISMA statement (Figure 1) was included for the selected apps. Table 1 shows the analyzed apps characteristics. The 18 erectile dysfunction apps were evaluated by four members of the research team on a 5-point Likert scale based on MARS characteristics. App inclusion criteria We included in the analysis all apps regarding ED providing a service to patients. The apps are geared to patients, in English, and free to download. Apps not specifically focused on ED, apps not allowing access to all users and those not available in English were excluded. Then all reviewers downloaded and installed the apps on their personal mobile device. They interacted for fifteen minutes with each app to explore its features before

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Producer Ninja Chemist LLC Putu Angga Risky Raharja Back2Medical Prognoix Pte Ltd PERGALI LTD Roman Health Medical LLC GangareBoy R L fellner Dr. Zio Maftal almafary Revolxa inc. Maftal almafary StatesApps Cutepad studio Funny psychology Dr. kareem zaher imedical apps NovaRadix

Category Health & wellness Medicine Medicine Medicine Health & wellness Health & wellness Health & fitness Health & fitness Health & fitness Health & fitness Medicine Instruction Health & fitness Medicine Entertainment Health & fitness Health & fitness Medicine

Focus Treatment Test Diagnosis, Informative, Test Test Informative, Test Diary of morning erection Informative Informative, Test Treatment Information, Treatment Information, Risk factors, Treatment Information, Risk factors, Treatment Treatment Treatment Test Test Test Treatment

completing the MARS and evaluated their adherence to EAU guidelines. To assess apps, they were downloaded to either an Android (Huawei p20 lite) or iPhone (iPhone 13 pro). If apps were available in both app stores, the iPhone version was assessed.

Erectile dysfunction and mobile phone applications

score was calculated based on the aggregated mean values for each of the four domains. The mean score for subjective quality was also calculated (15).

Data extraction We conducted a data extraction using a predefined Excel form. On 17 January 2022 reviewers discussed methods of recording data to ensure standardized modality. The following data were extracted from MHA: title, language, customers, costs, source (Google Play Store or Apple App Store), field/disease, rating/feedback from the users, service provided. Assessment of app quality Apps’ quality was assessed using the MARS, which showed a very acceptable reliability and validity (12). MARS is a multidimensional instrument of 23 structured questions evaluating engagement, functionality, esthetics, information, app subjective quality, and app-specific (17). The scale is composed of 19 items grouped in four categories of perceived app quality: engagement (five items assessing the extent to which the app engages target users); functionality (four items assessing how easy the app is to navigate and the overall app performance); aesthetics (three items assessing visual appearance and style); information (seven items assessing accuracy, quality, and quantity of the app), and 1 category of subjective quality. Each category score is the mean of the different items, rated on a 5-point Likert-type scale (from 1 = inadequate to 5 = excellent) within its category. The overall quality score was calculated by taking the mean of the 4 app quality category scores, with a final score ranging from 0 to 5. A score of between 1 and 2/5 is considered as ‘poor’ quality, while 3/5 is ‘acceptable’ and at least 4/5 is ‘good’ quality. If scores differed by a single point, the mean of the two ratings was used, with any scores differing by more than a single point being resolved through discussion and consensus agreement between reviewers. Mean scores were calculated for each domain and an overall quality Table 2. MARS scale scores. Name of application ED test - risk calculator of erectile dysfunction IIEF-5 Erectile Dysfunction iDi - Erectile dysfunction myED - impotence IIEF-5 test SMART SAA Morning Glory Tracker Men Sexual Health Erectile dysfunction self-test Erectile dysfunction cure yoga Erectile dysfunction treatment Erectile dysfunction treatment Erectile dysfunction remedy 2021 Erectile dysfunction remedies Home remedies Erectile dysfunction questionnaire Erection test iief-5 for erectile dysfunction Herbal cure

Engagement (section A) 2.6 1

Functionality (section B) 2.75 2.75

Aesthetics (section C) 3 1.67

4 2 3.6 1 3 2 2 2 3 2 1,2 3 1,4 1,2 1,4 1,2

3.75 3.5 3.75 1.5 4 3,75 3,50 3,5 3,75 3,5 4,25 3,5 2,5 2,5 2,5 3,5

3 2.67 3 1 3 3,66 3,33 3,33 3,33 3,33 1 2,66 2 2,66 2 1

Assessment of app adherence to EAU guidelines We create an adherence checklist of five items (definition, physiopathology, diagnosis, risk factors and treatment) based on section 5 of the EAU guidelines of ED. Two independent reviewers coded separately apps for their adherence to EAU guidelines. Both raters were resident in urology with experience in male sexual dysfunction. According to criteria used in similar studies, raters gave each app a score from 0 to 3 for each of the five items. A score of ‘‘0’’ indicated no adherence to guidelines. A score of ‘‘1’’ indicated a weak adherence. A score of ‘‘2’’ indicated a partial or moderate adherence. A score of ‘‘3’’ indicated strong adherence. Where coding scores differed by 1 point, the average of the two ratings was taken. If there was a greater than 1-point discrepancy, a third author (a full professor) reviewed apps and resolved the discrepancy. The possible score on the checklist ranged from 0 to 15 for each app. To facilitate evaluation, adherence to the checklist was arbitrarily considered low with a total score ranging from 0 to 5, medium (6-10), and high (11-15) (18, 19).

RESULTS

Out of the 18 apps included in the final analysis, 6 from the Apple store and 12 from the Google play store, had limited functionality: 6 of them offered IIEF-5 tests, the other 12 ones offered information about symptoms, diagnosis and treatment, including tools for nutraceutical treatments. In particular, 8 apps (44.4%) included information about treatment options; 1 of them (5.6%) specifically gave information about diagnosis; 7 (38.9%) were overall informative apps, some of them mentioning risk factors. Data about downloads were available for 12 apps out of the 18 reviewed. Downloads were not Information Mean App subjective quality available for MHA pre(section D) (A+B+C+D) (section E) sented in the Apple App 1.67 2.5 1.5 Store. The most down2.71 2.03 1.75 loaded apps were Home 2.71 3.36 2.75 remedies (Android) and 2.8 2.74 2.25 Herbal cure (Android), of which 100000 down3.6 3.49 2.75 loads were reported. All 1.4 1.22 1.25 the apps were planned to 2 3 2 be used by patients. No 3 3,10 2,75 information about MHA 2,86 2,92 2,75 rating was available. 2,43 2,82 2 MARS scale scores are 3 3,27 2,25 represented in Table 2. 2,43 1,43 1,85 1,14 1,43 1,43 1,85

2,82 1,97 2,75 1,76 1,95 1,84 2,14

2 1,25 1,75 1,25 1,75 1,25 1,75

Engagement The score in this section was based on a 5-point Likert scale in 5 subscales (Entertainment, Interest, Customization, Interactivity and Target-

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group). The mean score was 2.09. Scores ranged from 1 to 4 out of 5. The “iDi - Erectile dysfunction” app (iOS) produced by Back2medical received the highest score for the engagement. This app contains tips for ED self-diagnosis and management, information and a follow-up form that helps the patient to keep track of his eventual improvements. Functionality The score of the functionality section was based on a 5point Likert scale in 4 subscales (Performance, Ease of use, Navigation and Gestural design) and the mean score was 3.26. Scores ranged from 1.5 to 4.25. The “Erectile Dysfunction Remedies” app (Android) produced by StatesApps achieved the maximum score. This app contains home remedies for ED. Aesthetics The aesthetics section was formed by a 5-point Likert scale in 3 subscales (Layout, Graphics, Visual Appeal) and the average score was 2.54. Scores ranged from 1 to 3.66 out of 5. The “Erectile Dysfunction Self-test” app (Android) developed by RL Fellner and designed to self-screen ED and to give tips and info about ED-risk and prostate enlargement, reached the maximum aesthetics score. Information The information section was formed by a 5-point Likert scale in 7 subscales and the mean score was 2.21. Score ranged from 1.14 to 3.6. The SMART SAA app (iOS) developed by PERGALI LTD achieved the highest score. This app offers the IIEF-5 test and other questionnaires, informative tips and advice to manage ED and other sexual conditions. It is produced by the Sexual Advice Association, a charitable organization created to help improve the sexual health and wellbeing of men and women. Subjective quality The subjective quality section consisted of 4 items. The mean score was 1.94, with scores ranging from 1.25 to 2.75. The “iDi - Erectile dysfunction”, “SMART SAA”, “Erectile Dysfunction self-test”, “Erectile dysfunction cure yoga” reached the maximum score. EAU adherence checklist We evaluated the EAU guidelines adherence in 13 apps. Five apps were not analyzed because they represent a IIEF-5 test, a validated diagnostic tool consisting of five selected items to clearly discriminate between subjects with and without ED. EAU adherence scores are represented in Table 3. The ED definition was reported in 10 (76.9%) apps, the score ranged

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from 0 to 3 (mean 1.8); physiopathology was reported in 9 (69.2%) apps, the score ranged from 0 to 2 (mean 1.1); risk factors were reported in 10 (76.9%) apps, the score ranged from 0 to 3 (mean 1.7); diagnosis was reported in 8 (61.5%), the score range from 0 to 2 (mean 0.61); treatment was reported in 11 (84.6%), the score ranged from 0 to 3 (mean 1.2). The overall score ranged from 0 to 12 (mean 4.92). The highest score was reported by “Erectile dysfunction treatment” (Android) produced by Revolxa inc. that mainly contains information about erectile dysfunction risk factors, diagnosis and treatment. The maximum definition score of 3 was only reached by three apps out of thirteen, while none of the apps achieved 3 in physiopathology and diagnosis. Finally, only three apps and two apps out of the thirteen evaluated, scored 3 respectively in risk factors and treatment.

DISCUSSION

Nowadays many studies focus on the evaluation of medical apps in order to understand whether the developers use a validated scientific approach to their creation (2022). Although a standardized evaluation method does not exist, a reasonable way to qualify those apps is to combine different scores. This is the reason why in the present study we decided to pursue such an approach for the evaluation of erectile dysfunction apps. To the best of our knowledge this is the first study reviewing the currently available MHA for ED, reporting either an assessment of quality, and the adherence to EAU guidelines. The most important findings in our study is that at the present time MHA for ED have poor quality and highlight low adherence to EAU guidelines. First of all we evaluated the quality of the apps using the MARS. The mean scores of the four categories were dramatically low. In particular the “Engagement” and the “Information” scores were lowest 2.09 and 2.21 respectively. Engagement assessed the design and interest of the app and software functionality. Information assessed accuracy, quality, credibility of the source and evidence basis of information presented in the apps. On the other hand Functionality mean score was

Table 3. EAU adherence checklist scores. Name of application iDi - Erectile dysfunction myED - impotence IIEF-5 test SMART SAA Morning Glory Tracker Men Sexual Health Erectile dysfunction self-test Erectile dysfunction cure yoga Erectile dysfunction treatment Erectile dysfunction treatment Erectile dysfunction remedy 2021 Erectile dysfunction remedies Home remedies Herbal cure

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Definition (0-3) 3 1 2 0 2 2 n.a. 3 2 3

Physiopathology (0-3) 1 n.a. 0 0 1 2 n.a. 2 2 2

Risk factors (0-3) 2 2 1 0 1 2 n.a. 3 3 3

Diagnosis (0-3) 0 1 0 0 0 2 n.a. n.a. 2 n.a.

Treatment (0-3) 3 n.a. 1 0 1 n.a. 1 1 3 1

0 n.a. n.a

0 n.a. n.a.

1 1 1

Erectile dysfunction and mobile phone applications

the best performance among all categories (3.26). Functionality assessed how easy the app and the overall app performance. The same results were reported by O’ Connor et al. which evaluated the quality of mobile apps supporting lifestyle changes following a transitory ischemic attack (TIA) or ‘minor’ stroke. This suggested that MHA were designed and developed in particular for their usability and not to assist, inform and educate patients. MHA were developed only for commercial use, without supporting of healthcare (23). This is due to a lack of scientific validation of MHA, indicating the necessity to develop high-quality apps and to improve the existing ones. Giunti et al. showed in their paper an evident absence of health professionals in the development of healthcare apps. Apps are mostly developed by nonhealth professionals who are creative and skilled in design but lack scientific knowledge (24). Our study demonstrates that MHA for ED lacked quality and most of all did not report to the patients what EAU guidelines suggest. Our results confirm and corroborate findings of other studies that analyze MHA in different clinical and surgical tools. There is a wide range of products not developed in collaboration with healthcare professionals or according to guidelines. To support this idea, each app underwent a EAU guidelines adherence test in order to assess the scientificity of those. Interestingly the mean score was 4.92 out of 12. Only four (30.7%) apps had medium adherence and only one app (7.69%) high adherence respectively. The highest adherence was reported in ED definition although definition has been adequately reported only in three apps. This is a point highlighting the lack of scientific validation of these products. In fact ED definition is reported in several scientific papers and widely available on the internet. “Erectile dysfunction treatment” (Android) produced by Revolxa Inc. is the app with the highest guideline adherence. This is not surprising because Revolxa Inc. produces many MHA in different medical fields. Regarding treatment our data were in line with the results of Vagger et al. in a study about urinary tract infections apps. As shown MHA about treatment of urinary tract infections were deficient in these information. In our study the overall treatment median score according to EAU guidelines was 1.2 and only two apps reported a score of 3 points. Nowadays treatment regimens available for ED include psychotherapy, sex therapy, oral pharmacological agents, androgen replacement therapy, intraurethral therapy, intracavernosal injections, vacuum devices, and surgery. Herbal supplements are widely used, but often lack rigorous scientific evidence of their efficacy. Four apps suggest use of natural products in ED treatments but many of these are non common and showed poor scientific evidence (garlic, carrots, promenade juice), while only ginseng reported several scientific evidence. Balasubramanian et al. in a recent meta-analysis reported the most popular erectile dysfunction supplements available on online marketplaces. Ginseng is the most popular followed by L-arginine, and Tongkat ali. None of the supplements reported by apps analyzed are present in this list. Furthermore, ginseng and L-arginie as shown by Borrelli et al. are the only two supplements as an effective efficacy in ED treatment (25). The search strategy also reported several apps

suggesting Kegel exercise in ED treatments. Published studies reported that these exercises to improve pelvic floor muscle could be useful as first line treatment of ED. Contractions of the ischiocavernosus and bulbocavernosus muscles (two muscles which are part of pelvic floor) seem to increase the intracavernous pressure, influencing penile rigidity, and compresses the deep dorsal vein of the penis preventing the outflow of blood from penis (26). Although in literature many studies have been published, currently guidelines do not report pelvic floor exercises as treatment in ED management. Another important point is that despite the high numbers of downloads any MHA has a rating. Many factors influenced the download of MHA, and no studies have been published about the mechanism that generated the rating (27). Strengths of our study include: the first study which examines the content, the quality, and the adherence to EAU guidelines; the rigorous approach in search strategy, screening, and analysis; the test among the reviewers regarding MARS scale use before initiation of the study. The limitations are related to: the reproducibility by different users due to the working method of App Store and Google Play Store (the visibility of apps depends on the device and on the country where the search is performed); the exclusion of paid applications; guidelines are developed for healthcare and not for patients; the high proliferation of MHA. Our study shows that there are a multitude of inaccurate apps resulting from a search in a store even when using appropriate terminology, so patients searching for health information must choose and discern the quality on their own. An ideal MHA must be based on scientific evidence, be simple and intuitive to use. MHA should provide correct and simple information abouts disease, make the individual confident to change behavior, inform patients about their progress, and provide adequate information about treatments.

CONCLUSIONS

The use of MHA for ED is a new and unexplored topic, with much potential for future investigation. MHA are now an integral part of patients’ lives, from year to year, the number of apps that provide services for male sexual dysfunction is constantly increasing, but the overall quality is still low. Although many of these devices are useful in ED, the problems of scientific validation, content, and quality are not yet solved. Further work is needed to improve the quality of apps and developing new accessible, user designed, and high-quality apps.

REFERENCES

1. Deng W, Bivalacqua TJ, Hellstrom WJG, Kadowitz PJ. Gene and stem cell therapy for erectile dysfunction. Int J Impot Res. 2005; 17(Suppl 1):S57-63. 2. Çayan S, Kendirci M, Yaman Ö, et al. Prevalence of erectile dysfunction in men over 40 years of age in Turkey: Results from the Turkish Society of Andrology Male Sexual Health Study Group. Turk J Urol. 2017; 43:122-9. 3. Mirone V, Napolitano L, D’Emmanuele di Villa Bianca R, et al. A new original nutraceutical formulation ameliorates the effect of Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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Tadalafil on clinical score and cGMP accumulation. Arch Ital Urol Androl. 2021; 93:221-6. 4. Romano L, Granata L, Fusco F, et al. Sexual Dysfunction in Patients With Chronic Gastrointestinal and Liver Diseases: A neglected Issue. Sex Med Rev. 2021; S2050-0521(21)00039-1. 5. Romano L, Pellegrino R, Sciorio C, et al. Erectile and sexual dysfunction in male and female patients with celiac disease: A cross-sectional observational study. Andrology. 2022; Apr 14. 6. Creta M, Celentano G, Napolitano L, et al. Inhibition of androgen signalling improves the outcomes of therapies for bladder cancer: results from a systematic review of preclinical and clinical evidence and meta-analysis of clinical studies. Diagn (Basel). 2021; 11:351. 7. Napolitano L, Barone B, Crocetto F, et al. The COVID-19 pandemic: Is It a wolf consuming fertility? Int J Fertil Steril. 2020; 14:159-60. 8. 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; 92:292-296.

otolaryngology: a systematic review of the literature, Apple app store and the Google play store. Ann Otol Rhinol Laryngol. 2021; 130:7891. 21. Dantas LO, Carvalho C, Prando BC, et al. Mobile health technologies for the management of rheumatic diseases: a systematic review of online stores in Brazil. Clin Rheumatol. 2021; 40:2601-9. 22. Vega M, Mckay ER, Halani PK. Evaluation of mobile applications for patients with fecal incontinence using a modified APPLICATIONS scoring system. Int Urogynecology J. 2021; 32:2529-36. 23. O’Connor SR, Kee F, Thompson DR, et al. A review of the quality and content of mobile apps to support lifestyle modifications following a transient ischaemic attack or «minor» stroke. Digit Health. 2021; 7:20552076211065270. 24. Giunti G, Giunta DH, Guisado-Fernandez E, et al. A biopsy of Breast Cancer mobile applications: state of the practice review. Int J Med Inf. 2018; 110:1-9. 25. Balasubramanian A, Thirumavalavan N, Srivatsav A, et al. An analysis of popular online erectile dysfunction supplements. J Sex Med. 2019; 16:843-52.

9. Verze P, Arcaniolo D, Imbimbo C, et al. General and sex profile of women with partner affected by premature ejaculation: results of a large observational, non-interventional, cross-sectional, epidemiological study (IPER-F). Andrology. 2018; 6:714-9.

26. Dorey G, Speakman M, Feneley R, et al. Randomised controlled trial of pelvic floor muscle exercises and manometric biofeedback for erectile dysfunction. Br J Gen Pract J R Coll Gen Pract. 2004; 54:819-25.

10. Krzastek SC, Bopp J, Smith RP, Kovac JR. Recent advances in the understanding and management of erectile dysfunction. F1000Research. 2019; 8:F1000 Faculty Rev-102.

27. Biswas M, Tania MH, Kaiser MS, et al. ACCU3RATE: A mobile health application rating scale based on user reviews. PloS One. 2021; 16:e0258050.

11. Zhao J, Freeman B, Li M. Can mobile phone apps influence people’s health behavior change? An evidence review. J Med Internet Res. 2016; 18:e287. 12. Martín-Martín J, Muro-Culebras A, Roldán-Jiménez C, et al. Evaluation of Android and Apple store depression applications based on mobile application rating scale. Int J Environ Res Public Health. 2021; 18:12505. 13. Mirone V, Creta M, Capece M, et al. 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. Arch Ital Urol Androl. 2021; 93:450-4. 14. Arean PA, Hallgren KA, Jordan JT, et al. The Use and Effectiveness of Mobile Apps for Depression: Results From a Fully Remote Clinical Trial. J Med Internet Res. 2016; 18:e330. 15. Dantas LO, Carvalho C, Santos BL de J, et al. Mobile health technologies for the management of urinary incontinence: A systematic review of online stores in Brazil. Braz J Phys Ther. 2021; 25:387-95. 16. Moglia ML, Nguyen HV, Chyjek K, et al. Evaluation of smartphone menstrual cycle tracking applications using an adapted APPLICATIONS scoring system. Obstet Gynecol. 2016; 127:1153-60. 17. Stoyanov SR, Hides L, Kavanagh DJ, et al. Mobile app rating scale: a new tool for assessing the quality of health mobile apps. JMIR MHealth UHealth. 2015; 3:e27. 18. Vaggers S, Puri P, Wagenlehner F, Somani BK. A Content analysis of mobile phone applications for the diagnosis, treatment, and prevention of urinary tract infections, and their compliance with European Association of Urology guidelines on urological infections. Eur Urol Focus. 2021; 7:198-204. 19. Rajani NB, Weth D, Mastellos N, Filippidis FT. Adherence of popular smoking cessation mobile applications to evidence-based guidelines. BMC Public Health. 2019; 19:743. 20. Trecca EMC, Lonigro A, Gelardi M, et al. Mobile applications in

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Correspondence Luigi Napolitano, MD luiginap89@gmail.com Giovanni Maria Fusco, MD giom.fusco@gmail.com Luigi Cirillo, MD (Corresponding Author) cirilloluigi22@gmail.com Marco Abate, MD marcoabate5@gmail.com Biagio Barone, MD biagio.barone@unina.it Giuseppe Celentano, MD dr.giuseppecelentano@gmail.com Roberto La Rocca, MD robertolarocca87@gmail.com Vincenzo Mirone, MD mirone@unina.it Massimiliano Creta, MD max.creta@gmail.com Marco Capece, MD drmarcocapece@gmail.com Department of Neurosciences, Reproductive Sciences and Odontostomatology, Urology Unit, University of Naples "Federico II" Via Sergio Pansini n 5, Naples (Italy) Claudia Mirone, MD claudiamirone@outlook.it Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli", Naples (Italy)

DOI: 10.4081/aiua.2022.2.217

ORIGINAL PAPER

Platelet volume parameters as a tool in the evaluation of acute ischemic priapism in patients with sickle cell anemia Essa A. Adawi, Mazen A. Ghanem Department of Urology, Jazan University, KSA, Jazan, Saudi Arabia.

Summary

Objective: This study aimed to evaluate the predictive value of platelet volume indices (PVIs), such as mean platelet volume (MPV), platelet distribution width (PDW), and plateletcrit (PCT), as prognostic parameters of detumescence in acute ischemic priapism (IP) patients with sickle cell anemia (SCA) in steady-state who received intracavernosal injections of phenylephrine with aspiration and saline irrigation. Methods: Fifty-six SCA patients with acute IP and 54 healthy male control subjects were included in the research. Priapism was diagnosed by penile Doppler ultrasound and corporal blood gas tests before intervention. Measurements of PVIs (MPV, PDW, and PCT) and TLC were ordered for all participants. Additionally, the duration of priapism was recorded. The area under the curves was calculated by receiver operating characteristic (ROC) regression analysis. Results: The detumescence rate was 71.4% after the intervention. Compared to the control group, priapic SCA patients showed significantly higher PLT (p = 0.011), MPV (p = 0.002), PDW (p = 0.032), PCT values (p = 0.022), and TLC (p = 0.027). Higher MPV, PDW, and PCT values were observed in unsuccessful detumescence patients compared to the resolution group (p < 0.05). Statistically significant cutoff values for persistent priapism were measured by ROC as PLT: ⩾ 254x103/µL; MPV: ⩾ 13.2 fL; PDW: ⩾ 15.6 fL; PCT: ⩾ 24%; and TLC ≥ 8.5x103/L. Priapism duration of ≤ 17.9 hours was significantly related to detumescence rate (p = 0.000). Multivariable logistic regression analysis showed that priapism duration and higher MPV are prognostic parameters for detumescence in SCA. Conclusions: The higher MPV and duration of priapism can be used as parameters for evaluating detumescence outcomes in steady-state SCA with acute IP.

KEY WORDS: Sickle cell anemia; Acute ischemic priapism; Platelet volume indices.

Among the pathophysiologic mechanisms proposed for priapism development in the SCA population, the acute ischemic priapism (IP) (veno-occlusive, low flow) type is represented by painful and rigid penile erection (1, 4). Acute IP is a medical emergency that should be prevented and managed immediately to preserve the function of erectile tissue (5). In this IP population, aspirated blood gas analysis of the corpus cavernosum usually reveals hypoxia, hypercapnia, and acidosis (4). In addition, penile Doppler ultrasound (PDUS) has improved the diagnosis of IP by demonstrating very low or absent arterial blood flow in the corpus cavernosum (6). Nevertheless, the risk of corpora cavernosal fibrosis and partial or complete impotence in SCA patients with IP suggests the need for careful evaluation and new diagnostic techniques (4). Because of the vasculopathy, chronic hemolysis, and veno-occlusive pathogenesis of SCA, multiple hematologic markers are needed to predict the outcome of IP in SCA patients. The role of platelet count (PLT) and mean platelet volume (MPV) in these veno-occlusive mechanisms is well documented (7-11). Previous studies confirmed the association between IP, defined as a vasculogenic disease, and platelet activation leading to higher MPV (9, 10). Therefore, platelet volume indices (PVIs) can be measured as potential laboratory parameters for diagnosis and treatment of IP. To our knowledge, the role of laboratory PVIs, such as MPV, platelet distribution width (PDW), and plateletcrit (PCT), as prognostic markers for IP in SCA patients at steady-state has not yet been analyzed. The aim of this paper was to determine the diagnostic and cutoff values of PVIs such as MPV, PDW, and PCT for the detumescence outcomes of acute IP in SCA patients.

Submitted 31 May 2022; Accepted 4 June 2022

PATIENTS INTRODUCTION

Sickle cell anemia (SCA) is a polymorphic genetic disorder characterized by recurrent inflammatory damage and episodic vaso-occlusive complications such as acute chest syndrome, acute scrotal pain, and priapism (1, 2). Priapism is a persistent and prolonged penile erection lasting > 4 hours that occurs in 35% of SCA patients (3, 4).

AND METHODS

Study population One hundred thirteen (113) SCA patients with steadystate were admitted to the emergency room with priapism. Of those case series, only 56 cases presenting acutely with IP were included in this research and required immediate intervention to avoid fibrosis of cavernosal tissues and subsequent erectile dysfunction. Fifty-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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four (54) healthy control males from the subjects undergoing medical examination in our hospital were included in our study for comparison. Ages of the patients and controls were similar. The control participants had no history of priapism, malignancy, pelvic trauma, surgery, or hematologic disease. The research protocol for the study was approved by the Institutional Reviewer Board of the Faculty of Medicine at Jazan University, Saudi Arabia and was conducted in accordance with the principles of the Helsinki Declaration. Selection criteria Inclusion criteria: Patients (aged 19-54 years) with SCA who complained of an acute episode of priapism for the first time and were aware of having SCD were included. Suspected IP was diagnosed by PDUS by demonstration of absent or low cavernous blood flow (6). IP was confirmed by aspiration of hypoxic and dark blood from the corpora cavernosa and typical blood gas analysis values (pO2 < 30 mmHg, pCO2 > 60 mmHg, pH < 7.25) before any intervention (4). Included SCA participants were identified by qualitative and/or quantitative hemoglobin electrophoresis at pH 8.6 on cellulose acetate paper. Steady-state SCA was diagnosed according to criteria defined by Ballas SK et al. (12). Exclusion criteria: SCA patients were included after excluding non-IP by blood gas analysis in the corporeal aspiration and normal blood flow levels in the cavernosal arteries in PDUS. Excluded patients were also those with myeloproliferative disorders and leukemic diseases. Patients with a history of strokes, recurring or previous priapism attacks, or hospitalization for an acute painful crisis within the previous year were excluded. Patients with a history of pelvic surgery and trauma, newly diagnosed coronary artery disease, active infectious disease, malignancy, immunological disease, or those taking antiplatelet or anticoagulant medication were all excluded. Clinical examination All SCA patients underwent a complete physical examination with a detailed history as soon as possible after initial presentation of priapism. Abdominal, perineal, and digital rectal examinations were also performed to exclude any evidence of trauma, pelvic infection or malignancy or the presence of any other systemic symptomatology associated with SCD, such as a sickle crisis. A comprehensive history included information on the duration of priapism, any medication used, the presence of pain, and any previous history of priapism. Physical examination of the penis was essential to determine the extent and degree of rigidity, the involvement of the corpora cavernous bodies, and the presence of penile tenderness. In this study, priapism was defined as a persistent painful erection lasting more than 1 hour without orgasm and ejaculation and requiring medical therapy (13). During intervention, decisions regarding continuing the combination of aspiration, irrigation, and intracavernous injection (ICI) or proceeding with immediate surgical interventions were guided by the clinicians. All acute IP cases were treated by ICI therapy with phenylephrine in combination with aspiration and irrigation with 0.9% saline. ICI can be repeated every 3-5 minutes until

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detumescence occurs, with a maximum of 1 mg administered within one hour. A physician should monitor the heart rate and blood pressure (14). After repeated intervention, patients were evaluated for the resolution of priapism, which was indicated by the disappearance of corporal rigidity by exam, the absence of acidosis by cavernous blood gas testing, and the return of cavernosal artery flow by PDUS (14, 15). Laboratory evaluation Peripheral blood samples were collected in tubes containing EDTA-K2 (potassium ethylenediaminetetraacetic acid) anticoagulant before any form of priapism intervention from patients and control subjects. Samples were analyzed within one hour of the patient’s referral (16-18). An automated blood cell counter (Sysmex Corp., Japan) was used to measure PLT, PVIs (MPV, PDW, and PCT), and total leukocyte count (TLC). Statistical analysis Analyses were conducted using IBM SPSS version 24.0 (Armonk, NY). Continuous variables were tested for normality of distribution with the Kolmogorov-Smirnov test. Depending on the distribution, data was presented as means, standard deviation (SD), or medians with the interquartile range (IQR). Differences in the means were compared using the unpaired Student’s t-test for normally distributed data, whereas the non-parametric MannWhitney U test was carried out for comparing medians of non-normally distributed data. Chi-squared tests were carried out to analyze categorical variables. Receiver operating characteristic (ROC) curve analysis was performed to find out cut-off values and areas under the curve (AUC) for potential predictive values. Multivariable logistic regression analysis was conducted to identify the potential risk factors. A p-value of 0.05 was used as a threshold of significance.

RESULTS

The demographic and clinical characteristics of the studied patients are summarized in Table 1. In the IP and the control group, the median ages were 41.2 (IQR: 33.245.2) and 42.7 (IQR: 34.2-46.2) years, respectively. The median time of duration of priapism was 17.9 (IQR: 8.526.4) hours. Forty (71.4%) SCA patients were found to have detumescence during intracavernosal intervention. The remaining 16 (28.6%) patients received immediate spongiocavernosal surgical shunting with tunneling for persistent priapism. In terms of duration of priapism, a priapism event ≤ 17.9 hours in duration (n = 25, 44.6%) was statistically significantly correlated to the detumescence rate in SCA patients (p = 0.000).On the contrary, PLT and PVIs (MPV, PDW, and PCT) had no significant relationship with the duration of priapism (p = 0.130, p = 0.087, p = 0.145, and p = 0.245, respectively). In the acute IP group, the medians of PLT, MPV, PDW, and PCT were 254 x103/µL (IQR: 227-296), 13.2 fL (IQR: 10.5-14.1), 16.9 fL (IQR: 15.8-19.2), and 0.35% (IQR: 0.23-0.38), respectively. The medians of PLT, MPV, PDW, and PCT of the IP cases were detected to be significantly higher than those in the control group (p =

Acute ischemic priapism and platelets indices

Table 1. Demographic and clinical data amongst steady-state SCA patients with acute ischemic priapism (IP). Numbers of patients Age at presentation, yrs * Follow-up, yrs * Priapism duration, hrs * Penile Doppler US (blood flow) n (%) Absent Low Penile aspiration outcome †, n (%) Non-resolution with full rigidity Detumescence

56 41.2 (33.2-45.2) 3.4 (2.6-4.2) 17.9 (8.5-26.4) 53 (94.6) 3 (5.4) 16 (28.6) 40 (71.4)

Values are presented as median (interquartile range, IQR). † Intracavernosal injections (ICI) of phenylephrine with aspiration and 0.9% saline irrigation.

Table 2. Hematologic parameters amongst steady-state SCA men with acute ischemic priapism and controls in men without SCA. Parameter Platelet count (PLT) (X 103/µL) Mean platelet volume (MPV) (fL) Platelet Distribution width (PDW) (fL) Plateletcrit (PCT) (%) Total leucocyte count (TLC) (x103 L)

Ischemic priapism group 254 (227-296) 13.2 (10.5-14.1) 16.9 (15.8-19.2) 0.35 (0.23-0.38) 14.3 (7.4-21.1)

Values are presented as median (interquartile range, IQR). * Mann-Whitney U Test.

Control group P-value * 249 (238-253) 0.011 7.6 (7.3-13.4) 0.002 14.3 (5.7-15.7) 0.032 0.32 (0.27-0.38) 0.022 11.2 (8.4-13.2) 0.027

Table 4. Multivariate analysis of the risk factors for the corporal detumescence outcomes. Platelet count (PLT) (x103/µL) Mean platelet volume (MPV) (fL) Platelet distribution width (PDW) (fL) Plateletcrit (PCT) (%) Total leucocyte count (TLC) (x103 L) Priapism duration (hrs)

OR 0.623 8.895 2.005 0.602 0.267 26.079

95% CI 0.177-2.195 1.000-79.089 0.219-18.362 0.129-2.800 0.051-1.389 2.401-283.259

P-value 0.462 0.050 0.538 0.517 0.117 0.007

OR: odds ratio; CI: confidence interval.

12.5%, 37.5%, 42.5%, and 62.5%. The area under the curves (AUC) for PLT, MPV, PDW, PCT, TLC, and duration of priapism were 0.652 (p = 0.079), 0.811 (p = 0.000), 0.630 (p = 0.130), 0.548 (p = 0.574), 0.521 (p = 0.807), and 0.842 (p = 0.000), respectively (Table 3). Based on a multivariable logistic regression model after grouping predictor factors, both duration of priapism and MPV showed their independent prognostic impact on the outcome of priapism in steady-state SCA patients (Table 4).

DISCUSSION

The potential pathogenic and diagnostic roles of platelets in vascular pathologies have been described in many papers. The PLT and related platelet volume indices (PVIs) 0.011, p = 0.002, p = 0.032, and p = 0.022, respectively) have been identified as markers of thrombocyte reactivity (Table 2). Ppersistent priapism in SCA cases had higher in various vascular and urological diseases (17-20). MPV, PCT, and PDW than those in the detumescence Priapism is a vascular disease with a veno-occlusive group, which was statistically significant (p = 0.001, p = mechanism and endothelial damage as its main patho0.042, and p = 0.035, respectively). physiological basis (20). Platelet hematological parameRegarding the median TLC, there was a statistically sigters play a significant role in IP pathophysiology. nificant difference among groups (p = 0.027) (Table 2). However, there is relatively little data on PVIs (MPV, Additionally, SCA cases with priapism resolution had a PDW, and PCT) in priapic patients, as well as, their relasignificantly lower TLC than those in the persistent group tionship with the outcome of primary emergency ICI of (p = 0.046). phenylephrine and the combination of aspiration and The evaluation made with ROC curve analysis detected irrigation in SCA patients with acute IP (9, 10). that cut-off levels for PLT, MPV, PDW, PCT, TLC, and In the study by Sönmez et al. (9), the relationship between duration of priapism for the prediction of priapism resoIP and high PLT and MPV was confirmed to be signifilution were 254x103/µL, 13.2 fL, 15.6 fL, 24%, 8.5x103/L cant, similarly to the study by Ufuk et al. (10). However, and 17.9 hours, respectively. The corresponding sensitivPCT was not included in the platelet parameters analyzed ities were 62.5%, 81.3%, 75%, 69.8%, 68.8%, and 87.5%, in this series, and statistical studies were performed with and the corresponding specificities were 55.0%, 67.5%, predictive and cutoff values in IP patients without SCA. The significance of our study was the addition of PCT, besides PLT, MPV, Table 3. and PDW, and the statistical calculaPrediction of the corporal detumescence outcomes according to the cut-off values tion of their cutoff values as suspectof PLT, MPV, PDW, PCT, TLC, and duration of priapism. ed predictive factors in acute IP with SCA. Cut-off value AUC P-value 95% CI Sensitivity (%) Specificity (%) In this study, IP men with SCA had Platelet count (PLT) 254x103/µL 0.652 0.079 0.499-0.804 62.5% 55% higher PVIs (MPV, PDW, and PCT) Mean platelet volume (MPV) 13.2 fL 0.811 0.000 0.676-0.946 81.3% 67.5% when compared to men who had Platelet distribution width (PDW) 15.6 fL 0.630 0.130 0.442-0.819 75% 12.5% never experienced priapism. Even so, Plateletcrit (PCT) 24% 0.548 0.574 0.370-0.727 69.8% 37.5% MPV had a strong sensitivity (81.3%) effect on IP pathogenesis. PLT, MPV, Total leucocyte count (TLC) 8.5x103 µL 0.521 0.807 0.360-0.682 68.8% 42.5% PDW, and PCT levels of the detumesPriapism duration 17.9 hrs 0.842 0.000 0.709-0.977 87.5% 62.5% cence cases also revealed a statisticalAUC, area under curve; CI, confidence interval. ly significant cut-off of 254x103/µL, Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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13.2 fL, 15.6 fL, and 24% in priapic SCA patients as an indicator for cavernosal function. Moreover, the MPV value of unsuccessful detumescence patients revealed a higher significant cut-off of 13.2 fL than that of 9.11 fL for priapic cases without SCA as a parameter for erectile tissue function (10). According to this study, the MPV has been suggested to have a role in the detumescence response in SCA patients who received ICI phenylephrine with aspiration and saline irrigation. Despite the encouraging resolution of corporal rigidity in this study, 28.6% of patients are still experiencing persistent priapic attacks. Those patients have a negatively significant correlation with higher MPV. Those patients with a higher MPV had a very low chance of improvement in their corporal rigidity in terms of the absence of cavernosal artery inflow and persistent acidosis. This finding was supported by increased thrombocyte activity, which is associated with increased thromboxane A2 synthesis, soluble P-selectin, and intravascular thrombosis in SCA (21). In our report, the high incidence of hemolysis in SCA results in a lowering of NO bioavailability and down regulation of phosphodiesterase type 5 protein expression, which impairs penile vascular reactivity (22). Also, the increased MPV triggers and increases corporal veno-occlusive dysfunction, leading to hypoxia and microvascular thrombosis of the corpora cavernosa (1, 7, 23). Consequently, high MPV can be used as a biomarker for the recovery of erectile tissue function in SCA patients with acute IP. Interestingly, we found a significantly increased PDW in acute IP patients with SCA compared to healthy controls, with a positive relationship with detumescence. Even so, PDW levels of unresolved priapism showed a higher significant cut-off of 15.6 fL for cavernosal damage. However, Ufuk et al. found that the PDW levels were similar between IP patients without SCA and control healthy subjects, even though the platelet count was significantly lower in IP patients than in controls (10). Nonetheless, other investigators have observed that PDW is a specific sign of active platelet release for developing thromboembolic disorders (7, 24). The increased PDW in SCA with priapism is mainly related to the up-regulated production and average volume of megakaryocytes. Additionally, we detected a higher PCT with its effect on priapism resolution among those patients. This is in accordance with the Adawi et al. study that demonstrated higher PCT levels with significant implications on testicular torsion outcome among patients with steady-state SCA (18). Mutlu et al. found that values of PCT are low with little effect on thrombosis processes (19). These findings demonstrated the significant role of priapism in the regulation of platelet count, and PVIs values in steady-state SCA patients. In our study, TLC was significantly increased in acute IP with a predictive outcome on detumescence found in SCA as a result of acute inflammation and excessive hemolysis, which is associated with active hematopoiesis (10). This inflammation promotes vascular endothelial adherence to sickle erythrocytes, which is associated with the release of cytokines, causing veno-occlusion dysfunction (25). Moreover, the high TLC in SCA patients with and without priapism was demonstrated by Ahmed et al.

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(26). Interestingly, Madu et al. found a positive relationship between low levels of TLC and the development of priapism, which is contrary to our observation (8). These conflicting studies could be related to differences in various factors such as study design, sickle cell genotype, precipitating factors, genetic factors, effects of intervention, and laboratory methods, all of which can change the hematological values of priapic patients with SCA (8, 16, 27). In general, the prognostic value of a complete blood count includes other biomarkers (eosinophil, and reticulocyte count), has been associated with the development of acute IP in men with SCA (8, 11, 13). Furthermore, in this report, patients with priapism > 17.9 hours had a positive correlation for predicting erectile tissue recovery. Similar results were found in other retrospective studies that observed cavernosal necrosis was more common with prolonged durations of > 12 hours. In IP, the histological damage in the erectile tissue appears to be time dependent. In patients with priapism < 12 hours, interstitial edema and minor endothelial defects predominate in the smooth muscle. On the contrary, extensive necrosis of the smooth muscle cells was detected after priapism lasting > 48 hours (28, 29). Moreover, the presence of intravascular clots inside the cavernous sinuses causes venous obstruction and recurrent priapism (30). Nonetheless, the duration of priapism had no significant effects on the PVIs in this retrospective case series. This may be due to the fact that not all cases who presented with a prolonged duration had a complete venous outflow occlusion, which may be related to stuttering priapism, which is associated with intermittent periods of detumescence, or because of focal necrosis/ fibrosis in the infracted corpora secondary to ischemic compartment syndrome in acute IP (4, 6, 14). Our results confirmed an independent poor outcome of IP management for SCA patients with both increased MPV and longer priapism duration. Their measured cutoff levels were detected to have a significant relationship with the priapism outcome. However, such retrospective analysis has many limitations. The number of IP cases included in the analysis was relatively small. We did not evaluate other etiologies of acute priapic attacks, such as leukemia or thalassemia. In addition, the normal ranges of platelet indicators need adjustment. Also, the lack of association between priapism and genetic factors associated with SCA may indeed limit the statistical power of our study. Moreover, the diagnosis of IP was established mainly after clinical parameters and cavernosal aspiration, both of which are prone to error (6). Also, these populations should be investigated for asymptomatic erectile dysfunction because of the high risk of vascular dysfunction associated with SCA.

CONCLUSIONS

In summary, this study shows that increased PVIs in SCA may have a beneficial role in the veno-occlusive pathogenesis of IP, which was associated with cavernosal damage. Furthermore, prolonged duration of priapism with a high MPV may be a predictive parameter for the development of corpora fibrosis in men with acute priapic attacks. Additionally, the use of laboratory MPV factor

Acute ischemic priapism and platelets indices

may guide the physician to identify high-risk sickle cell men presenting with acute IP, which is considered for primary nonsurgical resolution of the priapic event. Prospective clinical protocols involving large populations and different priapism types are also warranted to improve this issue.

ACKNOWLEDGMENTS

The authors would like to thank Manaji M. Ba-Baeer for his editorial and valuable assistance.

REFERENCES

1. Bivalacqua TJ, Musicki B, Kutlu O, Burnett AL. New insights into the pathophysiology of sickle cell disease-associated priapism. J Sex Med. 2012; 9:79. 2. Claudino MA, Fertrin KY. Sickling cells, cyclic nucleotides, and protein kinases: the pathophysiology of urogenital disorders in sickle cell anemia. Anemia. 2012; 2012:1-13. 3. Adeyoju AB, Olujohungbe AB, Morris J, et al. Priapism in sickle cell disease; incidence, risk factors and complications-an international multicenter study. BJU Int. 2002; 90:898. 4. Broderick GA, Kadioglu A, Bivalacqua TJ, et al. Priapism: Pathogenesis, epidemiology, and management. J Sex Med. 2010; 7:476. 5. Berger R, Billups K, Brock G, et al. Report of the American Foundation for Urologic Disease (AFUD) Thought Leader Panel for evaluation and treatment of priapism. Int J Impotence Res. 2001; 13(Suppl 5):S39. 6. von Stempel C, Zacharakis E, Allen C, et al. Mean velocity and peak systolic velocity can help determine ischaemic and nonischaemic priapism. Clin Radiol. 2017; 72:611. 7. Ciftci H, Yeni E, Demir M, et al. the mean platelet volume be a risk factor for vasculogenic erectile dysfunction? World J Mens Health. 2013; 31:215. 8. Madu AJ, Ubesie A, Ocheni S, et al. Priapism in homozygous sickle cell patients: important clinical and laboratory associations. Med Princ Pract. 2014; 23:259. 9. Sönmez MG, Kara C, Karaibrahimoglu A, et al. Ischemic priapism: Can eosinophil count and platelet functions be positive predictive factors in etiopathogenesis. Can Urol Assoc J. 2017; 11:E297. 10. Ufuk Y, Hasan Y, Murat U, et al. Does platelet activity play a role in the pathogenesis of idiopathic ischemic priapism? Int Braz J Urol. 2016; 42:118. 11. Alkindi S, Almufargi SS, Pathare A. Clinical and laboratory parameters, risk factors predisposing to the development of priapism in sickle cell patients. Exp Biol Med. 2020; 245:79.

need time adjusted mean platelet volume measurements? Lab. Hematol. 2010; 16:28. 17. Ghanem MA, Adawi EA, Hakami NA, et al. The predictive value of the platelet volume parameters in evaluation of varicocelectomy outcome in infertile patients. Andrologia 2020; 52:e13574. 18. Adawi EA, Ghanem MA, Ghanem AM, et al. High platelet distribution width can independently predict testicular survival in testicular torsion among steady state sickle cell anemia patients. World Jnl Ped Surgery. 2022; 5:e000358. 19. Mutlu H, Artis T, Erden A, Akca Z. Alteration in mean platelet volume and platelet crit values in patients with cancer that developed thrombosis. Clin Appl Thromb Hemost. 2013; 19:331. 20. Chu SG, Becker RC, Berger PB, et al. Mean platelet volume as a predictor of cardiovascular risk: A systematic review and metaanalysis. J Thromb Haemost. 2010; 8:148. 21. Ridgley J, Raison N, Sheikh MI, et al. Ischaemic priapism: A clinical review. J Urol. 2017; 43:1. 22. Champion HC, Bivalacqua T, Takimoto E, et al. Phosphodiesterase-5A dysregulation in penile erectile tissue is a mechanism of priapism. Proc Natl Acad Sci USA. 2005; 102:1661. 23. Braekkan SK, Mathiesen EB, Njølstad I, et al. Mean platelet volume is a risk factor for venous thromboembolism: the Tromsø Study, Tromsø, Norway. J Thromb Haemost. 2010; 8:157. 24. Wang JJ, Wang YL, Ge XX, et al. Prognostic values of plateletassociated indicators in resectable lung cancers. Technol Cancer Res Treat. 2019; 18:1533033819837261. 25. Makis AC, Hatzimichael EC, Bourantas KL. The role of cytokines in sickle cell disease. Ann Hematol. 2000; 79:407. 26. Ahmed SG, Ibrahim UA, Hassan AW. Hematological parameters in sick cell anemia patients with and without priapism. Ann. Saudi Med. 2006; 26:439. 27. Conran N, Fattori A, Saad STO, Costa FF. Increased levels of soluble ICAM-1 in the plasma of sickle cell patients are reversed by hydroxyurea. Am J Hematol. 2004; 76:343. 28. Zacharakis E, Raheem AA, Freeman A, et al. The efficacy of the t-shunt procedure and intracavernous tunneling (snake maneuver) for refractory ischemic priapism. J Urol. 2014; 191:164. 29. Ortac M, Cevik G, Akdere H, et al. Anatomic and functional outcome following distal shunt and tunneling for treatment ischemic priapism: A single-center experience. J Sex Med. 2019; 16:1290. 30. Upadhyay J, Shekarriz B, Dhabuwala CB. Penile implant for intractable priapism associated with sickle cell disease. Urology. 1998; 5:638.

12. Ballas SK, Lieff S, Benjamin LJ, et al. Definitions of the phenotypic manifestations of sickle cell disease. Am J Hematol. 2010; 85:6. 13. Cita KC, Brureau L, Lemonne N, et al. Men with sickle cell anemia and priapism exhibit increased hemolytic rate, decreased red blood cell deformability and increased red blood cell aggregate strength. PLoS One. 2016; 11:e0154866. 14. Salonia A, Eardley I, Giıliano F, et al. European Association of Urology guidelines on priapism. Eur Urol. 2014; 65:480. 15. Burnett AL, Sharlip ID. Standard operating procedures for priapism. J Sex Med. 2013; 10:180. 16. Lancé MD, van Oerle R, Henskens YMC, Marcus MA. Do we

Correspondence Essa A. Adawi, MD dr.adawi@gmail.com Mazen A. Ghanem, MD (Corresponding Author) mazenghanem99@yahoo.co.uk Department of Urology, Jazan University, KSA, Jazan, Saudi Arabia

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DOI: 10.4081/aiua.2022.2.222

ORIGINAL PAPER

The distribution of the clinical variables in a population of adult males circumcised for phimosis: A contribution to the clinical classification of phimosis Giuseppe La Pera 1, Stefano Lauretti 2 1 Urology

UPMC Salvator Mundi International Hospital, Rome, Italy; and Regenerative Surgery, S. Caterina della Rosa Health Center, ASL Roma 2, Rome, Italy.

2 Andrological

Summary

Background: The literature regarding the quality of the sex life in adult males after circumcision, due to phimosis, is scarce and sometimes contrasting. This could be due to comparisons of a nonhomogeneous distribution of the clinical variables of men who have undergone circumcision. Objective: The objective of this study was to evaluate the distribution of the clinical variables in the adult male population who had circumcision for phimosis, and to propose a clinical classification of the phimosis to characterize it in adult males in more homogeneous sub-groups for the common clinical variables. Materials: A population of 244 adult male patients with phimosis was evaluated retrospectively. The mean age was 50.7 years. Each patient was classified according to the most common clinical variables. The variables that make up this classification of the phimosis were: Position (P1-2) to indicate if phimosis is present when the penis is at rest (P2) or only during an erection (P1); Grade (G 0-4) in relation to the extent of glans visibility; Complexity (Co 0-4) of comorbidities; Timespan (T 1-10) of the phimosis. Results: The distribution of the variables was the following: Position P1:30.73%, P2:69.26%; Grade G0:30.73%, G1:23.77%, G2:27.45%, G3:12.29%, G4:5.73%; Complexity (associated penile comorbidities): C0:48.36%, C1:4.5%, C2:0.8%, C3:43.03%, C4:3.27% Timespan: 57.78% of the patients had phimosis for less than a year; 18.03% between 1 and 2 years; 11.88% between 2 and 10 years; and 12.29% for more than 10 years. Conclusions: The distribution of the clinical variables in the adult male population who underwent circumcision due to phimosis was not homogeneous regarding the appearance, severity, comorbidity, and timespan. This non-homogeneity could explain, in some cases, the contrasting results regarding the quality of sex life after circumcision in the literature. The proposed classification can offer an objective tool for researchers and clinicians group the patients into more homogeneous subgroups.

KEY WORDS: Phimosis; Circumcision; Classification. Submitted 13 April 2022; Accepted 3 May 2022

INTRODUCTION

Male circumcision is one of the most common surgical procedures performed in the world and it is estimated that

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around one third of men are circumcised for a variety of reasons, including religious, cultural or medical (1). While many studies have been made dealing with the theme of sexual satisfaction and orgasm in males who were circumcised during infancy, the effects on the quality of sexual life, orgasm and sensitivity following circumcision performed in adulthood on patients with phimosis have not been fully clarified (2-3). Regarding this theme, the systematic revision of literature and analysis show contrasting results (2) and evidence of low quality (3). Probably, this is due not only to a heterogeneity of the studies (3), but also the lack of objective evaluation, relative to the initial clinical conditions of the adult patients’ penis prior to circumcision surgery. Furthermore, in the Systematic Reviews and Meta-analyses (2-5), there is no mention as to whether the considered patients for analysis were circumcised for ritual, esthetic or medical reasons, the most common being sclero-atrophic lichen (6-11), or if the data were mixed all together. Consequently, if we want to analyze the effects of the circumcision on the quality of sexual life and orgasm in male adults circumcised for medical reasons, we must ask ourselves whether the patients undergoing this intervention all start with the same clinical conditions. In light of this data, in our opinion, it is therefore reasonable to believe that the differences in the results could be due, in some cases, to the fact that those male samples who got circumcised could have a distribution of the clinical variables that characterize the phimosis in a profoundly different way from each other, and which could affect the quality of the sex life after surgery in a different way. For example, how could post-operative sexual satisfaction be compared in men with an adherence to glans mucosa or a macroscopic anatomic prepuce alteration or men with sclero-atrophic lichen, or with a condition of a Queyrat erythroplasia to those with an uncomplicated phimosis? The actually available classification of phimosis in literature, like that of Kirikos (12), is insufficient in analyzing sub-groups and rendering the case histories homogeneous and comparable, because they were obtained from a population of boys. Kirikos classification doesn’t consider either the role of the erection and sexual activity or the presence of eventual clinical comorbidities of the prepuce and penis, which could develop in later life, that could be No conflict of interest declared.

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Phimosis classification

able to modify the context of phimosis in a pejorative sense. In addition, the Kirikos classification doesn’t consider the time span of the phimosis, which, in adults, can be of several decades, while in children, the maximum is only a few years. The primary objectives of this paper are two: 1) to highlight the heterogeneous distribution of the main clinical variables in a non-selected sample of adult males undergoing a circumcision, and 2) to propose a classification of the phimosis for them, able to make clinically homogenous sub-groups, in order to obtain a reliable statistical analysis.

METHODS

This classification is based on the common clinical variables that normally characterize a phimosis, such as the presentation of the phimotic prepuce (P) in relation to the state of the penis (in flaccidity or in erection), the severity of the phimosis (G) based on the proportion of the visible glans during the prepuce retraction or difficulty in prepuce sliding (13), the eventual comorbidities associated with the foreskin or penis (Co) and the timespan (T) of the phimosis, according to what is referred to in the patient’s medical history. Variable description The presentation of the phimosis The fundamental criteria for a consistent and homogeneous application of the classification is to evaluate if the presence of the preputial stenosis and the difficulty in prepuce sliding is observed only in the phase of detumescence, or in the phase of the erection. This variable is obtained by an attentive medical history. The patient is asked if the glans is visible in the phase of erection, or whether he has had any difficulty in prepuce sliding during an erection, as referred to in a self-reported photo of his erected penis, which is to be brought to the subsequent check-up. We have indicated this variable with the letter “P” for Presentation or Position. The first variable will be indicated as follows: P0: Absence of preputial stenosis both at rest and during an erection. P1: Preputial stenosis visible only during the erection; arbitrarily called here “functional phimosis,” because connected only to the dynamic state (Figure 1) and leading to prepuce sliding difficulties P2: Preputial stenosis visible during the retraction of the foreskin, with the penis in the resting position. We arbitrarily call this an “anatomic phimosis”. The severity of the phimosis The second variable of this classification evaluates the severity of the phimosis, according to the amount of the glans exposed during the foreskin retraction. The less visibility of the glans during the foreskin retraction, the greater the severity of the phimosis. Different from the classification of Kirikos (12) that considers, at the same time, both the state of the skin and the extension of the phimosis, we’ve provided for 2 different categories: the severity of the phimosis and the comorbidity, which can be described in a more precise way. We have indicated with G, the grade

of the phimosis severity, and have attributed a score of 0-4 for the progressively worse levels (G0-G4) G0: Manual retraction of the foreskin consents the visualization of the entire glans and the coronal sulcus is overcome. G1: Manual retraction of the foreskin consents the visualization of almost all of the glans, without overcoming the coronal sulcus. G2: Manual retraction consents the visualization of the meatus and half of the glans. G3: Manual retraction of the foreskin consents to visualize only the meatus (Figure 2). G4: Visualizing the meatus during manual retraction of the foreskin is impossible (Figure 3). The prepuce is completely closed. Figure 1. This patient has a phimosis visible only during erection. The presentation of the phimosis is referred to as functional phimosis or P1 in the PGCT classification.

Figure 2. In this patient, manual retraction of the foreskin consents to visualize only the meatus. This condition in the PGCT classification is called G3.

Figure 3. Patient with Grade 4 phimosis, according to the PGCT classification. Visualizing the meatus during manual retraction of the foreskin is impossible. The prepuce is completely closed.

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Complexity of prepuce and glans-associated pathologies The third variable in this classification that best characterizes the phimosis in an adult male, with respect to a child, is defined as the description of eventual other pathologies frequently associated with the prepuce and glans, which can be distinguished during a physical exam. We have indicated this comorbidity variable with the letters C. The order of the classification of this variable is an ordinal scale of severity/complexity, where the C0 indicates the absence of the pathology.

Figure 4. Patient with coexisting dermatologic or sexually transmitted pathology such as Condyloma Acuminata, here classified in the PGCT classification as C2.

Figure 5. Patient with Scleroatrophic Lichen. Phimosis is associated with inflammatory dermatologic pathologies and classified according to the PGCT as C3.

Figure 6. Patient with Queyrat Disease (on the right) and Verrucous Carcinoma and Squamous Cell Carcinoma (on the left). In the PGCT classification, this leads to a C4 case.

The progression of C1 to C4 corresponds to a greater severity/complexity of comorbidities, reaching higher values, describing pre-cancerous or cancerous lesions. CX: When this variable is unknown. C0: No pathology of the penis glans or prepuce, associated with phimosis. C1: Pathologies of the penis or previous penis surgeries (previous circumcisions, preputial plastic or frenulectomy, surgery of cavernous bodies, urethral pathologies, history of paraphimosis). C2: Coexisting dermatologic or sexually transmitted pathologies (Figure 4). C3: Phimosis is associated with inflammatory dermatologic pathologies (Figure 5). C4: Phimosis coexists with pre-cancerous and/or cancerous pathologies (Queyrat, verrucous carcinoma, squamous cell carcinoma) (Figure 6). This classification could be implemented with a histologic exam, and at that point, there would be “p,” as for pathologic, before the letter “C,” that is to say, “pC.” In this classification, we have used the clinical evaluation, because the histologic exam is available only after surgery, after the decision to perform the circumcision has been made. The time span of the phimosis The last variable refers to the time span of the phimosis, based on the patient’s history. During the exam, the patient is asked how much time he has had the phimosis. We have indicated this variable with the letter “T” and have identified it with a number of 2 digits, corresponding to the number of years, in which 01 indicates a time span of less than 1 year, and 02 a time span of less than 2 years, etc. Setting and participants Over the past two years, 252 consecutive patients submitted to circumcision have been retrospectively evaluated in Rome, Italy and classified on the basis of this PGCT classification. Eight patients were excluded for incomplete data in the charts. The remaining 244 patients were evaluated for statistical analysis with a minimum follow up of 3 months. Histological examination has been performed in all patients. The ages of these 244 patients ranged from 15 to 91 years old, with an average age of 50.7 years and a mean of 53 years +/- 22.7 SD. The variables has been collected during our routine clinical practice and therefore have been retrieved in the medical records of all single recruited patients for this observational study. Ethics committee All patients gave their informed consent and were guaranteed anonymity for both images and data. The Rome 2 Ethics Committee, after has been informed of the whole procedure in accordance with the GPC rules, published the resolution number DD 396 on February 11th 2022.

RESULTS

The results and the 95% Confidence Limit (C.L.), according to this classification, are the following and are reported in Table I.

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Table 1. Distribution of phimosis clinical variables according to the PGCT classification in patients circumcised for phimosis. Presentation of phimosis P1 P2 Total 244 Grade of phimosis G0 G1 G2 G3 G4 Total 244 Complexity of associated comorbidity C0 C1 C2 C3 C4 Total 244 Timespan of phimosis < 1 year 1-2 years 2-10 years > 10 years Total 244

Cases

IC95%

75 169

30.7% 69.3%

25.0%-36.0% 63.1%-75.0%

75 58 67 30 14

30.7% 23.8% 27.5% 12.3% 5.7%

25.0%-36.9% 18.6%-29.6% 22.0%-33.5% 8.5%-17.1% 3.2%-9.4%

118 11 2 105 8

48.4% 4.5% 0.8% 43.0% 3.3%

41.9%-54.8% 2.3%-7.9% 0.1%-2.9% 36.7%-49.5% 1.4%-6.4%

141 44 29 30

57.8% 18.0% 11.9% 12.3%

51.3%-64.1% 13.4%-23.4% 8.1%-16.6% 8.5%-17.1%

Presentation P1: 30.73% (C.L. 95%: 25.0%-36.0%), P2: 69.26% (C.L. 95%: 63.1%-75-0%) Severity G0: 30.73% (C.L, 95% 25.0%-36.9%), G1: 23.77% (C.L.95%: 18.6%-29.6%), G2: 27.45% (C.L.95%: 22.0%-33.5%), G3:12.29% (C.L. 95%: 8.5%-17.1%), G4: 5.73% (C.L.95%: 3.2%-9.4%) Complexity Associated Penile Comorbidities C0: 48.36% (C.L.95%: 41.9%-54.8%), C1: 4.5% (C.L.95%: 2.3%7.9%), C2: 0.8% (C.L. 95%: 0.1%-2.9%), C3: 43.03% (C.L. 95% 36.7%-49.5%), C4: 3.27% (C.L. 95%: 1.4%6.4) Time span: Regarding the results, we have grouped the phimosis time span into 4 periods. About 57.78% (C.L. 95%: 51.3%-64.1%) of the cases had a phimosis for less than a year; 18.03% (C.L.95%: 13.4%23.4%) had it for more than one year, but less than 2 years; 11.88% (C.L.95% 8.1%-16.6%) had it for more than 2 years but less than 10 years and about 12.29% (C.L. 95% 8.5%-17.1%) of the cases had a phimosis for more than 10 years.

DISCUSSION

As can be observed in Table 1, 30.73% of the patients in our sample group, who asked to be circumcised, belonged to P1 category, experiencing a “phimosis” only during the erection. Regarding this connection, the term phimosis due to a stenosis of the foreskin that does not allow the glans to be visible during skin retraction, should be re-evaluated and re-defined instead as a sliding disorder of the foreskin (13). In fact, the most frequent definitions of phimosis (14-15) refer only to a retraction disorder of the foreskin

that would not allow the glans to be uncovered. As can be observed in our series, about 30% of the subjects require circumcision due to a preputial stenosis that does not allow the foreskin to slide during erection, despite the glans being completely visible during retraction of the foreskin at rest. According to the classification proposed here, this condition will be classified as P1 G0 (Figure 1). If we analyzed the sub-groups according to the comorbidities, we observed that 43.03% of the patients had inflammatory dermatological diseases and were included in the C3 category. Such data demonstrates that the male population undergoing a circumcision is not homogeneous in the distribution of the clinical variables that characterize the phimosis. Further, the “phimosis” can be considered as being a diagnosis corresponding to a framework composed of completely different clinical pictures, possibly leading to different results and potentially important biases. Therefore, the proposal of a classification of the genital context has the objective of rendering the results of the circumcision comparable in all of its variables including surgical, esthetic, and that of sexual satisfaction. Consequently, such a classification containing comparable and useful data, is necessary, in order to define guidelines about circumcision in adult males, which are currently inexistent (15). In our opinion, this second objective of our paper, the proposal of the clinical classification of phimosis, has three limitations: The first limitation of this classification is that it deals with a retrospective, rather than a prospective study. This should be kept in mind in the case that clinical decisions must be taken on the basis of this classification, which, so far, is still only a proposal. The second limitation is that this classification is primarily clinical because the histological exam can be acquired only after the surgery has been done. As soon as we obtain this histological exam, we can add the letter “p” to the value of the acronym. The third limitation is that the choice of the 4 clinical variables derives from clinical practice, and that in the future, it could be necessary to add other clinical variables. Finally, the fourth limitation is that the time variable is obtained by the patients’ recollection, which could be imprecise. Nevertheless, in our experience, the patients’ recollection is very precise if the time in question is not greater than 3-4 years. Possible developments The PGCT (P: presentation, G: grade of severity, C: Complexity of associated comorbidities and T: time span) classification is proposed and offered to researchers and clinicians in order to provide an objective instrument of evaluation that reduces the variability of recruited patients. In this way, the quality of the Randomized Clinical Trials, Systematic Reviews and Meta-Analyses regarding the quality of the sex life in patients affected by phimosis following a circumcision and in those not circumcised can be improved. Furthermore, this classification, in defining more homogenous sub-groups, can contribute to identifying and better characterizing the cause-effect relationship for imporArchivio Italiano di Urologia e Andrologia 2022; 94, 2

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tant diseases, such as cancer of the penis (16-17). In fact, although there is a lot of evidence demonstrating this relationship, such as the different lifetime risks of penile cancer in circumcised men (1 in 50.000-120.000) (1718) and in those uncircumcised (1 in 600-900) (19) and the observation that the benefits of the circumcision are greater if the surgery is done precociously (20). However, it has never been demonstrated that the risk of developing cancer increases with the increase of the time span of the onset of phimosis as well as the severity of the disease (21-24). Also, for other pathologies, an association between phimosis and circumcision and prostate cancer has been described, although not exclusively (25-28). In all of these pathologies, the ability to demonstrate if the risk of getting the pathology increases with time of onset and severity of the phimosis, would provide elements of evaluation regarding public health decisions. In fact, in all of the studies, an association has been reported rather than a causal relationship. Therefore, the public health policy makers could have more elements of evaluation if they could add the variables of time span and severity of phimosis to their various epidemiologic studies, an information never considered until now. A further application of this classification could be evaluating the Patient Related Outcomes (PRO). Comparing homogeneous groups of patients with regards to the initial pathology that had led them to request a circumcision, could have an impact on the choice of surgical techniques, esthetic preferences and on the evaluation of the quality of the patient’s sex life after the circumcision.

CONCLUSIONS

3. Tian Y, Liu W, Wang JZ, et al. Effects of circumcision on male sexual functions: a systematic review and meta-analysis. Asian J Androl. 2013; 15:662-6. 4. Perovic SV. Atlas of congenital anomalies of the external genitalia. Refot Arka. 1999: p.13 5. Bañuelos Marco B, García Heil JL Circumcision in childhood and male sexual function: a blessing or a curse? Int J Impot Res. 2021; 33:139-148. 6. Morris BJ, Krieger JN. Does male circumcision affect sexual function, sensitivity or satisfaction? A systematic review. J Sex Med. 2013; 10:2644-2657. 7. Lewis FM, Tatnall FM, Velangi SS, et al. British Association of Dermatologists guidelines for the management of lichen sclerosus, 2018. Br J Dermatol. 2018; 178:839-853. 8. Kravvas G, Muneer A, Watchorn RE, et al. Male genital lichen sclerosus, microincontinence and occlusion: mapping the disease across the prepuce. Clin Exp Dermatol. 2022 Feb 12. doi: 10.1111/ced.15127. Epub ahead of print. PMID:35150005. 9. Gkalonaki I, Anastasakis M, Psarrakou IS, Patoulias I. Balanitis Xerotica Obliterans: an underestimated cause of secondary phimosis. Folia Med Cracov. 2021; 61:93-100. 10. Paulis G, Berardesca E. Lichen sclerosus: the role of oxidative stress in the pathogenesis of the disease and its possible transformation into carcinoma. Res Rep Urol. 2019; 11:223-232. 11. Edmonds EV, Hunt S, Hawkins D, et al. Clinical parameters in male genital lichen sclerosus: a case series of 329 patients. J Eur Acad Dermatol Venereol. 2012; 26:730-7.

The PGCT classification, applied to our sample, shows that adult male patients who require circumcision for phimosis, is heterogeneous for clinical presentation, severity, coexistence of comorbidity and time span. This could be one of the possible reasons for the contrasting data in the sex life quality results of adult males after circumcision in literature. The classification of more homogeneous sub-groups for these 4 variables could grant an objective and comparable evaluation of the different clinical cases of phimosis. In addition, it could highlight the possible direct correlation between the severity and persistence of phimosis, with the increasing risk for other important genital pathologies. Further revision of this classification should be done with a prospective multi-center and larger sample of patients.

12. Kirikos CS, Beasley SW, Woodward AA. The response to phimosis to local steroid application. Pediatric Surg Intern. 1993; 8:329332.

ACKNOWLEDGEMENT

17. Larke NL, Thomas SL, dos Santos Silva I, Weiss HA. Male circumcision and penile cancer: a systematic review and meta-analysis. Cancer Causes Control 2011; 22:1097-1110.

The authors would like to thank prof. Martha B. Scherr for her help in the translation of all part of the paper and dr. Marco Giustini from the National Institute of HealthmSocial and Environmental Epidemiology Unit.

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1. Joint United Nation Programm on HIV/AIDS (UNAIDS) Neonatal and Child male circumcision: a global review 2010.

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2. Morris BJ, Krieger JN The contrasting evidence concerning the effect of male circumcision on sexual function, sensation and pleasure: a systematic review. Sex Med. 2020; 8:577-598.

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13. La Pera G, De Luca F, Guerani A, et al. Prevalence of phimosis and foreskin sliding abnormalities in male adolescents and their correlation with later onset of first sexual intercourse. Arch Ital Urol Androl. 2017; 89:310-312. 14. Schöeder A. Circumcision: case against surgery without medical indication in DA Bolnick, M Koyle, A Yosha (Eds) Surgical guide to circumcision, Springer 2012; pp 185-186. 15. Perovic SV. Atlas of congenital anomalies of the external genitalia, Refot Arka. 1999; 13. 16. Czajkowski M, Czajkowska K, Zaranska K, et al. Male circumcision due to phimosis as the procedure that is not only relieving clinical symptoms of phimosis but also improves the quality of sexual life. Sex Med. 2021; 9:100315.

18. Micali G, Nasca MR, Innocenzi D, Schwartz RA. Penile cancer. J Am Acad Dermatol. 2006; 54:369-391. 19. Kochen M, McCurdy S. Circumcision and the risk of cancer of the penis. A life-table analysis. Am J Dis Child. 1980; 134:484-6. 20. Wiswell T, Circumcision Circumspection. N Engl J Med. 1997; 336:1244-5.

Phimosis classification

21. Wiswell TE. Neonatal circumcision: a current appraisal Focus Opin Pediat 1995; 1:93-99.

25. Nakata S, Imai K, Yamanaka H. Study of risk factors for prostatic cancer. Hinyokika Kiyo. 1993; 39:1017-24.

22. Tsen HF, Morgenstern H, Mack T, Peters RK. Risk factors for penile cancer: results of a population-based case-control study in Los Angeles County (US). Cancer Causes Control. 2001; 12:267-277.

26. Kupferschmid C. Commentary on "Countries with high circumcision prevalence have lower prostate cancer mortality". Asian J Androl. 2016; 18:949.

23. Vieira CB, Feitoza L, Pinho J, et al. Profile of patients with penile cancer in the region with the highest worldwide incidence. Sci Rep. 2020; 10:2965. 24. Vieira CB, Teixeira-Júnior A, Feitoza L, et al. A cohort study among 402 patients with penile cancer in Maranhao, Northeast Brazil with the highest worldwide incidence BMC Res Notes. 2020; 13:442.

27. Wachtel MS, Shengping Yang S, Morris BJ. Countries with high circumcision prevalence have lower prostate cancer mortality Asian J Androl. 2016; 18:39-42. 28. Morris BJ, Waskett JH. Circumcision reduces prostate cancer risk. Asian J Androl. 2012; 14:661-2.

Correspondence Giuseppe La Pera, MD (Corresponding Author) dr.giuseppelapera@gmail.com Urology UPMC Salvator Mundi International Hospital, Rome (Italy) Stefano Lauretti, MD stefanolauretti@gmail.com Andrological and Regenerative Surgery, S. Caterina della Rosa Health Center, ASL Roma 2, Rome (Italy)

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DOI: 10.4081/aiua.2022.2.228

ORIGINAL PAPER

Cyber pornography use and masturbation outburst. Considerations on 150 italian patients complaining erectile dysfunction and trying to solve it Diego Pozza 1, Mariangela Pozza 1, Augusto Mosca 2, Carlotta Pozza 3 1 Studio

di Andrologia e di Chirurgia Andrologica, Roma, Italy; Urologia e Andrologia, San Sebastiano Hospital, Frascati (RM), Italy; 3 Department Experimental Medicine, Sapienza University, Rome, Italy. 2 UO

Summary

Objective: We aimed to verify the rate of masturbation (Mst) in a group of 150 Italian patients complaining Erectile Dysfunction (ED). Materials and methods: Our diagnostic protocol for penile and sexual problems included the collection of the patient's history, general and local clinical examination, and metabolic and hormonal analyses. Selected patients were also submitted to nocturnal penile tumescence test (Rigiscan), Duplex ultrasound of the penis, Magnetic Resonance Imaging, neurological tests and cardiological examination. A group of 150 Italian males (aged between 20 and 86 years) who complained ED and who presented to our Andrological Center to research the possibility of correcting their ED and being able to recover adequate sexual erectile activity were included in this study. In this group of patients suffering from ED we decided to evaluate the practice of Mst by asking specific questions: 1. Do you sometimes practice Mst? 2. How often in a week? 3. Is Mst hidden or known by the partner? 4. What do you use as a masturbatory sexual stimulus? The frequency of Mst was assessed according to a Likert scale as follow: a: No Mst; b:1-2/week; c: 2-3/week; d: > 3/week; e: daily or more. We also asked if it was possible to have penetrative marital intercourse on the same day as Mst (1-10 hours). We also asked what they used as a triggering sexual stimulus: press magazines, TV movies, the WEB. Results: Only 5/150 patients did not report Mst while 27/145 pts (aged 20-30 years) reported it more than 3 times a week; 44/145 (aged 31-50 years) 1-3 times a week and 27/145 (51-86 years) 1-2 times a week. Almost all patients used WebPorn as a stimulus for Mst. A group of patients over the age of 50 said they were quite satisfied with the physical results of Mst even though they would prefer to have sex as part of a couple relationship. Conclusions: The outburst of Mst in this web-dominated era could affect the sexual activity of individual males and couples.

KEY WORDS: Masturbation; Cyber pornography; WEB porn; Erectile dysfunction; ED therapy; Penile prosthesis. Submitted 8 May 2022; Accepted 29 May 2022

INTRODUCTION

The practice of Mst in Western, Christian and even more Catholic realities has always been considered an improper sexual practice, not advisable, often deplorable, not

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really to be trumpeted and hardly shareable even with the closest ones (1). Up until 50 years ago, in Italy the influence of the Church, its priests and the religious educational and leisure facilities tended to instill the idea that Mst was a sin, as men should deliver their sperm only for reproductive purposes and therefore during a penetrative sexual intercourse (2). In the Sacro Cuore Catholic University of Rome (Medical Center of excellence in Rome and in Italy) it was not possible to carry out a spermiogram to assess the fertility because this catholic facility would have had to accept a sperm sample not delivered in the vagina (hence for reproductive purposes), but collected in a container and for the only purpose to "assess" the quality of the ejaculate with no other ongoing disease. The sperm sample was accepted only for bacteriological examination in case of suspected infection (alleged or actual disease). Mst is one of the first sexual dexterities men begin to experience (at 11-13 years of age) in conjunction with the production of testicular androgens and the onset of adolescence (3). In the past, at this stage of life, adolescent males did not have the possibility or the opportunity to have a sexual partner, and therefore the resort to Mst was a need, a rule until they reached the age (20 and older) to start going out with women, marry and therefore have the possibility of enjoying regular penetrative intercourse (4). Up until 50-60 years ago, in the Italian social-economiccultural reality the vast majority of women carried out mainly domestic activities and the work and life rhythms were influenced by the sunlight cycle; no home lighting, no TV and no nightlife implied that after dinner, and with the onset of darkness, couples went to bed and men had the possibility to have a sexual intercourse with orgasm and ejaculation, regardless of the desire and availability of the woman, who traditionally could not refuse the sexual requests of the man, also because women had to provide for the reproduction of the species through extremely frequent pregnancies, even one every year. Given such a context, men did not have specific physical reason to resort to Mst. It shall also be considered that, to masturbate men had to envisage sexual fantasies, visions, erotic behaviors linked also to environmental and cultural factors. All cultures No conflict of interest declared.

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have produced images or figures of a sexual nature (statues, frescoes, paintings, objects), which could stimulate the men’s fantasy, but that could, in the majority of cases, not be taken home (5). With the advent of writing, "licentious" texts started to appear, that could be enjoyed by the upper classes, since they were able to read, but not by the vast majority of the population. The introduction of the press allowed to produce in large number also “licentious” or “erotic” texts and more clearly “erotic” figures, drawings and representations, that could be enjoyed also by people unable to read and not having books to stimulate their sexual fantasies (6). In the late 1800s the first photographs (daguerreotypes) allowed to reproduce sexually stimulating female silhouettes and sex scenes easily enjoyable also by men unable to read but longing for an imaginative sexual stimulus for masturbatory or erotic-sexual purposes. However, the issues with those first photographs or books, not easy to be found, was keeping them at home without the wife, children or housekeeper being able to find them out. In 1941 the first periodical magazine with porn images, SWANK, was released in the USA, followed in 1953 by Playboy, which could be easily purchased at newsstands or by subscription in all countries of the world, and then by a variety of other periodicals (7). Also in that case, the problem was how to buy those magazines. Almost always they were bought at newsstands away from home, frequently at the station, and the purchase had to be concealed (i.e. “hiding” those magazine among other newspapers or magazines). Keeping them home could become a problem, as they had to be kept in places hardly visited by the other family members and yet easily accessible for masturbatory purposes. In some cases, such magazines were read together with the female partner as a “stimulus” to foster a freer sexuality. Nevertheless, keeping those magazines at home could imply serious problems, as well as discomfort in case they were discovered by the partner, who could have felt almost “betrayed” by such discovery. In the first postwar years, in 1950s, we saw the advent of television, which led to substantial changes in the life of the couple. Couples no longer went to bed after dinner, with the onset of darkness, but after spending a few hours watching TV and going to bed late, knowing that early in the morning, at dawn, they would have had to wake up to go to work. That resulted in less time and availability for sexual activity. In that same period many women took up a job, while continuing to take care of the house, the husband, and the children. Working outside their own home, spending time with other women, a certain economic and cultural independence, the first mechanical contraceptives and the pill changed the concept of pregnancy, which was no longer perceived as an inevitable necessity or obligation, but as the result of a choice of the couple with the possibility for the woman to refuse sexual intercourse perhaps requested by the men but not solicited by the woman. In many couple realities, the man no longer had the possibility to have an almost daily orgasm and ejaculation, and had to accept the decision of the woman, who might

be little interested in the sexual activity (endocrine factors) or who could fear a pregnancy with all the associated negative aspects (8). In such cases, many men resort to masturbation to get that emotional and urological pleasure, regardless of the availability of the women (9). Internet opened up a whole new world to pornography (10). With the discovery of the WEB, the potential for the supply and consumption of porn material rocketed to the extent of becoming a real global industry (11). Men longing to stimulate their more or less correct or distorted sexual fantasy no longer had to buy a magazine or a videotape, nor to find a “secret” place, but simply use a PC or smartphone without “concealing” any material. They could use it everywhere and anytime, paradoxically even in the presence of their partner without her knowing about it (12).

MATERIALS

AND METHODS

in our Andrology Center in Rome, since 2020, we examined 150 male patients (aged 20 to 86 years) with penile and/or sexual problems according a diagnostic protocol including the collection of the patient's history, the general and local clinical examination, metabolic analyses, and hormonal analyses (in all patients). In selected cases Nocturnal Penile Tumescence test (Rigiscan) (86 pts), dynamic penile Duplex sonography (138 pts), magnetic resonance imaging (36 pts), neurological tests (26 pts) and cardiological examination (100 pts) were performed (13-15). Since 2020, we administered a specific questionnaire to investigate masturbatory activity, including the following questions: 1. Do you sometimes practice Mst? Answers: No-Yes 2. With which frequency/week? Answers: 1-2-3-more, all days? 3. Is Mst concealed to the partner? Answers: No -Yes 4. What do you use as Mst sexual stimulus? Answer: fantasy - printed materials -WEB In our experience with the IIEF test utilized for other reasons, we had acknowledged that to some given questions many patients preferred to give false answers that put them in a "better light". On the other hand, all our patients, who came to undergo specific tests because their Erectile Function was not effective (being well aware of the need to solve their erectile problem) had no reason to withhold information on their masturbatory activity.

RESULTS

When asked by the Andrologist, during medical examinations, whether they practiced Mst, 145/150 (96,6%) patients answered positively. To the question about the Mst frequency (16): 27 pts (20-30 yrs; 18.0%) reported > 3 times/week, even every day; 44 pts (31-50 yrs; 29.3%)1-3 times/week; 56 Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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pts (51-70 yrs; 37.3%) 1-3 times/week, even every day;18 pts (71-86 yrs; 12%) 1-2 times/week; 5 pts (29, 36, 56, 75, and 80 yrs; 3.3%) no masturbation. Ten (6.8%) patients reported that their partner was aware of the Mst activity they practiced and did not show disappointment. When asked if it was possible to have a penetrative marital intercourse on the same day of Mst (within 1-10 hours): 10 patients aged 20-30 years (37.0%) and 5 patients aged 31-90 (0.4%) answered affirmatively. When asked what did they use as triggering sexual stimulus 132 pts (20-86 years; 91%) reported using the web and 18 pts (> 60 years; 12%) reported to watch TV movies The sexual desire to have intercourse with their “stable partner” appeared rather reduced among the patients practicing Mst. In the following cases it is not simple to discriminate: 1. When the woman, perhaps no longer young and with children, showed no initiative to involve the man in a sexual activity. 2. When the woman was aware of the difficulty, often the impossibility of the man to have a satisfactory penetrative intercourse and therefore did not take any initiative. 3. When the woman, knowing that the man often was not capable to have an adequate erection (i.e. had an insufficient or short-lasting or totally unsatisfactory erection) preferred not to induce a depressive attitude of the partner. 4. When, due to erectile dysfunction a preliminary masturbatory activity tended to make the penetrative intercourse even more difficult resulting in disappointment, frustration, a sense of deficiency, and depression.

imagination, scents, visions, contiguity that needs a certain psychological “commitment” as well as plenty of time. Even in ancient civilizations and societies it was possible to reproduce “sexually exciting" images which, however, were graphic, pictorial or statuary images affixed in specific places, often public, and difficult to be used in private. With the advent of the press, books with erotic content began to be published, that, however, could be enjoyed only by people able not only to read but also to buy, preserve and consult a book. The possibility to paint and print images and pictures led to publications with sexually explicit images, which could be appreciated also by people, who were not able to read. The classic images in barber shops (men-only places) with more or less naked ladies became outmoded in the 40-50s due to the first publications (magazines, tabloids) with naked women which one could also purchase in more popular environment, such as newsstands, and easily usable at home, although they had still to be hidden from mother, wife or partner. On the one hand, the erotic-porn publication boom could make Mst easier and more evocative but still with a set of practical problems, such as: – the purchase, (normally, never the usual newsstand near home, perhaps attended by some family member or acquaintance; men who bought a porn publication usually avoid doing it in a noticeable way, almost always buying other newspapers to hide it away from other customers of the newsstand, even if unknown), – the preservation at home of the magazines in an easily accessible place, but hidden from the women at home, – the possibility to read them in a place that had to be “secret” not to be seen by other family members and also lit enough to allow the reading.

DISCUSSION

The development of the WEB in the 70s combined with the widest spreading of smartphones allowed to basically solve those problems. Men in need of a visual sexual stimulus no longer have to go to a newsstand to buy “in public” porn material, nor to worry about hiding the material at home. They can check it out anytime, everywhere, even in the dark. For the sake of argument, they can watch porn images or movies even when in close proximity to their partner, or use it just before having a sexual intercourse to strengthen the sexual performance with a woman who, perhaps, no longer excites him (17). However, porn web has specific consequences. Many functionally active and sexually capable young men report "web-masturbating" because they can do it at any time of the day even when their woman is not available or has to carry out other activities: web sex allows men to imagining to have sexual intercourse with extremely exciting, provocative women available in any situation, even extreme ones, without having to worry about a too quick ejaculation, an erection that is not sufficiently stiff and lasting to give enough pleasure to the partner (8). Moreover, they are not exposed to the “unpleasant and frustrating” judgement of the unsatisfied partner. Clearly teenagers, young men who had had a sexual intercourse with their partner could also be able to have

We are not aware of other cultural and religious realities, where the Mst practice can be easily accepted and revealed, but for sure in the Italian reality with a strict Christian-Catholic culture and education, it is quite uncommon that, among men talking about their sexual "performances" or "adventures", Mst is one of the issues discussed and revealed even if practiced frequently. Masturbation could and was practiced by men, who for different reasons could not have sexual intercourse with a woman (adolescence, celibacy, religious activity, illnesses, separation, widowhood, distance for work, emigration, wars, calamities). In principle, men could have a sexual activity leading to an orgasm and ejaculation on a regular basis because, until a few decades ago, most women had to accept a sexual intercourse for cultural, educational, economic, total dependence reasons, regardless of their will and the sexual prowess of the man (8). From the beginning of the twentieth century with women starting going to school, working and gaining economic independence, the awareness of the family context, the changes in the legislation, many women gained the power and started refusing the absolute duty of accepting a sexual intercourse with their partner. Mst requires a state of sexual excitement triggered by

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another sexual intercourse if explicitly requested (18), but with maturity and senescence it could be difficult to get a new conjugal erection after a masturbation (19). In other cases, after 50 years of age, or in case of metabolic, hormonal or vascular pathologies, men tend to masturbate to directly verify if their penis can deliver a good stiffness and maintain it, which triggers a complicated psychological mechanism. However, we have verified that in many patients over 50, who had had various sexual relationships in the past, the practice of masturbation was experienced and reported in a different way from those who had not had interpersonal relationships. A certain amount of patients reported obtaining with the Mst an acceptable erection, an orgasm (with or without ejaculation) quite satisfactory without having to worry about having induced a specific pleasure and having procured an orgasm in the woman and without having to expect a judgment of the woman on the ability to have procured a substantially pleasant intercourse and an orgasm. In the past, even recently, a male would never have bothered with the judgment of the woman. This aspect should be the subject of in-depth evaluations. Should sexual intercourse be considered only as a reproductive act, as a source of pleasure for the male or as a source of pleasure also for the woman and for the couple?

AKNOWLEDGMENTS

We thank the strict collaboration of Stefania Rosini for translation and revision of the article.

10. Ross MW. Typing, doing and being: sexuality and Internet. J Sex Res. 2005; 42:342. 11. Brown J. Pornography addiction: an exploration of the association between use, perceived addiction, erectile dysfunction, premature (early) ejaculation, and sexual satisfaction in males aged 18-44 years. J Sex Med. 2021; 13:1. 12. Park BY, Wilson G, Berger J, et al. Is Internet pornography causing sexual dysfunction? A review with clinical reports. Behav Sci. 2016; 6:17. 13. Pozza D, Marcantonio A, Mosca A, Pozza C. Penile prosthesis and complications: results from 577 Implants. Arch Ital Urol Androl. 2020; 92:302. 14. Jannini EA, Maggi M, Lenzi A. Evaluation of premature ejaculation. J Sex Med. 2011; 8:328. 15. Pozza D, Berardi A, Pozza M, et al. The woman and the penile prosthetic implant. Primary or secondary role? Personal experiences on 365 implanted patients. Arch Ital Urol Androl. 2021; 93:53. 16. Likert R. On managing human assets. Bull Train. 1978; 3:1. 17. Fritz N, Malic V, Fu Tsung-chien, et al. Porn sex versus real sex: Sexual behaviors reported by a U.S. probability survey compared to depictions of sex in mainstream Internet-based male-female pornography. Arch Sex Behav. 2022; 51:1187. 18. Kaestle CE, Allen KR. The role of masturbation in healthy sexual development: perceptions of young adults. Arch Sex Behav. 2011; 40:983 19. Bell S, Reissing ED, Henry LA, Van Zuylen H. Sexual activity after 60: A systematic review of associated factors. Sex Med Rev. 2017; 5:52.

REFERENCES

1. Fischer N, Graham CA, Traeen S, Hald GM. Prevalence of masturbation and associated factors among older adults in four European countries. Arch Sex Behav. 2021; 51:1385. 2. Prause N. Porn is for masturbation. Arch Sex Behav. 2019; 483. 3. Donevan, M, Jonsonn L, Bladh M, et al. Adolescents’use of pornography trends over a ten year period in Sweden. Arch Sex Behav. 2022; 51:11254. 4. Das A. Masturbation in the United States. J Sex Marital Ther. 2007; 33:301. 5. Bothe B, Toth-Kiraly I, Potenza MN, et al. High-frequency pornography use may not always be problematic. J Sex Med. 2020; 17:793. 6. Perry SL. Does low-cost sexual gratification make men less eager to marry? Pornography use, masturbation, hookup sex, and desire to be married among single men. Arch Sex Behav. 2020; 49:3013.

Correspondence

7. Rowland DL, Hamilton BD, Bacys R, Hevesi K. Sexual response differs during partnered sex and masturbation in men with and without sexual dysfunction: implications for treatment. J Sex Med. 2021; 18:1835.

Diego Pozza, MD (Corresponding Author) diegpo@tin.it Mariangela Pozza, MD mariangela.pozza@gmail.com Studio di Andrologia e di Chirurgia Andrologica Via B. Gozzoli, 82 - 00142 Rome (Italy)

8. Brody C, Costa RM. Satisfaction (sexual, life, relationship, and mental health) is associated directly with penile-vaginal intercourse, but inversely with other sexual behavior frequencies. J Sex Med. 2009; 6:1947.

Augusto Mosca, MD moscaaugusto@gmail.com UO Urologia Andrologia, San Sebastiano Hospital Via Tuscolana, 2, 00044 Frascati, Rome (Italy)

9. Cavalheira A, Traeen B, Stulhofer A. Masturbation and pornography use among coupled heterosexual men with decreased sexual desire: how many roles of masturbation? J Sex Marital Ther. 2015; 41:626.

Carlotta Pozza, MD carlotta.pozza@gmail.com Dept Experimental Medicine, Sapienza University Viale Policlinico, 00161, Rome (Italy)

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DOI: 10.4081/aiua.2022.2.232

ORIGINAL PAPER

Erectile function in amateur cyclists Duarte Vieira e Brito 1, Mário Pereira-Lourenço 1, Jose Alberto Pereira 1, Miguel Eliseu 2, Carlos Rabaça 1 1 Portuguese 2 Urology

Institute of Oncology, Coimbra, Portugal; and Renal Transplantation Department, Coimbra University Hospital Centre, Coimbra, Portugal.

Summary

Introduction: Cycling is a popular means of transport and recreational activity; bicycles are also a source of genitourinary injuries and there is the idea that cycling may have a significant impact on sexual function. The objective of this study was to evaluate the effect of amateur cycling on erectile function. Methods: We used a questionnaire comparing amateur cyclists (n = 199) and footballers (n = 43), regarding sexual related comorbidities and hours of practice per week. The cyclists were also characterized in terms of road vs cross-country, breaks during cycling, saddle, and shorts. To evaluate erectile function, the International Index of Erectile Function questionnaire was applied. Results: there was no difference in International Index of Erectile Function total score between groups. Age and presence of erectile dysfunction associated comorbidity were negative factors in the International Index of Erectile Function score in cyclists but not in the footballers. Conclusions: Cycling is usually associated with perineal numbness, but that numbness did not lead to lower International Index of Erectile Function scores. In conclusion amateur cycling has no effect on EF.

KEY WORDS: Cycling; Football; Erectile function; Perineal numbness. Submitted 9 April 2022; Accepted 4 June 2022

INTRODUCTION

Cycling is a popular means of transport and recreational activity for many people in a wide age range. It is an economical and efficient form of aerobic non-impact exercise with well-established cardiovascular beneficial effects and with a positive effect on quality of life (1, 2). Bicycles are also a source of genitourinary injuries, that can be categorized into acute traumatic injuries versus chronic overuse injuries (3). Exercise is a well-known preventer of erectile dysfunction, in an Italian study patients with lower physical activity were associated with higher levels of erectile disfunction (4). Since the 80’s, there is the idea that cycling may have a significant impact on sexual function (including erectile dysfunction (ED), perineal numbness and chronic pain) (1, 5, 6). The most frequently proposed pathophysiological mechanisms for ED in cyclists are vascular and nerve injuries (related to nerve entrapment and vascular occlusion with continuous compression of the pudendal nerve and pudendal artery) (1).

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Studies have shown that ED and numbness occur, respectively in up to 24% and 61% of selected groups of riders. However, most studies were conducted on longdistance/intensive cyclists, so there is little information about the true effects of cycling in the sexual life of amateur practitioners (6-11). With this study, we aimed to evaluate the effects of amateur cycling in erectile function using a comparative athlete group and a validated sexual questionnaire.

METHODS Recruitment and sporting clubs’ outreach 199 amateur cyclists (cyclists that do not receive financial support or sponsorship) were recruited in person in several cycling meetings and completed an anonymous survey. We chose four mountain cycling events with high participation. The comparison group consisted of 43 amateur footballers (sport without perineal contact) recruited in person from two amateur clubs. Institutional review board approval was obtained. Survey predictor variables The two groups of athletes were characterized and compared regarding their age, body mass index, alcohol intake, smoking, medication (diuretics, high blood pressure drugs, excluding angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, anti-depressants, anti-anxiety drugs, antihistamines, Parkinson’s disease medications, prostate cancer medications, 5a-reductase inhibitors, chemotherapy), comorbidities (hypercholesterolemia, hypertriglyceridemia, arterial hypertension, myocardial infarction, stroke, diabetes mellitus, chronic kidney disease, chronic liver disease, thyroid disease, hormonal disorder, neurological disease, spine injury, prostate disease, perineal radiotherapy, penile/perineal trauma, depression, anxiety disorder) and hours per week of sports practice. The cyclists (group 1) were specifically characterized in terms of road vs cross-country, rest breaks during cycling (by questionnaire), saddle, shorts, and the riding position. The effect of each of these characteristics on sexual function was assessed. Survey outcome variables To evaluate EF, the International Index of Erectile Function (IIEF-5) questionnaire was applied. The presence of No conflict of interest declared.

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numbness was also registered, although in a subjective way (“yes or no” question). Statistical analysis Data was analysed using SPSS 21. Demographic and medical variables were compared across athletic groups using Pearson chi-square and Mann-Whitney tests. The effect of cycling variables in EF was calculated with Mann-Whitney, Pearson chi-square and Kruskal-Wallis tests. A p-value of ≤ 0.05 was considered statistically significant.

RESULTS

General characterization and comparison between the two groups is summarized in Table 1. The subjects in group 1 were older (38.1 vs 30.5 years old; p = 0.001), and less individuals consumed alcoholic beverages (60% vs 79%, p = 0.018). The remaining variables did not differ between the 2 groups.

Table 1. General characterization and homogeneity.

Table 3. Erectile Dysfunction severity by sport modality.

Cycling (n = 199)

Football (n = 43)

76.8% 38.1 77.3 24.9 60.3% 34.2%

86.0% 30.5 75.1 24.4 79.1% 46.5%

0.208 0.001 0.157 0.255 0.018 0.112

ED associated comorbidities Mean age (years) Mean weight (Kg) Mean BMI (Kg/m2) Alcohol consumption Smoking BMI: Body Mass Index.

Table 2. Effect of Erectile Dysfunction associated variables on IIEF-5 total score by sport modality. BMI < 25 Kg/m2 Yes No Alcohol Yes No Tobacco Yes No ED associated medication Yes No ED associated comorbidity Yes No Age ≤ 20 21-30 31-40 41-50 > 50

Cycling IIEF-5

Football IIEF-5

22.57 (n = 119) 22.26 (n = 80)

0.423

21.80 (n = 30) 21.46 (n = 13)

0.759

22.24 (n = 119) 22.75 (n = 80)

0.363

21.35 (n = 34) 23.00 (n = 9)

0.200

22.27 (n = 67) 22.54 (n = 132)

0.159

21.00 (n = 20) 22.30 (n = 23)

0.081

23.00 (n = 34) 22.30 (n = 165)

0.565

22.13 (n = 8) 21.60 (n = 35)

0.987

21.79 (n = 57) 22.71 (n = 142)

0.036

21.73 (n = 11) 21.69 (n = 32)

0.623

22.67 (n = 9) 23.08 (n = 37) 22.88 (n = 78) 21.67 (n = 55) 21.60 (n = 20)

0.032

18.78 (n = 9) 22.81 (n = 16) 21.08 (n = 10) 23.00 (n = 6) 21.50 (n = 2)

0.120

BMI: Body Mass Index; ED: Erectile Dysfunction.

There was also no difference in the IIEF-5 total score between groups (22.45 vs 21.70; p = 0.071). Group 1 showed better results in question 3 of the IIEF-5, which concerns the ability to maintain erection after penetration (4.49 vs 4.14, p = 0.014). Age and the presence of ED associated comorbidities were negative factors in the IIEF-5 total score in cyclists (p = 0.032 and p = 0.036, respectively) but not in footballers (p = 0.120 and p = 0.623, respectively). No other variables influenced IIEF-5 in the cycling group or in the football group when evaluated separately (Table 2). The IIEF-5 total score ≤ 21 included 37.2% of cyclists and 26.6% of footballers (p = 0.164), with no difference regarding ED severity between the two groups (p = 0.173) (Table 3). Regarding cycling specific variables (Table 4), there was no relation between IIEF-5 and number of hours per week of practice (p = 0.666), type of shorts (p = 0.254), type of saddle (p = 0.611), frequency of resting pauses (p = 0.288) and predominant position of the trunk while cycling (p = 0.371).

ED severity (IIEF-5 score) Severe ED (1-7) Moderate ED (8-11) Mild-Moderate ED (12-16) Moderate ED (17-21) No ED (22-25)

Cycling n = 0; 0% n = 3; 1.5% n = 7; 3.5% n = 43; 21.6% n = 46; 73.4%

Football n = 0; 0% n = 0; 0% n = 3; 7.0% n = 13; 30.2% n = 27; 62.8%

0.173

ED: Erectile Dysfunction.

Table 4. Effect of cycling related variables on erectile function. ED severity (IIEF-5 score) Hours per week

Shorts

Saddle

Continuous exercise until pause *

Modality Perineal numbness Predominant position

Cycling < 5 (n = 73) 5-8 (n = 75) > 8 (n = 51) Uncoated (n = 2) Gel (n = 107) Sponge (n = 77) Hard (n = 29) Gel (n = 105) Sponge (n = 55) 30 min (n = 29) 60 min (n = 60) 120 min (n = 29) No pauses (n = 92) Only cross-country (n = 136) Cross-country + road (n = 63) Yes (n = 50) No (n = 149) No (n = 64) 30º (n = 4) 45º-60º (n = 124) 90º (n = 7)

Football 22.18 21.30 21.67 23.00 22.40 22.34 22.70 22.51 22.32 21.90 22.49 23.28 22.34 22.13 23.13 22.54 22.42 21.97 21.75 22.77 21.57

P 0.666

0.254

0.611

0.288

0.023 0.508 0.371

* Time from start until stopping for rest.

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Athletes that also practice road cycling had better IIEF-5 scores (p = 0.023). Perineal numbness during or after exercise was present in 25.1% (n = 50) of cyclists and 7.0% (n = 3) of footballers (p = 0.009). Athletes (both groups included) without perineal numbness (n = 189), with numbness during the exercise (n = 46) and with numbness only after exercise (n = 7) had an IIEF-5 score of 22.35, 22.46 and 20.43, respectively (p = 0.301). Regarding only cyclists, athletes without perineal numbness (n=149), with numbness during exercise (n = 46) and with numbness only after exercise (n = 4) had an IIEF-5 score of 22.42, 22.46 and 23.5, respectively (p = 0.752).

DISCUSSION

We choose amateur footballers as a control group for two main reasons: 1) the aerobic metabolism is used in 90% of movements in football players and cycling is an aerobic sport (12, 13); 2) football might be the most practiced sport among Portuguese males. Our study shows that amateur cycling does not cause erectile dysfunction, when compared with amateur footballers. Among cyclists, only age, presence of ED related comorbidities and the exclusive practice of cross-country cycling were related to lower IIEF-5 scores. Age is strongly associated with ED, being erectile function reduced in men particularly after the age of forty due to multiple causes (14). In a study analysing a Spanish population, a culturally similar population to the one in our study, higher rate of ED was found when the IIEF-5 score was used versus direct questioning. A rate of 8.48% and 13.72% was found for men between 25-39 and 40-49 respectively, and rate almost doubled in men between 5059 years (15). In our population with a median age difference of 8 years, the cycling group should in theory present with higher rates of ED that were not observed in our study. In the 80s, some case reports began to relate cycling with sexual dysfunction (1). In the 90s, Andersen et al. showed a relation between cycling and ED (13% of 160 cyclists who rode in a 540 km touring race, but only 1.9% lasted more than a month) (8). In fact, ED and perineal numbness are the most common described bicycle related sexual symptoms in literature, occurring, respectively, in up to 24 and 61% of selected groups of riders (6). In relation to the possible pathophysiology responsible for this association, the most frequently proposed causes are vascular and nerve injuries. Sommer et al. described nerve entrapment and vascular occlusion related to continuous compression (compression of the pudendal nerve and pudendal arteries through Alcock’s canal) as the more plausible cause (1). Rider/saddle interaction, namely the type of saddle, shorts, preferential riding position, cycling modality (low impact vs. high impact) and hours of practice can explain possible different rate of cycling related ED. We did not find ED differences between types of saddles or shorts, but we only evaluated coating. In literature, the saddle plays a major role in cycling related ED (6). The best saddle (for ED protection) seems to be a wide, unpadded, no nose saddle that allows proper placement

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of the sit bones (more weight on the ischial tuberosities and less on the perineal soft tissues) (1, 6, 16-21). A more horizontal or even downward-pointing position of the saddle has been associated with reduced pressure on the perineum (22). In relation to shorts, a study showed that the saddle is more important for compression than shorts pad, suggesting that cyclist should choose self-reported comfortable shorts (23). We also did not find ED differences between the rider preferential position, although there is some literature evidencing that the rider’s position influences compression on perineal structures. Cycling in the seated position decreases perineal blood flow and this decrease is inversely related with body weight (1, 6, 10, 21). Cycling in a reclined position reduces compression, while leaning forward in the “aero” position (as the nose of the saddle bears almost all of the rider’s weight) decreases blood flow by approximately 70% (10). Adjusting the handlebars, stem length and angle, and crank, has shown to have beneficial effect on perineal pressure. Related to position, riders should cycle in a more upright position and changing a seat to a “standing” position (1). In our study, cyclists that only practiced cross-country had lower IIEF-5 score. Cross-country cycling (mountain bike) is associated with perineal numbness and incident ED, that can be explained by the vibrations associated with this modality (6, 9, 21). In our study, cyclists had more perineal numbness, but that numbness did not lead to lower IIEF-5 scores. Numbness in perineum, penis, scrotum or buttocks, usually referred to as “genital numbness” is probably the most common and most recognized symptom of pudendal compression. Most of the times it is the only symptom or the earliest one to indicate compression syndrome. Genital numbness may occur unrelated to ED although cycling related ED is invariably associated with genital numbness, which may serve as a marker for increased risk for erectile dysfunction (24). As in our study, recent works failed to show cycling as a risk factor for ED. An internet survey on 3932 cyclists showed that low and high intensity cyclists had better sexual function than swimmers and runners (25). We also did not find IIEF-5 differences related to hours of practice per week (older studies, focused on elite longdistance riders, related intensive cycling with ED) (24). Marceau et al (7) investigated ED incidence in the general population, in recreational cyclists (< 3 hours per week) and in intensive cyclists (> 3 hours per week). The ED incidence was 21%, 11% and 17%, respectively, showing that intensive cyclists may have worse erectile function than recreational riders (although both have better results than non-cyclists). A recent large-scale observational study on 5282 cyclists, also did not find differences in ED incidence between several intensity groups < 3.75, 3.75-5.75, 5.76-8.5, and > 8.5 hours/week) (26). We must understand that the practice of sport can influence sexual behaviour, interfering with the hypothalamicpituitary-testicular axis function. However, competitive sports can lead to both reproductive or sexual tract injuries, dysfunction that can be transient (genital pain, hypoesthesia of the genitalia, hypogonadism, ED, altered sexual drive, etc.) or permanent (hypogonadism, ED,

Erection in cyclists

etc.), by direct action (traumas of the external genitalia, saddle-related disorders in cyclists, etc.) or indirect (exercise-related hypogonadism, drug abuse, doping, stress, etc.) (27). A recent systematic review and meta-analysis indicates that moderate-intense physical activity improves erectile dysfunction problems (28). Results of a cross-sectional study show a sexual function benefit for those exercising at least 18 metabolic equivalent (MET) hours of activity weekly, an amount translating to 2 hours of strenuous exercise such as running or swimming, 3.5 hours of moderate exercise, or 6 hours of light exercise (29). Our study has some limitations, namely its cross-sectional design (it does not evaluate the temporal sexual evolution of the athlete), the low number of athletes in the control group and age differences between groups with an average age difference of 8 years, as erectile disfunctions in strongly associated with age (although our older group did not present with higher rates of ED). We also did not evaluate all the important saddle characteristics (presence of nose, width, cut-outs) and we did not investigate cyclists that only practice road cycling. Another limitation was the higher percentage of alcohol and tobacco consumption in the football group, although when statistically analysed no significant difference was found. The numbness outcome was self-reported and was investigated with a non-validated question. The questionnaire utilized was not validated but being the questions made in person by the researcher, the subjectivity was reduced. Another possible limitation is selection bias as healthier cyclist might have been chosen as there are the ones that usually participate in competing events, having been excluded cyclist in poorer condition and with more comorbidities. A final limitation might be the lack of questioning about the use of anabolic steroids, that alter erectile function. However, the authors believe that there was no important impact on the quality of the study by this, because the use of such substances is limited in the Portuguese population.

CONCLUSIONS

Amateur cycling has no effect on EF and the intensity of practice seems to have no influence on EF. However, cycling is associated with perineal numbness, but ED was not found in conjunction to this.

REFERENCES

1. Sommer F, Goldstein I, Korda JB. Bicycle riding and erectile dysfunction: a review. J Sex Med. 2010; 7:2346-58. 2. Sundquist K et al. Frequent and occasional physical activity in the elderly: a 12-year follow-up study of mortality. Am J Prev Med. 2004; 27:22-7. 3. Thompson MJ, Rivara FP. Bicycle-related injuries. Am Fam Physician. 2001; 63:2007-14. 4. Parazzini F, et al. Effect of body mass and physical activity at younger age on the risk of prostatic enlargement and erectile dysfunction: Results from the 2018 #Controllati survey. Arch Ital Urol Androl. 2020; 91:245-250.

5. Desai KM, Gingell JC. Hazards of long distance cycling. BMJ. 1989; 298:1072-3. 6. Baran C, Mitchell GC, Hellstrom WJ. Cycling-related sexual dysfunction in men and women: a review. Sex Med Rev. 2014; 2:93-101. 7. Marceau L, et al. Does bicycling contribute to the risk of erectile dysfunction? Results from the Massachusetts Male Aging Study (MMAS). Int J Impot Res. 2001; 13:298-302. 8. Andersen KV, Bovim G. Impotence and nerve entrapment in long distance amateur cyclists. Acta Neurol Scand. 1997; 95:233-40. 9. Dettori JR, et al. Erectile dysfunction after a long-distance cycling event: associations with bicycle characteristics. J Urol. 2004; 172:637-41. 10. Sommer F, et al. Impotence and genital numbness in cyclists. Int J Sports Med. 2001; 22:410-3. 11. Baek S, et al. Bicycle riding: impact on lower urinary tract symptoms and erectile function in healthy men. Int Neurourol J. 2011; 15:97-101. 12. Silva JF, et al. Aerobic evaluation in soccer. Rev. bras. cineantropom. desempenho hum. (Online) 2011; p. 384-391. 13. McMillan K, et al. Lactate threshold responses to a season of professional British youth soccer. Br J Sports Med. 2005; 39:432-6. 14. Feldman HA, et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol. 1994; 151:54-61. 15. Martin-Morales A, et al. Prevalence and independent risk factors for erectile dysfunction in Spain: results of the Epidemiologia de la Disfuncion Erectil Masculina Study. J Urol. 2001; 166:569-74. 16. Jeong SJ, et al., Bicycle saddle shape affects penile blood flow. Int J Impot Res. 2002; 14:513-7. 17. Lowe BD, Schrader SM, Breitenstein MJ. Effect of bicycle saddle designs on the pressure to the perineum of the bicyclist. Med Sci Sports Exerc. 2004; 36:1055-62. 18. Munarriz R, et al. Only the nose knows: penile hemodynamic study of the perineum-saddle interface in men with erectile dysfunction utilizing bicycle saddles and seats with and without nose extensions. J Sex Med. 2005: 2:612-9. 19. Schrader SM, Breitenstein MJ, Lowe BD. Cutting off the nose to save the penis. J Sex Med. 2008; 5:1932-40. 20. Goldstein I, Lurie AL, Lubisich JP. Bicycle riding, perineal trauma, and erectile dysfunction: data and solutions. Curr Urol Rep. 2007; 8:491-7. 21. Michiels M, Van der Aa F. Bicycle riding and the bedroom: can riding a bicycle cause erectile dysfunction? Urology. 2015; 85:72530. 22. Spears IR, et al. The effect of saddle design on stresses in the perineum during cycling. Med Sci Sports Exerc. 2003; 35:1620-5. 23. Marcolin G, et al. Biomechanical comparison of shorts with different pads: an insight into the perineum protection issue. Medicine (Baltimore) 2015; 94: e1186. 24. Leibovitch I, Mor Y. The vicious cycling: bicycling related urogenital disorders. Eur Urol. 2005; 47:277-86. 25. Awad MA, Gaither TW, Murphy GP, et al. Cycling, and male sexual and urinary function: results from a large, multinational, cross-sectional study. J Urol. 2018; 199:798-804. Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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26. Hollingworth M. Harper S, Hamer M. An observational study of erectile dysfunction, infertility, and prostate cancer in regular cyclists: Cycling for Health UK Study. Journal of Men´s health. 2014; 11:75-79. 27. Sgrò P, Di Luigi L. Sport and male sexuality. J Endocrinol Invest. 2017; 40:911-923.

Correspondence Duarte Vieira e Brito, MD (Corresponding Author) duartevbrito@hotmail.com Mario Pereira Lourenço, MD mariolourenco88@gmail.com Jose Pereira, MD joseaclpereira@gmail.com Carlos Rabaça carlosrabaca@gmail.com Portuguese Institute of Oncology, Coimbra (Portugal) Casa da Aveleira, Pencelo Guimaraes (Portugal) Miguel Eliseu, MD duartevbrito@gmail.com Urology and Renal Transplantation Department. Coimbra University Hospital Centre, Coimbra (Portugal)

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28. Silva AB, et al. Physical activity and exercise for erectile dysfunction: systematic review and meta-analysis. Br J Sports Med. 2017; 51:1419-1424. 29. Simon RM, et al. The association of exercise with both erectile and sexual function in black and white men. J Sex Med. 2015; 12:1202-10.

DOI: 10.4081/aiua.2022.2.237

REVIEW

An update on the management algorithms of priapism during the last decade Mohamad Moussa 1, Mohamad Abou Chakra 1, Athanasios Papatsoris 2, Athanasios Dellis 2, 3, Michael Peyromaure 4, Nicolas Barry Delongchamps 4, Hugo Bailly 4, Sabine Roux 4, Ahmad Abou Yassine 5, Igor Duquesne 4 1 Department

of Urology, Al Zahraa Hospital, University Medical Center, Lebanese University, Beirut, Lebanon; Department of Urology, School of Medicine, Sismanoglio Hospital, National and Kapodistrian University of Athens, Athens, Greece; 3 Department of Surgery, School of Medicine, Aretaieion Hospital, National and Kapodistrian University of Athens, Athens, Greece; 4 Department of Urology, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris Descartes University, Paris, France. 5 Internal Medicine, Staten Island University Hospital, Staten Island, NY, United States. 2 2nd

Summary

Priapism is a persistent penile erection lasting longer than 4 hours, that needs emergency management. This disorder can induce irreversible erectile dysfunction. There are three subtypes of priapism: ischemic, non-ischemic, and stuttering priapism. If the patient has ischemic priapism (IP) of less than 24-hours (h) duration, the initial management should be a corporal blood aspiration followed by instillation of phenylephrine into the corpus cavernosum. If sympathomimetic fails or the patient has IP from 24 to 48h, surgical shunts should be performed. It is recommended that distal shunts should be attempted first. If distal shunt failed, proximal, venous shunt, or T-shunt with tunneling could be performed. If the patient had IP for 48 to 72h, proximal and venous shunt or T-shunt with tunneling is indicated, if those therapies failed, a penile prosthesis should be inserted. Non-ischemic priapism (NIP) is not a medical emergency and many patients will recover spontaneously. If the NIP does not resolve spontaneously within six months or the patient requests therapy, selective arterial embolization is indicated. The goal of the management of a patient with stuttering priapism (SP) is the prevention of future episodes. Phosphodiesterase type 5 (PDE5) inhibitor therapy is considered an effective tool to prevent stuttering episodes but it is not validated yet. The management of priapism should follow the guidelines as the future erectile function is dependent on its quick resolution. This review briefly discusses the types, pathophysiology, and diagnosis of priapism. It will discuss an updated approach to treat each type of priapism.

KEY WORDS: Priapism; Ischemic priapism; Non-ischemic priapism; Stuttering priapism. Submitted 9 May 2022; Accepted 23 May 2022

INTRODUCTION

Priapism is defined as a persistent erection due to abnormal mechanisms regulating penile tumescence, rigidity, and flaccidity. The rapid diagnosis and management of priapism are necessary to spare patients ineffective interventions and maintain erectile function outcomes (1). The use of intracavernous injections of papaverine rapidly increases the number of men seeking attention for priapism, a previously rare disease. The use of recreational

drugs (cocaine) and perineal trauma leading to presentations of priapism seem to be rising in incidence (2). There are essentially two main types of priapism: high flow and low flow. Low flow priapism is more common, and it is associated with a decrease in venous outflow and vascular stasis that, in turn, cause tissue hypoxia and acidosis. High flow priapism is usually due to trauma, although, on rare occasions, it has been idiopathic. The hallmark of this type of priapism is an increase in arterial inflow in the setting of normal venous outflow (3). A general overview of the types of priapism is summarized in Table 1. The primary goals of medical therapy for ischemic priapism (IP) are to decompress the corporal bodies and restore arterial blood flow. Management of IP should progress in an aggressive and stepwise fashion. Management of acute IP starts with the aspiration of blood and the irrigation of the corpora cavernosa, in combination with the use of intracavernous a-agonist injection therapy. Phenylephrine is the preferred sympathomimetic agent, but other a-adrenergic agonists may be used, such as ephedrine, epinephrine, norepinephrine, or metaraminol. Caution should be taken when using those agents based on the patient’s cardiovascular profile and time used for injection (4). If conservative therapies failed to resolve IP, it is recommended to perform distal shunting first (5). European Urology Association (EAU) guidelines currently recommended that if priapism persists despite the use of first-line treatments including shunting procedures, ED is inevitable. Immediate PP insertion is recommended to avoid the corporal fibrosis associated with later insertion (6). It is crucial to prevent future episodes of IP due to its high morbidity. Many drugs have been used for this purpose such as oral use of terbutaline, digoxin, baclofen, estrogens, gonadotropin-releasing hormone agonists (GnRH), antiandrogens, and PDE5 inhibitors (7). Table 2 summarizes the advantages and the disadvantages of each type of therapy used in priapism. It is reasonable to presume that patients diagnosed to have non-ischemic priapism (NIP) can undergo observation and conservative management, then pursue embolization if possible with temporary agents (8). Angiography with super-selective embolization is the treatment of choice if

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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Table 1. Overview of each type of priapism. Characteristics of each type Etiologies

Symptoms

Corporal blood aspirate

Color Doppler findings

Ischemic priapism • Iatrogenic • Medications • Intracavernous injection • Idiopathic • Penile pain • Rigid corpora • Blood is dark • Acidity (pH < 7.25) • High PCO2 (> 60 mmHg) • Low PO2 (< 30 mmHg) • Lack of cavernous artery blood flow • Very high-resistance flow pattern in the cavernous artery

Non Ischemic priapism • Traumatic rupture of the cavernous artery or its branches

Stuttering priapism • Similar to the causes of ischemic priapism • Sickle cell disease is the common cause

• Erection without full rigidity • No pain • Penile trauma • Blood is bright red • PO2 > 90 • PCO2 < 40 • PH of 7.4 • Doppler waveforms with peak systolic velocity > 50 cm/s, and end-diastolic velocity that is 0 or negative

• Same as ischemic type • Multiple recurrent episodes are usually noted • Same as ischemic type

• Low peripheral resistance waveform • Elevated, variable cavernosal artery velocity

Table 2. Advantages and disadvantages of each type of therapy used in priapism. Type of therapy

Advantages

Disadvantages

Penile aspiration and irrigation used in IP

• Easy to learn • Minimally invasive

• High failure rate • Contraindicated in patients with bleeding disorders or using anticoagulation

Intracavernosal injections of pharmacological agents used in IP

• Easy to learn • Minimally invasive

• Cardiac side effects • Require cardiovascular monitoring • Less than 60% efficacy

Shunt surgery used in IP

• Usually, proximal shunt procedures are easy to learn • Can be used in patients whose intracavernous injections are contraindicated

• Usually, proximal shunt procedures are difficult to learn • Invasive procedures • Duration of priapism affects resolution rates

Penile prosthesis used in IP

• Allow recovery of sexual function

• Increased risk of prosthetic infection • In chronic cases, penile prosthesis surgery is difficult due to fibrosis

Hormonal therapy used in SP

• Allow fistula to heal more easily

• It may cause erectile dysfunction • Multiple side effects such as hot flashes, fatigue, decreased libido

Selective arterial embolization used in SP cases

• Minimally invasive

• It may cause erectile dysfunction • High failure rate • Can cause penile gangrene • Can cause perineal abscess

IP: Ischemic priapism; NIP: non ischemic priapism; SP: Stuttering priapism

prompt definitive management of NIP is desired. Cavernosal artery ligation is another option reserved in case of failures of embolization (9). We performed a narrative review to discuss briefly the types, pathophysiology, and diagnosis of priapism. This review will focus on updates in the treatment of each type of priapism.

review, we initially excluded papers that were not relevant: 96 articles. At the completion of the review, 154 articles were selected based on their clinical relevance related to the aim. Data extraction was performed by all authors. Table 3 resumes the research summary.

MATERIALS

Types of priapism There are three different types of priapism: low-flow or ischemic; high-flow or non-ischemic priapism; and recurrent or stuttering priapism (10). Stuttering priapism (SP) manifests in recurring episodes of IP incidents of varying duration and should be distinguished from the persistence or rapid recurrence of a single episode of acute priapism. Although many of these episodes are self-limited, they can increase in duration and incidence, leading to acute major IP events requiring emergency medical management (11).

AND METHODS

We searched electronic databases including PubMed and the Scopus database for published studies that analyzed the role of the following Medical Subject Headings (MeSH) terms: ‘priapism’ (AND) ‘erectile dysfunction’ (OR) ‘ischemic priapism’ (AND) ‘management’ (OR) ‘nonischemic priapism’ (AND) ‘management’ (OR) ‘stuttering priapism’ (AND) ‘management’. This was done in order to ensure the comprehensive inclusion of articles related to the management of priapism. The initial search resulted in 250 articles. After

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Overview of priapism

An update on the management algorithms of priapism during the last decade

Table 3. Search summary used in our review. Section of our review Priapism definition

Number of articles screened related to the topic 10

Number of articles excluded from the review process 5

Number of articles that were relevant to the review aims 5

Priapism types

Priapism etiologies

Priapism diagnosis

Treatment of IP

Treatment of NIP

Treatment of SP

Reasons to exclude articles from our review Not relevant to the aims Repetitive content Not relevant to the aims Repetitive content Not relevant to the aims Repetitive content Not relevant to the aims Repetitive content Editorials/comments Not relevant to the aims Repetitive content Preclinical studies Pilot studies Editorials/comments Same intervention, different outcomes Not relevant to the aims Repetitive content Preclinical studies No relevant outcomes No comparison group Not relevant to the aims Repetitive content Preclinical studies No outcomes Editorials/comments Studies from the same author(s)

IP: Ischemic priapism; NIP: non ischemic priapism; SP: Stuttering priapism.

Epidemiology of priapism Epidemiologic studies reported an overall incidence rate of 1.5 per 100,000 man-years. The incidence rate in men 40 years old and older was 2.9 per 100,000 person-years (12). Roghmann et al. reported 32,462 visits to the emergency department for priapism between 2006 and 2009 in the United States, which represents a national incidence of 5.34 per 100,000 male subjects per year (13). Kulmala et al. reviewed all cases of priapism in Finland during the years 1975-90. When cases due to intracorporal injections were excluded, the incidence of priapism was stable and varies from 0.34 to 0.52/100000 males per year. Most cases of priapism were seen during the lighter half of the year, between March and August (14). The incidence of priapism among patients with sickle-cell disease (SCD) is high (35%). The implications of priapism for erectile and sexual function are significant (15). 30% of males with SCD under the age of 20 years reported at least one episode of priapism, whereas frequencies of 30% to 45% are estimated for adult men (16). Etiology of priapism Numerous etiologies of priapism are considered. The excess release of contractile neurotransmitters, obstruction of draining venules, prolonged relaxation of intracavernosal smooth muscle may lead to an abnormal detumescence (17). Various possible etiologies for IP have been described in the literature including hemoglobinopathies (SCD), iatrogenic causes like intracavernosal

injections, phosphodiesterase 5 (PDE5) inhibitors, psychiatric medications (such as risperidone and clozapine), and alpha-1 blockers (18). Veno-occlusive crisis can occur in the penis of SCD patients, that is often due to stasis and low blood flow rates within the sinusoids of the erectile tissue. In SCD patients, there is abnormal signaling of the nitric oxide (NO) pathway. This can be the main pathophysiology of priapism in those patients (19). NIP is mostly due to the traumatic rupture of the cavernous artery or its branches. Most of the time, the venous channels remain open, and the penis is partially erect. NIP is usually caused by perineal or penile trauma and can occur after shunt procedures for the management of IP (20). Diagnosis of priapism The diagnosis of IP is based on the history and physical examination and may be done by penile blood gas analysis and penile ultrasound (21). A physical examination of the penis should be performed to ascertain whether it is fully erect (as in IP) or partially erect (as in NIP) (22). A perineal examination may reveal evidence of trauma in NIP cases (8). A recent penile injection site is sometimes found in IP cases examination (23). The diagnosis of IP can be made by a cavernous blood gas analysis to confirm the storage of venous blood within the corpora cavernosa manifesting as a lower partial oxygen pressure (pO2 < 30 mmHg), higher partial carbon dioxide pressure (pCO2 > 60 mmHg), and a decline of pH (< Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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Figure 1. Algorithm used for the management of ischemic priapism.

damage to the muscle has been occurred leading to poor muscle response to aadrenergic agonists. Previous studies have concluded that priapism episodes of greater than 24 h were associated with a 90% rate of erectile dysfunction (31). Cavernous smooth muscle will not respond to alpha-adrenergic agonists if the episodes last more than 48h because of impaired intracavernous circulation and tissue swelling. T-shunt or T-shunt with tunneling should be performed first because doing aspiration and irrigation could delay the therapy (32). A duration-directed therapy for IP is crucial. The treatment algorithm of IP is summarized in Figure 1. Non surgical options

7.25) (24). A penile Doppler study is the key radiological tool in the assessment of a patient with priapism. In the ischemic subgroup, cavernosal blood flow typically will be absent, with a high-resistance, low-velocity trace. The diastolic flow will be low or absent. In NIP, the Doppler study demonstrates normal or elevated cavernosal artery velocities with a high diastolic flow (25). In all patients with priapism, blood count, coagulation tests, sickle cell screen, and hemoglobin electrophoresis with reticulocyte counts should be performed (26). Men with SP had a unique baseline Doppler ultrasound waveform, with a low peripheral resistance waveform and an elevated, variable cavernosal artery velocity. As proposed by Patel et al., this may be the sonographic manifestation of a reduced, fluctuating smooth muscle tone (27). There are two main indications for MRI in priapism. In IP, the degree of corporal infarction may influence the decision to intervene. In NIP, a fistula can be suspected in the dynamic post-contrast images (28). Arteriography may be utilized to precisely localized arterial fistulae in NIP; typically this is only undertaken in the context of attempted treatment with super-selective embolization of the affected vessel (29). Management of ischemic priapism A duration-directed therapy for IP is crucial. Management of IP should progress in a stepwise fashion to achieve resolution as urgent as possible. When the priapism episodes are lasting more than 24 to 36 hours, patients are less likely to respond to corporal blood aspiration and instillation of a-adrenergic agonists because of the presence of irreversible smooth muscle damage. If IP is reversed within 24 hours, there is usually a recovery of erectile function in approximately 50% of patients (30). If based on history, the duration of erection is between 1-2 hours, hypoxic

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• Corporal aspiration The first step in the management of IP is doing corporal aspiration with or without corporal irrigation. This should be performed with a 18 or 19 gauge needle placed at the base of the penis in the 3 o'clock and/or 9 o'clock position. Saline solution 0.9% is used for irrigation. An important trick is to continue aspiration till oxygenated blood appeared (33). Corporal aspiration and irrigation with 10 degrees C saline for patients with prolonged penile erection were tested. The complete detumescence rate is improved after the cold saline usage (34). An easily constructed priapism task trainer was developed and tested. It is was found that is realistic and useful for resident education. The use of the model in a simulation session can improve resident comfort in performing corpus cavernosa aspiration and phenylephrine injection (35). • Intracavernosal injections of pharmacological agents Phenylephrine is considered the drug of choice for intracavernosal injection due to its high selectivity for the alpha1-adrenergic receptor, without concomitant beta-mediated inotropic and chronotropic cardiac effects. Phenylephrine is injected after adequate dilution in normal saline at a concentration of 100-500 μg/mL. Usually, 200 μg is given every three to five minutes directly into the corpora. The maximum dosage is 1 mg within one hour. It is recommended that blood pressure and pulse are monitored every 15 minutes for an hour after phenylephrine injection to monitor any serious cardiovascular side effects (36). According to some studies, patients with IP that fail to respond to conventional doses of an alpha-agonist cannot benefit from continual or high-dose phenylephrine injection, as the cavernosal smooth muscle is damaged and cannot contract (37). Wen et al. assessed the efficacy of highdose phenylephrine in treating patients with acute IP. Injection of high-dose phenylephrine (1.000 mg q 5 minutes) was given for 17 consecutive cases of iatrogenic IP that occurred after vascular assessment. Intracavernosal therapy with high-dose phenylephrine was effective in all cases. Phenylephrine at doses higher than previously

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reported may be necessary to overcome the effect of acidosis on ligand dissociation from adrenergic receptors (38). Sympathomimetic drugs include epinephrine, ephedrine, norepinephrine, and metaraminol. There are no published data that compare the efficacy of these drugs. The summary data developed by the expert panel showed that for all patients with IP, the resolution occurred in 81% of cases treated with epinephrine, 70% with metaraminol, 43% with norepinephrine, and 65% with phenylephrine (39). Other options for pharmacologic agents include methylene blue (MB). Intracavernosal injection of adrenergic agents can rarely cause systemic toxicity. In rare cases, intracavernosal phenylephrine was associated with subarachnoid hemorrhage and intracavernosal epinephrine injection resulted in severe hypertension and angina pectoris (40). Intracavernosal adrenalin was used for patients with IP due to intracavernosal vasoactive agent use. A 2 ml adrenalin (1/100 000) was injected in each cavernosal body. In the patients who did not respond to the first injection, repeated adrenalin injections were performed at 20 min intervals, up to 5 times. Intracavernosal adrenalin injection alone had shown to be an effective therapy for the treatment of IP with a short duration of erection (41). Etilefrine is an a1-selective agonist that has been used by intracavernous injection for the management of acute priapic episodes showing fewer cardiovascular effects than other drugs (42). MB, a guanylate cyclase inhibitor, is considered a potent inhibitor of endothelial-mediated cavernous relaxation. Five ml of MB were injected within the corpora cavernosa and left for 5 minutes. MB is a safe and highly effective treatment agent for short-term pharmacologically induced priapism (43). Intracorporal injection of MB is free of complications and as effective as a sympathomimetics treatment for priapism (44). • Oral agents Terbutaline, a beta-agonist, can be used in the management of priapism. A placebocontrolled study was implemented to study the efficacy of oral medical therapy in the treatment of priapism. A total of 75 patients with pharmacologically induced (prostaglandin E1) prolonged erections were randomized to receive terbutaline, pseudoephedrine, or placebo. Detumescence occurred in 36 percent, 28 percent, and 12 percent, respectively. Terbutaline was significantly better than placebo (p < 0.05) in achieving detumescence (45). In another study, terbutaline was used in a prolonged erection. The dosage was 5 mg and its effect was observed for 15 min. An additional dosage of 5 mg was given if detumescence did not occur after 15 min and 30 min. Results showed that oral terbutaline can be used to treat pharmacologically induced prolonged erection. Terbutaline is given cautiously in patients with coronary artery disease, pulmonary edema, and hypokalemia (46). Midodrine administered orally is a simple and efficient treatment for the priapism induced by intra-

cavernous injection of prostaglandin E1 in spinal cord injured patients (47). Criteria to move to 2nd line therapy for ischemic priapism Surgery for IP should be considered only when conservative management options fail. However, there is no experimental evidence detailing the amount of time allowed for first-line treatment before moving on to second-line therapy (36). In the early stages of priapism (< 24-36 hours), conservative measures and aspiration, with or without intracorporeal instillation of a-adrenergic agonists, are usually successful. The shunt surgery is less effective if the duration of priapism is > 48 hours (48). Surgical intervention • Surgical shunts Shunt surgery for priapism diverts blood from the corpus cavernosum into another area such as the corpus spongiosum (glans or urethra) or the venous system (saphenous vein). Both the EAU and AUA guidelines recommend using firstly distal shunts and then proximal shunts in cases where aspiration and instillation of pharmacological agents failed (49). Surgical shunts are divided into four anatomical subcategories: percutaneous distal, open distal, open proximal (corporospongiosal) shunts, and vein anastomosis/shunts (50). Their types are summarized in Figure 2. Winter shunt consists of the insertion of a large-bore needle from the glans to the distal side of the corpus cavernosum. The Ebbehoj procedure consists of creating a shunt from the glans to the distal corpora using a small incision with the number 10 scalpel (30). T shunt involves passing a number 10 blade vertically through the glans into the corporal bodies bilaterally, rotating the

Figure 2. Surgical shunts used for ischemic priapism.

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blade laterally 90° (to avoid urethral injury), and then removing (4). In IP of > 3 days duration and/or when the penis is quite firm after repeated ‘milking’, bilateral Tshunts followed by intracavernous tunneling using a straight urethral sound or dilator are indicated. To create tunneling of the corpora cavernosa, a straight 20-24 F straight urethral sound or dilator is inserted through each glans incision and advanced to the penile crura (51). Although a T-shaped shunt operation has the advantages of simple operation, and fewer complications, it is not used in case of tumor-induced IP (52). An open distal shunt may be performed if the previous shunt failed to achieve detumescence. The Al-Ghorab shunt involves a transversal incision that was made on the penile glans, 1 cm distal of the coronal sulcus. Two 5-mm circular cone segments of the tunica albuginea create a corporoglandular shunt (53). This shunt procedure can incise the dorsal nerve of the penis and thereby denervate the glans penis. A novel modification to the Al-Ghorab shunt in which incisions are made on the ventral aspect of the glans in an effort to prevent destruction and preserve the sensations of the glans penis (54). Burnett and Pierorazio described the corporal "snake" procedure as a modification of the Al-Ghorab shunt (55). The modified Al-Ghorab corporoglanular shunt using the Burnett snake maneuver is successful in resolving IP, particularly in cases refractory to first-line therapy (56). A shunt cuts a new wound through the collagen-rich tunica albuginea. To prevent the collagen-activated platelets and fibrin phenomena begin to form a clot within minutes to seal off the shun, a perioperative anticoagulant should always be administered in this type of surgery (57). When distal shunts failed, other treatment options included proceeding to open proximal shunts and venous shunts, namely the Quackels (unilateral corporospongiosal) or Sacher (bilaterally staggered corporospongiosal) shunts (4). The creation of a venous shunt requires microsurgical skills. Saphenous vein shunt (Greyhack), and dorsal vein graft (Barry) has been often used (32). • Penile prosthesis More than 90% of patients with priapism lasting > 24 h complain of subsequent erectile dysfunction. The choice of an early penile prosthesis insertion has many advantages. It allows the recovery of sexual function, it may prevent penile shortening, and it is easier to implant a penile prosthesis in the acute setting, with fewer complications (58). Early penile prosthesis insertion for acute IP is simple and successful even though distal cylinder can protrude through a defective corpora due to previous shunt surgery. Nonabsorbable sling suture of the cylinder to the tunica albuginea is an effective, simple, and safe treatment for this complication (59). Immediate insertion of a penile prosthesis for acute refractory IP can treat the acute episode and the erectile dysfunction that will occur with the preservation of penile length (60). No RCT assess the use of penile prosthesis in IP. The best type of prosthesis and the timing of its placement is not determined yet. An increased risk of prosthetic infection occurred if a penile prosthesis procedure is performed during the acute phase of priapism.

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Delayed procedure could have technical challenges due to corporal fibrosis (33). The implantation of penile prosthesis in chronic priapism is technically much more challenging and often requires the use of downsized shorter cylinders (61). Palmisano et al. used a soft penile prosthesis (sPP) for patients with refractory IP in the acute phase. They found that sPP insertion can lead to immediate pain relief, preservation of sexual function, and penile size, with a higher surgery reproducibility in an emergency situation (62). The EAU recommends that penile prosthesis (either malleable or a three-piece inflatable prosthesis) at the time of presentation could be taken into consideration if ischemia has been presented for more than 36 hours (mainly in sickle cell disease patients), aspiration and sympathomimetic intracavernous injections have failed and distal and proximal shunting have also failed (36). Management of non-Ischemic Priapism NIP is not an emergency and will often resolve without treatment. Acute conservative treatment, such as ice and site-specific compression to the injury, may be used. However, there are no data that can demonstrate the benefit of those conservative measures (39). Super-selective transcatheter embolization of the proximal artery supplying arterial-lacunar fistula should be the present treatment of choice in these cases of high-flow priapism refractory to conservative treatment. Autologous clots and gelatine sponge have been used as the embolic agent. More recently, platinum microcoils have been proposed to achieve more precise and selective embolization (63). Microcoils are permanent occlusive agents. Hence, there are theoretically increased risks of permanent vascular occlusion and subsequent erectile dysfunction with their use (64). Temporary materials are initially preferred in most cases of NIP. However, cases with arterial embolism using absorbable materials often have a recurrence of priapism, with the recurrence rate reported to be 30% to 40% (24). Super-selective transcatheter embolization and transient occlusion of the fistula with an autologous blood clot is an effective therapy for the treatment of NIP. Numan et al. reviewed their experience with super-selective transcatheter embolization in the treatment of NIP. In three (27.2%) of 11 cases, a second embolization was required due to recurrence of priapism. In all patients, erectile function was restored within 6 weeks of the procedure (65). Kim et al. reported the effectiveness and safety of super-selective transcatheter embolization in the treatment of NIP at nine university hospitals. 27 patients were included in the study. In 24 of 27 patients (89%), a single embolization was sufficient for the complete resolution of priapism. Repeat embolization was required in two patients (7%), and in the remaining patient (4%), shunt surgery was performed after embolization (66). Using angioembolisation to treat NIP, reduced sexual function is the primary adverse effect of interest, with small sample observational studies reporting 19-20% had reduced erection quality after the procedure. Preliminary estimates of recurrence rates are between 30 and 40% (67). The type of vessels that are involved in refilling the fistula after embolization is of concern for the outcome of the

An update on the management algorithms of priapism during the last decade

patients. The fistulas supplied only by cavernosal-spongiosal communications closed spontaneously within 1 month. Watchful waiting should be preferred to repeated embolization to avoid the risk of unnecessary procedures (68). Color Doppler ultrasound allows the confirmation of successful embolization by demonstrating disappearance or size reduction of the fistula (69). Surgical treatment consists of selective ligation of the fistula through a transcorporal approach under the guidance of color duplex ultrasound. Although surgery has been successful in treating arterial priapism, it is technically challenging and may pose significant risks, mainly erectile dysfunction due to accidental ligation of the cavernous artery instead of the fistula (36). Two surgical approaches are used for NIP, one extracorporal, and the other transcorporal. Despite that transcorporal dissection is a risky procedure, it is appropriate for arterial priapism of prolonged duration, especially if a well-formed vascular pseudocapsule is identified (70). Androgen blockade (AB) to suppress nocturnal erections is an alternative treatment for NIP. Mwamukonda et al. reported the outcomes of 7 patients with NIP that were treated with AB. Priapism resulted from trauma in three patients and a persistent high-flow state after shunt procedures in four. Therapy consisted primarily of 7.5 mg intramuscular monthly leuprolide injections, although bicalutamide and ketoconazole were also utilized as adjunct treatments. Therapy duration ranged from 2 months to 6 months. One patient discontinued daily ketoconazole after 1 week because of severe hot flashes. The remaining six patients reported complete resolution of NIP (71). The management algorithm of NIP is summarized in Figure 3. Figure 3. Algorithm used for the management of non-ischemic priapism.

Management of stuttering priapism SP is a variant of the ischemic type that is characterized by repetitive, transient, painful, self-limiting episodes of priapism. It is associated with various hematological disorders, including sickle cell disease and pharmacological treatments (72). Typically, the priapic events in SP are self-limited, resolving in under 3 h, some lasting for only minutes before spontaneous resolution. It has been reported that 77% of the transitory attacks are sleep-related, 17% are associated with sexual activity (11). If these episodes are not treated, it may evolve into a classic IP and eventually lead to irreversible corporal fibrosis with permanent erectile dysfunction. The goal of the management of a patient with SP is the prevention of future episodes, while the management of each episode should follow the specific treatment recommendations for acute IP (73). Hormonal therapy The use of hormonal therapy for the prevention of SP has been a successful medical management option for some patients. Caution is strongly advised in using hormonal treatments for prepubertal or adolescent men who have not reached sexual maturation and or in those desiring children, as side effects often result in castrate levels of testosterone creating a contraceptive effect, interfere with closure of the epiphyseal plates and have significant impairments on sexual function (42). Hormonal therapy using gonadotropin-releasing hormone analogues (GnRH) has been successful in treating episodes of priapism refractory to classic drugs. It is associated with significant adverse effects, in particular the loss of libido and erectile dysfunction (74). Patient with sickle cell disease and recurrent priapism was treated successfully for more than a year with monthly GnRH analogue therapy after failure of standard medical management (75). The use of low-dose estrogen shows is considered an effective and relatively rapid treatment option for some cases of idiopathic SP (76). Baker et al. reviewed their 12-year experience with the 5-a reductase inhibitor dutasteride as a potential long-term treatment option for SP. Patients were started on a dose of 0.5 mg daily and tapered to a more infrequent dosing schedule, ranging from 0.5 mg every other day to once weekly: 85% of men treated with dutasteride had some degree of improvement, 38% had complete resolution of their symptoms. Side effects were minimal and included gynecomastia (8%), decreased libido (8%), and fatigue (8%) (77). RachidFilho et al. demonstrating that the use of finasteride could decrease and control the number of priapism recurrences in patients with sickle cell anemia (78). Oral ketoconazole reversibly inhibits testosterone production and has been used to decrease postoperative erections (79). Abern et al. used ketoconazole and prednisone with dosing titrated according to Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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serum testosterone levels to prevent recurrent priapism episodes. Eight patients with recurrent IP were treated with ketoconazole and prednisone. Patients were seen monthly and therapy was withdrawn after 6 months. One patient had 2 recurrent IP episodes while on ketoconazole and prednisone treatment. Another patient had an increase in testosterone from 361 to 432 ng/dl after initiation of therapy, and 3 recurrent IP episodes requiring emergency corporal irrigation. After dose titration testosterone was 184 ng/dl and the patient had no subsequent episodes (80). Hoeh et al. reported their experience to prevent recurrent IP using ketoconazole, 16 of 17 patients (94%) had complete resolution of priapism while on ketoconazole. After 6 months, it was recommended to stop the medication (81). The duration of hormonal treatment for effective suppression of recurrent priapic events is still unknown. Of the hormonal agents suggested for preventing priapism, GnRH agonists, and anti-androgens appear to be the most efficacious and safe (37). Non hormonal therapies Baclofen is a centrally acting gamma-amino-butyric acid B (GABAB) agonist used to treat spasticity. As baclofen inhibits penile reflex responses. Sexual side effects of intrathecal baclofen including the decrease or loss of penile erections (82). Oral baclofen, starting with a daily dose of 10 mg that was increased to 30 mg can achieve control of priapism (83). Oral baclofen 10 mg, three times a day can be used to treat prolonged erections. After 24 h of therapy, the erection of penis occurred less frequently and each episode lasted for a shorter duration (84). Digoxin is a known inhibitor of sodium/potassium adenosine triphosphatase (sodium pump), a plasma membrane enzyme that has a role in the regulation of smooth muscle tone. Gupta et al. investigated the effects of digoxin on human corpus cavernosum smooth muscle contractility and overall erectile function. In vitro digoxin caused inhibition of contraction of corporal smooth muscle. In vivo digoxin diminished the penile rigidity during visual sexual stimulation and nocturnal penile tumescence testing compared to placebo without influencing libido or serum testosterone, estrogen, or luteinizing hormone levels (85). Oral gabapentin was used to treat refractory idiopathic priapism in three patients. They responded to treatment within 48 h. Two men continue not to experience prolonged erections while treated with lower doses of gabapentin for 16 and 24 months, respectively. The third, after successful treatment for 6 months, stopped gabapentin and priapism recurred (86). The rationale for the treatment of priapism with this medication was based on the reported sexual dysfunction possibly caused by gabapentin. Although the molecular targets of gabapentin remain unknown, the inhibition of Ca2+ efflux from muscle cells in the corpora, with consequent inhibition of smooth muscle relaxation, may explain the effectiveness of gabapentin in the management of refractory priapism (87). Also, gabapentin can reduce both testosterone and FSH levels (88). Hydroxyurea (HU) has been reported to decrease the number of stuttering priapism episodes in patients who retained erectile function. The beneficial effects may stem

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from its role as an NO donor, as HU has been shown to interact with hemoglobin to form NO (89). In a study HU has been used for preventing priapism in patients with SP, HU was introduced at the initial dose of 10 mg/kg, and as the HU dosage increased, the number or length of priapism episodes decreased. The data suggests that HU may prevent priapism attacks in SCD (90). Phosphodiesterase type 5 (PDE5) inhibitors The molecular mechanism of priapism is not clear. Champion et al. suggested aberrant downstream signaling of the NO pathway based on the finding that mice lacking the gene for endothelial nitric oxide synthase tend to have more a priapic activity (91). Dysregulation of the NO/cGMP signaling pathway in the penis is thought to be the primary molecular mechanism of recurrent IP. Studies identified transcriptional and translational down-regulation of PDE5, owing to basally decreased cGMP (92). In a study done by Burnett et al. to test the use of PDE5 inhibitors to treat recurrent priapism, 13 patients with SCD reporting priapism recurrences at least twice weekly were randomized to receive sildenafil 50 mg or placebo daily for 8 weeks. Priapism frequency reduction by 50% did not differ between sildenafil and placebo groups by intention-to-treat or per-protocol analyses (p = 1.0) (93). In another study, PDE5 inhibitors were used as a longterm therapeutic regimen in seven men with recurrent priapism. Six men had idiopathic priapism recurrences and one man had sickle cell disease-associated priapism recurrences. Tadalafil 5 mg was administered daily. Daily long-term oral PDE5 inhibitor therapy alleviated priapism recurrences in all patients. Five (71.4%) had no episodes of priapism and two (28.6%) referred decrease in their episodes of priapism (94). PDE5 inhibitors should be first used under conditions of full detumescence and their efficacy is obtained after 2-4 weeks of use (11). Self-injection of intracavernosal sympathomimetics The AUA recommends that intracavernosal self-injection of phenylephrine should be considered in patients who either fail or reject the systemic treatment of SP (39).

CONCLUSIONS

Priapism must be determined as ischemic or nonischemic because the treatments and the prognosis for these two types are different. As priapism is a rare urological emergency, multicenter randomized clinical trials are needed to recommend the best treatment options.

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53. Afriansyah A, Yuri P, Hutasoit YI. Intracorporeal dilatation plus Al-Ghorab corporoglandular shunt for salvage management of prolonged ischemic priapism. Urol Case Rep. 2017; 12:11-13.

73. Kheirandish P, Chinegwundoh F, Kulkarni S. Treating stuttering priapism. BJU Int. 2011; 108:1068-1072.

54. Dangle PP, Patel MB, Pandya LK, Firlit CF. A modified surgical approach to the Al-Ghorab shunt - an anatomical basis. BJU Int. 2012; 109:1872-1874. 55. Burnett AL, Pierorazio PM. Corporal "snake" maneuver: corporoglandular shunt surgical modification for ischemic priapism. J Sex Med. 2009; 6:1171-1176. 56. Segal RL, Readal N, Pierorazio PM, et al. Corporal Burnett "Snake" surgical maneuver for the treatment of ischemic priapism: long-term followup. J Urol. 2013; 189:1025-1029. 57. Lue TF, Garcia M. Should perioperative anticoagulation be an integral part of the priapism shunting procedure?. Transl Androl Urol. 2013; 2:316-320. 58. Sedigh O, Rolle L, Negro CL, et al. Early insertion of inflatable prosthesis for intractable ischemic priapism: our experience and review of the literature. Int J Impot Res. 2011; 23:158-64. 59. Salem EA, El Aasser O. Management of ischemic priapism by penile prosthesis insertion: prevention of distal erosion. J Urol. 2010; 183:2300-2303. 60. Ralph DJ, Garaffa G, Muneer A, et al. The immediate insertion of a penile prosthesis for acute ischaemic priapism. Eur Urol. 2009; 56:1033-8. 61. Garaffa G, Ralph DJ. Penile prosthesis implantation in acute and chronic priapism. Sex Med Rev. 2013; 1:76-82. 62. Palmisano F, Vagnoni V, Franceschelli A, et al. Immediate insertion of a soft penile prosthesis as a new option for a safe and costeffective treatment of refractory ischemic priapism. Arch Ital Urol Androl. 2021; 93:356-360. 63. Colombo F, Lovaria A, Saccheri S, et al. Arterial embolization in the treatment of post-traumatic priapism. Ann Urol (Paris). 1999; 33:210-218. 64. Kim KR. Embolization treatment of high-flow priapism. Semin Intervent Radiol. 2016; 33:177-181.

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67. Fergus KB, Baradaran N, Tresh A, et al. Use of angioembolization in urology: a review. Transl Androl Urol. 2018; 7:535-544.

74. Dahm P, Rao DS, Donatucci CF. Antiandrogens in the treatment of priapism. Urology. 2002; 59:138. 75. Levine LA, Guss SP. Gonadotropin-releasing hormone analogues in the treatment of sickle cell anemia-associated priapism. J Urol. 1993; 150:475-477. 76. Shamloul R, el Nashaar A. Idiopathic stuttering priapism treated successfully with low-dose ethinyl estradiol: a single case report. J Sex Med. 2005; 2:732-734. 77. Baker RC, Bergeson RL, Yi YA, et al. Dutasteride in the long-term management of stuttering priapism. Transl Androl Urol. 2020; 9:8792. 78. Rachid-Filho D, Cavalcanti AG, Favorito LA, et al. Treatment of recurrent priapism in sickle cell anemia with finasteride: a new approach. Urology. 2009; 74:1054-1057. 79. Evans KC, Peterson AC, Ruiz HE, Costabile RA. Use of oral ketoconazole to prevent postoperative erections following penile surgery. Int J Impot Res. 2004; 16:346-349. 80. Abern MR, Levine LA. Ketoconazole and prednisone to prevent recurrent ischemic priapism. J Urol. 2009; 182:1401-1406. 81. Hoeh MP, Levine LA. Prevention of recurrent ischemic priapism with ketoconazole: evolution of a treatment protocol and patient outcomes. J Sex Med. 2014; 11:197-204. 82. Saval A, Chiodo AE. Sexual dysfunction associated with intrathecal baclofen use: a report of two cases. J Spinal Cord Med. 2008; 31:103-105. 83. Moreira DM, Pimentel M, da Silva Moreira BF, et al. Recurrent priapism in the young patient treated with baclofen. J Pediatr Urol. 2006; 2:590-591. 84. Vaidyanathan S, Watt JW, Singh G, et al. Management of recurrent priapism in a cervical spinal cord injury patient with oral baclofen therapy. Spinal Cord. 2004; 42:134-5.

65. Numan F, Cantasdemir M, Ozbayrak M, et al. Posttraumatic nonischemic priapism treated with autologous blood clot embolization. J Sex Med. 2008; 5:173-9.

85. Gupta S, Salimpour P, Saenz de Tejada I, et al. A possible mechanism for alteration of human erectile function by digoxin: inhibition of corpus cavernosum sodium/potassium adenosine triphosphatase activity. J Urol. 1998; 159:1529-36.

66. Kim KR, Shin JH, Song HY, et al. Treatment of high-flow priapism with superselective transcatheter embolization in 27 patients: a multicenter study. J Vasc Interv Radiol. 2007; 18:1222-6.

86. Perimenis P, Athanasopoulos A, Papathanasopoulos P, Barbalias G. Gabapentin in the management of the recurrent, refractory, idiopathic priapism. Int J Impot Res. 2004; 16:84-85.

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87. Yuan J, Desouza R, Westney OL, Wang R. Insights of priapism mechanism and rationale treatment for recurrent priapism. Asian J Androl. 2008; 10:88-101. 88. Daoud AS, Bataineh H, Otoom S, Abdul-Zahra E. The effect of Vigabatrin, Lamotrigine and Gabapentin on the fertility, weights, sex hormones and biochemical profiles of male rats. Neuro Endocrinol Lett. 2004; 25:178-183.

91. Champion HC, Bivalacqua TJ, Takimoto E, et al. Phosphodiesterase-5A dysregulation in penile erectile tissue is a mechanism of priapism. Proc Natl Acad Sci U S A. 2005; 102:16611666. 92. Anele UA, Morrison BF, Burnett AL. Molecular pathophysiology of priapism: emerging targets. Curr Drug Targets. 2015; 16:474483.

89. Anele UA, Mack AK, Resar LMS, Burnett AL. Hydroxyurea therapy for priapism prevention and erectile function recovery in sickle cell disease: a case report and review of the literature. Int Urol Nephrol. 2014; 46:1733-1736.

93. Burnett AL, Bivalacqua TJ, Champion HC, Musicki B. Long-term oral phosphodiesterase 5 inhibitor therapy alleviates recurrent priapism. Urology. 2006; 67:1043-1048.

90. Saad ST, Lajolo C, Gilli S, et al. Follow-up of sickle cell disease patients with priapism treated by hydroxyurea. Am J Hematol. 2004; 77:45-9.

94. Nardozza A Junior, Cabrini MR. Daily use of phosphodiesterase type 5 inhibitors as prevention for recurrent priapism. Rev Assoc Med Bras (1992). 2017; 63:689-692.

Correspondence Mohamad Moussa mohamadamoussa@hotmail.com Mohamad Abou Chakra mohamedabouchakra@hotmail.com Department of Urology, Al Zahraa Hospital, University Medical Center, Lebanese University, Beirut, Lebanon Athanasios Papatsoris agpapatsoris@yahoo.gr Athanasios Dellis aedellis@gmail.com 2nd Department of Urology, School of Medicine, Sismanoglio Hospital, National and Kapodistrian University of Athens, Athens, Greece Michael Peyromaure michael.peyromaure@aphp.fr Nicolas Barry Delongchamps nicolas.barry-delongchamps@aphp.fr Hugo Bailly h.bailly.md@gmail.com Sabine Roux sabine.roux@aphp.fr Igor Duquesne igor.duquesne@aphp.fr Department of Urology, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris Descartes University, Paris, France Ahmad Abou Yassine ahmad.a.y.8@gmail.com Internal Medicine, Staten Island University Hospital, Staten Island, NY, United States Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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The association of bladder cancer and Cannabis: A systematic review Vahid Mehrnoush 1, Stacy Grace de Lima 2, Ahmed Kotb 1, Matthew Eric Hyndman 3 1 Department

of Urology, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada; Research Network-Snyder Institute for Chronic Disease, Departments of Physiology & Pharmacology and Medicine, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; 3 Department of Urology, Southern Alberta Institute of Urology, Calgary, Alberta, Canada. 2 Inflammation

Summary

Objective: To assess the association between Cannabis use and bladder cancer. Methods: A systematic literature review was performed using studies published in electronic databases including PubMed, MEDLINE, and Google Scholar. Due to the scarcity of literature on this topic, the search was not limited to a specific design, year of publication, or human studies. The studies were screened by two reviewers in the following steps; first, the studies were discovered according to the predetermined search strategy; second, the unrelated studies and duplicates were eliminated by screening the abstracts, titles, and keywords; third, the full text of relevant and eligible papers were critically appraised and assessed for the risk of bias using the respective tool. The two review authors independently assessed the risk of bias and outcome levels using the Newcastle-Ottawa Scale for the outcomes in observational studies. Any disagreements were settled by a third party. Results: The search strategy yielded 39 research articles. After removing 21 duplicates, 18 publications were eligible for title and abstract review. Thirteen studies were found to be irrelevant and subsequently excluded. Only three full-text articles were evaluated and included in the qualitative synthesis. Conclusions: The role of Cannabis in bladder cancer has been seldom studied. The small number of studies show contradictory findings; potential carcinogenic versus protective effect. The growing interest in Cannabis use after legalization necessitates further investigations with a robust design to assess the long-term effect of Cannabis on bladder cancer.

KEY WORDS: Bladder cancer; Cannabis; Cannabinoids; Marijuana; Legalization. Submitted 18 March 2022; Accepted 5 April 2022

INTRODUCTION

Cannabis (also known as marijuana) is a term used to describe a vast array of products that can be produced from any part of the Cannabis sativa, Cannabis indica, or Cannabis ruderalis plants individually, or in combination. The three most common administration routes for Cannabis are smoking, vaporizing, and eating (1). When it comes to elimination, Cannabis and its byproducts pass through both the gastrointestinal and urinary tracts that can lead to a direct contact and respective responses in the corresponding organs (2). Accordingly, many studies

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on the role of Cannabis in different types of cancer have mainly focused on the oral cavity, the lungs, the gastrointestinal tract, and genitourinary system. Upon legalization of Cannabis in Canada in October 2018, social acceptance and prevalence of Cannabis use have been rising dramatically in parallel with the concern about the disadvantageous and long-term consequences. Considering the direct exposure, bladder can be potentially impacted by Cannabis use to a considerable extent, i.e. general bladder health, and bladder cancer occurrence and prognosis (3). However, there is a scarcity of data on the link between Cannabis use and bladder cancer. To investigate the link between Cannabis use and bladder cancer, we conducted a systematic review.

MATERIALS

AND METHODS

Study objective Study objective was to assess the association between Cannabis use and bladder cancer. It is noteworthy that the review method was established prior to the conduct of the review, from which there was no significant deviation. Search strategy A systematic literature review was performed using studies published in electronic databases including PubMed, MEDLINE, and Google Scholar. Based on the Boolean search strategy, a variety of combinations contained the following search terms were applied in different search engines to ensure the comprehensiveness of the result. In addition, the reference lists of the retrieved studies were manually screened. The search terms included “marijuana OR marihuana OR tetrahydrocannabinol OR dronabinol OR cannabinoid OR Cannabis, AND bladder cancer OR bladder carcinoma OR bladder tumor OR bladder neoplasm OR urothelial carcinoma OR transitional cell carcinoma. Selection criteria We did not restrict the search with specific design, year of publication or human studies due to existing scarcity of literature on this topic. We just excluded the commentary and letter to editor. We enquired two experts in the fields to avoid missing any published or unpublished papers. No conflict of interest declared.

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Bladder cancer and Cannabis

Figure 1. PRISMA flowchart of the results of the literature search.

assessed for the risk of bias using the respective tool. Data extraction The following information was extracted from each selected study: Population characteristics, type of study, country, and key relevant findings. As noted, the data extraction was performed in duplicate by the two reviewers. The consensus on what information should be extracted and included was achieved. M ethodological quality (R isk of Bias) The two review authors (VM and SDL) independently assessed the risk of bias and outcome levels using the Newcastle-Ottawa Scale for the outcomes in observational studies (6). Any disagreements were settled by a third party (AK and MEH).

RESULTS

Screening data The studies were screened by two reviewers in the following steps; first, the studies were discovered according to the predetermined search strategy; second, the unrelated studies and duplicates were eliminated by screening the abstracts, titles, and keywords; third, the full text of relevant and eligible papers were critically appraised and

Study selection Figure 1 depicts the PRISMA flowchart of the study selection process. The search strategy yielded 39 research articles. After removing 21 duplicates, 18 publications were eligible for title and abstract review. Thirteen studies were found to be irrelevant and subsequently excluded. Following full-text evaluation, two papers (one commentary and one letter to the editor) were excluded. Only three full-text articles were evaluated and included in the qualitative synthesis.

Table 1. Summary of clinical studies on Cannabis and bladder cancer. Author Chacko et al. 2006 (4)

Study design Case control

Country USA

Population 124 Patients with bladder cancer

Intervention/Exposure Use of marijuana

Comparator Age-matched control

Thomas et al. 2015 (5)

Cohort

USA

Cannabis users

Not reporting Cannabis use

Nieder et al. 2006 (11)

Case report

USA

84170 Participants in a multiethnic cohort of men aged 45-69 years 1 Case with bladder cancer

Use of marijuana

Outcome A history of habitual marijuana use in 88.5% and 69.2% of transitional cell carcinoma patients and age-matched controls, respectively (p = 0.008). The association between marijuana use and tumor stage, grade, and number of recurrences of transitional cell carcinoma. Incident bladder cancer 0.3% among Cannabis users versus 0.4% among men not reporting Cannabis use (p < .001). Cannabis use associated with a 45% reduction in bladder cancer incidence (HR, 0.55; 95% CI, 0.31-1.00). Inhaling up to five marijuana cigarettes per day for 30 days as the only risk factor for transitional cell carcinoma.

ROB Moderate

Moderate

ROB: Risk of bias. NA: Not applicable.

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V. Mehrnoush, S.G. de Lima, A. Kotb, M.E. Hyndman

Included studies characteristics Three studies with moderate risk of bias (mainly due to limited information regarding the average marijuana exposure and inadequate adjustment for key confounders) were included for review. Table 1 shows the specific details of each.

DISCUSSION

Cannabinoids have been shown in studies to inhibit tumor cell growth and induce apoptosis in a variety of cancer cells (5-7). Despite widespread Cannabis use and evidence of cannabinoids' antitumor activity, little is known about the carcinogenic effects of Cannabis, which has been highlighted after Cannabis legalization. The findings on the effect of Cannabis on other urinary malignancies vary. The only clinical study on penile cancer and Cannabis found no link (7). Cannabis use appears to be an independent risk factor for the development of testicular germ cell tumors (9-11). The result of a study on the effect of Cannabis on prostate cancer did not find a link between Cannabis and prostate cancer risk (8); however, in vitro and animal studies strongly suggest that cannabinoids protect against prostate cancer development (9). The clinical studies on renal cancer merely characterized cannabinoid receptor expression in renal neoplasms (10). Two studies yielded contradictory results on Cannabis and bladder cancer according to our review. Chacko et al. compared 52 men under the age of 60 with transitional cell urothelial carcinoma to 104 age-matched controls. Their findings revealed that habitual marijuana use was present in 88.5% of patients with bladder cancer while 69.2% of the control group (p = 0.008), implying that marijuana use is associated with an increased risk of bladder cancer (4). This is consistent with the findings of a case report of 45-year-old man in whom excessive marijuana smoking (up to five marijuana cigarette daily more than 30 years was found to be the only risk factor for developing bladder cancer (11). A recent study by Thomas et al., which examined the records of 84170 men aged 45-69 years from the California Men's Health Study and followed them for 11 years, discovered that bladder cancer developed in 0.3% of men who used Cannabis and 0.4% of men who did not use Cannabis (p = 0.001), leading the authors to conclude that Cannabis use was associated with a 45% risk reduction in the bladder cancer incidence (5). However, the studies were limited by insufficient adjustment for confounders. Knowing the physiology of the tissue expression of cannabinoid receptors can shed more light on the potential role of Cannabis in bladder cancer. Tyagi et al. found CB1 and CB2 receptors in the urothelium of human bladder (12). Both receptors were present in the bladder urothelium and detrusor muscles, but CB1 expression was found to be significantly higher than CB2. CB1 and CB2 receptor expression was twice as high in urothelium as it was in detrusor muscles (12). Cannabis has primarily been studied in terms of regulating inflammation and urgency in the treatment of bladder conditions. CB2 agonists have been shown to reduce the severity of murine

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Archivio Italiano di Urologia e Andrologia 2022; 94, 2

bladder inflammation when locally administered after acrolin, an inflammatory agent (13). As part of the Cannabinoids in Multiple Sclerosis (CAMS) study, Freeman et al. investigated the effect of cannabinoids on urge incontinence. They assigned 630 patients with multiple sclerosis to receive either Cannabis extract, THC, or a matched placebo via oral administration. Urge incontinence was significantly reduced with Cannabis (38%), and THC (33%), versus placebo (18%) (14). Kavia et al. also found that Sativex (THC + cannabidiol) can also a positive impact on overactive bladder symptoms in patients with multiple sclerosis (15). The existing small body of evidence indicates that Cannabis has a direct effect on the bladder during elimination where the resulting direct contact with the bladder urothelium can cause change in urine peptides and urothelial expression of CB1 and CB2 receptors. Although it is currently difficult to study Cannabis's effects on the bladder, legalization may increase this possibility due to the increased openness of the population regarding their use of Cannabis. Because of the long latency nature of bladder cancer development, more robustly designed studies with long-term follow-up are warranted. Given the gaps in current knowledge, the authors pose the following dire questions for future observation and study: Will Cannabis reduce or increase the incidence of BC? Will Cannabis influence BC aggression in a positive or negative way? Will new pathological types of BC emerge? Many questions may arise, but only observation and ongoing research will allow us to begin finding true, conclusive evidence.

CONCLUSIONS

The role of Cannabis in bladder cancer has been seldom studied. The small number of studies show contradictory findings; potential carcinogenic vs protective effect. The growing interest in Cannabis use after legalization necessitates further investigations with a robust design to assess the long-term effect of Cannabis on bladder cancer.

REFERENCES

1. Russell C, Rueda S, Room R, et al. Routes of administration for Cannabis use - basic prevalence and related health outcomes: A scoping review and synthesis. Int J Drug Policy. 2018; 52:87-96. 2. Felder CC, Dickason-Chesterfield AK, Moore SA. Cannabinoid biology: The search for new therapeutic targets. Mol Interv. 2006; 6:149-61. 3. Skeldon SC, Goldenberg SL. Urological complications of illicit drug use. Nat Rev Urol. 2014; 11:169-77. 4. Chacko JA, Heiner JG, Siu W, et al. Association between marijuana use and transitional cell carcinoma. Urology. 2006; 67:100-4. 5. Thomas AA, Wallner LP, Quinn VP, et al. Association between Cannabis use and the risk of bladder cancer: results from the California Men’s Health Study. Urology. 2015; 85:388-92. 6. Wells G, O’Connell D, Peterson J. The Newcastle-Ottawa Scale (NOS) for assessing the quality of non-randomized studies in metaanalysis | Request PDF. 2000; Available from: https://www.researchgate.net/publication/261773681_The_Newcastle-Ottawa_Scale_

Bladder cancer and Cannabis

NOS_for_Assessing_the_Quality_of_Non-Randomized_Studies_ in_Meta-Analysis.

associated with marijuana: case report and review of the literature. Urology. 2006; 67:200.

7. Maden C, Sherman KJ, Beckmann AM, et al. History of circumcision, medical conditions, and sexual activity and risk of penile cancer. J Natl Cancer Inst. 1993; 85:19-24.

12. Tyagi V, Philips BJ, Su R, et al. Differential expression of functional cannabinoid receptors in human bladder detrusor and urothelium. J Urol. 2009; 181:1932-8.

8. Sidney S, Quesenberry CPJ, Friedman GD, Tekawa IS. Marijuana use and cancer incidence (California, United States). Cancer Causes Control. 1997; 8:722-8.

13. Wang Z-Y, Wang P, Bjorling DE. Activation of cannabinoid receptor 2 inhibits experimental cystitis. Am J Physiol Regul Integr Comp Physiol. 2013; 304:R846-53.

9. Ramos JA, Bianco FJ. The role of cannabinoids in prostate cancer: Basic science perspective and potential clinical applications. Indian J Urol. 2012; 28:9-14.

14. Freeman RM, Adekanmi O, Waterfield MR, et al. The effect of Cannabis on urge incontinence in patients with multiple sclerosis: a multicentre, randomised placebo-controlled trial (CAMS-LUTS). Int Urogynecol J Pelvic Floor Dysfunct. 2006; 17:636-41.

10. Rajanahally S, Raheem O, Rogers M, et al. The relationship between Cannabis and male infertility, sexual health, and neoplasm: a systematic review. Andrology. 2019; 7:139-47. 11. Nieder AM, Lipke MC, Madjar S. Transitional cell carcinoma

15. Kavia RBC, De Ridder D, Constantinescu CS, et al. Randomized controlled trial of Sativex to treat detrusor overactivity in multiple sclerosis. Mult Scler. 2010; 16:1349-59.

Correspondence Vahid Mehrnoush, MD vahidmehrnoush7@gmail.com Department of Urology, Northern Ontario School of Medicine Thunder Bay, Ontario (Canada) Stacy Grace de Lima, BSc stacy.ggibson@gmail.com Inflammation Research Network-Snyder Institute for Chronic Disease, Departments of Physiology & Pharmacology and Medicine, University of Calgary Cumming School of Medicine, Calgary, Alberta (Canada) Ahmed Kotb, MD, FRCSC (Corresponding Author) drahmedfali@gmail.com Northern Ontario School of Medicine TBRHDC, 980 Oliver Road Thunder Bay, Ontario (Canada) P7B 6V4 Matthew Eric Hyndman, MD, FRCSC (Corresponding Author) erichyndman@shaw.ca Southern Alberta Institute of Urology, 7007 14 Street SW, Calgary, AB, Canada. T2V 1P9

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REVIEW

Effect of alpha-adrenoceptor antagonists on sexual function. A systematic review and meta-analysis Rawa Bapir 1, 13, Kamran Hassan Bhatti 2, 13, Ahmed Eliwa 3, 13, Herney Andrés García-Perdomo 4, 13, Nazim Gherabi 5, 13, Derek Hennessey 6, 13, Vittorio Magri 7, 13, Panagiotis Mourmouris 8, 13, Adama Ouattara 9, 13, Gianpaolo Perletti 10, 13, Joseph Philipraj 11, 13, Alberto Trinchieri 12, 13, Noor Buchholz 13 1 Smart

Health Tower, Sulaymaniyah, Kurdistan region, Iraq; Department, HMC, Hamad Medical Corporation, Qatar; 3 Department of Urology, Zagazig University, Zagazig, Sharkia, Egypt; 4 Universidad del Valle, Cali, Colombia; 5 Faculty of Medicine Algiers 1, Algiers, Algeria; 6 Department of Urology, Mercy University Hospital, Cork, Ireland; 7 ASST Nord Milano, Milan, Italy; 8 2nd Department of Urology, National and Kapodistrian University of Athens, Sismanoglio Hospital, Athens, Greece; 9 Division of Urology, Souro Sanou University Teaching Hospital, Bobo-Dioulasso, Burkina Faso; 10 Department of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, University of Insubria, Varese, Italy; 11 Department of Urology, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth, Puducherry, India; 12 Urology School, University of Milan, Milan, Italy; 13 U-merge Ltd. (Urology for emerging countries), London-Athens-Dubai *. 2 Urology

Authors 1-12 have equally contributed to the paper and share first authorship. *U-merge Ltd. (Urology for Emerging Countries) is an academic urological platform dedicated to facilitate knowledge transfer in urology on all levels from developed to emerging countries. U-merge Ltd. is registered with the Companies House in London/ UK. www.U-merge.com.

Summary

Background: Alpha-adrenoreceptor antagonists or alpha-blockers are used in the treatment of hypertension, in the therapy of benign prostatic hyperplasia and in medical expulsive treatment of ureteral stones. These agents may affect the sexual function, with differences between drugs within the same class, depending on their selectivity for receptor subtypes. The aim of this review was to analyze the effects of alpha-blockers on sexual function. Materials and methods: We conducted a systematic review and meta-analysis by searching PubMed, EMBASE and other databases for randomized controlled trials (RCTs) reporting sexual adverse effects in patients treated with alpha-blockers. Odds ratios for sexual dysfunction were calculated using random effects Mantel-Haenszel statistics. Results: Out of 608 records retrieved, 75 eligible RCTs were included in the meta-analysis. Compared with placebo, alphablockers were associated with increased odds of ejaculatory disorders both in patients with lower urinary tract symptoms (LUTS) associated to benign prostatic hyperplasia (BPH) (OR: 7.53, 95% CI: 3.77-15.02, Z = 5.73, p < 0.00001, I2 = 55%) and in patients with ureteral stones (OR: 2.88, 95% CI: 1.50-5.44, Z = 3.19, p < 0.001, I2 = 31%). Uroselective alpha-blockers showed higher odds of ejaculatory disorders. Conversely, nonselective alpha-blockers were not associated with higher odds of ejaculatory dysfunction. Silodosin was associated with increased odds of ejaculatory dysfunction compared with tamsulosin (OR: 3.52, 95% CI: 2.18-5.68, 15 series, 1512 participants, Z = 5.15, p < 0.00001, I2 = 0%). Naftopidil and alfuzosin showed lower odds of ejaculatory dysfunction compared to uroselective alpha-blockers.

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No statistically significant differences in the odds of erectile dysfunction were observed when alpha-blockers were compared to placebo.

KEY WORDS: Alpha-blockers; Ejaculation; Erectile dysfunction; Silodosin; Tamsulosin; Alfuzosin; Doxazosin; Terazosin. Submitted 11 February 2022; Accepted 24 March 2022

INTRODUCTION

Alpha adrenergic receptor (or adrenoreceptor) antagonists, also known as alpha-blockers, are a class of pharmacological agents acting as antagonists on various alphaadrenergic receptors. Depending on receptor specificity, they bind and inhibit alpha1-receptors, alpha2-receptors, or both (1). Alpha-1 adrenergic antagonists bind to type-1 alphaadrenergic receptors, thus inhibiting smooth muscle contraction. Several subtypes of postsynaptic alpha1 receptors are present in vascular and nonvascular smooth muscle. Alpha 1A receptors are predominantly located in the smooth muscle of the genitourinary tract, where they regulate the tone of the bladder neck and of the smooth muscle fibers within the prostate. Alpha 1B receptors are more represented in the vascular smooth muscle, and are involved in the regulation of the vascular tone. Receptors belonging to the alpha1D subtype regulate the contraction of the urinary bladder (2). The effects of alphaNo conflict of interest declared.

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adrenergic blocking agents depend on their selectivity (or non-selectivity) for specific receptor subtypes. Nonselective alpha-1-adrenergic antagonists have been used for decades against hypertension. Blockade of alpha1B receptors can decrease vascular resistance in peripheral arterioles and increase venous capacitance, ultimately lowering blood pressure (3). At present, alpha1 adrenergic antagonists are no longer recommended as monotherapy, but only as adjunctive treatment of hypertension (4). Alpha-1-blockers are used for the treatment of symptoms of urinary obstruction due to benign prostatic hyperplasia because they can relax the smooth muscle fiber in the bladder neck and in the prostate acting on alpha1A receptors. Initially, nonselective alpha-1 adrenergic antagonists such as doxazosin, terazosin and alfuzosin were used for the management of bladder neck obstruction (5). Selective alpha1A blockers with high affinity for the alpha1A adrenergic receptor, as tamsulosin and silodosin, have been subsequently developed to be specifically used in benign prostatic hyperplasia. Selectivity of these agents was aimed at decreasing their effect on blood pressure and at reducing the risk of unwanted effects, such as postural hypotension. Alpha1D-adrenoceptor antagonists have also been shown to be effective in alleviating both voiding and storage LUTS associated with BPH. Naftopidil is an alpha-1 adrenoceptor antagonist with a distinct selectivity for the alpha1D receptor showing a threefold selectivity for the alpha1D-adrenoceptor compared to the alpha1A-adrenoceptor (6). It is used for BPH management in Japan because of its fewer side effects, but there is limited evidence of its effectiveness in other populations (7). Alpha-1-adrenergic antagonists are also used to facilitate the spontaneous passage of stones in the distal ureter. When alpha-1-adrenergic antagonists are administered for benign prostatic hyperplasia and for medical expulsive therapy, their effect at various sites of the uro-genital tract may affect sexual function, with differences between drugs within the same class. The aim of this study is to review the existing evidence on the effect of alpha-1-adrenergic antagonists on sexual function.

MATERIALS

AND METHODS

The review was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and MetaAnalyses) guidelines (8). It was registered on the PROSPERO platform as CRD42021283385. We included in this review randomized controlled trials (RCTs), with single/double blinded design involving participants of any age or ethnicity who were treated with alpha adrenergic receptor antagonists for different conditions such as arterial hypertension, bladder neck obstruction by benign prostatic hyperplasia (BPH) or ureteral obstruction by ureteral stones (medical expulsive treatment or MET). The following outcomes were considered: (i) rate of ejaculatory disorders, (ii) rate of erectile disorders, (iii) scores of tests measuring erectile (IIEF-5) or ejaculatory activity (MSHQ-EjD, DAN-PSSsex). Two electronic databases (PubMed and EMBASE) were

searched for articles published up to September 30th, 2021. Database interrogation was performed using specific search strings; for example, the PubMed search was preferentially based on MeSH terms {('adrenergic alphaantagonists'/exp OR 'adrenergic alpha-antagonists' OR (adrenergic AND 'alpha antagonists') OR 'alfuzosin'/exp OR alfuzosin OR 'silodosin'/exp OR silodosin OR 'tamsulosin'/exp OR tamsulosin) AND ('ejaculation'/exp OR ejaculation OR 'erectile dysfunction'/exp OR 'erectile dysfunction' OR (erectile AND dysfunction)) AND [randomized controlled trial]/lim}. Relevant data were also hand searched by browsing various sources (e.g., reference lists from reviews and study reports, congress abstracts, clinical trial registers such as www.clinicaltrials.gov, www.clinicaltrialsregister.eu, etc.). Title and abstract screening to exclude documents that did not meet the inclusion criteria was performed independently by two authors. Duplicate references were deleted. Controversies were resolved by a third researcher. Full texts were downloaded to confirm or reject inclusion and to extract relevant information. Data extraction was conducted by two authors using a standardized form. The following information was obtained from each study: authors, publication year, study design, population, intervention, effect on sexual function (erectile, ejaculatory). In case of missing or insufficient information, we analyzed the impact of missing data on the meta-analysis results and evaluated the potential risk of bias. Two authors independently performed the quality assessment by identifying potential biases using the Risk of Bias (ROB)-2 assessment tool of the Cochrane Collaboration (9). Study quality was evaluated based on pre-defined criteria in relation to randomization process (D1), deviations from the intended interventions (D1), missing outcome data (D3), measurement of the outcome (D4) and selection of the reported result (D5). For each ROB domain, an evaluation was given, based on a specific algorithm, resulting in the following rating: low risk, some concern, high risk. Disagreements were resolved by discussion. The presence of risk of bias did not influence the decision to include/exclude a study from quantitative analysis. Statistical analysis Statistical analysis was performed using the RevMan5 software. Dichotomous data (presence/absence of sexual dysfunction) and number of per-protocol or intent-totreat patients were extracted to calculate odds ratios (OR), 95% confidence intervals (CI) to odds-ratios, and Z statistics (Random-effects model, Mantel-Haenszel method). Study heterogeneity was assessed by calculating I^2 (and 95% CI), which was interpreted as of lesser importance (I^2 ≤ 40%), moderate (I^2 = 30%-60%), substantial (I^2 = 50%-90%) or considerable (I^2 ≥ 75%), according to Cochrane criteria. Funnel plots were drawn and visually evaluated to detect publication bias and small study effects. If publication bias was suspected, the Egger’s and Begg’s tests were implemented to assess funnel plot symmetry or asymmetry. Asymmetry tests were performed using the MetaEssentials1 software (Rotterdam School of Management, Erasmus University, The Netherlands). The ‘trim and fill’ missing study imputation approach was applied to funnel plots; if Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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missing studies were imputed by this procedure, adjusted overall effect sizes (odds ratios) were calculated.

RESULTS

A PRISMA flow diagram illustrates the results of study selection process (Figure 1). We retrieved 612 records (Pubmed, 152; EMBASE, 456; other sources, 4). After title and abstract screening, we selected 125 articles by title and abstract screening (PubMed = 45 papers, EMBASE = 80). Following removal of 23 duplicates, the full text of the remaining 102 articles were examined. Twenty-seven articles were excluded (2 because alpha-blockers were expressly used to treat premature ejaculation or as male oral contraceptives, 6 open-label studies, 5 non-controlled studies, 4 studies not reported in English, 3 reviews, 4 short term experimental studies in healthy subjects, 3 studies not reporting sexual function outcomes). The remaining 75 papers were included in three analyses: alpha-blockers versus placebo (N=36) (10-45), comparison of different alpha-blockers (N=31) (46-76) and comparison of alpha-blockers administered at different dosages (N=8) (77-84) (Supplementary Materials - PICO Tables). Risk of bias Among the 75 studies included in qualitative analysis, the method of randomization was deemed to be at low risk of bias in 46 cases, and to unclear risk in 29. Figure 1. Flow chart.

The risk of deviation from the intended intervention was rated as low in 62 studies, unclear in 12 and high in one. The ROB associated to missing outcome data was considered to be low in 63 studies and unclear in 12. The risk of bias in measurement of outcome was considered to be low in 70 studies and unclear in 5. The risk of bias generated by selection of the reported results was rated as low in 73 studies and as unclear in 2. In total risk of bias was considered low in 37 studies, unclear in 35 and high in 3 (Supplementary Materials Risk of Bias). Analysis of funnel plots symmetry by Egger’s and Begg’s tests, and adjusted odds ratios when missing studies were imputed by the trim-and-fill procedure are shown in the (Supplementary Materials - Funnel plots & Symmetry tests). Significant asymmetry was detected by at least one test for any kind of alpha blockers (uroselective, nonuroselective or both) compared to placebo in BPH patients (endpoint: ejaculation), in the alpha blockers vs. standard care comparison in stone patients (endpoint: ejaculation), and in the alpha blockers vs. standard care or placebo comparison in stone patients (endpoint: ejaculation). Imputation of missing studies by the trim-andfill procedure was implemented in 4 comparisons. In 3 cases, the significance or non-significance of adjusted odds ratios was not modified by imputation. Conversely, the adjusted odds ratio for ejaculatory disorders in stone patients treated with alpha adrenoceptor blockers compared to placebo lost statistical significance. Alpha-blockers versus placebo A total of 36 studies were included in this analysis: 15 studies evaluated ejaculatory disorders secondary to treatment with alpha-blockers compared to placebo (9 in patients with BPH, 1 in patients with CP/CPPS, 5 in patients with ureteral stones) (10-24). In 7 studies ejaculatory disorders were compared in patients on treatment with alpha-blockers compared with standard conservative treatment of ureteral stones (25-31). In 9 studies, both ejaculatory and erectile dysfunction after treatment with alpha-blockers were compared to placebo in patients with BPH (32-40). Finally, 5 studies reported the effect on erectile function of alphablockers compared to placebo in BPH patients (41-45). Endpoint: ejaculatory disorders Compared to placebo, alpha-blockers were associated with significantly increased odds of ejaculatory disorders in patients with LUTS associated to BPH (OR: 7.53, 95% CI: 3.77 to 15.02, 23 series from 19

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studies, 13006 participants, Z = 5.73, p < 0.00001, I2 = 55%) (Figure 2). Similarly, in patients with ureteral stones, patients taking alpha-blockers showed significantly higher odds for ejaculatory disorders, compared to patients receiving placebo or standard care (OR: 2.86, 95% CI: 1.50 to 5.44, 12 series from 12 studies, 3192 participants, Z = 3.19, p < 0.001, I2 = 31%) (Figure 3). Significantly higher odds for ejaculatory disorders were

confirmed in patients with ureteral stones taking alphablockers compared to patients either on placebo or on standard treatment (Forest plots shown in Supplementary Materials - Forest plots Figures 1-2). Compared to placebo, uroselective alpha-blockers showed significantly higher odds of ejaculatory disorders (OR: 11.46, 95% CI: 5.58 to 23.54, 16 series from 13 studies, 8580 participants, Z = 6.64, p < 0.00001, I2 = 49% (Figure 4), whereas nonselective alpha-blockers were not associated with higher

Figure 2. Odds for ejaculatory disorders in patients with LUTS associated to BPH taking alpha-blockers. Data to the right of the vertical no-effect axis indicate higher odds for ejaculatory disorders in patients treated with alpha adrenoceptor blockers (both uroselective and non-uroselective), compared to placebo.

Figure 3. Odds for ejaculatory disorders in patients with ureteral stones taking alpha-blockers for medical expulsive treatment. Data to the right of the vertical no-effect axis indicate higher odds for ejaculatory disorders in patients treated with alpha adrenoceptor blockers compared to placebo or standard treatment.

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Figure 4. Odds for ejaculatory disorders in patients in patients with LUTS associated to BPH taking uroselective alpha-blockers. Data to the right of the vertical no-effect axis indicate higher odds for ejaculatory disorders in patients treated with uroselective alpha adrenoceptor blockers compared to placebo.

Figure 5. Odds for ejaculatory disorders in patients in patients with LUTS associated to BPH taking non-uroselective alpha-blockers. Data to the right of the vertical no-effect axis indicate higher odds for ejaculatory disorders in patients treated with non-uroselective alpha adrenoceptor blockers compared to placebo.

odds of ejaculatory dysfunction (OR: 2.22, 95% CI: 0.72 to 6.84, 7 series, 4426 participants, Z = 1.38, p = 0.17, I2 = 12%) (Figure 5). Endpoint: erectile dysfunction The presence of erectile dysfunction in patients treated with alpha-blockers was investigated in 14 studies. Eleven studies (12 series) reported the rates of erectile dysfunction in patients on treatment with alpha-blockers (any kind) in comparison with placebo (32-39, 43-45). There was no statistically significant difference between the odds of erectile dysfunction assessed in the alphablocker treatment arm compared to placebo (OR: 0.88, 95% CI: 0.42 to 1.82, 12 series, 6631 participants, Z = 0.35, p = 0.73, I2 = 36%) (Figure 6). The lack of a significant inter-arm difference versus placebo was confirmed when uroselective and non-selective alpha-blockers were analyzed separately (Forest plots shown in Supplementary Materials - Forest plots Figures 3, 4). In three of the above reported studies, erectile function alterations were also evaluated by administering questionnaires to enrolled patients. Hofner et al. (33) evaluat-

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ed the effect of alpha-blockers on sexual function by administering a quality-of-life assessment questionnaire including three questions on sexual function (interest in sex, erection, ejaculation). The authors reported the overall evaluation of sexual function without showing the results of the three separate domains. A trend to improvement of the overall sexual function was observed after tamsulosin (p = 0.042), whereas no differences were observed when tamsulosin was compared to alfuzosin. Rosen et al. (39) reported changes of the DAN-PSSsex score after alfuzosin treatment. The DAN-PSSsex tool includes questions on erectile and ejaculatory function, and on bother associated with these two functions. Alfuzosin treatment was associated with a significant improvement of erectile function compared with placebo (p = 0.02), whereas treatment didn’t appear to influence the ejaculatory function. Shelbaia et al. (44) observed that the use of tamsulosin was associated with increased IIEF scores (p = 0.047) in patients with LUTS and erectile dysfunction. Three additional studies were not included in our quantitative analysis. One study evaluated the effects of the oral administration of the nonselective alpha-

Sexual function and alpha-blockers

Figure 6. Odds for erectile dysfunction in BPH patients taking alpha-blockers. Data to the left of the vertical no-effect axis indicate lower odds for erectile dysfunction in patients treated with placebo compared to alpha adrenoceptor blockers.

adrenergic antagonist phentolamine in patients with erectile dysfunction. Full erection was achieved after ondemand administration of phentolamine at different doses (from 20 to 60 mg) more frequently than after placebo. However, the sample size was too small for statistical analysis (41). Another study evaluated the effect of a single dose of the selective, orally-active alpha1-Aadrenoceptor antagonist Ro70-0004 on the erectile function in a group of men with erectile dysfunction. Ro700004 did not improve the erectile function when compared to placebo (42). Finally, in patients with painful ejaculation, Safarinejad et al. (40) found that the intercourse satisfaction domain IIEF scores were not significantly improved after tamsulosin (p = 0.08). Other endpoints Few studies reported about the alterations of sexual desire

after administration of alpha-blockers. No significant differences of desire after alfuzosin or tamsulosin and placebo were reported. Kirby et al. (34) reported similar decreases of libido after alfuzosin or placebo (-3.6% vs 1.9%, P = 0.58). Van Kerrebroeck et al. (45) reported no cases of decreased desire after alfuzosin 10 mg/day, 0.7% cases after alfuzosin 2.5 mg t.i.d. and 0.7% cases after placebo. Hofner et al. (33) reported no differences between tamsulosin and placebo (0.8% vs 0%, p = 0.306) and Singh et al. (19) no cases of decreased desire after both tamsulosin or placebo. Hofner et al. (33) found no cases of decreased libido after tamsulosin or alfuzosin. Comparisons between alpha-blockers A total of 31 studies compared the effect of different alpha-blockers on sexual function (46-76). Out of 31 trials, 15 compared the risk of ejaculatory disorders after

Figure 7. Odds for ejaculatory disorders in patients taking silodosin or tamsulosin. Data to the right of the vertical no-effect axis indicate higher odds for ejaculatory disorders in patients treated with silodosin.

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Figure 8. Odds for ejaculatory disorders in patients taking naftopidil or uroselective alpha-blockers. Data to the left of the vertical no-effect axis indicate lower odds for ejaculatory disorders in patients treated with naftopidil compared to uroselective alpha adrenoceptor blockers.

Figure 9. Odds for ejaculatory disorders in patients taking alfuzosin compared to uroselective alpha-blockers. Data to the left of the vertical no-effect axis indicate lower odds for ejaculatory disorders in patients treated with alfuzosin.

tamsulosin compared with silodosin (49-54, 60, 62, 64, 65, 70, 71, 73-75), 5 studies evaluated the effect of naftopidil compared with a uroselective alpha-blocker on ejaculation (including a study comparing naftopidil with both tamsulosin and silodosin) (59, 61, 68, 72, 73), 7 studies compared alfuzosin with uroselective alphablockers (46-48, 55-57, 60), 4 studies compared terazosin or doxazosin with tamsulosin (58, 63, 66, 76) and one study terazosin with doxazosin (67). Silodosin was associated with significantly increased odds of ejaculatory dysfunction compared with tamsulosin (OR: 3.52, 95% CI: 2.18 to 5.68, 15 series, 1512 participants, Z = 5.15, p < 0.00001, I2 = 0%) (Figure 7). Naftopidil showed significantly lower odds of ejaculatory dysfunction compared to uroselective alpha-blockers (OR: 0.29, 95% CI: 0.13 to 0.64, 6 series from 5 studies, 474 participants, Z = 3.04, p = 0.002, I2 = 0%) (Figure 8). Alfuzosin was associated with significantly lower odds of ejaculatory disorders compared to uroselective alphablockers (OR: 0.17, 95% CI: 0.07 to 0.38, 8 series from 7 studies, 877 participants, Z = 4.27, p < 0.0001, I2 = 0%) (Figure 9). Summary of findings Summary of finding (SOF) tables, containing illustrative

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comparative risks (assumed control risks and corresponding intervention risks) and odds ratios relative to each single meta-analysis are presented as Supplementary Materials. SOF tables also contain evaluations of the quality of the evidence relative to each meta-analysis, rated according to GRADE criteria. Single studies not included in quantitative analysis Zaytoun et al. (2/50 vs 0/50) (76), Pompeo et al. (4/83 vs 2/82) (66) and Kirby et al. (2/50 vs 0/48) (58) observed more frequently ejaculatory disorders after tamsulosin compared to doxazosin. Narayan et al. (63) described higher rates of ejaculatory dysfunction after tamsulosin compared to terazosin [37/1002 (3.7%) vs 3/981 (0.3%)]. Samli et al. (67) observed similar rates of erectile dysfunction after doxazosin versus terazosin (0/25 vs 1/25). Comparison between different dosages of alpha-blockers We retrieved 8 studies (77-84) designed to compare the clinical efficacy and tolerability of different alpha-blockers administered at different doses and time intervals. The designs of the studies were too heterogenous for quantitative analysis. No differences in the rate of ejaculatory disorders were observed with different formulations and different doses

Sexual function and alpha-blockers

of doxazosin (4 mg vs 8 mg) (77, 78). The improvement in IIEF scores after extended-release doxazosin (4 or 8 mg once daily) was similar to the one observed after fastrelease doxazosin (1-8 mg once daily) (78). Similarly, the administration of tamsulosin at different doses resulted in similar effects on ejaculatory function (81-83). Rates of ejaculatory disorders were not different after tamsulosin 0.4 mg versus 0.2 mg (81, 82), or 0.4 mg once daily every other day (83). The timing of administration of silodosin appears to change the effects of the drug on sexual function. Silodosin 4 mg twice-daily induced a higher rate of ejaculatory disorders compared to silodosin 4 mg taken once a day (10/115 vs 67/115) or silodosin 8 mg administered after breakfast (46/208 vs 32/212) (79, 80).

DISCUSSION

Alpha-1 adrenoceptor blockers have been shown to be very effective in counteracting lower urinary tract symptoms associated with benign prostatic hyperplasia (85, 86), as well as in facilitating the spontaneous passage of stones from the distal ureter (87, 88). However, this class of drugs can lead to cardiovascular side effects and sexual dysfunction, thus potentially worsening the quality of life of patients and possibly causing a reduction in the compliance to long-term treatment. Since alpha-adrenergic receptors are highly expressed in male genital organs, adrenergic blockade can potentially affect erection, ejaculation, and sexual desire. Ejaculation The influence of alpha-blockers on ejaculation is well known, although the underlying physiological mechanism for such effect is not yet well defined. Our analysis confirms that the odds for ejaculation disorders are greater in patients taking alpha-blockers of any kind, compared to placebo. Moreover, when the effects of different alpha-blocking agents are analyzed separately, the odds for abnormal ejaculation are greater upon administration of uroselective alpha blockers (tamsulosin and silodosin). Conversely, comparison between alfuzosin and placebo does not result in statistically significant results. The comparison between different alpha-blocking agents showed that silodosin and tamsulosin were more frequently associated with ejaculation disorders when compared to non-selective alpha-blockers. Tamsulosin and, to a greater extent, silodosin, show super-selective binding with the alpha1A receptor, while alfuzosin, doxazosin and terazosin show comparable affinity with the three subtypes of alpha1-adrenergic receptors. Naftopidil on the other hand exhibits a unique selectivity for alpha1B receptors. The different binding affinity (or selectivity) for alpha1-adrenergic receptor subtypes explains the different effects of alpha-blockers on ejaculation. Ejaculatory disorders associated with administration of alpha-1 blockers were initially thought to be a consequence of bladder neck relaxation, causing in turn retrograde ejaculation. Further studies clarified the mechanisms whereby ejaculation disorders occur following the use of uroselective alpha-blockers. Disorders of ejaculation after tamsulosin and silodosin have been

related to both a peripheral effect on the vas deferens and/or seminal vesicles and a central effect in the coordination of ejaculation (89). At the peripheral level, ejaculation disorders have been related to the decreased capacity of contraction of the seminal vesicles and of the vas deferens. This is supported by the evidence that alpha-1A adrenoceptor subtype mRNA is predominant in human seminal vesicles, and that spermatic cells are not detected in the urine after ejaculation following silodosin administration. This shows that ejaculatory dysfunction caused by silodosin is not related to retrograde ejaculation but rather to a loss of seminal emission (90, 91). Similarly, administration of 0.8 mg tamsulosin to healthy volunteers resulted in reduction of the ejaculatory volume in almost all subjects, without causing a significant difference in post-ejaculation urinary sperm concentrations when compared to placebo or alfuzosin (92). Unlike other alpha1-blockers, tamsulosin can cross the bloodbrain barrier and bind to dopaminergic and/or serotonergic receptors that are involved in the central coordination of ejaculation (93). A strong affinity of alpha1-adrenoceptor antagonists for D2- and 5HT1A-like receptors for has been demonstrated, suggesting that these drugs may act as antagonists of dopaminergic receptors mediating the contraction of the vas deferens (94). Erection There are conflicting data about the effect of alpha-blockers on erection, mainly because the erectile function is the result of a complex interplay between multiple biochemical signals responding to several neurotransmitters and vasoactive agents. Basically, penile tumescence is associated with relaxation of the erectile tissue whereas detumescence is caused by contraction of the erectile tissue. Postsynaptic alpha1-adrenoceptor activation causes the contraction of the erectile tissue, leading to penile flaccidity and detumescence. For this reason, alphaadrenoceptor antagonists can promote the relaxation of the muscles of the trabeculae of the corpora cavernosa and induce erection, as demonstrated by erection induced by intra-cavernous injection of alpha-adrenoceptor antagonists (95, 96). In addition, alpha-blocker-induced priapism is a rare but well documented side effect of treatment (97). At the systemic level, blockage of adrenergic receptors has a more complex effect on the regulation of erectile function because it can occur at both peripheral and central levels (through ascending pathways to the brain and descending pathways to the spinal cord) and involve various alpha1- or alpha2-adrenoceptor subtypes. The effect of each drug will depend on the central and peripheral effects exerted on the different receptors, causing in turn specific effects on erectile function (98). Finally, hemodynamic effects of non-selective alpha-blockers may harm erectile function because of symptomatic hypotension side effects (99). Our meta-analysis demonstrated neither greater odds of erectile dysfunction or impotence upon exposure to alpha-blockers, nor differences of odds of erectile dysfunction evoked by treatment with uroselective or nonselective alpha-blockers compared to placebo. Thus, the potential effect of alpha-blockers on erectile Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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function therefore remains unknown. In our analysis we excluded studies that evaluated the effects of combination therapy with alpha-1 adrenergic antagonists and phosphodiesterase-5 (PDE5) inhibitors on sexual function. Interestingly, some studies have shown an additive favorable effect of the combined use of alpha-blockers and PDE5 inhibitors on erectile dysfunction (100). In 2014, a meta-analysis demonstrated that alpha-blockers may enhance the efficacy of PDE5 inhibitors on erectile dysfunction in men with LUTS suggestive of BPH (101). However, a more recent review found no significant difference of the mean change of IIEF between combination therapy and PDE5 inhibitors-monotherapy concluding that benefits regarding the treatment of ED are not clear (102).

3. Graham RM. Selective alpha 1-adrenergic antagonists: therapeutically relevant antihypertensive agents. Am J Cardiol. 1984; 53:16A-20A.

Limitations A limitation of this meta-analysis is the disparity of assessment criteria and definitions used to describe sexual dysfunction associated with alpha-blockers. Ejaculation disorders have been defined indifferently as abnormal ejaculation, ejaculatory disorders, decreased ejaculatory volume, anejaculation, and retrograde ejaculation. Some of these terms are generic, others imply specific pathophysiological alterations that may not correspond to clinically observable manifestations. The presence of retrograde ejaculation has been questioned by recent studies which have shown that the ejaculatory alterations caused by alpha-blockers are due to a lack of semen emission, that should be better defined as anejaculation. The different physiological mechanisms that are at the origin of failure of semen emission, or of retrograde ejaculation, can be associated with different orgasmic dysfunctions. On the other hand, ejaculation disorders have rarely been evaluated with specific questionnaires such as DAN-PSS or MSQH. Erectile dysfunction was also not uniquely defined in the different studies that used both the term impotence and erectile dysfunction, with only a few studies assessing the latter with the IIEF questionnaire. In order to take into account the diversity of diagnostic methods and tools used to ascertain ejaculatory or erectile dysfunction in included studies, we have used in all metanalyses a random-effect model (103).

8. 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.

CONCLUSIONS

In conclusion, because of the different effects of alpha1adrenergic antagonists on sexuality, the sexual function of each patient should be assessed and discussed when alpha-blocker therapy is planned, and patients should be informed about the potential side effects of such treatment. When prescribing a specific alpha-blocker, the specialist should consider the needs and expectations of the patient, to ensure the best possible quality of life.

5. Lepor H. Alpha-blockers for the Treatment of Benign Prostatic Hyperplasia. Urol Clin North Am. 2016; 43:311-23. 6. Ishihama H, Momota Y, Yanase H, et al. Activation of alpha1D adrenergic receptors in the rat urothelium facilitates the micturition reflex. J Urol. 2006; 175:358-64. 7. Hwang EC, Gandhi S, Jung JH, et al. Naftopidil for the treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia. Cochrane Database Syst Rev. 2018; 10:CD007360.

9. Sterne JAC, Savovic J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366:l4898. 10. Chapple CR, Al-Shukri SH, Gattegno B, et al. Tamsulosin oral controlled absorption system (OCAS) in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH): Efficacy and tolerability in a placebo and active comparator controlled phase 3a study Eur Urol. (Supplements) 2005; 4:33-44. 11. Chapple CR, Montorsi F, Tammela TL, et al. European Silodosin Study Group. Silodosin therapy for lower urinary tract symptoms in men with suspected benign prostatic hyperplasia: results of an international, randomized, double-blind, placebo- and active-controlled clinical trial performed in Europe. Eur Urol. 2011; 59:342-52. 12. Homma Y, Kawabe K, Takeda M, Yoshida M. Ejaculation disorder is associated with increased efficacy of silodosin for benign prostatic hyperplasia. Urology 2010; 76:1446-1450. 13. Kawabe K, Yoshida M, Homma Y, Silodosin Clinical Study Group. Silodosin, a new alpha1A-adrenoceptor-selective antagonist for treating benign prostatic hyperplasia: results of a phase III randomized, placebo-controlled, double-blind study in Japanese men. BJU Int. 2006; 98:1019-24. 14. Lepor H. Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Tamsulosin Investigator Group. Urology. 1998; 51:892-900. 15. Marks LS, Gittelman MC, Hill LA, et al. Rapid efficacy of the highly selective alpha(1A)-adrenoceptor antagonist silodosin in men with signs and symptoms of benign prostatic hyperplasia: pooled results of 2 phase 3 studies. J Urol. 2013; 189(1 Suppl):S122-8. 16. Mehik A, Alas P, Nickel JC, et al. Alfuzosin treatment for chronic prostatitis/chronic pelvic pain syndrome: a prospective, randomized, double-blind, placebo-controlled, pilot study. Urology. 2003; 62:425-9. 17. Mohanty NK, Nayak RL, Malhotra V, Arora RP. A double-blind placebo controlled study of tamsulosin in the management of benign prostatic hyperplasia in an Indian population. Ann College of Surgeons of Hong Kong. 2003; 7:88-93.

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22. Singh I, Tripathy S, Agrawal V. Efficacy of tamsulosin hydrochloride in relieving "double-J ureteral stent-related morbidity": a randomized placebo controlled clinical study. Int Urol Nephrol. 2014; 46:2279-83. 23. Sur RL, Shore N, L'Esperance J, et al. Silodosin to facilitate passage of ureteral stones: a multi-institutional, randomized, doubleblinded, placebo-controlled trial. Eur Urol. 2015; 67:959-64. 24. Ye Z, Zeng G, Yang H, et al. Efficacy and safety of tamsulosin in medical expulsive therapy for distal ureteral stones with renal colic: a multicenter, randomized, double-blind, placebo-controlled trial. Eur Urol. 2018; 73:385-391. 25. Cho HJ, Shin SC, Seo DY, et al. Efficacy of alfuzosin after shock wave lithotripsy for the treatment of ureteral calculi Korean J Urol. 2013; 54:106-110. 26. El Said NO, El Wakeel L, Kamal KM, Morad Ael R. Alfuzosin treatment improves the rate and time for stone expulsion in patients with distal uretral stones: a prospective randomized controlled study. Pharmacotherapy. 2015; 35:470-6. 27. Ferre RM, Wasielewski JN, Strout TD, Perron AD. Tamsulosin for ureteral stones in the emergency department: a randomized, controlled trial. Ann Emerg Med. 2009; 54:432-9, 439.e1-2. 28. Itoh Y, Okada A, Yasui T, et al. Efficacy of selective alpha1A adrenoceptor antagonist silodosin in the medical expulsive therapy for ureteral stones. Int J Urol. 2011; 18:672-4. 29. Moursy E, Gamal WM, Abuzeid A. Tamsulosin as an expulsive therapy for steinstrasse after extracorporeal shock wave lithotripsy: a randomized controlled study. Scand J Urol Nephrol. 2010; 44:315-9. 30. Naja V, Agarwal MM, Mandal AK, et al. Tamsulosin facilitates earlier clearance of stone fragments and reduces pain after shockwave lithotripsy for renal calculi: results from an open-label randomized study. Urology. 2008; 72:1006-11. 31. Resim S, Ekerbicer HC, Ciftci A. Role of tamsulosin in treatment of patients with steinstrasse developing after extracorporeal shock wave lithotripsy. Urology. 2005; 66:945-8. 32. Chung JH, Oh CY, Kim JH, et al. Efficacy and safety of tamsulosin 0.4 mg single pills for treatment of Asian patients with symptomatic benign prostatic hyperplasia with lower urinary tract symptoms: a randomized, double-blind, phase 3 trial. Curr Med Res Opin. 2018; 34:1793-1801. 33. Höfner K, Claes H, De Reijke TM, et al. Tamsulosin 0.4 mg once daily: effect on sexual function in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol. 1999; 36:335-41. 34. Kirby RS, Roehrborn C, Boyle P, et al. Prospective European Doxazosin and Combination Therapy Study Investigators. Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial. Urology. 2003; 61:119-26. 35. Nordling J. Efficacy and safety of two doses (10 and 15 mg) of

38. Roehrborn C.G. Alfuzosin 10 mg once daily prevents overall clinical progression of benign prostatic hyperplasia but not acute urinary retention: Results of a 2-year placebo-controlled study BJU Int. 2006; 97:734-741. 39. Rosen R, Seftel A, Roehrborn CG. Effects of alfuzosin 10 mg once daily on sexual function in men treated for symptomatic benign prostatic hyperplasia. Int J Impot Res. 2007; 19:480-5. 40. Safarinejad MR. Safety and efficacy of tamsulosin in the treatment of painful ejaculation: a randomized, double-blind, placebocontrolled study. Int J Impot Res. 2006; 18:527-33. 41. Becker AJ, Stief CG, Machtens S, et al. Oral phentolamine as treatment for erectile dysfunction. J Urol. 1998; 159:1214-6. 42. Choppin A, Blue DR, Hegde SS, et al. Evaluation of oral ro700004/003, an alpha1A-adrenoceptor antagonist, in the treatment of male erectile dysfunction. Int J Impot Res. 2001; 13:157-61. 43. Resnick MI, Roehrborn CG. Rapid onset of action with alfuzosin 10 mg once daily in men with benign prostatic hyperplasia: A randomized, placebo-controlled trial Prostate Cancer Prostatic Dis. 2007; 10:155-159. 44. Shelbaia A, Elsaied WM, Elghamrawy H, et al. Effect of selective alpha-blocker tamsulosin on erectile function in patients with lower urinary tract symptoms due to benign prostatic hyperplasia. Urology. 2013; 82:130-5. 45. van Kerrebroeck P, Jardin A, Laval KU, van Cangh P. Efficacy and safety of a new prolonged release formulation of alfuzosin 10 mg once daily versus alfuzosin 2.5 mg thrice daily and placebo in patients with symptomatic benign prostatic hyperplasia. ALFORTI Study Group. Eur Urol. 2000; 37:306-13. 46. Agrawal M, Gupta M, Gupta A, et al. Prospective randomized trial comparing efficacy of alfuzosin and tamsulosin in management of lower ureteral stones. Urology. 2009; 73:706-9. 47. Agrawal MS, Yadav A, Yadav H, et al. A prospective randomized study comparing alfuzosin and tamsulosin in the management of patients suffering from acute urinary retention caused by benign prostatic hyperplasia. Indian J Urol. 2009; 25:474-478. 48. Ahmed A.-F.A.-M., Al-sayed A.-Y.S. Tamsulosin versus alfuzosin in the treatment of patients with distal ureteral stones: Prospective, randomized, comparative study. Korean J Urol. 2010; 51:193-197. 49. Dell'Atti L. Silodosin versus tamsulosin as medical expulsive therapy for distal ureteral stones: a prospective randomized study. Urologia. 2015; 82:54-7. 50. De Nunzio C, Brassetti A, Bellangino M, et al. Tamsulosin or silodosin adjuvant treatment is ineffective in improving shockwave lithotripsy outcome: A short-term follow-up randomized, placebocontrolled study J Endourol. 2016; 30: 817-821. 51. Elgalaly H, Sakr A, Fawzi A, et al. Silodosin vs tamsulosin in the management of distal ureteric stones: A prospective randomised study.Arab J Urol. 2016; 14:12-17. Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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Sexual function and alpha-blockers

82. Lojanapiwat B, Kochakarn W, Suparatchatpan N, Lertwuttichaikul K. Effectiveness of low-dose and standard-dose tamsulosin in the treatment of distal ureteric stones: a randomized controlled study. J Int Med Res. 2008; 36:529-36. 83. Yanardag H, Goktas S, Kibar Y, et al. Intermittent tamsulosin therapy in men with lower urinary tract symptoms. J Urol. 2005; 173:155-7. 84. Hareendran A, Abraham L. Using a treatment satisfaction measure in an early trial to inform the evaluation of a new treatment for benign prostatic hyperplasia. Value Health. 2005; 8(Suppl 1):S35-40. 85. Lepor H. Alpha-blockers for the Treatment of Benign Prostatic Hyperplasia. Urol Clin North Am. 2016; 43:311-23. 86. Nickel JC, Sander S, Moon TD. A meta-analysis of the vascularrelated safety profile and efficacy of alpha-adrenergic blockers for symptoms related to benign prostatic hyperplasia. Int J Clin Pract. 2008; 62:1547-59. 87. Hollingsworth JM, Canales BK, Rogers MA, et al. Alpha blockers for treatment of ureteric stones: systematic review and meta-analysis. BMJ. 2016; 355:i6112. 88. Sentürk AB, Aydin C, Ekici M, et al. Comparison of three most frequently used alpha blocker agents in medical expulsive therapy for distal ureteral calculi, result of a retrospective observational study. Arch Ital Urol Androl. 2018; 90:25-28. 89. Giuliano F. Impact of medical treatments for benign prostatic hyperplasia on sexual function. BJU Int. 2006; 97 (Suppl 2):34-8; discussion 44-5. 90. Hisasue S, Furuya R, Itoh N, et al. Ejaculatory disorder caused by alpha-1 adrenoceptor antagonists is not retrograde ejaculation but a loss of seminal emission. Int J Urol. 2006; 13:1311-6.

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Correspondence Rawa Bapir Dr.rawa@yahoo.com Smart Health Tower, Sulaymaniyah, Kurdistan region, Iraq Kamran Hassan Bhatti kamibhatti92@gmail.com Urology Department, HMC, Hamad Medical Corporation, Qatar. Ahmed Eliwa ahmedeliwafarag@gmail.com Department of Urology, Zagazig University, Zagazig, Sharkia, Egypt. Herney Andrés García-Perdomo herney.garcia@correounivalle.edu.co Universidad del Valle, Cali, Colombia

91. Kobayashi K, Masumori N, Hisasue S, et al. Inhibition of seminal emission is the main cause of anejaculation induced by a new highly selective alpha1A-blocker in normal volunteers. J Sex Med. 2008; 5:2185-90.

Nazim Gherabi, MD ngherabi@gmail.com Faculty of Medicine Algiers 1, Algiers, Algeria

92. Hellstrom WJ, Sikka SC. Effects of acute treatment with tamsulosin versus alfuzosin on ejaculatory function in normal volunteers. J Urol. 2006; 176:1529-1533.

Derek Hennessey, MD derek.hennessey@gmail.com Department of Urology, Mercy University Hospital, Cork, Ireland

93. Yeung HEL, Sena SJ, Calopedos RJ, Woo HH. Alfuzosin and its effect on ejaculatory dysfunction: a systematic review. World J Mens Health. 2021; 39:186-194

Vittorio Magri, MD vittorio.magri@virgilio.it ASST Nord Milano, Milan, Italy

94. Britto-Júnior J, Ribeiro A, Ximenes L, et al. Alpha1-adrenergic antagonists block 6-nitrodopamine contractions on the rat isolated epididymal vas deferens. Eur J Pharmacol. 2022; 915:174716.

Panagiotis Mourmouris, MD thodoros13@yahoo.com 2nd Department of Urology, National and Kapodistrian University of Athens, Sismanoglio Hospital, Athens, Greece

95. Blum MD, Bahnson RR, Porter TN, Carter MF. Effect of local alpha-adrenergic blockade on human penile erection. J Urol. 1985; 134:479-481.

Adama Ouattara, MD adamsouat1@hotmail.com Division of Urology, Souro Sanou University Teaching Hospital, Bobo-Dioulasso, Burkina Faso

96. Brindley GS. Pilot experiments on the actions of drugs injected into the human corpus cavernosum penis. Br J Pharmacol. 1986; 87:495500. 97. Marconi M, Pavez P, San Francisco I, Narvaez P. Priapism induced by use of tamsulosin: A case report and review of the literature. Arch Ital Urol Androl. 2019; 91:193. 98. Rampin O. Pharmacology of alpha-adrenoceptors in male sexual function. Eur Urol. 1999; 36 Suppl 1:103-6. 99. van Dijk MM, de la Rosette JJ, Michel MC. Effects of alpha(1)adrenoceptor antagonists on male sexual function. Drugs. 2006; 66:287-301. 100. Kaplan SA, Gonzalez RR, Te AE. Combination of alfuzosin and sildenafil is superior to monotherapy in treating lower urinary tract symptoms and erectile dysfunction. Eur Urol. 2007; 51:1717-1723.

Gianpaolo Perletti gianpaolo.perletti@uninsubria.it Department of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, University of Insubria, Varese, Italy Joseph Philipraj, MD josephphilipraj@gmail.com Department of Urology, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth, Puducherry, India. Alberto Trinchieri, MD (Corresponding Author) alberto.trinchieri@gmail.com Urology School, University of Milan, Milan (Italy) Noor Buchholz noor.buchholz@gmail.com Sobeh's Vascular and Medical Center, Dubai Health Care City, Dubai, United Arab Emirates

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REVIEW - SUPPLEMENTARY MATERIAL

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No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 2

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1. Chapple CR, Al-Shukri SH, Gattegno B, et al. Tamsulosin oral controlled absorption system (OCAS) in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH): Efficacy and tolerability in a placebo and active comparator controlled phase 3a study Eur Urol (Supplements) 2005; 4:33-44. 2. Chapple CR, Montorsi F, Tammela TL, et al. European Silodosin Study Group. Silodosin therapy for lower urinary tract symptoms in men with suspected benign prostatic hyperplasia: results of an international, randomized, double-blind, placebo- and active-controlled clinical trial performed in Europe. Eur Urol. 2011; 59:342-52. 3. Homma Y, Kawabe K, Takeda M, Yoshida M. Ejaculation disorder is associated with increased efficacy of silodosin for benign prostatic hyperplasia. Urology 2010; 76: 1446-1450. 4. Kawabe K, Yoshida M, Homma Y; Silodosin Clinical Study Group. Silodosin, a new alpha1A-adrenoceptor-selective antagonist for treating benign prostatic hyperplasia: results of a phase III randomized, placebo-controlled, double-blind study in Japanese men. BJU Int. 2006; 98:1019-24.

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5. Lepor H. Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Tamsulosin Investigator Group. Urology. 1998; 51:892-900. 6. Marks LS, Gittelman MC, Hill LA, et al. Rapid efficacy of the highly selective α(1A)-adrenoceptor antagonist silodosin in men with signs and symptoms of benign prostatic hyperplasia: pooled results of 2 phase 3 studies. J Urol. 2013; 189(1 Suppl):S122-8. 7. Mehik A, Alas P, Nickel JC, et al. Alfuzosin treatment for chronic prostatitis/chronic pelvic pain syndrome: a prospective, randomized, double-blind, placebo-controlled, pilot study. Urology. 2003; 62:425-9. 8. Mohanty NK, Nayak RL, Malhotra V, Arora RP. A double-blind placebo controlled study of tamsulosin in the management of benign prostatic hyperplasia in an Indian population. AnnCollege of Surgeons of Hong Kong. 2003; 7: 88-93. 9. Roehrborn CG, Kaplan SA, Lepor H, Volinn W. Symptomatic and urodynamic responses in patients with reduced or no seminal emission during silodosin treatment for LUTS and BPH. Prostate Cancer Prostatic Dis. 2011; 14:143-8. 10. Singh P, Singh A, Indurkar M, Raj B. Efficacy and safety of tamsulosin (0.4 mg) once daily for treating symptomatic benign prostatic hyperplasia. Asian Journal of Pharmaceutical and Clinical Research 2012; 5(Suppl 4):87-91.

PATIENTS WITH URETERAL STONE (EFFECTS ON EJACULATION) (CONTROLLED WITH PLACEBO)

1. Al-Ansari A, Al-Naimi A, Alobaidy A, et al. Efficacy of tamsulosin in the management of lower ureteral stones: a randomized double-blind placebo-controlled study of 100 patients Urology 2010; 75:4-7. 2. Meltzer AC, Burrows PK, Wolfson AB, et al. Effect of tamsulosin on passage of symptomatic ureteral stones: A randomized clinical trial JAMA Internal Medicine 2018; 178:1051-1057. 3. Singh I, Tripathy S, Agrawal V. Efficacy of tamsulosin hydrochloride in relieving "double-J ureteral stent-related morbidity": a randomized placebo controlled clinical study. Int Urol Nephrol. 2014; 46:2279-83. 4. Sur RL, Shore N, L'Esperance J, et al. Silodosin to facilitate passage of ureteral stones: a multi-institutional, randomized, double-blinded, placebo-controlled trial. Eur Urol. 2015; 67:959-64. 5. Ye Z, Zeng G, Yang H, et al. Efficacy and safety of tamsulosin in medical expulsive therapy for distal ureteral stones with renal colic: a multicenter, randomized, double-blind, placebo-controlled trial. Eur Urol. 2018; 73:385-391.

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PATIENTS WITH URETERAL STONE (EFFECTS ON EJACULATION) (CONTROLLED WITH STANDARD TREATMENT)

1. Cho HJ, Shin SC, Seo DY, et al. Efficacy of alfuzosin after shock wave lithotripsy for the treatment of ureteral calculi Korean Journal of Urology 2013:; 54:106-110. 2. El Said NO, El Wakeel L, Kamal KM, Morad Ael R. Alfuzosin treatment improves the rate and time for stone expulsion in patients with distal uretral stones: a prospective randomized controlled study. Pharmacotherapy. 2015; 35:470-6. 3. Ferre RM, Wasielewski JN, Strout TD, Perron AD. Tamsulosin for ureteral stones in the emergency department: a randomized, controlled trial. Ann Emerg Med. 2009; 54:432-9, 439.e1-2.

4. Itoh Y, Okada A, Yasui T, et al. Efficacy of selective α1A adrenoceptor antagonist silodosin in the medical expulsive therapy for ureteral stones. Int J Urol. 2011; 18:672-4. 5. Moursy E, Gamal WM, Abuzeid A. Tamsulosin as an expulsive therapy for steinstrasse after extracorporeal shock wave lithotripsy: a randomized controlled study. Scand J Urol Nephrol. 2010; 44:315-9. 6. Naja V, Agarwal MM, Mandal AK, et al. Tamsulosin facilitates earlier clearance of stone fragments and reduces pain after shockwave lithotripsy for renal calculi: results from an open-label randomized study. Urology. 2008; 72:1006-11. 7. Resim S, Ekerbicer HC, Ciftci A. Role of tamsulosin in treatment of patients with steinstrasse developing after extracorporeal shock wave lithotripsy. Urology. 2005; 66:945-8.

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1. Chung JH, Oh CY, Kim JH, et al. Efficacy and safety of tamsulosin 0.4 mg single pills for treatment of Asian patients with symptomatic benign prostatic hyperplasia with lower urinary tract symptoms: a randomized, double-blind, phase 3 trial. Curr Med Res Opin. 2018; 34:1793-1801. 2. Höfner K, Claes H, De Reijke TM, et al. Tamsulosin 0.4 mg once daily: effect on sexual function in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol. 1999; 36:335-41. 68. 3. Kirby RS, Roehrborn C, Boyle P, et al. Prospective European Doxazosin and Combination Therapy Study Investigators. Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the Prospective European Doxazosin and Combination Therapy (PREDICT) trial. Urology. 2003; 61:119-26. 4. Nordling J. Efficacy and safety of two doses (10 and 15 mg) of alfuzosin or tamsulosin (0.4 mg) once daily for treating symptomatic benign prostatic hyperplasia. BJU Int. 2005; 95:1006-12. 5. Roehrborn CG. Efficacy and safety of once-daily alfuzosin in the treatment of lower urinary tract symptoms and clinical benign prostatic hyperplasia: a randomized, placebo-controlled trial. Urology. 2001; 58:953-9. 6. Roehrborn CG, Van Kerrebroeck P, Nordling J. Safety and efficacy of alfuzosin 10 mg once-daily in the treatment of lower urinary tract symptoms and clinical benign prostatic hyperplasia: a pooled analysis of three double-blind, placebo-controlled studies. BJU Int. 2003; 92:257-61. 7. Roehrborn CG. Alfuzosin 10 mg once daily prevents overall clinical progression of benign prostatic hyperplasia but not acute urinary retention: Results of a 2-year placebo-controlled study BJU International 2006; 97:734-741. 8. Rosen R, Seftel A, Roehrborn CG. Effects of alfuzosin 10 mg once daily on sexual function in men treated for symptomatic benign prostatic hyperplasia. Int J Impot Res. 2007; 19:480-5. 9. Safarinejad MR. Safety and efficacy of tamsulosin in the treatment of painful ejaculation: a randomized, double-blind, placebo-controlled study. Int J Impot Res. 2006; 18:527-33.

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PATIENTS WITH LUTS ASSOCIATED TO BPH (EFFECTS ON ERECTION)

1. Becker AJ, Stief CG, Machtens S, et al. Oral phentolamine as treatment for erectile dysfunction. J Urol. 1998; 159:1214-6. 2. Choppin A, Blue DR, Hegde SS, et al. Evaluation of oral ro70-0004/003, an alpha1A-adrenoceptor antagonist, in the treatment of male erectile dysfunction. Int J Impot Res. 2001; 13:157-61. 3. Resnick MI, Roehrborn CG. Rapid onset of action with alfuzosin 10 mg once daily in men with benign prostatic hyperplasia: A randomized, placebo-controlled trial Prostate Cancer and Prostatic Diseases 2007; 10:155-159. 4. Shelbaia A, Elsaied WM, Elghamrawy H, et al. Effect of selective alpha-blocker tamsulosin on erectile function in patients with lower urinary tract symptoms due to benign prostatic hyperplasia. Urology. 2013; 82:130-5. 5. van Kerrebroeck P, Jardin A, Laval KU, van Cangh P. Efficacy and safety of a new prolonged release formulation of alfuzosin 10 mg once daily versus alfuzosin 2.5 mg thrice daily and placebo in patients with symptomatic benign prostatic hyperplasia. ALFORTI Study Group. Eur Urol. 2000; 37:306-13.

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COMPARISON BETWEEN ALPHA-BLOCKERS

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1. Agrawal M, Gupta M, Gupta A, et al. Prospective randomized trial comparing efficacy of alfuzosin and tamsulosin in management of lower ureteral stones. Urology 2009; 73:706-9. 2. Agrawal MS, Yadav A, Yadav H, , et al. A prospective randomized study comparing alfuzosin and tamsulosin in the management of patients suffering from acute urinary retention caused by benign prostatic hyperplasia. Indian Journal of Urology 2009; 25:474-478. 3. Ahmed A.-F.A.-M., Al-sayed A.-Y.S. Tamsulosin versus alfuzosin in the treatment of patients with distal ureteral stones: Prospective, randomized, comparative study. Korean Journal of Urology 2010; 51:193-197. 4. Dell'Atti L. Silodosin versus tamsulosin as medical expulsive therapy for distal ureteral stones: a prospective randomized study. Urologia. 2015; 82:54-7. 5. De Nunzio C, Brassetti A, Bellangino M, et al. Tamsulosin or silodosin adjuvant treatment is ineffective in improving shockwave lithotripsy outcome: A short-term follow-up randomized, placebo-controlled study Journal of Endourology. 2016; 30:817-821. 6. Elgalaly H, Sakr A, Fawzi A, et al. Silodosin vs tamsulosin in the management of distal ureteric stones: A prospective randomised study.Arab Journal of Urology 2016; 14:12-17. 7. Georgescu D, Ionita-Radu F, Multescu R, et al. The role of α1-blockers in the medical expulsive therapy for ureteral calculi - a prospective controlled randomized study comparing tamsulosin and silodosin. Farmacia. 2015; 63:184-188.

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8. Gharib T, Mohey A, Fathi A, et al. A. Comparative Study between Silodosin and Tamsulosin in Expectant Therapy of Distal Ureteral Stones. Urol Int. 2018; 101:161-166. 9. Gupta S, Lodh B, Kaku Singh A et al. Comparing the efficacy of tamsulosin and silodosin in the medical expulsion therapy for ureteral calculi. Journal of Clinical and Diagnostic Research. 2013; 7:1672-1674. 10. Hellstrom WJ, Sikka SC. Effects of acute treatment with tamsulosin versus alfuzosin on ejaculatory function in normal volunteers. J Urol. 2006; 176:1529-33. 11. Ibrahim AK, Mahmood IH, Mahmood NS. Efficacy and safety of tamsulosin vs. alfuzosin as medical expulsive therapy for ureteric stones. Arab Journal of Urology. 2013; 11:142-147. 12. Karadag E, Öner S, Budak YU, Atahan O. Randomized crossover comparison of tamsulosin and alfuzosin in patients with urinary disturbances caused by benign prostatic hyperplasia. International Urology and Nephrology. 2011; 43:949-954. 13. Kirby RS. A randomized, double-blind crossover study of tamsulosin and controlled-release doxazosin in patients with benign prostatic hyperplasia. BJU Int. 2003; 91:41-4. 14. Kumar S, Kurdia KC, Ganesamoni R et al. Randomized controlled trial to compare the safety and efficacy of naftopidil and tamsulosin as medical expulsive therapy in combination with prednisolone for distal ureteral stones. Korean Journal of Urology. 2013; 54:311-315. 15. Manohar CMS., Nagabhushana M. Karthikeyan VS et al. Safety and efficacy of tamsulosin, alfuzosin or silodosin as monotherapy for LUTS in BPH - a double-blind randomized trial. Central European Journal of Urology 2017; 70:148-153. 16. Masumori N, Tsukamoto T, Iwasawa A et al. Hokkaido Urological Disorders Conference Writing Group. Ejaculatory disorders caused by alpha-1 blockers for patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: comparison of naftopidil and tamsulosin in a randomized multicenter study. Urol Int. 2009; 83:49-54. 17. Miyakita H, Yokoyama E, Onodera Y et al. Short-term effects of crossover treatment with silodosin and tamsulosin hydrochloride for lower urinary tract symptoms associated with benign prostatic hyperplasia. International Journal of Urology 2010; 17:869-875. 18. Narayan P, O'Leary MP, Davidai G. Early efficacy of tamsulosin versus terazosin in the treatment of men with benign prostatic hyperplasia: A randomized, open-label trial. The Journal of Applied Research 2005; 5:237-245. 19. Pande S, Hazra A, Kundu AK. Evaluation of silodosin in comparison to tamsulosin in benign prostatic hyperplasia: A randomized controlled trial Indian Journal of Pharmacology 2014; 46:601-607. 20. Patil SB, Ranka K, Kundargi VS, Guru N. Comparison of tamsulosin and silodosin in the management of acute urinary retention secondary to benign prostatic hyperplasia in patients planned for trial without catheter. A prospective randomized study Central European Journal of Urology 2017; 70:259-263. 21. Pompeo AC, Rosenblatt C, Bertero E et al. Doxazosin and Tamsulosin Study Investigator Group. A randomised, double-blind study comparing the efficacy and tolerability of controlled-release doxazosin and tamsulosin in the treatment of benign prostatic hyperplasia in Brazil. Int J Clin Pract. 2006; 60:1172-7. 22. Samli MM, Dincel C. Terazosin and doxazosin in the treatment of BPH: Results of a randomized study with crossover in non-responders. Urologia Internationalis 2004; 73:125-129. 23. Shirakawa T, Haraguchi T, Shigemura K et al. Silodosin versus naftopidil in japanese patients with lower urinary tract symptoms associated with benign prostatic hyperplasia: A randomized multicenter study International Journal of Urology. 2013; 20:903-910. 24. Takahashi S, Yamaguchi K. Treatment of benign prostatic hyperplasia and aging: Impacts of alpha-1 blockers on sexual function. Journal of Men's Health 2011; 8 (Suppl 1):S25-S28. 25. Takeshita H, Moriyama S, Arai Y et al. Randomized Crossover Comparison of the Short-Term Efficacy and Safety of Single Half-Dose Silodosin and Tamsulosin Hydrochoride in Men With Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia. Low Urin Tract Symptoms. 2016; 8:38-43. 26. Watanabe T, Ozono S, Kageyama S. A randomized crossover study comparing patient preference for tamsulosin and silodosin in patients with lower urinary tract symptoms associated with benign prostatic hyperplasia. Journal of International Medical Research 2011; 39:129-142. 27. Yamaguchi K, Aoki Y, Yoshikawa T et al. Silodosin versus naftopidil for the treatment of benign prostatic hyperplasia: a multicenter randomized trial. Int J Urol. 2013; 20:1234-8. 28. Yokoyama T, Hara R, Fukumoto K et al. Effects of three types of alpha-1 adrenoceptor blocker on lower urinary tract symptoms and sexual function in males with benign prostatic hyperplasia. Int J Urol. 2011; 18:225-30. 29. Yokoyama T, Hara R, Fujii T et al. Comparison of Two Different α1-Adrenoceptor Antagonists, Tamsulosin and Silodosin, in the Treatment of Male Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia: A Prospective Randomized Crossover Study LUTS: Lower Urinary Tract Symptoms 2012; 4:14-18. 30. Yu HJ, Lin AT, Yang SS et al. Non-inferiority of silodosin to tamsulosin in treating patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). BJU Int. 2011; 108:1843-8. 31. Zaytoun OM, Yakoubi R, Zahran ARM, et al. Tamsulosin and doxazosin as adjunctive therapy following shock-wave lithotripsy of renal calculi: Randomized controlled trial. Urological Research 2012; 40:327-332.

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COMPARISON BETWEEN ALPHA-BLOCKERS AT DIFFERENT DOSE AND TIMING OF ADMINISTRATION

1. Keten T, Aslan Y, Balci M, et al. Determination of the efficiency of 8 mg doxazosin XL treatment in patients with an inadequate response to 4 mg doxazosin XL treatment for benign prostatic hyperplasia Urology 2015; 85:189-194. 2. Kirby RS, O'Leary MP, Carson C. Efficacy of extended-release doxazosin and doxazosin standard in patients with concomitant benign prostatic hyperplasia and sexual dysfunction. BJU Int. 2005; 95:103-9. 3. Choo MS, Song M, Kim JH, et al. Safety and efficacy of 8-mg once-daily vs 4-mg twice-daily silodosin in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (SILVER Study): a 12-week, double-blind, randomized, parallel, multicenter study. Urology. 2014; 83:875-81. 4. Seki N, Takahashi R, Yamaguchi A, et al. Non-inferiority of silodosin 4 mg once daily to twice daily for storage symptoms score evaluated by

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the International Prostate Symptom Score in Japanese patients with benign prostatic hyperplasia: a multicenter, randomized, parallel-group study. Int J Urol. 2015; 22:311-6. 5. Kim JJ, Han DH, Sung HH, et al. Efficacy and tolerability of tamsulosin 0.4 mg in Asian patients with lower urinary tract symptoms secondary to benign prostatic hyperplasia refractory to tamsulosin 0.2 mg: a randomized placebo controlled trial. Int J Urol. 2014; 21:677-82. 6. Lojanapiwat B, Kochakarn W, Suparatchatpan N, Lertwuttichaikul K. Effectiveness of low-dose and standard-dose tamsulosin in the treatment of distal ureteric stones: a randomized controlled study. J Int Med Res. 2008; 36:529-36. 7. Yanardag H, Goktas S, Kibar Y, et al. Intermittent tamsulosin therapy in men with lower urinary tract symptoms. J Urol. 2005; 173:155-7. 8. Hareendran A, Abraham L. Using a treatment satisfaction measure in an early trial to inform the evaluation of a new treatment for benign prostatic hyperplasia. Value Health. 2005; 8 (Suppl 1):S35-40.

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RISK

BIAS

PATIENTS WITH LUTS ASSOCIATED TO BPH (EFFECTS ON EJACULATION)

PATIENTS WITH LUTS ASSOCIATED TO BPH (EFFECTS ON EJACULATION AND ERECTION)

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PATIENTS WITH LUTS ASSOCIATED TO BPH (EFFECTS ON ERECTION)

PATIENTS WITH URETERAL STONE (EFFECTS ON EJACULATION)

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COMPARISON BETWEEN ALPHA-BLOCKERS (UROSELECTIVE VS NONSELECTIVE)

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PUBLICATION BIAS Funnel plots for publication bias analysis. The combined effect size of each meta-analysis is presented as the natural logarithm of the odds ratio (green dots). M issing studies (orange circles) imputed by the trim-and-fill procedure were merged with included studies (blue dots) to calculate adjusted combined effect sizes (red dots).

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SYMMETRY TESTS Results of Funnel Plot Symmetry tests. Missing studies imputed to asymmetric plots and the adjusted odds ratio according to the Trim-and-fill method are presented. Comparison

Imputed data points, “Trim and Fill”

Adjusted Odds Ratio (95% CI), “Trim and Fill”

Egger’s test, significance (*)

Begg’s test, significance (*)

Alpha-blockers vs. Placebo; Condition: BPH; Endpoint: Ejaculation

None

Same as non-adjusted

p = 0.001 (*)

p = 0.102

Uroselective Alpha-blockers vs. Placebo; Condition: BPH; Endpoint: Ejaculation

None

Same as non-adjusted

p = 0.142

p = 0.024 (*)

0.97 (0.37 to 2.48)

p = 0.005 (*)

p = 0.176

Alpha-blockers vs. Placebo; Condition: BPH; Endpoint: Erection

None

Same as non-adjusted

p = 0.493

p = 0.064

Uroselective alpha-blockers vs. Placebo; Condition: BPH; Endpoint: Erection

None

Same as non-adjusted

p = 0.720

p = 0.999

Non-uroselective alpha-blockers vs. Placebo; Condition: BPH; Endpoint: Erection

1.16 (0.36 to 3.66)

p = 0.229

p = 0.174

Alpha-blockers vs. Placebo; Condition: Stones; Endpoint: Ejaculation

1.69 (0.78 to 3.70) (a)

p = 0.104

p = 0.999

None

Same as non-adjusted

p = 0.071

p = 0.042 (*)

1.58 (1.05 to 2.36)

p = 0.007 (*)

p = 0.144

Silodosin vs. Tamsulosin; Endpoint: Ejaculation

None

Same as non-adjusted

p = 0.158

p = 0.729

Naftopidil vs. Uroselective alpha-blocker; Condition: BPH; Endpoint: Ejaculation

None

Same as non-adjusted

p = 0.800

p = 0.573

Alfuzosin vs. Uroselective alpha-blocker; Condition: BPH; Endpoint: Ejaculation

None

Same as non-adjusted

p = 0.228

p = 0.881

Non-uroselective alpha-blockers vs. Placebo; Condition: BPH; Endpoint: Ejaculation

Alpha-blockers vs. Standard care; Condition: Stones; Endpoint: Ejaculation Alpha-blockers vs. Placebo or Standard care; Condition: Stones; Endpoint: Ejaculation

(a) After imputation of 3 missing studies, the adjusted odds ratio lost statistical significance (non-adjusted OR, 2.60; 95% CI, 1.20 to 5.65).

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FOREST PLOTS NOT SHOWN IN THE TEXT

Figure 1. Odds of ejaculatory disorders in patients with ureteral stones. Data to the right of the vertical no-effect axis indicate higher odds for ejaculatory disorders in patients treated with alpha adrenoceptor blockers compared to placebo.

Figure 2. Odds of ejaculatory disorders in patients with ureteral stones. Data to the right of the vertical no-effect axis indicate higher odds for ejaculatory disorders in patients treated with alpha adrenoceptor blockers compared to standard treatment.

Figure 3. Odds of erectile dysfunction in BPH patients. Data to the right of the vertical no-effect axis indicate higher odds for ejaculatory disorders in patients treated with uroselective alpha adrenoceptor blockers compared to placebo.

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Figure 4. Odds of erectile dysfunction in BPH patients. Data to the right of the vertical no-effect axis indicate higher odds for ejaculatory disorders in patients treated with non-uroselective alpha adrenoceptor blockers compared to placebo.

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SUMMARY

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FINDINGS

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