Archivio Italiano di Urologia e Andrologia - Vol. 94 - n. 1 - 2022 by Edizioni Scripta Manent

ISSN 1124-3562

Vol. 94; n. 1, March 2022 ORIGINAL PAPERS 1

Predictive features of pre-operative computed tomography and magnetic resonance imaging for advanced disease in renal cell carcinoma Musab Ali Kutluhan, Selman Unal, Serhan Eren, Asim Ozayar, Emrah Okulu, Hüseyin Cetin, Onder Kayigil

Laparoscopic radical nephroureterectomy with only three trocars: Results of a prospective single centre study Yazan Al Salhi, Andrea Fuschi, Alessia Martoccia, Gennaro Velotti, Paolo Pietro Suraci, Silvio Scalzo, Onofrio Antonio Rera, Alice Antonioni, Fabio Maria Valenzi, Giorgio Bozzini, Antonio Carbone, Antonio Luigi Pastore

Does routine intraoperative Double J stent insertion avoid urine leakage after open partial nephrectomy? Efe Bosnali, Ozdal Dillioglugil, Kerem Teke, Hasan Yilmaz, Busra Yaprak Bayrak, Ali Kemal Uslubas, Ibrahim Erkut Avci, Omer Burak Argun, Onder Kara

Predictive value of PSA density in the diagnosis of prostate cancer in lebanese men Ali Msheik, Mohamed Mohanna, Ali Mhanna, Ali Kanj, Mohamad Moussa, Assaad Mohanna

The role of MRI in the detection of local recurrence: Added value of multiparametric approach and Signal Intensity/Time Curve analysis Caterina Gaudiano, Federica Ciccarese, Lorenzo Bianchi, Beniamino Corcioni, Antonio De Cinque, Francesca Giunchi, Riccardo Schiavina, Michelangelo Fiorentino, Eugenio Brunocilla, Rita Golfieri

Do all patients with suspicious prostate cancer need Multiparametric Magnetic Resonance Imaging before prostate biopsy? Sara Teixeira Anacleto, Joana Neves Alberto, Emanuel Carvalho Dias, Pedro Sousa Passos, Mário Cerqueira Alves

Minimally invasive simple prostatectomy: Robotic-assisted versus laparoscopy. A comparative study Michele Amenta, Francesco Oliva, Biagio Barone, Alfio Corsaro, Davide Arcaniolo, Antonio Scarpato, Gennaro Mattiello, Lorenzo Romano, Carmine Sciorio, Tommaso Silvestri, Giovanni Costa, Felice Crocetto, Antonio Celia

Lower urinary tract symptoms and mental health during COVID-19 pandemic Biagio Barone, Luigi De Luca, Luigi Napolitano, Pasquale Reccia, Felice Crocetto, Massimiliano Creta, Raffaele Vitale, Vincenzo Francesco Caputo, Raffaele Martino, Luigi Cirillo, Giovanni Maria Fusco, Massimiliano Trivellato, Giuseppe Celentano, Roberto La Rocca, Domenico Prezioso, Nicola Longo

Non-invasive diagnosis of under active bladder: A pilot study Mehmet Yoldas

Looking for cystoscopy on YouTube: Are videos a reliable information tool for internet users? Carmine Turco, Claudia Collà Ruvolo, Simone Cilio, Giuseppe Celentano, Gianluigi Califano, Massimiliano Creta, Marco Capece, Roberto La Rocca, Luigi Napolitano, Francesco Mangiapia, Lorenzo Spirito, Simone Morra, Alberto Melchionna, Ferdinando Fusco, Vincenzo Mirone, Nicola Longo

Propionibacterium acnes in urine and semen samples from men with urinary infection Lucrezia Manente, Umberto Gargiulo, Paolo Gargiulo, Giuseppe Dovinola

Trends in treatments for erectile dysfunction in Chile between 2010 and 2020 with special focus on penile prostheses Marcelo Marconi, Cristian Palma, Sergio Moreno, Jose Miguel Flores, Santiago Escobar-Urrejola continued on page III

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Official Journal of SIEUN, UrOP, SSCU and GUN

EDITORIAL BOARD EDITOR IN CHIEF Alberto Trinchieri (Milan, Italy)

ASSOCIATE EDITORS Emanuele Montanari, Department of Urology, IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Italy – Gianpaolo Perletti, Department of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, University of Insubria, Varese, Italy; Department of Human Structure and Repair, Ghent University, Ghent, Belgium - Angelo Porreca, Robotic Urology and Mini Invasive Urologic Surgery Unit, Abano Terme Hospital, Abano Terme, Italy EXECUTIVE EDITORIAL BOARD Alessandro Antonelli, Department of Urology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), Verona, Italy - Antonio Celia, Department of Urology, San Bassiano Hospital, Bassano del Grappa, Italy - Luca Cindolo, Department of Urology, Villa Stuart Hospital, Rome, Italy - Andrea Minervini, Department of Urology, University of Florence, Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy - Bernardo Rocco, Department of Urology, University of Modena and Reggio Emilia, Modena, Italy - Riccardo Schiavina, Department of Urology, University of Bologna, Bologna, Italy ADVISORY EDITORIAL BOARD Pier Francesco Bassi, Urology Unit, A. Gemelli Hospital, Catholic University of Rome, Italy – Francesca Boccafoschi, Health Sciences Department, University of Piemonte Orientale in Novara, Italy – Alberto Bossi, Department of Radiotherapy, Gustave Roussy Institute, Villejuif, France –Tommaso Cai, S. Chiara Hospital, Trento, Italy – Paolo Caione, Department of Nephrology-Urology, Bambino Gesù Pediatric Hospital, Rome, Italy – Luca Carmignani, Urology Unit, San Donato Hospital, Milan, Italy – Liang Cheng, Department of Urology, Indiana University School of Medicine, Indianapolis, IN; Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN – Giovanni Colpi, Retired Andrologist, Milan, Italy – Giovanni Corona, Department of Urology, University of Florence, Careggi Hospital, Florence, Italy – Antonella Giannantoni, Department of Surgical and Biomedical Sciences, University of Perugia, Italy – Paolo Gontero, Department of Surgical Sciences, Molinette Hospital, Turin, Italy – Steven Joniau, Organ Systems, Department of Development and Regeneration, KU Leuven, Belgium – Frank Keeley, Bristol Urological Institute, Southmead Hospital, Bristol UK – Laurence Klotz, Division of Urology, Department of Surgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada – Börje Ljungberg, Urology and Andrology Unit, Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden – Nicola Mondaini, Uro-Andrology Unit, Santa Maria Annunziata Hospital, Florence, Italy – Gordon Muir, Department of Urology, King's College Hospital, London, UK – Giovanni Muto, Urology Unit, Bio-Medical Campus University, Turin, Italy – Anup Patel, Department of Urology, St. Mary's Hospital, Imperial Healthcare NHS Trust, London, UK – Glenn Preminger, Division of Urologic Surgery, Duke University Medical Center, Durham, NC, USA – David Ralph, St. Peter's Andrology Centre and Institute of Urology, London, UK – Allen Rodgers, Department of Chemistry, University of Cape Town, Cape Town, South Africa – Francisco Sampaio, Urogenital Research Unit, State University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil – Kemal Sarica, Department of Urology, Kafkas University Medical School, Kars, Turkey – Luigi Schips, Department of Urology, San Pio da Pietrelcina Hospital, Vasto, Italy – Hartwig Schwaibold, Bristol Urological Institute, Southmead Hospital, Bristol, UK – Alchiede Simonato, Department of Urology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy – Carlo Terrone, Department of Urology, IRCCS S. Martino University Hospital, Genova, Italy – Anthony Timoney, Bristol Urological Institute, Southmead Hospital, Bristol, UK – Andrea Tubaro, Urology Unit, Sant’Andrea Hospital, “La Sapienza” University, Rome, Italy – Richard Zigeuner, Department of Urology, Medical University of Graz, Graz, Austria BOARD OF REVIEWERS Maida Bada, Department of Urology, S. Pio da Pietrelcina Hospital, ASL 2 Abruzzo, Vasto, Italy - Lorenzo Bianchi, Department of Urology, University of Bologna, Bologna, Italy - Mariangela Cerruto, Department of Urology, Azienda Ospedaliera Universitaria

Integrata (A.O.U.I.), Verona, Italy - Francesco Chessa, Department of Urology, University of Bologna, Bologna, Italy - Daniele D’Agostino, Robotic Urology and Mini Invasive Urologic Surgery Unit, Abano Terme Hospital, Abano Terme, Italy - Fabrizio Di Maida, Department of Urology, University of Florence, Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy - Antonio Galfano, Urology Unit, Niguarda Hospital, Milan, Italy - Michele Marchioni, Department of Medical, Oral and Biotechnological Sciences, "G. d'Annunzio" University of Chieti, Laboratory of Biostatistics, Chieti, Italy - Andrea Mari, Department of Urology, University of Florence, Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy - Antonio Porcaro, Department of Urology, Azienda Ospedaliera Universitaria Integrata (A.O.U.I.), Verona, Italy - Stefano Puliatti, Department of Urology, University of Modena and Reggio Emilia, Modena, Italy - Daniele Romagnoli, Robotic Urology and Mini Invasive Urologic Surgery Unit, Abano Terme Hospital, Abano Terme, Italy - Chiara Sighinolfi, Department of Urology, University of Modena and Reggio Emilia, Modena, Italy - Tommaso Silvestri, Urology Clinic, Department of Medical, Surgical and Health Science, University of Trieste, Trieste, Italy - Petros Sountoulides, Aristotle University of Thessaloniki, Department of Urology, Thessaloniki, Greece SIEUN EDITOR Pasquale Martino, Department of Emergency and Organ Transplantation-Urology I, University Aldo Moro, Bari, Italy SIEUN EDITORIAL BOARD Emanuele Belgrano, Department of Urology, Trieste University Hospital, Trieste, Italy Francesco Micali, Department of Urology, Tor Vergata University Hospital, Rome, Italy Massimo Porena, Urology Unit, Perugia Hospital, Perugia, Italy – Francesco Paolo Selvaggi, Department of Urology, University of Bari, Italy – Carlo Trombetta, Urology Clinic, Cattinara Hospital, Trieste, Italy – Giuseppe Vespasiani, Department of Urology, Tor Vergata University Hospital, Rome, Italy – Guido Virgili, Department of Urology, Tor Vergata University Hospital, Rome, Italy UrOP EDITOR Carmelo Boccafoschi, Department of Urology, Città di Alessandria Clinic, Alessandria, Italy UrOP EDITORIAL BOARD Renzo Colombo, Department of Urology, San Raffaele Hospital, Milan, Italy – Roberto Giulianelli, Department of Urology, New Villa Claudia, Rome, Italy – Massimo Lazzeri, Department of Urology, Humanitas Research Hospital, Rozzano (Milano), Italy – Angelo Porreca, Department of Urology, Polyclinic Abano Terme, Abano Terme (Padova), Italy – Marcello Scarcia, Department of Urology, "Francesco Miulli" Regional General Hospital, Acquaviva delle Fonti (Bari), Italy – Nazareno Suardi, Department of Urology, San Raffaele Turro, Milano, Italy. GUN EDITOR Arrigo Francesco Giuseppe Cicero, Medical and Surgical Sciences Department, Sant’Orsola-Malpighi University Hospital, Bologna, Italy GUN EDITORIAL BOARD Gianmaria Busetto, Department of Urology, Sapienza University of Rome, Italy – Tommaso Cai, Department of Urology, Santa Chiara Regional Hospital, Trento, Italy – Elisabetta Costantini, Andrology and Urogynecological Clinic, Santa Maria Hospital of Terni, University of Perugia, Terni, Italy – Angelo Antonio Izzo, Department of Pharmacy, University of Naples, Italy – Vittorio Magri, ASST Nord Milano, Milano, Italy – Salvatore Micali, Department of Urology, University of Modena and Reggio Emilia, Modena, Italy – Gianni Paulis, Andrology Center, Villa Benedetta Clinic, Rome, Italy – Francesco Saverio Robustelli della Cuna, University of Pavia, Italy – Giorgio Ivan Russo, Urology Department, University of Catania, Italy – Konstantinos Stamatiou, Urology Department, Tzaneio Hospital, Piraeus, Greece – Annabella Vitalone, Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

ORIGINAL PAPERS 70

Retinal vessel diameters: Can they predict future risk of infertility in patients with varicocele? Mazen A. Ghanem, Essa A. Adawi, Ahmed M. Ghanem, Manal A. Safan, Asaad A. Ghanem

Quality of life of patients with La Peyronie's disease undergoing local iontophoresis therapy: A longitudinal observational study Tatiana Bolgeo, Roberta Di Matteo, Menada Gardalini, Denise Gatti, Antonio Maconi, Carmelo Boccafoschi

The importance of inquiring the ejaculation function in men with premature ejaculation who do not actively seek treatment Erhan Ates, Ahmet Emre Yildiz, Hakan Gorkem Kazici, Saparali Sulaimanov, Arif Kol, Haluk Erol

The use of a polyglycolic acid polymer graft in Peyronie’s disease - preliminary outcomes Pedro Caetano Edler Zandoná, Nivio Pascoal Teixeira, Henrique Eduardo Oliveira, Jorge Hamilton Soares Garcia

Antegrade placement of JJ catheter in the treatment of malignant ureteral obstruction: Retrospective analysis of a single centre Eser Ordek, Mehmet Kolu, Mehmet Demir, Bulent Kati, Eyyup Sabri Pelit, Ismail Yagmur

REVIEWS 97

Infectious complications of endourological treatment of kidney stones: A meta-analysis of randomized clinical trials Rawa Bapir, Kamran Hassan Bhatti, Ahmed Eliwa, Herney Andrés García-Perdomo, Nazim Gherabi, Derek Hennessey, Panagiotis Mourmouris, Adama Ouattara, Gianpaolo Perletti, Joseph Philipraj, Alberto Trinchieri, Noor Buchholz

107

Perspectives on the urological care in Parkinson’s disease patients Mohamad Moussa, Mohamed Abou Chakra, Athanasios G. Papatsoris, Athanasios Dellis, Baraa Dabboucy, Michael Peyromaure, Nicolas Barry Delongchamps, Hugo Bailly, Igor Duquesne

LETTERS TO EDITOR 118

Core urological surgical training: The pivotal role of feminizing genital reconstruction for gender dysphoria Gianmartin Cito, Elena Rovero, Francesco Sessa, Simone Sforza, Girolamo Morelli, Arturo Lo Giudice, Lorenzo Masieri, Andrea Minervini, Riccardo Bartoletti, Giorgio Ivan Russo, Andrea Cocci

121

COVID-19 vaccination and penile Mondor disease. There is any relationship? Andrea Fabiani, Alessandra Filosa, Daniele Maglia, Emanuele Principi, Silvia Stramucci

123

Aristolochic acid: What urologists should know Mohanarangam Thangavelu, Asmaa Ismail, Ahmed Zakaria, Hazem Elmansy, Walid Shahrour, Owen Prowse, Ahmed Kotb

126

Overweight and obesity: The allies of prostate inflammation Juan Sebastián Moncada López, Jenniffer Puerta Suárez, Walter Darío Cardona Maya

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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, 1

III

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ORIGINAL PAPER

DOI: 10.4081/aiua.2022.1.1

Predictive features of pre-operative computed tomography and magnetic resonance imaging for advanced disease in renal cell carcinoma Musab Ali Kutluhan 1, Selman Unal 1, Serhan Eren 2, Asim Ozayar 1, Emrah Okulu 1, Hüseyin Cetin 3, Onder Kayigil 1 1 Department

of Urology, Yildirim Beyazit University, School of Medicine, Ankara, Turkey; of Radiology, University of Health Sciences, Etlik Zubeyde Hanım Research and Training Hospital, Ankara, Turkey; 3 Department of Radiology, Yildirim Beyazit University, School of Medicine, Ankara, Turkey. 2 Department

Summary

Objective: We evaluated predictive features of pre-operative computed tomography and magnetic resonance imaging for advanced disease in renal cell carcinoma. Materials and methods: 92 patients with pathologically confirmed diagnosis of renal cell carcinoma were included in our study. Patients were divided into two groups according to preoperative imaging as computed tomography (CT) (55 patients) and magnetic resonance imaging (MRI) (37 patients). Within the imaging groups, the patients were divided into two groups according to pathological tumor stage: 1-2 (pT1-2) versus ≥ pT3a. It was evaluated whether there was a difference between the two groups in terms of the presence of pre-operative imaging (CT and MRI) features. Predictive value of these features for ≥ pT3a disease was evaluated both for CT and MRI. Results: The cut-off value for the Gerota’s fascia thickness in predicting ≥ pT3a disease was calculated as 0.205 cm. Positive predictive value (PPV) for Gerota's fascia thickness was 52.4% (31.0-73.7) and 66.7% (40.0-93.3) for CT and MRI respectively. The PPV value for renal capsule invasion was 75.0% (53.8-96.2) and 90.0% (71.4-108.6) for CT and MRI respectively. PPV of perirenal fat invasion for CT and MRI was 69.2% (44.1-94.3) and 81.8% (59.0-104.6) respectively. Conclusion: Renal capsular invasion and perirenal fat invasion are reliable signs for locally advanced (≥ pT3a) renal cell carcinoma both in CT and MRI. Gerota’s fascia thickness has relatively low PPV value for prediction of locally advanced disease. Presence of enlarged collateral vessels, tumor necrosis, perinephric stranding are not reliable signs. For all predictors MRI seems more reliable than CT.

KEY WORDS: Renal cell carcinoma; Computed tomography; Magnetic resonance imaging; Predictive features. Submitted 9 December 2021; Accepted 18 January 2022

INTRODUCTION

Renal cell carcinoma (RCC) is one of the most common urinary system cancers and accounts for 3% of all cancers (1). With the frequent use of imaging methods most renal masses are detected when localized (2). The standard treatment option in localized RCC is radical nephrectomy (RN) or nephron-sparing surgery (NSS). NSS is preferred in

patients with tumor stage 1 (T1) and has been shown to be comparable to RN in terms of oncologic outcomes (3). Although there is no prospective randomized study comparing NSS with RN in terms of oncological and renal functions in T2 patients, there are retrospective studies conducted to date (4). According to the current European Urology Association guideline, the standard approach in patients with ≥ T2 is RN (5). Pre-operative clinical staging is performed with computed tomography (CT) or magnetic resonance imaging (MRI), and patients may develop local recurrence despite surgical procedures based on clinical stage (6). In clinical practice, pre-operative CT and MRI provide information about tumor size, tumor localization, presence of tumor invasion into vascular structures and adjacent organs (7). However, apart from these frequently reported findings, there are CT and MRI findings that can be used to predict advanced disease. According to 2017 Tumor, Node, and Metastasis (TNM) classification, invasion of the pelvicalyceal system, perirenal or renal sinus fat invasion has been included in the T3a category (8). There are studies evaluating predictive value of CT to indicate renal sinus fat or perirenal fat invasion (9). Although not included in the standard TNM classification, it has been shown that renal capsule invasion is an independent prognostic variable for advanced disease and can be detected on CT (10, 11). On the other hand, it has been indicated that thickening of the Gerota’s fascia, the presence of enlarged collateral vessels, and the presence of intra-tumoral necrosis may be imaging findings that can be used to predict advanced disease (12). We also think that these markers can be used in prediction of advanced disease in RCC. Although renal capsule invasion and perirenal fat invasion has been considered reliable markers in advanced disease, additional markers can make imaging more reliable. Consequently, in our study we decided to investigate these markers that could be used for prediction of ≥ pT3a disease. We also think that the predictive value of MRI may be higher than CT. Therefore, in this study we evaluated the role of some features (renal capsule invasion, perirenal fat invasion, thickening of the Gerota’s fascia, presence of enlarged collateral vessels, tumor necrosis, perinephric stranding) of pre-operative computed tomography and magnetic

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 1

M. Ali Kutluhan, S. Unal, S. Eren, A. Ozayar, E. Okulu, H. Cetin, O. Kayigil

resonance imaging for predicting advanced disease in renal cell carcinoma.

MATERIALS

AND METHODS

Study design and patient selection After local ethics committee approval (26379996/58), patients who had RN or NSS operation due to renal mass in our clinic were retrospectively screened. In total, 92 patients with pathologically confirmed diagnosis of RCC and pre-operative CT or MRI images were included in our study. Patients who had metastatic RCC, who had unclear CT or MRI images, who had undergone surgery on the same side before the onset of kidney mass due to other urological pathologies, and who had pathology results other than RCC (oncocytoma, etc.) were excluded from the study. Patients were divided into two groups according to pre-operative imaging as CT (55 patients) and MRI (37 patients). Pre-operative CT and MRI images were evaluated by a dedicated blinded radiologist. Postoperative pathology results of the patients were screened. Within the imaging groups, the patients were divided into two groups according to pathological tumor stage as 1-2 (pT1-2) (Group 1) and ≥ pT3a (Group 2). It was evaluated whether there was a difference between the two groups in terms of the presence of pre-operative imaging (CT and MRI) features (renal capsule invasion, perirenal fat tissue invasion, thickening of the Gerota’s fascia, presence of enlarged collateral vessels, intra-tumoral necrosis, perinephric stranding). Predictive value of these features for ≥ pT3a disease was evaluated both for CT and MRI. Radiological evaluation CT acquisition CT examination was performed using a 128-slice multidetector CT scanner (GE, Revolution EVO, USA). The CT parameters and scanning sequence were as follows: 1:1 pitch, 200-250 mAs, 120 kVp, and 0.5-0.625 isotropic spatial resolution, window width 250~450 HU, and window level 30-50 HU; for cortical phase, medullary phase, and excretion phase, the duration of scanning was 30-35, 50-60, and 180 s after the injection of contrast agent, respectively. 100 mL of non-ionic intravenous contrast agent was administered through antecubital veins with an automated injector at 3 mL/sec (Ulrich Medizin version, 2004, Germany). All patients were examined in a supine position with 6-8 hours fasting. MRI acquisition MRI examinations were performed with 1.5-Tesla MRI (Signa, GE Medical Systems) with 5 mm slice thickness and 2.0 mm gap spacing by using surface phased array coil. MRI sequence parameters were coronal T2-weighted halfFourier single-shot fast spin-echo (TR/TE msec 8001100/60; slice thickness 4 mm; gap 1 mm; matrix size 192 × 256; flip angle 130°-155°), axial T1-weighted inphase and opposed-phase gradient-echo (180-205/2.22.7, 4.5-5.2; flip angle, 80°; slice thickness, 6-8 mm; gap, 1 mm; matrix, 160 × 256), and 3D T1-weighted liver imaging with volume acceleration (LAVA) with fat suppres-

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

sion (TR/TE msec 1.4/4.3; slice thickness 2.5 mm; matrix size 132x320; flip angle, 10-12°; FOV 25x35 cm). In dynamic imaging, the delay time was 20 seconds for corticomedullary phase, 60 seconds for nephrographic phase, and 120 seconds for the coronal delayed phase after the intravenous injection of 15 ml of Magnevist (0.1 mmol/kg; Bayer Schering, Pharma AG, Berlin, Germany) at a rate of 2 ml/s. Diffusion weighted imaging (DWI) was performed with two b values (0 and 600 mm2/s). Image analysis One dedicated radiologist for abdominal radiology reviewed all images in archiving system blinded to histopathologic information. Imaging features of perinephric fat tissue, perinephric stranding, perinephric vascularity, and irregular contours was evaluated both in CT (Figure 1) and MRI. Tumor margins were identified as smooth or lobulated for evaluation of capsule invasions (Figure 2). In quantitative measurements, Gerota’s fascia thickness was measured in magnified images of CT and MRI (Figure 3). Presence of tumor necrosis and collateral vessels were also evaluated both in MRI and CT. Statistical analyzes Statistical analyses of the study were performed using SPSS 23.0 program (SPSS, Version 23.0; IBM Corp, Armonk, NY). Number, percentage, mean and standard deviation were used for descriptive statistics. Analyses of differences between groups were performed with t-test and chi-square test in independent groups as significance tests. Crosstabs were used for sensitivity, specificity, and predictive value calculations. The diagnostic value of Gerota’s fascia thickness in predicting cancer stage was analyzed by ROC curve by considering 0.05 as the significance threshold for p-value. Figure 1. A 50-year-old woman with high-grade clear cell RCC (Fuhrman grade IV) in left kidney. Axial contrast-enhanced computed tomography image shows a 15-cm hyper vascular centrally necrotic renal mass. Gerota.s fascia (anterior perirenal fascia) thickness was 0.41 cm.

Predictive imaging features in renal cell carcinoma

Figure 2. A 62-year-old man with high-grade clear cell RCC (Fuhrman grade IV) in left kidney. Axial computed tomography image shows lesion margin was ill-defined and lobulated. The tumor showed invasion of the renal capsule and perirenal fat. Perirenal fat stranding was prominent.

In addition, there was a statistically significant difference between the groups in terms of perinephric stranding and perirenal fat invasion (p = 0.04, p < 0.001). Comparison of CT predictors according to groups was summarized in Table 2. When the groups were compared in terms of pre-operative MRI features, the mean Gerota’s fascia thickness of group 2 was statistically significantly thicker than group 1 (0.38 ± 0.24 vs 0.13 ± 0.06 cm, p < 0.001). There was a statistically significant difference between the groups in terms of the presence of collateral vessels and intratumoral necrosis (p = 0.015, p = 0.015). There was a statistically significant difference between the groups in terms of renal capsule invasion (p < 0.001). In addition, there was a statistically significant difference between the groups in terms of perinephric stranding and perirenal fat

Table 1. Characteristics of the patients. Number of patients Mean age (years) Pre-operative imaging

Figure 3. A 58-year-old man with 8 cm high-grade clear cell RCC (Fuhrman grade III) in left kidney. Axial T2 weighted fat saturated images show heterogenous ill-defined tumor in left kidney. Gerota fascia was thickened and measured 0.3 cm.

Tumor side Operation Pathological T stage

Pathological type

92 58.08 ± 11.58 n (%) 55 (59.8) 37 (40.2) 50 (54.3) 42 (45.7) 42 (45.7) 50 (54.3) 37 (40.2) 17 (18.5) 7 (7.6) 6 (6.5) 16 (17.4) 6 (6.5) 3 (3.3) 71 (77.2) 12 (13.0) 9 (9.8)

CT MRI Right Left Radical nephrectomy Partial nephrectomy T1a T1b T2a T2b T3a T3b T4 Clear cell RCC Papillary RCC Chromophobe RCC

CT: Computed tomography; MRI: Magnetic resonance imaging; T: Tumor; RCC: Renal cell carcinoma.

Table 2. Comparison of CT predictors according to pT stage. Pre-operative CT predictors

RESULTS

The mean age of the patients included in the study was 58.08 ± 11.58. 59.8% of patients had CT as pre-operative imaging, while 40.2% had MRI. The clinical features of the patients are summarized in Table 1. When the groups were compared in terms of pre-operative CT features, the mean Gerota’s fascia thickness of group 2 was statistically significantly thicker than group 1 (0.15 ± 0.01 vs 0.30 ± 0.12 cm p < 0.001). There was a statistically significant difference between the groups in terms of the presence of collateral vessels (p = 0.008). There was a statistically significant difference between the groups in terms of renal capsule invasion (p < 0.001).

Gerota’s fascia thickness mean sd (cm) Presence of enlarged collateral vessels Positive Negative Tumor necrosis Positive Negative Renal capsule invasion Positive Negative Perirenal fat invasion Positive Negative Perinephric stranding Positive Negative

pT stage Group 1 = Group 2 = < T3a (n = 40) ≥ T3a (n = 15) 0.15 ± 0.01

0.30 ± 0.12

19 (47.5%) 21 (52.5%)

13 (86.7%) 2 (13.3%)

19 (47.5%) 21 (52.5%)

11 (73.3%) 4 (26.7%)

5 (10.3%) 35 (89.7)

12 (80.0%) 3 (20.0%)

4 (10.0%) 36 (90.0%)

9 (60.0%) 6 (40.0%)

17 (42.5%) 23 (57.5%)

11 (73.3%) 4 (26.7%)

p-value

< 0.001 0.008

0.078

< 0.001

0.040

CT: Computed tomography; pT: Pathological tumor.

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

M. Ali Kutluhan, S. Unal, S. Eren, A. Ozayar, E. Okulu, H. Cetin, O. Kayigil

DISCUSSION

Table 3. Comparison of MRI predictors according to pT stage. Pre-operative MRI predictors

pT stage Group 1 = Group 2 = < T3a (n = 27) ≥ T3a (n = 10) 0.13 ± 0.06

0.38 ± 0.24

9 (33.3%) 18 (66.6%)

8 (80.0%) 2 (20.0%)

9 (33.3%) 18 (66.6%)

8 (80.0%) 2 (20.0%)

1 (3.7%) 26 (96.3%)

9 (90.0%) 1 (10.0%)

2 (7.4%) 25 (92.6%)

9 (90.0%) 1 (10.0%)

7 (25.9%) 20 (74.1%)

10 (10.0%) 0 (0.0%)

p-value

< 0.001 0.015

0.015

< 0.001

MRI: Magnetic resonance imaging; pT: Pathological tumor.

invasion (p < 0.001, p < 0.001). Comparison of MRI predictors according to groups was summarized in Table 3. The diagnostic value of Gerota's fascia thickness in estimating pathological stage was evaluated with the ROC curve. According to this evaluation, the cut-off value for the Gerota’s fascia thickness in predicting ≥ pT3a disease was calculated as 0.205 cm. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CT and MRI predictors was summarized in Table 4. Accordingly, the PPV value for Gerota's fascia thickness was 52.4% (31.0-73.7) and 66.7% (40.0-93.3) for CT and MRI respectively. The PPV value for renal capsule invasion was 75.0% (53.896.2) and 90.0% (71.4-108.6) for CT and MRI respectively. PPV of perirenal fat invasion for CT and MRI was 69.2% (44.1-94.3) and 81.8% (59.0-104.6) respectively.

In patients with renal mass, tumor stage is important for the prognosis of the disease. Perirenal fat invasion, renal sinus fat invasion, renal capsule invasion and renal vein invasion are important factors that may affect the prognosis. In a study conducted on 563 patients with pT3a tumor and negative node (N0), Shah et al. demonstrated that although there was no difference between perirenal fat invasion, renal sinus fat invasion and renal vein invasion in terms of the prognosis of the disease, the combination of these factors could negatively affect the prognosis of the disease (13). In another multicentric study by BrookmanMay et al., it was shown that perirenal fat invasion may be an independent prognostic factor for cancer specific survival (14). It has also been shown that renal capsule invasion may be an independent prognostic factor for RCC (10). Pre-operative detection of prognostic factors has recently become more important for the management of the disease, with the increase in neo-adjuvant and adjuvant treatment modalities. In a study conducted by Renard et al., the predictive value of CT for pT3a disease was evaluated and the PPV values of perirenal fat invasion, renal sinus fat invasion and venous invasion were detected to be 49%, 68% and 90%, respectively (15). In another study by EL-Hefnawy et al. including 693 patients, the PPV value of CT in predicting pT3a disease was reported as 43.7% (16). In our study, PPV of perirenal fat invasion in predicting ≥ pT3a was 69.2% and 81.8% in CT and MRI respectively. When compared to literature (15, 16), PPV of perirenal fat invasion seems to be higher according to CT. In addition, MRI seems to be more reliable for detecting perirenal fat invasion. Although it is thought that it is difficult to detect renal capsule invasion in pre-operative imaging, it has been reported in studies that some CT findings may indicate renal capsule invasion (11). In addition, in a study conducted by Nazım et al. PPV of renal capsule invasion in CT was 75.3% in predicting local advanced RCC (17). In our study PPV of renal capsule invasion was 75.0% (53.8-96.2) and 90.0 (71.4-108.6) for CT and MRI respectively. Our results demonstrated that PPV value of renal capsule invasion on CT in predicting T3a and above

Table 4. CT and MRI predictions for pT Stage > pT3a. Predictors Gerota’s fascia thickness 0.205 cm < Presence of enlarged collateral vessels Positive Tumor necrosis Positive Renal capsule invasion Positive Perinephric stranding Positive Perirenal fat invasion Positive

Sensitivity (%) BT (CI) MR (CI)

Specificity (%) BT (CI) MR (CI)

NPV (%) MR (CI)

BT (CI)

MR (CI)

73.3 (51.0-95.7)

80.0 (55.2-104.8)

75.0 (61.6-88.4)

85.2 (71.8-98.6)

52.4 (31.0-73.7)

66.7 (40.0-93.3)

88.2 (77.4-99.1)

92.0 (81.4-102.6)

86.7 (69.5-103.8)

80.0 (55.2-104.8)

52.5 (37.0-67.8)

66.7 (48.9-84.4)

40.6 (23.6-57.6)

47.1 (23.3-70.8)

91.3 (79.8-102.8)

90.0 (76.9-103.1)

73.3 (51.0-95.7)

80.0 (55.2-104.8)

52.5 (37.0-68.0)

66.7 (48.9-84.4)

36.7 (19.4-53.9)

47.1 (23.3-70.8)

84.0 (69.6-98.4)

90.0 (76.9-103.1)

80.0 (59.8-100.2)

90.0 (71.4-108.6)

89.7 (80.2-99.3)

96.3 (89.2-103.4)

75.0 (53.8-96.2)

90.0 (71.4-108.6)

92.1 (83.5-100.6)

96.3 (89.2-103.4)

73.3 (50.1-95.7)

100.0

57.5 (42.2-72.8)

74.1 (57.5-90.6)

39.3 (21.2-57.4)

58.8 (35.4-82.2)

85.2 (71.8-98.6)

100.0

60.0 (35.2-84.8)

90.0 (71.4-108.6)

90.0 (80.7-99.3)

92.6 (82.7-102.5)

69.2 (44.1-94.3)

81.8 (59.0-104.6)

85.7 (75.1-96.3)

96.2 (88.8-103.5)

CT: Computed tomography, MRI: Magnetic resonance imaging, pT: Pathological Tumor, PPV: Positive predictive value, NPV: Negative predictive value.

PPV (%) BT (CI)

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Predictive imaging features in renal cell carcinoma

disease is similar to the literature. In addition, MRI seems to be more reliable for detecting renal capsule invasion. In locally advanced RCC, thickening of the Gerota's fascia adjacent to the tumor may be expected due to the spread of the tumor. However, increase in the thickness of Gerota's fascia may also develop due to other reasons such as infectious pathologies. In a study by Bradley et al., it was stated that the Gerota’s fascia thickness on CT has 90% specificity and 81% PPV for T3a and above disease, and it has been shown that Gerota’s fascia thickness is a reliable predictor of locally advanced disease (12). In our study, we measured the thickness of the Gerota’s fascia adjacent to the tumor for the first time in the literature, and in our ROC analysis, we determined that the cut-off value for the Gerota’s fascia thickness in predicting advanced disease was 0.205 cm. According to this cut-off value, the specificity of the Gerota’s fascia thickness in predicting a stage > T3a is 75% and 85% for CT and MRI respectively. We also determined that the PPV value was 52% and 66% for CT and MRI respectively. According to our results, we think that the Gerota’s fascia thickness has less predictive value for locally advanced disease in contrast to literature and that MRI is more reliable than CT. Presence of enlarged collateral vessels and tumor necrosis are thought to be predictive markers for advanced RCC. In meta-analyses, indication of tumor necrosis as a factor that adversely affects prognosis in RCC makes the predictive value of the presence of necrosis in advanced stage disease more important in pre-operative imaging (18). There are studies indicating that tumor necrosis on CT has high specificity and PPV in predicting T3a disease (12). In our study, even though there was a significant difference between the groups in terms of the presence of necrosis, we found that the presence of necrosis had a low predictive value for advanced disease in both CT and MRI (PPV= 37% and 47% respectively). However, the absence of tumor necrosis indicates that pathological stage could be < T3a (NPV= 84% and 90% for CT and MRI). On the other hand, in a study conducted by Suo et al., it was shown that patients with collateral vessel diameter > 0.2 cm had a higher pT stage than patients with < 0.2 cm. They also showed that the presence of a collateral vessel is an independent prognostic factor for overall survival in RCC (19). In another study, the presence of enlarged collateral vessels was shown to have an 88% PPV value in predicting > pT3a disease (12). In our study, there was a significant difference between the groups in terms of the presence of enlarged collateral vessels on CT and MRI (p = 0.008 and p = 0.015 respectively). However, although the NPV value of the presence of enlarged collateral vessels in both CT and MRI was high in predicting > pT3a disease (91% and 90% respectively), the PPV value was low (41% and 47% respectively). In contrast to literature, we don’t think that presence of enlarged collateral vessels can predict locally advanced disease in RCC. Perinephric fat stranding develops mostly due to pyelovenous or pyelolymphatic backflow due to acute ureteral obstruction (20). Studies have shown that perinephric fat stranding has a low predictive value for locally advanced disease in RCC (10, 14). In our study, we found that the

power of perinephric fat standing to predict local advanced disease was low in both CT and MRI (PPV = 39% and 58% respectively). On the other hand, MRI seems more reliable than CT. Nevertheless, our study has some limitations. Firstly, our study is retrospective and the number of patients in the groups is limited. Secondly, the patients in the MRI and CT groups were different, and not every patient had both CT and MRI as imaging so CT and MRI were not statistically compared for predictive values of preoperative imaging markers. However, it can be said that MRI may be more reliable because it has higher PPV values than CT for all predictors. Thirdly, we did not measure the diameter of the collateral vessels. We considered patients with significant enlarged collateral vessels to be positive.

CONCLUSIONS

In conclusion, renal capsular invasion, perirenal fat invasion are reliable signs for locally advanced (> pT3a) renal cell carcinoma both in CT and MRI. Gerota’s fascia thickness has relatively low PPV value for prediction of locally advanced disease. Presence of enlarged collateral vessels, tumor necrosis, perinephric stranding are not reliable signs. On the other hand, for all predictors MRI seems more reliable than CT. Prospective large cohort studies are needed for more defined conclusions.

REFERENCES

1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin 2018; 68:394-424. 2. Novara G, Ficarra V, Antonelli A, et al. Validation of the 2009 TNM version in a large multi-institutional cohort of patients treated for renal cell carcinoma: are further improvements needed? Eur Urol, 2010; 58:588-95. 3. 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. 4. Mir MC, Derweesh I, Porpiglia F, et al. Partial nephrectomy versus radical nephrectomy for clinical T1b and T2 renal tumors: a systematic review and meta-analysis of comparative studies. Eur Urol, 2017; 71:606-617. 5. Ljungberg B, Albiges L, Abu-Ghanem Y, et al. European Association of Urology guidelines on renal cell carcinoma: The 2019 update. Eur. Urol.2019; 75:799-810. 6. Antonelli A, Furlan M, Tardanico R, et al. Features of ipsilateral renal recurrences after partial nephrectomy: a proposal of a pathogenetic classification. Clin Genitourin Cancer 2017; 15:540-547. 7. Hotker AM, Karlo CA, Zheng J, et al. Clear cell renal cell carcinoma: Associations between CT features and patient survival. AJR Am. J. Roentgenol. 2016; 206:1023-1030. 8. Amin MB, Greene FL, Edge SB, et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin. 2017; 67:93-99. 9. Sokhi HK, Mok WY, Patel U. Stage T3a renal cell carcinoma: staging accuracy of CT for sinus fat, perinephric fat or renal vein invasion. Br J Radiol 2015; 88:20140504 Archivio Italiano di Urologia e Andrologia 2022; 94, 1

M. Ali Kutluhan, S. Unal, S. Eren, A. Ozayar, E. Okulu, H. Cetin, O. Kayigil

10. Ha U-S, Lee KW, Jung J-H, et al. Renal capsular invasion is a prognostic biomarker in localized clear cell renal cell carcinoma Sci Rep 2018; 8:202.

15. Renard AS, Nedelcu C, Paisant A, et al. Is multidetector CT-scan able to detect T3a renal tumor before surgery? Scand J Urol 2019; 53:350-35.

11. Zhang Y, Tian H, Zhang S, et al. Multislice spiral computed tomography signs of invasion of the renal capsule by renal cell carcinoma Medicine 2018; 97:e13075.

16. El-Hefnawy AS, Mosbah A, El-Diasty T, et al. Accuracy of multidetector computed tomography (MDCT) in staging of renal cell carcinoma (RCC): analysis of risk factors for mis-staging and its impact on surgical intervention World J Urol 2013; 31:887-91.

12. Bradley AJ, MacDonald L, Whiteside S, et al. Accuracy of preoperative CT T staging of renal cell carcinoma: which features predict advanced stage? Clin Radiol 2015; 70:822-9. 13. Shah PH, Lyon TD, Lohse CM, et al. Prognostic evaluation of perinephric fat, renal sinus fat, and renal vein invasion for patients with pathological stage T3a clear-cell renal cell carcinoma BJU Int 2019; 123:270-276. 14. Brookman-May SD, May M, Wolff I, et al. Evaluation of the prognostic significance of perirenal fat invasion and tumor size in patients with pT1-pT3a localized renal cell carcinoma in a comprehensive multicenter study of the CORONA project. Can we improve prognostic discrimination for patients with stage pT3a tumors? Eur Urol 2015; 67:943-51.

Correspondence Musab Ali Kutluhan, MD dr.musab151@gmail.com Selman Unal, MD (Corresponding Author) drselmanunal@gmail.com Universiteler District Bilkent Avenue No: 1 Ankara, 06800 (Turkey) Serhan Eren, MD serhanerenhu@gmail.com Etlik Avenue No: 55 Kecioren/Ankara, 06010 (Turkey) Asim Ozayar, MD aozayar@gmail.com Emrah Okulu, MD eokulu@yahoo.com Huseyin Cetin, MD hcetinrad@gmail.com Onder Kayigil, MD kayigilo@yahoo.com.tr Universiteler District Bilkent Avenue No: 1 Ankara, 06800 (Turkey)

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

17. Nazım SM, Ather MH, Hafeez K, et al. Accuracy of multidetector CT scans in staging of renal carcinoma Int J Surg 2011; 9:86-90. 18. Zhang L, Zha Z, Qu W, et al. Tumor necrosis as a prognostic variable for the clinical outcome in patients with renal cell carcinoma: a systematic review and meta-analysis BMC Cancer 2018; 18:870. 19. Suo X, Chen J, Zhao Y, et al. Clinicopathological and radiological significance of the collateral vessels of renal cell carcinoma on preoperative computed tomography Sci Rep 2021; 11:518. 20. Farrell MR, Papagiannopoulos D, Ebersole J, et al. Perinephric fat stranding is associated with elevated creatinine among patients with acutely obstructing ureterolithiasis. J Endourol 2018; 32:891-89.

DOI: 10.4081/aiua.2022.1.7

ORIGINAL PAPER

Laparoscopic radical nephroureterectomy with only three trocars: Results of a prospective single centre study Yazan Al Salhi 1, 2, Andrea Fuschi 1, 2, Alessia Martoccia 1, Gennaro Velotti 1, Paolo Pietro Suraci 1, Silvio Scalzo 1, Onofrio Antonio Rera 1, Alice Antonioni 1, Fabio Maria Valenzi 1, Giorgio Bozzini 3, Antonio Carbone 1, Antonio Luigi Pastore 1 1 Urology

Unit, Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Latina, Italy; 2 ICOT-Surgery, Orthopedics, Traumatology Institute, Latina, Italy; 3 Urology Unit, ASST Lariana, Como, Italy.

Summary

Introduction: Radical nephroureterectomy (RNU) with full bladder cuff excision is the gold standard for treatment of non-metastatic upper tract urothelial cancer (UTUC). We describe our technique of laparoscopic nephroureterectomy (LNU) with bladder cuff excision technique with modified port placement, reporting our long-term follow-up outcomes. Methods: Patients affected by UTUC were prospectively enrolled and undergone to LNU. Perioperative outcomes, oncological data at 6, 12, 24 and 36 months after surgery, and all the surgical complications according to Clavien-Dindo classification were evaluated in all subjects. Results: A total of 50 patients with UTUC underwent LNU, using this new technique without patient and port repositioning. The mean operative time was 168 minutes, estimated blood loss was 75 mL, mean length of hospital stay was 3 days. There were no intraoperative complications while four late complications occurred (two grade IIIb and two grade II according to Clavien-Dindo classification, incisional hernias and fever, respectively). Postoperative pathology was T1 in 12 patients, T2 in 17 patients, and T3 in 21 patients. Tumor grade was low in 12 patients and high in 38 patients. Conclusions: In our study the described LNU technique was related to a significant reduction in terms of operative time and length of hospital stay, with a faster patients’ recovery and no peri and postoperative complications. The long-term oncological outcomes were similar to data reported in literature.

KEY WORDS: Nephroureterectomy; Laparoscopy; Oncological outcomes; Hospital stay; Estimated blood loss. Submitted 29 December 2021; Accepted 7 January 2022

INTRODUCTION

Upper tract urothelial carcinoma (UTUC) is rare, accounting for only 5-7% of all urothelial carcinoma cases, with a high frequency of both local and secondary bladder recurrence (1-2). Radical nephroureterectomy (RNU) with full bladder cuff excision is the gold standard for treatment of non-metastatic UTUC (3). Laparoscopic nephroureterectomy (LNU) was firstly report-

ed by Clayman in 1991 (4) and several studies described, compared to the open technique, a minimized morbidity in terms of blood loss, perioperative pain, faster convalescence, and less perioperative complications (5, 6). A recent meta-analysis and multicenter studies reported comparable oncologic results between the two surgical approaches (7-11). One of the most important surgical steps during LNU is the access to the distal ureter in order to perform the excision of the bladder cuff. Different techniques have been described regarding open, endoscopic or trans-vesical approach (12-14) but no one has been shown to be significantly better than the others. The ideal technique is represented, on one side, by removing of the specimen en bloc without spillage of tumor cells during the bladder cuff excision in respect of oncological criteria and, on the other side, by performing the entire procedure without patient and port repositioning to decrease operative time. Herein, we describe our totally LNU with bladder cuff excision technique with modified port placement, which allows access to both kidney and ureterovesical junction without requiring patient repositioning.

MATERIALS

AND METHODS

From January 2014 to June 2020, patients with diagnosis of UTUC, were prospectively enrolled and treated with LNU using our surgical technique performed by the same experienced surgeon (AC) at our University Department. The study was performed in accordance with the Ethical Principles for Medical Research Involving Human Subjects (World Medical Association, The Declaration of Helsinki Principles, 2000). The study was approved by the local ethical committee of Sapienza University Pharmacy and Medicine Faculty, Latina, Italy (DSBMC LT approval n. CE14/0924/2014 UROL). Written informed consent forms were obtained from all the patients before study enrollment. The patient demographic and clinic-pathologic data were prospectively collected and are summarized in Table 1. None of these patients had prior or concomitant bladder tumors and/or distant metastasis.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 1

Y. Al Salhi, A. Fuschi, A. Martoccia, et al.

All tumors were staged based on the 2002 TNM classification of malignant tumors and were graded by the World Health Organization classification of 1998. After the induction of general anesthesia, the patient is placed in a modified flank position (60° oblique position) with the lesion side up (the right side, e.g.) (Figure 1). The first port (12 mm port used for the 30 degrees camera) is placed by Hasson technique supraumbilical on the pararectal line at the caudal rim of the umbilicus. Peritoneal insufflation is established, and pneumoperitoneum is created by applying 12 mm Hg of CO2 pressure. The second port is a 12 mm port placed on the paramedian line between the optical trocar and the costal arch. The third port is a 5 mm port placed in the midline between the anterior superior iliac spine (ASIS) and the umbilicus.

Standard laparoscopic transperitoneal nephrectomy is performed with a radiofrequency device (LigasureTM, 5 mm Covidien®, U.S.) placed in the second port and a Johan forceps in the third port. First surgical time (nephrectomy) includes mobilization of the colon, ligation of the renal hilum and circumferential mobilization of the kidney, while leaving the ureter intact. Retroperitoneal lymphadenectomy is performed in clinical indicated cases based on the preoperative CT scan, included the interaortocaval dissection plus hilar and precaval-paracaval-retrocaval regions for right-sided disease, and hilar with preaortic-paraaortic-retroaortic tissues for left-sided disease. During further mobilization, the ureter is clipped distal to the tumor site to prevent intraluminal tumor seeding. By carefully dissecting the ureter over the iliac vessels down to the ureterovesical junction, the peritoneal covering overlying the dome of the bladFigure 1. der is incised and the detrusor muscle fibers are Configuration of the three trocars positioning: A for 12 mm optical trocar, encountered. Using a combination of blunt and B for 12 mm right trocar, C for 5 mm left trocar. sharp dissection, the intramural ureter is separated from the surrounding detrusor muscle and down to the bladder mucosa. Prior to complete detachment of the cuff, a 15 cm 3-0 barbed stay suture is placed at the superior margin of the planned cystotomy to provide traction during subsequent closure of the cystotomy. Bladder cuff is excised through monopolar scissors. At this point, after traction on the previously placed stay suture, the same barbed suture is used to close the first layer of the cystotomy. A second 3-0 barbed suture is then used to close a second imbricating layer (Figure 2). The bladder is checked to be water-tight by instilling 120 cc or more of irrigation via the Foley catheter. A perivesical drain is placed and Figure 2. the specimen is entrapped and extracted intact Sequential surgical steps of bladder cuff excision, by low paramedian transverse abdominal inciplacement of stay suture and subsequent cystotomy. sion in the ipsilateral lower quadrant of the abdomen. Patients with bilateral tumor, tumor with node metastasis or bladder carcinoma, adenocarcinoma and squamous cell carcinoma, simultaneous pelvis tumor were excluded from the study.

RESULTS

A total of 50 patients (37 males, 13 females) underwent to LNU performed with our described technique. All cases were completed uneventfully without conversion to open surgery or patient repositioning. Mean age was 67 years old (range 58-83 years), mean BMI was 24.7 kg/m2 (range 23.1-27.8). The mean operative time was 168 minutes (range: 132-215 min), estimated blood loss was 75 mL (range 50-125 mL), mean length of hospital stay was 3 days (range: 2-8 days). There were no intraoperative complications while four late complications occurred (two grade IIIb and two grade II according to Clavien-Dindo classification, incisional hernias, and fever respectively). No open conversion was required,

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Laparoscopic nephroureterectomy with three trocars

Table 1. Patients’ demographic and pathological characteristics. N° patient Mean age (range) Sex BMI (range) Side Tumor site

TNM staging

Grade Surgical margins Lymph node

50 67 (58-83) Males Females Right Left Renal pelvis Ureter Mean tumor size

37 13 24.7 (23.1-27.8) 24 26 29 21 3.3 (2.7 - 5.2)

pT1 pT2 pT3

12 17 21

Low grade High grade

12 38

Negative Positive

50 0 3.4 (1-5)

and no blood transfusion needed. Regarding postoperative pathology (Table 1), 29 tumors were in the renal pelvis with a mean diameter of 3.9 cm (range: 3.1-5.2). The other twenty-one were localized as follows: 14 in the proximal ureter and the remaining 7 in the distal ureter, with a mean diameter of 2.9 cm (range: 2.7-3.2). There were no positive margins in any patients. Lymph node dissection was performed in 6 patients (16%) according to the pelvic and abdominal CT scan findings. Of those patients who underwent a lymph node dissection, the median lymph node count was 3.4 (range: 1-5). The pathologic stage was T1 in 12 patients, T2 in 17 patients, and T3 in 21 patients. The tumor grade was low in 12 patients and high in 38 patients. No concomitant carcinoma in situ was found. The median follow-up duration was 41 months (range: 9-62 months). At the first cystoscopy examination (3 months after surgery), we observed that the ureteral orifice of the affected side was absent in all the patients. No patients have presented with evidence of local or secondary bladder recurrence and none of the patients was shown to have stone formation at the routine postoperative follow-up cystoscopy. Moreover, at CT scan study (performed every 6 months for the first 24 months, and then yearly) no distant metastases were reported.

DISCUSSION

During the past twenty years, due to the widespread diffusion of laparoscopy and the development of new devices, LNU has become a feasible and safe mini-invasive procedure for the treatment of UTUC (15, 16). When compared to open RNU, LRN has shown overall remarkable benefits in terms of blood loss, perioperative pain, hospital stay and faster convalescence (17-19). Several minimally invasive surgical procedures have been described regarding nephroureterectomy, particularly focusing on distal ureterectomy and bladder cuff excision

management. It is still under debate which must be considered the optimal technique, with several approaches described such as traditional open trans vesical (stripping, detachment), endoscopic (transurethral resection of ureteral orifice, TUR) or laparoscopic extravesical. Open excision, through a Gibson, low midline or Pfannesteil incision during LNU, is still the procedure of choice for ensuring the complete bladder cuff excision in terms of oncological principles, but its main drawback is the requirement of a larger incision in comparison to the one needed as the extraction site. TUR, known as “pluck” technique, can be used in patients with proximal tumor and absence of concomitant bladder disease (20, 21); it avoids the need for an extra incision with a shorter operative time compared with open excision (22). Several concerns about the chance of extravesical space tumor seeding have caused the sequential decreasing use of this technique (23). The stripping technique, using a ureteral catheter, can intussuscept the ureter into the bladder; then, the ureteral orifice is excised cystoscopically with a Collins knife (14). This procedure is contraindicated in the presence of ureteral tumor because of the potential tumor seeding. The laparoscopic transvesical technique describes the placement of two transvesical laparoscopic ports and subsequently of an endoloop around the ureteral orifice, creating a closed urothelium with an en bloc removal of specimen. The disadvantages are represented by the difficult learning curve and the need for the patient repositioning for the nephrectomy surgical time (15). Regarding pure laparoscopic techniques, the extravesical stapling technique has a shorter operative time and avoids incision into the urinary tract. However, this procedure has been associated with a higher risk of positive surgical margins and local recurrence due to the inadequate bladder cuff resection (24), as well as an increased risk of stone formation (25). Recently, a new pure laparoscopic technique has been described, involving the use of a bulldog clamp applied distal to the tent shaped ureteral orifice and bladder cuff (26). The advantage of this approach is the en bloc removal without tumor spillage, however the use of the bulldog clamp does not ensure the direct visualization of the ureteral orifice and necessitates the addition of an extra port. Regarding robot assisted laparoscopic nephroureterectomy (RALNU), Hemal et al. firstly described their technique for successful performance of robotic nephroureterectomy with bladder cuff excision, without patient repositioning and robot redocking (27). The authors concluded that all procedures were performed successfully without complications, and with excellent short-term oncological outcomes. Veccia et al. in a systematic review and meta-analysis compared robotic nephroureterectomy with open, laparoscopic, and hand-assisted ones in over 87.000 patients; the authors highlight how the robotic approach offers advantages in terms of hospital stay, peri and post-operative complications, blood loss and transfusion compared to the open NU without compromising oncological outcomes; these advantages are on the other hand comparable between robotic and laparoscopic procedures (28, 29). Our technique is a simple modificaArchivio Italiano di Urologia e Andrologia 2022; 94, 1

Y. Al Salhi, A. Fuschi, A. Martoccia, et al.

tion of the pure laparoscopic RNU placing the ports sites in a new more ergonomic and easier position in order to perform the distal ureterectomy and bladder cuff excision without the disadvantage of port or patient repositioning. Dissection of the intramural part represents a difficult step of the RNU because of several risks during the excision of the bladder cuff, such as tumor spillage or contralateral ureteric orifice injury. However, the association between the laparoscopic magnified view and the use of laparoscopic instruments leads to a careful dissection under direct vision of the urothelium at risk away from the detrusor muscle. We used this surgical technique for both proximal and distal ureteric tumor localization without reporting any injury of the tumor site during dissection, thanks to the combination of blunt and sharp dissection, separating the intramural ureter from the surrounding detrusor muscle and down to the bladder mucosa and utilizing cold scissors after placing the stay suture. However, suturing during laparoscopy is not easy, but, in our technique, only two stitches are required in order to secure the bladder and ensuring the closure of the urinary tract during the whole procedure. In the present study, we performed an en-bloc bladder cuff excision with clear surgical margins for all cases. Shoma described the use of a purse-string suture in order to secure the bladder, but the author does not recommend this technique for distal ureter UTUC (30). In the present study we treated 7 distal ureter UTUCs (14%) that did not show evidence of local and bladder recurrence at a mean follow-up of 38 months (range: 661 months). Main limitations of the study included the small number of patients. Points of strength of the present investigation were the prospective study design, the long-term followup (38 months), all procedures performed by a single experienced surgeon, the inclusion of all localization sites of UTUCs (rarely reported in literature). In our opinion, the improvement of this purely laparoscopic technique is to ensure the reduction of surgical trauma, hospital stay and estimated blood loss concurrently with the same oncologic outcomes.

CONCLUSIONS

In our study the described technique was related to a significant reduction in terms of operative time and length of hospital stay, with a faster patients’ recovery and no peri and postoperative complications. The technique enabled complete LNU without patient or port repositioning. Our study reported successful operative and oncological outcomes with a long-term follow-up. Major limit of this technique is the need of an advanced laparoscopic skill, but the port setup presented gives maximum maneuverability and good visual field in both upper and lower urinary tract surgery without requirement of extra patient or port repositioning. This technique appears to be safe and feasible; however, studies with longer follow-up periods and larger patient cohorts are required to confirm our findings.

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

REFERENCES

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Laparoscopic nephroureterectomy with three trocars

19. Waldert M, Remzi M, Klingler HC, et al. The oncological results of laparoscopic nephroureterectomy for upper urinary tract transitional cell cancer are equal to those of open nephroureterectomy. BJU Int. 2009; 103:66-70.

25. Baughman SM, Sexton W, Bishoff JT. Multiple intravesical linear staples identified during surveillance cystoscopy after laparoscopic nephroureterectomy. Urology. 2003; 62:351-56.

20. Abercrombie GF, Eardley I, Payne SR, et al. Modified nephroureterectomy: long-term follow-up with particular reference to subsequent bladder tumors. Br J Urol. 1988; 61:198-200.

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21. Palou J, Caparros J, Orsola A, et al. Transurethral resectionof the intramural ureter as the first step of nephroureterectomy. J Urol. 1995; 154:43-44.

27. Hemal AK, Stansel I, Babbar P, Patel M. Robotic-assisted nephroureterectomy and bladder cuff excision without intraoperative repositioning. Urology 2011; 78:357-64.

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23. Arango O, Bielsa O, Carles J, et al. Massive tumor implantation in the endoscopic resected area in modified nephroureterectomy. J Urol. 1997; 157:1839-1844. 24. Matin SF, Gill IS. Recurrence and survival following laparoscopic radical nephroureterectomy with various forms of bladder cuff control. J Urol. 2005; 173:395-400.

29. Mourmouris P, Argun OB, Tzelves L, et al. Is robotic radical nephroureterectomy a safe alternative to open approach: The first prospective analysis. Arch Ital Urol Androl. 2021; 93:408-11. 30. Shoma AM. Purse-string technique for laparoscopic excision of a bladder mucosal cuff in patients with transitional cell carcinoma of the upper urinary tract: initial report with intermediate follow-up. BJU Int. 2009; 104:1505-9.

Correspondence Yazan Al Salhi yazan5585@gmail.com Andrea Fuschi andrea.fuschi@uniroma1.it Alessia Martoccia martoccia.alessia@gmail.com Gennaro Velotti gennaro.vel88@gmail.com Paolo Pietro Suraci spaolopietro@gmail.com Silvio Scalzo silvioscalzo@hotmail.it Onofrio Antonio Rera onofrioantonio.rera@uniroma1.it Alice Antonioni alice.antonioni@gmail.com Fabio Maria Valenzi fabiovalenzi@gmail.com Giorgio Bozzini gioboz@yahoo.it Antonio Carbone antonio.carbone@uniroma1.it Antonio Luigi Pastore, MD (Corresponding Author) antopast@hotmail.com Urology Unit, Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, Sapienza University of Rome, 04100 Latina, Italy

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

DOI: 10.4081/aiua.2022.1.12

ORIGINAL PAPER

Does routine intraoperative Double J stent insertion avoid urine leakage after open partial nephrectomy? Efe Bosnali 1, Ozdal Dillioglugil 1, Kerem Teke 1, Hasan Yilmaz 1, Busra Yaprak Bayrak 2, Ali Kemal Uslubas 1, Ibrahim Erkut Avci 1, Omer Burak Argun 3, Onder Kara 1 1 Kocaeli

University, School of Medicine, Department of Urology, Kocaeli, Turkey; University, School of Medicine, Department of Pathology, Kocaeli, Turkey; 3 Acibadem Mehmet Ali Aydinlar University, Department of Urology, School of Medicine, Istanbul, Turkey. 2 Kocaeli

Summary

Objective: To evaluate the impact of Double J stent (DJS) insertion during open partial nephrectomy (OPN) on postoperative prolonged urinary leakage. Materials and methods: A retrospective study was made in consecutive cases of OPN performed between 2002 and 2020 for localized kidney tumors at our tertiary center. Urinary leakage was defined as drainage > 72 hours after surgery by biochemical analysis consistent with urine or radiographic evidence of urine leakage. The patients were divided into two groups according to intraoperative DJS placement, and compared regarding clinicopathologic characteristics, perioperative and postoperative outcomes. Univariate and multivariate logistic regression analyses were performed to determine the factors associated with urinary leakage after the operation. Results: Review of records identified 182 patients who were included in the study. In 73 (40%) patients PN was performed without insertion of a DJS. Thus, 109 (60%) of patients had a DJS inserted. Apart from higher preoperative eGFR values among patients with DJS (96.6 vs. 94.3 mL/min/1.73 m²; p = 0.03), demographic characteristics were similar between groups. The two groups were not different regarding perioperative, postoperative and clinicopathologic outcomes. Patients with DJS had longer ischemia times (31 vs. 23 min; p = 0.02) and longer length of stay (6 vs. 5 days; p = 0.04). Urinary leakage was seen in 7.6% (n = 14) of all patients and it did not differ according to DJS placement (DJS+ 9.2 vs. DJS- 5.5%; p = 0.41). On multivariate analysis, the tumor nearness to the collecting system was the sole independently significant factor (p = 0.04) predicting postoperative urine leak. Conclusions: Routine intraoperative DJS insertion during OPN does not appear to reduce the probability of postoperative urine leak.

KEY WORDS: Kidney tumor; Double J stent; Urine leakage; Partial nephrectomy. Submitted 5 February 2022; Accepted 10 February 2022

INTRODUCTION

Kidney tumors are the third most common type of cancer among the urological malignancies and constitute 23% of adult cancers (1). Following rapid developments in imaging techniques and their more widespread use, incidental detection of renal tumors has increased to

60% in some reports (2). Increased diagnosis of earlystage, incidental renal tumors in tandem with advances in surgical techniques preventing ischemic renal damage and current oncologic outcomes equivalent to the results of radical nephrectomy (RN) at medium-long term, have increased interest in partial nephrectomy (PN) worldwide. However, the risk of postoperative complications is higher in patients who have undergone PN compared to RN (3). Among these, postoperative urine leakage is a clinically important complication, adversely affecting patient recovery, and is reported to occur in 0.8% to 15.2% of the patients (4-7). Inadequate repair of a collection system during deep layer renorraphy is the main cause of urine leakage. Ureteral catheterization during PN has been applied to obviate this risk and to visualize an opened renal calyx for closure and impact on urinary leakage after PN has been fully established (7-9). For each patient Double J stent (DJS) ureteral catheterization in our clinic is at the surgeon's own discretion. In this study, the usefulness of DJS placement in detecting and preventing urinary leakage during open PN (OPN) was assessed retrospectively.

MATERIALS

AND METHODS

Patients After the ethical committee board approval, we designed a retrospective study for OPN patients performed between 2002 and 2020 for localized RCC at our center. Due to limited access to the previous hospital patient record system, patients who underwent OPN between 1996 and 2001 were excluded. The analysis was done with a total of 182 patients. Pathological and clinical variables Patient demographics included age, gender, comorbidities (presence of Diabetes Mellitus and hypertension), estimated glomerular filtration rate (eGFR), American Society of Anesthesiology (ASA) score, incidence of solitary kidney, and Charlson Comorbidity Index (CCI). To assess tumor complexity RENAL score was used, which considers the size, location, depth, and exophytic characteristics of the tumor. The RENAL score is categoNo conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

Use of Double J stent during partial nephrectomy

rized as low score (4-6), moderate score (7-9), and high score (10-12). Tumor characteristics considered included tumor size, pathological T stage, histology (including subtype), and Fuhrman-ISUP Grade. Nuclear tumor grading was performed using Fuhrman-ISUP nuclear grading system and grades were classified as low grade (1-2) and high grade (3-4). All histological specimens were analyzed by our institution’s dedicated urological pathologists. Main intraoperative parameters such as insertion of DJS, operation time, cold and warm ischemia time (CIT, WIT), estimated blood loss (EBL), intraoperative blood transfusion and complication rates were recorded. Postoperative variables included were 30-day postoperative complication rate, length of hospital stay, and 30-day readmission rate. Clavien-Dindo classification system (10) was used for grading complications that were characterized as minor complications (Clavien 1-2) and major complications (Clavien 3-5). Preoperative and postoperative functional results were assessed by using serum creatinine, and MDRD formula to calculate eGFR (11). eGFR preservation was defined as follow-up postoperative eGFR divided by preoperative eGFR x 100. Chronic kidney disease (CKD) was defined as GFR < 60 mL/min/1.73m2. Surgical technique In most patients, DJS was inserted immediately after induction in the lithotomy position. Under the cystoscopy guidance 4.8 French DJS placement through guidewire was performed under fluoroscopic guidance. In a small proportion of these patients DJS insertion was performed immediately after PN at the surgeon’s discretion. In the remaining patients PN was performed without insertion of DJS. We used extraperitoneal flank approach. Ice slush was used for parenchymal cooling in almost all cases. In a small proportion of the cases non-ischemic PN was performed without clamping the renal artery. During PN, all renal tumors were excised with sufficient resection margin. The defect was closed with two layers of suture method, one to close the bleeding vessels and collecting system, the other to approximate the parenchyma over reconstructed fat pad (12). A single surgical drain (Jackson-Pratt drain) was inserted at the operative site. In patients who had intraoperative DJ stent placement, urethral catheter was removed at postoperative (PO) 5th day. In these patients, the Jackson-Pratt was removed next day if the drain output was not increased after a day period of ureteral urine reflux within the DJ stent during active voiding. This was a kind of DJ stent reflux test developed by one of us (OD) to make sure that the collecting system was completely closed. In other cases, the Jackson-Pratt was removed on the 3rd PO day, provided that the output was less than 50 cc per 24 hours. Outcomes Urinary leakage was defined as a biochemical analysis consistent with urine persisting for more than 72 hours and/or a radiology finding suggestive of urine leakage. As a routine procedure, in patients with no complications, DJSs were removed from the patients on the third week after surgery under local anesthesia. For the purposes of this study, according to intraoperative DJS placement, the

patients were divided into two groups. Perioperative postoperative outcomes, and clinicopathologic characteristics were compared between the two groups (DJS+ vs. DJS-). Furthermore, to determine the variables associated with urinary leakage after OPN, univariate and multivariate logistic regression analyses were performed. Statistical analysis For variables with normal distribution, the data are expressed as mean ± SD. Chi-squared test was used to compare categorical variables. For non-normal distributed variables, we presented the data as median [interquartile range (IQR)] and compared the respective groups with Mann-Whitney U-test. All analyzes were made within 95% confidence interval and the p < 0.05 value was accepted as significant. For the analysis SPSS v23 (IBM SPSS Statistics, Armonk, NY, USA) was used.

RESULTS

In the analysis, a total of 182 patients were included. OPN was technically successful in all cases using a retroperiTable 1. Patient’s demographics, tumor characteristics, and surgical outcomes. Variables Age years; mean (± SD) Male; n (%) White race; n (%) BMI; mean (± SD) CCI; med (IQR) ASA; med (IQR) Diabetes; n (%) Hypertension; n (%) Prior abdominal surgery; n (%) Solitary kidney; n (%) Pre-op eGFR; med (IQR) R.E.N.A.L score; med (IQR) Tumor size, cm; mean (±SD) Surgical approach; n (%) Retroperitoneal Operation time, min; med (IQR) Double-J stent; n (%) Routinely (Pre-PN) As required (Post-PN) None EBL, ml.; med (IQR) Technique of ischemia; n (%) Warm Cold Zero Ischemia time, minutes; mean (±SD) Intraoperative complication; n (%) Intraoperative transfusion; n (%) Urine leak; n (%) Length of stay, days; med (IQR) Follow up times, months.; med (IQR)

Total open partial nephrectomy (n = 182) 54.4 (± 10.8) 79 (43.4) 182 (100) 28.3 (± 5.3) 1 (0-1) 2 (2-2) 51 (28) 90 (49.5) 48 (26.4) 6 (3.3) 96 (82.4-105.9) 6 (5-8) 3.1 (± 1.2) 180 (98.9) 240 (180-240) 109 (60) 95 (52.3) 14 (7.7) 73 (40) 400 (300-600) 15 (8.2) 161 (88.5) 6 (3.3) 26.1 (± 7.7) 10 (5.5) 52 (28.6) 14 (7.6) 5 (4-7) 42 (21.3-84.6)

ASA: American Society of Anesthesiologists; BMI: Body mass index; CCI: Charlson comorbidity index; eGFR: Estimated glomerular filtration rate; EBL: Estimated blood loss; IQR: Interquartile range; OPN: Open partial nephrectomy; SD: Standard deviation.

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Table 2. Comparison of patients and tumor characteristics between pre-PN Double-J insertion and no insertion populations. Age, years; mean (± SD) Male; n (%) BMI; mean (±SD) CCI; med (IQR) ASA; med (IQR) Diabetes; n (%) Hypertension; n (%) Prior abdominal surgery; n (%) Solitary kidney; n (%) Pre-op eGFR; med (IQR) Tumor size, cm; mean (± SD) Side, right; n (%) Cystic lesion; n (%) Hilar location; n (%) R.E.N.A.L score; med (IQR) R.E.N.A.L complexity; n (%) Simple (4-6) Intermediate (7-9) Complex (10-12) (R)adius, max diameter in cm; n (%) ≤4 > 4 but < 7 ≥7 (E)xophytic/Endophytic; n (%) ≥ 50% < 50% Entirely endophytic (N)earness of the tumor to pelvicalyceal system or renal sinus; mm ≥7 > 4 but < 7 ≤4 (L)ocation relative to the polar lines, points; n (%) 1 2 3

DJS+ (n = 109) 53.8 (±10.9) 59 (54.1) 28.1 (±5.8) 1 (0-1) 2 (2-2) 33 (30.3) 55 (50.4) 27 (24.8) 3 (2.8) 96.6 (87.2-107.3) 3.2 (±1.1) 67 (60.5) 30 (33) 2 (2.3) 6 (5-8)

DJS- (n = 73) 55.3 (±10.8) 44 (60.3) 28.7 (4.5) 1 (0-2) 2 (2-2) 18 (24.7) 35 (47.9) 21 (28.8) 3 (4.1) 94.3 (78.8-101) 3 (±1.3) 43 (58.9) 16 (33.3) 2 (4.5) 5 (5-7)

P value 0.38 0.44 0.54 0.09 0.8 0.5 0.8 0.6 0.6 0.03 0.26 0.7 1 0.6 0.26

53 (60.2) 33 (37.5) 2 (2.3)

28 (65.1) 15 (34.9) 0

0.5

87 (80.6) 20 (18.5) 1 (0.9)

59 (83.1) 20 (15.5) 1 (0.6)

0.8

42 (47.7) 41 (46.6) 5 (5.7)

25 (58.1) 16 (37.2) 2 (1.5)

0.5

41 (46.6) 26 (29.5) 21 (23.9)

18 (41.9) 15 (34.9) 10 (23.3)

0.8

45 (51.1) 21 (23.9) 22 (25)

26 (60.5) 14 (32.6) 3 (2.3)

0.04

ASA: American Society of Anesthesiologists; BMI: Body mass index; CCI: Charlson comorbidity index; eGFR: Estimated glomerular filtration rate; IQR: Interquartile range; OPN: Open partial nephrectomy; SD: Standard deviation.

toneal approach. Of these, 95 (52.3%) had DJS insertion immediately after induction of general anesthesia, 14 (7.7%) had DJS inserted immediately after performance of the OPN while in the other 73 (40%) patients PN was performed without insertion of a DJS. Thus, 109 (60%) of patients had a DJS inserted. Table 1 summarizes the main demographical and clinical outcomes for the entire series. Apart from higher preoperative eGFR values among patients with DJS+ compared to the DJS- (96.6 vs 94.3 mL/min; p = 0.03), demographic variables were similar (Table 2). No statistically significant differences were seen in RENAL nephrometry score (p = 0.26) and tumor size (p = 0.26). Tumors in the DJS+ group presented with a high L score (p = 0.04). Between the two groups estimated blood loss (p = 0.12),

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

intraoperative complication (p = 0.71), and transfusion rates (p = 0.4) were not significantly different (Table 3). Patients in the DJS+ group had significantly longer ischemia times (31 vs. 23 min; p = 0.02). In addition, DJS+ group patients had a longer length of stay due to reflux test (6 vs. 5 days; p = 0.04). Postoperative (p = 0.74) complication rates were similar between groups (p = 0.74) (Table 3). Urinary leakage was seen in 7.6% (n = 14) of all patients, and it did not differ according to DJS placement (DJS+ 9.2 vs. DJS- 5.5%; p = 0.41). On univariate analysis, neither DJS stenting rates nor urine leakage rates were associated with distribution of cases by years (Supplementary Table 1). On univariate analysis, RENAL nephrometry score (OR= 1.39; p = 0.04) and tumor nearness (proximity) to the collecting system (p = 0.04) had a significantly higher probability of experiencing urine leak (Table 4) whereas it was observed that intraoperative DJS placement did not have significant effect on urine leak (OR = 1.74; p = 0.36). On multivariate analysis, the tumor nearness to the collecting system was the sole independently significant factor (p = 0.04) predicting postoperative urine leak. Table 3. Comparison of pre-PN Double-J insertion and no insertion populations. Intraoperative variables Operation time, min; med (IQR) EBL, ml.; med (IQR) Ischemia time, min; mean (± SD) Use of hemostatic agents; n (%) Intraoperative complication; n (%) Intraoperative transfusion; n (%) Postoperative variables Length of stay, days; med (IQR) Postoperative transfusion; n (%) ES Units; med (IQR) Need for post-op angioembolisation, n (%) Overall post-op complications; n (%) Major (Clavien-Dindo 3-5) Minor (Clavien-Dindo 1-2) Acute kidney injury; n (%) Readmission for urologic reasons; n (%) < 30 days ≥ 30 days Urine leak; n (%) Malignant disease; n (%) Pathological tumor stage; n (%) T1a T1b T2a T3a Positive surgical margin; n (%) Fuhrman/ISUP grade; n (%) Low FG (1-2) High FG (3-4) Follow up times, months; med (IQR) Latest eGFR; med (IQR) Latest follow up eGFR preservation; % med (IQR)

DJS+ (n = 109)

DJS- (n = 73)

P value

240 (180-240) 400 (300-525) 31 (± 5.9) 11 (10.1) 7 (3.8) 29 (26.6)

220 (180-220) 500 (262-900) 23 (± 7.4) 6 (8.2) 3 (4.1) 23 (31.5)

0.3 0.12 0.02 0.79 0.71 0.4

6 (5-7) 7 (6.4) 2 (1-3) 1 (0.9) 31 (28.4) 6 (5.4) 25 (23) 13 (12) 7 (6.4) 4 (3.6) 3 (2.2) 10 (9.2) 89 (81.7)

5 (4-6) 7 (9.6) 2 (1-2) 1 (1.4) 23 (31.5) 7 (9.4) 16 (22.1) 14 (19.7) 4 (5.4) 3 (4.1) 1 (1.3) 4 (5.5) 56 (80)

0.04 0.57

91 (85) 16 (15) 0 0 4 (3.7)

56 (82.4) 8 (11.8) 1 (1.5) 3 (4.4) 1 (1.4)

68 (80) 17 (20) 27.7 (12.6-53.4) 89 (70.4-102.9)

47 (87) 7 (13) 51 (9.1-113) 83.7 (70.7-96)

93.1 (82.2-99.3)

92.3 (80-99.6)

0.64 0.74 0.16 0.81 0.41 0.84 0.1

0.1 0.36 0.02 0.16 0.94

EBL: Estimated blood loss; ES: Erythrocyte suspension; FG: Fuhrman grade; ISUP: International Society of Urological Pathology; eGFR: Estimated glomerular filtration rate; IQR: Interquartile range; SD: Standard deviation..

Use of Double J stent during partial nephrectomy

Supplementary Table 1. Distribution of urine leakage and DJ stenting by years.

the treatment of small renal tumors (1) and the clinical target is to leave as much functional renal parenchyma as possible, Variables Urine leakage (+) Urine leakage (-) P value DJS (-) DJS (+) P value without obviating the oncological princi14 (7.6%) 168 (92.4%) 73 (40.1%) 109 (59.9%) ples. With increasing surgical experience, Total cases 0.8 0.1 larger and deeper infiltrating lesions were 2002 (n = 1) 0 1 (100) 1 (100) 0 also approached, requiring surgical access 2004 (n = 2) 0 2 (100) 2 (100) 0 to the pelvicalyceal system to ensure ade2006 (n = 4) 0 4 (100) 4 (100) 0 quate margins of tumor resection. 2007 (n = 3) 0 3 (100) 3 (100) 0 Incomplete repair of the collecting system 2008 (n = 9) 1 (11.1) 8 (88.9) 3 (33.3) 6 (66.6) during renorraphy causes urine leak 2009 (n = 7) 0 7 (100) 3 (42.8) 4 (57.2) which most probably results in consider2010 (n = 6) 0 6 (100) 3 (50) 3 (50) able morbidity (14-17). 2011 (n = 9) 1 (11.1) 8 (88.9) 3 (33.3) 6 (66.6) In this study, we evaluated the impact of 2012 (n = 13) 1 (7.7) 12 (92.3) 6 (46.2) 7 (53.8) intraoperative routine DJS placement on 2013 (n = 8) 2 (25) 6 (75) 3 (37.5) 5 (62.5) urinary leakage after OPN. 2014 (n = 11) 2 (18.2) 9 (81.8) 4 (36.3) 7 (63.7) The incidence rate of urine leakage 2015 (n = 15) 2 (13.3) 13 (86.7) 5 (33.3) 10 (66.6) reported after PN varies between institu2016 (n = 14) 0 14 (100) 5 (35.8) 9 (64.2) tions. In the current study, urinary leak2017 (n = 18) 1 (5.6) 17 (94.4) 6 (33.3) 12 (66.6) age occurred in 7.6% of the patients. In 2018 (n = 28) 2 (7.1) 26 (92.9) 8 (29.6) 20 (71.4) early OPN series the rate of urine leakage 2019 (n = 30) 2 (6.7) 28 (93.3) 12 (40) 18(60) was reported to average 6.5%, ranging 2020 (n = 4) 0 4 (100) 2 (50) 2 (50) from 2.1-17% (18, 19). In the new PN series, the rate of urine leakage is around 1-5% (15, 20, 21). The clinical manageTable 4. Logistic regression analysis for predicting urine leakage after partial nephrectomy. ment of urine leakage after PN varies from patient to patient (22). Follow-up with Univariate Multivariate serial imaging options is the most preOR 95 % CI P value OR 95 % CI P value ferred approach. Another option, ureteral Age 1.05 0.97-1.08 0.15 1.02 0.97-1.08 0.34 stent insertion, creates a low-pressure sysFemale Ref tem facilitating urine drainage from the Male 1.02 0.34-3.08 0.96 collection system and that promotes healBMI (continuous variable) 0.93 0.82-1.07 0.35 ing. Patients may need percutaneous Tumor size (per cm) 1.18 0.80-1.74 0.39 drainage or repeat surgical intervention Baseline eGFR (per mL/min/1.73m2) 0.99 0.97-1.02 0.9 when they have complex urine leaks (23). Ischemia time (per min) 1.07 0.82-1.39 0.6 In addition, minimally invasive techPre-op hypertension 1.04 0.38-1.14 0.97 niques are a safe option to resolve urinary Pre-op diabetes mellitus 1.03 0.3-3.4 0.96 leakage after PN. Application of gelatin CCI = 0 Ref sponge (Spongostan®) and N-butyl2 CCI > 0 1 0.33-3 1 cyanoacrylate improves results without R.E.N.A.L score (continuous variable) 1.39 1.00-1.93 0.04 increasing the risk of urinary obstruction, Exophytic/endophytic 0.88 ≥ 50% Ref especially in the cases of persistent urine < 50% 1.19 0.36-3.9 leakage (24). Entirely endophytic 1.69 0.17-16.5 In the present study, preoperative DJS Nearness 0.04 0.04 placement did not significantly reduce the ≥7 Ref Ref incidence of urinary leakage after PN. > 4 but < 7 9.9 1.14-86.5 0.03 9.8 1.14-85.9 0.03 For each patient DJS ureteral catheteriza≤4 13.9 1.5-121.7 0.01 15.7 1.76-140.7 0.01 tion in our clinic is at the surgeon's own Location, relative to polar lines 1 Ref discretion. As described above, preopera2 1.39 0.36-5.3 tive DJS placement was a part of DJS 3 1.47 0.34-6.4 reflux test to make sure that the collecting Double J stent + (vs. -) 1.74 0.52-5.7 0.36 system was completely closed. In patients Estimated blood loss (continuous variable) 1 0.99-1 0.8 who had positive DJS reflux test Ischemia time, (continuous variable) 1.07 0.82-1.39 0.6 (increased drain urine output following Intraoperative transfusion+ 1.98 0.65-6.04 0.2 Foley removal), a new Foley catheter was BMI: Body mass index; CCI: Charlson comorbidity index; eGFR: Estimated glomerular filtration rate. placed again to wait for sufficient time for the self-sealing of the collecting system, during which a number of intervals retroDISCUSSION grade testing pyelography were performed. It was The RCC incidence has increased in the last four decades; observed that use of a DJS, which was usually placed as a beginning from the mid 90's there has been a more rapid treatment when a urinary leak developed, did not prevent increase in diagnosis (13). PN is the preferred method in urinary leakage when applied before surgery. At the same Archivio Italiano di Urologia e Andrologia 2022; 94, 1

E. Bosnali, O. Dillioglugil, K. Teke, et al.

time, although not statistically significant, DJS inserted patients tended to have more urinary leakage compared to the group that was not inserted although the difference was not significant. It could be suggested that making a preoperative clinical decision to place a DJS, based on surgeon preference and tumor complexity, may create a bias in the analysis. However, we believe that there is no such bias because of both groups are comparable in terms of patient and tumor characteristics. During PN routine ureteral catheterization has been used to reduce the risk of urine leakage in open, laparoscopic, and robotic cases (7, 9, 25-27). In these studies, it was reported that ureteral catheterization did not reduce the risk of urinary leakage after PN. Common feature for these studies, and the difference between these and our study, was that if there was no evidence of urinary leakage, the ureteral catheter was generally removed within two days postoperatively. As far as we know, we report the first study to evaluate the impact of intraoperatively inserted long term DJS on urinary leakage after PN. Our results showed that OPN patients who had a DJS inserted can safely be discharged because the rate of urine leakage is similar in these patients compared to patients who did not have. We found that urine leakage following OPN was associated with tumor characteristics, rather than DJS insertion, consistent with previous reports (5, 28). In our multivariate analysis, nearness of the tumor to the collecting system was the sole independently significant factor predicting urine leakage. This is intuitively reasonable and is thus not an unexpected result. In a considerable proportion of the operations it is not possible to completely remove these tumors without entering the collecting system; inherently, likelihood of later urine leakage increases in such cases. This relationship has been reported previously (15, 29). Our study does have some limitations, including its retrospective, non-randomized, single institution design. In addition, as there was a small number of events, multivariable analysis was limited. Therefore, our results need to be verified in a large, prospective, multi-institutional studies. In addition, our findings may have limited applicability to other settings because OPN was performed using a single technique. In this context, the effect of surgical technique should also be evaluated in any future study. Despite these limitations, and although generally not used routinely and mostly used only for therapeutic purposes in the presence of urinary leak, we think our results answer the question of the association between routine DJS application in OPN and the risk of urinary leakage.

CONCLUSIONS

Routine intraoperative DJS insertion during PN does not appear to reduce the probability of postoperative urine leak. It causes additional costs and does not eliminate the risk of urine leakage but may provide a reasonable means to test urine leakage (DJS reflux test) which allows for safety Foley catheter reinsertion before the patient had been discharged.

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

REFERENCES

1. Ljungberg B, Albiges L, Abu-Ghanem Y, et al. European Association of Urology Guidelines on Renal Cell Carcinoma: The 2019 Update. Eur Urol. 2019; 75:799. 2. Volpe A, Panzarella T, Rendon RA, et al. The natural history of incidentally detected small renal masses. Cancer. 2004; 100:738. 3. Mir MC, Derweesh I, Porpiglia F, et al. Partial nephrectomy versus radical nephrectomy for clinical T1b and T2 renal tumors: a systematic review and meta-analysis of comparative studies. Eur Urol. 2017; 71:606. 4. Lesage K, Joniau S, Fransis K, Van Poppel H. Comparison between open partial and radical nephrectomy for renal tumours: perioperative outcome and health-related quality of life. Eur Urol. 2007; 51:614. 5. Potretzke AM, Knight BA, Zargar H, et al. Urinary fistula after robot-assisted partial nephrectomy: a multicentre analysis of 1 791 patients. BJU Int. 2016; 117:131. 6. Spana G, Haber GP, Dulabon LM, et al. Complications after robotic partial nephrectomy at centers of excellence: multi-institutional analysis of 450 cases. J Urol. 2011; 186:417. 7. Zargar H, Khalifeh A, Autorino R, et al. Urine leak in minimally invasive partial nephrectomy: analysis of risk factors and role of intraoperative ureteral catheterization. Int Braz J Urol. 2014; 40:763. 8. Bove P, Bhayani SB, Rha KH, et al. Necessity of ureteral catheter during laparoscopic partial nephrectomy. J Urol. 2004; 172:458. 9. Yoo S, You D, Jeong IG, et al. Does ureteral catheter insertion decrease the risk of urinary leakage after partial nephrectomy in patients with renal cell carcinoma? Clin Genitourin Cancer. 2017; 15:707. 10. Clavien PA, Barkun J, de Oliveira ML, et al. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg. 2009; 250:187. 11. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999; 130:461. 12. Ozkan L, Saribacak A, Taneri C, et al. A new technique-"lipocorticoplasty"-for the closure of partial nephrectomy defects and its comparison with the standard technique. Int Urol Nephrol. 2011; 43:737. 13. Chow WH, Devesa SS, Warren JL, Fraumeni JF, Jr. Rising incidence of renal cell cancer in the United States. JAMA. 1999; 281:1628. 14. Kim FJ, Rha KH, Hernandez F, et al. Laparoscopic radical versus partial nephrectomy: assessment of complications. J Urol. 2003; 170:408. 15. Tanagho YS, Kaouk JH, Allaf ME, et al. Perioperative complications of robot-assisted partial nephrectomy: analysis of 886 patients at 5 United States centers. Urology. 2013; 81:573 16. Permpongkosol S, Link RE, Su LM, et al. Complications of 2,775 urological laparoscopic procedures: 1993 to 2005. J Urol. 2007; 177:580. 17. Wheat JC, Roberts WW, Hollenbeck BK, et al. Complications of laparoscopic partial nephrectomy. Urol Oncol. 2013; 31:57. 18. Campbell SC, Novick AC, Streem SB, et al. Complications of nephron sparing surgery for renal tumors. J Urol. 1994; 151:1177. 19. Steinbach F, Stockle M, Muller SC, et al. Conservative surgery of

Use of Double J stent during partial nephrectomy

renal cell tumors in 140 patients: 21 years of experience. J Urol. 1992; 148:24.

tomy. Case report and review of the literature. Arch Ital Urol Androl. 2020; 92:200

20. Kundu SD, Thompson RH, Kallingal GJ, et al. Urinary fistulae after partial nephrectomy. BJU Int. 2010; 106:1042.

25. Haber GP, Gill IS. Laparoscopic partial nephrectomy: contemporary technique and outcomes. Eur Urol. 2006; 49:660.

21. Minervini A, Vittori G, Antonelli A, et al. Open versus roboticassisted partial nephrectomy: a multicenter comparison study of perioperative results and complications. World J Urol. 2014; 32:287.

26. Kaouk JH, Hillyer SP, Autorino R, et al. 252 robotic partial nephrectomies: evolving renorrhaphy technique and surgical outcomes at a single institution. Urology. 2011; 78:1338.

22. Meeks JJ, Zhao LC, Navai N, et al. Risk factors and management of urine leaks after partial nephrectomy. J Urol. 2008; 180:2375.

27. Gill IS, Desai MM, Kaouk JH, et al. Laparoscopic partial nephrectomy for renal tumor: duplicating open surgical techniques. J Urol. 2002; 167:469

23. French DB, Marcovich R. Fibrin sealant for retrograde ureteroscopic closure of urine leak after partial nephrectomy. Urology. 2006; 67:1081.

28. Peyronnet B, Seisen T, Oger E, et al. Comparison of 1800 Robotic and open partial nephrectomies for renal tumors. Ann Surg Oncol. 2016; 23:4277.

24. De Concilio B, Vedovo F, Mir MC, et al. Gelatin sponge (Spongostan(R)) and N-butyl-2-cyanoacrylate: Utility on percutaneous treatment of persistent urinary leakage after partial nephrec-

29. Ficarra V, Bhayani S, Porter J, et al. Predictors of warm ischemia time and perioperative complications in a multicenter, international series of robot-assisted partial nephrectomy. Eur Urol. 2012; 61:395.

Correspondence Efe Bosnali, MD efebosnali415@gmail.com Ozdal Dillioglugil, MD odillioglugil@gmail.com Kerem Teke, MD drtekekerem@gmail.com Hasan Yilmaz, MD hasanyilmazm.d@gmail.com Ali Kemal Uslubas, MD ali.kemalu@gmail.com Ibrahim Erkut Avci, MD erkutavci@gmail.com Onder Kara, MD (Corresponding Author) onerkara@yahoo.com Kocaeli University, School of Medicine, Department of Urology, Kocaeli (Turkey) Busra Yaprak Bayrak, MD bsr2004_86@hotmail.com Kocaeli University, School of Medicine, Department of Pathology, Kocaeli (Turkey) Omer Burak Argun, MD drburakargun@gmail.com Acibadem Mehmet Ali Aydinlar University, Department of Urology, School of Medicine, Istanbul, (Turkey)

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

DOI: 10.4081/aiua.2022.1.18

ORIGINAL PAPER

Predictive value of PSA density in the diagnosis of prostate cancer in lebanese men Ali Msheik 1, Mohamed Mohanna 2, Ali Mhanna 3, Ali Kanj 4, Mohamad Moussa 5, Assaad Mohanna 4 1 PGY-1

Neurosurgery, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon; Internal Medicine, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon; 3 PGY-1 General Surgery, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon; 4 Radiology Department, Bahman Hospital, Beirut, Lebanon; 5 Chairman of General Surgery and Urology Department, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon. 2 PGY-1

Summary

Objective: Being the second most common cancer in men, prostate cancer detection relies on laboratory tests, imaging, and surgical procedures, although biopsy remains the mainstay in diagnosis of prostate cancer. No clear cut-off of prostate specific antigen density (PSAD) for suspecting prostate cancer has been established in the Lebanese population. Our primary objective was to evaluate the diagnostic strength of the PSAD value versus total prostate specific antigen (tPSA) level in the Lebanese men in correlation with biopsy outcome to avoid unnecessary prostate biopsy. Methods: A retrospective study of 347 patients with history of prostate biopsy done for cancer suspicion included tPSA, prostate volume, and prostate density values and results of prostate biopsy. Data was collected from Bahman hospital and statistical analysis of the mean values of tPSA, prostate volume and PSAD in different age groups was done. Significance of the results was tested using. Results: On average, patients with negative biopsies were younger and they had lower tPSA levels, lower PSAD values and larger prostate volume compared to patients with positive biopsies. A PSAD cutoff of 0.185 ng/ml2 revealed the highest predictive strength for prostate cancer (6 times risk) compared with other parameters. These findings were mainly referred to patients with PSA > 10 ng/ml. Conclusions: A multifactorial approach must be conducted including all parameters in order to decide upon the need for prostate biopsy. PSAD proved to be a good marker in favor or against a prostate biopsy with a cut-off of 0.185 ng/ml2, especially in patients with tPSA level higher to 10 ng/ml. A multicenter study was recommended for better and more reliable results and more precise cut-offs.

KEY WORDS: PSAD; Prostate biopsy; PSA; Age; Prostate volume. Submitted 22 September 2021; Accepted 15 October 2021

INTRODUCTION

Normal ranges of prostate specific antigen (PSA) and prostate volume vary among ethnicities and communities at different geographic locations and of different socioeconomic statuses (3). Therefore, pathological PSA and prostate volume values might as well vary between ethnicities (3). In the Lebanese men, prostate cancer incidence is expected to reach 69 cases per 100000 by 2020, the highest

prevalence in the region (4). Prostate cancer is expected to become the most common cancer in males in 2020 (4). A general goal of this study was to estimate the level at which PSA value and prostate volume value are indicative for a biopsy procedure in the Lebanese population. The primary objective was to evaluate the diagnostic strength of prostate specific antigen density (PSAD) versus PSA level in the Lebanese men in correlation with biopsy outcomes to avoid unnecessary prostate biopsy. The secondary objectives of the study were: 1) to identify age-related cutoffs which may be used in the clinical practice for the diagnosis of prostate cancer, 2) to identify a cutoff for the PSA level which may be used in the clinical practice for the diagnosis of the prostate cancer, 3) to identify a cutoff for the PSAD level which may be used in the clinical practice for the diagnosis of the prostate cancer.

METHODS Study design and patient population This study was a retrospective chart review, conducted in Bahman hospital, including patients who were screened for prostate cancer and underwent prostate biopsy. All patients were admitted to Bahman hospital during the last 15 years, between January 2006 and December 2019. Patients were selected according to predefined inclusion and exclusion criteria (Table 1) and PSA testing was primarily used to screen for prostate cancer. Accordingly, patients were chosen, and data was collected and submitted for statistical calculation and further analysis. The protocol was reviewed and granted written study approval from the research committee in the Lebanese University, and approval from the ethical committee of the hospital. The study was conducted in accordance with the US Code of Federal Regulation 45-CFR-46.107, 21-CFR56.107, Good Clinical Practice ICH Section 3 and the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) and all applicable amendments. All participants had a designated code. Records will be stored, and none can access the sheets except the researchers. The sample size was estimated on the assumption of an incidence of prostate cancer in the Lebanese males of No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

PSA density in the diagnosis of prostate cancer

1503 new cases in 2018 and a 5-year prevalence of 3405 according to GLOBOCAN (5). Hence, we estimated a minimum sample size of 10% of the estimated prevalence that is 300 patients who must fulfill the inclusion and exclusion criteria as shown in Table 1. Table 1. Inclusion and exclusion criteria utilized in the study. Inclusion criteria PSA level ≥ 3 ng/ml Transabdominal prostate US result available Histologically confirmed diagnosis of csPca

Exclusion criteria Past diagnosis of prostate cancer Incomplete patient record

Table 2. Prostate volume and density. Mean Median Std. Deviation Minimum Maximum Percentiles

25 50 75

Prostate volume (ml) 59.25 53.00 30.84 12.00 214.00 39.00 53.00 72.00

Density (ng/ml2) 0.56 0.18 1.15 0.04 9.75 0.12 0.18 0.44

Figure 1. Distribution of PSA levels.

Data collection The researchers contacted the “Archive Department” manager at Bahman and set a schedule to reach the medical records and collect the data. An electronic validated database was used in the data collection process. The data includes the following: demographic characteristics (age), laboratory results (PSA ng/ml), transabdominal prostate ultrasound results (prostate volume ml) and histology results (Gleason score). Prostate specific antigen density was calculated by dividing the PSA value by the prostate volume. A Gleason Score ≥ 7 was used to define a clinically significant prostate cancer (csPCa). Statistical analysis Data was analyzed using the SPSS version 22. A descriptive analysis was done, and variables were presented as per their type. The categorical variables were presented as frequency and proportions. The continuous variables were presented as frequency, mean, median and standard deviation. A binary logistic analysis was done to test the factors predicting the biopsy outcome. The dependent variable was “Biopsy outcome”. The correlation was tested between the dependent variable and the secondary variables using the Chi-square and Fisher exact test. In addition, non-parametric tests were used as Kruskas Wallis test and Mann-Whitney test. A statistically significant correlation was set at 5% (p-value less than 0.05).

RESULTS Demographic results The mean age of the patients was 66.2 (± 8.8) with a minimum of 43 years and a maximum of 90 years. The median age was 66 years.

Table 3. Correlation between variables and biopsy outcome.

Age PSA ng/ml Prostate volume (ml) Density (ng/ml2)

Biopsy outcome

Mean

Std. deviation

Benign Prostate cancer Benign Prostate cancer Benign Prostate cancer Benign Prostate cancer

172 175 172 175 172 175 172 175

63.38 69.03 11.47 37.42 64.66 53.92 0.23 0.89

8.30 8.42 11.89 55.93 34.40 25.92 0.30 1.52

Prostate cancer and laboratory values The mean prostate volume was 59.2 (± 30.8) ml with a minimum of 12 ml and a maximum of 214 ml. The median prostate volume was 53 ml. The mean PSAD was 0.56 (± 1.15) ng/ml2 with a minimum of 0.04 ng/ml2 and a maximum of 9.75 ng/ml2. The median prostate density was 0.18 ng/ml2 (Table 2). The mean PSA level was 24.56 (± 42.57) ng/ml with a minimum of 2 ng/ml and a maximum of 394 ng/ml. The median PSA level was 10 ng/ml (Figure 1).

95% Confidence interval for mean Lower bound Upper bound 62.13 64.63 67.77 70.28 9.68 13.26 29.07 45.76 59.48 69.84 50.06 57.79 0.18 0.27 0.66 1.11

Min-max

P value

44-87 43-90 2-100 3.5-394 13-214 12-175 0.04-1.98 0.05-9.75

0.000 0.000 0.003 0.000

Histology results Histology demonstrated that 49.6% of patients had benign prostatic tissue (BPH, prostatitis), 5.2% had low-grade prostate cancer (Gleason score = 6), and 45.2% had clinically significant prostate cancer csPCa (Gleason Score ≥ 7) (Figure 2).

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

A. Msheik, M. Mohanna, A. Mhanna, A. Kanj, M. Moussa, A. Mohanna

patients with benign prostatic tissue (mean = 0.23 ng/ml2) (p < 0.0001). A binary logistic analysis was done to identify the factors predicting the biopsy outcome. The results showed that the biopsy outcome is affected by three variables: patients’ age (p = 0.000), PSA (p = 0.000), and prostate volume (p = 0.000). The logistic analysis showed that the biopsy outcome is at risk times “1” to deviate to be “csPCa” when patient’s age is high, PSA level is high and prostate volume is low.

Figure 2. Distribution of the patients according to biopsy outcome.

Factors affecting the biopsy outcome A statistically significant correlation existed between age, PSA, prostate volume, and PSAD and the biopsy outcome (Mann-Whitney test; p < 0.05) (Table 3). The results showed that age was higher in prostate cancer patients (mean = 69.03 years) in comparison to patients with benign prostatic tissue (mean = 63.4 years) (p < 0.0001); PSA was significantly higher in prostate cancer patients (mean = 37.4 ng/ml) in comparison to patients with benign prostatic tissue (mean = 11.5 ng/ml) (p < 0.0001); prostate volume was significantly higher in patients with benign prostatic tissue (mean = 66.7 ml) in comparison to prostate cancer patients (mean = 53.9 ml) (p = 0.003) and PSAD was significantly higher in prostate cancer patients (mean = 0.89 ng/ml2) in comparison to Table 4. Correlation between age and biopsy outcome.

Biopsy outcome

Benign Prostate cancer

Total

Age

65-90 years 75 43.6% 124 70.9% 199 57.3%

Total

P value

172 100.0% 175 100.0% 347 100.0%

< 0.0001

Age

Variables

Biopsy outcome

Mean

Std. deviation

40-64 Years

PSA ng/ml

Benign prostate cancer Benign prostate cancer Benign prostate cancer Benign prostate cancer Benign prostate cancer Benign prostate cancer

97 51 97 51 97 51 75 124 75 124 75 124

10.35 33.15 57.10 47.73 0.23 0.81 12.91 39.17 74.45 56.47 0.23 0.92

11.32 67.00 29.98 14.82 0.30 1.67 12.52 50.89 37.36 28.95 0.30 1.46

Prostate volume (ml) Density (ng/ml2) 65-90 Years

PSA ng/ml Prostate volume (ml) Density (ng/ml2)

40-64 years 97 56.4% 51 29.1% 148 42.7%

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

Cutoff by age: factors affecting the biopsy outcome Patients were distributed into two groups according to median of age (65). The first group was aged less than 65 (148 patients) and the second group was aged 65 years and more (199 patients). A statistically significant correlation existed between the age groups and the biopsy outcome (Chi-square; p < 0.0001) (Table 4). The results showed that 70.9% of the patients aged 65 years and more, had prostate cancer and 56.4% of the patients aged less than 65 years had no prostate cancer. In the group of patients aged less than 65 years, a statistically significant correlation existed between PSA, and PSAD and biopsy outcome (Mann-Whitney test; p < 0.05) (Table 5). The results showed that PSA was higher in prostate cancer patients (mean = 33.1 ng/ml), and PSAD was significantly higher in prostate cancer patients (mean = 0.81 ng/ml2) comparing to patients with benign prostatic tissue. In the group of patients aged more than 65 years, a statistically significant correlation existed between PSA, prostate volume, and PSAD and the biopsy outcome (MannWhitney test; p < 0.05) (Table 5). The results showed that PSA was higher in prostate cancer patients (mean = 39.2 ng/ml), prostate volume was lower in prostate cancer patients (mean = 56.5 ng/ml), and PSAD was significantly higher in prostate cancer patients (mean = 0.92 ng/ml2) comparing to patients with benign prostatic tissue. A binary logistic analy95% Confidence interval for mean Min-max P value sis was done to identify Lower bound Upper bound the factors affecting the 8.07 12.63 2-85 0.010 biopsy outcome in the 14.30 51.99 4-394 patients aged less than 51.05 63.14 13-200 0.038 43.56 51.89 22-78 65 years. 0.17 0.34 10.03 30.13 65.85 51.33 0.16 0.66

0.29 1.28 15.79 48.22 83.04 61.62 0.30 1.18

0.04-1.98 0.05-7.30 3.7-100 3.5-300 21-214 12-175 0.04-1.89 0.06-9.75

0.002

0.000 0.000 0.000

Table 5. Correlation between the variables and biopsy outcome.

PSA density in the diagnosis of prostate cancer

Table 6. Correlation between the PSA and the biopsy outcome.

PSA

PSA 3–9.9 ng/ml PSA 10–19.9 ng/ml

Biopsy outcome Benign Prostate cancer 106 62 63.1% 36.9% 66 113 36.9% 63.1%

P value

CI (95%)

< 0.0001

2.927

1.89-4.53

Table 7. Correlation between the PSA density and the biopsy outcome.

PSA

PSAD < 0.184 PSAD > 0.185

Biopsy outcome Benign Prostate cancer 114 59 65.9% 34.1% 58 115 33.5% 66.5%

P value

CI (95%)

< 0.0001

3.831

2.45-5.98

Table 8. Correlation between the PSA density and the biopsy outcome in terms of the age groups. Age

PSAD

40-64 years

PSAD < 0.184 PSAD > 0.185

65-90 years

PSAD < 0.184 PSAD > 0.185

* Chi-Square Test.

Gleason score P value Benign Prostate cancer 65 23 0.010 73.9% 26.1% 32 28 53.3% 46.7% 49 36 < 0.0001 57.6% 42.4% 26 87 23.0% 77.0%

Risk

CI (95%)

2.473 1.234-4.956

4.554 2.465-8.416

A patient with a PSA equal to 10 ng/ml and more had a risk of 2.9 to have a prostate cancer. A binary logistic analysis was performed to predict the factors affecting the biopsy outcome in patients having a PSA level less than 10 ng/ml. The results showed that the biopsy outcome is affected by two variables: the age (p = 0.000), and the prostate volume (p = 0.049). The logistic analysis showed that the biopsy outcome is at risk times “1” to deviate to be “csPCa” when: the age is high and prostate volume is low. A binary logistic analysis was performed to predict the factors affecting the biopsy outcome in the patients having a PSA level equal to 10 ng/ml and more. The results showed that the biopsy outcome was affected by two variables: age (p = 0.004), and PSAD (p = 0.000). The logistic analysis showed that the biopsy outcome is at risk times “1” to deviate to be “csPCa” when the age is high and at risk of “6” times” when PSAD is high. Cutoff by PSA density: factors affecting the biopsy outcome A statistically significant correlation existed between PSAD groups and the biopsy outcome (chi-square; p < 0.0001) (Table 7). The results show that 66.5% of the patients, who had a PSAD more than 0.185, were diagnosed with prostate cancer and 65.9% of the patients who had a PSAD less than 0.185 were not diagnosed with prostate cancer. A patient with a high PSAD had a risk of 3.8 to have a prostate cancer. A statistically significant correlation existed between the PSA density groups and the biopsy outcome in each of the two age groups (Chi-square; p < 0.05) (Table 8). The results showed that 46.7% of the patients aged less than 65 years, who had a PSA equal to 10 ng/ml and more, were diagnosed with prostate cancer with an odds Ratio equal to 2.5. In addition, 77% of the patients aged 65 years and more, who had a PSA equal to 10 ng/ml and more, were diagnosed with prostate cancer with an odds Ratio equal to 4.5. A statistically significant correlation existed between the median PSAD and the biopsy outcome when the PSA level was ≥ 10 ng/ml. The risk of being diagnosed with prostate cancer was 4.2% higher (95% CI 0.263-0.691) when the PSA was more than 10 ng/ml (p < 0.0001) (Table 9).

The results showed that the Gleason score was affected by PSA (p = 0.012), and prostate volume (p = 0.048). The logistic analysis showed that the biopsy outcome was at risk times “1” to deviate to be “csPCa” when PSA level was high and prostate volume was low. A binary logistic analysis was done to identify the factors affecting the biopsy outcome in the patients aged more than 65 years. The results showed that the biopsy outcome was affected by two variables: PSA (p = 0.000), and prostate volume (p = 0.003). The logistic analysis showed that the biopsy outcome was at risk times “1” to deviate to be “csPCa” DISCUSSION when: PSA level was high and prostate volume was low. In this study, the profiles of patients submitted to prostate Cutoff by PSA: factors affecting the biopsy outcome biopsy were outlined. The variables considered were tPSA Patients were distributed into two groups according to (total PSA), prostate volume, PSAD, age and prostate biopmedian of PSA (10). The first group had a PSA level less than 10 ng/ml (168 patients) Table 9. and the second group had a PSA level 10 Individual risk of benign and prostate cancer with PSA level ≥ 3 ng/ml ng/ml and more (179 patients). A statisticalby PSA density. ly significant correlation existed between the PSA PSAD Biopsy outcome P value Risk CI (95%) PSA groups and the biopsy outcome (ChiBenign Prostate cancer Lower Upper square; p < 0.0001) (Table 6). The results PSA 3–9.9 ng/ml < 0.184 ng/ml2 87 82.1% 47 77.0% 0.432* 0.827 0.522 1.309 showed that 63.1% of the patients, who had > 0.185 ng/ml2 19 17.9% 14 23.0% a PSA equal to 10 ng/ml and more, were PSA > 10 ng/ml < 0.184 ng/ml2 27 40.9% 12 10.6% 0.000* 0.427 0.263 0.691 diagnosed with prostate cancer and 63.1% > 0.185 ng/ml2 39 59.1% 101 89.4% of the patients who had a PSA less 10 ng/ml * Chi-Square Test. were not diagnosed with prostate cancer. Archivio Italiano di Urologia e Andrologia 2022; 94, 1

A. Msheik, M. Mohanna, A. Mhanna, A. Kanj, M. Moussa, A. Mohanna

sy findings. The results showed that age, tPSA level, prostate volume, and PSAD were important factors to consider in the decision of whether to do a biopsy of prostate or not. This study showed that each of these factors has a certain median relative to which the positive predictive value (PPV) of prostate cancer at prostate biopsy differs. Age First, about age, the results showed that above two thirds of the biopsies proved evidence of high grade cancer (Gleason > 7) in patients older than 65 years, while less than half biopsies done in patients younger than 65 years diagnosed csPCa. Accordingly, advanced age added one times risk to the detection of csPca. Hence, patients older than 65 years who had urinary symptoms that advocated prostate pathology proved to be candidates for a prostate biopsy with a high PPV for prostate cancer. These findings were anticipated in the literature. More than 65% of prostate cancer patients are expected to be above 65 years of age (6). Volume We reported a one-time risk of prostate cancer detection in association with a low prostate volume in both age groups. Of note, the mean of prostate volume was higher in BPH patients compared to prostate cancer patients in either age groups. However, we observed an increase of mean volume with age in both BPH and prostate cancer patients. This sheds light of the possibility of concomitant occurrence of BPH and of its evolution before or along with prostate cancer. Many studies in the literature confirmed that in patients with small volume prostates, PSA levels superior to 4 ng/ml and suspicious on digital rectal examination (DRE) were more likely to show pathological evidence of prostate cancer at biopsy (7, 8). A retrospective study by Camur et al. noted that prostate volume has no significant effect on upgrading in active surveillance of appropriate patients9. This result addressed the prostate volume as a single factor, conversely correlation of volume with PSA level proved that volume has a role in the of prostate cancer in the indication to prostate biopsy. PSA Evaluation of PSA levels showed that a value of 10 ng/ml (0.38 nmol/l) represented a median that departed values similarly to what was observed for age with a median value of 65 years. In fact, 52% of the patients in this study had a PSA superior to 10 ng/ml. The prevalence of prostate cancer in this PSA group was remarkably differentiable with the PSA value. Nearly, two-thirds of patients whose PSA level was below 10 ng/ml have benign biopsy outcome compared to two-thirds of patients who have proved csPca on their prostate biopsy with a PSA level above 10 ng/ml. These values were concordant with the findings reported by Schmid et al. (10), whereas according to Park et al. (11) and Kobayashi et al. (12), there is no significant different detection rate of cancer and pathological findings between the group with tPSA 2-4 ng/ml and 4-10 ng/ml. In the present study patients were divided in only two groups according to PSA (4-9.9 ng/ml and > 10 ng/ml). Nevertheless, a tPSA level higher to the 10 ng/ml median

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

added a risk of 1 times to the detection of csPca, similarly to the age factor. Of note, the mean PSA level increased in either BPH or prostate cancer patients as they grow old similarly to the increase of prostate volume observed between the two age groups (19-28% relative increase in mean prostate volume versus 18-29% increase in mean PSA levels). The joint increase of both age and PSA in relation to the outcome of prostate biopsy demonstrated that none of the two factors could be a major predictive value by itself. A PSA value higher to the cutoff (10 ng/ml) was predictive of a high risk of prostate cancer if the patient’s age was higher of the age cutoff (65 years old). In fact, for a PSA value above 10 ng/ml, no more than 50% of prostate biopsies demonstrated a prostate cancer unless the age was superior to 65 years. DRE, TRUS and tPSA level are commonly used methods of screening for prostate cancer. The detection of any abnormality in the prostate volume through DRE or TRUS, and the detection of a higher than age-related tPSA level are usually followed by an ultrasound or MRI-guided biopsy of the prostate to rule out prostate cancer. On note, tPSA was initially utilized as a post-operative laboratory test for recurrence detection. Its implementation as a screening method has lowered morbidity associated with prostate biopsies and the number of unnecessary biopsies, and allowed earlier detection of csPca up to 81% as compared to DRE alone (13). PSAD Benson et al. in 1992, introduced the concept of PSAD, to correct PSA value by prostate volume to differentiate patient with high volume benign disease from those with prostate cancer (14). However, many authors questioned this concept, because the utilization of PSAD with a cutoff of 0.15 ng/ml2 showed a sensitivity of only 60% (14). The diagnostic efficacy of PSA density has been thoroughly discussed in relation to its stratification for each PSA level interval showing that for tPSA levels higher than 10ng/ml, a high prostate density indicated a 6 times risk of csPca detection on a prostate biopsy. This finding defined prostate density as an extremely important tool for the indication of a biopsy for this tPSA level interval. When the tPSA level is higher to 10 ng/ml, the risk of diagnosing a prostate cancer for a prostate density higher than 0.185 ng/ml2 was 4.2% (95% CI 0.2630.691) higher. On the contrary, when PSA level is below 10 ng/ml, a high prostate density value proved to be unreliable using the 0.185 ng/m2 cut-off. Conversely, in the PSA interval with higher incidence of prostate cancer, the risk of prostate cancer at biopsy dropped when PSAD is below the 0.184 ng/ml2 cut-off. In addition, the joint evaluation of age and prostate density showed that higher values of both was predictive of a higher risk of prostate cancer detection on a prostate biopsy (77% of the patients whose PSAD and age were superior to the considered cutoffs had prostate cancer compared to only 26% when both parameters were inferior to the considered cutoffs). The results from this study confirmed previous reports on the value of PSAD in the biopsy indication. Jue et al. demonstrated that PSAD is better in predicting prostate

PSA density in the diagnosis of prostate cancer

Table 10. Redistribution of patients with PSA > 10 ng/ml after lowering PSAD cut-off to 0.09 ng/ml2. PSAD > 0.09 ng/ml2 < 0.09 ng/ml2

Biopsy outcome Prostate cancer 109 4

Benign 43 23

cancer versus the use of PSA level or prostate volume alone (15). Similarly, Stephan et al. showed the PSA density to perform better than the tPSA level for patients whose PSA level ranged between 2 and 20 ng/ml (16). Van Iersel et al., similarly to many other authors, concluded that the PSAD cutoff to distinguish between prostate cancer and BPH could be 0.15 ng/ml2 where a higher value is significant of a higher malignancy probability (17). Although similar results were obtained in this retrospective study with a PSAD cut-off of 0.185 ng/ml2 and 0.13 ng/ml2, these values are population specific and their variance relied on a multitude of factors (18). The reliability of the prostate volume measurement dramatically affects the significance of cut-offs used for biopsy decisions. Two methods were implemented in the calculation of the prostate volume: the ellipsoid method or planimetric method. Stone et al. found that the three plane method (ellipsoid method) had a variability of 30% compared to the 3D-planimetric method which showed only 5% variation. Furthermore, Holmang et al. stated that the 3-plane method underestimated the volume by 20% compared to the 3D-planimetric method (19). Hence, the higher is the accuracy of the method of volume assessment, the better PSAD would assess the need for a prostate biopsy and the less unnecessary biopsies would be made. In a multi-centric study of 773 patients, Catalona et al. (20) considered lowering the PSAD cut-off to 0.078 ng/ml2, because at that cut-off, 95% of tumors would be detected. In the present study, for a tPSA level between 3 and 9.9 ng/ml, when the PSAD cut-off value of 0.184 ng/ml2 was utilized, only 42.4% of csPca patients would have been diagnosed with prostate biopsy with a 57% specificity. A p-value of 0.432 for this tPSA level rendered the results less reliable. For a tPSA > 10 ng/ml, using a PSAD cut-off of 0.184 ng/ml2, the utilization of prostate biopsy was 89.4% sensitive and 40.9% specific, with a p-value of < 0.0001. Lowering the cut-off to 0.09 ng/ml2, sensitivity increased to 96% while specificity decreased to 35%. This result could be justified by the fact that 89.4% of csPca patients have a PSAD superior to 0.185 ng/ml2 compared to only 59.1% of benign patients being superior to the aforementioned value. Lowering the PSAD cut-off led to a new distribution of patients as shown in Table 10 and consequently to a change of sensitivity. It can be intuitive of the fact that most prostate cancer patients have relatively high PSAD and that lowering the PSAD cut-off recruited more patients into this category and favored an increase of the sensitivity and decrease in the specificity. Therefore, this study proved PSAD was a good predictor of the biopsy outcome for tPSA ranging between 4 to 20

ng/ml. PSAD cut-off of 0.18 ng/ml/cc could minimize the number of unnecessary biopsies. Consideration of a lower cutoff may promote better sensitivity with a slight decrease in the false negative results, which remains acceptable for a screening test. However, the acknowledgment of a PSAD cut-off mandates further studies for an optimal value that balances the sensitivity and false negative results of the prostate biopsy. Study limitations Every study has limitations and this study is no exception. The limitations can be sorted under two titles. Population The number of the patients and the fact that they were from the same hospital limited the credibility of our results. A multicenter study with a larger population size will impart to those results more credibility, render them more reliable, help achieve more precise cut-offs, averages of minimal standard deviation, and allow generalization of the findings as representative of the whole population. Retrieval of data The missing data prevented the estimation of the positive predictive value (PPV), negative predictive value (NPV), sensitivity and specificity of the prostate biopsy procedure. This limited the comparison of the results versus other studies.

REFERENCES

1. Rogers OC, Anthony L, Rosen DM, et al. PSA-selective activation of cytotoxic human serine proteases within the tumor microenvironment as a therapeutic strategy to target prostate cancer. Oncotarget. 2018; 9:22436-22450. 2. Prcic A, Begic E, Hiros M. Usefulness of total PSA value in prostate diseases diagnosis. Acta Inform Med. 2016; 24:156-61. 3. Mittal RD. Reference range of serum prostate-specific antigen levels in Indian men. Indian J Med Res. 2014; 140:480-1. PMID: 25488440; PMCID: PMC4277132. 4. Shamseddine A, et al. Cancer trends in Lebanon: a review of incidence rates for the period of 2003-2008 and projections until 2018. Popul Health Metr. 2014; 12:4. 5. https://gco.iarc.fr/today/data/factsheets/populations/422-lebanonfact-sheets.pdf 6. Instituto Brasileiro de Geografia e Estatística; Ministério do Planejamento, Orçamento e Gestão. Estimativas populacionais 1980-2010: Brasil, regiões geográficas e unidades da federação. Rio de Janeiro (Brasil): IBGE; 2010. [citado em 15 de junho de 2010]. Disponível em: http://www.ibge.gov.br 7. Nickel JC. Inflammation and benign prostatic hyperplasia. Urol Clin North Am. 2008; 35:109-15 8. Çamur E, Coskun A, Kavukoglu O, et al. Prostate volume effect on Gleason score upgrading in active surveillance appropriate patients. Arch Ital Urol Androl. 2019; 91:93. 9. Babaian RJ, Fritsche HA, Evans RB. Prostate-specific antigen and prostate gland volume: correlation and clinical application. J Clin Lab Anal. 1990; 4:135-7. 10. Bell N, et al. Canadian Task Force on Preventive Health Care. Archivio Italiano di Urologia e Andrologia 2022; 94, 1

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Recommendations on screening for prostate cancer with the prostatespecific antigen test. CMAJ. 2014; 186:1225-34.

ty to predict prostate cancer using extended template biopsy. Urology. 2017; 105:123-128.

11. Park HK, Hong SK, Byun SS, Lee SE. Comparison of the rate of detecting prostate cancer and the pathologic characteristics of the patients with a serum PSA level in the range of 3.0 to 4.0 ng/mL and the patients with a serum PSA level in the range 4.1 to 10.0 ng/mL. Korean J Urol. 2006; 47:358-61.

16. Stephan C, et al. The ratio of prostate-specific antigen (PSA) to prostate volume (PSA density) as a parameter to improve the detection of prostate carcinoma in PSA values in the range of < 4 ng/mL. Cancer. 2005; 104:993-1003.

12. Kobayashi T, Nishizawa K, Ogura K, et al. Detection of prostate cancer in men with prostate-specific antigen levels of 2.0 to 4.0 ng/mL equivalent to that in men with 4.1 to 10.0 ng/mL in a Japanese population. Urology. 2004; 63:727-31. 13. Gomes R, Rebello LEFS, Araújo FC, et al. A prevenção do câncer de próstata: uma revisão da literatura. Ciencia & Saude Coletiva. 2008; 13:235-46. 14. Benson MC, et al. Prostate specific antigen density: a means of distinguishing benign prostatic hypertrophy and prostate cancer. J Urol. 1992; 147:815-6. 15. Jue JS, et al. Re-examining prostate-specific antigen (PSA) density: defining the optimal PSA range and patients for using PSA densi-

Correspondence Ali Msheik, (Corresponding Author) newpie@mail.com PGY-1 Neurosurgery, Faculty of Medical Sciences, Lebanese University, Beirut (Lebanon) Mohamed Mohanna PGY-1 Internal Medicine, Faculty of Medical Sciences, Lebanese University, Beirut (Lebanon) Ali Mhanna PGY-1 General Surgery, Faculty of Medical Sciences, Lebanese University, Beirut (Lebanon) Ali Kanj, MD Radiologist, Bahman Hospital, Beirut (Lebanon) Mohamad Moussa, MD Urologist, Chairman of General Surgery and Urology Department, Faculty of Medical Sciences, Lebanese University, Beirut (Lebanon) Assaad Mohanna. MD Radiologist, Head of Radiology Department, Bahman Hospital, Beirut (Lebanon)

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

17. Van Iersel MP, Witjes WP, de la Rosette JJ, Oosterhof GO. Prostate-specific antigen density: correlation with histological diagnosis of prostate cancer, benign prostatic hyperplasia and prostatitis. Br J Urol. 1995; 76:47-53. 18. Ediz C, Akan S, Temel MC, Yilmaz O. The importance of PSADensity in active surveillance for prostate cancer. Arch Ital Urol Androl. 2020; 92:136. 19. Holmäng S, Lindstedt G, Mårin P, Hedelin H. Serum concentration of prostate-specific antigen in relation to prostate volume in 50 healthy middle-aged men. Scand J Urol Nephrol. 1993; 27:15-20. 20. Catalona WJ, et al. Comparison of percent free PSA, PSA density, and age-specific PSA cutoffs for prostate cancer detection and staging. Urology. 2000; 56:255-60.

DOI: 10.4081/aiua.2022.1.25

ORIGINAL PAPER

The role of MRI in the detection of local recurrence: Added value of multiparametric approach and Signal Intensity/Time Curve analysis Caterina Gaudiano 1, Federica Ciccarese 1, Lorenzo Bianchi 2, Beniamino Corcioni 1, Antonio De Cinque 1, Francesca Giunchi 3, Riccardo Schiavina 2, Michelangelo Fiorentino 4, Eugenio Brunocilla 2, Rita Golfieri 1 1 Department

of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; of Urology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; 3 Department of Pathology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; 4 Department of Specialty, Diagnostic and Experimental Medicine, University of Bologna, Bologna, Italy. 2 Department

Summary

Objective: The aim of the study was to evaluate the accuracy of multiparametric Magnetic Resonance Imaging (mpMRI) in the detection of local recurrence of prostate cancer (PCa) with the evaluation of the added value of signal Intensity/Time (I/T) curves. Materials and methods: A retrospective analysis of 22 patients undergoing mpMRI from 2015 to 2020 was carried out, with the following inclusion criteria: performing transrectal ultrasound guided biopsy within 3 months in the case of positive or doubtful findings and undergoing biopsy and/or clinical follow-up for 24 months in the case of negative results. The images were reviewed, and the lesions were catalogued according to morphological, diffusion-weighted imaging (DWI) and dynamic contrast-enhanced (DCE) features. Results: The presence of local recurrence was detected in 11/22 patients (50%). Greater diameter, hyperintensity on DWI, positive contrast enhancement and type 2/3 signal I/T curves were more frequently observed in patients with local recurrence (all p < 0.05). Of all the sequences, DCE was the most accurate; however, the combination of DCE and DWI showed the best results, with a sensitivity of 100%, a specificity of 82%, a negative predictive value of 100% and a positive predictive value of 85%. Conclusions: The utility of MRI in the detection of local recurrence is tied to the multiparametric approach, with all sequences providing useful information. A combination of DCE and DWI is particularly effective. Moreover, specificity could be additionally improved using analysis of the signal I/T curves.

KEY WORDS: Multiparametric magnetic resonance imaging; Prostate cancer; Radical prostatectomy; Prostate cancer recurrence. Submitted 14 July 2021; Accepted 25 August 2021

INTRODUCTION

Radical prostatectomy (RP) is a common treatment option in patients with organ confined prostate cancer (PCa). However, approximately 10-53% of patients undergoing primary intended curative therapy will develop a biochemical recurrence (BCR), depending on their preoperative risk and stage of cancer (1). Measurement of the prostate specific antigen (PSA) is a cornerstone of the fol-

low-up after local treatment. In fact, PSA is expected to be undetectable within 6 weeks after a successful RP. A rising serum PSA level is considered to be a BCR (1). Specifically, a BCR is defined by as a serum PSA measurement ≥ 0.2 ng/mL, followed by a second confirmatory level (1). Once a BCR has been diagnosed, it is important to determine whether the recurrence has developed at local or at distant sites in order to optimise salvage treatment. Although PSA alone does not differentiate local from distant disease, the pattern of its rise has been incorporated into clinical nomograms to predict whether recurrence is more likely to be local or systemic; patients with late BCR (> 24 months after local treatment) and prolonged PSA doubling time (> 6 months) most likely have local recurrent disease (1). Of the imaging modalities, multiparametric magnetic resonance imaging (mpMRI) is the most accurate in the detection of local recurrence, being superior to choline positron emission tomography/computed tomography (PET/CT) and to transrectal ultrasonography (TRUS) (2-5). Dynamic ContrastEnhanced (DCE) is reported to be the most effective sequence in detecting recurrence while the role of Diffusion Weighted imaging (DWI) is still controversial (2-5). Thus, the aim of the present study was to evaluate the accuracy of mpMRI in detecting local recurrence by evaluating both the accuracy of each sequence and the combination of DCE-DWI, considering clinical and histopathological data as the reference standard. The value of the signal Intensity/Time (I/T) curves was also assessed.

MATERIALS

AND METHODS

Study population This study was an observational, retrospective, single centre study; it was approved by the Authors’ local institution review board and conducted in accordance with institutional guidelines, including the Declaration of Helsinki. All patients were notified of the investigational nature of this study and gave their written informed consent (Approval code: STUD-OF, Prot. N. 323). Patients with clinical suspicion of local recurrence after

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 1

C. Gaudiano, F. Ciccarese, L. Bianchi, et al.

RP who had undergone mpMRI at the Authors’ Institute from February 2015 to January 2020 and had performed TRUS guided biopsy within 3 months in the case of positive or doubtful findings or had undergone biopsy and/or clinical follow-up (PET/CT with 11C-Choline and PSA) in the case of negative results for up to 24 months, were enrolled. Patients with uni or bilateral hip prostheses causing artefacts in image interpretation were excluded from the analysis. Overall, a total of 48 patients were enrolled, and 22 were included in the final analysis as showed in Figure 1. For each patient, PSA levels as well as Digital Rectal Examination (DRE) and TRUS data were recorded. mpMRI protocol study The mpMRI examinations were performed using a 1.5T whole-body scanner (Signa HDxt; GE Healthcare, Milwaukee, WI, USA) and a standard 8-channel pelvic phased-array surface coil combined with a disposable endorectal coil. The morphological study was carried out using high-resolution Fast Relaxation Fast Spin Echo T2-weighted (T2w) sequences in the sagittal, axial and coronal planes, including the prostate bed. The DWI and DCE acquisition were also carried out in the axial plane, with the same parameters as the T2w axial sequence in order to obtain a match. The DWI was carried out using a single-shot echo-planar imaging sequence with high b-value acquisition (2000 s/mm2) and another sequence with two b-values (50 and 1000 s/mm2), useful for the calculation of the apparent diffusion coefficient (ADC) map. The DCE acquisition was obtained using three-dimensional (3D) T1-weighted Spoiled Gradient Recalled sequences during the intravenous injection of a gadolinium-based contrast agent at a flow rate of 3 ml/sec followed by 15 ml of saline solution. The 3D data sets were acquired with 10 second temporal resolution; the acquisitions before contrast agent administration can be used to detect foci of haemorrhage. Figure 1. Flowchart for patient selection.

The DWI and DCE images were processed on an independent workstation with dedicated software (Functool, 4.5.5, GE Healthcare, Milwaukee, WI, USA). For the DWI, the high b-value images and the ADC map were evaluated to identify suspected areas. Semiquantitative perfusion was carried out using analysis of the DCE datasets and signal I/T curve generation. Image analysis All the mpMRI images were reviewed by two genitourinary radiologists with 10 and 5 years of experience, respectively, in prostate MRI, with a consensus reading blinded to the patients’ clinical information. All the lesions were catalogued according to morphological, DWI and DCE features. At morphological examination, the presence of soft tissue in the prostate bed slightly hyperintense to muscle was considered suspicious for local recurrence. Location and maximum diameter were also recorded. At DWI, a suspicious lesion was defined by hyperintensity at high b-value acquisition. For DCE evaluation, contrast enhancement was evaluated according to a negative/positive binary criterion. A lesion was considered suspicious if characterised by positive contrast enhancement. The signal I/T curve was assessed and classified as type 1 (progressive), type 2 (plateau) or type 3 (wash-in and wash-out). At the overall evaluation, mpMRI was considered suspicious if all three sequences were in agreement regarding recurrence, negative if all three were in agreement regarding the absence of recurrence and doubtful if agreement existed for 2/3 sequences. Cognitive fusion biopsy All patients with suspicious or doubtful lesions at mpMRI underwent a TRUS-guided biopsy by two experienced radiologists, after antibiotic prophylaxis and a cleansing rectal enema, using a non-disposable biopsy gun (Medgun, Medax, Modena, Italy) with a disposable 18-gauge needle and an Ultrasound Platform with an end-fire TRUS probe (Canon-Toshiba Aplio 500™, Japan). All the biopsies were performed within three months from the mpMRI. The biopsy procedures were conducted in an outpatient setting, with the patient in a left flank lateral position, after a peri-prostatic nerve blockade with local anaesthesia (lidocaine 2%), using a cognitive approach. The mean number of samples was 3 (from 2 to 6), depending on lesion size and recognisability; in the case of negative results on mpMRI, the biopsies were carried out around the vesicourethral anastomosis. Each biopsy sample was placed inside a single container with a specific progressive number corresponding to a specific description relating to the site. After the procedure, the patients were observed for 1 hour before discharge. Pathological analysis The biopsy samples were analysed by the same dedicated genitourinary pathologist who primarily highlighted the presence or absence of a neoplastic pathology on the samples. Each neoplastic lesion defined as a "positive result" was graded according to the Grade Group System (GGS) from 1 to 5 and to the International Society of Urological

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

mpMRI for prostate cancer recurrence

Pathology (ISUP) 2014 classification (6). For each nonneoplastic lesion defined as a “negative result”, the type of benign finding was reported, including fibrotic tissue or residual benign prostate tissue. Statistical analysis The continuous variables were described in terms of medians, with interquartile range (IQR), and were compared using the Mann-Whitney test. The categorical variables were described as absolute and relative frequencies and were compared using the Fisher’s exact test. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for each sequence (T2w, DWI, DCE). Receiver operating characteristic (ROC) analysis and area under curve (AUC) were used to assess diagnostic accuracy, using the histopathological and clinical data as the reference standard. The data were collected and digitised using Microsoft Excel 2016 software; all analyses were carried out using SPSS IBM Statistics® v. 22.0 (IBM Corp., Armonk, NY, USA). A P value of < 0.05 was considered statistically significant. Table 1. Demographics and clinical characteristics of the overall population and of the two groups of patients stratified according to the pathological or clinical evidence of local recurrence.

Patients, n (%) Age Median (IQR) PSA Median (IQR) TRUS, n (%) Positive Negative DRE, n (%) Positive Negative

Total

Positive biopsy

Negative biopsy/ clinical follow-up

22 (100)

11 (50)

69 (64-72)

69 (64.5-72)

69 (63-72.5)

0.29

1.16 (0.35-2.32)

1.76 (0.67-2.44)

0.9 (0.32-1.62)

9 (41) 13 (59)

6 (54) 5 (46)

3 (27) 8 (73)

0.002 0.73

9 (41) 13 (59)

5 (46) 6 (54)

4 (36) 7 (64)

0.91

N: Number; IQR: Interquartile range; PSA: Prostate specific antigen; TRUS: Transrectal ultrasound; DRE: Digital rectal examination.

RESULTS

The presence of local recurrence was histologically detected in 11/22 patients (50%) while, in the other 11/22 (50%), no local recurrence was assessed by means of biopsy in 7 patients and by means of clinical follow-up and PET/CT in 4 patients. The demographics and clinical features of the patients are described in Table 1. Patients with evidence of local recurrence at histopathologic analysis had significantly higher PSA levels as compare with patients with no evidence of local recurrence (p = 0.002). Table 2 shows the histopathological findings and clinical outcome in the two groups of patients. In patients with a diagnosis of local recurrence, mpMRI was suspicious in 8/11 (73%) and doubtful in 3/11 (27%) while, in the patients with no evidence of local recurrence, it was suspicious in 3/11 (27%), doubtful in 1/11 (9%) and negative in 7/11 (64%) (Figures 2, 3). The mpMRI features of all patients are described in Table 3. Regarding the location, local recurrence was found around the vesicourethral anastomosis in 8/11 (73%) and within the retained seminal vesicles in the other 3/11 (27%) patients. On T2w, there were no statistically significant differences related to morphology or signal intensity while local recurrences were found to present a greater maximum diameter as compared to the benign tissue (p < 0.001). On DWI, hyperintense lesions were more frequently consistent with local recurrence (p = 0.03). On DCE, positive contrast enhancement was most frequently detected in patients with local recurrence (p = 0.008) as were types 2 Figure 2. Suspected local recurrence at mpMRI in a 75-year-old man with PSA = 0.91. Axial T2-weighted sequence (a) shows the presence of a hyperintense nodule in the prostate bed behind the vesicourethral anastomosis (arrow), characterised by hyperintensity at Diffusion Weighted Imaging (arrow in b) and hypervascularity at Dynamic Contrast Enhanced evaluation (green circle in c). The signal Intensity/Time curve was classified as type 2 (green line in d). Biopsy sampling documented prostate cancer Gleason Score 3+4 (ISUP 2). CFA = Common femoral artery.

Table 2. Histopathological data and clinical outcome of the two groups of patients stratified according to the pathological or clinical evidence of local recurrence. Total 22 (100)

Positive biopsy 11 (50)

Negative biopsy/clinical follow-up 11 (50)

Biopsy results, N (%)

18 (82)

7 (64) Benign prostate tissue 2 (28) Fibrotic tissue 5 (72)

11C-Choline PET/CT Follow-up

11 (50)

11 (100) ISUP 1 - 2 (18) ISUP 2 - 5 (46) ISUP 3 - 0 (0) ISUP 4 - 4 (36) ISUP 5 - 0 (0) -

Local uptake 2 *(18) No local uptake 8 (73) Other side uptake 6 (54)

* Corresponding to benign prostate tissue. N: Number; ISUP: International Society of Urologic Pathology; PET/CT: Positron Emission Tomography/Computed Tomography.

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Figure 3. Doubtful findings at mpMRI in a 73-year-old man with PSA = 0.33. Axial T2-weighted sequence shows the presence of a slightly hyperintense nodule in the prostate bed, adjacent to the vesicourethral anastomosis (arrow in a), characterised by slight hyperintensity at Diffusion Weighted Imaging (arrow in b) and negative contrastenhancement with a type 1 Signal Intensity/Time curve (green line in c). Biopsy sampling documented fibrotic tissue.

Table 3. Morphological and functional characteristics of all lesions identified on mpMRI in the two groups of patients stratified according to the pathological evidence of local recurrence.

N (%) T2w Maximum diameter (mm) (median; IQR) Morphology, n (%) Nodule Amorphous tissue Signal intensity, n (%) Hypointense Hyperintense DWI Signal intensity, n (%) Hypointense Hyperintense DCE Contrast enhancement, n (%) Negative Positive Signal I/T curve, n (%) Type 1 Type 2 Type 3

Total

Positive biopsy

11 (50)

Negative biopsy/ clinical follow-up 11 (50)

22 (100) 10.5 7-14

13 9.5-18

8 6-11.5

< 0.001

12 (55) 10 (45)

5 (45) 6 (55)

7 (64) 4 (36)

10 (45) 12 (55)

3 (27) 8 (73)

7 (64) 4 (36)

10 (45) 12 (55)

2 (18) 9 (82)

8 (73) 3 (27)

9 (41) 13 (59)

1 (9) 10 (91)

8 (73) 3 (27)

9 (41) 10 (45) 3 (14)

1 (9) 7 (64) 3 (27)

8 (73) 3 (27) 0 (0)

N: Number; T2w: T2-weighted sequence; DWI: Diffusion Weighted Imaging; DCE: Dynamic Contrast-Enhanced; I/T: Intensity/Time.

0.6 0.2

0.03

0.008 0.03

and 3 at the signal I/T curve while a type 1 curve was most frequent in benign tissue (p = 0.03). For each sequence, the values of sensitivity, specificity, NPV and PPV obtained using ROC analysis were as follows: 73%, 64%, 70% and 67% for the T2w; 82%, 73%, 80% and 75% for DWI; 91%, 73%, 87% and 71% for DCE, and 100%, 82%, 100% and 85% for the combination DWI+DCE, respectively. Figure 4 shows the ROC curve analysis.

DISCUSSION

Prostate cancer is primarily managed by four standard methods, i.e. RP, radiation therapy, androgen deprivation therapy and active surveillance, although new focal therapy methods have rapidly been evolving (1). Treatment choice is based on tumour stage, histology and grade, and is also influenced by patient clinical condition or preference. Of these, RP has been performed for more than a century and remains the most common treatment choice. The procedure involves removing the entire prostate with its capsule intact and the seminal vesicles, followed by carrying out a vesicourethral anastomosis. Surgical techniques have expanded from perineal and retropubic open approaches to laparoscopic and robotic-assisted techniques, with nerve-sparing intent whenever possible (7); the role of pelvic lymph-node dissection (PLND) is still controversial and is mainly based on a clinical nomogram. However, the majority of authors have agreed that PLND is

Figure 4. Receiver operating characteristic (ROC) curves. a) Comparison between T2 weighted (T2), Diffusion Weighted Imaging (DWI) and Dynamic Contrast Enhanced (DCE); the area under the curve (AUC) was 0.682 for T2; 0.773 for DWI; 0.773 for DCE. b) Combined DWI+DCE increased the AUC to 0.909.

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mpMRI for prostate cancer recurrence

the most accurate staging procedure. Moreover, extensive PLND could also have a therapeutic effect due to removal of micrometastasis, thus reducing the risk of BCR (7). Several factors could increase the risk of recurrence, such as seminal vesicle invasion, positive surgical margins, extra-prostatic extension, perineural and lymphovascular invasion, tumour volume, ISUP score > 2 and nodal metastasis (8). However, recurrences in the early setting are extremely difficult to detect with conventional imaging modalities due to low tumour volume. The mean PSA values at the time of imaging have often varied in the literature from 0.2 to 10 or even higher, which is actually far above the level at which the clinician currently wants to know whether the patient suffers from local or distant recurrence (8). Transrectal ultrasonography can be used in patients with suspected local recurrence, but the reported detection rates at PSA levels < 0.5 ng/ml vary notably from 28.1 to 73.0%; moreover, specificity seems to be lower than DRE for possible false positives due to postoperative fibrosis (1). Although several efforts have been made to improve the accuracy of TRUS, such as the addition of colour Doppler and contrast sonography (9), it is not routinely recommended in the setting of local recurrence (1). Currently, mpMRI is most frequently used to assess local recurrence and is combined with whole-body choline PET/CT to find regional or distant recurrence (10); in fact, the role of choline PET/CT in the detection of local recurrence is limited because a mild focal uptake of choline in the prostate bed and vesicourethral junction is difficult to differentiate from radioactive urine accumulation (10). Moreover, detection rates are only 5-24% when the PSA level is < 1 ng/mL but rises to 67-100% when the PSA level is > 5 ng/mL, i.e. when metastatic disease is suspected (1). In this setting, hormone treatment withdrawal may also not be necessary (1). Great interest has recently developed in new prostate-specific tracers, such as Prostate Specific Membrane Antigen (PSMA) which seems substantially more sensitive than choline PET/CT, especially for PSA levels < 1 ng/ml, having a detection rate of 34.4% with PSA level < 0.5 ng/ml (11), so that the use of PSMAPET/CT was introduced by the European Association of Urology guidelines. However, the majority of studies are limited by their retrospective design, and whether this approach is really cost-effective remains unknown (1). Thus, mpMRI, by means of the combination of high resolution morphological T2w images and functional imaging, seems to be particularly accurate in evaluating local recurrence. At mpMRI, knowledge of the normal post-surgical anatomy is essential for avoiding a misdiagnosis. Normal findings show that the bladder neck is anastomosed to the extraprostatic distal urethra which has a conical shape and falls far more caudally than normal on the sagittal plane; the tissue around the vesicourethral anastomosis is low in signal on T2w, reflecting postoperative scarring and fibrosis. Occasionally, the anastomosis may demonstrate an intermediate T2w signal which mimics recurrence, particularly if there was extensive haemorrhage at the time of surgery. Extensive fat stranding is often encountered sur-

rounding the bladder base. Potential pitfalls could be represented by retained seminal vesicles, residual prostatic tissue or postoperative fibrosis (12). In the present study, local recurrences were more frequently characterised by a greater diameter, hyperintensity on DWI and positive contrast-enhancement. Of all the sequences, T2w was the least accurate while DCE was the most reliable. These results are in line with what has previously been reported. Casciani et al. found that the addition of DCE to T2w increased sensitivity from 48 to 88% and specificity from 52 to 100% (13); similar results have also been reported by others (5, 14, 15). Moreover, DCE was found to increase interobserver agreement and to facilitate the detection of local recurrence, even by relatively inexperienced readers (15). Sciarra et al. demonstrated that the combination of spectroscopic imaging and DCE could also increase the detection rate (sensitivity of 86% and specificity of 100%); however, spectroscopic imaging is a more complex technique and requires additional expertise and longer acquisition time; therefore, it is less commonly used in clinical practice (16). The role of DWI is still more controversial as it could be affected by artefacts caused by surgical clips. Panebianco et al. found that the combination of T2w+DWI could produce a detection rate comparable to T2w+DCE (93% sensitivity, 89% specificity, 88% accuracy) (5); however, other studies have reported lower values, with a detection rate of 25-69% depending on tumour size (14) and a sensitivity of 46-49% (16). Our results showed a reduced sensitivity for DWI as compared to DCE sequences (82% vs. 91%, respectively), probably due to artefacts and tumour size affecting the detectability of recurrent lesions. Therefore, while the general trend in prostate MRI is to develop a “less is better strategy”, improving the application of biparametric MRI to reduce execution time and improve patient tolerability and safety, this could not be applied in the setting of local recurrence for the wellestablished additional value of DCE (17). Furthermore, new MRI protocols have been investigated, such as the combination of whole-body and mpMRI in order to assess both local recurrence and metastatic disease (18). From the results of our study, the combination of DCE+DWI showed better accuracy, having a sensitivity of 100%, a specificity of 82%, an NPV of 100% and a PPV of 85%. Specificity can be additionally improved by the analysis of the signal I/T curve: in fact, while benign tissue most frequently has a type 1 curve, the recurrences generally showed type 2 and 3 curves. This was an interesting observation since the signal I/T curves obtained from the perfusion sequence were not effective in differentiating between benign and neoplastic tissue in the clinical setting of the diagnosis (19). Even if T2w was the least reliable sequence, it provided important information regarding the postsurgical anatomy and was able to localise the site of recurrence. In this series, the most frequent site of recurrence was the vesicourethral anastomosis as previously reported (3, 10), followed by retained seminal vesicles while recurrences in the retrovesical region were not found, as was frequently observed by Sella et al. (20). The present study had some limitations; first, our results Archivio Italiano di Urologia e Andrologia 2022; 94, 1

C. Gaudiano, F. Ciccarese, L. Bianchi, et al.

were obtained at a single high-volume tertiary care centre with significant experience in mpMRI, thus radiologist experience could have influenced the detection rate. Second, it was a retrospective study with a small sample size. Third, the histopathological results were considered to be the reference standard, even if a negative cognitive biopsy could not completely rule out a local recurrence; the anastomotic biopsy, in fact, suffers from low sensitivity such as 40-71% for PSA level > 1 ng/ml and 14-45% for PSA < 1 ng/ml (21). Targeted biopsy, with TRUS fusion software-assisted or MRI in-bore technique, could increase the detection rate of local recurrence, although the procedure may be more complex in this setting and its effectiveness still to be demonstrated. However, the majority of patients included in this population were treated before the fusion software was available in our centre, so each anastomotic biopsy was performed by cognitive technique. For the reasons described above, in patients with negative anastomotic biopsy it is very important to establish a correct follow-up. First of all, pathologic features (such as pGS, pT and margins and nodal status) should be considered to assess the risk of local recurrence and the kinetics value of PSA (including PSA doubling time and PSA velocity) should be the most important parameters to manage the follow-up. For example, a salvage radiotherapy can be considered or further mpMRI and targeted biopsy may be repeated at 6 months in case of persistent PSA increase with low PSA doubling time, while other examinations (i.e PSMA-PET/CT) should be considered in case of high PSA doubling time due to the increased risk of nodal or systemic recurrence (11). However, in our population a negative clinical follow-up for up 2 years was considered to reduce this bias.

4. Patel P, Mathew MS, Trilisky I, Oto A. Multiparametric MR Imaging of the prostate after treatment of prostate cancer. Radiographics. 2018; 38:437-449.

CONCLUSIONS

13. Casciani E, Polettini E, Carmenini E, et al. Endorectal and dynamic contrast-enhanced MRI for detection of local recurrence after radical prostatectomy. AJR Am J Roentgenol. 2008; 190:11871192.

Some important conclusions can be reached. Although mpMRI is rarely used by urologists in the clinical setting of local recurrence (22), many evidences have actually shown its high diagnostic performance. We confirm that DCE is the most accurate sequence in the detection of local recurrence; however, the combination of DWI+DCE was found to be particularly reliable. Moreover, specificity could be further improved by the analysis of the signal I/T curve. T2w imaging provided a morphological evaluation by identifying the site and the dimensions of the recurrences. Thus, the utility of MRI in the detection of local recurrences is tied to the multiparametric technique, with all sequences providing useful information.

REFERENCES

1. Expert Panel on Urologic Imaging: Froemming AT, Verma S, Eberhardt SC et al. ACR appropriateness criteria® post-treatment follow-up prostate cancer. J Am Coll Radiol. 2018; 15(5S):S132S149. 2. Potretzke TA, Froemming AT, Gupta RT. Post-treatment prostate MRI. Abdom Radiol. 2020; 45:2184-2197. 3. Gaur S, Turkbey B. Prostate MR Imaging for posttreatment evaluation and recurrence. Radiol Clin North Am. 2018; 56:263-275.

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5. Panebianco V, Barchetti F, Sciarra A, et al. Prostate cancer recurrence after radical prostatectomy: the role of 3-T diffusion imaging in multi-parametric magnetic resonance imaging. Eur Radiol. 2013; 23:1745-1752. 6. Epstein JI, Egevad L, Amin MB, et al; Grading Committee. The 2014 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma: definition of grading patterns and proposal for a new grading system. Am J Surg Pathol. 2016; 40:244-252. 7. Bianchi L, Gandaglia G, Fossati N, et al. Pelvic lymph node dissection in prostate cancer: indications, extent and tailored approaches. Urologia. 2017; 84:9-19. 8. Bianchi L, Schiavina R, Borghesi M, et al. Patterns of positive surgical margins after open radical prostatectomy and their association with clinical recurrence. Minerva Urol Nefrol. 2020; 72:464-473. 9. Drudi FM, Giovagnorio F, Carbone A, et al. Transrectal colour Doppler contrast sonography in the diagnosis of local recurrence after radical prostatectomy--comparison with MRI. Ultraschall Med. 2006; 27:146-151. 10. De Visschere PJL, Standaert C, Fütterer JJ, et al. A systematic review on the role of imaging in early recurrent prostate cancer. Eur Urol Oncol. 2019; 2:47-76. 11. Ceci F, Bianchi L, Borghesi M, et al. Prediction nomogram for 68Ga-PSMA-11 PET/CT in different clinical settings of PSA failure after radical treatment for prostate cancer. Eur J Nucl Med Mol Imaging. 2020; 47:136-146. 12. Allen SD, Thompson A, Sohaib SA. The normal post-surgical anatomy of the male pelvis following radical prostatectomy as assessed by magnetic resonance imaging. Eur Radiol. 2008; 18:12811291.

14. Cirillo S, Petracchini M, Scotti L, et al. Endorectal magnetic resonance imaging at 1.5 Tesla to assess local recurrence following radical prostatectomy using T2-weighted and contrast-enhanced imaging. Eur Radiol. 2009; 19:761-769. 15. Kitajima K, Hartman RP, Froemming AT, et al. Detection of local recurrence of prostate cancer after radical prostatectomy using endorectal coil MRI at 3 T: addition of DWI and dynamic contrast enhancement to T2-weighted MRI. AJR Am J Roentgenol. 2015; 205:807-816. 16. Sciarra A, Panebianco V, Salciccia S, et al. Role of dynamic contrast-enhanced magnetic resonance (MR) imaging and proton MR spectroscopic imaging in the detection of local recurrence after radical prostatectomy for prostate cancer. Eur Urol. 2008; 54:589-600. 17. Girometti R, Cereser L, Bonato F, Zuiani C. Evolution of prostate MRI: from multiparametric standard to less-is-better and different-is better strategies. Eur Radiol Exp. 2019; 3:5. 18. Robertson NL, Sala E, Benz M, et al. Combined whole body and multiparametric prostate magnetic resonance imaging as a 1-step approach to the simultaneous assessment of local recurrence and metastatic disease after radical prostatectomy. J Urol. 2017; 198:65-70.

mpMRI for prostate cancer recurrence

19. Turkbey B, Rosenkrantz AB, Haider MA, et al. Prostate imaging reporting and data system version 2.1: 2019 update of prostate imaging reporting and data system version 2. Eur Urol. 2019; 76:340-351. 20. Sella T, Schwartz LH, Swindle PW, et al. Suspected local recurrence after radical prostatectomy: endorectal coil MR imaging. Radiology. 2004; 231:379-385.

21. Rouvière O, Vitry T, Lyonnet D. Imaging of prostate cancer local recurrences: why and how? Eur Radiol. 2010; 20:1254-66. 22. 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; 92:291-296.

Correspondence Caterina Gaudiano, MD (Corresponding Author) caterina.gaudiano@aosp.bo.it caterina.gaudiano@gmail.com Federica Ciccarese, MD Beniamino Corcioni, MD Antonio De Cinque, MD Rita Golfieri, MD Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna Via Albertoni, 15 - 40138 Bologna, Italy Francesca Giunchi, MD Department of Pathology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna (Italy) Michelangelo Fiorentino, MD Department of Specialty, Diagnostic and Experimental Medicine, University of Bologna, Via Massarenti 9, Bologna, Italy Lorenzo Bianchi, MD Riccardo Schiavina, MD Eugenio Brunocilla, MD Department of Urology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna (Italy)

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

ORIGINAL PAPER

DOI: 10.4081/aiua.2022.1.32

Do all patients with suspicious prostate cancer need Multiparametric Magnetic Resonance Imaging before prostate biopsy? Sara Teixeira Anacleto 1, Joana Neves Alberto 2, Emanuel Carvalho Dias 1, 2, Pedro Sousa Passos 3, Mário Cerqueira Alves 2 1 Department

of Urology - Hospital of Braga, Braga, Portugal; and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal; 3 Department of Urology - Hospital da Senhora da Oliveira, Guimarães, Portugal. 2 Life

Summary

Objectives: Multiparametric magnetic resonance imaging (mpMRI) is a useful tool to diagnose prostate cancer (PCa) but its cost is not negligible. In order to reduce costs and minimize time to diagnosis, it is necessary to establish which patients benefit the most from doing mpMRI prior to prostate biopsy (PB). Our aim was to test if mpMRI still predicts PCa and clinically significant PCa (csPCa) in patients with high clinical suspicion of cancer, defined as prostate specific antigen (PSA) > 10 ng/ml, PSA-Density (PSAD) > 0.15 ng/ml/cc or suspicious digital rectal examination (DRE). Materials and methods: We retrospectively collected data on 206 patients who underwent mpMRI before PB at our Department from January 2017 to July 2018. mpMRI results were classified using Prostate Imaging Reporting and Data System (PI-RADS) version 2. In primary analysis, we evaluated the association of mpMRI with PCa and csPCa and stratified this model for low and high clinical suspicion of cancer. In secondary analysis, we determined the rate of negative PB results in patients with high suspicion of cancer and compared theses rates with those obtained if only those with PI-RADS 3-5 would be biopsied. Results: In primary analysis and overall, mpMRI was predictive of PCa and csPCa. In stratified analysis, mpMRI was still significantly associated with csPCa in patients with PSA > 10 ng/ml and PSAD > 0.15 ng/ml/cc, but not in those with suspicious DRE. In secondary analysis, negative result rates were lower if only patients with PI-RADS 3-5 were biopsied, even in subgroups with high suspicion of cancer based on PSA and PSAD. In patients with suspicious DRE, however, the rate of negative results did not change significantly if only patients with PI-RADS 3-5 were biopsied. Conclusions: mpMRI is still useful in predicting csPCa in patients with PSA > 10 ng/mL and PSAD > 0.15 ng/ml/cc. If DRE is suspicious, though, mpMRI might be no longer useful in the prediction of PCa.

KEY WORDS: Prostate cancer; PSA; PSA density; Digital rectal examination; mpMRI; PI-RADS. Submitted 17 February 2022; Accepted 21 February 2022

INTRODUCTION

Prostate cancer (PCa) is the second most common cancer among men worldwide (1). Serum prostate specific antigen

(PSA) and digital rectal examination (DRE) are the common initial assessments for detection. A suspicious DRE or a PSA higher than 4 ng/ml are generally considered an indication for prostate biopsy (PB) (2). In fact, a suspicious DRE is associated with a higher risk of PCa independently of the PSA levels (3). The gold standard for PCa diagnosis is the transrectal ultrasound (TRUS)-guided PB. Nonetheless this technique has some limitations. TRUS-guided PB may miss up to 20% of cancers (4). Additionally, a large proportion of detected cancers are clinically insignificant (5), contributing to overdiagnosis and overtreatment of indolent tumors which may adversely impact quality of life without altering survival (6). Multiparametric magnetic resonance imaging (mpMRI) promises to overcome these problems, distinguishing significant from insignificant disease and avoiding unnecessary PB (7, 8). Compared with radical prostatectomy specimens, mpMRI detects 85-95% of clinically significant PCa (csPCa) (9) and has negative predictive values of 8394% (9, 10). Additionally, mpMRI preferentially detects csPCa and thus may help to avoid unnecessary PB for benign or insignificant lesions, reducing overtreatment (8, 11). As a result, 64% of urologists consider mpMRI useful to detect PCa in biopsy-naïve men, while 97% consider it valuable in men with a prior negative biopsy (12). However, the systematic use of mpMRI as a triage test in patients with suspicion of PCa is still a matter of debate (13, 14). Moreover, mpMRI cost is not neglectable (8) and may delay PB. In order to avoid unnecessary costs and minimize time to diagnosis, it is necessary to establish which patients benefit the most from doing mpMRI prior to TRUS-guided PB. We hypothesize that mpMRI may not add value to the detection of PCa in patients with a high clinical suspicion of cancer and mpMRI could be dispensable in this group of patients, saving costs and time to diagnosis. The aim of this study is to determine if mpMRI prior to PB is still useful in predicting PCa and csPCa in patients with high clinical suspicion of cancer, defined as PSA > 10 ng/ml, PSA-Density (PSAD) > 0.15 ng/ml/cc or suspicious digital rectal examination (DRE). No conflict of interest declared.

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Is magnetic resonance imaging always needed?

MATERIALS

AND METHODS

Patients demographics and variables This study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Hospital de Braga. We retrospectively collected data on 594 patients who underwent TRUS-guided PB at the Urology Department of Hospital de Braga from January 2017 to July 2018. 206 patients who underwent mpMRI before PB were included in our study. For patients who underwent repeated PB during this period, the last biopsy was taken as reference. Data on age, previous biopsies, DRE, PSA, prostate volume (assessed by TRUS), PSAD, PI-RADS and PB histological results were recorded. PSAD was determined only in patients who underwent TRUS before biopsy (PSAD = PSA/Prostate volume). DRE was described as unequivocal (normal and abnormal) or doubtful (if no definitive conclusions could be made). mpMRI mpMRI was performed using a 1.5 Tesla system. Three sequences were used: T2-weighted, dynamic contrastenhanced and diffusion weighed images. For diffusion weighed images, b-values 0-1700 were used. Apparent diffusion coefficient-maps were calculated using diffusion weighed images. Suspicious lesions were scored according to the validated PI-RADS version 2. In our study, the highest PI-RADS score of each mpMRI scan was used. Taking into account the meaning of PI-RADS categories (15) and similarly to other studies (16), PI-RADS score was categorized in 1-2 (used as reference) and 3-5. TRUS-guided PB All men underwent randomized TRUS guided-PB. Twelve randomized cores (6 from right lobe and 6 from left lobe) were taken with no additional cores to suspicious lesions. Histopathological analysis was performed at our Hospital. PCa was classified according to the International Society of Urological Pathology standards and csPCa was defined as Gleason score ≥ 7 (3+4).

RESULTS Patients’ demographics 206 patients underwent mpMRI and were included in our study. Patient’s characteristics, PI-RADS scores and histological results are shown in Table 1. Median (IQR) age was 67 (61-72) years and median prostate volume was 45.9 (35-66) cc. Median PSA and PSAD were 8.55 (5.74-12.7) ng/ml and 0.17 (0.11-0.26) ng/ml/cc, respectively. DRE was described as unequivocal for 130 patients, with 51 patients (24.76%) classified as suspicious. 79 patients (38.35%) patients had previously undergone PB for suspicious PSA or DRE. 34 patients (16.5%) had a normal mpMRI PI-RADS score (PI-RADS 1-2) and 172 patients (83.5%) had a suspicious PI-RADS (PI-RADS 3-5). PB result was normal in 78 (37.86%) patients, while 128 (62.14%) had PCa and 100 (48.54%) had csPCa. Prediction of prostate cancer and clinically significant prostate cancer As primary analysis, chi-squared test was used to test if PI-RADS was a predictor of PCa and csPCa, with results shown in Table 2. After, we stratified these results for low versus high clinical suspicion of PCa, defined as PSA ≤ 10 versus PSA > 10 ng/ml, PSAD ≤ 0.15 versus PSAD > 0.15 ng/ml/cc and norTable 1. Patients’ characteristics. Variable Age (years) median (IQR) Previous biopsy No n (%) Yes n (%) DRE Doubtful Unequivocal Normal Suspicious Prostate volume (cc) median (IQR) PSA (ng/ml) median (IQR) PSA density (ng/ml/cc) median (IQR) PI-RADS

Statistical analysis Variables analyzed were age, previous biopsy (yes/no), DRE, prostate volume, PSAD, PI-RADS, PCa and csPCa. Continuous variables were expressed as median and interquartile range (IQR). Categorical variables were Prostate cancer No % (n) expressed as absolute and relative frequencies. Yes % (n) For the primary analysis, the chi-squared test was perClinically significant prostate cancer formed to evaluate the association of mpMRI with PCa and No % (n) csPCa. Thereafter, this model was stratified for different Yes % (n) PSA and PSAD cutoffs as well as DRE. When n was low, Fisher’s-Exact Test Table 2. was used to evaluate this association. Association of PI-RADS with PCa and csPCa. A p < 0.05 was considered to indicate statistical significance. Prostate cancer For the secondary analysis, negative N No cancer PCa P PB result rates and false negative rates 206 PI-RADS 1-2 22 (64.71%) 12 (35.29%) < 0.001* of mpMRI were also calculated. PI-RADS 3-5 56 (32.56%) 116 (67.44%) Statistical analysis was performed P: p-value; *Chi-Squared Test. using Stata version 15.

N 206 206 206

1 2 3 4 5

138 206 138 206

206 206

Value 67 (61-72) 127 (61.65%) 79 (38.35%) 76 (36.89%) 79 (38.35%) 51 (24.76%) 45.9 (35-66) 8.55 (5.74-12.7) 0.17 (0.11-0.26) 18 (8.74%) 16 (7.77%) 38 (18.45%) 66 (32.04%) 68 (33.01%) 78 (37.86%) 128 (62.14%) 106 (51.46%) 100 (48.54%)

Significant prostate cancer No Cancer csPCa P 29 (85.29%) 5 (14.71%) < 0.001* 76 (44.19%) 96 (55.81%)

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Table 3. Association of PI-RADS with PCa and csPCa stratified for PSA ≤ 10 ng/ml and > 10 ng/ml and PSAD ≤ 0.15 ng/ml/cc and > 0.15 ng/ml/cc. N PSA ≤ 10 ng/ml

127

PSA > 10 ng/ml

PSAD ≤ 0.15 ng/ml/cc

PSAD > 0.15 ng/ml/cc

No cancer PI-RADS 1-2 PI-RADS 3-5 PI-RADS 1-2 PI-RADS 3-5 PI-RADS 1-2 PI-RADS 3-5 PI-RADS 1-2 PI-RADS 3-5

12 (60.0%) 38 (35.51%) 10 (71.43%9 18 (27.69%) 10 (71.43%) 21 (47.73%) 8 (66.67%) 10 (14.71%)

Prostate cancer PCa

8 (40.0%) 0.004* 69 (64.49%) 4 (28.57%) 0.004** 47 (72.31%) 4 (28.57%) 0.139** 23 (52.27%) 4 (33.33%) < 0.001** 58 (85.29%)

Significant prostate cancer No Cancer csPCa P 16 (80.0%) 55 (51.40%) 13 (92.86%) 21 (32.31%) 13 (92.86%) 27 (61.36%) 10 (83.33%) 17 (25.0%)

4 (20.0%) 0.018* 52 (48.60%) 1 (7.14%) < 0.001** 44 (67.69%) 1 (7.14%) 0.044** 17 (38.64%) 2 (16.67%) < 0.001** 51 (75.0%)

P: p-value; *Chi-Squared Test; **Fisher’s Exact Test.

Table 4. Association of PI-RADS with PCa and csPCa stratified for normal and suspicious DRE. N Normal DRE

Suspicious DRE

PI-RADS 1-2 PI-RADS 3-5 PI-RADS 1-2 PI-RADS 3-5

No cancer

Prostate cancer PCa

14 (70.0%) 21 (35.59%) 2 (50.0%) 8 (17.02%)

6 (30.0%) 38 (64.41%) 2 (50.0%) 39 (82.98%)

P 0.007* 0.168**

Significant prostate cancer No Cancer csPCa P 18 (90.0%) 32 (54.24%) 2 (50.0%) 13 (27.66%)

P: p-value; *Chi-Squared Test; **Fisher’s Exact Test.

mal DRE versus suspicious DRE, respectively (Tables 3, 4). In our primary analysis, we found that PI-RADS 3-5 was a significant predictor of both PCa and csPCa (p < 0.001). Low vs. high risk based on PSA After stratification in low vs. high risk based on PSA, we found that in patients with low clinical suspicion of PCa (PSA ≤ 10 ng/ml), PI-RADS 3-5 was a significant predictor of PCa and csPCa (p = 0.004 and p = 0.018, respectively) and that in patients with high PSA levels (PSA > 10 ng/ml), PI-RADS 3-5 was also significantly associated with PCa and csPCa (p = 0.004 and p < 0.001, respectively). Low vs. high risk based on PSAD In stratified analysis by clinical suspicion based on PSAD, we found that in patients with low clinical suspicion of cancer (PSAD ≤ 0.15 ng/ml/cc), PI-RADS 3-5 was a predictor of csPCa (p = 0.044). However, in this group, PIRADS 3-5 was not significantly associated with PCa (p = 0.139). In patients with high clinical suspicion of PCa (PSAD > 0.15 ng/ml/cc), PI-RADS 3-5 was significantly associated with both PCa and csPCa (p < 0.001). Low vs. high risk based on DRE In stratified analysis by clinical suspicion based on DRE, we found that in patients with low clinical suspicion of cancer (normal DRE), PI-RADS 3-5 was a predictor of both PCa and csPCa (p = 0.007 and p = 0.004, respectively). Conversely, in patients with suspicious DRE, PIRADS 3-5 was neither associated with PCa nor with csPCa (p = 0.168 and p = 0.571, respectively). Noticeably, in this group of patients, only 4 patients (7.84%) with suspicious DRE had normal mpMRI findings (PI-RADS 1-2) and out of them 2 (50%) had csPCa.

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Negative prostate biopsy (PB) result rates of prostate cancer and clinically significant prostate cancer As secondary analysis, we evaluated the rate of negative PB in the subgroup of patients with PI-RADS 3-5. These results are shown in Table 5. In total, 37.9% of patients biopsied had no PCa and 51% no csPCa. If only patients with PI-RADS 3-5 were considered, negative PB rate dropped to 27.2% and 36.9% for PCa and csPCa respectively. The rate of patients with PCa and csPCa and PIRADS 1-2 who would not be biopsied or diagnosed with this approach (false negative rate) would be 5.8% and 2.4%, respectively.

Patients with high risk based on PSA Among patients with PSA > 10 ng/ml, 2 (10.0%) 0.004* the rate of negative PB was 35.4% for 27 (45.76%) PCa and 43% for csPCa. 2 (50.0%) 0.571** Patients with PSA > 10 ng/ml and PI34 (72.34%) RADS 3-5 did not have PCa and csPCa in 22.8% and 26.6% respectively. If among patients with PSA > 10 ng/m, only those with PI-RADS 3-5 were biopsied, the false negative rates would be 5.1% for PCa and 1.3% for csPCa. Patients with high risk based on PSAD Patients with PSAD > 0.15 ng/ml/cc had a negative PB result rate of 22.5% for PCa and of 33.8% for csPCa, respectively. Patients with PSAD > 0.15 and PI-RADS 3-5 had no PCa in 12.5% and no csPCa in 21.3%. If only patients with PIRADS 3-5 were biopsied, 5.0% of patients with PCa and 2.5% of patients with csPCa would be missed. Patients with high risk based on DRE Patients with suspicious DRE had no PCa in 19.6% and no csPCa in 29.4%. If only patients with suspicious DRE and PI-RADS 3-5 had undergone biopsy, 15.7% would have no PCa and 25.5% would have no csPCa. According to this approach, 3.9% of patients with suspicious DRE and PI-RADS 1-2 bearing PCa or csPCa would be missed. Table 5. Negative PB result rates and false negative rates for PCa and csPCa globally and in patients with PI-RADS 3-5 in different subgroups.

Total PSA > 10 ng/ml PSAD > 0.15 ng/ml/cc Suspicious DRE

Total NPBR 37.9% 35.4% 22.5% 19.6%

PCa PI-RADS 3-5 NPBR FNR 27.2% 5.8% 22.8% 5.1% 12.5% 5.0% 15.7% 3.9%

NPBR: Negative PB result rates; FNR: False negative rates.

Total NPBR 51% 43% 33.8% 29.4%

csPCa PI-RADS 3-5 NPBR FNR 36.9% 2.4% 26.6% 1.3% 21.3% 2.5% 25.5% 3.9%

Is magnetic resonance imaging always needed?

DISCUSSION

To our knowledge, this is the first study to test mpMRI accuracy in detection of PCa stratified by clinical suspicion of cancer based on various clinical markers, including PSA, PSAD, and DRE. According to the European Association of Urology guidelines, mpMRI before biopsy could improve the detection csPCa in two different ways. First it allows to target specific lesions visible on mpMRI. Secondly, mpMRI could be used as a triage test before biopsy, so that mpMRI-PB would be performed only in case of a positive mpMRI whereas patients with negative mpMRI findings would not undergo prostate biopsy at all. Based on this assumption most studies focused on using mpMRI to avoid PB and diagnosis of clinical insignificant PCa (17), rather than evaluating where mpMRI can add value compared to standard clinical tools alone. The PROMIS trial showed high sensitivity and high negative predictive value of mpMRI for the detection of csPCa, defined as Gleason score ≥ 7 (4+3) or cancer core length ≥ 6 mm. However, the false-positive rate for mpMRI was 49%, needing follow-up biopsy sampling to confirm suspicious findings. Moreover, as negative and positive predictive values depend on prevalence, it becomes mandatory to pre-evaluate the risk of csPCa in patients with a suspicion of PCa (16). Biomarkers and nomograms are very helpful in this setting, but standard clinical examination should remain of pivotal importance (18). Our primary analysis among all included patients unsurprisingly demonstrated that mpMRI PI-RADS 3-5 was associated both with PCa and csPCa, as previously described (7-10). After stratification by clinical suspicion of PCa, also as expected, in patients with low clinical suspicion of PCa, defined as PSA ≤ 10 ng/ml, PSAD ≤ 0.15 ng/ml/cc and normal DRE, mpMRI PI-RADS 3-5 was significantly associated with PCa in most evaluations (except for lowest PSAD values ≤ 0.15 ng/ml/cc) and with diagnosis of csPCa in all evaluations. However, importantly we observed that among patients with high clinical suspicion of PCa, defined as PSA > 10 ng/ml and PSAD > 0.15 ng/ml/cc, mpMRI PI-RADS 3-5 remained significantly associated with csPCa and PCa. However, in patients with high clinical suspicion of PCa based on DRE, mpMRI PI-RADS 3-5 was not significantly associated with PCa or csPCa. The main explanation of this finding is that almost all patients with an unequivocal abnormal DRE have a mpMRI PI-RADS of 3-5. Altogether, these findings demonstrate an added value of mpMRI even among patients with PSA > 10 ng/ml and PSAD > 0.15 ng/ml/cc. Patients with suspicious DRE, however, might not benefit from mpMRI for the PB diagnosis of cancer. Our secondary analysis showed that the rate of negative PB results would drop significantly if PB was only performed in patients with PI-RADS 3-5. The rate of negative PB results was 37.9% vs 27.2% for PCa and 51% vs 36.9% for csPCa when the total rate was compared with the rate in patients with PI-RADS 3-5. Even in subgroups with high clinical suspicion of cancer, defined as PSA > 10ng/ml and PSAD > 0.15 ng/ml/cc, mpMRI would be useful to avoid unnecessary PB. The rate of negative PB results was 35.4% vs 22.8% for PCa and 43% vs 26.6%

for csPCa when total rate was compared with the rate in patients with PI-RADS 3-5 and PSA > 10 ng/ml and 22.5% vs 12.5% for PCa and 33.8% vs 21.3% for csPCa when total rate was compared with the rate in patients with PI-RADS 3-5 and PSAD > 0.15 ng/ml/cc. mpMRI was thus helpful in selecting patients with PCa and csPCa who needed to undergo PB even in the subgroup with high clinical suspicion of cancer, defined as PSA > 10 ng/ml and PSAD > 0.15 ng/ml/cc. However, in patients with suspicious DRE performing PB only in those with PI-RADS 3-5 would not change significantly the rate of negative PB results. The negative PB result rate was 19.6% vs 15.7% for PCa and 29.4% vs 25.5% for csPCa when total rate was compared with the rate in patients with PI-RADS 3-5. In addition, this 4% reduction was obtained at the cost of a false negative rate of 3.9%. Therefore, in line with primary analysis’ findings, patients with suspicious DRE do not benefit from mpMRI before PB. For the first time, we specifically report the utility of mpMRI in patients with high clinical suspicion of cancer. Contrary to our hypothesis, when PSA was > 10 ng/ml and PSAD > 0.15 ng/ml/cc, mpMRI was still useful in discriminating PCa and csPCa. However, according to our hypothesis, if DRE is suspicious, mpMRI might no longer be necessary to aid in the PB diagnosis of cancer. It is true that omitting mpMRI, many PCas of anterior gland could be undetected to the standard TRUS guidedPB (19), but several studies assessed the importance to detect anterior PCa with discordant findings (20). The optimization of the TRUS guided-PB technique is, anyway, decisive. This study has some limitations. Firstly, our gold standard was systematic PB and not targeted PB or final prostatectomy specimens and therefore some men with negative PB result may have had PCa. Secondly, mpMRI images were reviewed by different radiologists, which may weaken internal validity, although this condition could represent better every day clinical practice.

CONCLUSIONS

We think to report the first study to evaluate the accuracy of mpMRI in patients with different clinical suspicion of PCa. PI-RADS 3-5 was predictive of csPCa even when PSA was > 10 ng/ml and PSAD > 0.15 ng/ml/cc. Therefore, mpMRI should be performed also in this set of patients with high clinical suspicion of cancer. In patients with suspicious DRE, mpMRI seems not to be significantly associated with cancer and it may be avoided to reduce costs and save time to diagnosis in this particular group of patients.

REFERENCES

1. Center MM, Jemal A, Lortet-Tieulent J, et al. International variation in prostate cancer incidence and mortality rates. Eur Urol. 2012; 61:1079-92. 2. Aminsharifi A, Howard L, Wu Y, et al. Prostate specific antigen density as a predictor of clinically significant prostate cancer when the prostate specific antigen is in the diagnostic gray zone: defining the optimum cutoff point stratified by race and body mass index. J Urol. 2018; 200:1-9. 3. Galosi AB, Palagonia E, Scarcella S, et al. Detection limits of sigArchivio Italiano di Urologia e Andrologia 2022; 94, 1

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nificant prostate cancer using multiparametric MR and digital rectal examination in men with low serum PSA: up-date of the Italian Society of Integrated Diagnostic in Urology. Arch Ital Urol Androl. 2021; 93:92-100.

12. 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; 92:291-296.

4. Rabbani F, Stroumbakis N, Kava BR, et al. Incidence and clinical significance of false-negative sextant prostate biopsies. J Urol. 1998; 159:1247-50.

13. Panebianco V, Barchetti G, Simone G,, et al. Negative multiparametric magnetic resonance imaging for prostate cancer: what’s next? Eur Urol. 2018; 74:48-54.

5. Grenabo Bergdahl A, Wilderang U, Aus G, et al. Role of magnetic resonance imaging in prostate cancer screening: a pilot study within the Goteborg randomised screening trial. Eur Urol. 2016; 70:566-73.

14. Mottet N, Cornford P, van den Bergh RCN, et al. EAU-EANMESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer. https:// uroweb.org/wp-content/uploads/EAU-EANM-ESTRO_ESUR_ISUP_ SIOG-Guidelines-on-Prostate-Cancer-2021.pdf

6. Pokorny MR, de Rooij M, Duncan E, et al. Prospective study of diagnostic accuracy comparing prostate cancer detection by transrectal ultrasound-guided biopsy versus magnetic resonance (MR) imaging with subsequent MR-guided biopsy in men without previous prostate biopsies. Eur Urol. 2014; 66:22-9. 7. Brizmohun Appayya M, Sidhu HS, Dikaios N, et al. Characterizing indeterminate (Likert-score 3/5) peripheral zone prostate lesions with PSA density, PI-RADS scoring and qualitative descriptors on multiparametric MRI. Br J Radiol. 2018; 91:20170645. 8. Barnett CL, Davenport MS, Montgomery JS, et al. Cost-effectiveness of magnetic resonance imaging and targeted fusion biopsy for early detection of prostate cancer. BJU Int. 2018; 122:50-8. 9. Radtke JP, Wiesenfarth M, Kesch C, et al. Combined clinical parameters and multiparametric magnetic resonance imaging for advanced risk modeling of prostate cancer-patient-tailored risk stratification can reduce unnecessary biopsies. Eur Urol. 2017; 72:888-96. 10. Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet (London, England). 2014; 384:2027-35. 11. Meng X, Rosenkrantz AB, Mendhiratta N, et al. Relationship between prebiopsy multiparametric magnetic resonance imaging (MRI), biopsy indication, and MRI-ultrasound fusion-targeted prostate biopsy outcomes. Eur Urol. 2016; 69:512-7.

Correspondence Sara Teixeira Anacleto, MD (Corresponding Author) sara.anacleto241@gmail.com Emanuel Carvalho Dias, MD emanueldias@med.uminho.pt Department of Urology, Hospital of Braga, Braga (Portugal) Joana Neves Alberto, MD joana.alberto26@gmail.com Mário Cerqueira Alves, MD mario.alves@hb.min-saude.pt Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga (Portugal) Pedro Sousa Passos, MD pedrosousapassos@gmail.com Department of Urology, Hospital da Senhora da Oliveira, Guimarães (Portugal)

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15. Weinreb JC, Barentsz JO, Choyke PL, et al. PI-RADS Prostate Imaging - Reporting and Data System: 2015, Version 2. Eur Urol. 2016; 69:16-40. 16. Washino S, Okochi T, Saito K, et al. Combination of prostate imaging reporting and data system (PI-RADS) score and prostatespecific antigen (PSA) density predicts biopsy outcome in prostate biopsy naive patients. BJU Int. 2017; 119:225-33. 17. Ahmed HU, El-Shater Bosaily A, Brown LC, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet (London, England). 2017; 389:815-22. 18. Cormio L, Cindolo L, Troiano F, et al. Development and internal validation of novel nomograms based on benign prostatic obstructionrelated parameters to predict the risk of prostate cancer at first prostate biopsy. Front Oncol. 2018; 8:438. 19. Komai Y, Numao N, Yoshida S, et al. High diagnostic ability of multiparametric magnetic resonance imaging to detect anterior prostate cancer missed by transrectal 12-core biopsy. J Urol. 2013; 190:867-73. 20. Ekin RG, Zorlu F, Akarken I, et al. Anterior apical cores in the initial prostate biopsy does not increase detection of significant prostate cancer. Urol J. 2015; 12:2084-9.

DOI: 10.4081/aiua.2022.1.37

ORIGINAL PAPER

Minimally invasive simple prostatectomy: Robotic-assisted versus laparoscopy. A comparative study Michele Amenta 1, Francesco Oliva 1, Biagio Barone 2, Alfio Corsaro 1, Davide Arcaniolo 3, Antonio Scarpato 2, Gennaro Mattiello 2, Lorenzo Romano 2, Carmine Sciorio 4, Tommaso Silvestri 5, Giovanni Costa 5, Felice Crocetto 2, Antonio Celia 5 1 Urology

Unit, Azienda ULSS n.4 Veneto Orientale, Portogruaro, Italy; of Neuroscience, Reproductive Sciences and Dentistry, University of Naples Federico II, Naples, Italy; 3 Department of Woman, Child and General and Specialized Surgery, Urology Unit, University of Campania Luigi Vanvitelli, Naples, Italy; 4 Unit of Urology, ASST Manzoni, Lecco, Italy; 5 Department of Urology, San Bassiano Hospital, Bassano del Grappa, Italy. 2 Department

Summary

Purpose: Robotic-assisted simple prostatectomy (RASP) is a novel surgical procedure for the management of obstructive symptoms caused by enlarged prostate glands. Before the introduction of minimally invasive techniques, the standard approach was the open simple prostatectomy (OSP). The aim of our study was to compare intraoperative and perioperative outcomes of robotic (RASP) and laparoscopic (LSP) simple prostatectomy. Methods: We retrospectively analyzed data from patients who underwent minimally invasive simple prostatectomy at the Urological Department of Portogruaro Hospital, Portogruaro, and at the Urological Department of “San Bassiano” Hospital, in Bassano del Grappa, from March 2015 to December 2020. Data collected from medical records included age, body mass index, prostate volume, operative time, preoperative International Prostatic Symptoms Score (IPSS), postoperative IPSS, time with drainage, blood transfusion, intraoperative complications, perioperative complications and length of hospital stay. Results: Robotic-assisted (n = 25) and laparoscopic simple prostatectomy (n = 25) were performed with a transvesical approach. No significant differences were observed regarding baseline characteristics, body mass index, prostate volume and IPSS. Operative time was lower in the laparoscopic group (122 min vs 139 min) (p = 0.024), while hospital stay was lower in the robotic group (4 days vs 6 days) (p = 0.047). Conclusions: Robotic-assisted simple prostatectomy is a safe technique with results comparable to laparoscopic simple prostatectomy, encompassing the advantage of a shorter hospitalization. Considering the costs and the limited availability of robotic-assisted simple prostatectomy, laparoscopic simple prostatectomy is a valid and safe alternative for experienced surgeons.

KEY WORDS: Minimally invasive simple prostatectomy; Benign prostatic hyperplasia; Laparoscopy; Robotic-assisted surgery. Submitted 3 February 2022; Accepted 9 February 2022

INTRODUCTION

Benign prostatic hyperplasia (BPH) represents one of the most common diseases in ageing men, affecting over 210 million men worldwide. Up to 50% of men over 50 years experience lower urinary tract symptoms (LUTS) from BPH, requiring medical or surgical therapy (1). Although medical therapy could provide, in selected patients, satisfying results, the superior efficacy and cost-effectiveness of surgery have led more patients and physicians to prefer the surgical approach (2, 3). In addition, urinary retention, impaired renal function and dilatation of the upper urinary tract secondary to obstruction represents a strong indication toward a surgical approach (4). The European Association of Urology (EAU) guidelines currently recommends, for prostate larger than 80 ml, simple prostatectomy, bipolar or monopolar enucleation or laser enucleation/vaporization of the prostate (5). Before the introduction of minimally invasive techniques, as well as novel endoscopic laser approach, open simple prostatectomy (OSP) was considered the gold standard treatment. Despite favorable functional outcomes, which comprehend decreased symptoms score, increased flow and decreased post-void residual, OSP is usually associated with substantial peri and postoperative complications (including prolonged catheterization time, increased estimated blood loss and length of hospital stay), reaching a morbidity rate of 42% and a transfusion rate of 24% (6). In order to overcome those limitations, a variety of minimally invasive surgical techniques have been explored to treat large obstructing prostate adenomas. Since the first laparoscopic simple prostatectomy (LSP) described by Mariano et al., the minimally invasive approach for BPH has widely and quickly extended, up to include the robotic approach, the robot-assisted simple prostatectomy (RASP) (7, 8). Minimal invasive simple prostatectomy, including laparoscopic or robot-assisted approach, presents similar efficacy and safety compared to OSP, although data are still lacking and both procedures should be considered as under investigation (9, 10). The aim of our study was to compare peri and postoperative outcomes of RASP and LSP in two experienced centers.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 1

M. Amenta, F. Oliva, B. Barone, et al.

METHODS

Consecutive patients who underwent minimally invasive prostatectomy from March 2015 to December 2020 at the Urological Department of Portogruaro Hospital, Portogruaro, and Urological Department of “San Bassiano” Hospital, Bassano del Grappa, were retrospectively analyzed. No specific criteria were used to assign patients to either laparoscopic or robotic procedures. Prostate volume was assessed by transrectal ultrasound (TRUS). All procedures, in both hospitals, were performed by an experienced surgeon as first operator. Data collected from medical records were age, body mass index, prostate volume, surgical approach, operative time, blood loss, time with drainage, blood transfusions, intraoperative complications, pre and postoperative International Prostate Symptom Score (IPSS) (collected at least 6 months after surgery), perioperative complications and length of hospital stay. No patients underwent prior abdominal/pelvic surgery. Laparoscopic simple prostatectomy After the induction of general anesthesia, the patient was positioned supine and in slight Trendelenburg on the surgical table. The procedure was performed via transperitoneal approach. A skin incision was made at the umbilical level, entering the abdominal cavity using the Hasson technique and inducing the pneumoperitoneum at 20 mmHg. Five trocars were successively positioned, after the insertion of a 18 F urinary catheter. A 12-mm Hasson trocar for the insertion of 0° optic was placed at the umbilical incision while another 12 mm trocar was positioned along the right margin of lateral rectus, a finger lower on umbilical line, for the insertion of the Harmonic, monopolar scissors, or needle driver. A 5 mm trocar was positioned on the contralateral side (left margin of lateral rectus) for the insertion of a bipolar grasper or needle driver while a 12 mm trocar was placed laterally (8-10 cm from the umbilical trocar) on the right side. Finally, a 5 mm trocar for the suction device was similarly positioned, contralaterally (Figure 1). Figure 1. Trocar configuration for laparoscopic simple prostatectomy.

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The fat covering the prostatic capsule was dissected, while bladder and prostate were identified by moving the urinary catheter. A longitudinal incision was performed approximately 1cm below the bladder neck. Stay sutures were placed between the edges of the open bladder to skin on each side. Ureteral ostia were consequently identified while Harmonic was used for the exposure and development of the plane between the surgical prostate capsule and the adenomatous tissue, proceeding, bluntly, towards the prostatic apex. Using the urinary catheter to facilitate the identification of nearby structures, the dissection proceeded until the whole adenomatous tissue has been freed, separating, carefully, the urethra. After the excision of the adenoma, the specimen was temporarily placed in the lateral prostatic fossa, waiting for further removal. Trigonization was accomplished by two or four sutures of 2-0 Vycril placed posteriorly to the bladder neck and to the internal posterior prostatic fossa. The urinary bladder catheter was then replaced with a 22F irrigation catheter. Robotic-assisted simple prostatectomy Camera port (12 mm) was placed in a midline supraumbilical position. A 12-mm assistant port was placed about 3 cm medially to the right iliac crest. On the lefthand side, an 8-mm robotic port, for the fourth arm, was inserted exactly in the corresponding position of the 12mm assistant port on the right side. Two robotic 8-mm trocars were placed para-rectally on the left- and righthand sides in a more caudal position, at a distance of about 10 cm from the camera port. Lastly, a 5-mm assistant port was placed midway between the camera port and the right robotic port. The procedure was then identical to the laparoscopic one (Figure 2). Statistical analysis Descriptive statistics were reported as median and interquartile range (IQR) for continuous variables, while frequencies and percentages were obtained for categorical Figure 2. Trocar configuration for robotic-assisted simple prostatectomy.

Minimally invasive simple prostatectomy

variables. According to the non-normality of data, assessed via the Kolmogorov-Smirnov test, Mood’s Median Test was utilized, considering, as statistically significant, p < 0.05. Statistical analysis was performed using IBM SPSS Statistics® software (IBM Corp. Released 2017; IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY).

RESULTS

50 simple prostatectomies were performed with a minimally invasive approach. 25 were performed as LSP and 25 as RASP. All cases were successfully performed without proceeding to open surgery conversion and no patient repositioning or change in port assignment/redocking was needed. Median age of patients involved was 71.5 (58-81) while median BMI was 25 (20-38) kg/m2. Both groups were comparable in terms of age, BMI, prostate volume and preoperative IPSS (Table 1). Regarding operative findings, both groups were comparable in terms of blood loss, transfusion rate and complications, albeit patients who underwent RASP reported a longer operative time (139 min; IQR 108225) compared to patients who underwent LSP (122 min; IQR 110-150) (p = 0.024). Overall, median length of hospitalization was 5 days, with a slightly shorter hospitalization in RASP patients (4 days; IQR 3-6) compared to LSP patients (6 days; IQR 4-10) (p = 0.047). Median drainage time was 4 days. All patients had urinary catheter until hospital discharge. Five patients needed a transfusion, and four intraoperative complications were recorded. Postoperative IPSS score was comparable in both groups.

DISCUSSION

Our results suggest that both laparoscopic and robotic prostatectomy can be associated with limited blood loss, short postoperative recovery, and low postoperative complications. Compared to OSP, those characteristics represent a clear advantage. OSP is indeed a demanding procedure, associated with significant perioperative morbidity, that correlates with prostate volume, and blood loss (6). Minimally invasive approaches as LSP and RASP allow minimizing blood losses due to different factors: the use of cauterizing instruments during the enucleation of the adenoma from the surgical capsule; the compressive effect of Table 1. Baseline and perioperative outcomes. Age, years BMI Prostate volume, ml Operative time, min Blood loss, ml Preop IPSS Postop IPSS Drainage time, days Blood transfusion Intraop complication Periop complication Lenght of hospital stay, days

LSP n = 25 72 (65–79) 25,5 (21–30) 141 (100–210) 122 (110–150) 150 (100-500) 29.5 (23–35) 7 (3–9) 5 (3–7) 4 (16%) 2 (8%) 2 (8%) 6 (4–10)

RASP n = 25 71 (58–81) 25 (20–38) 135 (94–245) 139 (108–225) 150 (50-250) 29 (22–32) 3 (2–7.25) 5 (2–12) 1 (4%) 2 (8%) 4 (16%) 4 (3–6)

P 0.572 0.776 0.777 0.024 0.753 0.777 0.396 0.396 0.346 0.602 0,663 0.047

insufflation gas on vessels; the better visualization of bleeding points provided by a better view. The increased field of view associated with both techniques permit, indeed, to manage perioperative bleeding and avoid potentially serious complications as urethral injury, ostia injury or improper dissection plane. As result, the utilization of OSP is steadily decreasing, in favor of minimally and endoscopic approaches, considering, in particular, comparative results in terms of functional outcomes (11-13). In addition, the use of a minimally invasive approach reduces operative time and length of hospital stay, although its cost-effectiveness is still controversial (14, 15). In our study, we sought to compare operative and functional outcomes of both minimally invasive approaches, LSP and RASP. Despite both techniques could be performed via transperitoneal or extraperitoneal approach, in order to minimize potential biases and further considering our higher experience with the laparoscopic transperitoneal approach, both procedures were performed as transperitoneal (16). In addition, we performed in both techniques (LSP and RASP) a transvesical approach. The reason is related, partly to the higher experience with this technique, partly to the possibility of directly visualizing the prostatic adenoma, exploring the bladder and, more importantly, the bladder neck. A possible limitation of this approach, however, is related to the limited visualization of the apex and the potential difficulty in controlling bleeding compared to the retropubic (or Millin) technique. The latter permit, indeed, to properly visualize the remnant adenoma and properly expose the prostate, allowing better control of bleeding (17). Despite those differences, however, clinical outcomes are similar (18). Although data are quite explicative, a few comments are interesting. As reported by our findings, LSP reported a shorter operative time compared to RASP. This could be related, however, to the time needed to dock and prepare the robot, consistently with data reported in the literature (19). Similarly, blood loss and transfusion rates among both approaches were comparable, as well as complications rates (20). Finally, the length of hospital stay was slightly favoring RASP and this could be explained by an improved field of view which permit to avoid unnecessary maneuvers on the gastrointestinal tract and, consequently, a faster recovery. Anyway, this difference was quite clinically insignificant and could be also related to differences related to nonmedical factors. Lastly, although we did not mainly consider the transurethral approach, it has to be acknowledged that the use of novel and powerful lasers which permit, safely and effectively, the enucleation of large prostatic adenomas, represents an important and feasible alternative to OSP in minor centers which do not have the robotic-assisted surgery or enough experience with the laparoscopic approach. In particular, as reported by Schiavina et al., with the same effectiveness in clinical outcomes, Holmium laser enucleation of the prostate (HoLEP) yielded significantly lower costs compared to OSP (2174.15€ versus 4064.97€) (21). However, a relative limitation of HoLEP is related to the necessity of performing at least 25-50 cases to achieve a significant efficacy in this approach (22). We are conscious of several limitations afflicting our study. Firstly, the retrospective nature of our work. Secondly, the Archivio Italiano di Urologia e Andrologia 2022; 94, 1

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limited sample size, partly explained by the limited use of robotic-assisted surgery for non-oncologic diseases. Thirdly, the lack of a standardized follow-up and the potential differences in non-medical factors among hospitals.

CONCLUSIONS

RASP is a safe and efficient technique, showing results comparable to LSP, with the advantage of lower blood loss and hospitalization. Taking into consideration the costs of RASP and the unavailability of robot-assisted surgery in small centers, LSP still represents a valid and safe alternative in the hand of an experienced surgeon. Further studies are necessary to properly evaluate the costeffectiveness of minimally invasive surgery compared to endoscopic approaches.

REFERENCES

15. Demir A, Günseren K, Kordan Y, et al. Open vs laparoscopic simple prostatectomy: a comparison of initial outcomes and cost. J Endourol. 2016; 30:884-9. 16. Stolzenburg JU, Kallidonis P, Kyriazis I, et al. Robot-assisted simple prostatectomy by an extraperitoneal approach. J Endourol. 2018; 32:S39-s43. 17. Noguera RS, Rodríguez RC. Open adenomectomy: past, present and future. Curr Opin Urol. 2008; 18:34-40. 18. Carneiro A, Sakuramoto P, Wroclawski ML, et al. Open suprapubic versus retropubic prostatectomy in the treatment of benign prostatic hyperplasia during resident's learning curve: a randomized controlled trial. Int Braz J Urol. 2016; 42:284-92. 19. Pavan N, Zargar H, Sanchez-Salas R, et al. Robot-assisted versus standard laparoscopy for simple prostatectomy: multicenter comparative outcomes. Urology. 2016; 91:104-10.

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20. Autorino R, Zargar H, Mariano MB, et al. Perioperative outcomes of robotic and laparoscopic simple prostatectomy: a European-American multi-institutional analysis. Eur Urol. 2015; 68:86-94.

2. Fogaing C, Alsulihem A, Campeau L, Corcos J. Is early surgical treatment for benign prostatic hyperplasia preferable to prolonged medical therapy: pros and cons. Medicina. 2021; 57:368

21. 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.

3. Gul ZG, Kaplan SA. BPH: why do patients fail medical therapy? Cur Urol Rep. 2019; 20:1-7. 4. Bortnick E, Brown C, Simma-Chiang V, Kaplan SA. Modern best practice in the management of benign prostatic hyperplasia in the elderly. Ther Adv Urol. 2020; 12:1756287220929486. 5. Gratzke C, Bachmann A, Descazeaud A, et al. EAU guidelines on the assessment of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol. 2015; 67:1099-109. 6. Elshal AM, El-Nahas AR, Barakat TS, et al. Transvesical open prostatectomy for benign prostatic hyperplasia in the era of minimally invasive surgery: Perioperative outcomes of a contemporary series. Arab J Urol. 2013; 11:362-8. 7. Mariano MB, Graziottin TM, Tefilli MV. Laparoscopic prostatectomy with vascular control for benign prostatic hyperplasia. J Urol. 2002; 167:2528-9. 8. Kordan Y, Canda AE, Köseoglu E, et al. Robotic-assisted simple prostatectomy: a systematic review. J Clin Med. 2020; 9:1798. 9. Xia Z, Li J, Yang X, Jing H, et al. Robotic-assisted vs. open simple prostatectomy for large prostates: a meta-analysis. Front Surg. 2021; 8:695318. 10. Lucca I, Shariat SF, Hofbauer SL, Klatte T. Outcomes of minimally invasive simple prostatectomy for benign prostatic hyperplasia: a systematic review and meta-analysis. World J Urol. 2015; 33:563-70. 11. Pariser JJ, Pearce SM, Patel SG, Bales GT. National trends of simple prostatectomy for benign prostatic hyperplasia with an analysis of risk factors for adverse perioperative outcomes. Urology. 2015; 86:721-6. 12. Li J, Cao D, Peng L, et al. Comparison between minimally invasive simple prostatectomy and open simple prostatectomy for large prostates: a systematic review and meta-analysis of comparative trials. J Endourol 2019; 33:767-76. 13. Esposito C, Masieri L, Castagnetti M, et al. Letter to the Editor: robot-assisted and minimally invasive pediatric surgery and urology during the COVID-19 pandemic: a short literature review. J Laparoendosc Adv Surg Tech A. 2020; 30:915-8.

14. Ahmed K, Ibrahim A, Wang TT, et al. Assessing the cost effectiveness of robotics in urological surgery - a systematic review. BJU International. 2012; 110:1544-56.

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

22. Gürlen G, Karkin K. Does Holmium laser enucleation of the prostate (HoLEP) still have a steep learning curve? Our experience of 100 consecutive cases from Turkey. Arch Ital Urol Androl. 2021; 93:412-7.

Correspondence Michele Amenta, MD michele.amenta@aulss4.veneto.it Francesco Oliva, MD francesco.oliva88@gmail.com Alfio Corsaro, MD alfio.corsaro@aulss4.veneto.it Urology Unit, Azienda ULSS n.4 Veneto Orientale, Portogruaro (Italy) Biagio Barone, MD (Corresponding Author) biagio.barone@unina.it Antonio Scarpato, MD antonioscarpato1992@gmail.com Gennaro Mattiello, MD drmattiellogennaro@gmail.com Lorenzo Romano, MD loryromano@hotmail.it Felice Crocetto, MD felice.crocetto@unina.it Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples Federico II, Naples (Italy) Davide Arcaniolo, MD davide.arcaniolo@unicampania.it Department of Woman, Child and General and Specialized Surgery, Urology Unit, University of Campania Luigi Vanvitelli, Naples (Italy) Carmine Sciorio, MD Unit of Urology, ASST Manzoni, Lecco (Italy) carmine.sciorio@gmail.com Tommaso Silvestri, MD tommaso.silve@gmail.com Giovanni Costa, MD gioc30@hotmail.it Antonio Celia, MD antoniocelia@virgilio.it Department of Urology, San Bassiano Hospital, Bassano del Grappa (Italy)

DOI: 10.4081/aiua.2022.1.41

ORIGINAL PAPER

Adverse pathological outcomes of patients with de novo muscle invasive bladder cancer in Northern Ontario Vahid Mehrnoush, Shahrzad Keramati, Asmaa Ismail, Waleed Shabana, Ahmed Zakaria, Hazem Elmansy, Walid Shahrour, Owen Prowse, Ahmed Kotb Urology Department, Northern Ontario School of Medicine, Thunder Bay Regional Health Centre, Ontario, Canada.

Summary

Objective: This study aimed to investigate the clinical and pathological characteristics of patients with de novo muscle-invasive bladder cancer (MIBC) who underwent radical cystectomy in Northern Ontario. Methods: This is a retrospective cross-sectional study of patients with de novo T2 MIBC who underwent radical cystectomy over a 2-year-period in Thunder Bay Regional Health Sciences Centre. Clinical and pathological characteristics of Trans Urethral Resection of Bladder Tumors and cystectomy specimens were analyzed. Results: Of the 59 patients aged 67 ± 8.8 years, predominated by males (80%), 27.1% were younger than age 60. After surgery, upstaging was noted in 59.3% (T3 in 27.1% and T4 in 32.2%) while node positive was noted in 36% of patients. Prostate adenocarcinoma was incidentally discovered in 20 (34%) of patients with 50% considered significant (Gleason score ≥ 7). Downstaging was found in those who had neoadjuvant chemotherapy (p = 0.001). Conclusions: The high prevalence of younger ages (less than 60), a high rate of upstaging, the presence of high-grade incidental prostate cancer, and lymph node positives in T2 de novo MIBC in Northern Ontario, warrants further investigation of potential causes and risk factors at individual, public, and population health levels in the region.

KEY WORDS: Bladder cancer; Cystectomy; Northern Ontario.

sought to provide an overview of de novo T2 muscle invasive bladder cancer of patients who underwent a radical cystectomy in Thunder Bay in order to identify the characteristics of patients with clinically localized muscle invasive bladder carcinoma and to determine their clinical and pathological outcomes.

METHODS

This is a cross-sectional study that retrospectively examined the medical records of 59 patients with documented organ confined de novo T2 muscle invasive bladder cancer confirmed on a diagnostic TURBT who underwent radical cystectomy over a 2 year-period. Clinical and pathological characteristics of TURBT and cystectomy were retrieved. The analysis was conducted using IBM SPSS Software (version 19.0, SPSS Inc., Illinois, USA). The continuous data was presented as mean or median with standard deviation and compared using independent t-test while the categorical data was in percentages and compared using the chisquare test. Statistical significance was defined as p < 0.05. A multivariate regression analysis was performed to identify the significant risk factors for upstaging.

Submitted 10 November 2021; Accepted 8 December 2021

RESULTS INTRODUCTION

According to global cancer statistics, 3% of all new diagnosed cancer and 2.1% of all cancer mortality are due to bladder cancer (1). Bladder cancer is linked to a number of important risk factors, the most prominent of which are smoking, occupational and environmental exposure to carcinogens, and conditions that cause chronic bladder irritation (2). Toxins found in the environment, such as aromatic amines like benzidine and 2-naphthylamine, have been linked to up to 27% of bladder cancers (3). A recent study could identify that patients older than 70year-old with significant comorbidities have less favourable outcomes (4). The projected average annual new cases of bladder cancer in 2018-2022 in Ontario has been estimated at 1950 for males and 660 for females (5). With this knowledge, we

The mean age of the patients was 67 ± 8.8 years. Those aged under 60 years old accounted for 27.1% of the sample. Eighty percent of patients were male. Based on final pathological results, upstaging was noted in 59.3% (T3 in 27.1% and T4 in 32.2%). Thirty-six percent had node-positive disease. Prostate adenocarcinoma was incidentally discovered in 20 (34%) of patients. Significant high-grade prostate cancer was found in 50% of patients. Twenty patients (34%) had their surgery delayed for more than 12 weeks. Overall, 14 patients received neoadjuvant chemotherapy (NAC) (Table 1). Younger patients (aged ≤ 60 years) had a higher prevalence of pathological upstaging (68.7% vs. 45.8%), as well as a higher chance of positive lymph nodes (37.5% vs. 34.9%), whereas older patients (age > 60) had a higher rate of incidental prostate cancer (34.9% vs. 31.3%). However, these findings were not statistically significant (Table 2). Upstaging was observed in 30% of patients who had sur-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 1

V. Mehrnoush, S.Keramati, A. Ismail, W. Shabana, A. Zakaria, H. Elmansy, W. Shahrour, O. Prowse, A. Kotb

Table 1. Characteristics of patients with preoperative T2 transitional cell carcinoma. Variable Mean age (years) Age groups ≤ 60 > 61 Sex Males Females Stage T0 Ta/T1 T2 T3 T4 Positive Lymph Nods No Yes Incidental prostate cancer

Table 3. Comparison of operation waiting time categories against clinical and pathological staging. Waiting time to surgery

Value 67 ± 8.8 (51-88)

Mean age Stage < T3 T3/T4 Lymph nodes Negative Positive Neoadjuvant chemotherapy (NAC) Yes No

16 (27.1%) 43 (72.9%) 47 (80.0%) 12 (20.0%) 9 (15.3%) 6 (10.1%) 9 (15.3%) 16 (27.1%) 19 (32.2%)

39 (66.0%) 20 (34.0%) 10 (50.0%) 8 (40.0%) 2 (10.0%) 13 ± 8 21 (36.0%) 18 (30.0%) 20 (34.0%) 45 (76.0%) 14 (24.0%)

Sex

Males Females Waiting time to surgery < 12 > 12 Neoadjuvant chemotherapy (NAC) No Yes Stage < T3 T3/ T4 Lymph nodes invasion Negative Positive Prostate cancer No Yes

< 60 n = 16

> 60 n = 43

65 ± 9

0.2

10 (25.7%) 29 (74.3%)

14 (70%) 6 (30%)

0.001

23 (59%) 16 (41%)

15 (75%) 5 (25%)

0.2

1 (2.6%) 38 (97.4%)

13 (65%) 7 (35%)

0.001

Neoadjuvant chemotherapy (NAC)

No n = 45

Yes n = 14

P value

Mean age (years) Stage < T3 T3/T4 Lymph nodes Negative Positive

68 ± 9

64 ± 7

0.1

13 (28.9%) 32 (71.1%)

11 (78.6%) 3 (21.4%)

0.001

28 (62.2%) 17 (37.8%)

10 (71.4%) 4 (28.6%)

0.7

95% Confident interval Lower limit Upper limit

P value

Age

-0.23

-0.51

0.04

0.097

Gender

0.04

-0.28

0.36

0.809

P value

Neoadjuvant chemotherapy

-0.38

-0.74

-0.02

0.041 *

Waiting time to surgery

-0.08

-0.44

0.28

0.659

* P-value < 0.05 is significant.

13 (81.2%) 3 (18.8%)

34 (79.1%) 9 (20.9%)

1.0

9 (56.2%) 7 (43.8%)

30 (69.8%) 13 (30.2%)

0.3

11 (68.7%) 5 (31.3%)

34 (79.1%) 9 (20.9%)

0.5

5 (31.3%) 11 (68.7%)

19 (44.2%) 24 (45.8%)

0.5

10 (62.5%) 6 (37.5%)

28 (65.1%) 15 (34.9%)

1.0

11 (68.7%) 5 (31.3%)

28 (65.1%) 15 (34.9%)

1.0

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

68 ± 8

Odds ratio

gery delayed for more than 12 weeks, whereas upstaging was found in 74.3% of those who had surgery within 12 weeks, which is statistically different (p = 0.001). Not surprisingly, NAC was performed more in the delayed

P value

Table 5. Multivariate regression analysis for factors associated with upstaging.

Table 2. Comparison of the findings based on age. Age

< 12 weeks n = 20

Table 4. Comparison of patients with or without neoadjuvant chemotherapy (NAC) against clinical and pathological staging.

38 (64.0%) 21 (36.0%)

No Yes Grade of prostate cancer 3+3 3+4 4+3 Waiting time to surgery (weeks) Mean ± SD Wait time (weeks) <6 6- 12 > 12 Neoadjuvant chemotherapy (NAC) No Yes

< 12 weeks n = 39

group (92.8%) (Table 3). A significant difference in upstaging was found between those who had NAC, 3 (21.4%), and those who did not, 11 (78.6 %) (p = 0.001). However, the invasion to the lymph nodes was not lower in those who received NAC compared to those who did not (Table 4). Multivariate regression analysis revealed that NAC was the only factor associated with upstaging, while there was no significant association with other risk factor including age, gender, and waiting time to surgery (Table 5). The pathology in those who received NAC are approximately 60% less likely to show upstaging (OR = -0.38, CI 95% = -0.74- -0.02) (Table 5).

DISCUSSION

The current case series in Northern Ontario draws attention to the high prevalence of MIBT in patients younger

Muscle invasive bladder cancer in Northern Ontario

than 60 years (27.1%), with a high rate of upstaging (68.7%) in this young group of patients. The findings indicate that approximately 60% of clinically T2 MIBC were T3/T4 at final pathology. Another highlight is the high rate of clinically significant prostate cancer (50%) in patients with incidental prostate cancer. In terms of treatment, the findings showed that NAC was underutilized in Northern Ontario (76% did not receive NAC) and that no significant association was found between receiving NAC or delaying surgery and upstaging. The majority of our patients were male, which was consistent with the literature (80% male vs. 20% female). Our findings suggest that bladder cancer should not be emphasized in a purely geriatric population in Northern Ontario. The causes of bladder cancer in the younger age group, however, have not been well documented in the literature. According to the findings of a study conducted in Montreal (Canada), natural gas combustion products, aromatic amines, cadmium compounds, photographic products, acrylic fibers, polyethylene, titanium dioxide, and chlorine were found to have weak evidence of being risk factors for bladder cancer. Occupational exposures such as motor vehicle drivers, particularly among drivers in the motor transport industry, who were more likely to drive full time than drivers in other industries, textile dyers, construction painters, metal machinists and sheet metal workers, and aromatic amines were responsible for 6.5 percent of bladder cancer incidence (6). Another Canadian case control study discovered that miners, metal workers, mechanics, and male hairdressers were more likely to develop bladder cancer. They assumed that exposure to various combustion products and/or oils was a common theme in these occupations (7). Epidemiological studies in Canada and other countries, including the United States, Italy, and France discovered that carcinogenic chemicals in tap water, such as chloroform and other trihalomethanes, are linked to an increased risk of bladder cancer (8, 9). Peculiar environmental conditions can also expose this population to risk factors. Northern Ontario is one of the leading mining regions for nickel, copper, uranium, zinc, gold, platinum, and silver. Northern Ontario's economy is built on forestry, transshipment, and manufacturing industries such as textile, steel, pulp, and paper. Moreover, Northern Ontario is the transshipment point of agriculture products across Canada (10). From the standpoint of public health, the high prevalence of younger age (60 years old) with MIBC in Northern Ontario appears to necessitate a transdisciplinary approach that includes medical, logistical, and municipal sectors to identify the risk factors and implement a multilevel strategy to address this issue. The findings of our study revealed that a high percentage of patients with clinically T2 MIBC turned into T3/T4 with positive lymph nodes after cystectomy, and that the majority of these patients undergo surgery in less than 12 weeks. According to the pathological results of radical cystectomy, 59.3% of patients were diagnosed at the most advanced stages (T3/T4), and 36% developed node-posi-

tive disease. It is concerning to diagnose patients at such advanced stages. These findings also emphasize early investigation which leads to earlier diagnosis and intervention with the expectation of a better outcome. In our study; the use of NAC was associated with 60% less likely finding of upstaging on final pathology and so a part of adverse pathological outcomes may be explained by the underutilization of NAC. In general, delay in cancer diagnosis and treatment is classified into patient delay, health care provider delay, delay in service provider, and finally, treatment delay (11). It has been proposed that differences in socioeconomic status, rural or urban residency, and immigration status can all contribute to disparities in screening, diagnosis staging on presentation, and treatment services (12). Despite enormous efforts to provide equity in health care, the distribution of the population due to the geographic characteristics of Northern Ontario impede some regions from timely access and health monitoring. Moreover, there is only one hospital in all of Northern Ontario that provide urological cancer care. This results in a long waiting list, making timely access to equitable care more difficult for the population. Further research is also needed to investigate and identify the factors associated with bladder cancer patients' delayed diagnosis and late-stage presentation in Northern Ontario. According to our findings, prostate cancer, which is the third leading cause of cancer death in Canadian males (5), was discovered incidentally (34%) during a cystectomy, which is consistent with literature reported 23-54% (13, 14). However, 50% of our patients had significant prostate cancer (Gleason score ≥ 7 out of 10), which is notably higher than literature. Djaladat et al. studied 1964 patients with primary transitional cell carcinoma of the bladder who underwent radical cystectomy. Thirty six percent of the patients (n = 559) had incidental prostate cancer with the Gleason scores ≤ 6 for 458 (82%) patients (14). Another study by Mazzucchelli et al. found that the majority (81.3%) of incidentally detected prostate cancers by radical cystoprostoctomy had a Gleason score of 4 or less (15). Hiros et al. reported 68% of incidental prostate cancer were low grade (Gleason scores less than 6) and 32% were high grade (16). One study found that overall survival for patients with incidental prostate cancer was lower than for patients without (28.1 ± 27.5 month vs 45.5 ± 35 month). Given the significant impact on overall survival, they highlighted the importance of paying closer attention to this concurrent pathology (13). Therefore, given the high prevalence of high grade prostate cancer in our population, it may be practical to assign a greater importance to performing prostate cancer screening during bladder cancer work-up, regardless of the patients’ age. Furthermore, additional workup such as MRI to rule out prostate cancer is required if a patient chooses trimodal therapy. Radical cystectomy is the standard treatment for patients with MIBC (17). However, the time of performing cystectomy is controversial. Some literature has shown that cysArchivio Italiano di Urologia e Andrologia 2022; 94, 1

V. Mehrnoush, S.Keramati, A. Ismail, W. Shabana, A. Zakaria, H. Elmansy, W. Shahrour, O. Prowse, A. Kotb

tectomy after 12 weeks is not associated with an unfavorable outcome (18, 19) while a population-based study and the European Association of Urology have recommended to not delay cystectomy for more than 3 months due to the increasing risk of progression and mortality (20). Based on Canadian Urological Association guideline, the optimal timing of radical cystectomy where NAC has not been administered is within six weeks of TURBT (21). According to our findings, upstaging was observed in 29 (74.3%) and 6 (30%) of patients who had surgery < 12 weeks and > 12 weeks, respectively. The lower likelihood of upstaging in > 12 week surgery waiting time can be interpreted that the delay in surgery for the sake of receiving NAC does not negatively affect the staging and progression. In our study, a lower upstaging rate was found in those who had NAC compared to those who did not (21.4% vs 71.1%). However, NAC did not significantly decrease the invasion to lymph nodes. The advantages of NAC in patients with MIBC have been reported in literature. NAC is recommended to improve the outcome of radical cystectomy which is the gold standard of treatment in MIBC with a 5-year survival of about 50% (22). Accordingly, it seems that the rate of perioperative NAC in Ontario, Canada follows an increasing trend from 19% in 2009 to 27% in 2013 (23). However, the rate of perioperative NAC in our study was only 23.7%. Despite the survival benefit, practicing NAC has been underutilized in Northern Ontario. The finding of this study may prompt urologists and medical oncologists to incorporate NAC more frequently in their practice. Due to the lack of clinical outcomes, our findings cannot be interpreted as supporting or opposing the controversial opinions on surgery before or after 12 weeks. However, the findings suggest that the surgical delay of more than 12 weeks due to the NAC may not negatively impact the pathological outcomes. The interpretation of the current study's results may be limited by the small sample size. Furthermore, including only one center negatively affects the external validity of the results while having a positive impact on improving the internal validity of the study. We can conclude that the high rate of pathological upstaging detected in more than half of the patients undergoing radical cystectomy in this study warrants performing multidisciplinary quality improvements including pathology, medical and radiation oncology, and urology. Moreover, the high prevalence of younger ages (aged less than 60), upstaging, lymph positive in T2 de novo MIBC, call for further investigation of possible causes of delay and potential risk factors for bladder tumors at individual, public, and population health levels in Northern Ontario.

REFERENCES

1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68:394424. 2. Bachir BG, Kassouf W. Cause-effect? Understanding the risk factors associated with bladder cancer. Expert Rev Anticancer Ther. 2012; 12:1499-1502.

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3. Delclos GL, Lerner SP. Occupational risk factors. Scand J Urol Nephrol. Suppl 2008; 218:58-63. 4. 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 di Urol e Androl. 2021; 93:15-20. 5. Pless B. Health promotion and chronic disease prevention in Canada: Research, policy and practice. [updated 2021 February 4 , cited 2016 April 21. https://www.canada.ca/en/public-health/services/reports-publications/health-promotion-chronic-disease-prevention-canada-research-policy-practice/vol-41-no-2-2021.html. Accessed June 28,2021. 6. Siemiatycki J, Dewar R, Nadon L, et al. Occupational risk factors for bladder cancer: results from a case-control study in Montreal, Quebec, Canada. Am J Epidemiol. 1994; 140:1061-80. 7. Gaertner RRW, Trpeski L, Johnson KC. A case-control study of occupational risk factors for bladder cancer in Canada. Cancer Causes Control. 2004; 15:1007-19. 8. Villanueva CM, Fernández F, Malats N, et al. Meta-analysis of studies on individual consumption of chlorinated drinking water and bladder cancer. J Epidemiol Community Health. 2003; 57:166-73. 9. Villanueva CM, Cantor KP, King WD, et al. Total and specific fluid consumption as determinants of bladder cancer risk. Int J Cancer. 2006; 118:2040-47. 10. Wise S, Horn M, Geoffrey E. “Ontario.” Encyclopedia Britannica, October 29 2020. https://www.britannica.com/place/Ontarioprovince. Accessed May 19, 2021. 11. Ukwenya AY, Yusufu LMD, Nmadu PT, et al. Delayed treatment of symptomatic breast cancer: the experience from Kaduna, Nigeria. S Afr J Surg. 2008; 46:106-10. 12. Singh GK, Williams SD, Siahpush M, et al. Socioeconomic, ruralurban, and racial inequalities in US cancer mortality: Part I-All cancers and lung cancer and part II-Colorectal, prostate, breast, and cervical cancers. J Cancer Epidemiol. 2011; 2011:107497. 13. Sruogis A, Ulys A, Smailyte G, et al. Incidentally found prostate cancer and influence on overall survival after radical cystoprostatectomy. Prostate Cancer 2012; 2012:1-5. 14. Djaladat H, Bruins MH, Skinner EC, et al. Incidental prostate cancer in patients with radical cystectomy for bladder cancer. J Clin Oncol. 2013; 31:S225. 15. Mazzucchelli R, Barbisan F, Scarpelli M, et al. Is incidentally detected prostate cancer in patients undergoing radical cystoprostatectomy clinically significant? Am J Clin Pathol. 2009; 131:279-83. 16. Hiros M, Selimovic M, Spahovic H, et al. Transrectal ultrasoundguided prostate biopsy, periprostatic local anesthesia and pain tolerance. Bosn J Basic Med Sci. 2010 Feb; 10:68-72. 17. DeGeorge KC, Holt HR, Hodges SC. Bladder cancer: diagnosis and treatment. Am Fam Physician. 2017; 96:507-14. 18. Nielsen ME, Palapattu GS, Karakiewicz PI, et al. A delay in radical cystectomy of >3 months is not associated with a worse clinical outcome. BJU Int. 2007; 100:1015-20. 19. Ayres BE, Gillatt D, McPhail S, et al. A delay in radical cystectomy of >3 months is not associated with a worse clinical outcome. BJU Int. 2008; 102:10-45. 20. Milowsky MI, Rumble RB, Booth CM, et al. Guideline on muscle-

Muscle invasive bladder cancer in Northern Ontario

invasive and metastatic bladder cancer (European Association of Urology Guideline): American society of clinical oncology clinical practice guideline endorsement. J Clin Oncol. 2016; 34:1945-52.

22. Porter MP, Kerrigan MC, Donato BMK, et al. Patterns of use of systemic chemotherapy for Medicare beneficiaries with urothelial bladder cancer. Urol Oncol. 2011; 29:252-58.

21. Kulkarni GS, Black PC, Sridhar SS, et al. Canadian Urological Association guideline: Muscle-invasive bladder cancer. Can Urol Assoc J. 2019; 13:230-38.

23. Booth CM, Karim S, Brennan K, et al. Perioperative chemotherapy for bladder cancer in the general population: Are practice patterns finally changing? Urol Oncol. 2018; 36:89.e13-89.e20.

Correspondence Vahid Mehrnoush, MD vahidmehrnoush7@gmail.com Shahrzad Keramati, MD shz.keramati@gmail.com Asmaa Ismail, MD asmaaismail0782@gmail.com Waleed Shabana, MD waleed.shabana@gmail.com Ahmed Zakaria, MD aszakaria81@yahoo.com Hazem Elmansy, MD hazemuro100@yahoo.com Walid Shahrour, MD walid.shahrour@gmail.com Owen Prowse, MD owenprowse@rogers.ca Ahmed Kotb, MD, PhD, FRCS Urol, FEBU (Corresponding Author) drahmedfali@gmail.com Assistant Professor Northern Ontario School of Medicine TBRHSC 980 Oliver Road, Thunder Bay, ON, Canada. P7B 6V4

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

DOI: 10.4081/aiua.2022.1.46

ORIGINAL PAPER

Lower urinary tract symptoms and mental health during COVID-19 pandemic Biagio Barone *, Luigi De Luca *, Luigi Napolitano, Pasquale Reccia, Felice Crocetto, Massimiliano Creta, Raffaele Vitale, Vincenzo Francesco Caputo, Raffaele Martino, Luigi Cirillo, Giovanni Maria Fusco, Massimiliano Trivellato, Giuseppe Celentano, Roberto La Rocca, Domenico Prezioso, Nicola Longo Department of Neurosciences, Reproductive and Odontostomatological Sciences of University of Naples "Federico II", Naples, Italy. * Equally

contributing authors.

Summary

Objective: Coronaviruses (CoVs) are a group of RNA viruses involved in several human diseases affecting respiratory, enteric, hepatic, and neurological systems. COVID-19 was identified in 2020 and was named SARS-CoV-2. To limit worldwide contagion, many countries instituted a lockdown, which conducted to disruption of routine life. In fact, pandemic was associated with several stresses among population, such as loss of employment, deaths of family members, friends, or colleagues, financial insecurity, and isolation. This led to long-lasting psychosocial effects as anxiety and depression, increasing the prevalence of stress and traumarelated disorders in the population. The aim of this study was to investigate the correlation between lower urinary tracts symptoms (LUTS) and stress/depressive symptoms during COVID-19 pandemic. Materials and methods: An anonymous cross-sectional webbased survey (comprehending anthropometric data, education level, occupation status, smoking and alcohol habits, current therapies, quarantine and COVID-19 infection status) was conducted from March to May 2020 in Italy. LUTS were examined through National Institute of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) and Genitourinary Pain Index (GUPI). Hamilton Depression Rating Scale (HDRS) was utilized to evaluate depressive and anxiety symptoms. Non-parametric Kruskal-Wallis H Test was used for statistical analysis. Results: A total of 356 out of 461 subjects fully completed the survey, with a response rate of 77.2%. Data showed that subjects involved in economic difficulties, quarantine measures or with increased HDRS reported a significative statistic worsened urinary symptoms (H(3) = 11.731, p = 0.008), quality of life, (H(3) = 10.301, p = 0.016), total NIH-CPSI/GUPI score (H(3) = 42.150, p = 0.000), and quality of life (H(3) = 48.638, p = 0.000). Conclusions: COVID-19 pandemic provoked several alterations in everyday life. Although general lockdown, quarantine and social distancing have been necessary to prevent virus spreading, this had long term effects on all population in terms of mental and physical health. NIH-CPSI and GUPI scores increased linearly with stress and anxiety levels measured at HDRS, confirming worse LUTS in subjects who suffered anxiety and stress from COVID-19 pandemic.

KEY WORDS: COVID-19; LUTS; NIH-CPSI; Anxiety; Stress; HDRS. Submitted 3 February 2022; Accepted 9 February 2022

INTRODUCTION

Coronavirus disease 2019 (COVID-19) is caused by a novel beta-coronavirus known as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), firstly isolated in Wuhan, Hubei province of China (1-3). Since the first cases of SARS-Cov-2 reported in December 2019 in China, other Asian countries, such as Thailand, Japan and the Republic of Korea, reported increasing cases of COVID-19 in January 2020, leading the World Health Organization (WHO) to declare international public health emergency in the same month and, with the diffusion of contagion in Europe and North America, world pandemic in March 2020 (4). In order to limit the contagion, many countries instituted strict lockdown to flatten the epidemic curve and relieve the pressure on hospitals, permitting the activity only for essentials supply chains businesses and emergency/oncological healthcare services. The consequences related to social isolation, fear of infection and, particularly, the disruption of routine life, provoked severe detrimental and long-lasting psychosocial effects as anxiety and depression, increasing the prevalence of stress and trauma-related disorders in the population (5). Due to these premises and to the evidence that several urological conditions (as benign prostatic hyperplasia, overactive bladder, urge urinary incontinence, interstitial cystitis and bladder pain syndrome) were triggered or worsened after or during stressful events, the aim of our study was to explore how psychosocial consequences of COVID-19 affected lower urinary tract symptoms, considering in addition economic consequences and quarantine measures (6, 7).

MATERIALS

AND METHODS

Study design An anonymous cross-sectional, web-based closed survey between healthy subject was conducted, timed from March to May 2020, during lockdown period. The participants were recruited by an invitation distributed through direct e-mail and Facebook. Since its introduction in 2004, Facebook is the third most popular website in the world, with 1.65 billion monthly active users. Facebook is widely used among midlife and older adults, No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

LUTS and mental health during COVID-19 pandemic

as well as reported by published studies with 63% of adults aged 50-64 and 56% of people 65 and older that use this platform. Several published studies reported this platform as a validated method of recruiting study participants for survey research (8, 9). The questionnaire was designed using the Google Form application included in the Google Drive office suite (Google LLC) and formulated in Italian, with the aim of increasing the response rate. The study was conducted according to the guidelines of the World Medical Association Declaration of Helsinki and to the current European GDPR privacy policy. Webbased survey was conducted according to the Checklist for Reporting Results of Internet E-Surveys (10). Subjects were informed at the beginning of the survey about purpose of the study, data storing and principal investigators (L.D and B.B). Data obtained were collected and stored on personal cloud of principal investigators, utilizing a two-step verification. Survey comprehended a first section with inclusion criteria, anthropometric data, education level, occupation status, smoking and alcohol habits, current therapies, quarantine and COVID-19 infection status. We defined as positive infection status, subjects with a diagnosis through nasopharyngeal swab at the time of the survey; suspicion infection status, subjects with clinical diagnosis (imaging or symptoms) in absence of nasopharyngeal swab at the time of the survey. Regarding quarantine status, we considered, in addition to the patients with diagnosed COVID-19 infection, subjects without COVID-19 infection but who had a close contact with a positive patient, according to the definition of Center for Disease Control and Prevention (CDC) (individual who has had closer than < 6 feet for ≥ 15 min with people with a positive diagnosis for COVID-19, whether symptomatic or asymptomatic). Inclusion criteria were: subjects over 18 years-old, without explainable urinary symptoms (urolithiasis, urinary infection, stress incontinence). Surveys not completely filled out were excluded by further analysis. Second section of the survey comprehended National Institute of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) for males and Genitourinary Pain Index (GUPI) for females (11, 12). Third section of the survey comprehended, finally, Hamilton Depression Rating Scale (HDRS) (13). Survey was tested by all investigators in order to verify usability and technical functionality. Successively, survey was submitted, through Google Forms, to the most used social networks.

All statistical analyses were performed using International Business Machines Corporation Statistical Product and Service Solutions (IBM SPSS) software for Windows (version 25.0., IBM Corp, Armonk, NY, USA). Statistical significance was defined as p < 0.05.

Statistical analysis Descriptive statistics included means and standard deviations for continuous variables while frequencies and percentages were obtained for categorical variables. Nonparametric Kruskal-Wallis H Test was used to determine differences between groups, according to normality assumptions examined with Kolmogorov-Smirnov Test, and was performed on NIH-CPSI/GUPI subscales (pain, urinary symptoms, quality of life) and total results, stratifying the analysis for: COVID-19 infection status, economic consequences, quarantine measures, and HDRS total score. Finally, Kruskal-Wallis H Test was performed to compare HDRS score grading (0-7: no depression; 817: mild depression; 18-24: moderate depression; > 24: severe depression) to NIH-CPSI/GUPI parameters.

RESULTS

A total of 356 out of 461 subjects fully completed the survey, for a completion rate of 77.2%. Descriptive statistics obtained are reported in Table 1. COVID-19 Infection status We compared the results of NIH-CPSI/GUPI and HDRS in subjects with diagnosed (n = 4), negative (n = 329) and suspected (n = 23) COVID-19 infection. COVID-19 infection status reported statistically significant differences for pain (H(2) = 6.825, p = 0.033) and quality of life (H(2) = 6.187, p = 0.045) subscales, while no statistically significant differences were reported for urinary symptoms subscale (H(2) = 0.716, p = 0.699), total score (H(2) = 5.667, p = 0.059) and HDRS score (H(2) = 3.491, p = 0.175). In particular, negative infection status subjects reported in pain subscale a mean rank of 178.64 Table 1. Descriptive statistics of subjects involved. Age Height (in m) Weight BMI Sex Male Female Marital status Single Married/in a couple Divorced Widow/widower Education level Low Medium High Working status Employed Unemployed COVID-19 infection status Negative Suspicion Positive Economic consequences Financial hardship Job loss Quarantined Diabetes Hypertension Obese Depression Asthma COPD Cardiovascular disease Alcohol Smoking

Mean 36.49 1.70 72.28 24.77

Standard deviation 12.236 0.08 17.11 4.65

Frequency

Percentage

182 174

51.1 48.9

201 135 16 4

56.5 37.9 4.5 1.1

10 110 236

2.8 30.9 66.3

237 119

66.6 33.4

329 23 4

92.4 6.5 1.1

113 13 68 10 30 20 7 34 3 10 76 103

31.3 3.6 19.1 2.8 8.4 5.6 2 9.6 0.8 2.8 21.3 28.9

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while suspicious infection status subjects reported a mean rank of 158.65 and, finally, positive infection status subjects reported a mean rank of 281.13. Analogously, negative infection status subjects reported in quality-of-life subscale a mean rank of 179.97 compared to suspicious infection status subjects (mean rank of 143) and positive infection status subjects (mean rank of 261.88).

similarly: 148.84 (no depression), 198.70 (mild depression), 249.77 (moderate depression) and 279.10 (severe depression). Finally, mean ranks for total score were 140.25 (no depression), 208.18 (mild depression), 254.56 (moderate depression) and 301.35 (severe depression).

Economic consequences We compared the results of NIH-CPSI/GUPI and HDRS in subjects who suffered financial hardship (n = 113) or job loss (n = 13) compared to no economic consequences (n = 230). Economic consequences were classified as none, financial hardship, or job loss. Statistically significant differences were reported for urinary symptoms (H(3) = 11.731, p = 0.008), quality of life (H(3) = 10.301, p = 0.016), total score (H(3) = 14.537, p = 0.002) and HDRS score (H(3) = 20.706, p = 0.000), while no statistically significant difference was reported for pain subscale (H(3) = 6.242, p = 0.100). Mean ranks for urinary symptoms were 165.27 for no economic consequences, 204.9 for financial hardship and 175.46 for job loss. Mean ranks for quality of life were, similarly: 167.68 (no consequences), 193.12 (financial hardship) and 237.85 (job loss). Mean ranks for total score were 163.01 (no consequences), 205.54 (financial hardship), and 212.69 (job loss). Finally, mean rank for HDRS score were 158.88 (no consequences), 209.19 (financial hardship), and 226.35 (job loss).

DISCUSSION

Quarantine measures We compared the results of NIH-CPSI/GUPI and HDRS in subjects who underwent to quarantine measures (n = 68) compared to who had no restrictions (n = 288). HDRS score was statistically significant different between subjects who underwent to quarantine measures (e.g: direct contact with infected patients) and not (H(1) = 7.179, p = 0.007), reporting a mean rank of 208.53 for subjects in quarantine versus 171.41 for those who underwent no measures. No statistically significant differences were instead reported for pain (H(1) = 3.130, p = 0.077), urinary symptoms (H(1) = 0.596, p = 0.440) and quality of life subscales (H(1) = 2.616, p = 0.106). Similarly, no statistically significant difference was reported for NIHCPSI/GUPI total score (H(1) = 2.088, p = 0.148) HDRS score grading According to HDRS score grading, we divided subjects in four groups: no depression (n = 187), mild depression (n = 133), moderate depression (n= 26) and severe depression (n = 10). We further correlated HDRS score grading with NIH-CPSI/GUPI results, reporting statistically significant differences for pain (H(3) = 40.093, p = 0.000), urinary symptoms (H(3) = 42.150, p = 0.000), quality of life (H(3) = 48.638, p = 0.000) and total score (H(3) = 66.480, p = 0.000). In particular, mean ranks for pain were 155.02 for no depression, 195.76 for mild depression, 217.10 for moderate depression and 287.70 for severe depression. Similarly, mean ranks for urinary symptoms were 147.97 (no depression), 203.04 (mild depression), 245.33 (moderate depression) and 249.40 (severe depression). Mean ranks for quality of life were

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

The COVID-19 pandemic has embodied several stresses such as loss of employment, deaths of family members, friends, or colleagues, financial insecurity, and isolation from others (14). The social isolation, the fear of contagion and the imposed limitations, have created a fertile substrate for anxiety and post-traumatic stress disorders development (15). In addition, the impossibilities to work, socialize with others and to engage in physical activities produced increased distress levels and contributed to overall decline in health, further aggravating the psychobiological impact of the outbreak (16). Stressful events could alter body homeostasis, triggering and/or aggravating several pathologies and diseases (17). However, if this relation is well-known and demonstrated for gastrointestinal, dermatologic and cardiovascular diseases, interactions between elevated stress levels and urological conditions remain controversial (18). In the urological field, COVID-19 pandemic has increased sexual disturbances, as reported by the decreased erectile function and increased premature ejaculation incidence in men, together with a decreased PDE5i interest (as reported on Google trend analysis) (19, 20). Regarding urinary disturbances, animal models have indeed shown how social stress could impair bladder function, up to developing a proper generalised bladder mucosal inflammation (21). A study by Ullrich et al. showed on men with BPH a worsening of symptoms when subjects were exposed to standardized laboratory stress tasks (22). Similarly in women, the prevalence of overactive bladder and other LUTS were increased among subjects with increased occupational stress (23). Lower urinary tract symptoms (LUTS) conversely, have been associated with acute and chronic stress, and with other stress-related pathologies, such as gastroenterological complaints, irritable bowel syndrome, vulvodynia, dyspareunia and even odontostomatological conditions (24, 25). Due to these premises, we evaluated the relationship between stressful events, as COVID-19 worldwide pandemic, and urological manifestations, excluding subjects with explainable causes for LUTS. Furthermore, we analysed how mental health correlated with LUTS. In addition, although we reported in our cohort of subjects different comorbidities which could have impacted the results of our survey, none of them reached the statistical significance at the statistical analysis. Regarding COVID-19 infection status, we reported increased NIH-CPSI/GUPI score for pain and quality of life subscales in subjects with active or suspicion infection. Although we suggest that these results were associated more with the stressful event itself rather than a direct interaction of coronavirus, our data is consistent with recent hypotheses reported in literature. Dhar et al. indeed, reported 39 COVID-19 patients who developed

LUTS and mental health during COVID-19 pandemic

de novo urinary symptoms while Kaya et al. similarly, reported 46 COVID-19 patients with increased storage symptoms during hospitalization (26, 27). However, due to the limited number of subjects diagnosed with COVID-19 infection in our study, the results obtained are obviously weakened and limited. When economic consequences of lockdown and worldwide pandemic were analysed, we reported increased score in urinary symptoms and quality of life subscales together with an increased overall NIH-CPSI/GUPI score. HDRS score was increased as well. Although the definition of financial hardship is quite subjective, job and financial insecurity have serious consequences on physical and mental health of individuals (28). Among several adverse health outcomes, increased psychosomatic symptoms as anxiety and depression are reported(29). The presence of increased HDRS score for subjects with financial hardship or job loss was indeed perfectly consistent with data reported in literature. Similarly, subjects which suffered financial hardship or job loss during lockdown reported increased urinary symptoms and a worsened quality of life. Also in this case, we suggest that the increased psychological burden linked to the difficult socioeconomical situation influenced symptoms manifestations (30). Similarly, when quarantine measures were considered, HDRS score increased in subjects quarantined. As reported by Giallonardo et al., social distancing and quarantine have detrimental effects on mental health, both in general population and in psychiatric patients, thus confirming the consistence of our data (31). No significant differences in NIH-CPSI/GUPI score however were reported. Finally, we correlated HDRS score with NIH-CPSI/GUPI score. We reported significant differences for every subscale and total score. As far as we know, there is only a study correlating HDRS score and LUTS: Skalski et al. used HDRS and IPSS score on 102 patients treated for depression, reporting a significant correlation between severity of depressive symptoms and severity of LUTS (32). Our study confirms this correlation, showing increasing NIH-CPSI/GUPI score with increasing results of HDRS score. We are conscious of several limitation of our study: firstly, the retrospective and self-reported nature or our study; secondly, a relatively low sample size for exploring interactions between COVID-19 infection or quarantine measures and LUTS; thirdly, the geographical limitation of our results; fourthly, an overall low mean age which could represent the decreased and heterogeneous use of internet-based instruments of older subjects, potentially excluding them from our study (33). Finally, the restricted number of properly diagnosed COVID-19 patients limits the reliability of our results regarding COVID-19 and urinary symptoms.

CONCLUSIONS

COVID-19 pandemic has provoked notable alterations in everyday life. Although general lockdown, quarantine and social distancing have been necessary in order to prevent virus spreading, detrimental effects of strict lockdown could have long term effects on population in terms of mental and physical health. The association between stressful events and increased LUTS has been explored

during lockdown in southern Italy, confirming a preponderant role of stress and anxiety in LUTS development and suggesting a bidirectional relationship between mental health and urological symptoms. Further studies are required to fully evaluate this relationship and explore the direct effect of SARS-CoV-2 on LUTS.

REFERENCES

1. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of Coronavirus disease 2019 in China. N Engl J Med. 2020; 382:1708-20. 2. Creta M, Sagnelli C, Celentano G, et al. SARS-CoV-2 infection affects the lower urinary tract and male genital system: A systematic review. J Med Virol. 2021; 93:3133-3142. 3. Napolitano L, Barone B, Crocetto F, et al. The COVID-19 Pandemic: Is It A Wolf Consuming Fertility? Int J Fertil Steril. 2020; 14:159-160. 4. World Health O. Novel Coronavirus (2019-nCoV): situation report, 19. Geneva: World Health Organization, 2020 2020-02-08. Report No. 5. Rossi R, Socci V, Talevi D, et al. COVID-19 Pandemic and lockdown measures impact on mental health among the general population in Italy. Front Psychiatry. 2020; 11:790. 6. Breyer BN, Cohen BE, Bertenthal D, et al. Lower urinary tract dysfunction in male Iraq and Afghanistan war veterans: association with mental health disorders: a population-based cohort study. Urology. 2014; 83:312-9. 7. Martin S, Vincent A, Taylor AW, et al. Lower urinary tract symptoms, depression, anxiety and systemic inflammatory factors in men: a population-based cohort study. PLoS One. 2015; 10:e0137903. 8. Bosak K, Park SH. Characteristics of Adults' Use of Facebook and the potential impact on health behavior: secondary data analysis. Interact J Med Res. 2018; 7:e11-e. 9. Jung EH, Walden J, Johnson AC, Sundar SS. Social networking in the aging context: Why older adults use or avoid Facebook. Telematics and Informatics. 2017; 34:1071-80. 10. Eysenbach G. Improving the quality of Web surveys: the Checklist for Reporting Results of Internet E-Surveys (CHERRIES). J Med Internet Res 2004; 6:e34-e. 11. Clemens JQ, Calhoun EA, Litwin MS, et al. Validation of a modified National Institutes of Health chronic prostatitis symptom index to assess genitourinary pain in both men and women. Urology. 2009; 74:983-7. 12. Wagenlehner FM, van Till JW, Magri V, et al. National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) symptom evaluation in multinational cohorts of patients with chronic prostatitis/chronic pelvic pain syndrome. Eur Urol. 2013; 63:953-9. 13. Bobo WV, Angleró GC, Jenkins G, et al. Validation of the 17-item Hamilton Depression Rating Scale definition of response for adults with major depressive disorder using equipercentile linking to Clinical Global Impression scale ratings: analysis of Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) data. Hum Psychopharmacol. 2016; 31:185-92. 14. Sani G, Janiri D, Di Nicola M, et al. Mental health during and after the COVID-19 emergency in Italy. Psychiatry and clinical neurosciences. 2020; 74:372. 15. Castelli L, Di Tella M, Benfante A, Romeo A. The spread of COVID-19 in the Italian population: anxiety, depression, and posttraumatic stress symptoms. Can J Psychiatry. 2020; 65:731-732. 16. Stanton R, To QG, Khalesi S, et al. Depression, anxiety and stress Archivio Italiano di Urologia e Andrologia 2022; 94, 1

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during COVID-19: associations with changes in physical activity, sleep, tobacco and alcohol use in Australian adults Int J Environ Res Public Health 2020; 17:4065.

25. Crocetto F, Coppola N, Barone B, et al. The association between burning mouth syndrome and urologic chronic pelvic pain syndrome: A case-control study. J Oral Pathol Med 2020; 49:829-34.

17. Yaribeygi H, Panahi Y, Sahraei H, et al. The impact of stress on body function: A review. EXCLI J. 2017; 16:1057-72.

26. Dhar N, Dhar S, Timar R, et al. De Novo Urinary Symptoms Associated With COVID-19: COVID-19-Associated Cystitis. J Clin Med Res. 2020; 12:681-2.

18. Dimsdale JE. Psychological stress and cardiovascular disease. J Am Coll Cardiol. 2008; 51:1237-46. 19. Deger MD, Madendere S. Erectile dysfunction treatment with Phosphodiesterase-5 Inhibitors: Google trends analysis of last 10 years and COVID-19 pandemic. Arch Ital Urol Androl. 2021; 93:361-5. 20. Ates E, Kazici HG, Yildiz AE, et al. Male sexual functions and behaviors in the age of COVID-19: Evaluation of mid-term effects with online cross-sectional survey study. Arch Ital Urol Androl. 2021; 93:341-7. 21. Mingin GC, Peterson A, Erickson CS, et al. Social stress induces changes in urinary bladder function, bladder NGF content, and generalized bladder inflammation in mice. Am J Physiol Regul Integr Comp Physiol. 2014; 307:R893-R900. 22. Ullrich PM, Lutgendorf SK, Kreder KJ. Physiologic reactivity to a laboratory stress task among men with benign prostatic hyperplasia. Urology. 2007; 70:487-92. 23. Zhang C, Hai T, Yu L, et al. Association between occupational stress and risk of overactive bladder and other lower urinary tract symptoms: A cross-sectional study of female nurses in China. Neurourol Urodyn 2013; 32:254-60. 24. Li Z, Huang W, Wang X, Zhang Y. The relationship between lower urinary tract symptoms and irritable bowel syndrome: a metaanalysis of cross-sectional studies. Minerva Urol Nefrol. 2018; 70:386-92.

Correspondence Biagio Barone, MD biagio.barone@unina.it Luigi De Luca, MD luigideluca86@gmail.com Luigi Napolitano, MD (Corresponding Author) dr.luiginapolitano@gmail.com Pasquale Reccia, MD reccia.pasquale1@gmail.com Felice Crocetto, MD felice.crocetto@unina.it Massimiliano Creta, MD max.creta@gmail.com Raffaele Vitale, MD r.vitale0210@gmail.com Vincenzo Francesco Caputo, MD vincitor@me.com Raffaele Martino, MD raffaele.martino88@yahoo.it Luigi Cirillo, MD cirilloluigi22@gmail.com Giovanni Maria Fusco, MD giomfusco@gmail.com Massimiliano Trivellato, MD massimiliano.trivellato@gmail.com Giuseppe Celentano, MD dr.giuseppecelentano@gmail.com Roberto La Rocca, MD robertolarocca87@gmail.com Domenico Prezioso, MD domenico.prezioso2@unina.it Nicola Longo, MD nicolalongo.20@yahoo.it Department of Neurosciences, Reproductive and Odontostomatological Sciences of University of Naples "Federico II", Naples, Italy

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27. Kaya Y, Kaya C, Kartal T, et al. Could LUTS be early symptoms of COVID-19. Int J Clin Pract. 2020:e13850. 28. Nella D, Panagopoulou E, Galanis N, et al. Consequences of job insecurity on the psychological and physical health of Greek civil servants. Biomed Res Int 2015; 2015:673623. 29. Mucci N, Giorgi G, Roncaioli M, et al. The correlation between stress and economic crisis: a systematic review. Neuropsychiatr Dis Treat. 2016; 12:983-93. 30. Alradhawi M, Shubber N, Sheppard J, Ali Y. Effects of the COVID-19 pandemic on mental well-being amongst individuals in society- A letter to the editor on "The socio-economic implications of the coronavirus and COVID-19 pandemic: A review". Int J Surg 2020; 78:147-8. 31. Giallonardo V, Sampogna G, Del Vecchio V, et al. The impact of quarantine and physical distancing following COVID-19 on mental health: study protocol of a multicentric Italian population trial. Front Psychiatry. 2020; 11:533 32. Skalski M, Przydacz M, Sobanski JA, et al. Coexistence of lower urinary tract symptoms (LUTS) with depressive symptoms in patients suffering from depressive disorders. Psychiatria polska. 2019; 53:939-53. 33. van Boekel LC, Peek ST, Luijkx KG. Diversity in older adults' use of the Internet: identifying subgroups through latent class analysis. J Med Internet Res. 2017; 19:e180.

DOI: 10.4081/aiua.2022.1.51

ORIGINAL PAPER

Non-invasive diagnosis of under active bladder: A pilot study Mehmet Yoldas Tepecik Training and Research Hospital Urology Clinic, Izmir, Turkey.

Summary

Objective: We assessed the efficacy of voiding efficiency (VE) to distinguish between underactive bladder (UB) and bladder outlet obstruction (BO) without using pressure flow studies (PFS). Materials and methods: in male patients, uroflowmetry and post-void residual (PVR) urine data and subsequent pressure flow studies (PFS) data were examined retrospectively. Bladder outlet obstruction index (BOI) and bladder contractility index (BCI) were calculated from patients' PFS values. Patients with BCI < 100 and BOI < 40 were grouped as UB group and patients with BCI > 100 and BOI > 40 were grouped as BOO group. VE was computed as a percentage of volume voided compared to the pre-void bladder volume. Results: In total we examined 93 patients, 44 in UB and 49 in BO group. There was no statistically significant difference between the two groups in relation to Qmax value (p = 0.38). However, total voiding time, time to reach the maximum urinary flow rate and voided volume showed statistically significant difference between the two groups (p < 0.001). Average VE was 63.6 + 2.43% and 46.2 + 2.63%) for UB and BO groups respectively and the difference was statistically significant (p < 0.001). UB can be diagnosed with at least 95% sensitivity and 88% specificity in men over age 80. Conclusions: Non-invasive uroflowmetry and VE measurements were able to differentiate between UB and BOO patients, presenting with identical clinic features, but different findings of PFS.

KEY WORDS: Underactive bladder; Bladder outlet obstruction; Voiding efficiency; Urodynamics. Submitted 20 January 2022; Accepted 2 February 2002

INTRODUCTION

Reduced detrusor contraction, also named Detrusor Underactivity or Underactive Bladder (UB), means prolonged voiding at low pressure, without any obstruction from urodynamic and clinical point of view. This definition has been frequently included in the terminology. In his study published in 2015, Chapple defined UB as a symptom complex including prolonged voiding time with or without a feeling of complete bladder emptying, difficulty in initiating voiding, diminished sense of bladder filling and a slow voiding flux (1). UB may interfere with BO, which also leads to lower urinery tract (LUT) symptoms. This interference leads to failure of the planned surgery in these patients. Conversely, chronic retention or progression to surgery were not frequently

observed during long-term conservative follow-up of these patients (2). UB is generally seen in patients over age 80 in both genders, although identified more precisely in men, in terms of standardization. A Korean study reported higher frequencies for UB in men (40.2%) than in women (12%) over age 80 (3). There are studies reporting symptom recovery after prostate surgery in these patients (4), although other studies claimed only slight clinical recovery (5). Low urine flow rate is a common feature among the patients with UB and BO. Voiding pressure-flow study can be used for differentiation in indeterminate cases. (2). Because of the invasive nature of the pressure-flow study, a non-invasive method is welcomed. There may be a correlation between detrusor contraction index and the ratio of micturition volume and average physiological bladder capacity. This ratio, also known as voiding efficiency (VE), was addressed in the articles on pressure-flow studies and UB in the literature, although the topic is insufficiently studied.

MATERIALS

AND METHODS

Clinical data of the patients and the algorithm In the study, data of 4454 patients who underwent PFS in the period between January 2007-January 2015 was examined. Male patients having a minimum of 2 uroflowmetry and postvoid residual urine measurements were enrolled. Patients of female gender (n = 1208), patients with urological malignancies that may affect LUT symptoms (bladder cancer, prostate cancer, etc.) (n = 386), calculi in the bladder and lower end of the ureter (n = 102), active infection and asymptomatic bacteriuria (n = 406), transurethral intervention history (n = 908), previous LUT symptoms due to neurogenic causes (n = 1005), catheter before and after urodynamics or performing clean intermittent catheterization (CIC) (n = 155), decayed patients, bedridden patients suffering mobilization problems (n = 102), and patients with missing data (n = 89) were excluded from the study. A total of 93 patients with complete data and without exclusion criteria were included in the study. Detailed urological history and physical examination data were evaluated in all the included patients. Uroflowmetric measurements (Aymed urodynamic sys-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 1

Mehmet Yoldas

tems, Istanbul, Turkey) were performed at least two times before urodynamic testing and residual urine volume after uroflowmetry was assessed by suprapubic ultrasound measurement (LOGIQ C2, GE medicalsystems, Jiangsu P. R. CHINA). Figure 1. Algorithm of the study.

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

Those with uroflowmetry measurement ≥ 150 ml were included in the evaluation. Algorithm The algorithm of the study is shown in Figure 1.

Non-invasive diagnosis of underactive bladder

Uroflowmetry and measurement of postvoid residual urine All patients performed at least 2 uroflowmetric measurements prior to urodynamic evaluation and the average was calculated. They were asked to come to test with a full bladder. Uroflowmetry was performed while the patient was standing comfortably and alone. Uroflowmetry data including maximum urinary flow rate (Qmax) and voided volume were noted. For each patient, postvoid residual urine volume was determined by ultrasonography (US) by multiplying distances at sagittal, transverse and vertical axis of the bladder by 3.14/6 and noted for all patients (6). Voiding efficacy was calculated as voided volume on uroflow/pre-void bladder capacity measured on ultrasound. Urodynamic evaluation Before urodynamics, patients interrupted 3 days in advance drugs that can affect LUT symptoms, in accordance with the International Continence Society guidelines (7). Urine culture and antibiogram were done in all cases to exclude any possible risk of infection. Patients with a negative culture were eligible for pressure flow studies with prior quinolone prophylaxis. For pressure flow studies, a two-way 6 F urodynamic catheter (Mediana, ADS, Ankara, Turkey) and a 12 F rectal balloon catheter (UD-CATH, Aymed, Istanbul, Turkey) were used. Pressure flow studies started with an empty bladder while the patient was alone in a quiet room in sitting position. Bladder contractility index (BCI) was determined during pressure-flow studies, by adding 5 times the maximum urinary flow (Qmax) value following the voiding command, to the detrusor pressure at the moment of maximum flow volume following the voiding command, (5 Qmax + PdetQmax). The values ≤ 100 were defined as Underactive bladder (UB) (8). Bladder outlet obstruction index (BOI), also known as the Abrams-Griffiths (AG) number, was also determined during pressure-flow studies, by substracting twice the maximum flow value following the voiding command, from the value of detrusor pressure during the moment of maximum flow (PdetQmax) - 2Qmax). BOI was considered positive for the values ≥ 40 (9). BOI < 40 and BCI > 100 (healthy normal population), BOI > 40 and BCI < 100 (patıents Figure 2. wıth both bladder outlet Patient groups by age. obstructıon and hypoactıve bladder) were excluded.

Table 1. Demographic, uroflowmetric and postvoid residual urine data of the patients. Parameters Number of patients Mean age (year) Uroflowmetric parameters Time to start voiding after the command (sec) Maximum urinary flow (ml/sec) Mean urinary flow (ml/sec) Postvoid residual urine volume (ml)

UB Group 44 78.54 ± 11.6

BO Group 49 64.18 ± 11.1

P value

11.95 ± 1.82 11.36 ± 0.70 7.59 ± 0.43 381.4 ± 45.53

10.89 ± 1.06 10.46 ± 0.59 6.53 ± 0.40 296.93 ± 25.57

0.731 0.387 0.061 0.208

< 0.001

determined by Mann-Whitney U-test. Statistically significance was accepted as p < 0.05. Cut-off values of the statistically significant parameters were evaluated by the ROC curve.

RESULTS

A total of 93 patients with eligible and complete data were assigned to group UB (BOI < 40 and BCI < 100; n = 44) and group BO (BOI > 40 and BCI > 100; n = 49). Mean age was 64.18 ± 1.66 years for group BO and 78.54 ± 1.68 years for the group UB. Mean age was higher in the UB group, with a statistically significant difference between two groups (p < 0.001) (Table 1). A Korean study evaluated relationship between clinical pictures of UB and BO with age and gender, and reported higher prevalance of UB with aging when compared to BO in the male group, whereas an inverse relationship was observed for the female group that showed higher increase of BO prevalence with age compared to UB (3). In our study which included only male patients age was higher in the UB group compared to the BO group. According to the Korean study, UB group displayed an accelerated increase with age compared to BO group. Patients over 85 years of age constituted 40% of the UB group and 26% of the BO group. Interestingly, BO showed a decrease after the age of 75 (Figure 2). We explain this finding as some kind of compensation caused by BO as the result of an increased effort against

Statistical methods SPSS 15.0 (Statistical Package for the Social Sciences) (SPSS Inc, Chicago, IL, USA) statistical package was used in the statistical analysis of the data. Kolmogorov-Smirnov goodness-of-fit test was used to assess compliance with the normal distribution of data. Descriptive statistics of the data were calculated. Significance of differences between the groups was Archivio Italiano di Urologia e Andrologia 2022; 94, 1

Mehmet Yoldas

Figure 3. ROC curves voiding efficiency.

increased resistance preventing UB development at advanced ages. In accordance with this explanation, a decreased UB incidence and an increased BO incidence was shown among female aged over 75 years in the Korean study (3). Additionally, we think UB has a closer correlation with aging but BO pathogenesis is multifactorial. In the analysis of the two groups with regard to uroflow parameters; mean time to start voiding after the command was 11.95 ± 1.82 seconds in the UB group and 10.89 ± 1.06 seconds in the BO group and there was no statisticaly significant difference between the groups (p = 0.731). Mean value for maximum urinary flow was 10.46 ± 0.59 ml/sec in the UB group and 11.36 ± 0.70 ml/sec in the BO group, with a not significant difference between the groups (p = 0.387). Mean flow rate was 7.59 ± 0.43 and 6.53 ± 0.40 ml/sec, respectively for UB and BO, again with an insignificant difference (p = 0.061). Measurement of postvoid residual urine volume showed that, mean residual volume was 381.47 ± 45.53 ml in the Table 2. Urodynamic data of the patients. Bladder sensation during filling First sensation of bladder filling (early desire to void) First desire to void Strong desire to void (urgency) Maximum bladder capacity Pressure-volume studies Qmax (ml/sec.) PdetQmax (cmH2O) Bladder contractility index (PdetQmax + 5Qmax) A-G number (PdetQmax –2Qmax)

UB Group 150.8 ± 64.77 ml absent in 6 patients 243.5 ± 100.62 ml 355.6 ± 130.66 ml 544.7 ± 167.45 ml

BO Group 117.7 ± 64.52 ml absent in 1 patient 177.1 ± 83.86 ml 294.4 ± 145.78 ml 355.1 ± 133.48 ml

4.2 ± 3.96 ml/sec 34.1 ± 21.31 cmH2O 48.8 ± 27.21 20.0 ± 8.82

6.5 ± 3.98 ml/sec 101.1 ± 40.02 cmH2O 132.5 ± 37.83 88.0 ± 40.69

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

UB group and 296.93 ± 45.0 ml in the BO group, with an insignificant difference between the groups (p = 0.208). Mean voided volume was 666.90 ± 38.84 ml in the UB group and 213.46 ± 13.67 in the BO group, with a statistically significant difference between the groups (p < 0.001). With regard to bladder voiding efficiency, UB group performed at 66.02 ± 2.43% and BO group at 45.53 ± 2.63% efficiency (p < 0.001). A statistically significant difference was detected between the two groups for VE. In the analysis for determining the cut-off by the ROC curve, the area under the curve of maximum diagnostic value for VE was 0.771(±0.052) (Figure 3). From this study, we can deduce that patients in the BO group were able to empty their bladders more effectively than UB group. As the best cut-off points, separate ROC curve analysis for VE showed 93% sensitivity and 60% specificity. In short, UB group performed voiding at high efficiency while BO at lower efficiency levels (Table 1). In the pressure-flow study; first sensation of bladder filling (early desire to void) was detected at mean volumes of 150.8 ± 64.77 ml in UB group, although not detected in 6 patients, and 117.7 ± 64.52 ml in BO group. First desire to void occurred at average bladder filling of 243.5 ± 100.62 ml in UB group and 177.1 ± 83.86 ml in BO group. Strong desire to void (urgency) occurred at average bladder filling of 355.6 ± 130.66 ml in UB group and 294.4 ± 145.78 ml in BO group. Mean maximum bladder capacity was 544.7 ± 167.45 ml in UB group and 355.1 ± 133.48 ml in BO group. All parameters were determined to be higher, in the patients of UB group. Mean Qmax valus measured during pressure-flow studies was 4.2 ± 3.96 in UB group and 6.5 ± 3.98 ml/sn in BO group. Mean vesical pressure value recorded at maximum measured flow was 34.1 ± 21.31 cm H2O in UB group and 101.1 ± 40.02 cm H2O in BO group. Vesical pressure values were higher in BO group, as expected. Average bladder contractility index was 48.8 ± 27.21 in UB group and 132.5 ± 37.83 in BO group. Average A-G number was 20.0 ± 8.82 in UB group and 88.0 ± 40.69 in BO group (Table 2).

DISCUSSION

Bladder's ability to contract is well known to decrease with increasing age in both genders, causing pathologies resulting in UB and BO as well as causing LUT symptoms. Age-dependant impairment in UB is closely related with structural impairment of detrusor muscle. Structural changes are related with intense band decreases, decreased density of axonal connections, decreased colla-

Non-invasive diagnosis of underactive bladder

gen/muscle ratio, changes in muscarinic receptors, as determined by ultrastructural studies by electron microscopy (10). BO secondary to benign prostatic hyperplasia is well known to increase with age. Clinical features and prognosis of UB are not clearly defined and any diagnostic method has not been developed but the gold standard of urodynamics. Its prevalence in the elderly population is unclear (11). Diagnosis of BO with urodynamic testing has been shown to increase success rate of transurethral resection of the prostate. Up to date, many studies emphasized the need for urodynamic diagnosis of BO to define three different conditions as obstructive, intermediate and non-obstructive (12). These studies are mostly based on post-operative observations of the patients who underwent an operation for BO having previously had a TUR-P. Pdet/Qmax values decreased postopeartively in the obstructive group, decreased insignificantly in the equivocal group and remained unchanged in the non-obstructive group (13, 14, 15). UB and BO present with the same clinical symptoms and uroflowmetric findings although they are totally opposite clinical entities requiring completely different treatment. Surgery is usually the treatment of choice for BO, while it is rather unusual for UB, where medical treatment (cholinergic agonists, cholinesterase inhibitors, etc.), clean intermittent catheterization and conservative approach are more prominent. Urodynamic testing, which is the gold standard method, is an invasive diagnostic method used for differential diagnosis in these two clinical entities. In this context, in order to differentiate between these two types of clinical conditions, we attempted to use the non-invasive VE parameter for differential diagnosis. To the best of our knowledge, such a study has not been performed so far. VE was defined for the first time by Abrams in 1979 as a measure of bladder contractility against urethral resistance and presented as a percentage figure representing the degree of bladder emptying (13). Subsequent studies of Abrams developed a combination nomogram of 6 groups according to the BCI and the BOI. They noted that including VE to this nomogram would be more appropriate to decide both surgical and medical treatment modalities and to interpret the progression of the disease. In 1995, Bosch has evaluated the correlation and variation of this percentage value with aging, bladder contractility and urethral resistance (16), but voiding efficiency was calculated after urodynamic testing and was not utilized as a differential diagnostic tool. A Korean study evaluated relationship between clinical pictures of UB and BO with age and gender, and reported higher prevalance of UB with aging when compared to BO in the male group, whereas an inverse relationship was observed for the female group that showed higher increase of BO prevalence with age compared to UB (3). In our study, which included only male patients, age was higher in the UB group compared to the BO group. According to the Korean study, UB group displayed an accelerated increase with age compared to BO group. Patients over 85 years of age constituted 40% of the UB group and 26% of the BO group. Interestingly, BO showed a decrease after

the age of 75 (Figure 1). We explain this finding as some kind of compensation caused by BO as the result of an increased effort against increased resistance preventing UB development at advanced ages. In accordance with this explanation, a decreased UB incidence and an increased BO incidence was shown among female aged over 75 years in the Korean study (3). Additionally, we think UB has a closer correlation with aging bevause BO pathogenesis is multifactorial. Our patients in the UB group displayed higher values for voided volume, total voiding time and VE percentage than those in the BO group. Average values for VE were 66.02 ± 2.43% and 45.53 ± 2.63% (p < 0.001) for the patients of UB and BO group, respectively. To conclude, patients in the UB group voided larger volumes in longer time periods and more efficiently. Even if not exactly the same as in our study, in the study by Bosch et al., the relationship of VE with age, urethral resistance and bladder contractility were evaluated and a closer and directly proportional relationship was determined between urethral resistance and VE (16). A nomogram with the VE values was developed in the study by Bosch et al. suggesting its use for analysing potential future retention risks of these patients in the future, although longterm results were not obtained in this study. Unlike our study, Bosch et al. measured post-voidal residual urine volume by catheterization. They checked if the bladder was completely emptied or not by instilling an opaque material obtaining much more realistic values, although the measurements were performed just after the pressureflow studies. In our study VE was used for differential diagnosis between UB and BO achieving statistically significant difference. Abrams et al. developed a nomogram divided into 9 separate columns according to Qmax and Pdet/Qmax values obtained by flowmetric measurements to estimate whether medical, surgical or conservative approach is needed. It was also mentioned that addition of VE to this nomogram would provide a stronger estimation of correlations (13). It is apparent that voiding time increases with increased voided volume for UB and BO groups, having equal average flow rates in the uroflowmetric measurements. Voided volume was found considerably higher in the UB group. We realized that our patients in the UB group had larger bladder capacity, which is the main factor affecting voided volume and voiding time. In a different way, it can be stated that patients with BO have smaller bladder capacity and thus void in lesser volumes and for shorter time. A limitation of our study may be not having examined BOI between 20 to 40 and using a cut-off of 40 (AG-number) as in the Korean study.

CONCLUSIONS

In this retrospective study on 93 male patients, we intended to develop an alternative non-invasive diagnostic tool instead of invasive pressure-flow testing, which is recognized as the gold standard for differential diagnosis between UB and BO patients presenting with identical clinical pictures. In conclusion, UB can be diagnosed with at least 93% sensitivity and 60% specificity in men over the age of 80, with uroflowmetry measurment showing a Archivio Italiano di Urologia e Andrologia 2022; 94, 1

Mehmet Yoldas

46% voiding efficiency. However, long-term prospective studies with larger populations are obviously needed in the follow-up of these patients to evaluate retention and upper urinary tract involvement rates.

REFERENCES

9- Tubaro A, La Vecchia C. Uroscreening Study Group. The relation of lower urinary tract symptoms with life style factors and objective measures of benign prostatic enlargementand obstruction:an Italian survey. Eur Urol. 2004; 45:767.

1. Chapple CR, Osman NI, Birder L, et al. The underactive bladder: a new clinical concept? Eur Urol. 2015; 68:351-3.

10. Hotta H, Morrison JF, Sato A, et al. The effects of aging on the rat bladder and its innervation. Jpn J Physiol. 1995; 45:823.

2. Thomas AW, Cannon A, Bartlett E, et al.The natural history of lower urinary tract dysfunction in men: minimum 10-year urodynamic follow-up of untreated detrusor underactivity. BJU Int. 2005; 96:1295.

11. Taylor JA 3rd, Kuchel GA. Detrusor underactivity: Clinical features and pathogenesis of an underdiagnosed geriatric condition. J Am Geriatr Soc. 2006; 54:1920-32.

3. Jeong SJ, Kim HJ, Lee YJ, et al. Prevalence and clinical features of detrusor underactivity among elderly with lower urinary tract symptoms: a comparison between men and women. Korean J Urol. 2012; 53:342.

12. Abrams P, Buzelin JM, Griffiths D, et al. The urodynamic assessment of lower urinary tract symptoms. Proceedings of the 4th International Consultation of Benign Prostatic Hyperplasia (BPH) 1997. Edited by Denis L, Griffiths K, Khoury S, et al. Plymouth: Plymbridge Distributors. 1998; 323-77.

4. Han DH, Jeong YS, Choo MS, et al. The efficacy of trans urethral resection of the prostate in the patients with weak bladder contractility index. Urology. 2008; 71:657.

13. Abrams P, Griffiths D. The assessment of prostatic obstruction from urodynamic measurements and from residual urine. Br J Urol. 1979; 51:129.

5. Thomas AW, Cannon A, Bartlett E, et al. The natural history of lower urinary tract dysfunction in men: the influence of detrusor underactivity on 23 the outcom eafter trans urethral resection of the prostate with a minimum 10-year urodynamic follow-up. BJU Int. 2004; 93:745.

14. Schafer W. Basic principles and clinical application of advanced analysis of bladder voiding function. Urol Clin N Am. 1990; 17:553.

6. Hakenberg OW, Ryall RL, Langlois SL, Marshall VR. The estimation of bladder volume by sonocystography. J Urol. 1983; 130:249-51. 7. Schafer W, Abrams P, Liao L, et al. Good urodynamic practices: uroflowmetry, filling cystometry,and pressure-flow studies. Neurourol Urodyn. 2002; 21:261.

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

8. Abrams P. Bladder outlet obstruction index, bladder contractility index and bladder voiding efficiency: three simple indices to define bladder voiding function. BJU Int. 1999; 84:14.

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15. Griffiths DJ, vanMastrigt R, Bosch R. Quantification of urethral resistance and bladder function during voiding, to the with special reference to the effects of prostate size reduction on urethral obstruction due to benign prostatic hyperplasia. Neurourol Urodyn. 1989; 8:29. 16. Bosch JLHR, Kranse R, vanMastrigt R, et al Dependence of male voiding efficiency on age, bladder contractility and urethral resistance: development of a voiding efficiency nomogram. J Urol. 1995; 154:190.

DOI: 10.4081/aiua.2022.1.57

ORIGINAL PAPER

Looking for cystoscopy on YouTube: Are videos a reliable information tool for internet users? Carmine Turco 1, Claudia Collà Ruvolo 1, Simone Cilio 1, Giuseppe Celentano 1, Gianluigi Califano 1, Massimiliano Creta 1, Marco Capece 1, Roberto La Rocca 1, Luigi Napolitano 1, Francesco Mangiapia 1, Lorenzo Spirito 1, Simone Morra 1, Alberto Melchionna 1, Ferdinando Fusco 2, Vincenzo Mirone 1, Nicola Longo 1 1 Department

2 Department

of Neurosciences, Reproductive Sciences and Odontostomatology, Urology Unit, University of Naples “Federico II”, Italy; of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Naples, Italy.

Summary

Objective: The Internet is an important and easily accessible source of information. The aim of the current study was to investigate the quality of YouTube videos on cystoscopy and to establish if they can be used as a reliable information tool for internet users. Materials and methods: The search term “cystoscopy” was used on YouTube platform and the first 120 YouTube videos were analyzed. To assess the video quality Patient Education Materials Assessment Tool (PEMAT) for Audiovisual (A/V) Materials (Understandability and Actionability sections), Misinformation score and Global Quality Score (GQS) were used. Results: Of all 120 videos, 72 were included in the analyses. Of all videos, 59.7% (n = 43), and 40.3% (n = 29) were targeted to General Public and Healthcare Workers. Moreover, “technical aspects” was the main topic addressed (n = 29, 40.3%). The median PEMAT A/V Understandability and Actionability scores were 50.0% (IQR: 39.1-70.0) and 66.7% (IQR: 33.3100.0), respectively. The median Misinformation score ranged from 1.0 to 3.0. According to GQS, 22 (30.6%), 26 (36.1%), 16 (22.2%), 8 (11.1%) videos were poor, generally poor, moderate, and good, respectively. No video was evaluated as excellent. Conclusions: Today, YouTube videos on cystoscopy are more frequently uploaded by healthcare workers, who share information about specific aspects of this procedure. However, the quality of YouTube contents on cystoscopy is still poor. Therefore, currently users interested in cystoscopy cannot rely on YouTube to get good informative material on this topic. In consequence, future authors should focus on improving the quality of video contents on cystoscopy.

KEY WORDS: Urethrocystoscopy; Social media; Urology; Internet; PEMAT. Submitted 5 November 2021; Accepted 20 December 2021

INTRODUCTION

Cystoscopy is an endoscopic procedure used to explore the bladder and the urethra in their entirety. It is used with diagnostic, therapeutic and follow-up purposes in oncological, such as bladder cancer or upper tract urothelial carcinoma, and non-oncological conditions, such as lower tract urinary symptoms, urinary incontinence, chronic pelvic pain, recurrent urinary tract infections or

urologic trauma (1-9). The Internet is an important and easily accessible source of information. More than 80% of patients look for medical advice or informative contents about their conditions on the web (10). Among all social media, YouTube is a video-sharing platform which allows people to upload or watch videos. It is the second most visited website, with more than 500 hours of content uploaded every minute, from 80 different countries and five billion videos watched every day (11). In current literature, several previous studies have already examined YouTube video on medical topic (11-14). Internet users may look for information on cystoscopy on YouTube to be aware of what to expect from the procedure to reduce possible distress, pain or anxiety (15). To the best of our knowledge, we are the first to analyze the quality of YouTube information on cystoscopy. The aim of the current study was to investigate the quality of YouTube videos on cystoscopy and to establish if they can be used as a reliable information tool for internet users.

MATERIALS

AND METHODS

Search strategy and video selection criteria On the 26th of February 2021, a systematic search on YouTube was conducted. The key word used was “cystoscopy”. Before selecting the videos, to avoid suggestions based on previous research, any personal accounts were logged out and a Virtual Private Network (VPN) software was set in the United States. No research filter was applied. The first 120 videos (6 pages) were examined (16). As a YouTube default setting, the videos were sorted by relevance. The exclusion criteria applied were (Figure 1): videos showing different procedures (n = 14), videos without audio (n = 13), videos about topic of other disciplines (n = 7), webinars (n = 7), and videos not in English language (n = 4). For duplicates (n =3), only one was considered. Finally, videos part of a compilation were considered as single. For each suitable video, the variables collected were length (in seconds), number of thumbs up and thumbs down, number of channel subscribers, number of views, number of comments, number of videos with disabled comments,

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 1

C. Turco, C. Collà Ruvolo, S. Cilio

Figure 1. PRISMA diagram depicting inclusion and exclusion criteria of YouTube video search.

persistence on YouTube (defined as days between the date of upload and the date of analysis), video author (defined as Associations, Academic Hospitals/University, No Academic Hospitals, Healthcare worker, Patients, Others), video target (General public or Healthcare workers) and video topic (explanation to patient, personal experience, and technical aspects). Finally, Video Power Index (VPI), calculated as LIKE ratio (thumbs up x 100/thumbs up + thumbs down) multiplied by VIEW ratio (views/persistence time) divided by 100, was used as an indicator of popularity, as previously done (11). Quality and misinformation assessment tools The videos quality was independently assessed by two urology residents [a junior (third year) and a senior (fifth year)]. A third investigator (an Associate Professor) sorted any differences, and consensus was achieved among reviewers. The following video quality assessment tools were used: the Patient Education Materials Assessment Tool for audio-visual content (PEMAT A/V), the Misinformation score and the Global Quality Score (GQS). First, the PEMAT A/V is an instrument to establish the Understandability and the Actionability of informative audiovisual contents for patients on different topics. Understandability and Actionability are respectively evaluated by 13 plus 4 questions. Each question can be answered with three options: “Agree”, “Not Agree” and “Not Applicable”. The final score is a percentage: the higher is the percentage, the more understandable and/or actionable is the material (11). Second, a Misinformation score was appositely created

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

for the study. It consisted of five items: 1) Good explanation of the topic, 2) Indications are clear, 3) Good execution of the procedure, 4) European Association of Urology (EAU) guidelines concordance and 5) Pathological cases are showed. Each item was evaluated by five possible different levels of agreement/disagreement (1 = strongly disagree, 2 = disagree, 3 = not agree or disagree, 4 = agree, 5 = strongly agree) (11). The lower was the result, the higher was the misinformation level. Finally, GQS is a scale evaluating the overall quality and the clinical utility of each video (11). The five permitted options ranged from 1 (Poor quality, poor flow of the site, most information missing, not at all useful for patients) to 5 (Excellent quality and excellent flow, very useful for patients). The higher was the score, the better was the quality of the video.

Statistical analyses Descriptive statistics were presented as medians and Interquartile ranges (IQR) for continuously coded variables or counts and percentages for categorically coded variables. Chi-square test and Kruskal-Wallis test examined the statistical significance in proportions and medians differences. Cohen kappa statistics was used to measure the reliability of the investigator's evaluations of the videos. Pearson’s test was used to assess potential correlations between the variables. In all statistical analyses, R software (www.rproject.org) environment for statistical computing and graphics (R version 4.0.0) and Microsoft Excel 2019 were used. All tests were two-sided with a level of significance set at p < 0.05.

RESULTS Videographic characteristics Of all 120 videos examined, 72 were eligible (Table 1). The median length was 160.5 seconds (IQR: 109.8-403.5, range: 39-1092), the median number of views was 13787.5 (IQR: 2306.2-52604, range: 94-910019) and the median persistence time on YouTube was 1437.5 days (IQR: 835.8-2029.8, range: 75-4105). Moreover, across the sample, the median number of thumbs up, thumbs down, comments and subscribers were 40.0 (IQR: 7.0147.0, range: 0-2151), 5.0 (IQR: 1.0-18.5, range: 0-278), 2.0 (IQR: 0-16.8, range: 0-475) and 5930.0 (IQR: 653.822025, range: 5-3160000), respectively. Furthermore, 15 videos (20.8%) had disabled comments. Of all videos, 43.1% (n = 31), 1.4% (n = 1), 8.4% (n = 6), 18.0% (n = 13), 19.4% (n = 14) and 9.7% (n = 7) were produced by Associations, Academic Hospitals or Universities, No Academic Hospitals, Healthcare Worker, Patients, Others, respectively. Additionally, 59.7% (n = 43), and 40.3%

Quality of videos about cystoscopies on YouTube

Table 1. Videographic characteristics of 72 YouTube videos on “Cystoscopy” recorded on the 26th of February 2021. Videographic characteristics Length, sec

Overall value 160.5 (109.8-403.5) 39-1092 40.0 (7.0-147.0) 0-2151 5.0 (1.0-18.5) 0-278 5930.0 (653.8-22025) 5-3160000 13787.5 (2306.2-52604) 94-910019 2.0 (0-16.8) 0-475 57 (79.2) 15 (20.8) 1437.5 (835.8-2029.8) 75-4105 31 (43.1) 1 (1.4) 6 (8.4) 13 (18.0) 14 (19.4) 7 (9.7) 43 (59.7) 29 (40.3) 29 (40.3) 27 (37.5) 16 (22.2) 8.8 (2.2-31.1) 0-4609.88853

Median (IQR) Range Thumbs up, n Median (IQR) Range Thumbs down, n Median (IQR) Range Subscribers, n Median (IQR) Range Views, n Median (IQR) Range Comments, n Median (IQR) Range Disabled comments, n (%) No Yes Persistence on YouTubeTM (days) Median (IQR) Range Author, n (%) Associations Academic Hospitals - Universities No Academic Hospitals Healthcare worker Patients Others Target, n (%) General public Healthcare workers Video topic, n (%) Technical aspects Explaination to patient Personal experience VPI, n Median (IQR) Range IQR: Interquartile range; VPI: Video power index.

(n = 29), were targeted to General public and Healthcare workers, respectively. Finally, technical aspects was the main topic addressed (n = 29, 40.3%), followed by explanation to patient (n = 27, 37.5%) and personal experience (n = 16, 22.2%). Video quality assessment The median PEMAT A/V Understandability score was 50.0% (IQR: 39.1-70.0), and the median PEMAT A/V Actionability score was 66.7% (IQR: 33.3-100.0). According to video target (General public vs Healthcare workers) a statistically significant difference was recorded for Understandability (55.6 vs 40.0%, p = 0.01), but not for Actionability (66.7 vs 66.7%, p = 0.7) (Table 2A). The Cohen kappa statistic was used to measure the reliability of the investigator’s assessments between the two evaluation times. The Cohen kappa recorded was 0.46 for the Actionability score and 0.17 for the Understandability score. The median Misinformation score ranged from 1.0 (item 3: Good execution of the procedure; item 5: Pathological cases are showed) to 3.0 (item 1: Good explanation of the topic; item 4: EAU guidelines concordance). According to video target (General public vs Healthcare workers), no statistically significant difference was recorded. Moreover, a median overall Misinformation score ≤ 2.5 was recorded in 68.1% (n = 49) videos vs 31.9% (n = 23) videos with a median overall Misinformation score > 2.5 (Table 2B). According to GQS, 22 (30.6%), 26 (36.1%), 16 (22.2%), 8 (11.1%) videos were poor, generally poor, moderate, and good, respectively. No video was evaluated as excellent. According to video target (General public vs Healthcare workers), no statistically significant differences were recorded (Table 2C).

Table 2. A) Patient Education Materials Assessment Tool for audio-visual content (PEMAT A/V) score, B) Misinformation score and C) Global Quality Score (GQS) of 72 YouTube videos on “Cystoscopy” recorded on the 26th of February 2021. Variable A) PEMAT A/V, (%) Understandability Actionability B) Misinformation 1) Good explanation of the topic 2) Indications are clear 3) Good execution of the procedures 4) EAU guidelines concordance 5) Pathological cases are showed Overall misinformation score

Overall value n = 72

General public Healthcare workers p-value n = 43 (59.7%) n = 29 (40.3%)

Median (IQR) Median (IQR)

50.0 (39.1-70.0) 66.7 (33.3-100.0)

55.6 (40.8-72.7) 66.7 (33.3-100.0)

40.0 (30.0-58.3) 66.7 (33.3-100.0)

0.01 0.7

Median (IQR) Median (IQR) Median (IQR) Median (IQR) Median (IQR) ≤ 2.5 > 2.5

3.0 (2.0-4.0) 2.0 (1.0-3.0) 1.0 (1.0-1.0) 3.0 (2.0-3.0) 1.0 (1.0-2.0) 49 (68.1) 23 (31.9)

3.0 (2.0-4.0) 3.0 (1.5-3.0) 1.0 (1.0-1.0) 3.0 (2.0-3.0) 1.0 (1.0-1.5) 30 (69.8) 13 (30.2)

3.0 (2.0-4.0) 2.0 (1.0-3.0) 1.0 (1.0-2.0) 3.0 (2.0-3.0) 1.0 (1.0-4.0) 19 (65.5) 10 (34.5)

0.3 0.2 0.4 0.2 0.7

13 (30.2) 15 (34.9) 10 (23.3) 5 (11.6) 0 (0)

9 (31.0) 11 (37.9) 6 (20.7) 3 (10.3) 0 (0)

C) GQS Poor Generally poor Moderate Good Excellent IQR: Interquartile range; EAU: European Association of Urology.

22 (30.6) 26 (36.1) 16 (22.2) 8 (11.1) 0 (0)

0.9

Variable correlations We tested for possible correlations. First, we examined possible correlations between videographic characteristics (length in seconds, thumbs up, thumbs down, number of views, persistence on YouTube, channel subscribers and VPI) and quality assessment tools (PEMAT Understandability and Actionability scores, Misinformation score and GQS). Second, possible correlations within quality assessment tools were performed. We recorded a statistically significant positive correlation between PEMAT A/V Understandability and Misinformation score (r = 0.50, p ≤ 0.001) and between PEMAT A/V Actionability scores and Misinformation score (r = 0.42 p ≤ 0.001). Conversely, no statistically significant result was recorded between the other correlations (r coefficients ranged from -0.14 to 0.21, all p ≥ 0.1).

0.9

DISCUSSION

YouTube is the second most visited platform and allows people to upload video Archivio Italiano di Urologia e Andrologia 2022; 94, 1

C. Turco, C. Collà Ruvolo, S. Cilio

regarding health topics. However, currently, no filter or revision progress of video contents exists. In consequence, YouTube can represent a risk for misinformation. Since cystoscopy is recommended both for diagnosis and follow up of oncological and non-oncological conditions, we took into consideration the importance of this procedure and the impact of a correct information on YouTube. Therefore, the aim of the current study was to evaluate the quality of YouTube videos on cystoscopy and to establish if they can be used as a reliable information tool for internet users. To the best of our knowledge, no previous investigators examined the quality of YouTube contents on cystoscopy procedure. We addressed this void and identified several noteworthy observations. First, we recorded that approximately 80% of videos were uploaded by hospitals and/or healthcare workers and approximately 60% of videos were targeted to General public. Moreover, the main topic addressed concerned technical aspects (40%), such as the assembly of a cystoscope or the preparation of a sterile draping. In consequence, according to our results, today YouTube is more frequently managed by people with a medical background, rather than no-medical educated individuals, in terms of uploading contents regarding cystoscopy. Therefore, it would be expected that videos uploaded by healthcare workers should be characterized by good quality contents. Thus, it is important to evaluate video contents to confirm or not this expectation. Second, considering the PEMAT A/V tool, we recorded an overall Understandability score of 50.0% and, specifically, a higher Understandability score was recorded in video targeted to General public (55.6%), relative to Healthcare workers (40.0%). Conversely, we recorded a higher overall Actionability score (66.7%), relative to Understandability, and no differences were recorded between video targets. According to Shoemaker at al., a PEMAT A/V score < 70% is considered poorly understandable and poorly actionable (17). In consequence, nowadays YouTube videos regarding cystoscopy are more actionable than understandable but are still considered as not sufficient quality videos. Similarly, to our results, previous studies regarding other medical topics recorded low Understandability and Actionability scores. For example, Salama et al. (18) evaluated 53 videos on hypospadias recording an Understandability and an Actionability score of 54.5 and 21.8%, respectively. Moreover, Rubel et al. (19) analyzed the quality of 40 YouTube videos on sinusitis and obtained an Understandability and an Actionability score of 46.3 and 57.7%, respectively. In conclusion, future authors should focus on uploading better quality videos to achieve higher PEMAT A/V scores, regardless of the topic. Third, considering the Misinformation score, the lowest median score was recorded for item 3 (“Good execution of the procedure”) and item 5 (“Pathological cases are showed)”. Consequently, viewers interested in cystoscopy may not be sufficiently informed on how the procedure is executed or how their conditions appear. Moreover, none of the questions proposed reached the maximum score. Consequently, according to the Misinformation score appositely created for this study, none of the video analyzed could grant a complete information to viewers. Fourth, similarly to the results recorded from the other

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

quality assessment tools applied, GQS also indicated a low video quality. Indeed, almost 70% of videos were considered as poor or generally poor and none was evaluated as excellent. These observations were confirmed even when the videos were analyzed according to video target: both General public and Healthcare workers targeted videos were mostly evaluated as low quality. Fifth, we recorded a positive correlation between PEMAT A/V Understandability score and Misinformation score (r = 0.50) and between PEMAT A/V Actionability score and the Misinformation score (r = 0.42). In consequence, the more the video was understandable and/or actionable, the higher was the quality of information. These results corroborated our findings, implying that all the tools used demonstrated concordantly a low YouTube video quality on cystoscopy. Conversely, no statistically significant correlations were found between quality assessment tools and videographic characteristics. The lack of correlations may be interpreted as an independent relationship between the quality content and the users’ interaction with the YouTube videos. In consequence, today videos aspects such as views, thumbs up, thumbs down or number of subscribers cannot be used as a quality indicator, in a positive or negative interpretation. For example, Loeb et al. recorded a negative correlation between scientific quality and viewer engagement, measured as views/mo (-0.24; p = 0.004) or thumbs up/views (-0.20; p = 0.015), indicating that even videos highly watched were characterized by poor quality information (20). Taken together, although mostly of YouTube videos on cystoscopy are uploaded by hospitals and/or healthcare workers, the quality is still low according to PEMAT A/V score, Misinformation score and GQS. YouTube users, that may be even represented by patients undergoing a cystoscopy, could not get access to sufficiently good quality contents. In consequence, YouTube today cannot be recommended as a reliable source of medical information about this procedure. Therefore, since the Internet searching is becoming an everyday habitude, future video authors need to focus on uploading higher quality videos to provide better contents to avoid misinformation. As a practical implication, it could be useful to create a proper guideline on cystoscopy approved by urological associations with the intent to guide authors in the video making process. On the other hand, new quality assessment tools might be developed to verify medical contents which are continuously uploaded on YouTube. Our work is not devoid of limitations. First, search results could change in every moment based on the interactions video-users, so our study represented only a frame of the current situation. Second, due to the methodology used, which allowed us to include 72 videos, contents providing different information could have been excluded. Third, some videos might not be included in our analysis due to search terms. Nonetheless, we assumed that video authors meant to use “cystoscopy” in the title or as keyword. Finally, the video quality assessment was a subjective evaluation. To reduce this problem, three different investigators independently analyzed the videos. Although these limitations, the present study may be considered as a snapshot of the current information on YouTube videos regarding cystoscopy.

Quality of videos about cystoscopies on YouTube

CONCLUSIONS

Today, YouTube videos on cystoscopy are more frequently uploaded by healthcare workers, who share information about specific aspects of this procedure. However, the quality of YouTube contents on cystoscopy is still poor. Therefore, currently users interested in cystoscopy cannot rely on YouTube to get good informative material on this topic. In consequence, future authors focus on improving the quality of video contents on cystoscopy.

REFERENCES

1. Dobé T-R, Califano G, von Rundstedt F-C, et al. Postoperative chemotherapy bladder instillation after radical nephroureterectomy: Results of a European survey from the Young Academic Urologist Urothelial Cancer Group. Eur Urol Open Sci. 2020; 22:45-50. 2. Creta M, Sagnelli C, Celentano G, et al. SARS-CoV-2 infection affects the lower urinary tract and male genital system: A systematic review. J Med Virol. 2021; 93:3133-42. 3. Califano G, Ouzaid I, Verze P, et al. New immunotherapy treatments in non-muscle invasive bladder cancer. Arch Esp Urol. 2020; 73:945-53.

15. Kim HJ, Kim JW, Park HS, et al. The use of a heating pad to reduce anxiety, pain, and distress during cystoscopy in female patients. Int Urogynecology J. 2019; 30:1705-10. 16. Megaly M, Khalil C, Tadros B, Tawadros M. Evaluation of educational value of YouTube videos for patients with coeliac disease. Int J Celiac Dis. 2016; 4:102-4. 17. Shoemaker SJ, Wolf MS, Brach C. Development of the Patient Education Materials Assessment Tool (PEMAT): A new measure of understandability and actionability for print and audiovisual patient information. Patient Educ Couns. 2014; 96:395-403. 18. Salama A, Panoch J, Bandali E, et al. Consulting «Dr. YouTube»: an objective evaluation of hypospadias videos on a popular videosharing website. J Pediatr Urol. 2020; 16:70.e1-70.e9. 19. Rubel KE, Alwani MM, Nwosu OI, et al. Understandability and actionability of audiovisual patient education materials on sinusitis. Int Forum Allergy Rhinol. 2020; 10:564-71. 20. Loeb S, Sengupta S, Butaney M, et al. Dissemination of misinformative and biased Information about prostate cancer on YouTube. Eur Urol 2019; 75:564-7.

4. Capece M, Spirito L, La Rocca R, et al. Hexaminolevulinate blue light cystoscopy (Hal) assisted transurethral resection of the bladder tumour vs white light transurethral resection of the bladder tumour in non-muscle invasive bladder cancer (NMIBC): a retrospective analysis. Arch Ital Urol Androl 2020; 92:17-20. 5. Verze P, Califano G, Sokolakis I, et al. The impact of surgery for lower urinary tract symptoms/benign prostatic enlargement on both erectile and ejaculatory function: a systematic review. Int J Impot Res. 2019; 31:319-27. 6. Peyrottes A, Ouzaid I, Califano G, et al. Neoadjuvant immunotherapy for muscle-invasive bladder cancer. Med Kaunas Lith. 2021; 57:769. 7. 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 Switz. 2021; 11:351. 8. Califano G, Collà Ruvolo C, Creta M, et al. Focus on silodosin: pros and cons of uroselectivity. Res Rep Urol. 2020; 12:669-72. 9. Imperatore V, Creta M, Di Meo S, et al. Intravesical administration of combined hyaluronic acid and chondroitin sulfate can improve symptoms in patients with refractory bacillus Calmette-Guerininduced chemical cystitis: Preliminary experience with one-year follow-up. Arch Ital Urol Androl. 2018; 90:11-4. 10. Ullrich PFJ, Vaccaro AR. Patient education on the Internet: opportunities and pitfalls. Spine. 2002; 27:E185. 11. Morra S, Collà Ruvolo C, Napolitano L, et al. YouTubeTM as a source of information on bladder pain syndrome: A contemporary analysis. Neurourol Urodyn. 2022; 41:237-245. 12. Gerundo G, Ruvolo CC, Puzone B, et al. Personal protective equipment in Covid-19: evidence-based quality and analysis of YouTubeTM videos after one year of pandemic. Am J Infect Control. 2021; S0196-6553(21)00758-6. 13. Passos PS, Carvalho N, Anacleto ST, et al. Digital informed consent on radical prostatectomy surgery - A turning point on patient communication means. Arch Ital Urol Androl. 2021; 93:366-9. 14. Capece M, Di Giovanni A, Cirigliano L, et al. YouTube as a source of information on penile prosthesis. Andrologia. 2021; e14246.

Correspondence Carmine Turco, MD car.turco87@gmail.com Claudia Collà Ruvolo, MD (Corresponding Author) c.collaruvolo@gmail.com Simone Cilio, MD simocilio.av@gmail.com Giuseppe Celentano, MD dr.giuseppecelentano@gmail.com Gianluigi Califano, MD gianl.califano2@gmail.com Massimiliano Creta, MD max.creta@gmail.com Marco Capece, MD drmarcocapece@gmail.com Roberto La Rocca, MD robertolarocca87@gmail.com Luigi Napolitano, MD luiginap89@gmail.com Francesco Mangiapia, MD mangiapiaf@gmail.com Lorenzo Spirito, MD lorenzospirito@msn.com Simone Morra, MD simonemorra@outlook.com Alberto Melchionna, MD alb.melchionna@gmail.com Vincenzo Mirone, MD mirone@unina.it Nicola Longo, MD nicola.longo@unina.it Department of Neurosciences, Reproductive Sciences and Odontostomatology, Urology Unit, University of Naples “Federico II”, Italy Ferdinando Fusco, MD ferdinando-fusco@libero.it Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Naples, Italy

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

DOI: 10.4081/aiua.2022.1.62

ORIGINAL PAPER

Propionibacterium acnes in urine and semen samples from men with urinary infection Lucrezia Manente 1, Umberto Gargiulo 1, Paolo Gargiulo 1, Giuseppe Dovinola 2 1 Biodata

s.r.l Clinical, Molecular and Genetics Laboratory, Salerno, Italy; Urology and Andrology Clinic, Salerno, Italy.

2 Specialist

Summary

Objective: Propionibacterium acnes has been implicated in the pathogenesis of prostate disease as acute and chronic prostatic inflammation, benign prostatic hyperplasia and prostate cancer although it should still be clarified if Propionibacterium acnes (P. acnes) is a commensal or accidental prostate pathogen. Aiming to evaluate the pathogenic potential for genitourinary tract of Propionibacterium acnes, we investigated the frequency of P. acnes genome in urine or semen samples from men with recurrent symptoms of urinary infection and negative testing for the most common urinary tract pathogens and sexually transmitted infections (STI) agents as Chlamydia trachomatis, Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma parvum and Ureaplasma urealyticum. Materials and methods: The DNA extracted from urine and semen samples was analyzed for evaluating the P. acnes genome presence by real-time polymerase chain reaction (PCR). Infections were treated with vancomycin and cephalosporins antibiotics and then the search for the P.acnes genome by realtime PCR was repeated. Results: The P. acnes qualitative real-time PCR revealed the genome in 73 out of 159 samples examined (108 urine and 51 semen). After antibiotic therapy, P. acnes was never detected. Conclusions: These results suggested that P. acnes genome determination should be performed in cases of chronic inflammation in the urinary tract to identify an unknown potential pathogen of genitourinary tract.

KEY WORDS: Propionibacterium acnes; Prostate hyperplasia; Prostate cancer; Urinary tract infections. Submitted 18 October 2021; Accepted 3 December 2021

INTRODUCTION

Propionibacterium acnes (P. acnes) is a gram-positive, nonmotile, non-spore forming, anaerobic bacillus. It is ubiquitous and part of the normal flora of the skin. Despite it is considered part of our commensal microbiota there are a number of reports correlating P. acnes with several diseases. Indeed P. acnes contributes at the pathogenesis of acne vulgaris and was found to be implicated in a widerange of post-operative infectious conditions, such as endocarditis, endophthalmitis and intravascular nervous system infections. P. acnes is also frequently detected in prostate tissue of patients diagnosed with benign prostate hyperplasia (BPH) and cancer (1). Chronic infection and inflammation have been linked to cancer of several organs suggesting that also prostatic inflammation could

contribute to the etiology of prostate cancer as well as BPH. Kakegawa et al. showed in a series of repeat prostate biopsies that patients with high serum PSA and initial biopsy negative for cancer progressed more frequently to prostate cancer in subsequent biopsies if the initial biopsy was positive for the presence of P. acnes (2, 3). In the present paper we evaluated the potential pathogenic role of P. acnes in the genitourinary tract. For this purpose, we evaluated by real time PCR the presence of P. acnes DNA in urine or seminal fluid of patients with recurrent symptoms of urinary infection but negative testing for the most common urinary tract pathogens and sexually transmitted infections (STI) agents as Chlamydia trachomatis, Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma parvum and Ureaplasma urealyticum.

MATERIALS

AND METHODS

Patients Male patients with recurrent symptoms of urinary tract infection were considered in the present study. Patients sought medical attention of the urology specialist due to voiding symptoms (weak stream, straining and hesitancy) or storage problems (urgency, frequency and dysuria) and pain poorly localized in the lower back, hypogastrium, pelvis or genitalia. Digital prostate palpation showed tender, swollen and warm prostate or also nodularity. Patients with diabetes, spinal cord injury and catheter use were excluded. Patients were subjected to urinalysis and urine culture and to semen analysis in case of history of couple infertility. Samples were screened for predominant pathogens involved in urinary tract infections (UTI) as Escherichia coli, Klebsiella spp., Proteus spp., and Enterococcus spp. and for Sexually Transmitted Infection (STI) agents, by molecular methods. Patients with negative testing for the most common urinary tract pathogens and sexually transmitted infections (STI) agents were investigated for the presence of DNA P. acnes. Specimen Collection, Urinalysis, Urine and Semen Culture Urinary and semen specimens were obtained from patient with recurrent symptoms of urinary infection. All the urinary samples were subjected to urinalysis and urine culNo conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

Propionibacterium acnes genome in the urinary infection

ture. Midstream urine was collected in a clean vessel and analyzed within 2 h of collection. Urinalysis included physical, chemical and microscopic examinations. Chemical urinalysis was performed by Automated Urinalysis System U500 (InterMedical Diagnostics) detecting blood, protein, glucose, leukocyte esterase and nitrite. Microscopic examination was performed to identify cells, bacteria, casts and crystals. Physical and chemical findings were: hazy or cloudy appearance, blood presence, glucose > 1000 mg/dl, protein more than trace quantities, leukocyte esterase or nitrite positivity. Microscopic findings were: detection of red blood cells (RBC) and/or white blood cells (WBC) ≥ 4 for high power field (HPF) and/or bacteria (data not shown). Urine and semen samples for microbiology analysis were collected in sterile vessel. Selective and differential solid media (Integral System Enterobatteri, Liofilchem, Italy) were used for cultivable microorganisms. Lactobacillus species, coagulase-negative Staphylococcus and Streptococcus were considered normal flora or contaminants and thus urine or semen culture was considered negative. Growth and identification of Enterobacteriaceae, group B Streptococcus, Staphylococcus aureus, Staphylococcus saprophyticus, Enterococcus spp., Klebsiella spp., Proteus spp., Candida spp at > 10000 CFU/ml and 5000 CFU/ml for urine and semen respectively were considered positive culture. DNA extraction and Sexually Transmitted Infection (STI) agents detection The urine and semen samples were screened for Chlamydia trachomatis and Genital Mycoplasmas with real time PCR. Briefly, the DNA extraction was made using Prime DNA/RNA Rapid Extraction kit (Astra Biotech, Berlin, Germany) and the analysis was made by real-time PCR using the kit Mycoplasma genitalium/Mycoplasma hominis Multiplex PCR kit, Ureaplasma urealyticum/Ureaplasma parvum Multiplex kit and Chamydia trachomatis PCR kit (Astra Biotech, Berlin, Germany) according to the manufacturer’s instructions. Propionobacterium acnes identification The DNA extracted from urine and semen samples was analyzed for P. acnes genome presence using the P. acnes recA gene (Primer Design Genesig, UK) according to the manufacturer’s instructions. The kit is designed with the broadest possible detection profile to ensure that all clinically relevant strains and subtypes are detected. The analysis was made by realtime PCR and all amplification reactions of the genomic materials were performed with a AriaDX Real-time PCR System (Agilent Technologies). Antibiotic therapy The treatment of P. acnes infections can be made using antibiotics such as cephalosporine, vancomycin, penicillin, tetracyclines, rifampicin and erythromycin. In our study all the patients with P. acnes infections were treated, initially, with cephalosporins for three months. After cephalosporins therapy if the urine or semen samples were still positive for P. acnes an alternative antibiotic regimen with vancomycin for three months was proposed.

RESULTS DNA P. acnes detection from urine and semen sample Out of the 159 samples examined (108 urine and 51 semen samples) the genome of P. acnes was identified in 56 urine and 17 semen samples (Tables 1, 2). P. acnes positive patients were treated with cephalosporins therapy. After cephalosporins therapy, P. acnes real time was repeated in 56 urine and 17 semen samples and P. acnes genome was not detected in 51 urine and in 16 semen sample whereas 6 samples (5 urine and 1 semen) were still positive for P. acnes. These patients were treated with vancomycin, an alternative antibiotic therapy, and then were re-evaluated for presence of P. acnes genome. At the end of the vancomycin therapy, P. acnes real time testing was negative per P. acnes genome. Table 1. Total samples examined. Tot. n. samples Urine Semen

159 108 51

Table 2. Presence of P.acnes genome in urine and semen samples. Samples in which the P. acnes genome was identified Urine Semen

56 17

DISCUSSION

UTI is the most common urological infection with annual incidence increasing with age in men (4, 5). The presence of localized genitourinary symptoms and signs of urinary tract inflammations and a urine culture with an identified urinary pathogen are suggestive of UTI and antibiotic therapy is necessary for the treatment of the infection. Any microorganism, ascending the urethra or by reflux of urine into prostatic duct, can infect prostate gland and to cause chronic inflammation in connection with benign prostatic hyperplasia (BPH), chronic prostatitis (CP) and prostate cancer (6). In addition to bacterial infections, other factors such as hormone imbalances, dietary carcinogens and environmental factors promote prostate chronic inflammation and lead to injury of the prostate (7). Several studies showed that the P. acnes identification was associated with acute and chronic inflammation and, moreover, a high prevalence rates of this bacterium in prostate tissue samples from men with prostate cancer has been demonstrated (8, 9). P. acnes is a common skin anaerobic organism that is capable to resist to phagocytosis through complex cell wall structure, to persist intracellularly within macrophages and to produce exocellular enzymes that can damage the host tissue and induce pro inflammatory cytokines (10). In this study we analyzed, with molecular biology techniques, the urine and semen sample of patients with recurrent symptoms of urological Archivio Italiano di Urologia e Andrologia 2022; 94, 1

L. Manente, U. Gargiulo, P. Gargiulo, G. Dovinola

infections, that were negative for more common genitourinary pathogen and STI agents (11, 12). Patients with samples positive for P. acnes were treated with specific antibiotic therapy and showed a positive response in terms of improved clinical condition. A limitation of the present study is the lack of comparative date between urine and semen samples from the same patient, although it is conceivable that the pathogen could be detectable indifferently in both samples. A further objective of our work will be to assess the correlation between P. acnes infection and couple infertility. In fact, our preliminary experience has shown that three patients with a history of couple infertility were able to obtain the pregnancy after antibiotic therapy to eradicate the P. acnes infection. This finding should be confirmed by larger controlled series.

CONCLUSIONS

Our results show that real time PCR genome screening for P. acnes could be a useful diagnostic tool for UTIs. P. acnes infection could start a pathogenic cascade causing, in the long term, an inflammatory process of the prostate. Indeed, an amount of evidence suggests that the invasion of prostate epithelial cells by P. acnes contributes at the prostate gland diseases (13).

REFERENCES

1. Leheste JR, Ruvolo KE, Chrostowski JE, et al. P. acnes-driven disease pathology: current knowledge and future directions. Front Cell Infect Microbiol. 2017; 7:81. 2. Kakegawa T, Bae Y, Ito T, et al. Frequency of Propionibacterium acnes infection in prostate glands with negative biopsy results is an independent risk factor for prostate cancer in patients with increased serum PSA titers. PLoS One. 2017; 12:e0169984

Correspondence Lucrezia Manente, PhD (Corresponding Author) l_manente@yahoo.it Umberto Gargiulo u.gargiulo@hotmail.it Paolo Gargiulo info@biodatasalerno.it Biodata s.r.l Clinical, Via Diaz 22, Salerno (Italy) Giuseppe Dovinola, MD dovinolap@libero.it Specialist Urology and Andrology Clinic Via Lungomare Trieste 172, Salerno (Italy)

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

3. Shannon BA, Cohen RJ, Garrett KL. The antibody response to Propionibacterium acnes is an independent predictor of serum prostate-specific antigen levels in biopsy-negative men. BJU Int. 2008; 101:429-35. 4. Griebling TL. Urologic Diseases in America project: trends in resource use for urinary tract infections in men. J Urol. 2005; 173:1288-94. 5. Marques LP, Flores JT, de Barros O, et al. Epidemiological and clinical aspects of urinary tract infection in community-dwelling elderly women. Braz J Infect Dis. 2012; 16:436-41. 6. Gandaglia G, Zaffuto E, Fossati N, et al. The role of prostatic inflammation in the development and progression of benign and malignant diseases. Curr Opin Urol. 2017; 27:99-106. 7. De Marzo AM, Platz EA, Sutcliffe S, et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007; 7:256-269. 8. Alexeyev O, Bergh J, Marklund I, et al. Association between the presence of bacterial 16S RNA in prostate specimens taken during transurethral resection of prostate and subsequent risk of prostate cancer (Sweden). Cancer Causes Control. 2006; 17:1127-1133. 9. Fassi Fehri L, Mak TN, Laube B, et al. Prevalence of Propionibacterium acnes in diseased prostates and its inflammatory and transforming activity on prostate epithelial cells. Int J Med Microbiol. 2011; 301:69-78. 10. Perry AL, Lambert PA. Propionibacterium acnes. Lett Appl Microbiol. 2006; 42:185-8. 11. Cai T, Pisano F, Nesi G et al. Chlamydia trachomatis versus common uropathogens as a cause of chronic bacterial prostatitis: is there any differences? Results of a prospective parallel-cohort study. Investig Clin Urol. 2017; 58:460-467. 12. Horner PJ, Martin DH. Mycoplasma genitalium infection in men. J Infect Dis. 2017; 216:S396-405. 13. Davidsson, S, Mölling P, Rider JR, et al. Frequency and typing of Propionibacterium acnes in prostate tissue obtained from men with and without prostate cancer. Infect. Agent Cancer. 2016; 11:36.

DOI: 10.4081/aiua.2022.1.65

ORIGINAL PAPER

Trends in treatments for erectile dysfunction in Chile between 2010 and 2020 with special focus on penile prostheses Marcelo Marconi 1, Cristian Palma 2, Sergio Moreno 3, Jose Miguel Flores 4, Santiago Escobar-Urrejola 5 1 Andrology

Unit, Department of Urology, Pontificia Universidad Católica de Chile, Santiago, Chile; of Urology, Clínica Las Condes, Santiago, Chile; 3 Department of Urology, Clínica Santa Maria, Santiago, Chile; 4 Sexual and Reproductive Medicine Fellowship at Memorial Sloan Kettering Cancer Center, New York, USA; 5 Emergency Department, Complejo Asistencial Sótero del Río, Puente Alto, Chile. 2 Department

Submitted 17 December 2021; Accepted 26 January 2022

potential candidates. In the most important PP market, the USA, it is estimated that no more than 3% of the patients with erectile dysfunction (ED) will finally undergo PP surgery to treat the condition (3). There is a lack of information about PP implantation trends in South American countries. The main reason is that the number of devices sold annually is extremely low compared with bigger markets such as the USA. Particularly in Chile, the trends in PP implantation and other available treatments for ED are unknown. Chile has a population of 18.7 million people as of 2019 (4) and the second highest growth domestic product per capita (GDPPC) of South America (US $16,280 US) after Uruguay (US $17,870) (for reference, GDPPC is US $62,794 in the USA) (5). According to the World Health Organization (WHO), male life expectancy in Chile is 76.5 years (6). Among Chilean men over 50 years old, the prevalence of any degree of ED is 58% (7-9). During the last decade, the available treatments for ED in Chile have been phosphodiesterase 5 inhibitors (PD5is) (sildenafil, vardenafil, tadalafil), intracavernosal vaso-active agents, and PP (malleable and 3-piece inflatable). Neither public nor private insurance covers any pharmacological treatment for ED. Some health insurances partially cover hospital stay and operation costs including surgeon's fee for PP. However, the device must always be paid by the patient, with prices ranging from US $1,000 for a malleable PP to US $10,000 for a 3-piece inflatable PP. The aim of this study is to evaluate the trends in Chile over a 10-year period in regard to the available treatments for ED with special focus on PP. It also estimates the potential number of candidates for PP according to population demographics, sexually active men, and ED prevalence.

INTRODUCTION

MATERIALS

Summary

Objectives: Evidence regarding demand trends for erectile dysfunction (ED) treatments are scarce in South America. This study aims to evaluate trends in ED treatments in Chile over a 10-year period (20102020) and estimate the potential number of candidates for penile prosthesis. Materials and methods: Sales trends of pharmacological treatments and penile prosthesis were obtained from market studies. The potential number of candidates for penile prosthesis implantation was calculated by crossing epidemiological data with previously reported ED prevalence, proportion of sexually active men, percentage of men seeking medical assistance for ED, and the proportion of patients who are non-responders to ED oral drug therapies Results: In the 10-year studied period, the Chilean male population older than 50 years increased 34.7%, with an average annual variation (AAV) of 3.4%. For the same period, the sales of oral drug therapies for ED increased by 71.3% (AAV 6.2%), the sales of intracavernosal vasoactive agents (ICVA) decreased by 0.4% (AAV -0.2%), and penile prosthesis sales increased by 113% (AAV 6.7%). We estimated that only 0.05% of sexually active men older than 50 years old with ED who sought medical assistance finally had a penile prosthesis implanted to manage their condition. Conclusions: Demand for ED oral drug therapies significantly increased in Chile during the last decade, while ICVA remained stable. The annual rate of penile prosthesis implantation increased. However, the gap between the potential penile prosthesis candidates and the actual number of devices implanted is suspected to remain extremely high.

KEY WORDS: Erectile dysfunction treatment; Pharma-trends; Penile prosthesis.

Worldwide, penile prosthesis (PP) implantation has increased annually by an average of 8.1% in the period 2006-2011 and is expected to have a compound annual growth rate (CAGR) of 2.1% in the period 2017-2023 (1, 2). Despite this constant increase, the annual number of devices sold is still considered extremely low compared to the number of

AND METHODS

For our analysis we considered Chilean ED patients over 50 years old. We estimated the total number of this group by crossing demographic and clinical data. Demographic information was obtained from the Chilean National Institute of Statistics (4). Annually, male populations older than 50 years old examined from January 1, 2010 to

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 1

M. Marconi, C. Palma, S. Moreno, J.M. Flores, S. Escobar-Urrejola

January 1, 2020 were considered for analysis. The proportion of sexually active men and the ED prevalence were obtained from previous Chilean surveys (7-10). To calculate the number of Chilean men who could be potential candidates to receive a PP to treat their ED, we estimated the proportion of men who would suffer severe ED, defined as patients who are PD5is non-responders. This population was calculated by crossing the number of sexually active Chilean ED patients and the internationally reported percentage of men with ED who seek medical assistance (11, 12) and the estimated proportion of men with ED who are PD5is non-responders (13, 14). Finally, we compared the estimated number of potential candidates for PP implantation to the actual number of Chilean men who finally had a PP implanted in the same period. For the period of 2010-2020, the sales trends of pharmacological ED treatments were obtained from pharma-market studies performed annually (15). This information includes the sales of the generic and labeled drugs per unit of sildenafil, vardenafil, tadalafil, and intracavernosal vasoactive agents. For PP, six companies represented 100% of the Chilean market: Boston Scientific®, (Marlborough, Massachusetts, USA), previously named American Medical System® (Minnetonka, Minneapolis, USA), Coloplast® (Humlebaek, Denmark), Promedon® (Cordoba, Argentina), Zephyr® (Geneva, Switzerland), and Rigicon® (Ronkonkoma, New York, USA). All companies shared their unit sales data for the study period. With this information we calculated average annual variations (AAV) of ED drugs and PP, and modeled growth trends for the study period. Data were analyzed using the statistical software GraphPad® Prism 8.0 (GraphPad Software, San Diego, California, USA).

Descriptive statistics are reported as percentages and frequencies for categorical variables. Ethical and regulatory approvals were obtained from the Ethical Committee of the Faculty of Medicine of Pontificia Universidad Católica de Chile.

RESULTS

In the 10-year period (January 1, 2010, to January 1, 2020) the Chilean male population older than 50 years old increased by 34.7% (Figure 1) with an AAV of 3.4%. The total sales of PD5is (sildenafil, vardenafil, tadalafil) in the same period increased by 71.3% with an AAV of 6.2% (Figure 1). For the study period the mean market shares for each drug were: Sildenafil 71,9%, Tadalafil 28%, Vardenafil 0,1%. The sales trends of intracavernosal vasoactive agents for the same period time were negative (-0.4%) with an AAV of -0.2% (Figure 1). During the study period, a total of 1087 PP were implanted, 68% were malleable, while 32% were 3-piece inflatable PP (Figure 1). The 10-year increase was 113% (year 2010: 59 implants; year 2019: 126 implants) with an AAV of 6.7% per year. For the study period, we estimated the annual number of men affected with severe ED by crossing the demographic data with the percentage of sexually active men older than 50 years old and the ED prevalence, reported in Chile (7,8,9). In 2019, Chile had 2,569,856 men older than 50 years old, of which 77% declared being sexually active (n = 1,978,789), and 58% of these men report some degree of ED (n = 1,147,698). According to international data (11, 12), 22.5% of such men would seek medical assistance or treatment (n = 258.232).

Figure 1. a) Annual growth of men older than 50 years old in Chile. Ten-year variation 34.7%; average annual variation (AAV) 3.4%. b) Annual growth sales of PD5is in units of sildenafil, vardenafil, tadalafil. Ten-year variation 71.3%; AAV 6.2%. c) Annual sales growth of intracavernosal prostaglandin (units). Ten-year variation -0.4%, AAV -0.2%. d) Annual growth of PP implantation (units). Ten-year variation 113%, AAV 6.7%.

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ED treatment trends in Chile: Focus on penile prostheses

Figure 2. Estimation of net PP candidates in Chile according to demographic data, percentage of sexually active men, ED prevalence, ED patients who seek medical assistance, and estimated proportion of patients who are PD5is non-responders.

Figure 3. a) Estimated uncovered gap between all (100%) potential PP candidates and devices actually implanted in the 10-year study period. b) Estimated uncovered gap considering a scenario where only 1% of potential PP candidates would be willing to undergo surgery versus the devices actually implanted.

Finally, according to previous reports (13, 14), 30% of these patients would not respond to PD5is and become potential candidates for PP implantation (n = 77.470). In Figure 2, the estimated prevalence of ED and potential PP candidates are presented for each year of the study. If we consider that all potential PP candidates were willing to receive an implant during the study period, the estimated gap between this number (net PP candidates) and the actual number of implanted units is 99.83% (Figure 3). In order to perform a more realistic analysis, we considered an alternative scenario where only 1% of the PP potential candidates would be willing to undergo surgery. Even in this theoretical setting, the gap between the number of PP actually implanted and the potential demand was 83% (Figure 3). Finally, using the same methodology, we estimated that only 0.05% of sexually active men older than 50 years old

with ED who sought medical assistance finally had a PP procedure to manage the ED.

DISCUSSION

According to the Organization for Economic Cooperation and Development, Chile is an aging country in South America, and it is expected that age-related conditions such as ED will significantly increase in the next decades (16). This epidemiological data is consistent with the observed 10-year growth in the number of men older than 50 years old (34.7%). The combination of this fact with the proportion of them who declare being sexually active (77%) and the high prevalence of ED (58%), we believe explains the constant annual rate of increase in the sales of PD5is. Interestingly, the 10-year growth observed in the sales of Archivio Italiano di Urologia e Andrologia 2022; 94, 1

M. Marconi, C. Palma, S. Moreno, J.M. Flores, S. Escobar-Urrejola

PD5is (71.3%) and its AAV (6.2%) almost doubled the growth rates observed for the population of men older than 50 in the same period (10-year variation 34.7%; AAV 3.4%). This difference may be explained by three reasons. First, a significant number of PD5i consumers might be men under 50 years old (11, 12). Second, in Chile, PD5is are over-the-counter medicines (no prescription needed), with multiple new generic low-price drugs, which facilitates its access. Finally, as recently reported by Dogan and Madendere (17), Chile is in the top five worldwide for PD5is search trends on the internet, specifically for Sildenafil, which confirms the fact that these drugs are extremely well known in this country. In the last two decades, similar annual growth rates of PD5is sales have also been reported in other countries, and the worldwide market is expected to grow 6.5% annually by 2023 (7, 11), being Sildenafil the most prescribed drug by physicians, particularly among andrologists (18). For clinicians who treat ED patients regularly, it is not surprising to observe that the annual sales trends of intracavernosal vasoactive agents have remained stable or were even slightly negative in the study period (AAV -0.2%). A lack of spontaneity, pain, and risk of priapism, among others, may explain why the demand for intracavernosal vasoactive agents has remained unchanged in the last 10 years in Chile. Combining our clinical experience and results, we believe that intracavernosal vasoactive agents still have a role in the management of moderate/severe ED. However, in the whole spectrum of ED treatments available, it seems to occupy a specific niche without potential for growth. Penile prosthesis have been an option to treat ED for the last 40 years and are available in almost all countries around the world. Recently, in the period 2006-2010, Bass et al. reported an AAV of 8.1% in PP sales worldwide, which was based on information given by two companies: American Medical System® (Minnetonka, Minneapolis, USA) and Coloplast® (Humlebaek, Denmark) (1). In this study, the USA represented 85.9% of the worldwide market, followed by Germany (2.3%), the United Kingdom (2.1%), and Italy (2.0%). In the last two decades, other countries such as France and Saudi Arabia have reported AAVs of 4.9% and 31.3% respectively (19, 20). Compared to the global tendencies, our study shows a similar trend in the last decade (6.7%). Regarding the type of implant, we observed that 68% were malleable and 32% were 3-piece inflatable implants, which are similar to other countries where PP are not covered by either public or private insurance (20). On the other hand, in the USA, where most PP devices are covered by insurance, 90% of implanted PP were inflatable, and only 10% were malleable (21). This reveals that when it comes to choosing the type of PP, costs and insurance coverage play an important role. High satisfaction rates have been reported for PP (90%) (22), and the number of candidates for this treatment are presumed to have significantly increased in the last two decades. Nevertheless, the gap between the number of PP implanted annually and the net number of potential candidates remains extremely high. Only around 3% of ED patients finally undergo surgery in the USA, the country with the highest number of PP implanted and with a high percentage of patients who have insurance coverage (3). According to our data, this proportion in Chile would be

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

0.05%, and the potential uncovered gap between the net PP candidates and the actual number of implanted devices ranges from 99.83% (considering 100% of the net potential demand) to an extremely conservative 83% (considering 1% of the net potential demand). It is a fact that the number of ED patients has constantly increased worldwide in the last 40 years, the GDPPCs of developed and emerging economies have also increased constantly, the PP satisfaction rates are extremely high, and the costs have decreased. Thus, considering our results and the available information in peer-reviewed journals, it is worth examining why the implantation of PP has not increased substantially, as well as why the gap between potential candidates and actual PP implanted remains extremely high worldwide. We believe that the answers to this question are beyond the scope of this paper. However, considering our results, it is worth proposing some possible explanations. First, it may be that the number of men with severe ED who are sexually active and seek treatment is overestimated, which would make the estimated number of potential candidates for PP wrong. However, the rising demand for PD5is is evidence against this argument because even if we consider that a high proportion of men who consume PD5is do not suffer from ED, the remaining proportion still represents a high volume of men worldwide (11, 12). Second, it may be that the calculated proportion of ED patients who do not respond to PD5is might be overestimated (30%), meaning that there would be much fewer net PP candidates. However, our own clinical experience and the published evidence consistently indicate that 30% of men with ED will not experience clinical significant improvements in their erections (13, 14). Considering this analysis, it seems that our estimation of the net PP candidates comes from robust data. Third, as demonstrated by Pescatori et al. (23), oral drugs (PD5is) are extensively known in the general population as a treatment alternative for ED; however, second and third line treatments, such as PP are known by a minority of men (22.2-27.9%) and women (19.2-20.2%). The same study evaluated the attitude towards PP revealing that 50,7% of men and 48,4% of women would be willing to choose (men) or support (women) PP as a treatment option for severe ED. This evidence supports the idea that the low awareness that the general population and particularly men have about PP, may be one of most important facts behind the huge uncovered demand. If we consider the gap between the potential and the actual demand to be real (83 to 99.83%), we believe there is an important issue to address: how PP technology can be more efficiently provided to men who do not have other suitable treatment options? Strategies to improve transfer from manufacturers to the community could be, among others; increasing access through insurance coverage for devices in countries that still do not have them, such as Chile; lower device prices and finally, educating urologists and patients about the benefits of PP in order to increase awareness about this treatment option for patients with ED. Our study has several limitations. First, it is a retrospective study; second, the number of men with ED and severe ED (PP candidates) were estimated from previous reports that may not strictly represent all Chilean men;

ED treatment trends in Chile: Focus on penile prostheses

third, the proportion of men that consume PD5is and do not have ED is unknown, which may have impacted the annual sales trend results significantly; fourth, the number of PP that were re-operations is unknown, meaning that the number of men who actually received a PP as treatment for severe ED could be lower; finally, as mentioned, the actual proportion of men who are PP candidates but would be really willing to undergo the procedure is unknown; for the aim of the research, this number was estimated by crossing the available data.

CONCLUSIONS

In the 10-year period (2010-2020), PD5is significantly increased in demand, while intracavernosal injections of vasoactive agents remained stable. The average annual variation of PP in Chile is comparable to the rest of the world. However, the gap between potential PP candidates and the actual number of devices implanted is suspected to be extremely high. This phenomenon seems to be present worldwide, even in countries where the device is covered by insurance. The reasons behind this gap may be addressed by taking actions to increase the access to PP to treat patients with ED worldwide.

REFERENCES

1. Baas W, O'Connor B, Welliver C, et al. Worldwide trends in penile implantation surgery: data from over 63,000 implants. Transl Androl Urol. 2020; 9:31-37. 2. Penile implants or penile prosthesis market - Global industry analysis, size, share, trends and forecast, 2015-2023. https://www. researchandmarkets.com/. ID: 4209017, Report, March 2017. 3. Lee DJ, Najari BB, Davison W, et al. Trends in the Utilization of Penile Prostheses in the Treatment of Erectile Dysfunction in the United States. J Sex Med. 2015; 12:1638-45. 4. Instituto Nacional de Estadística de Chile. www.ine.cl

and older adults in Spain: a population survey. World J Urol .2005; 6:422-9. 13. McMahon C, Smith C, Shabsigh R. Treating erectile dysfunction when PDE5 inhibitors fail. BMJ. 2006; 332:589-92. 14. Goldstein I, Tseng L-J, Creanga D, et al. Efficacy and safety of Sildenafil by age in men with erectile dysfunction. J Sex Med. 2016; 13:852-59. 15. Consultora-IQVIA. Informe de evolución del mercado farmacéutico chileno. Santiago, Chile; 2020. www.iqvia.com 16. Old-age dependency ratio. In Pensions at a glance 2017: OECD and G20 indicators, OECD Publishing, Paris. DOI: https://doi.org/ 10.1787/pension_glance-2017-22-en 17. Deger MD, Madendere S. Erectile dysfunction treatment with Phosphodiesterase-5 Inhibitors: Google trends analysis of last 10 years and COVID-19 pandemic. Arch Ital Urol Androl. 2021; 93:361-365. 18. Palmieri A, Silvani M, Giammusso B, et al. A "real life" investigation on the prescriptive habits among Italian andrologists: The "CONSER" survey from Italian Society of Andrology (SIA) on Sildenafil oral film. Arch Ital Urol Androl. 2019; 91:115. 19. Léon P, Seisen T, Mozer P, et al. Trends in the placement of penile prosthesis over the last 17 years in France. Asian J Androl. 2015; 17:337-8. 20. Alwaal A, Al-Sayyad A. Utilization of penile prosthesis and male incontinence prosthetics in Saudi Arabia. J Urol Ann. 2017; 4:353-356. 21. Kashanian JA, Golan R, Sun T, et al. Trends in penile prosthetics: influence of patient demographics, surgeon volume, and hospital volume on type of penile prosthesis inserted in New York State. J Sex Med. 2018; 15:245-250. 22. Vakalopoulos I, Kampantais S, Ioannidis S, et al. High patient satisfaction after inflatable penile prosthesis implantation correlates with female partner satisfaction. J Sex Med. 2013; 10:2774-81. 23. Pescatori ES, Baldini A, Parazzini F, et al. How much do people know about male sexual problems? A survey in a selected population sample. Arch Ital Urol Androl. 2019; 91:182.

5. World Bank national accounts data, and OECD National Accounts data files. GDP per capita (current US$). https://data.worldbank.org/. 6. World health statistics 2020: monitoring health for the SDGs, sustainable development goals. Geneva: World Health Organization; 2020. www.who.org 7. Venegas JA, Baeza R. Prevalencia de disfunción eréctil en Chile. Rev Chil Urol. 2004; 69:199-202. 8. Acuña JI, Marió C, Salazar I, et al. Prevalence of erectile dysfunction in men screened for prostate cancer. Abstracts from the 36th Congress of the Société Internationale d'Urologie, Buenos Aires, Argentina. World J Urol. 2016; 34 (Suppl 1):1-248. 9. Santibañez C, Anchique C, Herdy A, et al. Prevalencia de disfunción eréctil y factores asociados en pacientes con indicación de rehabilitación cardíaca. Rev Chil Cardiol. 2016; 35:216-221. 10. La Sexualidad de lo Chilenos. Encuesta GFK Adimark, año 2017. https://www.gfk.com/es/ 11. Nicolosi A, Buvat J, Glasser DB, et al. Sexual behaviour, sexual dysfunctions and related help seeking patterns in middle-aged and elderly Europeans: the global study of sexual attitudes and behaviors. World J Urol. 2006; 4:423-8. 12. Moreira ED, Glasser DB, Gingell C, et al. Sexual activity, sexual dysfunction and associated help-seeking behaviours in middle-aged

Correspondence Marcelo Marconi, MD (Corresponding Author) mmarconi@andro.cl Andrology Unit, Department of Urology, Pontificia Universidad Católica de Chile - Cruz del Sur 177, Santiago (Chile) Cristian Palma, MD palmaceppi@gmail.com Department of Urology, Clínica Las Condes Estoril 450, Las Condes, Santiago (Chile) Sergio Moreno, MD Sergiomorenof@gmail.com Department of Urology, Clínica Santa Maria Avenida Santa María 500, Providencia, Santiago (Chile) Jose Miguel Flores, MD floresmartinezjm@gmail.com Sexual and Reproductive Medicine Fellowship at Memorial Sloan Kettering Cancer Center - 1275 York Avenue, New York (USA) Santiago Escobar-Urrejola, MD sescobar3@uc.cl Emergency Department, Complejo Asistencial Sótero del Río, Puente Alto García Moreno 1439, Ñuñoa (Chile)

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

DOI: 10.4081/aiua.2022.1.70

ORIGINAL PAPER

Retinal vessel diameters: Can they predict future risk of infertility in patients with varicocele? Mazen A. Ghanem 1, 2, Essa A. Adawi 1, Ahmed M. Ghanem 3, Manal A. Safan 4, Asaad A. Ghanem 5 1 Departments

of Urology, Jazan University, KSA and 2 Menoufia University, Egypt; Al-Ainy Faculty of Medicine, Cairo University, Egypt; 4 Medical Biochemistry and Molecular Biology, Menoufia University, Egypt; 5 Ophthalmic Mansoura Center, Mansoura University, Egypt. 3 Kasr

Summary

Objective: The objective of this study was to assess the relationship between retinal vessel diameters, such as retinal arteriolar diameter, retinal venular diameter, and arteriolar/venular ratio (AVR), as clinical parameters of fertility in varicocele patients. Materials and methods: Sixty-eight (68) infertile varicocele men with abnormal semen parameters and sixty-one (61) varicocele normozoospermic men were included in the study. Moreover, fifty-eight (58) healthy normozoospermic men without varicocele were enrolled as a control group. For each participant, retinal vascular diameters were measured from the digital retinal photographs as a central retinal arteriolar equivalent (CRAE), central retinal venular equivalent (CRVE), and AVR. In addition, hormones (total testosterone and FSH), and semen parameters were assessed and correlated with retinal vessel diameters. Results: The mean CRAE, CRVE, and AVR values were 147.8 ± 15.8 µm, 198.3 ± 39.3 µm, and 0.61 ± 0.01 in infertile varicocele patients, respectively. Significant difference of CRAE, CRVE, and AVR were found when comparing infertile varicocele patients with both varicocele and control normozoospermic male groups (p = 0.01, p = 0.006, and p = 0.007; respectively). Larger retinal venular caliber and smaller AVR ratio showed a significant inverse correlation with both sperm parameters and hormones (total testosterone and FSH) (p < 0.05). No significant correlations were found between CRAE with both sperm parameters and hormonal values (total testosterone and FSH) (p > 0.05). Conclusions: Infertile patients with varicocele showed a significant relationship with the retinal vascular diameter (CRVE and AVR ratio). This finding supports recommendation for regular eye examinations in the varicocele population.

KEY WORDS: Infertility; Reproductive hormone; Retinal vessels; Semen parameters; Varicocele. Submitted 31 August 2021; Accepted 21 November 2021

INTRODUCTION

Varicocele is a vascular disease affecting approximately 25% of infertile men (1). Varicocele is thought to play a crucial role in the pathophysiology of infertility (2). Assessment of varicocele pathophysiology effects on fertility requires many non-invasive and efficient procedures. The retinal microcirculation has allowed the physician to visualize the medical vascular diseases noninvasively in

humans and examine their association with such vascular pathologies (3, 4). The role of retinal microvascular diameters has been investigated in many medical vascular diseases, such as cardiovascular, hypertension, diabetes, and kidney diseases (4-7). Previous published reports confirmed the strong association of the retinal vasculature changes with predication of cardiovascular risks and nephropathy (6, 7). Based on the association of varicocele with medical vascular diseases and its vasculature progressive nature, alterations in retinal vasculature will be assumed to occur in men with varicocele (8, 9). In a previous report, retinal vasculature parameters such as retinal microvascular diameters central retinal venular equivalent (CRVE), central retinal arteriolar equivalent (CRAE), and the arteriolar-to-venular ratio (AVR) have been emerged to have a clinical correlation with varicocele patients (10). However, the possible relationship between retinal vasculature diameters and fertility was not investigated. In this study, we aimed to detect and evaluate the relationship of retinal vascular calibers with fertility-related parameters, including semen values, and reproductive hormone (serum total testosterone and FSH) in infertile patients with varicocele.

PATIENTS

AND METHODS

Study population The data of 413 infertile patients who were referred to our Andrology department were retrospectively analyzed. From these infertile men, only subjects with varicocele were selected and divided into two groups. Group 1 consisted of sixty-eight (68) infertile varicocele patients with abnormal semen parameters (ASP). Group 2 consisted of sixty-one (61) varicocele normozoospermic subjects. Fifty-eight (58) healthy normozoospermic men were enrolled in the study as a control group. None of the subjects in the control group had varicocele or scrotal symptoms. Age was similar between the three groups. The study was conducted according to the ethical guidelines of the Declaration of Helsinki for medical research and all procedures were approved by the Institutional Review Board of the Faculty of Medicine at Jazan University, Saudi Arabia. All participants gave a signed consent at enrollment. No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

Varicocele and retinal vessels changes

Selection criteria Patients with varicocele and infertility with abnormal semen parameters were assessed according to WHO guidelines (2010) (11). Patients with other urogenital diseases, erectile dysfunction medications, sperm antibodies, and systemic vascular problems affecting the retina (e.g., cardiovascular disease, atherosclerosis, hypertension, and diabetes) were excluded. Patients with refractive error within ± 6.0 diopters equivalent sphere and within ± 3.0 diopters astigmatism were excluded. Patients with a history of glaucoma, trauma, or previous ocular surgery, and corneal opacity were also excluded. The female partners were also investigated for exclusion of the others causes of infertility, such as ovulatory problems, or tubal obstruction. Clinical examination The varicocele diagnosis was confirmed by using 1993 WHO guidelines (12). Subclinical varicocele cases were excluded. Subjects of the control group underwent the same evaluation (13). The total testicular volume of all the participants was measured by Prader’s orchidometer. All the subjects included in the study underwent detailed ocular examination including slit-lamp anterior segment evaluation (Haag-Streit, Germany), fundus examination with Volk 90 diopter, and measurement of intraocular pressure using the Goldmann applanation tonometer AT 900. The serum concentration of total testosterone, FSH, and glucose and semen parameters were determined by using standardized protocols (14, 15).

group. Based on these data and with an alpha = 0.05, 52 subjects per group were necessary to achieve 95% statistical power of the study. Therefore, 68 patients with infertile varicocele group, 61 normozoospermic men with varicocele, and 58 healthy normozoospermic subjects (control group) were considered sufficient for the study. The statistical evaluations were performed using IBM SPSS version 24.0 (Armonk, NY). Continuous variables were tested for the normality of distribution with the Kolmogorov-Smirnov test. Results were expressed as means ± standard deviation (SD). Differences in the means were compared using the Student’s t-test and the MannWhitney U-test, when the data were normally and abnormally distributed, respectively. We performed the Fisher’s exact test, and Chi-square test to determine any statistical difference between the two groups. The correlations between retinal vessel data, seminal parameters, hormonal values, and testicular volume were investigated using the Spearman rank correlation. The level of the p-value < 0.05 was considered statistically significant.

RESULTS Descriptive findings The demographic data of the studied groups are shown in Table 1. The statistical analysis of the differences of demographic and clinical characteristics among the studied groups demonstrated no significant difference.

Retinal vessel measurements All the participants had simultaneous stereoscopic color transparency centered on the optic disc (45° fields) with pharmacological mydriasis in the ophthalmic department. Most photography sessions coincided with the annual visits. The retinal arterioles and venules caliber were measured by an automatic computed system. By using Knudtson et al. formula, the retinal vessel diameters were calculated as central retinal arteriolar equivalent (CRAE) and central venular equivalent (CRVE) (16). Arteriolar-venular-ratio (AVR) was calculated by using both the CRAE and CRVE, taking the mean of the results of right and left eye measurements. Assessment of the retinal vessels and other retinal diseases was performed by a single trained and certified examiner masked for participant characteristics.

Table 1. Demographic data and clinical characteristics of the studied groups.

Data analysis and statistics Sample size calculation was based on the outcome of CRVE as the primary variable of interest. For this calculation, 9 infertile patients with varicocele, 9 normozoospermic patients with varicocele, and 9 healthy normozoospermic subjects without varicocele were enrolled. Mean CRVE values were 197 ± 29.4 μm in the infertile varicocele group, 173 ± 25.6 μm in the varicocele normozoospermic group, and 171 ± 19.2 μm in the control group. Based on these numbers and with an alpha = 0.05, it was estimated that 23 subjects per group were necessary to achieve 95% statistical power of the study. Furthermore, AVR was found 0.62 ± 0.02 in the infertile varicocele group, 0.78 ± 0.01 in the normozoospermic group with varicocele, and 0.79 ± 0.01 in the control

Study of retinal vessel diameters The association between retinal vessel diameters with both seminal parameters and hormonal values are shown in Table 2. The mean CRAE, CRVE, and AVR values were statistically significant different in infertile varicocele patients with abnormal semen values compared to normozoospermic patients with varicocele and control patients (p = 0.01, p = 0.006, and p = 0.007; respectively). In varicocele infertile patients, CRVE showed a significant inverse correlation with sperm concentration, progressive motility and normal sperm morphology (r = -0.337, p < 0.005; r = -0.289, p < 0.017; r = -0.239, p < 0.049, respectively). In addition, CRVE had a significant inverse correlation with hormonal values (r = -0.442, p < 0.000

Parameters Number of patients Mean age (years) Varicocele grade Grade 1 Grade II Grade III Varicocele laterality Left Right

Varicocele with ASP * 68 28.7 ± 2.4

Varicocele with normozoospermia 61 27.9 ± 1.6

15 (22%) 51 (75%) 2 (3%)

16 (26%) 44 (72%) 1 (2%)

56 (82%) 12 (18%)

52 (87%) 8 (13%)

Control 58 29.1 ± 2.1 0

*ASP: Abnormal semen parameters.

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M.A. Ghanem, E.A. Adawi, A.M. Ghanem, M.A. Safan, A.A. Ghanem

Table 2. Changes in retinal vessels diameters, semen parameters, hormonal levels, and testicular volume of the studied groups. Parameters CRAE (µm) CRVE (µm) AVR Semen concentration (million/mL) Progressive motility (%) Morphology (% of normal) Total serum testosterone (ng/mL) FSH (mIU/mL) Total testicular volume (mL)

Varicocele with ASP 147.8 ± 15.8 198.3 ± 39.3 0.61 ± 0.01

Varicocele with normozoospermia 138.7 ± 9.3 171.4 ± 28.4 0.77 ± 0.02

Control

P value *

136.5 ± 7.5 169.8 ± 24.2 0.79 ± 0.02

0.01 0.006 0.007

12.9 ± 5.7 21.7 ± 8.2 14.7 ± 4.9

24.8 ± 13.2 36.9 ± 11.3 24.8 ± 13.9

27.5 ± 11.5 38.4 ± 13.7 26.6 ± 12.3

0.004 0.005 0.01

6.3 ± 1.6 15.1 ± 6.7 16.2 ± 4.8

13.7 ± 5.7 5.7 ± 2.6 28.7 ± 15.4

12.1 ± 8.3 6.1 ± 2.1 29.9 ± 18.2

0.04 0.001 0.002

* P-value (Comparison between varicocele group with ASP and both varicocele and control normozoospermic groups) Values are presented as mean ± SD. ASP: Abnormal semen parameters; AVR: Arteriolar-to-venular ratio; CRAE: Central retinal arteriolar equivalent; CRVE: Central retinal venular equivalent.

Table 3. Correlation of infertile varicocele patients’ retinal vessels diameters with semen parameters, hormones levels, and testicular volume. Parameters Sperm concentration (million/mL) Progressive motility Morphology (% of normal) Total serum testosterone (ng/mL) FSH (mIU/mL) Total testicular volume (mL)

CRAE (µm) R P* -0.221 0.071 - 0.191 0.119 - 0.160 0.192 - 0.182 0.137 -0.229 0.060 -0.135 0.272

CRVE (µm) R P* -0.337 0.005 -0.289 0.017 -0.239 0.049 -0.442 0.000 -0.338 0.005 -0.145 0.237

AVR R P* -0.360 0.003 -0.323 0.007 -0.284 0.019 -0.305 0.011 -0.367 0.002 -0.213 0.081

R = Correlation coefficient. * P-value (by Spearman rank correlation). AVR: Arteriolar-to-venular ratio; CRAE: Central retinal arteriolar equivalent; CRVE: Central retinal venular equivalent.

for total testosterone, and r = -0.338, p < 0.005 for FSH). A significant inverse association was found between AVR and sperm and hormonal values (r = -0.360, p < 0.003 for sperm concentration; r = -0.323, p < 0.007 for progressive sperm motility; r = - 0.284, p < 0.019 for normal sperm morphology; r = -0.305, p < 0.011 for total testosterone; and r = -0.367, p < 0.002 for FSH). On the contrary, CRAE did not have any significant correlation with sperm and hormonal values (Spearman rank correlation coefficient, p = 0.071 for sperm concentration, p = 0.119 for progressive sperm motility, p = 0.192 for normal sperm morphology, p = 0.137 for total testosterone, and p = 0.060 for FSH) (Table 3). Retinal vessel diameters (CRAE, CRVE, and AVR) had no significant correlation with total testicular volume (Spearman rank correlation coefficient p > 0.05) (Table 3). Furthermore, no significant correlation was found between the laterality and grade of varicocele with retinal vasculature diameter (p > 0.05) (data not shown). However, an increase in retinal venular calibration (CRVE) was prominent in the higher grade of varicocele, although it was not observed in the retinal arteriole. Statistically significant differences for seminal values

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

(sperm concentration, progressive sperm motility, and normal sperm morphology), hormonal values (serum total testosterone and FSH), and total testicular volume were observed in both normozoospermic patients with varicocele and controls compared to the infertile patients with varicocele (p < 0.05) (Table 2).

DISCUSSION

This study showed a significant association between CRVE diameter and sperm parameters in infertile varicocele patients. Based on this finding, we provide another evidence for the role of medical vascular diseases in the pathophysiology of both varicocele and retinopathy. This finding is consistent with the increased prevalence of peripheral varicose veins, and ectasic changes in the coronary arteries in varicocele patients (17, 1). Moreover, the changes of retinal vasculature caliber have been demonstrated and identified as markers in several vascular diseases (4-5, 18). The presence of larger retinal vascular caliber in patients with varicocele is initiated by the effect of hypoxia on retinal blood flow leading to retinal vasodilation. The dilatation of retinal micro-vasculature may also be affected by higher levels of inflammatory biomarkers and by local endothelial nitric oxide (NO) synthesis in vascular beds which is a potent vasodilator (19). These primary vascular pathogenetic processes are also involved in the pathogenesis of infertility (2, 9, 20, 21). The vasodilation of the retinal micro-vessels was observed before the onset of microvascular complications of chronic kidney diseases, such as nephropathy (22). Similarly, larger venular caliber was related to dyslipidemia, which may reflect a proinflammatory state associated with obesity (23). Noteworthy, generalized retinal arteriolar narrowing is shown to be a reflection for future onset of systemic hypertension (18). These previous clinical studies provide evidence that retinal vasculature changes may precede the development of clinical varicocele. Consequently, the CRVE can play a role as an early prediction marker for the severity of varicocele. Changes of AVR are more predictive than either arteriolar or venular diameter alone. In this study a smaller AVR was significantly correlated to sperm parameters. Smaller AVR values are related mainly to venular dilatation than to arteriolar dilatation. Therefore, prominent dilatation was recognized in retinal veins than in retinal artery in varicocele patients (10). However, arteriolar diameters are usually measured against venular ones during ophthalmoscopy clinical examination. This procedure may underestimate the arteriolar caliber and consequently the severity and complications of varicocele. Also, smaller AVR was associated and affected by the inflammatory mediators (5). Despite these previous studies, AVR values are more sensitive than CRVE alone to determine the risk of varicocele (10). In this study, we found a significant association of the caliber of retinal vessels with both total serum testosterone and FSH hormones. The potential role of the hormonal imbalance, induced by varicocele, on the retinal microvascular dilatation was supported in our series (24) showing a negative correlation between retinal vasculature parameters (CRVE and AVR) and the reproductive hormones in infer-

Varicocele and retinal vessels changes

tile varicocele patients. These retinal vasculature changes may be attributed to the testosterone imbalance associated with testicular insufficiency in men with varicocele. In fact, the severity of these hormonal changes, in this study, may be related to the greater loss of testicular volume in varicocele patients as compared to the normozoospermic healthy subjects. The diminished testicular function is associated with a substantial increase in the FSH and decrease of testosterone levels, resulting in an inverse ratio between serum testosterone and FSH levels. On the other hand, testosterone has a negative direct effect on the vessel vasculature through regulation of the vascular tone and regulation of apoptosis in vascular endothelial cells. On the contrary, it was reported that testosterone did not have any influence on micro-circulation and even that its inhibition improves microvascular dilatation (25). Since the vascularity of the testis plays a crucial role in normal testicular function (17), the retinal vessel parameters assessed in this study can be used as a prognostic clinical marker for the gonadal function in varicocele men. Our results demonstrated that most varicocele patients with abnormal semen values had higher CRVE and smaller AVR. Therefore, high CRVE and smaller AVR could be used as a negative prognostic factor for spermatogenesis quality in varicocele patients and young normal adults. The hemodynamic retinal arteriolar and venular caliber can be determined noninvasively and measured quantitatively, which may allow monitoring of clinical outcomes of varicocele. However, there are some limitations of this study. The number of participants might have been larger. Also, this study did not have data about intraocular pressure which may influence retinal vascular caliber measurements. Furthermore, photographs were not synchronized with both the fertility and Color-Doppler ultrasonography (CDUS) evaluation because vessel diameter may change because of systemic blood flow changes. Our study did not assess the relationship between diameters of the spermatic vessel and the retinal vessels because of the high risk of false-negative and false-positive diagnoses related to CDUS performed by different operators. These misinterpretations are related mainly to the mobility of the spermatic cord vessels and to the patient position during measurements (standing or lying). In addition, quantitative data of the scrotal veins (maximum diameter and the presence, velocity, and duration of reflux) were lacking in the reports of sonographic examinations of all participants with clinically diagnosed varicocele (13). Moreover, different cutoff considered and controversies about the diagnostic criteria for varicocele in Doppler procedures cause difficulty in the evaluation of the results. In consideration of all the previous described influential factors, Ediz et al. found that the maximum spermatic vein diameters measured during the Valsalva maneuver by CDUS were not significantly correlated with any of the sperm parameters (26) although Mahdavi et al. reported that sperm parameters correlated with CDUS findings in patients with varicocele (27). Finally, our results may not be applicable in patients with subclinical varicocele. The strengths of this study include high magnification of digital fundus images with correction for refractive errors

and the use of the automatic computed system for quantitative measurement of the retinal vascular parameters.

CONCLUSIONS

Our results revealed that changes in retinal vascular parameters have a relationship to both seminal parameters and hormonal values. The clinical implication of our results in varicocele patients is that the assessment of retinal arterioles and venules may be a possible prognostic marker for varicocele outcome. However, there is a great need for further experimental investigations with a larger number of patients.

ACKNOWLEDGEMENTS

The authors would like to thank all employees who agreed to participate in this study and all patients involved in this study for their co-operation. Also, we would like to thank Manaji M. Ba-Baeer for his editorial and valuable assistance.

REFERENCES

1. Yetkin E, Kilic S, Acikgoz N, et al. Increased prevalence of varicocele in patients with coronary artery ectasia. Coron Artery Dis. 2005; 16:261. 2. Nevoux P, Mitchell V, Chevallier D, et al. Varicocele repair: does it still have a role in infertility treatment? Curr Opin in Obstet Gynecol. 2011; 23:151. 3. Hubbard LD, Brothers RJ, King WN, et al. Methods for evaluation of retinal microvascular abnormalities associated with hypertension/sclerosis in the Atherosclerosis Risk in Communities Study. Ophthalmology. 1999; 106:2269. 4. Ikram MK, Witteman JC, Vingerling JR, et al. Retinal vessel diameters and risk of hypertension. The Rotterdam Study. Hypertension. 2006; 47:189. 5. Klein R, Klein BE, Knudtson M, et al. Are inflammatory factors related to retinal vessel caliber? The Beaver Dam Eye Study. Arch Ophthalmology. 2006; 124:87. 6. Wong TY, Islam FM, Klein R, et al. Retinal vascular caliber, cardiovascular risk factors, and inflammation: the multi-ethnic study of atherosclerosis (MESA). Invest Ophthalmol Vis Sci. 2006; 47:2341. 7. Sabanayagam C, Shankar A, Koh D, et al. Retinal microvascular caliber and chronic kidney disease in an Asian population. Am J of Epidemiol. 2009; 169:625. 8. Wang NN, Dallas K, Li S, et al. The association between varicoceles and vascular disease: an analysis of U.S. claims data. Andrology. 2018; 6:99. 9. 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. 10. Coskun M, IIhan N, Elbeyli A, et al. Changes in retinal vessels related to varicocele: a pilot investigation. Andrologia. 2016; 48:536. 11. World Health Organization: WHO laboratory manual for the examination and processing of human semen, Fifth edition, 2010. 12. World Health Organization: Manual for the standardized investigation and diagnosis of the infertile couple, Cambridge University Press, Cambridge, 1993. Archivio Italiano di Urologia e Andrologia 2022; 94, 1

M.A. Ghanem, E.A. Adawi, A.M. Ghanem, M.A. Safan, A.A. Ghanem

13. Cina A, Minnetti M, Pirronti T, et al. Sonographic quantitative evaluation of scrotal veins in healthy subjects: normative values and implications for the diagnosis of varicocele. Eur Urol. 2006; 50:345. 14. Ghanem MA, Safan MA, Ghanem AA, Dohle G. The role of varicocele sclerotherapy in men with severe oligo-astheno-teratozoospermia. Asian J Androl. 2011; 13:867. 15. Mitchell V, Robin G, Boitrelle F, et al. Correlation between testicular sperm extraction outcomes and clinical, endocrine and testicular histology parameters in 120 azoospermic men with normal serum FSH levels. Int J Androl. 2011; 34:299. 16. Knudtson MD, Lee KE, Hubbard LD, et al. Revised formulas for summarizing retinal vessel diameters. Curr Eye Res. 2003; 27:143. 17. Kilic S, Aksoy Y, Sincer I, et al. Cardiovascular evaluation of young patients with varicocele. Fertil Steril. 2007; 88:369. 18. Hanssen H, Siegrist M, Neidig M, et al. Retinal vessel diameter, obesity and metabolic risk factors in school children (JuvenTUM 3). Atherosclerosis. 2012; 221:242. 19. Sun C, Wang JJ, Mackey DA, Wong TY. Retinal vascular caliber: systemic, environmental, and genetic associations. Surv Ophthalmol. 2009; 54:74. 20. Barbieri ER, Hidalgo ME, Venegas A, et al. Varicocele associated decrease in antioxidant defenses. J Androl. 1999; 20:713.

Correspondence Mazen A. Ghanem, MD, PhD (Corresponding Author) mazenghanem99@yahoo.co.uk Department of Urology, Jazan University (KSA) Box: 45142, KSA-Jazan Essa A. Adawi, MD Department of Urology, Jazan University (KSA) Ahmed M. Ghanem, MD Kasr Al-Ainy Faculty of Medicine, Cairo University, Cairo (Egypt) Manal A. Safan, MD Medical Biochemistry and Molecular Biology, Menoufia University (Egypt) Asaad A. Ghanem, MD Ophthalmic Mansoura Center, Mansoura University (Egypt)

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21. Fraczek M, Sanocka D, Kamieniczna M, Kurpisz M. Proinflammatory cytokines as an intermediate factor enhancing lipid sperm membrane peroxidation in in vitro conditions. J Androl. 2008; 29:85. 22. Kawagishi T, Matsuyoshi M, Emoto M, et al. Impaired endothelium dependent vascular responses of retinal and intrarenal arteries in patients with type 2 diabetes. Arterioscler Thromb Vasc Biol. 1999; 19:2509. 23. Ouchi N, Kihara S, Funahashi T, et al. Obesity, adiponectin and vascular inflammatory disease. Curr Opin in Lipidol. 2003; 14:561. 24. Hsiao W, Rosoff JS, Pale JR, et al. Varicocelectomy is associated with increases in serum testosterone independent of clinical grade. Urology. 2013; 81:1213. 25. Chignalia AZ, Schuldt EZ, Camargo LL, et al. Testosterone induces vascular smooth muscle cell migration by NADPH oxidase and c-Src-dependent pathways. Hypertension. 2012; 59:1263. 26. Ediz C, Temel MC, Sahin Ediz S, et al. Contribution of pre-varicocelectomy color Doppler ultrasonography finding to surgery and its correlation with semen parameters. Arch Ital Urol Androl. 2021; 93:227. 27. Mahdavi A, Heidari R, Khezri M, et al. Can ultrasound findings be a good predictor of sperm parameters in patients with varicocele? A cross-sectional study. Nephrourol Mon. 2016; 8:e37103.

ORIGINAL PAPER

DOI: 10.4081/aiua.2022.1.75

Quality of life of patients with La Peyronie's disease undergoing local iontophoresis therapy: A longitudinal observational study Tatiana Bolgeo 1, Roberta Di Matteo 1, Menada Gardalini 1, Denise Gatti 1, Antonio Maconi 1, Carmelo Boccafoschi 2 1 SC

Infrastructure Research Training Innovation, Department of Integrated Activities Research Innovation, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy; 2 City of Alessandria Clinic Monza Polyclinic, Alessandria, Italy.

Summary

Objectives: La Peyronie's disease tends to be underdiagnosed and undertreated. In Italy it affects about 7% of the population aged between 50 and 70 years old. The aim of this study is to evaluate the quality of life of patients undergoing iontophoretic therapy with verapamil and treatment outcomes at a two-year interval. Materials and methods: This study evaluated 128 patients subjected to treatment cycles over a period of two years. Questionnaires were administered to the patients at the beginning and end of each cycle of iontophoretic therapy in order to monitor the degree of presumed anxiety, depression, pain and the associated quality of life. Result: This prospective descriptive observational study included 128 patients aged between 42 and 74 years presenting pain during erection and/or coital intercourse, which ceased in 108 cases, diminished in 12 and remained present in 4. Concerning the penile deviation, which was present in all patients (128 cases), it disappeared in 6 cases, regressed in 90 cases, while it remained unchanged in 32 cases. As for the plaque consistency on palpation, in 42 patients the plaque was no longer present, in 50 cases the consistency diminished, while in 36 patients it remained unchanged. None of the cases evidenced an aggravation of the clinical condition. 57% of the evaluated patients had high levels of anxiety in the first cycle of iontophoretic sessions and low levels of depression. Anxiety decreased in 32% of cases. Depression was not related to pain but to sexual dysfunction. About 80 % of the patients assessed had an increase in quality of life at the end of the two-year follow-up. Conclusions: In conclusion, it can be claimed that iontophoresis combined with verapamil therapy can improve patients' quality of life and offer them psychophysical well-being and an acceptable sexual relationship, thus decreasing anxiety and depression levels.

KEY WORDS: La Peyronie's disease; Penis induration; Iontophoresis; Local therapy; QOL. Submitted 12 November 2021; Accepted 21 December 2021

INTRODUCTION

Induratio Penis Plastica, or "La Peyronie’s disease", is a connective tissue disease involving the tunica albuginea of the corpora cavernosa of the penis and characterized by an inflammatory plaque that becomes progressively more

fibrous and inelastic; it often leads to penile deformation (the so-called 'recurvatum penis') (1). La Peyronie's disease tends to be underdiagnosed and undertreated, and in Italy it affects about 7% of the male population aged between 50 and 70. Several studies indicate a prevalence in adult men between 3.2 and 13.1% and an incidence of 15.9% after radical prostatectomy (2). Two stages of the disease are recognized: the first, the so-called inflammatory stage, characterized by painful erections and the development of fibrous nodules, and the second, the so-called stabilized fibrotic stage, in which the plaques are consistent, hard, fibrotic-calcific and cause deformities (recurvatum) of the penis, sometimes to the extent that coitus becomes difficult if not impossible. The disease is often unruly (3). Spontaneous resolution is rare (3-13%), with most patients either progressing with the disease (30-50%) or stabilizing (45-65%). General factors such as autoimmune diseases, vitamin deficiencies, enzymatic alterations, neurohormonal imbalance, local factors like microtrauma, local vasculitis and predisposing factors including age, family history and collagenopathies have been suggested as causes. The most common risk factors are diabetes, hypertension, smoking, alterations in lipid metabolism and the association with Dupuytren's disease (retraction of the palmar aponeurosis) (4-6). The treatment can be medical or surgical, thus medical treatment is mainly intended for patients in the early stages of the disease, i.e. when pain is present and the plaques are not yet intensely fibrotic or calcified (1). There are many therapeutic options, ranging from the use of oral treatments with drugs belonging to different pharmacological categories (anti-inflammatory drugs, vitamins, potassium paraminobenzoate, tamoxifen, etc.); shock waves; intraplate injections with steroid drugs, collagen, vasodilators, interferons; and iontophoresis (transdermal delivery of polarized drugs by means of a bipolar electric current) (1-3). Medical therapy with iontophoresis is a non-invasive therapy that enables the drug applied to penetrate inside the corpora cavernosa without using needles or other invasive procedures (7). Levine and Estrada in 2003 conclusively demonstrated the efficacy of iontophoresis after measuring Verapamil concentrations (very elevated) in the albuginea of patients operated for PPI and treated precociously with

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 1

T. Bolgeo, R. Di Matteo, M. Gardalini, D. Gatti, A. Maconi, C. Boccafoschi

iontophoresis (Verapamil) (8). The aim of the present study was to assess the quality of life of patients undergoing treatment with iontophoresis and treatment outcomes at a twoyear interval. Pain, quality of sexual life, stress and depression disorders were monitored (9, 10). The following questionnaires and scales were used: Numerical Rating Scale (NRS) (for pain assessment); GAD -7, General Anxiety Disorder-7 scale (for the assessment of anxiety); Beck Depression Inventory (BDI) (for the assessment of depression) and QOL Quality of Life Index questionnaire (for assessment of quality of life). All instruments are described in the following (Materials and Methods) paragraph.

tively on the cathode or anode, i.e., on the electrode of the same polarity, while the other electrode will be soaked in water. By applying the electric field, the electricity will carry the drug across the epidermal barrier. Verapamil is one of the most commonly used drugs. Injected into the plaque, it acts on fibroblasts by inhibiting the formation of extracellular collagen and free radicals. Levine administered to 38 men 4 mg of verapamil every 2 weeks for 24 weeks. All patients were assessed before and after treatment with an echography, rating scales and questionnaires. The results evidenced a remission of pain in 97%, an improvement in sexual function in 72% and a reduction in the curvature in 54% of patients (1, 4, 5).

MATERIALS

Local assessment The parameters used to assess the effectiveness of the treatment were: plaque consistency, penile deviation, and pain during erection and/or coitus. The development of the condition, both in a regressive as in a progressive sense, was evaluated both clinically and by echography and in some cases also by self-photography. In terms of the results, an overall assessment was given, distinguishing between: • unchanged or worsened; if the parameters described above had not undergone any change or had worsened. • Improved; when there had been a resolution of the pain or an improvement in one of the previously described parameters; • cured; when, in addition to the absence of pain and plaques, there was also complete resolution of the penile deviation.

AND METHODS

The study evaluated 128 patients treated as outpatients at the Città di Alessandria Clinic and at an outpatient private clinic. The patients underwent cycles of treatment over a two-year period according to the scheme illustrated below. Each cycle included 12 sessions (two sessions per week for about three months). At the end of each cycle the patient suspended treatment for a period of one month. Assessment scales and a questionnaire were administered before and at the end of each therapy cycle. Iontophoresis is a medical treatment, whereby a drug is released into the body through intact skin (transcutaneous administration) using a low-intensity electric current produced by a special generator. Essentially, it could be considered a 'needle-free' injection. The advantages of administering drugs in this way are mainly that: – without systemic administration (oral, intramuscular, intravenous) possible side effects of the drug can be minimized – applying the drug directly to the disease affected body site, treatment and symptom regression time can be reduced – enabling the introduction of the active ingredient alone, without the presence of conveyors (excipients), can protect against adverse reactions – allowing the ions to bind to certain protoplasmic proteins, increasing residence time (half-life) in the anatomical sites concerned, can reduce the quantity of drug implemented for the same disease compared to other administration approaches. – permitting to hyperpolarize nerve endings. Having overcome all the drawbacks of taking a drug orally or by infiltration, it is now an advantage to apply the substance directly to the area to be treated, thus reducing the treatment time, with consequent faster symptom regression. The second advantage is the possibility of introducing only the active ingredient of the drug, in an ionic form, without the excipients, which are often the source of variable adverse reactions. The third advantage is that the drug, in an ionic form, binds to specific protoplasmic proteins, increasing the time it spends in the anatomical sites concerned (half-life), which leads to a reduction in the quantities of drug needed for the same condition compared to other administration approaches. The drug used may have either a positive or negative polarity, and in accordance with this, it is placed respec-

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

Instruments used for evaluation At the beginning and at the end of each cycle of iontophoretic therapy, the scales and questionnaires listed below were submitted to the patients with the aim of monitoring the level of presumed anxiety, depression and pain and the consequent quality of life. Numerical Rating Scale - NRS (Downie, 1978; Grossi, 1983) This is a one-dimensional quantitative 11-point numerical pain rating scale; the scale requires the practitioner to ask the patient to select the number that best describes the intensity of his or her pain, from 0 to 10, at that precise moment. The Quality of Life Index - QL-Index (Spitzer et al., 1981) The EuroQol is a generic health questionnaire that includes 5 dimensions: mobility, self-care, usual activities, pain, anxiety/depression. For each dimension the questionnaire investigates whether the subject has severe problems, moderate problems, or no problems at all. The questionnaire also includes a visual analogical scale from 0 to 100 to indicate the perceived level of health status of the respondent. The EQ-5D is a widely used instrument in many countries. It is also recommended for use in studies evaluating the cost-effectiveness of interventions. Generalized Anxiety Disorder Scale (GAD-7) The GAD-7 (Spitzer et al., 2006) is a self-completed 7-question questionnaire (Likert scale 0 to 3) for the assessment of the anxiety condition (cut-off ≥ 8). The Beck Depression

La Peyronie's disease

Inventory (BDI) is a self-assessment tool consisting of 21 multiple-choice items. According to Beck, depressed patients are characterized by a negative triad, i.e. negative representations of themselves, the Present and the Future.

RESULTS

This is a prospective observational study. A total of 128 patients aged between 42 and 74 years were assessed. Twenty-four of these patients had never undergone any treatment before, while the remaining (104) had underStatistical analysis gone one or more treatments both systemically and locally. Since this is an exploratory observational study, the scales The total dosage in milligrams of the drug used is 4 mg used to measure the quality of life of patients have been per session. In no case was it necessary to suspend the analyzed with descriptive methods. As a bivariate correlatreatment due to complications. tion coefficient the Pearson correlation coefficient r was Considering the various parameters, pain in erection calculated. Descriptive statistics were used for all variand/or coitus disappeared in 108 (87.1%) cases while it ables using SPSS version 25. regressed in 12 and remained present in 4 patients. There were no cases of worsening (Table 1). Pain variations along the two years of treatment are presented in Figure 1. Table 1. Regarding penile deviation, which was present in 128 Clinical results. cases, it disappeared in 6 cases, regressed in 90 cases, while it remained unchanged in 32 cases and worsened in Clinical Parameters Patients Disappeared Regressed Unchanged Worsened N F % F % F % F % 0 cases. Finally, as far as the consistency of the plaque is Pain during erection concerned, in 42 patients the plaque disappeared, in 50 and/or coitus 124 108 87.1 12 9.7 4 3.2 0 0.0 cases the consistency of the plaque regressed, while in 36 Penile deviation 128 6 4.7 90 70.3 32 25.0 0 0.0 patients it remained unchanged. There were no cases of Plaque consistency 128 42 32.8 50 39.1 36 28.1 0 0.0 worsening (Figure 2). Regarding the levels of anxiety and depression we can state that about 57% of patients evaluTable 2. ated had high levels of anxiety (average 2 on Results of the scale GAD 7 (anxiety). the individual items of the scale) in the first GAD 7 0/3 I cycle II cycle III cycle IV cycle cycle of iontophoretic sessions and low levels Anxiety 3 months 3 months 3 months 3 months of depression (average 15). Anxiety decreased Total score Mean value Std dev Mean value Std dev Mean value Std dev Mean value Std dev in 32% of cases even though the treatment did First year 10.53 4.17 8.21 3.11 8.42 3.04 8.55 3.07 not bring immediate benefits (Table 2). In the Second year 8.38 3.11 8.52 3.18 8.37 3.25 8.11 3.02 following months depression scores averaged 18 by the end of the first year and averaged 14 (no depression) in the second year of treatTable 3. ment. Depression was not related to pain but Results BDI (depression). to sexual dysfunction (Table 3). BDI: 0/3 I cycle II cycle III cycle IV cycle The EQ-5 questionnaire in the examined popDepression 3 months 3 months 3 months 3 months ulation (128 patients) did not reveal any probTotal score Mean value Std dev Mean value Std dev Mean value Std dev Mean value Std dev lems in the areas of: ability to move, personal First year 15.34 5.42 15.47 4.92 17.63 5.71 18.44 6.17 care, habitual activities. Second year 14.92 6.55 14.47 5.40 14.23 5.30 13.98 5.15 Figure 1. Graphical representation of pain variation along the two years of treatment.

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T. Bolgeo, R. Di Matteo, M. Gardalini, D. Gatti, A. Maconi, C. Boccafoschi

Figure 2. Clinical results (graphics).

Table 4. Results of the scale EQ (quality of life).

DISCUSSION

Based on the above results, it can be observed that the most relevant data Patients n = 128 is that on the symptom of erection EQ 1/3 I cycle II cycle III cycle IV cycle and/or coital pain. In fact, this pain generic health 3 months 3 months 3 months 3 months First year Mean value Std dev Mean value Std dev Mean value Std dev Mean value Std dev disappeared or regressed in a high mobility 1.43 0.61 1.31 0.59 1.27 0.52 1.31 0.59 percentage of cases (120 patients, i.e., salf-care 1.22 0.42 1.18 0.39 1.14 0.35 1.18 0.39 97%). As far as penile deviation is usual activities 1.25 0.45 1.23 0.44 1.20 0.42 1.23 0.44 concerned, the results were extremely pain 2.75 0.43 2.72 0.53 2.70 0.55 2.71 0.53 encouraging, since in 90 cases (94%) anxiety/depression 2.88 0.32 2.90 0.30 2.87 0.36 2.88 0.32 there was regression and in 42 EQ: VAS scale 0/100 patients (70%) this also led to the disperceived level of health status 36.41 16.11 38.24 15.39 40.91 16.92 41 18.32 appearance of the plaque (p < 0.001). Second year Regarding the plaque, the results mobility 1.22 0.50 1.20 0.47 1.16 0.39 1.05 0.21 seem positive, particularly in cases salf-care 1.13 0.34 1.07 0.26 1.06 0.24 1.02 0.12 usual activities 1.16 0.36 1.13 0.33 1.12 0.32 1.06 0.24 where therapy was started at an early pain 2.53 0.59 2.41 0.69 2.41 0.69 2.23 0.81 stage, where the plaque was single anxiety/depression 2.52 0.57 2.49 0.58 2.42 0.60 2.20 0.60 with a fibrous consistency and its EQ: VAS scale 0/100 diameter was less than 2 cm. perceived level of health status 60.86 18.37 65.47 20.49 66.25 21.05 71.27 19.43 However, the reported results are difficult to compare with the case histories and experience of others because Critical issues emerged in the areas of pain and discomthey are not perfectly homogeneous, and under certain fort, anxiety, or depression. aspects, due to difficulty in objectively quantifying the In these domains the levels were almost always at a maxplaques. In our opinion, in fact, the diagnostic tool, rather imum for the first year of assessment and this resulted in than being useful for the morphological evaluation and/or low levels of quality of life. The most frequently reported for the extension of the plaque, it may help to monitor over value (according to a score between 0 and 100) was time disease progression or to evaluate the therapeutic effibetween 30 and 50 in the first year of treatment and cacy. between 60 and 80 in the second year of treatment. At the As to the questionnaire and scales submission, from the end of the two years of treatment, quality of life improved analysis of the relative data it is evident that pain diminand levels of anxiety and depression decreased in 68% of ished from the third session of the first iontophoresis cases (Table 4). cycle. Mean values are reported in the Table 5. NRS (0/10) pain First year Second year

I cycle II cycle III cycle IV cycle 3 months 3 months 3 months 3 months Mean value Std dev Mean value Std dev Mean value Std dev Mean value Std dev 7.73 2.08 6.38 2.42 4.27 1.95 3.43 2.03 3.28 1.94 3.04 1.85 2.40 1.68 1.13 1.07

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Table 5. Mean values of Numerical Rate Scale (pain) along the follow up of patients.

La Peyronie's disease

As illustrated in the table and in the graph, pain had a linear regression trend throughout the two-year period in patients who underwent regular cycles. The levels of anxiety and depression were variable, since patients associated many times the result of the therapy with the effectiveness of sexual performance, which unfortunately did not always improve with the disappearance of the plaques and there is a lack of patient awareness of other factors, which might influence their quality of life. There are no recent studies, that have examined the levels of anxiety and depression in patients suffering from this condition, so a monitoring over time and the involvement of other centres at a national level would be worthwhile. Another value of considerable importance emerged from the submission of the QOL 5. The data showed that about 80 % of the patients assessed had an increase in quality of life at the end of the two-year follow-up. The importance of including QOL among the parameters for assessing the quality of care is effectively underlined by the American College of Physicians, which states: "Assessment of the patient's physical, psychological, and social functioning is an essential part of clinical diagnosis, a crucial determinant of treatment choices, a measure of their effectiveness, and a guide for long-term care planning". In measuring health-related quality of life, there is broad consensus regarding its subjective, multidimensional nature and the aspects that are most likely to be affected by disease and should therefore always be considered. These aspects can be summarized in three main dimensions: physical, psychological, and social. The data analysis revealed that as pain decreased, the value of quality of life increased: cycle 1/year 1 r = -0.3 (p < 0.001 IC = 95%), cycle 1/year 2 r = -0.7 (p < 0.001 IC = 95%), cycle 4/year 2 r = -0.8 (p < 0.001 IC = 95%). In summary, we can affirm that therapy with iontophoresis gives good results from the first applications, i.e. in the inflammatory phase. It is therefore important to act in the phase preceding the formation of sclerotic plaques that is prior to the so-called degenerative phase.

the patients' quality of life induces them to continue therapy cycles with regularity and determination. Further national and international studies are required to strengthen the results obtained.

REFERENCES

1. Mulhall JP, Alex B, Choi JM. Predicting delay in presentation in men with Peyronie’s disease. J Sex Med. 2010; 7:2226-30. 2. Paulis G, Romano G, Paulis L, Barletta D. Recent Pathophysiological Aspects of Peyronie’s disease: role of free radicals, rationale, and therapeutic implications for antioxidant treatment-literature review. Adv Urol. 2017; 2017:4653512. 3. Di Maida F, Cito G, Lambertini L, et al. The natural history of Peyronie’s disease. World J Mens Health. 2021; 39:399-405. 4. La Pera G, Pescatori ES, Calabrese M, et al. Peyronie’s disease: prevalence and association with cigarette smoking. A multicenter population-based study in men aged 50-69 years. Eur Urol. 2001; 40:525-30. 5. Bivalacqua TJ, Purohit SK, Hellstrom WJ. Peyronie’s disease: advances in basic science and pathophysiology. Curr Urol Rep. 2000; 1:297-301. 6. Dibenedetti DB, Nguyen D, Zografos L, et al. A population-based study of Peyronie’s disease: prevalence and treatment patterns in the United States. Adv Urol. 2011; 2011:282503. 7. Montorsi F, Salonia A, Guazzoni G, et al. Transdermal electromotive multi-drug administration for Peyronie’s disease: preliminary results. J Androl. 2000; 21:85-90. 8. Trost LW, Gur S, Hellstrom WJG. Pharmacological management of Peyronie’s disease. Drugs. 2007; 67:527-45. 9. Coyne KS, Currie BM, Thompson CL, Smith TM. The test-retest reliability of the Peyronie’s disease questionnaire. J Sex Med. 2015; 12:543-8. 10. Coyne KS, Currie BM, Thompson CL, Smith TM. Responsiveness of the Peyronie’s Disease Questionnaire (PDQ). J Sex Med. 2015; 12:1072-9.

CONCLUSIONS

Depression and anxiety disorders occur in up to 25% of patients with medical conditions. About 85% of patients with depression have significant anxiety, and 90% of patients with an anxiety disorder have depression. The symptoms may initially seem vague and non-specific. A careful anamnesis and screening with appropriate tests should be used to make the diagnosis. Once the diagnosis has been made, rating scales can identify the severity of the condition and help monitor the progress of treatment. Both a depressive disorder and a specific anxiety disorder require appropriate treatment. For these reasons, in the case of a patient with Peyronie's disease, it is essential to monitor the progress of treatment from the very beginning of patient care. In conclusion, it can be asserted that iontophoresis combined with verapamil therapy can improve the patients’ quality of life and offer them psychophysical well-being with an acceptable sexual relationship, thus decreasing the levels of anxiety and depression. The improvement in

Correspondence Tatiana Bolgeo tbolgeo@ospedale.al.it Roberta Di Matteo (Corresponding Author) rdimatteo@ospedale.al.it Menada Gardalini MGardalini@ospedale.al.it Denise Gatti DGatti@ospedale.al.it Antonio Maconi AMaconi@ospedale.al.it SC Infrastructure Research Training Innovation, Department of Integrated Activities Research Innovation, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy Carmelo Boccafoschi cboccafoschi@virgilio.it City of Alessandria Clinic Monza Polyclinic, Alessandria, Italy

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

DOI: 10.4081/aiua.2022.1.80

ORIGINAL PAPER

Summary

Purpose: To evaluate the clinical characteristics of men presenting for other complaints whose ejaculatory function inquiry indicated premature ejaculation (PE). Methods: The data of 536 PE patients, including those who presented with the complaint of PE (group 1) and those presenting with other complaints who were diagnosed with PE (group 2) as a result of ejaculatory function inquiry using estimated intravaginal ejaculation latency time (IELT) and Premature Ejaculation Diagnostic Tool (PEDT), were retrospectively evaluated. Age, PE type, comorbidities, recommended treatments, and treatment acceptance status of all patients were recorded. These characteristics were compared for each group. Results: Among all the patients, those who presented with PE complaints constituted 22.4%. Among the patients with both PE and ED, 98.1% applied with ED complaint and only 1.9% with PE complaint. The percentage of patients with one comorbidity was significantly higher in group 2 (p = 0.032). 90.1% of all patients and 88.5% of patients in group 2 accepted the recommended treatment for PE. The mean age and comorbidities were significantly higher in patients that refused the treatment. The most common reason for treatment refusal was the patients' lack of expectation for treatment. Conclusions: This study shows that men more frequently tend to seek treatment for ED than PE, and treatment acceptance rate may be higher when the patients with PE complaints who don’t seek treatment are reached through ejaculatory function inquiry. The presence of comorbidities negatively affects the treatment expectation and acceptance as well as treatment seeking behavior of men with PE.

KEY WORDS: Sexual attitude; Ejaculatory function inquiry; Premature ejaculation; Treatment seeking; Comorbidity. Submitted 6 September 2021; Accepted 14 October 2021

INTRODUCTION

One of the main purposes of human sexuality is pleasure and this has led men to learn to control ejaculation in order to increase both their partner’s and their own pleasure. Over time, the ability to control ejaculation has become one of the most important indicators of a couple's sexual health (1). In 1970, Masters and Johnson defined premature ejaculation (PE) as “the inability to achieve the ejaculation period that will enable the partner to reach orgasm

in at least half of sexual intercourses” (2). Most recently, International Society for Sexual Medicine (ISSM) has defined PE as a male sexual dysfunction condition that has significant negative consequences for the man, his partner, and the couple as a whole, creates difficulties in interpersonal relationships, and is associated with a decrease in quality of life (3, 4). Despite this, most men do not seek help for PE, and most doctors do not sufficiently question this issue (5, 6). There are few studies and limited information on men's attitudes towards sexual problems and their seeking help for this. The Global Study of Sexual Attitudes and Behaviors (GSSAB), which surveyed 13625 men, reported that a large proportion of men (77.8%) did not consult a doctor or other healthcare professional about their sexual problems, and only 18.0% of the participants sought medical help (7). In the same study, 23.7% of men have reported PE and some of the reasons why men with a sexual dysfunction, including PE, did not consult a doctor were not taking it seriously and thinking that sexual dysfunction is an age-appropriate and acceptable condition. Patients may be reluctant to discuss their PE complaint with a doctor due to the feeling of embarrassment and stigma associated with sexual dysfunction and disabilities (8). The Premature Ejaculation Prevalence and Attitudes (PEPA) survey study reported that despite awareness of prescription treatments for PE, only 9.0% of men consulted a doctor regarding their PE complaints (9). Moreover, some studies have revealed that 45% of men expect their doctors to initiate the discussion about sexual problems (10) and 60% believe that doctors should routinely ask about patients’ sexual health (11). In this study, we evaluated men whose ejaculatory function inquiry indicated presence of PE. We aimed to evaluate their clinical characteristics, factors affecting their attitude towards the recommended treatment, and the effect of presence of comorbidity on treatment seeking behavior and treatment acceptance in these patients. We also compared these characteristics with those of men presenting with spontaneous complaint of PE.

MATERIALS

AND METHODS

After the approval of the local ethics committee (Protocol No: 2020/138), the data of male patients aged 18-75 No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

Treatment seeking in premature ejaculation

years who presented to the urology outpatient clinic between January 2015 and March 2020 were retrospectively reviewed. A total of 536 patients diagnosed with PE for the first time were included in the study. To avoid that our treatment proposal could be affected by the patient's previous treatment experiences we excluded from the study patients who had previously applied to any health institution due to PE or received previous treatment for PE. We also excluded patients who had delayed ejaculation or anejaculation, who were not sexually active or had multiple partners, and whose full data could not be accessed in the records. The patients were divided into two groups. Group 1 consisted of patients that applied to the urology outpatient clinic with complaints of PE. Group 2 included patients that presented with another urological complaint and were found to have PE when ejaculatory function was actively questioned. The ejaculatory functions of patients who reported having problems were evaluated using international questionnaires. The study was based on the estimated intravaginal ejaculation latency time (IELT) reported by the patients. Patients were classified as lifelong PE and acquired PE based on the definition of PE made by ISSM in 2014 (3, 12), where lifelong PE is defined as ejaculation within approximately 1 minute before or after vaginal penetration all the time or almost all the time since the first sexual experience, while acquired PE was defined as a clinically significant and disturbing reduction in IELT and ejaculation of about 3 minutes or less. In addition, men with incidental and situational experiences of decreased ability to delay ejaculation, and men with normal and even long ejaculation time were considered as subtypes of natural variable PE and premature-like ejaculatory dysfunction (PLED), respectively (13). Validated Turkish version of Premature Ejaculation Diagnostic Tool (PEDT) was used in the evaluation of PE (14). PEDT score was calculated according to the answers of the patients. Those with a total score > 9 were considered to have PE. The erectile status of those who reported erectile dysfunction (ED) was evaluated with the International Index of Erectile Function (IIEF-5) questionnaire which was translated and validated by the Turkish Andrology Association in 2002 (15). Total score < 22 was considered as ED. Patients’ age, PE type, smoking status, comorbidities, the recommended treatment for PE (medical or psychotherapy), the names of the medical agents, their acceptance of the treatment, and if not, the reasons for refusal were recorded. The relationship between the characteristics of PE and the factors affecting treatment acceptance according to the reasons for presentation was evaluated using appropriate statistical methods. Statistical methods Research data were evaluated using SPSS software (ver.21.0 for Windows; SPSS Inc, Chicago, IL, USA). The compliance of continuous variables to normal distribution was investigated using visual (histogram and probability graphs) and analytical methods (KolmogorovSmirnov/Shapiro-Wilk tests). The descriptive statistics of the study were shown as mean and standard deviation for data

conforming to the normal distribution and as median, minimum and maximum for data that did not conform to the normal distribution. The chi-square test was used to show whether there was a difference between categorical variables. When comparing independent groups, Student-t test was used to compare continuous variables with parametric properties, while Mann Whitney U test was used to compare continuous variables with nonparametric properties. P value of < 0.05 was considered statistically significant.

RESULTS

Of the 536 PE patients evaluated in the study, 22.4% (n: 120/536) were in group 1 and 77.6% (n: 416/536) were in group 2. The mean age of all patients was 43.06 ± 12.3 years and the mean age of group 1 (39.49 ± 11.29 years) was significantly lower than that of group 2 (44.09 ± 12.49 years) (p < 0.001) (Table 1). The PE type analysis showed that 41.8% of the patients (n: 224/536) had lifelong PE, 54.1% (n: 290/536) had acquired PE, and 4.1% had PE subtypes of natural variable PE (n: 14/536) and PLED (n: 8/536). The mean age of patients with lifelong PE was significantly lower than that of the acquired group (p < 0.001) and PE subtypes (p = 0.006) (Figure 1). The most common PE type in both groups 1 and 2 was acquired PE. IELT was < 1 min in 82.1% of patients with lifelong PE (n: 184/224) and between 1-2 min in 17.9% (n: 40/224). In total, 39.9% of the patients (n:214/536) had both ED and PE: 3.3% in group 1 (n: 4/120) and 50.5% in group 2 (n: 210/416). ED was the most common reason for application to the urology outpatient clinic, followed by infertility and lower urinary tract symptoms (LUTS) (Figure 2). As a result, while 98.1% (n: 210/214) of the patients with both ED and PE presented with ED complaints, only 1.9% (n: 4/214) gave priority to PE. Table 1. Comparison of groups according to application complaint.

Age (year) (Mean ± SD) PE type (n, %) Lifelong Acquired Natural variant PLED Treatment status (n, %) Accept Reject Smoking (n, %) Comorbidities (n, %) Single comorbidity Cardiovasculary diseases Oncological diseases Neurological diseases Endocrinological diseases Chronic systemic diseases Psychiatric disorder DM Multiple comorbidities

Total (n = 536)

Group 1 (n = 120)

Group 2 (n = 416)

P value

43.06 ± 12.3

39.49 ± 11.29

44.09 ± 12.49

224 (41.8) 290 (54.1) 14 (2.6) 8 (1.5)

51 (42.5) 64 (53.3) 5 (4.2) -

173 (41.6) 226 (54.3) 9 (2.2) 8 (1.9)

< 0.001 0.982

483 (90.1) 53 (9.9) 101 (18.8)

115 (95.8) 5 (4.2) 18 (15)

368 (88.5) 48 (12.5) 83 (20)

226 (42.1) 85 (37.6) 12 (5.3) 15 (6.6) 7 (3.1) 30 (13.3) 5 (2.2) 72 (31.9) 56 (10.4)

32 (26.7) 12 (37.5) 2 (6.2) 5 (15.6) 6 (18.8) 7 (21.9) 9 (7.5)

194 (46.6) 73 (37.6) 10 (5.2) 10 (5.2) 7 (3.6) 24 (12.4) 5 (2.6) 65 (33.4) 47 (11.3)

0.017

0.222 0.032 0.046 1.000 0.344 1.000 0.747 0.592 0.006 0.028

SD: Standard deviation; PE: Prematüre ejaculation; PLED: Prematüre like ejaculatory dysfunction; DM: Diabetes mellitus.

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

E. Ates, A. Emre Yildiz, H. Gorkem Kazici, S. Sulaimanov, A. Kol, H. Erol

Figure 1. Comparison of mean ages of premature ejaculation types.

Figure 2. The most common non-PE reasons for application to the urology outpatient clinic.

Among all patients, 18.8% (n: 101/536) were smokers and 14.1% (n: 76/536) had a concomitant disease such as diabetes mellitus (DM) and hyperthyroidism, which are risk factors for PE. At least one comorbidity was present in 42.1% (n: 226/536) of all patients, while 10.4% (n: 56/536) had multiple comorbidities. Among all comorbidities, the most common were cardiovascular system (CVS) diseases (37.6%) such as coronary artery disease, hypertension, hyperlipidemia and heart failure. The percentage of patients with a comorbidity was significantly higher in group 2 (46.6%) than in group 1 (26.7%) (p = 0.032). The increase in CVS disease (p = 0.046) and DM (p = 0.006) was statistically significant. In addition, the incidence of CVS diseases (p < 0.001) and DM (p < 0.001) was significantly higher in patients with acquired PE compared to the other groups. The percentage of patients that complied with the recommended treatment for PE was 90.1% (n: 483/536). While

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

at least one medical agent was given as PE treatment to 86% of these patients, psychotherapy was recommended to 4.1% of them. The most common medical agent recommended to the patients was Dapoxetine (Figure 3). Fifty-three patients (9.9%) refused the recommended treatment. In group 1, 95.8% of the patients (n: 115/120) accepted the recommended treatment, while in group 2 this number was 88.5% (n: 368/416). The number of patients that accepted the treatment in both groups was significantly higher than those who did not accept it (p = 0.017). The mean age of the patients that accepted the treatment (42.5 + 12 years) was significantly lower than the mean age of those who did not accept the treatment (47.3 + 14 years) (p = 0.017) (Table 2). As the age got older, the rate of accepting the treatment decreased. The age range with the lowest treatment acceptance rate was 60 years and over (p = 0.019). The percentage of

Treatment seeking in premature ejaculation

Figure 3. Recommended medical agents for treatment.

presence of CVS (p < 0.001), oncological (p < 0.001), neurological disease (p = 0.011) and endocrine disorders (p = 0.027) except hyperthyroidism in patients who refused treatment was significantly higher than the group that accepted the treatment. When asked about the reasons for not accepting the treatment, 66% of the patients (n: 35/53) stated that they did not care to prolong their ejaculation time with treatment, so there was no treatment expectation for PE and 13.2% (n: 7/53) did not want a new medical treatment due to the use of multiple Table 2. Comparison of groups according to treatment acceptance.

Age (year) (Mean ± SD) Age groups (year) (n, %) < 30 30-60 > 60 PE type (n, %) Lifelong Acquired Natural variant PLED Smoking (n, %) Comorbidities (n, %) Cardiovasculary diseases Oncological diseases Neurological diseases Endocrinological diseases - Hyperthyroidism - Others Chronic systemic diseases Psychiatric disorder DM

Total (n = 536)

Group 1 (n = 483)

Group 2 (n = 53)

P value

43.06 ± 12.3

42.5 + 12

47.3 + 14

100 (18.6) 389 (72.6) 47 (8.8)

93 (19.3) 353 (73.1) 37(7.7)

7 (13.2) 36 (67.9) 10 (18.9)

0.017 0.019

224 (41.8) 290 (54.1) 14 (2.6) 8 (1.5) 101 (18.8) 226 (42,1) 85 (15.8) 12 (2.3) 15 (2.8)

202 (41.8) 262 (54.2) 14 (2.9) 5 (1.1) 88 (18.2) 177 (36.6) 66 (13.7) 6 (1.2) 10 (2.1)

22 (41.5) 28 (52.8) 3 (5.7) 13 (24.5) 49 (92.4) 19 (35.8) 6 (11.3) 5 (9.4)

< 0.001 < 0.001 0.011

4 (0.7) 3 (0.6) 30 (5.6) 5 (0.9) 72 (13.4)

3 (1.9) 1 (0.2) 25 (5.2) 4 (0.8) 62 (12.8)

1 (0.6) 2 (3.8) 5 (9.4) 1 (1.9) 10 (18.9)

0.341 0.027 0.204 0.407 0.222

0.833

0.265

SD: Standard deviation; PE: Prematüre ejaculation; PLED: Prematüre like ejaculatory dysfunction; DM: Diabetes mellitus.

drugs for their comorbidities (Figure 4). In group 1, 4.2% of the patients (n: 5/120) that thought that the treatment might be effective and sought treatment for PE, did not accept the treatment due to high drug cost and concerns about drug side effects.

DISCUSSION

Premature ejaculation is considered the most common male sexual dysfunction with a prevalence rate of 20-30% (9, 16, 17). Despite this, patients suffering from PE do not easily seek medical treatment. They are mostly detected in epidemiological studies because of the use of the broad definition of sexual dysfunction. The very low help-seeking behavior of men who reported PE in previous prevalence studies indicates that referral to physician is much lower than reported (9). As a matter of fact, only 22.4% of our PE cases applied with the complaint of PE. It has been reported that cultural factors and health-related beliefs rather than socioeconomic factors such as education levels and income levels may play a more determining role in the frequency of seeking medical help for sexual problems (7). The belief that sexual problems are not medical problems, the thought that ejaculatory problems are temporary or caused by the daily stress of life, lack of information about current treatment strategies or confusion about which medical specialist to consult are listed as factors that may reduce the patient's desire to seek treatment (8). Embarrassment about discussing the situation with anyone, doubting that any medication could help them control their ejaculation, and worrying about being addicted to a drug have also been shown as reasons for not seeking treatment. In addition, nowadays there is a scientific understanding that assumes that ejaculation control is not a natural but a cultural phenomenon. Puppo V and Puppo G (18) reported that PE, in which ejaculation and orgasmic physiology is not impaired, is Archivio Italiano di Urologia e Andrologia 2022; 94, 1

E. Ates, A. Emre Yildiz, H. Gorkem Kazici, S. Sulaimanov, A. Kol, H. Erol

Figure 4. Reasons for patients to refuse treatment.

not a disease, and female orgasm can be achieved by continuing non-coital sexual acts after male ejaculation. Jannini et al. (1) stated that PE should be considered as a symptom rather than a disease. Consequently, 37% of men with PE reported that they have learned to live with this condition (9). Serefoglu et al. (19) evaluated 512 men with PE complaints and reported that 10.0% of them sought treatment for PE, 27.9% of them planned to receive treatment, and 66% did not think to consult a doctor. In the same study, the proportion of patients seeking treatment was higher in men with acquired PE (26.53%) and lifelong PE (12.77%), while it was lower in males with natural variable PE (6.47%) and PLED (1.75%). Gao et al. (20) showed that men with acquired PE seek more treatment (17.12% vs 14.58%) and plan to seek treatment (36.30% versus 27.08%) compared to men with lifelong PE. On the other hand, in another study Serefoglu et al. (21) reported that patients with lifelong PE (62.5%) seek more PE treatment than those with acquired PE (16.1%). Zhang et al. (22) supported this finding by reporting that the majority of 1,988 patients who applied to the outpatient clinic had lifelong PE (35.6%). These data reveal important evidence that the majority of patients seeking treatment for PE complaints are lifelong and acquired PE patients and that there is a difference in the prevalence of PE subtypes. In our study, the majority of patients seeking treatment had acquired (53.3%) and lifelong (42.5%) PE, followed by natural variable PE (4.2%) group. None of the patients presenting with PLED sought the treatment. In the GSSAB study, 23.7% of men reported PE and 17.0% reported ED (7). Although self-reported PE is more common than self-reported ED in the literature (23) and PE is considered to be the most common self-reported male sexual dysfunction, men seek far more medical help for ED than PE (7, 24). In our study, we found that 98.1% of the patients with both PE and ED applied to the clinic due to

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

ED and only 1.9% due to PE. Therefore, ED appeared as a sexual problem requiring more medical help. Various studies have shown that the presence of a comorbidity such as hypertension, obesity, DM, coronary artery disease, and stroke is associated with sexual dysfunction such as decreased libido, ED and ejaculatory dysfunction in men (25, 26). Serefoglu et al. (19) reported that men with PE complaints had more comorbidities compared to those without, and the incidence of all comorbidities except for neurological disorders is significantly higher in patients with acquired PE. Other studies have also revealed that men with acquired PE have a high incidence of comorbid diseases such as high mean body mass index (BMI), DM, hypertension, chronic prostatitis, sexual desire disorder, and ED (20, 21, 27, 28). Similarly, mean age is higher in patients with acquired PE compared to other PE subtypes (21, 22, 27). In our study, age, presence of CVS diseases and DM were significantly higher in patients with acquired PE. The PEPA study reported that although men with PE see PE as a problem for themselves or their partners, a significant portion of them think that PE is a normal part of aging or that the problem will be solved with increasing sex frequency, therefore these patients do not seek treatment (9). In our study, the mean age of patients that applied with the complaint of PE was lower, and as the patients got older, the treatment seeking behavior and treatment acceptance rate for PE decreased significantly. In this study, we evaluated the effects of comorbidities on seeking treatment and accepting the recommended treatment for PE and observed that people seeking treatment for PE had less comorbidities. In addition, we found that the rate of acceptance of treatment decreased significantly in the presence of CVS, neurological, oncological, and endocrine diseases. We think that decrease in treatment expectation and treatment seeking behavior for PE in presence of comorbidities is associated with unwilling-

Treatment seeking in premature ejaculation

ness to use multiple medications and possible side effects. Although majority of men do not seek help for PE, one study reported that 45% of men expected their doctors to initiate the discussion about sexual problems (10), and 60% believed that physicians should routinely question the sexual health of patients (11). While this is the case, in order to increase their general well-being, sexual health, and quality of life, it is apparent that men should be more active participants of the conversation with their physicians. As a matter of fact, we questioned the ejaculatory function of patients who applied for reasons other than PE, identified PE in 416 patients and treated PE in 88.5% of them. The majority of those who did not want treatment for PE were people who did not expect treatment to be beneficial. Although 4.2% of the patients applied to the clinic with complaints of PE, they did not accept the recommended medical treatment due to high drug cost and concern for drug side effects. To the best of our knowledge, this study is the first study in the literature that investigated the importance of ejaculation function inquiry in the detection of patients not seeking help for PE, and the effect of comorbidity on treatment seeking behavior as well as acceptance of treatment for PE. However, our study had some limitations. It is not a routine procedure of our clinic to question the sexual function of every male patient who applies to the outpatient clinic for reasons other than sexual function complaints. Physicians who do not deal with andrology do not tend to question sexual health. This situation prevented us from detecting more PE patients. There are studies suggesting that the partner should also be evaluated so that PE treatment can be optimized and results can be measured accurately (29). The absence of an evaluation about the partner can be considered as a limitation. In addition, retrospective design of the study, the fact that some of the patients who were given treatment were not followed up regularly, and the inability to evaluate the treatment compliance and treatment results can be considered as the limitations of the study.

3. Althof SE, McMahon CG, Waldinger MD, et al. An update of the International Society of Sexual Medicine’s guidelines for the diagnosis and treatment of premature ejaculation (PE). J Sex Med. 2014; 11:1392-422.

CONCLUSIONS

15. Akkus E, Kadioglu A, Esen A, et al. Prevalence and correlates of erectile dysfunction in Turkey: a population-based study. Eur Urol. 2002; 41:298-304.

The results of this study show that men tend to seek more treatment for ED compared to PE. The treatment acceptance rate may be higher if patients that did not seek treatment for their PE complaints are reached through sexual health inquiry that include PE. This reveals the importance of such inquiry. In addition, the presence of comorbidity emerges as a factor that negatively affects the treatment-seeking behavior of men with PE, as well as treatment expectation and acceptance. Therefore, we find it useful and recommend that every patient who applies to the andrology or even urology outpatient clinic is questioned about their ejaculatory function.

4. Rowland DL, Patrick DL, Rothman M, Gagnon DD. The psychological burden of premature ejaculation. J Urol. 2007; 177:1065-70. 5. Read S, King M, Watson J. Sexual dysfunction in primary medical care: prevalence, characteristics and detection by the general practitioner. J Public Health Med. 1997; 19:387-91. 6. Shabsigh R, Rowland D. The Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision as an appropriate diagnostic for premature ejaculation. J Sex Med. 2007; 4:1468-78. 7. Moreira EDJ, Brock G, Glasser DB, et al. Help-seeking behaviour for sexual problems: the global study of sexual attitudes and behaviors. Int J Clin Pract. 2005; 59:6-16. 8. Rowland DL. Psychological impact of premature ejaculation and barriers to its recognition and treatment. Curr Med Res Opin. 2011; 27:1509-18. 9. Porst H, Montorsi F, Rosen RC, et al. The Premature Ejaculation Prevalence and Attitudes (PEPA) survey: prevalence, comorbidities, and professional help-seeking. Eur Urol. 2007; 51:816-23; discussion 824. 10. Aschka C, Himmel W, Ittner E, Kochen MM. Sexual problems of male patients in family practice. J Fam Pract. 2001; 50:773-8. 11. Laumann EO, Glasser DB, Neves RCS, Moreira EDJ. A population-based survey of sexual activity, sexual problems and associated help-seeking behavior patterns in mature adults in the United States of America. Int J Impot Res. 2009; 21:171-8. 12. Serefoglu EC, McMahon CG, Waldinger MD, et al. An evidencebased unified definition of lifelong and acquired premature ejaculation: report of the second international society for sexual medicine ad hoc committee for the definition of premature ejaculation. Sex Med. 2014; 2:41-59. 13. Waldinger MD. Recent advances in the classification, neurobiology and treatment of premature ejaculation. Adv Psychosom Med. 2008; 29:50-69. 14. Serefoglu EC, Cimen HI, Ozdemir AT, et al. Turkish validation of the premature ejaculation diagnostic tool and its association with intravaginal ejaculatory latency time. Int J Impot Res. 2009; 21:139-44.

16. Nicolosi A, Laumann EO, Glasser DB, et al. Sexual behavior and sexual dysfunctions after age 40: the global study of sexual attitudes and behaviors. Urology. 2004; 64:991-7. 17. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA. 1999; 281:537-44. 18. Puppo V, Puppo G. Comprehensive review of the anatomy and physiology of male ejaculation: Premature ejaculation is not a disease. Clin Anat. 2016; 29:111-9.

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20. Gao J, Zhang X, Su P, et al. Prevalence and factors associated with the complaint of premature ejaculation and the four premature ejaculation syndromes: a large observational study in China. J Sex Med. 2013; 10:1874-81.

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21. Serefoglu EC, Cimen HI, Atmaca AF, Balbay MD. The distribution of patients who seek treatment for the complaint of ejaculating prematurely according to the four premature ejaculation syndromes. J Sex Med. 2010; 7:810-5. 22. Zhang X, Gao J, Liu J, et al. Distribution and factors associated with four premature ejaculation syndromes in outpatients complaining of ejaculating prematurely. J Sex Med. 2013; 10:1603-11. 23. McMahon CG, Lee G, Park JK, Adaikan PG. Premature ejaculation and erectile dysfunction prevalence and attitudes in the AsiaPacific region. J Sex Med. 2012; 9:454-65. 24. Moreira ED, Glasser DB, Nicolosi A, et al. Sexual problems and help-seeking behaviour in adults in the United Kingdom and continental Europe. BJU Int. 2008; 101:1005-11. 25. McCabe MP, Sharlip ID, Lewis R, et al. Risk Factors for Sexual Dysfunction Among Women and Men: A Consensus Statement From

Correspondence Erhan Ates, MD, Associate Professor of Urology (Corresponding Author) drerhanates@yahoo.com Ahmet Emre Yildiz, MD aemreyildiz@gmail.com Hakan Gorkem Kazici, MD hgkazici@yahoo.com Saparali Sulaimanov, MD sulaimanovsaparali@gmail.com Arif Kol, MD, Assistant Professor of Urology drarifkol@hotmail.com Haluk Erol, MD, Professor of Urology halukerol@yahoo.com Aydin Adnan Menderes University School of Medicine, Department of Urology, Aydin, (Turkey)

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

the Fourth International Consultation on Sexual Medicine 2015. J Sex Med. 2016; 13:153-67. 26. Monga TN, Lawson JS, Inglis J. Sexual dysfunction in stroke patients. Arch Phys Med Rehabil. 1986; 67:19-22. 27. Basile Fasolo C, Mirone V, Gentile V, et al. Premature ejaculation: prevalence and associated conditions in a sample of 12,558 men attending the andrology prevention week 2001--a study of the Italian Society of Andrology (SIA). J Sex Med. 2005; 2:376-82. 28. Porst H, McMahon CG, Althof SE, et al. Baseline characteristics and treatment outcomes for men with acquired or lifelong premature ejaculation with mild or no erectile dysfunction: Integrated analyses of two phase 3 dapoxetine trials. J Sex Med. 2010; 7:2231-42. 29. Verze P, La Rocca R, Spirito L, et al. Premature Ejaculation patients and their partners: arriving at a clinical profile for a real optimization of the treatment. Arch Ital Urol Androl. 2021; 93:42-7.

DOI: 10.4081/aiua.2022.1.87

ORIGINAL PAPER

The use of a polyglycolic acid polymer graft in Peyronie’s disease - preliminary outcomes Pedro Caetano Edler Zandoná 1, Nivio Pascoal Teixeira 1, Henrique Eduardo Oliveira 1, Jorge Hamilton Soares Garcia 2 1 Department 2 Department

of Urology of Hospital Governador Celso Ramos, Florianópolis, Brazil; of Anesthesiology of Hospital Governador Celso Ramos, Florianópolis, Brazil.

Summary

Objective: Plaque incision and grafting is indicated for patients with Peyronie’s Disease [PD] and severe curvature, complex deformities or for patients with significant penile shortening. To date, no graft studied has been considered ideal. The aim of this study is to conduct a descriptive analysis about functional results with the use of a bioabsorbable graft for PD treatment. Materials and methods: A single-center, retrospective evaluation of a cohort of patients who were treated by plaque incision and grafting with a polyglycolic acid polymer graft (Gore® Bio-A®) between 2018 and 2021 was conducted. Correction of penile curvature was the main outcome. Loss of penile sensitivity, de novo erectile dysfunction and any other adverse event were the secondary endpoints. Results: 14 patients were included in this study (mean age 59.5 ± 7.2 years). The median follow-up time was 12 months (range 3-12). The curvature correction rate was 78.5%. Glans hypoesthesia was present in one of 14 patients (7.1%) and refractory erectile dysfunction was reported in 64.2%. None of the patients presented any major adverse event based on Clavien-Dindo classification. Conclusions: Curvature correction and changes in penile sensitivity rates were similar to those found in the literature. No major surgical complications, such as graft rejection, infection, and extrusion, occurred in this sample. Although a population with a higher prevalence of erectile dysfunction was included in this sample, higher rates of refractory erectile dysfunction were observed and these findings should be confirmed in further studies.

KEY WORDS: Peyronie’s disease; Penile induration; Penile curvature; Erectile dysfunction; Bioabsorbable implants; Polyglycolic acid. Submitted 21 December 2021; Accepted 18 January 2022

INTRODUCTION

Peyronie's Disease (PD) is characterized by a disorder of the connective tissue of the penis that affects the tunica albuginea, which can lead to local pain and tortuosity. Although the etiology is unknown, the most accepted hypothesis is repetitive microvascular trauma, leading to inflammation, fibrinogenesis and excessive collagen deposition on the tunica albuginea, facilitated by risk factors such as hypertension, diabetes, dyslipidemias, smoking and alcoholism (1-3).

Clinically, PD has two distinct phases: inflammatory (acute), when there is pain and the onset and progression of penile deformity; and fibrotic (chronic), when there is stabilization of the penile curvature, cessation of the pain, and possibly the formation of a well-defined plaque on the corpora cavernosa (4). Surgical treatment for PD is reserved for patients who are in the second stage of the disease, with stable tortuosity for at least three to six months. There are basically two types of procedures for correction of penile curvature: tunical shortening and tunical lengthening techniques (5). The latter consists in plaque incision/excision and grafting, following this indication: patients without refractory erectile dysfunction (ED), with curvatures greater than sixty degrees, complex deformities or in patients with smaller curvatures but significant penile shortening for plication procedures (6, 7). The ideal graft should be traction resistant, easy to suture and manipulate, flexible, readily available, cost-effective and with minimal associated morbidity. So far, no material studied has met all these criteria. Several studies have analyzed the use of autografts, allografts and xenografts. Synthetic grafts are historically not recommended, due to the increased risk of infection, allergic reactions and material rejection. The use of bioabsorbable synthetic grafts, on the other hand, has been little studied to date (8-11). The aim of this study was to perform a descriptive analysis about functional results with the use of a bioabsorbable graft in the setting of Peyronie's disease surgical treatment.

MATERIALS

AND METHODS

The present study protocol was reviewed and approved by the Institutional Review Board of Hospital Governador Celso Ramos (approval No. 47537021.0.0000.5360). Informed consent was submitted by all subjects when they were enrolled. Psychological counseling was offered to all patients before the surgery, although it was not considered obligatory. A single-center, retrospective cohort study of patients undergoing treatment for Peyronie's disease using a bioabsorbable graft between 2018 and 2021 was conducted. The graft used was the Gore® Bio-A® (W.L. Gore & Associates, Inc. Flagstaff, Arizona, US), composed of a network of synthetic polymers (67% of polyg-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 1

P.C. Edler Zandoná, N.P. Teixeira, H.E. Oliveira, J. Hamilton Soares Garcia

Figure 1. lycolic acid and 33% trimethylene carbonate) which are Gore® Bio-A® graft being placed and secured with running gradually absorbed by the body and registered by sutures. An H-shaped incision was performed at the point of ANVISA for use in humans as a soft tissue substitute. maximum curvature, after degloving the penis. The defect is The inclusion criteria for this study were all patients measured and the graft is secured with Vicryl 3.0 stitches. ® undergoing treatment for PD using the Bio-A graft between 2018 and 2021 at Hospital Governador Celso Ramos, Florianópolis, State of Santa Catarina, Brazil. No exclusion criteria were applied. Data was obtained exclusively from medical charts retrospective review, and patients’ identity was kept confidential. Curvature correction, was the primary endpoint, characterized by the absence of residual curvature greater than 15 degrees. All patients underwent interview and physical examination during the routine postoperative follow-up visits. Patients who reported residual curvature underwent artificial erection in the office to confirm this finding. Secondary endpoints were penile sensory change, postoperative ED and surgical complications (based on using IBM® SPSS® Statistics, version 28.0.0.0. Variables Clavien-Dindo classification). The secondary outcomes and results related to the primary and secondary outwere also assessed through anamnesis and physical examcomes were presented descriptively for each patient. ination performed during routine follow-up visits and Continuous variables were described in the comparative described in the patients’ medical chats. Refractory ED, analysis as the median and respective interquartile range. identified pre- or postoperatively, was characterized as the Categorical variables were described as percentages of the self-reported inability to develop or maintain an erection total number of patients. despite the use of phosphodiesterase type 5 inhibitors (PDE5i). Patients were informed about the risks of erectile function worsening, and the possibility of penile prostheRESULTS sis implantation in a second-stage surgery. Patient characteristics, risk factors Surgical technique was similar in all cases. Under general and preoperative findings anesthesia, a subcoronal incision was made and the penis A total of 14 patients were included in this study. The was degloved. An artificial erection was performed at this mean age was 59.5 years (± 7.2).Overall, 42.8% (6/14) of point and the curvature was identified. In case of dorsal patients had hypertension, 21.4% (3/14) diabetes, 42.8% curvatures, the neurovascular bundle was carefully dissected from the corpora cavernosa. In case of ventral Table 1. curvature, the urethra was Patients characteristics and postoperative outcomes. This table describes important preoperative dissected from the corpora findings for each patient, as well as the main postoperative outcomes. cavernosa. Then again, an Patient Age Curvature Curvature Preoperative Curvature Penile Postoperative Surgical artificial erection was pernumber type degree ED correction sensory ED complications formed to identify the change (Clavien-Dindo grade) point of greatest curvature 1 64 Uniplanar a 65 Yes Yes No Yes Yes (I) of the plaque. An H-inci2 64 Uniplanar a 80 No Yes No No No sion was then made into 3 67 Biplanar 80 Yes Yes No Yes No the plaque and the defect (with ventral component) created was measured to 4 47 Biplanar b 50 No Yes No Yes No determine the size of the 5 64 Biplanar b 45 No Yes No No Yes (I) graft. Gore® Bio-A® graft 6 55 Uniplanar a 60 Yes Yes No Yes d No was then placed and fixed 7 51 Complex ᶜ 90 No No No No No over the defect with run8 61 Biplanar 80 Yes Yes No Yes ᵈ No ning sutures of its margins (with ventral component) with 3-0 Vicryl (Figure 1). 9 45 Biplanar ᵇ 90 No Yes No Yes Yes (I) The penis was then cov10 58 Uniplanar ᵃ 50 No No No No No ered and a circumcision 11 67 Biplanar ᵇ 45 No Yes Yes No No was performed. The average surgery time was 12 65 Uniplanar ᵃ 60 No Yes No Yes No 137.2 (± 19.5 minutes). 13 61 Biplanar ᵇ 50 Yes No Yes Yes ᵈ Yes (I) All patients were dis14 64 Biplanar ᵇ 60 No Yes No No No charged after 24 hours of ED: erectile dysfunction. the surgery and were prea. Uniplanar includes dorsal and lateral and excludes ventral curvatures. b. Biplanar includes dorso-lateral curvatures and excludes biplanar with ventral component curvatures. scribed 5 mg of tadalafil to c. Complex curvatures includes hour-glass and hinge deformities. use once a day. Statistical d. Patients that underwent malleable penile prosthesis implantationn. analyses were performed

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

Polyglycolic acid graft in Peyronie’s disease

(6/14) smoking habits and 21.4% (3/14) dyslipidemia. Regarding the presence of preoperative ED, 35.7% of patients (5/14) reported impaired erections even with PDE5i before the surgery. On the other hand, 64.3% reported satisfactory erections. The median curvature degree was 60° (range 45-90°). The median time of plaque stability was 36 months (range 12-72). Regarding the curvature type, 35.7% (5/14) had uniplanar curvatures (except ventral); 50% (7/14) had biplanar (except ventral) or complex (hourglass or hinge) deformities, and 14.2% (2/14) had curvatures with some ventral component.

DISCUSSION

This study described our initial experience with the Gore® Bio-A® graft, which, to our knowledge, has never been studied for Peyronie’s disease management before. Residual curvature after surgery was a concern, given the physiology of graft integration, which is based on complete replacement of the synthetic material by native scar tissue, which could again result in fibrosis and curvature (12, 13). What was obtained, in fact, was a similar rate to that found in other studies, even after 6 months, which is the time described by the manufacturer for complete absorption of the material (13). The European Association Surgical outcomes of Urology (EAU) 2021 guidelines describe curvature corThe median follow-up time was 12 months (range 3-12). rection average rates (involving different non-comparable In terms of curvature correction, 3 of the 14 patients studies), or success rates, for porcine intestinal submucosa (21.4%) reported residual curvature greater than 15°, (SIS) grafts of 83.9% (range 54 -91), 87.4% for bovine that was confirmed after performing artificial erection in pericardium (range 76.5-100) and 81.2% for dermis the office. The curvature correction rate, therefore, was (range 60-100) (14). Table 2 describes curvature correc78.5% (11/14). tion rates with different patches. Regarding the secondary endpoints, 1 of 14 patients Regarding decreased glans sensitivity, we obtained lower rates compared to those described in other series, such as (7.1%) reported glans hypoesthesia. Nine of 14 patients Chung et al. (15), with 13% impaired sensitivity after der(64.2%) reported refractory ED postoperatively (using 5 mis graft, and as Horstmann et al. (16), with 16%, after mg of tadalafil). Three of the these patients decided to using TachoSil®, but slightly higher compared to the series underwent a malleable penile prosthesis implantation by Sansalone et al. (17), with 3%, after bovine pericardium. after 12 months of the first surgery. Excluding sensory Table 3 describes penile sensory changes with different changes and erection impairment, four patients (24.5%) patches. This outcome, however, seems to be more related presented minor surgical complications (penile pain and to the technique used for dissection of the neurovascular swelling) classified as Clavien-Dindo grade I. None of the bundle, rather than to the type of material used (8). patients (0/14) presented major surgical complications, Furthermore, a recent study by Terrier JE et al. showed that Clavien-Dindo grade ≥ II. Table 1 describes the characpenile sensory changes tends to decrease in frequency and teristics and postoperative outcomes for each patient. severity with time, with only rare cases occurring Table 2. after 12 months (18). Curvature correction with different patches. In terms of postoperative This table describes the curvature correction rates, expressed as weighted average, with grafts that are frequently used worldwide, along with the rate found with Gore®Bio-A®. (de novo) erectile dysfunction, the EAU 2021 guideAuthor, year EAU 2021 average rates for EAU 2021 average rates EAU 2021 average rates Zandoná et al. (2021) – lines describe average rates and graft used porcine intestinal submucosa (SIS)a for bovine pericardiuma for Dermisa Gore® Bio-A® patch of 21.9% (range 7-54) for Curvature/deformity porcine intestinal submucorrection 83.9% (54-91) 87.4% (76.5-100) 81.2% (61-100) 78.5% cosal grafts (SIS), 26.5% a. Data are expressed as weighted average and range in parenthesis (from different non-comparable studies). (range 0-50) for bovine pericardium, and 20.5% Table 3. (range 7-67) for autoloPenile sensory changes with different patches. gous dermis (14). Other This table describes the rates of penile numbness, or penile hypoesthesia with grafts that series, as Fabiani et al. (19, are frequently used worldwide, along with the rate found with Gore®Bio-A®. 20), report even lower Author, year Chung et al. (2011) Horstmann et al. (2011) Sansalone et al. (2011) Zandoná et al. (2021) rates, with 5.8% and 7.2% and graft used dermis graft Tachosil® bovine pericardium Gore® Bio-A® patch of ED after buccal mucosa Penile Hypoesthesia 13% 16% 3% 7.1% graft. In our cohort, we a. Data are expressed as weighted average and range in parenthesis (from different non-comparable studies). found higher rates of refractory erectile dysfunction (Table 4). Table 4. However, a possible selecDe novo erectile dysfunction with different patches. This table describes the rates of postoperative erectile function worsening with different grafts, tion bias must be considthat are frequently used worldwide, along with the rate found with Gore®Bio-A®. ered, as 35.7% of patients (5/14) reported impaired Author, year EAU 2021 average rates for EAU 2021 average rates Fabiani et al. (2016/2021) Zandoná et al. (2021) – erectile function prior to and graft used porcine intestinal submucosa (SIS)a for bovine pericardiuma buccal mucosa patch Gore® Bio-A® patch the surgical procedure. In De novo erectile this study, all patients were dysfunction 21.9% (7-54) 26.5% (0-50) 5.8%/ 7.2% 64.2% enrolled to undergo curvaa. Data are expressed as weighted average and range in parenthesis (from different non-comparable studies). ture correction surgery – Archivio Italiano di Urologia e Andrologia 2022; 94, 1

P.C. Edler Zandoná, N.P. Teixeira, H.E. Oliveira, J. Hamilton Soares Garcia

plaque incision and grafting – as a first-stage procedure. Although penile prosthesis implantation can be offered as a second procedure, it’s possible to perform both surgeries at the same time, even with the use of grafts, for patients at high-risk of developing refractory ED (14). The absence of major surgical complications, especially graft rejection, infection or extrusion, seems to be a characteristic of bioabsorbable materials, as opposed to synthetic grafts. We know that the incorporation process, comprising graft cell infiltration, neovascularization, and collagen deposition, which occurs in bioabsorbable materials, seems to lead to a lower risk of infection and erosion, compared to encapsulation, which occurs with the use of non-absorbable materials (21, 22). This study has some limitations, and therefore it should be interpreted with caution. The "self-reported" assessment of patients regarding erectile dysfunction, residual curvature and sensitivity change parameters, although described and recognized in the literature, is based on a subjective parameter and, therefore, reduces the statistical value and the possibility of extrapolating the results (23). The loss of follow-up of patients in the expected returns after surgery, largely due to the COVID-19 pandemic and cancellation of elective appointments, also had a negative impact on the results of this sample.

CONCLUSIONS

In this study, it was possible to demonstrate our initial experience with the use of Gore® Bio-A® graft. The rates of curvature correction and change in glans sensitivity were similar to those found in the literature. The rates of major complications related to the graft, as rejection, infection, and extrusion, were negligible in this sample. Although a population with a higher prevalence of erectile dysfunction was included in this sample, higher rates of refractory erectile dysfunction were observed and these findings should be confirmed in further studies. We believe that this study brings the perspective that similar bioabsorbable grafts can be used as an alternative in PD’s treatment, although prospective studies with a larger population and longer follow-up are needed to validate such findings.

REFERENCES

1. Devine Jr CJ, Somers KD, Jordan SG, Schlossberg, SM. Proposal: trauma as the cause of the Peyronie’s lesion. J Urol. 1997; 157: 285. 2. Kadioglu A, Tefekli A, Erol B, et al. A retrospective review of 307 men with Peyronie’s disease. J Urol. 2002; 168:1075. 3. Rhoden EL, Riedner CE, Fuchs SC, et al. A cross-sectional study for the analysis of clinical, sexual and laboratory conditions associated to Peyronie’s disease. J Sex Med. 2010; 7:1529. 4. Ralph D, Gonzalez-Cadavid N, Mirone V, et al. The management of Peyronie’s disease: evidence-based 2010 guidelines. J Sex Med, 2010. 7:2359. 5. Chung E, Ralph D, Kagioglu A, et al. Evidence-based management guidelines on Peyronie’s disease. J Sex Med. 2016; 13:905. 6. Mulhall J, Anderson M, Parker M. A surgical algorithm for men with combined Peyronie’s disease and erectile dysfunction: functional and satisfaction outcomes. J Sex Med. 2005; 2:132.

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7. Zaid UB, Alwaal A, Zhang X, Lue TF. Surgical management of Peyronie’s disease. Current Urol Rep. 2014; 15:446. 8. Garcia-Gomez B, Ralph D, Levine L, et al. Grafts for Peyronie's disease: a comprehensive review. Andrology. 2018; 6:117-126. 9. Carson CC, Levine LA. Outcomes of surgical treatment of Peyronie's disease. BJU Int. 2014; 113:704-13. 10. Schiffman ZJ, Gursel EO, Laor E. Use of Dacron patch graft in Peyronie disease. Urology. 1985; 25:38. 11. Faerber GJ, Konnak JW. Results of combined Nesbit penile plication with plaque incision and placement of Dacron patch in patients with severe Peyronie’s disease. J Urol. 1993; 149:1319. 12. Klinge U, Schumpelick V, Klosterhalfen B. Functional assessment and tissue response of short- and long-term absorbable surgical meshes. Biomaterials. 2001; 22:1415. 13. Yeo KK, Park TH, Park JH, et al. Histologic changes of implanted gore bio-a in an experimental animal model. Biomed Res Int. 2014; 2014:167962. 14. Salonia A, Bettocchi C, Carvalho J, et al. Guidelines on Sexual and Reproductive Health. Edn. presented at the EAU Annual Congress Milan 2021. ISBN 978-94-92671-13-4. 15. Chung E, Clendinning E, Lessard L, Brock G. Five-year followup of Peyronie’s graft surgery: outcomes and patient satisfaction. J Sex Med. 2011; 8:594. 16. Horstmann M, Kwol M, Amend B, et al. A self-reported longterm follow-up of patients operated with either shortening techniques or a TachoSil grafting procedure. Asian J Androl. 2011; 13:326. 17. Sansalone S, Garaffa G, Djinovic R, et al. Long-term results of the surgical treatment of Peyronie’s disease with Egydio’s technique: a European multicentre study. Asian J Androl. 2011; 13:842. 18. Terrier JE, Tal R, Nelson CJ, Mulhall JP. Penile Sensory Changes After Plaque Incision and Grafting Surgery for Peyronie’s Disease. J Sex Med. 2018; 15:1491. 19. Fabiani A, Servi L, Fioretti F, et al. Buccal mucosa is a promising graft in Peyronie’s disease surgery. Our experience and a brief literature review on autologous grafting materials. Arch Ital Urol Androl. 2016; 88:115-21. 20. Fabiani A, Fioretti F, Pavia MP, et al. Buccal mucosa graft in surgical management of Peyronie's disease: Ultrasound features and clinical outcomes. Arch Ital Urol Androl. 2021; 93:107-110. 21. Trabuco EC, Zobitz ME, Klingele CJ, Gebhart JB. Effect of host response (incorporation, encapsulation, mixed incorporation and encapsulation, or resorption) on the tensile strength of graft-reinforced repair in the rat ventral hernia model. Am J Obstet Gynecol. 2007; 197: 638.e1. 22. Klinge U, Klosterhalfen B, Müller M, Schumpelick V. Foreign body reaction to meshes used for the repair of abdominal wall hernias. Eur J Surg. 1999; 165:665. 23. Revicki DA, Cella D, Hays RD, et al. Responsiveness and minimal important differences for patient reported outcomes. Health Qual Life Outcomes. 2006; 4:70. Correspondence Pedro Caetano Edler Zandoná, MD (Corresponding Author) uropedrozandona@gmail.com pedrozandona@outlook.com Rua Esteves Júnior, 574, ap 105, 88015-130 Florianópolis, Santa Catarina (Brazil) Nivio Pascoal Teixeira, MD - nivio@uromed.com.br Henrique Eduardo Oliveira, MD - henriqueoliveira02@hotmail.com Jorge Hamilton Soares Garcia, MD - jorge@anestesiologistas.com.br

DOI: 10.4081/aiua.2022.1.91

ORIGINAL PAPER

Antegrade placement of JJ catheter in the treatment of malignant ureteral obstruction: Retrospective analysis of a single centre Eser Ordek 1, Mehmet Kolu 2, Mehmet Demir 3, Bulent Kati 3, Eyyup Sabri Pelit 3, Ismail Yagmur 3 1 Kahta

State Hospital, Urology Department, Adiyaman/Turkey; University, Faculty of Medicine, Radiology Department, Sanliurfa, Turkey; 3 Harran University, Faculty of Medicine, Urology Department, Sanliurfa, Turkey. 2 Harran

Summary

Objective: The aim of the present study was to examine the results of antegrade JJ stent placement in upper urinary tract obstruction in patients where retrograde placement was not possible. Methods: In this retrospective study, patients who underwent antegrade JJ stent placement for malignant ureteral obstruction in the urology clinic of a university hospital between January 1, 2018 and December 31, 2020 were included in the study. JJ stent was placed under local or general anaesthesia guided by ultrasonography and fluoroscopy. Age, gender, kidney function values, pathologies causing obstruction, and complications of the patients were examined. Results: In this study, 40 patients (16 men, 24 women) who underwent antegrade JJ stent placement were included. The mean ages of the women and men included were 51 (31-91) years and 62.5 (26-81) years, respectively. In all, antegrade JJ stenting was performed in 61 renal units of these patients. Of these, 21 were bilateral, 11 in the right collecting system and 8 in the left collecting systems. Clinical and technical success was achieved in 59 of the 61 procedures (96.6%). Arteriovenous fistula developed in only one patient, whereas no serious complications such as massive bleeding, resistant hematuria or pseudoaneurysm occurred in the remaining patients. The procedure was completed in a mean time of 15-30 minutes. Conclusions: Antegrade JJ stent placement is a procedure with a high success rate and low risk of complications that can be used in patients with severe ureteral obstruction owing to malignant or benign aetiologies. This method should be applied in centres experienced in malignant ureteral obstruction and on patients where retrograde placement was not possible. Furthermore, it should be considered as an alternative treatment option to open surgery as it can be performed under local anaesthesia in patients at a high risk of anaesthesia.

KEY WORDS: Malignant ureteral obstruction; Obstructive uropathy; Genitourinary neoplasms; Antegrade JJ stenting. Submitted 9 March 2022; Accepted 16 March 2022

INTRODUCTION

Ureteral stents were first developed by Zimskind et al. (1) in 1967 and have since been used in the treatment of ureteral obstruction or various urogenital fistulas. Over time, indications of the use of ureteral stents have

expanded significantly (2). Today, they are almost considered a standard and indispensable urological tool. Ureteral obstruction is a complex and heterogeneous clinical condition therefore determining the ideal decompression method can be challenging for urologists. These obstructions may develop owing to malignant or benign aetiologies. Malignancy that leads to this type of complex obstruction may originate from organs external to the urinary system as colorectal or gynaecological tumors or from organs internal to urinary system such as bladder and prostate cancers (3) (Figure 1). The aetiology of benign ureteral obstructions can be intraureteral or extra-ureteral. Intra-ureteral causes are the result of various pathologies such as ureteropelvic junction obstruction, impacted chronic ureteral stones or strictures after recurrent endoscopic interventional procedures. Extra-ureteral benign obstructions may be caused by the obstetric causes, uterine leiomyomas or retroperitoneal fibrosis (4). In cases of malignancy that cause severe ureteral obstruction, the benefits of draining the upper urinary system include symptomatic relief, preservation and maintenance of renal function, reduction of hospital stay and minimisation of the negative effects on the patient's quality of life (3-5). However, there is still no clear guideline on ideal methods for how to free urinary flow in the management of ureteral obstructions (6). In patients without lower urogenital system pathologies and active urinary tract infection, retrograde ureteral stenting can be used as an alternative for long-term ureteral obstruction or fistula treatment. The JJ stents used in this procedure are normally inserted in a retrograde approach by using a guidewire placed by cytoscopic or ureterorenoscopic method (1). However, in this approach, it is sometimes not possible to advance the guidewire proximally to the site of obstruction due to technical shortcomings, especially in patients with anatomical dislocation of the bladder wall, abnormally localised ureteral orifice by the tumor or in patients with malignant obstruction involving a long ureteral segment. In addition, retrograde ureteral stenting can sometimes be difficult or even unsuccessful in patients with obstruc-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 1

E. Ordek, M. Kolu, M. Demir, B. Kati, E. Sabri Pelit, I. Yagmur

Figure 1. 3 × 3 × 4 cm bladder tumour localised to the left lateralbladder base that completely covers the left orifice (indicated by the arrow sign).

tive malignancy in the lower urogenital system, those who undergo urinary diversion surgery with ileal conduit, or patients with anatomical changes due to renal transplantation (7). In addition, retrograde ureteral stenting is usually performed under spinal or general anaesthesia that can be associated to serious complications and may be contraindicated in high-risk comorbid patients. In such cases, the best option is a permanent percutaneous nephrostomy or the placement of an ureteral JJ catheter in an antegrade manner with a percutaneous approach (8). Percutaneous nephrostomy is a minimally invasive treatment option commonly used in the treatment of acute hydronephrosis, which aims to maintain existing renal function by providing drainage of intra-renal content. Although percutaneous nephrostomy is a very useful and feasible method, it has certain disadvantages compared to antegrade JJ stenting such as a more negative effect on patient comfort, a high risk of infection and easy dislocation of the catheter (8-9). Antegrade JJ stenting is a minimally invasive alternative treatment technique (8) that is described by several studies in the literature. The aim of the present study was to provide a retrospective analysis of antegrade JJ stenting results in a patient population with malignant ureteral obstruction who could not undergo retrograde JJ stenting in a tertiary health centre.

MATERIALS

AND METHODS

Patient selection Ethical approval was obtained from the local ethics committee for the study (Decision no: HRU/21.11.29). The data were obtained from electronic medical records, diagnostic imaging and laboratory examinations of patients who underwent JJ stenting due to malignant ureteral obstruction in the urology clinic of our hospital between January 1, 2018 and December 31, 2020. Patients with ureteral obstruction who underwent retrograde JJ stenting with conventional technique were excluded from the study. Conversely, patients who could not undergo retrograde JJ stenting or who previously had percutaneous nephrostomy were included in the study. Antegrade JJ stenting procedures were performed with the guidance of a specialist interventional radiologist by a urologist with clinical experience. Absolute contraindications for antegrade JJ stenting included uncorrectable coagulopathy, severe vertebral bone and posture disorders, insufficient cardiopulmonary function, hemodynamic instability, pregnancy and severe uncontrolled hypertension. Antegrade JJ stenting technique After receiving informed consent from the patient or firstdegree patient relatives, the preoperative preparation process was completed. All patients were given preoperative iv (intravenous) antibiotic prophylaxis. All invasive procedures were performed under local or general anaesthesia by ultrasonography and fluoroscopy. After the patient was prepped, the procedure was usually performed in two stages. Percutaneous nephrostomy was first performed on patients who did not have previous nephrostomy. Then, in the same session, ureteral JJ stent was placed in the renal pelvis and ureter and by antegrade method. The patient was placed in the prone position and surgical area was sterilised. An 18-gauge-15 cm Chiba needle was used under the guidance of fluoroscopy and ultrasound, which ensured proper placement from the skin to the renal calyx with Seldinger technique (10). The location of renal puncture was determined in accordance with the access indication taking into account anatomical constraints (5-10). Punctures were normally performed using the posterolateral oblique approach to the upper collecting system along Brödel's avascular plane, through the safest and easiest access to the ureteropelvic system (Figure 2).

Figure 2. Schematic drawing of the kidney avascular plane, also known as the Brödel line. A: Magnification of the angle of entry of the needle into the right kidney, with the patient in the supine position. B: Axial slice obtained with the patient in the prone position, demonstrating the ideal entry point for the percutaneous nephrostomy (Reference 5).

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

Antegrade placement of JJ stents

The needle was placed in the renal calyx selected by ultrasonography and a urine sample was collected and sent for urinalysis. After the needle was properly positioned, antegrade pyelography was performed with injection of nonionic iodised contrast agent (350 mg I/mL) diluted with sterile saline in a ratio of 1/2 in order to reveal the collecting system anatomy fluoroscopically (Figure 3). All sort of pathologies such as obstruction, stenosis or extravasation in the ureter were verified. (Figure 4). According to the Seldinger technique, a 6 F introducer was placed towards the ureteropelvic junction. Using a hydrophilic 0.035-inch guidewire under serial scopy images, the 5 F diagnostic catheter was advanced by passing the obstruction site in the ureter and placed in the bladder. Hydrophilic guidewire was removed and a 0.035-inch J-tip teflon-coated guidewire was inserted into the bladder (Figure 5). The 5 F catheter was then removed and replaced with a 6 Fr × 45 cm introducer sheath. The JJ catheter was advanced with the help of the teflon-coated guidewire or with the help of the sheath dilator feeding on the introducer sheath without the guidewire, until the distal end of the stent entered the bladder. The introducer sheath was then pulled back onto the dilator until the sheath

remained only in the renal pelvis. At this point, with the help of the dilator, the proximal (renal) tip of the JJ catheter was advanced to the appropriate position within the collecting system. Serial scopy images were obtained to confirm that the tip of JJ stent was curled in the bladder and renal pelvis (Figure 6). Then, a 6 F percutaneous nephrostomy catheter was placed in the renal pelvis under the guidance of fluoroscopy and fixed to the skin. Abdominal ultrasonography was planned for all patients to exclude possible complications after antegrade JJ stenting. On postoperative day 1, DUSG (direct urinary system radiography) was done to observe the position of the JJ catheter and the excretion of the contrast agent used. The nephrostomy catheter of the patients who did not have major complications and who did not have severe hematuria was removed in the postoperative 1-2 days under the guidance of floroscopy. The correct placement of the ureteral stent and the completion of the interventional procedure without major complications was considered as technical success. Clinical success was defined Figure 5. Antegrade placement of the guidewire and curling in the bladder (indicated by the arrow sign).

Figure 3. Right antegrade pyelography.

Figure 4. Right antegrade pyelography, narrow segment in proximal urethra and antegrade advancement of guide (indicated by the arrow sign).

Figure 6. JJ and nephrostomy catheter placed by left antegrade percutaneous approach.

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as decreased blood creatinine levels to normal values, resolved hydronephrosis and complete recovery or decrease in symptoms in postop follow-ups.

RESULTS

During the study, antegrade JJ stenting procedure was performed on 40 patients (16 males, 24 females) who presented to our clinic. The mean age of the patients was 56.7 years. In all, antegrade JJ stenting was performed in 61 renal units of these patients. Of these, 21 were bilateral, 61 were in the right collecting system and 8 in the left collectinf system. Clinical and technical success was achieved in 59 of the 61 procedures (96.6%). Severe obstruction was caused by malignant causes (bladder-prostate and colorectal cancers, among others) in 34 (85%) of the patients, whereas 6 (15%) had benign etiologies (C-section and ureteroenoscopic interventions, among others) (Table 1). The clinical and technical success rate in the patients was 96.3% and 100% for neoplastic and non-neoplastic groups, respectively. In addition, 14 (35%) of the patients had important comorbidities such as coronary artery disease, cerebrovascular disease, diabetes and hypertension. In 33 patients that include those with high anaesthesia risk, the procedure was performed under local anaesthesia, while

Table 3. History of retrograde JJ and percutaneous nephrostomy according to aetiology.

Malignancies Endometrium carcinoma Colorectal carcinoma Bladder cancer Prostate cancer Ovarian carcinoma Cervix carcinoma Soft tissue carcinoma Benign causes Surgical ligation (caesarean section) Ureteral stone (ureterorenoscopy)

! 0 3 4 2 1 1 0 ! 3 0

Retrograde JJ history x 5 5 6 2 0 4 1 x 0 3

Percutaneous nephrostomy history ! x 0 5 3 5 6 4 2 2 1 0 2 3 0 1 ! x 0 3 3 0

general anaesthesia was used in 7 patients. The mean blood creatinine values decreased from a preoperative value of 2.3 mg/dl to 1.1 mg/dl after the procedure. In addition, the preoperative kidney antero-posterior (AP) diameter decreased from an average of 25.15 mm to 14.02 mm during postoperative follow-up. In two of the patients with bladder cancer aetiology, malignant ureteral obstruction could not be corrected due to lack of balloon dilatation material in our hospital and antegrade JJ stenting could not be performed. Therefore, percutaTable 1. neous nephrostomy was performed (Table 2). Patient distribution according to benign and malignant etiologies. When the past clinical records of the patients were examined, it was determined that 14 patients had a history of Malignancies 34 patients 85.0% retrograde JJ stenting and 17 had a history of percutaEndometrium carcinoma 5 12.5% neous nephrostomy (Table 3). In the present study, anteColorectal carcinoma 8 20.0% grade JJ stenting was performed through the existing Bladder cancer 10 25.0% nephrostomy in only three patients. Prostate cancer 1 2.5% During the follow-up, 75% of the patients developed Ovarian carcinoma 1 2.5% clinically insignificant minimal haematuria, while almost Cervix carcinoma 4 10.0% all patients had pain at the wound site that resolved with Soft tissue carcinoma 5 12.5% simple analgesic treatment. The percutaneous nephrostoBenign causes 6 patients 15.0% my catheter was fixed to the opening site for an average Surgical ligation (caesarean section) 3 7.5% of 24-48 hours until the haematuria was completely Ureteral stone (ureterorenoscopy) 3 7.5% resolved. Haematuria recovered spontaneously within a Total 40 patients 100.0% few hours, usually without the need for additional intervention. In one patient with colorectal malignancy, arteriovenous fistula, which can be considered a major complication, Table 2. developed and the necessary treatAetiology of malignant urological obstructions, together with the distribution ment with angioembolisation was of approaches, technical success, failures and complications. performed. No other patient develIndication Patients Unilateral Bilateral Technical Technical Complications oped serious complications such as approach approach success failure bleeding, resistant haematuria, arteEndometrium carcinoma 5 (12.5%) 2 3 5 __ __ riovenous fistula or pseudoaColorectal carcinoma 8 (20.0%) 3 5 8 __ 1 neurism requiring transfusion. Bladder cancer 10 (25.0%) 5 5 8 2 __ Control DUSG taken on postoperaProstate cancer 4 (10.0%) 2 2 4 __ __ tive day 1 was checked to ensure Ovarian carcinoma 1 (2.5%) __ 1 1 __ __ that JJ stents were in the correct Cervix carcinoma 5 (12. 5%) 1 4 5 __ __ localisation. JJ stents were usually removed and new stents were Soft tissue carcinoma 1 (2.5%) __ 1 1 __ __ placed within an average of 3 Surgical ligation (caesarean section) 3 (7.5%) 3 __ 3 __ __ months. The procedure was perUreteral stone (ureterorenoscopy) 3 (7.5%) 3 __ 3 __ __ formed either cystoscopically or

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ureterorenoscopically using a retrograde technique with guide wire. Procedures were completed between 15-30 minutes on average.

DISCUSSION

Ureteral obstructions may occur due to malignant or benign etiologies. In ureteral obstruction, options such as percutaneous nephrostomy or ureteral stenting are the most commonly used treatment methods (12). In the current retrospective study, we investigated the applicability of percutaneous antegrade ureteral stenting in the treatment of severe ureteral obstructions caused by both malignant and benign causes and we found that antegrade stenting is a safe and effective method in cases where the retrograde approach fails. Since both acute and chronic ureteral obstruction can cause impairment of renal function, these conditions may lead to severe morbidities. In addition, there is still no clear consensus in the literature on the treatment of malignant ureteral obstruction regarding the patient's clinical picture, emergency status, current technical equipment, or clinician's experience (6-11). The treatment method to be selected is usually determined depending on the physician's personal clinical experience, capabilities of the institution and patient preference (12). Percutaneous nephrostomy has various risks such as wound site and urinary tract infection due to mandatory external drainage bag, and it also negatively affects the daily life and comfort of the patient (9). Ureteral JJ stents are usually placed under cystoscopy with a retrograde approach in various obstruction cases. However, they have been successfully placed with antegrade approach by many years. Both techniques are promising and give similar long-term results, but in recent studies, the failure rates of retrograde ureteral stenting in malignant ureteral obstruction has been reported to range between 18.5% and 42% (1213-14). In addition, numerous studies have investigated the applicability of antegrade ureteral stenting (15-16). In addition to similar long-term results, both techniques have their advantages and disadvantages. Using a retrograde appoach, it is possible to simultaneously treat concomitant bladder and ureteral stones with endoscopic laser or pneumatic lithotripter or to take a punch biopsy sample from possible malignancies, or to expand existing strictures and relieve obstruction. Retrograde ureteral stenting is a one-step procedure but it has the disadvantage to be performed under general or spinal anaesthesia in operating room conditions (2-17). Particularly, general anaesthesia is a problem in patients with serious cardiac reserve or respiratory problems, and it is even contraindicated in some cases. In addition, in severe ureteral obstructions caused by malignant etiologies, factors such as external ureteral pressure or bladder invasion reduce the success rates of retrograde stenting method by up to 50% (7-15). Clinical trials and observations have proven that antegrade ureteral stenting has higher success rates in severe ureteral obstructions due to both malignant and benign etiologies. Success rates reported in the literature range from 80% to 92% (17-18). In addition, balloon dilatation

can be performed during antegrade ureteral stenting, increasing technical success rates significantly. Furthermore, antegrade ureteral stenting can be performed successfully even under local anaesthesia, as opposed to retrograde method (18). In the present study, clinical and technical success with the antegrade method was 96.6% and the success rate was consistent with the literature. In only two procedures, percutaneous nephrostomy has to be performed because JJ stent could not be inserted by antegrade method. Major complications associated with antegrade JJ stenting have been reported in the literature, but these occur in only 4-8% of cases (10). These complications include retroperitoneal bleeding, which can be treated with angiographic embolisation, perforation of the pleura or intraabdominal organs (such as intestine, liver, spleen) and urosepsis (8-19). Significant respiratory complications such as pneumothorax, hydrothorax and empyema are seen in less than 0.2% of patients (6). Minor complications such as the extravasation of urine into the retroperitoneal area, subcapsular hematoma and macroscopic hematoma can develop in 3-15% of cases (20). Mild haematuria caused by urothelial irritation is a common finding after ureteral stenting and usually improves spontaneously during follow-up. However, in the presence of severe and resistant haematuria that develops after the placement of ureteral stent, ureteroarterial fistula between the ureter and the major or internal iliac artery should be considered first and necessary interventions should be performed quickly (6). The clinician's mastery of urinary system anatomy and vascularisation is vital in choosing a safe pathway for percutaneous puncture and reducing the risk of complications (8-10-11). In the present study, only 3 (7.5%) of the patients developed minor complications including mild lumbar pain and minimal haematuria (Clavien Degree I), which usually recovered spontaneously within hours. Only one patient developed arteriovenous fistula, which is considered a major complication, and the necessary treatment was performed with angioembolisation. In addition, although parenteral antibiotic prophylaxis is applied to all patients before the procedure, urinary tract infection is also a common finding. However, usually these infections can be successfully treated with basic antibiotics. However, if the current infection does not respond to medical pharmacological treatment, JJ stents may need to be removed immediately. In the present study, no symptoms of urinary tract infection that required stent removal was observed in any of the patients. The present study has certain limitations. Firstm the study was designed and conducted retrospectively. Furthermore, the interventional radiology clinic in our hospital has just become operational, therefore the number of patients was limited. It becomes evident that the most important requirement at this stage is the clinical skill of an expert interventional radiology specialist.

CONCLUSIONS

The results of this retrospective study show that percutaneous antegrade JJ stenting is possible in ureteral obstruction caused by both malignant and benign causes with Archivio Italiano di Urologia e Andrologia 2022; 94, 1

E. Ordek, M. Kolu, M. Demir, B. Kati, E. Sabri Pelit, I. Yagmur

minimal risk of complications and high technical success rate. In addition, antegrade JJ stenting stands out as a good alternative option when conventional retrograde placement fails. To the best of our knowledge, there are no large-scale randomised controlled clinical trials in the literature comparing antegrade ureteral JJ stenting with retrograde JJ stenting. In addition, there is still no clear consensus in the literature on the treatment of malignant ureteral obstruction regarding the patient's clinical picture, emergency status, current technical equipment, or experience of the interventional radiologist. Therefore, in patients with malignant ureteral obstruction, randomised controlled trials with a larger population are needed to gain further information on the optimal approach to ureteral JJ stenting.

REFERENCES

1. Zimskind PD, Fetter TR, Wilkerson JL. Clinical use of long-term indwelling silicone rubber ureteral splints inserted cystoscopically. J Urol. 1967; 97:840-4. 2. Seymour H, Patel U. Ureteric stenting: Current status. Semin Intervent Radiol. 2000; 17:351-65. 3. Nunes TF, Tibana TK, Santos RFT, et al. Percutaneous insertion of bilateral double J stent. Radiol Bras. 2019; 52:104-105. 4. Fletcher HM, Wharfe G, Williams NP, et al. Renal impairment as a complication of uterine fibroids: a retrospective hospital-based study. J Obstet Gynaecol. 2013; 33:394-8. 5. Meira MS, Barbosa PNV, Bitencourt AGV, et al. Análise retrospectiva das nefrostomias percutâneas guiadas por tomografia computadorizada em pacientes oncológicos. Radiol Bras. 2019; 52:14854. 6. Hsu L, Li H, Pucheril D, et al. Use of percutaneous nephrostomy and ureteral stenting in management of ureteral obstruction. World J Nephrol. 2016; 5:172-81. 7. Chitale SV, Scott-Barrett S, Ho ET, Burgess NA. The management of ureteric obstruction secondary to malignant pelvic disease. Clin Radiol. 2002; 57:1118-21. 8. Venyo AKG, Hanley T, Barrett M, et al. Ante-grade ureteric stenting, retrospective experience in managing 89 patients: indications,

Correspondence Eser Ordek, MD (Corresponding Author) dr_eseser@hotmail.com Kahta State Hospital, Urology Department 02000Adiyaman (Turkey) Mehmet Kolu, MD drrdylg@gmail.com Harran University, Faculty of Medicine Hospital, Radiology, 63340 Sanliurfa (Turkey) Mehmet Demir, MD drdemir02@gmail.com Bulent Kati, MD bulentkati@harran.edu.tr Eyyup Sabri Pelit, MD dreyyupsabri@hotmail.com Ismail Yagmur, MD dr_iyagmur@hotmail.com Harran University, Faculty of Medicine Hospital, Urology, 63340 Sanliurfa (Turkey)

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complications and outcome. Journal of Biomedical Graphics and Computing. 2014; 4:47-56. 9. Bahu R, Chaftari AM, Hachem RY, et al. Nephrostomy tube related pyelonephritis in patients with cancer: epidemiology, infection rate and risk factors. J Urol. 2013; 189:130-5. 10. Dyer RB, Regan JD, Kavanagh PV, et al. Percutaneous nephrostomy with extensions of the technique: step by step. Radiographics. 2002; 22:503-25. 11. van der Meer RW, Weltings S, van Erkel AR, et al. Antegrade ureteral stenting is a good alternative for the retrograde approach. Curr Urol. 2016; 10:87-91. 12. Matsuura H, Arase S, Hori Y. Ureteral stents for malignant extrinsic ureteral obstruction: outcomes and factors predicting stent failure. Int J Clin Oncol. 2019; 24:306-312. 13. Kamiyama Y, Matsuura S, Kato M, et al. Stent failure in the management of malignant extrinsic ureteral obstruction: risk factors. Int J Urol. 2011; 18:379-82. 14. Yu SH, Ryu JG, Jeong SH, et al. Predicting factors for stent failure-free survival in patients with a malignant ureteral obstruction managed with ureteral stents. Korean J Urol. 2013; 54:316-21. 15. Turgut B, Bayraktar AM, Bakdık S, et al. Placement of double-J stent in patients with malignant ureteral obstruction: antegrade or retrograde approach? Clin Radiol. 2019; 74:976.e11-976.e17. 16. Kahriman G, Özcan N, Dogan A, et al. Percutaneous antegrade ureteral stent placement: single center experience. Diagn Interv Radiol. 2019; 25:127-133. 17. Uthappa MC, Cowan NC. Retrograde or antegrade double-pigtail stent placement for malignant ureteric obstruction? Clin Radiol. 2005; 60:608-12. 18. Adamo R, Saad WE, Brown DB. Management of nephrostomy drains and ureteral stents. Tech Vasc Interv Radiol. 2009; 12:193204. 19. Pabon-Ramos WM, Dariushnia SR, Walker TG, et al. Society of Interventional Radiology Standards of Practice Committee. Quality Improvement Guidelines for Percutaneous Nephrostomy. J Vasc Interv Radiol. 2016; 27:410-4. 20. Ganatra AM, Loughlin KR. The management of malignant ureteral obstruction treated with ureteral stents. J Urol. 2005; 174:2125-8.

DOI: 10.4081/aiua.2022.1.97

REVIEW

Infectious complications of endourological treatment of kidney stones: A meta-analysis of randomized clinical trials 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, Panagiotis Mourmouris 7, 13, Adama Ouattara 8, 13, Gianpaolo Perletti 9, 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 2nd Department of Urology, National and Kapodistrian University of Athens, Sismanoglio Hospital, Athens, Greece; 8 Division of Urology, Souro Sanou University Teaching Hospital, Bobo-Dioulasso, Burkina Faso; 9 Department of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, University of Insubria, Varese, Italy; 10 Faculty of Medicine and Medical Sciences, Ghent University, Belgium; 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

* 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

Objective: Endourological treatment is associated with a risk of postoperative febrile urinary tract infections and sepsis. The aim of this study was to review the reported rate of infectious complications in relation to the type and modality of the endourologic procedure. Methods: This systematic review was conducted in accordance with the PRISMA guidelines. Two electronic databases (PubMed and EMBASE) were searched. Out of 243 articles retrieved we included 49 studies after full-text evaluation. Results: Random-effects meta-analysis demonstrated that retrograde intrarenal surgery (RIRS) and percutaneous nephrolithotomy (PCNL) were associated with not significantly different odds of getting fever (OR = 1.54, 95% CI: 0.99 to 2.39; p = 0.06) or sepsis (OR = 1.52, 95% CI: 0.37 to 6.20, p = 0.56). The odds of getting fever were not significantly different for mini PCNL compared to standard PCNL (OR = 1.11, 95% CI: 0.85 to 1.44; p = 0.45) and for tubeless PCNL compared to standard PCNL (OR = 1.34 95% CI: 0.61 to 2.91, p = 0.47). However, the odds for fever after PCNL with suctioning sheath were lower than the corresponding odds for standard PCNL (OR = 0.37, 95% CI: 0.20 to 0.70, p = 0.002). The odds of getting fever after PCNL with perioperative prophylaxis were not different from the corresponding odds after PCNL with perioperative prophylaxis plus a short oral antibiotic course (before or after the procedure) (OR = 1.31, 95% CI: 0.71 to 2.39, p = 0.38). Conclusions: The type of endourological procedure does not appear to be decisive in the onset of infectious complications, although the prevention of high intrarenal pressure during the procedure could be crucial in defining the risk of infectious complications.

Summary

KEY WORDS: Kidney calculi; Percutaneous nephrolithotomy; Retrograde intrarenal surgery; Ureteroscopy; Lithotripsy; Systemic inflammatory response syndrome; Sepsis; Fever; Urinary tract infection. Submitted 15 January 2022; Accepted 1 February 2022

INTRODUCTION

Percutaneous and retrograde endourological procedures are widely used for the removal of renal stones. These treatments ensure high stone free rates and are associated with a relatively low morbidity. However, infectious complications are not uncommon in both. After retrograde intrarenal surgery (RIRS), the rate of febrile urinary tract infections can range between 7.6 and 13.4% (1). Risk factors include preoperative pyuria, stone size, struvite stone composition, operating time, irrigation flow rate and volume, size of ureteral access sheath, presence of residual fragments, history of urinary tract infections, and comorbidities (2-5). The incidence of fever after percutaneous nephrolithotomy (PCNL) was reported to range between 10.4% and to 18.9%, with urosepsis in 0.9% to 4.7% of cases. Longer operating time, higher number of punctures, tract size, staghorn stone, severe preoperative hydronephrosis, preoperative stenting, history of recurrent urinary tract infection, renal failure, and type 2 diabetes were found to be risk factors (6-9). The aim of this systematic review was to assess the reported rate of infectious complications in relation to the type of endourologic procedure, the methods used in the procedure and the antibiotic prophylaxis applied.

MATERIALS

AND METHODS

This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) guidelines (10) after being registered on the PROSPERO platform (CRD42021283094). Two electronic databases (PubMed and EMBASE) were searched for articles published up to September 30th, 2021.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 1

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Search was performed including MeSH terms (percutaneous nephrolithotomy, ureteroscopy, lithotripsy, kidney calculi, Systemic Inflammatory Response Syndrome, Sepsis, Fever, Urinary Tract Infections) and was implemented by free-text terms (micro-percutaneous nephrolithotomy, PCNL, miniPCNL, retrograde intrarenal surgery, flexible ureteroscopy, RIRS, FURS, ECIRS). The following search terms were used: (percutaneous nephrolithotomy OR ureteroscopy OR lithotripsy OR micro-percutaneous nephrolithotomy OR PCNL OR mini-PCNL OR retrograde intrarenal surgery OR flexible ureteroscopy OR RIRS OR FURS OR ECIRS) AND kidney calculi AND (systemic inflammatory response syndrome OR sepsis OR fever OR urinary tract infections). Relevant data were also hand searched by browsing various sources (e.g., reference lists from reviews and study reports, congress abstracts, www.clinicaltrials.gov, www.clinicaltrialsregister.eu, and others). During the initial screening of the retrieved records we considered randomized controlled trials (RCTs), with an open-label or single/double blinded design including participants without restriction of age or gender or ethnicity, treated for renal stones with percutaneous endoscopic procedures (including standard PCNL, mini-PCNL, ultraminior micro-PCNL) and retrograde endoscopic procedures (flexible ureteroscopy or RIRS). Article reporting comparisons between Endoscopic Combined Intrarenal Surgery (ECIRS) and single endoscopic procedures (both percutaneous and retro- Figure 1. Flow chart. grade) were also initially examined. In this systematic review we included articles reporting the comparison of infectious complication rates in: 1) PCNL vs RIRS, 2) standard PCNL vs miniaturized PCNL, 3) tubeless vs non tubeless PCNL, 4) PCNL or RIRS with/without use of suctioning sheath, and 5) PCNL/RIRS under different modalities of antibiotic prophylaxis. The following outcomes were considered: fever > 38°C or sepsis according to Systemic Inflammatory Response Syndrome (SIRS) or Sequential Organ Failure Assessment (SOFA) scores. The Systemic Inflammatory Response Syndrome (SIRS) score had been used since 1991. It is calculated based on the presence of the following criteria: temperature > 38°C or < 36°C, heart rate > 90/minute, respiratory rate > 20/minute, WBC > 12,000 or < 4,000 (11). The SOFA score was introduced by the Sepsis-3 Task Force in 2016. The quick SOFA (qSOFA) score is a simpler scoring system based on the presence of a respiratory rate ≥ 22 /min, a systolic blood pressure ≤ 100 mmHg, and altered mental status (12). Title and abstract screening to exclude documents that did not meet the inclusion criteria were performed

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independently by two authors. Controversies were resolved by a third researcher. Duplicate references were excluded and full texts of the screened articles were analyzed to confirm their inclusion in the review. A PRISMA flow diagram was drawn to illustrate the results of the study selection process (Figure 1). Data extraction was conducted by two authors using a standardized form. The following information was obtained from each study: author(s), publication year, study design, population, intervention, rate of infectious complications (fever, SIRS, sepsis) (see Supplementary Materials - PICO tables). The risk of bias of randomized controlled trials was assessed using the Risk of Bias (RoB) 2 assessment tool as prescribed by the Cochrane Handbook (13). The quality of each study was independently assessed by two reviewers (DH and HAG-P) against pre-defined criteria in relation to the 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). Disagreements were resolved by discussion. The presence of risk of bias was not used as a criterion to exclude studies from this review or from meta-analysis (see Supplementary Materials - RoB). Statistical analysis was performed using the RevMan5 software. Dichotomous data (presence/absence of infectious complications) and number of per-protocol or intent-to-

Infectious complications of endourology for kidney stones

treat patients were extracted to calculate odds ratios (OR), confidence intervals (CI) to odds-ratios, and Z statistics (Random-effects model, Mantel-Haenszel method). Forest plots were drawn in the presence of more than three studies. Heterogeneity was assessed by I^2 statistics, reported with 95% CIs, and interpreted as of lesser importance (≤ 40%), moderate (30%-60%), substantial (50%-90%) or considerable (≥ 75%), according to Cochrane criteria. Summary of Findings tables for comparisons outlined in Forest plots were prepared. The quality of evidence was rated according to GRADE criteria (see Supplementary Materials - Summary of findings). Funnel plots were drawn to assess report bias. Publication bias was assessed by visually inspecting the funnel plots (see Supplementary Materials - Publication bias). If a potential reporting bias was suspected, the Egger’s regression and Begg’s correlation tests were applied to assess the significance of funnel plot asymmetry and to confirm the perceived publication bias. Asymmetry tests were performed using the MetaEssentials 1 software (Rotterdam School of Management, Erasmus University, The Netherlands). The ‘trim and fill’ missing study imputation approach was applied to asymmetric funnel plots and adjusted overall effect sizes were calculated.

RIRS vs PCNL We retrieved 20 articles (6 from Pubmed, 11 from EMBASE, 3 from other sources). After removal of 4 duplicates and one article involving a pediatric population, 15 studies were included in the analysis (14-28). Out of 15 studies, 11 evaluated post-operative fever (14-16, 18, 2023, 25, 27, 28), 2 sepsis (17, 24), and 2 both post-operative fever and sepsis (19, 26). Standard PCNL vs mini/ultra mini/supermini/micro PCNL We retrieved 17 articles (1 from PubMed, 14 from EMBASE, 2 from other sources). After removal of one duplicate, 16 full-text articles were evaluated. Two articles were excluded because they reported data from the same study, and 5 more for insufficient data reporting. Finally, 8 articles were included in the analysis (29-36) and one article reporting a comparison of miniPCNL with ultramini-PCNL (37) was considered for qualitative analysis. Standard PCNL vs tubeless PCNL We retrieved 21 articles (4 from PubMed, 17 from EMBASE). After removal of 3 duplicates, 18 full-text articles were evaluated. Nine articles were excluded (one involving a pediatric population, 5 for insufficient reporting, 2 comparing tubeless PCNL within different size tracts, and 1 not randomized). Out of the 9 articles included in the analysis, 6 articles compared tubeless with standard PCNL (38-43), 2 articles compared tubeless PCNL with tubeless PCNL with use of sealant (44, 45), and one study tubeless PCNL with and without infiltration of the tract with bupivacaine (46).

RESULTS

From our primary search we retrieved 48 articles from PubMed, 176 from EMBASE and 19 from other sources. Title and abstract screening allowed us to select 91 articles (21 from PubMed, 62 from EMBASE and 8 from other sources), that were reduced to 76 after removal of 15 duplicates. After full-text evaluation, 27 articles were excluded (2 articles reporting about pediatric populations, 4 articles reporting data of patients which were part of studies already included in this review, 13 articles for insufficient reporting, 6 articles dealing with a topic not included in the analysis, and 2 articles reporting the results of non-randomized studies) (Table 1). Finally, 49 studies were included in qualitative analysis (14-62), of which 39 were suitable for quantitative analysis.

Standard PCNL/RIRS vs vacuum-assisted We retrieved 11 articles (2 from PubMed 9 from EMBASE). After exclusion of 2 duplicates, 9 articles were included for full text evaluation: 2 were excluded because they reported data of patients which were part of studies already included in this review, 2 because they reported series of ureteral stones, and 1 for its retrospective design. Table 1. Out of the remaining 4 articles, 3 Results of the selection process divided by topic and procedure. reported about the use of a vacuum-assisted access sheath for PubMed EMBASE Other sources Total Duplicates Evaluated Excluded Included RIRS vs PCNL 6 11 3 20 4 16 1 15 PCNL (47-49), and one the use of sPCNL vs mini 1 14 2 17 1 16 7 9 ureteral access sheaths for RIRS Tubeless 4 17 0 21 3 18 9 9 (50). Sheath Prophylaxis Total

Reasons for exclusion RIRS vs PCNL sPCNL vs mini Tubeless Sheath Prophylaxis Total

2 8 21

9 11 62

Pediatric population 1 1

0 3 8

11 22 91

2 5 15

Insufficient data reporting

Reporting same series

5 5

2 2

3 13

9 17 76

5 5 27

4 12 49

Reporting topics not included in the analysis

Not randomized

2 2 2 6

1 1 2

Perioperative prophylaxis We retrieved 22 articles (8 from PubMed, 11 from EMBASE and 3 from other sources). After removal of 5 duplicates, 17 articles were evaluated by full-text reading. Two articles were excluded because they were off-topic (comparison with open surgery, ureteral stones) and 3 because of incomplete reporting.

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Out of the 12 remaining articles (51-62), one study compared perioperative antibiotic prophylaxis with a short course of antibiotics in patients at high risk for infectious complications (51), 5 studies (52-56) compared the effect of perioperative antibiotic prophylaxis with a single dose (or with two doses 24-48 hours apart) with a more complex strategy associating perioperative prophylaxis with a short course of antibiotic in the preoperative or postoperative period, 2 studies compared the results of perioperative prophylaxis with different antibiotics (57, 58), and 2 studies compared both perioperative prophylaxis with different antibiotics and different strategies of antibiotic prophylaxis (59, 60). Finally, two randomized placebo-controlled studies evaluated the outcome of antibiotic prophylaxis in patients who underwent PCNL or RIRS (61, 62).

was considered low in 44 studies and unclear in 5 and risk of bias in selection of the reported results was judged low in 38 studies, unclear in 10 and high in one. In total risk of bias was considered low in 10, unclear in 28 and high in 11. Meta-analysis RIRS vs PCNL Random-effects meta-analysis revealed that retrograde intrarenal surgery (RIRS) and percutaneous nephrolithotomy (PCNL) were not associated with significantly different odds of getting fever (OR = 1.54, 95% CI: 0.99 to 2.39; 13 trials, 1285 participants, Z = 1.91, P = 0.06, I^2 = 0%) or sepsis (OR = 1.52, 95% CI: 0.37 to 6.20; 4 trials, 428 participants, Z = 0.59, P = 0.56, I^2=38%) (Figures 2a, 2b).

Figure 2a, b. Odds of getting fever (plot a) or sepsis (plot b) after RIRS or PCNL (plot labels: on the right: favors PCNL; on the left: favors RIRS) [explanation: the Gu trial favors PCNL because RIRS shows more febrile events: thus the Gu point is on the right: less febrile events with PCNL] a.

Risk of bias Of the 49 studies, 25 described methods of randomization with low risk of bias, 17 with unclear risk and 7 with high risk. We judged the risk of deviations from the intended intervention as low in 24 studies, unclear in 22 and high in 3. Missing outcome data was judged low in 35 studies and unclear in 14. Risk of bias in measurement of outcome

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Mini vs standard PCNL The odds of getting fever were not significantly different when mini-PCNL was compared to standard-PCNL (OR = 1.11, 95% CI: 0.85 to 1.44; 8 trials, 2774 participants, Z = 0.76, P = 0.45, I^2 = 0%) (Figure 3). A study of Sabnis et al., not included in the meta-analysis compared mini-PCNL (12 F) with ultramini-PCNL (7.5 F) for treating stone of a size < 1.5 cm, demonstrat-

Infectious complications of endourology for kidney stones

Figure 3. Odds of getting fever after miniaturized PCNL (mini-PCNL) compared to standard PCNL (S-PCNL). (plot labels: on the right: favors standard PCNL; on the left: favors mini-PCNL)

Figure 4. Odds of getting fever after tubeless PCNL (TL-PCNL) compared with standard PCNL (S-PCNL) (plot labels: on the right: favors S-PCNL; on the left: favors TL-PCNL)

ing comparable rates of postoperative sepsis (0/30 vs 1/30) (37). Tubeless PCNL vs standard PCNL The odds for fever were not significantly different when tubeless-PCNL was compared to standard-PCNL (OR = 0.75 95% CI: 0.34 to 1.63; 6 trials, 505 participants, Z = 0.73, P = 0.47, I^2 = 0%) (Figure 4). Two studies, not included in the pooled analysis, compared the rate of infectious complications after tubeless PCNL vs. tubeless PCNL with use of sealant. Shah et al (44) showed similar rates of fever after tubeless PCNL with or without sealant (1/32 vs 2/31). Similar results were obtained by Titaram et al. (45) with similar rates of fever (19/41 vs 15/41, P = 0.20), lower rate of SIRS with use of sealant (but one case of sepsis versus none). Another study compared the results of tubeless PCNL with or without infiltration with bupivacaine (rate of fever 7/46 vs 6/23, P = 0.49)(46). PCNL/RIRS with suctioning sheath vs standard PCNL The odds of getting fever for PCNL with suctioning sheath were significantly lower than the odds calculated for standard PCNL using a normal Amplatz sheath (OR =

0.37, 95% CI: 0.20 to 0.70; 3 trials, 351 participants, Z = 3.10, P = 0.002, I^2 = 0%) (Figure 5). A single randomized trial not included in the meta-analysis, evaluated the risk of getting fever after RIRS with the use of suctioning sheath compared to the standard procedure. Eisner et al. (50) presented the results of a randomized trial including 20 patients: no infectious complication was observed in the group treated with aspiration through the access sheath, while one patient in the control group had a urinary tract infection. Antibiotic prophylaxis (comparison with placebo) Two studies were retrieved and not pooled, as they compared different antibacterial agents with placebo (61, 62). A multicentre randomized trial (61) compared the result of preoperative prophylaxis in PCNL with a single dose of cefotaxime (1 gr) with placebo. The rate of postoperative bacteriuria was lower in patients treated with cefotaxime although the difference was not statistically significant, likely due to the low number of patients treated with PCNL included in the study. Similarly, clinical data about the rate of postoperative fever and urinary tract infection were not available because the data relative to PCNL were aggregated with those of ureterorenoscopy. A study presented the results of preoperative prophylaxis Archivio Italiano di Urologia e Andrologia 2022; 94, 1

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Figure 5. Odds of getting fever after PCNL with suctioning sheath (PCNL + SS) compared with standard PCNL (S-PCNL) (plot labels: on the right: favors S-PCNL; on the left: favors PCNL + SS).

of RIRS with ciprofloxacin compared with placebo (62). The rate of RIRS after placebo (9.9%) was not significantly different from the rate assessed following treatment with one (4.9%) or two doses of ciprofloxacin (4.2%). However, a subgroup analysis demonstrated a significantly higher risk of getting SIRS in patients who received placebo for treatment of stones > 200 mm^2 compared to patients who received ciprofloxacin (18% vs single dose 4.3%, P = 0.036; vs two doses 5.5%, P = 0.044). Antibiotic prophylaxis (comparison of antibiotics) Four studies were retrieved and not pooled, as they compared different antibacterial agents administered according to different treatment protocols (57-60). Song et al. (57) administered to patients who underwent PCNL a three-day course of oral fosfomycin (3 g/day) vs. intravenous cefuroxime (3 g/day). Fosfomycin proved to be more effective than cefuroxime, exerting a high antibacterial effect on pathogens localized in the stone, thus reducing the probability of infection. Postoperative fever was observed in 7/31 patients in the experimental group compared to 9/30 in the control group (p > 0.05) but SOFA score was > 2 in 3/31 versus 10/30 (p < 0.05). Seyrek et al. (58) did not observe significant differences in the risk of getting SIRS after PCNL in patients treated with sulbactam-ampicillin versus cefuroxime (13.7 vs 17.7%, P = 0.44), though one patient in the sulbactamampicillin died of septic shock. Similarly, Taken et al. (59)

observed no difference in the rate of SIRS following PCNL in patients treated with ceftriaxone (23.3%) or cefazoline (12.5%) (P = 0.264). Finally, Demirtas et al. (60) found no difference in the rate of SIRS after PCNL between ciprofloxacin (15.5%) and ceftriaxone (8.8% P = 0.52). Perioperative vs perioperative plus additional short antibiotic prophylaxis Seven studies reported the results of the comparison of perioperative antibiotic prophylaxis versus perioperative prophylaxis associated with prolonged oral administration of antibiotics in patients who underwent PCNL for stones. Patients were deemed to be at low risk for infectious complications (negative preoperative urine culture, absence of hydronephrosis). Two studies (Seyrek 2012 and Demirtas 2012) (58, 60) included data about the use of two different antibiotics, data were pooled separately. The odds for fever after PCNL with perioperative prophylaxis were not different than after PCNL with perioperative prophylaxis plus a short oral antibiotic course (before or after the procedure) (OR = 0.76, 95% CI: 0.42 to 1.40; 9 trials, 720 participants, Z = 0.87, P = 0.38, I^2 = 53%) (Figure 6). A study (not included in the meta-analysis) (51) compared the outcome of 2 days vs. 7 days of preoperative antibiotics in patients at moderate-to-high risk for sepsis undergoing percutaneous nephrolithotomy. The sepsis rates were not different between treatment arms on uni-

Figure 6. Odds of getting fever after PCNL with perioperative prophylaxis (PP) compared with PCNL with perioperative prophylaxis plus a short oral antibiotic course (PP + SOC)(plot labels: on the right: favors perioperative; on the left: favors PP + SOC).

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variate analysis. However multivariate analysis showed that the risk of sepsis was increased (OR = 3.1, 95% 1.18.9, P = 0.031) in patients who were treated for 2 days compared to patients who were treated for 7 days. Publication bias analysis Figure 1 a-f (see Supplementary Materials - Publication bias analysis) shows the funnel plots relative to the 6 pooled analyses performed in this systematic review. Table 1 (Supplementary Materials - Publication bias analysis) shows the significance values of the Begg’s and Egger’s asymmetry tests. The only pooled analysis showing significant asymmetry (Egger’s P = 0.011, Begg’s P = 0.004) was the one comparing perioperative prophylaxis vs. perioperative prophylaxis plus an additional short antibiotic prophylaxis. The “Trim-and-fill” strategy imputed two missing studies to the asymmetric funnel plot. The adjusted odds ratio of the funnel plot including the imputed missing studies was 0.62 (95% CI: 0.31 to 1.28). Thus, despite the addition of two imputed studies, the odds ratio for this comparison remains not significant. Summary of findings Tables 1 a-e (Supplementary Materials - Summary of findings) present the summary of the findings of the meta-analyses, also including an evaluation of the quality of the evidence, performed according to GRADE criteria. The quality of the evidence was rated as low for the comparisons (i) PCNL with suctioning sheath vs. standard PCNL, and (ii) PCNL with simple perioperative antibiotic prophylaxis (PAP) plus a short oral antibiotic course vs. PCNL with simple PAP. The reasons for downgrading the former were risk of bias (one point) and imprecision due to the low number of participants (one point). The reasons for downgrading the latter were risk of bias (one point) and publication bias (one point). The quality of the remaining evidence was rated as moderate, mainly due to the presence of risk of bias (one point).

DISCUSSION Endourological treatment of kidney stones represents a considerable improvement in the management of nephrolithiasis, thanks to the reduction of morbidity and the minimal surgical impact on the urinary tract. The complications associated with this form of treatment are relatively infrequent, though serious bleeding and infectious complications can be observed. PCNL and RIRS are treatment modalities that have specific indications. However, the choice of a specific procedure is based on the experience of the operating surgeon and sometimes on the patient’s preferences. In fact, kidney stones smaller than 20 mm can alternatively be treated with percutaneous or retrograde intracorporeal lithotripsy (63). In this case, the risk of complications should be taken into consideration when choosing between the two forms of treatment. Retrograde and percutaneous renal stone treatment can affect the risk of infectious complications in different ways.

Flexible ureteroscopy can increase intrarenal pressure in relation (i) to type and rate of irrigation, or (ii) to the use and size of ureteral sheaths promoting the anterograde outflow of irrigation fluid. The increase in pressure within the urinary tract can cause an intratubular reflux of urine, with increased risk of infectious complications. Percutaneous treatment does not generally involve a major increase of fluid pressure in the urinary tract, but it can cause greater local trauma and extravasation of irrigating fluid. Previous meta-analyses have compared the results of percutaneous nephrolithotomy with the outcomes of retrograde intrarenal surgery for the treatment of kidney stones. However, the risk for infectious complications was not included in such analyses. Zheng et al. (64) found no difference in the rate of postoperative fever (RR = 0.95, P = 0.85) between RIRS and PCNL. More recently, Chen et al. (65) reviewed 11 studies showing that the rate of postoperative fever or infection was not significantly different in the patients treated with PCNL compared to those treated with RIRS (RR = 1.26, P = 0.29). Our study included only 5 of the 11 studies considered by Chen et al. because we limited our search to randomized controlled studies. Furthermore, we found and included in the analysis 10 additional randomized studies. However, we were not able to demonstrate a significant superiority of one endourological procedure over the other with regards to the risk of postoperative fever or sepsis. However, we observed a trend for a higher risk of fever after RIRS (OR = 1.54, 95% CI: 0.99 to 2.39). It should be highlighted that most comparative studies had as a primary endpoint the evaluation of stone-free status after treatment rather than the occurrence of infectious complications. Based on the results of our meta-analyses, the choice of the procedure would not seem to be a relevant factor for infectious complications after treatment. However, the risk of infectious complications could depend on how PCNL and RIRS are performed. In our analysis, we were able to examine the impact of certain treatment procedures on the risk of infection. For PCNL, we considered the effect of the diameter of the scope and of the indwelling time of the nephrostomy after the procedure. For both PCNL and RIRS we considered the impact of the use of a suction system for the irrigating fluid and the use of different methods of antibiotic prophylaxis. Unfortunately, it was not possible to evaluate other characteristics of the interventions - such as prolonged operating time (> 1 hour), type and rate of irrigation, use of sheath and pre-operative stenting (for RIRS) - due to the lack of information within the reports of the studies included in the analysis. The comparison of standard PCNL with miniaturized PCNL including mini-PCNL, ultramini-PCNL, and micro-PCNL showed no significant difference in the odds for infectious complications despite a higher potential intra-renal pressure with the latter two. The benefits of reduced trauma due to the smaller diameter of the scope could be counteracted by lesser control of intrarenal pressure associated with miniaturized proceArchivio Italiano di Urologia e Andrologia 2022; 94, 1

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dures. In fact, a review on the evidence related to intrarenal pressures generated during percutaneous procedures found that standard PCNL is associated with the lowest pressure values. On the contrary, pressure values during mini-PCNL can be decreased by using the vacuum-cleaner effect, but pressure might still be uncontrolled during micro- and ultra-mini PCNL procedures (66). We also found that avoidance of nephrostomy drainage in the postoperative period is not associated with an increased risk of infection after a standard procedure. The use of suction systems through the access sheath seems to reduce the risk of infection, since in addition to the improved clearance of fragments after lithotripsy, it allows the intrarenal pressures to be controlled and kept in the lower range. Antibiotic prophylaxis to prevent the onset of infectious complications after endourological stone treatments is widely used although only limited evidence from RCTs was retrieved (67). Extension of oral antibiotic administration after intravenous perioperative prophylaxis, or administration of a course of antibiotic treatment in the days prior to surgery, does not seem to reduce the risk of infection in patients with low risk of infectious complications, (i.e., patients with negative preoperative urine culture and absence of hydronephrosis and urinary catheters). However, in a study that considered patients with moderate/high risk of infectious complications, administration of a 10-day course of oral nitrofurantoin before the procedure in addition to intraoperative prophylaxis was shown to reduce the risk of infectious complications after PCNL. EAU guidelines (63) state that there is no "clear-cut evidence” for prevention of infection following ureterorenoscopy and percutaneous stone removal, although a matched case control study demonstrated the efficacy of antibiotic prophylaxis to reduce infectious complications after PCNL in patients with negative baseline culture (68). Another study showed that a single dose administration was found sufficient to prevent post-ureteroscopic infections (69). In conclusion, infectious complications after endourological treatment of kidney stones appear to depend (i) on the characteristics of the stone, on the patients’ urinary tract, and on the patients’ comorbidities. The choice of a specific procedure for kidney stone treatment does not appear to be decisive for the onset of infectious complications, although the prevention of high intrarenal pressures during the procedure appears to be crucial in defining the risk of infectious complications. High intrarenal pressure depends on the modality of irrigation and on the use of the ureteral sheaths and suction systems to facilitate the outflow of urine. Antibiotic prophylaxis should be tailored to the characteristics of the stone and of the urinary tract, the history of the patient (comorbidities, previous UTI episodes) and the course of the procedure (operative time, method and volume of irrigation). In high-risk cases, prudence is recommended, avoiding prolonged operating times, and administering antibiotic treatment before the procedure in adjunct to perioperative prophylaxis.

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69. Chew BH, Flannigan R, Kurtz M, et al. A single dose of intraoperative antibiotics is sufficient to prevent urinary tract infection during ureteroscopy. J Endourol. 2016; 30:63-8.

53. Chew BH, Miller NL, Abbott JE, et al. A randomized controlled trial of preoperative prophylactic antibiotics prior to percutaneous nephrolithotomy in a low infectious risk population: a report from the EDGE consortium. J Urol. 2018; 200:801-808. 54. Dogan HS, Sahin A, Cetinkaya Y, et al. Antibiotic prophylaxis in percutaneous nephrolithotomy: prospective study in 81 patients. J Endourol. 2002; 16:649-653. 55. Mariappan P, Smith G, Moussa SA, Tolley DA. One week of ciprofloxacin before percutaneous nephrolithotomy significantly reduces upper tract infection and urosepsis: a prospective controlled study. BJU Int. 2006; 98:1075-9. 56. Tuzel E, Aktepe OC, Akdogan B. Prospective comparative study of two protocols of antibiotic prophylaxis in percutaneous nephrolithotomy. J Endourol. 2013; 27:172-6. 57. Song F, Liu C, Zhang J, et al. Antibacterial effect of Fosfomycin tromethamine on the bacteria inside urinary infection stones. Int Urol Nephrol. 2020; 52:645-654. 58. Seyrek M, Binbay M, Yuruk E, et al. Perioperative prophylaxis for percutaneous nephrolithotomy: randomized study concerning the drug and dosage. J Endourol. 2012; 26:1431-6. 59. Taken K., Asik A., Eryilmaz R., et al. Comparison of ceftriaxone and cefazolin sodium antibiotic prophylaxis in terms of SIRS/urosepsis rates in patients undergoing percutaneous nephrolithotomy. J Urol Surg. 2019; 6:111-117. 60. Demirtas A, Yildirim YE, Sofikerim M, et al. Comparison of infection and urosepsis rates of ciprofloxacin and ceftriaxone prophylaxis before percutaneous nephrolithotomy: a prospective and randomised study. Scientific World Journal. 2012; 2012:916381. 61. Fourcade RO. Antibiotic prophylaxis with cefotaxime in endoscopic extraction of upper urinary tract stones: a randomized study. The Cefotaxime Cooperative Group. J Antimicrob Chemother. 1990; 26(suppl A):77-83. 62. Zhao Z, Fan J, Sun H, et al. Recommended antibiotic prophylaxis regimen in retrograde intrarenal surgery: evidence from a randomised controlled trial. BJU Int. 2019; 124:496-503. 63. Türk C, Neisius A, Petrík A, et al. EAU Guidelines on Urolithiasis. Retrieved from: https://uroweb.org/guideline/urolithiasis/ Accessed on 30th December 2021. 64. Zheng C, Xiong B, Wang H, et al. Retrograde intrarenal surgery versus percutaneous nephrolithotomy for treatment of renal stones >2 cm: a meta-analysis. Urol Int. 2014; 93:417-24. 65. Chen Y, Wen Y, Yu Q, et al. Percutaneous nephrolithotomy versus flexible ureteroscopic lithotripsy in the treatment of upper urinary tract stones: a meta-analysis comparing clinical efficacy and safety. BMC Urol. 2020; 20:109.

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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 Nazim Gherabi ngherabi@gmail.com Faculty of Medicine Algiers 1, Algiers, Algeria Derek Hennessey derek.hennessey@gmail.com Department of Urology, Mercy University Hospital, Cork, Ireland Panagiotis Mourmouris thodoros13@yahoo.com 2nd Department of Urology, National and Kapodistrian University of Athens, Sismanoglio Hospital, Athens, Greece Adama Ouattara adamsouat1@hotmail.com Division of Urology, Souro Sanou University Teaching Hospital, BoboDioulasso, Burkina Faso 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 josephphilipraj@gmail.com Department of Urology, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth, Puducherry, India Alberto Trinchieri (Corresponding Author) alberto.trinchieri@gmail.com Urology School, University of Milan, Milan, Italy Noor Buchholz noor.buchholz@gmail.com Scientific Office, U-merge Ltd., Athens, Greece

DOI: 10.4081/aiua.2022.1.107

REVIEW

Perspectives on the urological care in Parkinson’s disease patients Mohamad Moussa 1, Mohamed Abou Chakra 2, Athanasios G. Papatsoris 3, Athanasios Dellis 4, Baraa Dabboucy 5, Michael Peyromaure 6, Nicolas Barry Delongchamps 6, Hugo Bailly 6, Igor Duquesne 6 1 Urology

Department, Zahraa Hospital, University Medical Center, Beirut, Lebanon; of Urology, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon; 3 2nd Department of Urology, School of Medicine, Sismanoglio Hospital, National and Kapodistrian University of Athens, Athens, Greece. 4 Department of Urology/General Surgery, Areteion Hospital, Athens, Greece; 5 Department of Neurosurgery, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon; 6 Department of Urology, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris Descartes University, Paris, France. 2 Department

Summary

Parkinson's disease (PD) is recognized as the most common neurodegenerative disorder after Alzheimer's disease. Lower urinary tract symptoms are common in patients with PD, either storage symptoms (overactive bladder symptoms or OAB) or voiding symptoms. The most important diagnostic clues for urinary disturbances are provided by the patient's medical history. Urodynamic evaluation allows the determination of the underlying bladder disorder and may help in the treatment selection. Pharmacologic interventions especially anticholinergic medications are the first-line option for treating OAB in patients with PD. However, it is important to balance the therapeutic benefits of these drugs with their potential adverse effects. Intra-detrusor Botulinum toxin injections, electrical stimulation were also used to treat OAB in those patients with variable efficacy. Mirabegron is a β3-agonist that can also be used for OAB with superior tolerability to anticholinergics. Desmopressin is effective for the management of nocturnal polyuria which has been reported to be common in PD. Deep brain stimulation (DBS) surgery is effective in improving urinary functions in PD patients. Sexual dysfunction is also common in PD. Phosphodiesterase type 5 inhibitors are first-line therapies for PD-associated erectile dysfunction (ED). Treatment with apomorphine sublingually is another therapeutic option for PD patients with ED. Pathologic hypersexuality has occasionally been reported in patients with PD, linked to dopaminergic agonists. The first step of treatment of hypersexuality consists of reducing the dose of dopaminergic medication. This review summarizes the epidemiology, pathogenesis, risk factors, genetic, clinical manifestations, diagnostic test, and management of PD. Lastly, the urologic outcomes and therapies are reviewed.

KEY WORDS: Parkinson’s disease; Lower urinary tract dysfunction; Neurogenic bladder, Urology. Submitted 4 December 2021; Accepted 6 January 2022

INTRODUCTION

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. In Europe, the prevalence and incidence rates for PD are estimated at approximately 108257/100 000 and 11-19/100 000 per year, respectively (1). Although the cause of PD is unknown, the pathologic

manifestation involves the loss or dysfunction of dopaminergic neurons in the substantia nigra pars compacta (2). The neuropathologic hallmark of PD is the presence of Lewy bodies composed mostly of alpha-synuclein and ubiquitin. It is believed that the occurrence of PD is due to a combination of genetic and environmental factors (3). The cardinal motor symptoms of PD are tremor, rigidity, bradykinesia/akinesia, and postural instability, but the clinical picture includes other motor and non-motor symptoms (4). A variety of non-motor symptoms are common in PD. They include disturbed autonomic function with orthostatic hypotension, constipation and urinary disturbances, a variety of sleep disorders and a spectrum of neuropsychiatric symptoms (5). Diagnosis of PD is based on history and examination. History can include prodromal features (rapid eye movement, sleep behavior disorder, hyposmia, constipation), characteristic movement difficulty (tremor, stiffness, slowness), and psychological or cognitive problems (cognitive decline, depression, anxiety). Examination typically demonstrates bradykinesia with tremor, rigidity, or both. Dopamine transporter single-photon emission computed tomography can improve the accuracy of diagnosis when the presence of parkinsonism is uncertain (6). Misdiagnoses between Parkinson’s tremor and essential tremor are relatively common. Electrophysiological and functional imaging examinations can be useful in the distinction of the two, but both approaches suffer from some limitations (7). PD interferes with various aspects of quality of life, particularly those related to physical and social functioning (8). The primary goal in the management of PD is to treat the symptomatic motor and nonmotor features of the disorder. Effective management should include a combination of nonpharmacological and pharmacological strategies to maximize clinical outcomes (9). Oral levodopa, the initial gold-standard therapy for PD, is still the most effective and widely used therapeutic option (10). In advanced PD, therapeutic interventions include device-aided therapies such as continuous subcutaneous apomorphine infusion, levodopa-carbidopa intestinal gel infusion, and deep brain stimulation (11). Supportive non-pharmaco-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 1

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logical therapies are used in early and advanced PD patients. It should include physical rehabilitation, psychological support, occupational therapy, speech, language, and swallowing therapy, and nutrition (12). Bladder dysfunctions are quite common in PD. They may occur at any stage of the illness and get worse with advancing and aggravating disease. The most prominent dysfunction is the so-called overactive bladder (OAB). The main clinical problem of PD patients consists in reduced inhibition with consequentially resulting overactivity of the detrusor muscle, meaning the urge to urinate in the absence of adequate bladder filling (13). The most common storage symptoms of patients with PD are nocturia, followed by frequency and urinary incontinence. Some patients presented functional obstructive symptoms. The most frequent obstructive symptom was incomplete emptying of the bladder (14). Obstructive symptoms may be secondary to anticholinergics, obstructive uropathy, or point to the presence of multiple system atrophy (MSA). Dysfunction of the striated urethral sphincter and pelvic musculature can be seen in variable numbers in PD (15). Antimuscarinic medications are the first-line treatment for OAB symptoms. Antimuscarininc drugs may exacerbate PD-related constipation and xerostomia, and caution is advised when using these medications in individuals where cognitive impairment is suspected. Desmopressin is effective for the management of nocturnal polyuria which has been reported to be common in PD. Intra-detrusor injections of botulinum toxin are effective therapy for detrusor overactivity, however, are associated with the risk of urinary retention (16). Subthalamic deep brain stimulation (DBS) has a significant and urodynamically recordable effect leading to a normalization of pathologically increased bladder sensibility (17). Percutaneous tibial nerve stimulation (PTNS) improves the urinary symptoms and urodynamic parameters in patients with PD (18). Sexual dysfunction (SD) in PD, which has been suggested as a result of central and autonomic dysfunction compounded by defective motor skills, reduced self-esteem, and comorbid psychiatric states like anxiety and depression (19). The prevalence of SD is reported high in male patients (65%), but much lower in female patients (36%). There are different types of SD: erectile dysfunction (ED) and loss of ejaculation control in male patients, and much lower self-esteem in female patients (20). Optimal dopaminergic treatment should facilitate sexual encounters of the couple. Appropriate counseling diminishes some of the problems (reluctance to engage in sex, problems with ejaculation, lubrication, and urinary incontinence). Treatment of ED with sildenafil and apomorphine is evidence-based (21). We performed a narrative review to briefly discuss the epidemiology, pathogenesis, risk factors, genetic contribution, clinical course, diagnosis, and treatment of PD. The urologist had an important role in the management of urologic manifestations of patients with PD. We reviewed the current literature regarding the urological outcomes and management of patients with PD.

MATERIALS

AND METHODS

We searched electronic databases including PubMed, the Scopus database for published studies that analyzed the

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role of the following Medical Subject Headings terms: ‘Parkinson’s disease’ (AND) ‘Management’ (AND) ‘Diagnosis’ (AND) ‘epidemiology’ (AND) ‘genetic contribution’ (AND) ‘risk factor’ (OR) ‘Parkinson’s disease’ (AND) ‘urologic dysfunction’ (AND) ‘Management’ (OR) ‘Parkinson’s disease’ (AND) ‘Erectile dysfunction’ (AND) ‘Management’. This was done to ensure the comprehensive inclusion of articles related to neurogenic bladder in PD patients. The initial search resulted in 350 articles. After review, we initially excluded papers that were not relevant (72). At the completion of the review, articles were selected based on their clinical relevance related to the aim. When all duplicates are thrown out, a total of 90 papers were used to extract necessary information.

OVERVIEW

Epidemiology of PD PD affects 1-2 per 1000 of the population at any time. PD prevalence is increasing with age, it affects 1% of the population above 60 years (22). The median age of onset is 60 years; the mean duration of the disease from diagnosis to death is 15 years. Male sex is recognized as a prominent risk factor in developing PD. Both incidence and prevalence of PD are 1.5 to 2.0 times higher in men than in women. Age at onset is 2.1 years later in women (53.4 years) than in men (51.3 years) (23). The overall prevalence of PD appears to be lower in Eastern studies compared to Western ones. In a metaanalysis of 39 European studies until 2004, the authors reported a prevalence rate of 108-257/100,000 when considering only high-quality studies that utilized a standard diagnostic criterion (24). Pathogenesis of PD The main pathological features of PD are the loss of dopaminergic neurons with subsequent depigmentation of the substantia nigra pars compacta and the presence of Lewy bodies (25). Lesions initially occur in the dorsal motor nucleus of the glossopharyngeal and vagal nerves and anterior olfactory nucleus. Thereafter, less vulnerable nuclear grays and cortical areas gradually become affected (26). The spinal cord lesions may contribute to clinical symptoms (pain, constipation, poor balance, lower urinary tract complaints, and sexual dysfunction) that occur during the premotor and motor phases of sporadic PD (27). PD does not fulfill key criteria to be diagnosed as prionopathy. Nonetheless, abnormal forms of a-synuclein seem to propagate in the brain of PD patients. The finding of Lewy bodies and a-synuclein deposits in nigral fetal neurons transplanted over a decade earlier into the striatum could support the existence of a prionlike pathogen as the cause of PD (28). Risk factors of PD Significant predictors of PD emerged (in order of strength): pesticide use, family history of neurologic disease, and history of depression. The predicted probability of PD was 92.3% (odds ratio = 12.0) with all three predictors positive (29). Other potential risk factors include

Urological care in Parkinson’s disease patients

Table 1. Motor and non-motor symptoms of Parkinson’s disease. Motor symptoms • Tremor • Rigidity • Bradykinesia, akinesia • Loss of balance • Speech and facial expression difficulties • Gait disturbance • Impaired handwriting and grip force

Non motor symptomse • Neuropsychiatric problems: cognitive impairment, depression, anhedonia, apathy, anxiety, panic attacks, delirium, hallucinations, illusions • Sleep problems • Oily skin, dandruff • Sensory impairment • Urinary disturbances: Urgency, frequency, urge incontinence, nocturia, sexual dysfunction • Gastrointestinal disturbances: Drooling, dyspepsia, constipation, abdominal pain, fecal incontinence • Blood pressure variations with orthostatic hypotension and tachycardia • Fatigue

environmental toxins, drugs, brain microtrauma, focal cerebrovascular damage, and genomic defects (30). There is an association between anemia experienced early in life and the later development of PD (31). Exposure to toxins in the environment has been linked to PD-associated neurodegeneration particularly heavy metals, pesticides, and illicit drugs (32). Some infectious diseases such as mumps, scarlet fever, influenza, whooping cough, and herpes simplex infections may play a role in the development of PD (33). Genetic contribution to PD A-synuclein (SNCA) was the first PD gene identified in a large Italian-American family (the Contursi kindred) with autosomal dominant inheritance (34). A total of 18 PD loci have been nominated through linkage analysis (PARK1-15) or genome wide association studies (PARK16-18). Mutations within the genes at 6 of these loci (SNCA, LRRK2, PRKN, DJ1, PINK1, and ATP13A2) have conclusively been demonstrated to cause familial parkinsonism. In addition, common polymorphisms within 2 of these same genes (SNCA and LRRK2) and variation in 2 other genes not assigned to a PARK locus (MAPT and GBA) are now well-validated risk factors for PD (35). Clinical Features of PD PD comprises a range of motor and non-motor features (Table 1). The presence of bradykinesia, rest tremor, rigidity, and loss of postural reflexes are the most commonly identified motor symptoms of PD, although other clinical features can also be identified during disease progressions, such as bulbar dysfunction, neuro-ophthalmological abnormalities, and respiratory disturbances (36). Most non-motor symptoms are not fully levodopa-responsive and are suggested to manifest extra-nigral pathology. These symptoms include autonomic, sleep, sensory, and neuropsychiatric symptoms (37). Diagnosis of PD The Movement Disorder Society (MDS) clinical diagnostic criteria for PD mentioned that the first essential criterion is parkinsonism, which is defined as bradykinesia, in combination with at least 1 of rest tremor or rigidity. Once parkinsonism has been diagnosed, the diagnosis of clinically established PD requires absence of absolute exclusion criteria, at least two supportive criteria, and no red flags (38). Those criteria and red flags are summarized in Table 2.

Early falls, poor response to levodopa, symmetry of motor manifestations, lack of tremor, and early autonomic dysfunction are probably useful in distinguishing other parkinsonian syndromes from PD. The levodopa or apomorphine challenge and olfactory testing are probably useful in distinguishing PD from other parkinsonian syndromes (39). Structural MRI is useful to differentiate PD from secondary and atypical forms of parkinsonism. 123I-ioflupane single-photon emission computed tomography (SPECT) is a valid tool in the differential diagnosis between PD and non-degenerative tremors. Cardiac 123I-metaiodobenzylguanindine SPECT and 18F-FDG positron emission tomography (PET) have the potential to differentiate PD from atypical parkinsonism (40). Differential diagnosis Although the most common cause of parkinsonism is PD, the differential diagnosis includes many other causes of parkinsonism. Aside from drug-induced parkinsonism, related to drug-induced changes in the basal ganglia motor circuit secondary to dopaminergic receptor blockade, the most common mimickers of PD are parkinsonian syndromes, such as MSA and progressive supranuclear palsy, dementia with Lewy bodies (DLB), vascular parkinsonism (VP), a parkinsonian syndrome that is associated with cerebrovascular disease (41). Management of PD There are several drugs available to treat motor impairments in PD. First, drugs that increase brain levels of dopamine such as Levodopa are used. In addition, drugs that mimic dopamine were used such as dopamine agonists. Lastly, drugs that inhibit dopamine breakdown has been used. MAO-B inhibitors can inhibit the activity of monoamine oxidase B. Usually, MOA-B inhibitors reduce the symptoms of PD. Selegiline or deprenyl is one of the inhibitors of MOA-B that is very active against PD along with levodopa. Tolcapone also reduces the requirement of levodopa to patients but it can induce severe hepatotoxicity. There are two types of catechol-O-methyl transferase (COMT) inhibitors being entacapone and tolcapone. COMT inhibitors are used to reduce the dose of levodopa (42). In most patients with PD, motor fluctuations and dyskinesias are relatively mild and can be adequately managed by adjustment of the oral medication. However, for patients experiencing disabling motor fluctuations and dyskinesias despite optimized medical therapy, device-assisted therapies should be considered (43). Archivio Italiano di Urologia e Andrologia 2022; 94, 1

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Table 2. Parkinson's disease diagnostic criteria of the movement disorder society. Movement disorder society criteria (53) Supportive criteria • Clear and dramatic beneficial response to dopaminergic therapy. • Presence of levodopa-induced dyskinesia • Rest tremor of a limb, documented on clinical examination (in past, or on current examination) • The presence of either olfactory loss or cardiac sympathetic denervation on MIBG scintigraphy Absolute exclusion criteria • Unequivocal cerebellar abnormalities, such as cerebellar gait, limb ataxia, or cerebellar oculomotor abnormalities • Downward vertical supranuclear gaze palsy, or selective slowing of downward vertical saccades • Diagnosis of probable behavioral variant frontotemporal dementia or primary progressive aphasia, defined according to consensus criteria within the first 5 y of disease • Parkinsonian features restricted to the lower limbs for more than 3 y • Treatment with a dopamine receptor blocker or a dopamine-depleting agent in a dose and time-course consistent with drug-induced parkinsonism • Absence of observable response to high-dose levodopa despite at least moderate severity of disease • Unequivocal cortical sensory loss, clear limb ideomotor apraxia, or progressive aphasia • Normal functional neuroimaging of the presynaptic dopaminergic system • Documentation of an alternative condition known to produce parkinsonism and plausibly connected to the patient’s symptoms, or, the expert evaluating physician, based on the full diagnostic assessment feels that an alternative syndrome is more likely than Parkinson's disease Red flags • Rapid progression of gait impairment requiring regular use of wheelchair within 5 y of onset • A complete absence of progression of motor symptoms or signs over 5 or more y unless stability is related to treatment • Early bulbar dysfunction: severe dysphonia or dysarthria or severe dysphagia (requiring soft food, nasogastric tube, or gastrostomy feeding) within first 5 y • Inspiratory respiratory dysfunction: either diurnal or nocturnal inspiratory stridor or frequent inspiratory sighs • Severe autonomic failure in the first 5 y of disease. • Recurrent (> 1/y) falls because of impaired balance within 3 y of onset • Disproportionate anterocollis (dystonic) or contractures of hand or feet within the first 10 y • Absence of any of the common non-motor features of disease despite 5 y disease duration. These include sleep dysfunction (sleep-maintenance insomnia, excessive daytime somnolence, symptoms of REM sleep behavior disorder), autonomic dysfunction (constipation, daytime urinary urgency, symptomatic orthostasis), hyposmia, or psychiatric dysfunction (depression, anxiety, or hallucinations) • Otherwise-unexplained pyramidal tract signs, defined as pyramidal weakness or clear pathologic hyperreflexia (excluding mild reflex asymmetry and isolated extensor plantar response) • Bilateral symmetric parkinsonism.

Many experimental studies are going to test the applications of antibodies to target and degrade extracellular asynuclein molecules. Passive and active immunization techniques against a-synuclein have been shown to convey neuroprotective effects in animal models (44).

UROLOGIC

OUTCOMES OF

Prevalence of urologic symptoms among the PD population Seventy-four percent of patients with early-to-moderate disease report more than one bladder disturbance symptom. Severe bladder symptoms are reported in 27-39% of PD patients. Both storage and voiding symptoms are highly prevalent in patients with PD. More than 50% of patients have OAB symptoms (45). The severity of the neurological disease is correlated with the occurrence of voiding dysfunction, these findings corroborate the results of other studies which showed that lower urinary tract symptoms (LUTS) increase accordingly with PD progression (46). Urologic clinical symptoms The pattern and mechanism of storage symptoms have been partly clarified as the hypothesis most widely proposed is that the basal ganglia output has an overall inhibitory effect on the micturition reflex in healthy individuals, and with cell loss in the substantia nigra, detrusor overactivity develops through an inability to activate the dopamine D1 receptor-mediated tonic inhibition.

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A parallel mechanism may be that in PD, the inhibitory dopaminergic neurons originating in the substantia nigra may be more damaged than the stimulatory dopaminergic neurons originating in the ventral tegmental area, thereby inducing urgency and frequency. Impaired sensory information from periaqueductal gray could also contribute to storage symptoms (47). However, those of voiding disorders have yet to be elucidated, and there have been only a few reports that dopa-responsive detrusor under-activity or impaired urethral relaxations exist, and post-void residual urine (PVR) does not occur frequently. These findings suggest that early and untreated PD patients also have not only storage disorders but also mainly subclinical voiding disorders (48). Detrusor underactivity or bladder outlet obstruction (BOO) underlie the mechanism of voiding symptoms in patients with PD. PD patients mostly maintain an acceptable voiding efficiency and low PVR volume. In the meantime, PD mostly affects the elderly, overlapping the age group with high morbidity of benign prostatic hyperplasia (BPH). Neurogenic BOO in PD patients still draws less attention (49). Detrusor sphincter dyssynergia (DSD) is a rare cause of voiding dysfunction in PD. DSD was observed on voiding at a rate of 0-3% (50). Underactive bladder in up to 50 % of patients with PD. The mechanism of detrusor weakness in PD remains unclear and warrants further exploration (51). A study suggested that a weak detrusor in PD might have a central origin. It is necessary to follow PVR carefully in PD patients with advanced gait disorder because PVR might

Urological care in Parkinson’s disease patients

Figure 1. Suggested mechanisms responsible for urinary symptoms in patients with PD.

PD = Parkinson’s disease; SN = Substantia nigra; VTA = Ventral tegmental area; PAG = Periaqueductal gray.

increase in such patients (52). Obstructive symptoms might possibly result from treatment with particular antiparkinsonian drugs. Also, it should be noted that Lewy bodies can be seen in several types of neurons, including central and peripheral components of the autonomic nervous system, in advanced PD. Thus, obstructive symptoms in patients with PD might result from micturition hyporeflexia due to impairment in the autonomic nervous system (53). The mechanisms responsible for urinary symptoms in PD patients are summarized in Figure 1. Neurogenic lower urinary dysfunction (NLUD) can induce anxiety and depression in patients. A study was implemented by Benli et al. to investigate whether NLUD, which is frequently seen in PD, has an effect on the development of anxiety and depression in these patients. The study included 32 males (66.6%) and 16 females (33.3%); in total 48 subjects were registered. It was concluded that the incidence of NLUD, anxiety and, depression was increased in PD. In addition, NLUD was found to be a risk factor for the development of anxiety and depression (54). Clinical scales The scale for outcomes in PD for autonomic symptoms (SCOPA-AUT) is a specific scale to assess autonomic dysfunction in PD patients. It includes six urinary items that assess both storage and voiding phases. SCOPA-AUT is an acceptable, consistent, reliable, and valid scale (55). The International Prostate Symptom Score (IPSS) has been used both in men and women for patients with neurological diseases; several teams used it in PD patients, including in advanced stage, and after DBS. Overactive Bladder Symptom Score (OABSS) has been used to evaluate urinary symptoms in PD patients but it needs further validation (56).

Findings on urodynamic studies The urodynamic examination is recommended for male PD patients with voiding dysfunction. It can show detrusor hyperreflexia associated with BOO or detrusor dysfunction with BOO (57). Urodynamic findings could differentiate patients with MSA from those with PD. Patients with MSA showed lower maximal flow rate, larger PVR with decreased compliance, and impaired contractility, whereas patients with PD had a higher incidence of detrusor overactivity and associated leakage (58). A study conducted by Vurture et al. strongly suggests that a vast majority of OAB symptoms in patients with PD can be attributed to DO on urodynamics (97.1%). However, the high rates of other abnormalities such as BOO (36.8%), detrusor underactivity (47%), and increased PVR (16.7%) suggest that neurogenic DO is not the only contributor of OAB symptoms in patients with PD (59). Special focus on nocturia in PD Nocturia is a common non-motor symptom in PD but has been poorly studied. Nocturia may manifest as a result of reduced functional bladder capacity or nocturnal polyuria; however, most often the cause is multifactorial. Disorders of circadian rhythm regulation are known to occur with sleep disturbances in PD that may also contribute to nocturia (60). The bladder diary provides a prospective real-time assessment of bladder symptoms, which is cost-effective and relatively straightforward for patients to complete. It provides a more accurate assessment of night-time frequency and voided nocturnal urine volumes. A bladder diary is an essential tool in the assessment of nocturia in patients with PD (61). Archivio Italiano di Urologia e Andrologia 2022; 94, 1

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Figure 2. Algorithm for the management of storage symptoms in PD patients.

PD = Parkinson’s disease; DO = Detrusor overactivity; DU = Detrusor underactivity; BOO = Bladder outlet obstruction; UUI = Urge urinary incontinence; SIC = Self-intermittent catheterization; PVR = Post void residual volume; BTX-A = Botulinum toxin A; TURP = Transurethral resection of the prostate; DBS = Deep brain stimulation.

UROLOGIC MANAGEMENT

Management of the storage symptoms (OAB symptoms) in PD patients A detailed algorithm for the management of the storage symptoms in PD patients is summarized in Figure 2. General measures and physical treatment Behavioral therapy included pelvic floor muscle exercises, bladder training, fluid and constipation management. Providers should consider behavioral therapy as an initial treatment for urinary symptoms in PD. It was demonstrated in a small study conducted by Vaughan et al. (62). A study was implemented by McDonald et al. to assess the feasibility and efficacy of bladder training (BT) for troublesome LUTS in PD. Thirty-eight participants were randomized (18 to conservative advice (CA), 20 to BT groups). Both CA and BT were associated with significant improvements in volume voided, number of micturitions, symptom severity scores, and measures of quality of life (all p < 0.05). At 12 weeks, compared to CA, BT was asso-

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ciated with significant superiority on patient perception of improvement (p = 0.001). At 20 weeks, BT remained associated with greater improvement in interference in daily life (63). Dopaminergic therapy It is uncertain whether L-dopa medication can improve micturition disorders. Some have reported that L-dopa improves micturition symptoms, but others have reported conflicting results. In addition, the effects of L-dopa on bladder function are unknown (64). The acute mixed stimulation of D1 and D2 receptors by apomorphine has been reported to reduce bladder outflow resistance. In contrast, acute dopaminergic stimulation by L-dopa challenge has been reported to worsen detrusor overactivity and to reduce bladder capacity in patients with PD. However, the worsening effect of acute L-dopa administration conflicts with the clinical experience of bladder function improvement reported by PD during L-dopa therapy (65). These findings suggest that the effects of dopaminergic treatment on bladder control are very different, according to their

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receptorial activity, producing a cumulative effect of a multidrug daily treatment difficult to predict. Combined, balanced activation of D1/D2 receptors could be beneficial for treating urinary symptoms caused by detrusor hyperreflexia in PD as demonstrated Brusa et al. They conducted an open-label study where extended-release levodopa at bedtime showed significant improvement of OAB symptoms, specifically nocturia (66). Winge et al. concluded in their trial that dopaminergic therapy relieves cognitive executive dysfunction, as it seems to improve functional bladder control in those of their patients, who benefit from medication during their storage phase (67). Antimuscarinic drugs Antimuscarinic agents are the first-line treatment for OAB symptoms. These include oxybutynin, tolterodine, solifenacin, darifenacin, fesoterodine, and trospium chloride. Only Solifenacin had a class of evidence (level 1a) for urinary dysfunction in PD (16). The central effects of these medications may result in alterations in cognition and consciousness in susceptible individuals. caution needs to be used in elderly patients with preexisting dementia (68). A randomized-controlled trial (RCT) that assesses the use of solifenacin succinate for OAB in PD was done by Zesiewicz et al. Patients were randomized to receive solifenacin succinate 5-10 mg daily or placebo for 12 weeks followed by an 8-week open-label extension. Twentythree patients were randomized in the study. There was no significant improvement in the primary outcome measure in the double-blind phase, but there was an improvement in the number of micturitions per 24 h period in the solifenacin succinate group compared to placebo at a mean dose of 6 mg/day (p = 0.01). In the open-label phase, the mean number of urinary incontinence episodes per 24 h period decreased (p = 0.03), as did the number of nocturia episodes per 24 h period (p = 0.01) (69). Yonguc et al. conducted an RCT to test the use of fesoterodine fumarate for OAB in PD. From May 2016 to May 2018, 63 patients were randomized to receive fesoterodine 4 mg or placebo for 4 weeks. At the end of 4 weeks of the randomization phase, patients have received fesoterodine fumarate 4 mg daily for another 4 weeks at the open-label extension phase. OAB symptoms were significantly improved in older adults with PD under fesoterodine fumarate treatment, and this advantage continued in the open-label portion in the short term (70). Mirabegron Mirabegron is an orally active, 3-adrenoceptor agonist approved for the treatment of OAB. The main theoretical advantage of 3-adrenoceptor agonists for the treatment of OAB is that they lack the typical side effects of antimuscarinics. There are only a few trials that test the efficacy of mirabegron in PD patients. Peyronnet et al. conducted a study that aimed to assess the outcomes of mirabegron for the treatment of OAB symptoms in patients with PD. Fifty patients (mean 74 years old) were included. Before being treated with mirabegron, 56% had failed prior anticholinergic therapy. After 6 weeks of mirabegron 50 mg, five patients (11.4%) had a complete resolution of their OAB symptoms; 25 patients (50%) reported improvement, 23 (46%) reported no change, and 2 (4%) reported worsening

of their OAB symptoms. The number of pads per day decreased from 1.5 to 0.9 (p = 0.01) and so did the number of nocturia episodes (from 3 to 2.6/night; p = 0.02). Mirabegron has an excellent safety profile in their trial (71). Gubbiotti et al. concluded in their pilot study that mirabegron is a safe and effective treatment in patients with PD and OAB refractory to anticholinergics in the shortterm follow-up (72). In another RCT conducted by Cho et al., it was concluded that mirabegron was effective in treating OAB symptoms in patients with parkinsonism with acceptable adverse events (73). Botulinum toxin therapy There are limited data on the efficacy of intravesical botulinum toxin (BT) injection in PD patients. Kulaksizoglu et al. implemented a trial to evaluate the efficacy of intravesical BT injection for OAB symptoms in patients with PD. Sixteen patients were followed for 12 months. Intradetrusor injection technique with 30-point template was employed. All patients received 500 international units of botulinum toxin-A. The follow-up was at week one and every 12 weeks thereafter for 12 months. The initial mean functional bladder capacity was 198.6 +/- 33.7 mL. At 3-month follow-up the mean bladder capacity increased to 319 +/- 41.1 mL. The quality of life assessment of the primary caregiver as well as the patients also statistically improved after the injections. No central nervous system side effects were noted (74). Vurture et al. conducted a study to test the outcomes of intradetrusor onabotulinum toxin A (BoNT-A) injection in patients with PD. All PD patients who underwent intradetrusor injections of BoNT-A for storage symptoms between 2010 and 2017 were included in their retrospective study. A 100 U dose of BoNT-A was used for the first injection in all patients. Out of 24 patients analyzed, 19 reported improvements of their OAB symptoms 4 weeks after the first injection (79.2%) with complete resolution of urgency urinary incontinence in seven patients (29.1%; p < 0.001). Three of the patients had to start clean intermittent catheterization (CIC) after the first injection (12.5%) (75). Some authors hypothesize that BoNTA might be better tailored to “OAB wet”/motor urgency (59). Intravesical BoNT-A might not be a good indication in patients with detrusor hyperactivity and impaired contractility (DHIC) and high PVR (76). It was mentioned in the International Continence Society (ICS) guidelines that intravesical BT injection is a promising method to treat intractable detrusor overactivity in PD. Also, guidelines state that it is important to differentiate MSA from PD before completing botulinum injections. But there was no recommendation for dosages, risk factors for retention or difficulty voiding or long-term effectiveness are available (77). Sacral neuromodulation Sacral neuromodulation (SNM) is an effective therapy that should be considered among the treatment options for PD patients with OAB symptoms. Urodynamic parameters associated with obstruction may be predictive of SNM failure in PD patients and may help guide patient selection (78). Few studies have been performed to determine the effects of percutaneous posterior tibial nerve stimulation (PTNS) on neurogenic DO in patients, especially, with PD. Archivio Italiano di Urologia e Andrologia 2022; 94, 1

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Kabay et al. conducted a trial to investigate the effect of PTNS treatment after 12 weeks on urodynamic and clinical findings in patients with PD with neurogenic DO. A total of 47 patients with PD with neurogenic DO were enrolled in the study. Their results have demonstrated that PTNS improves the lower urinary tract symptoms and urodynamic parameters in patients with PD (79). Transcutaneous tibial nerve home stimulation can be used in clinical practice as an effective nonpharmacological resource for the reduction of OAB symptoms in women with PD (80). Deep brain stimulation Deep brain stimulation (DBS) has been used as a surgical treatment for motor symptoms in advanced PD. An exploratory post hoc analysis was performed of specific LUTS items of questionnaires used in an RCT with 128 patients (NSTAPS study). Urinary incontinence and frequency improved after both globus pallidus pars interna (GPi) DBS and the subthalamic nucleus (STN) DBS at 12 months postoperatively, but this was only statistically significant for the STN DBS group (P = 0.004). The improvements after DBS were present in both men (p = 0.01) and women (p = 0.05). Nocturia and urinary incontinence did not improve significantly after any type of DBS, irrespective of sex (81). DBS is associated with increased bladder capacity and volume triggering bladder contraction, increased time to first desire to void. While DBS appears to be a promising therapy for modulating LUTS in PD patients, the current research is mostly limited to small cohorts. Larger clinical trials are needed to truly delineate how DBS affects urinary disturbances (82). Management of the voiding symptoms in PD patients Concern has existed about the risks of incontinence with transurethral resection of the prostate (TURP) in PD patients with BOO. Roth et al. investigated the outcome of TURP in patients with a secure neurological diagnosis of PD. A total of 23 patients with PD who underwent TURP for benign prostatic obstruction were evaluated retrospectively. It was concluded that TURP for benign prostatic obstruction in patients with PD may be successful in up to 70% and the risk of de novo urinary incontinence seems minimal (83). One of the greatest areas of concern for many patients considering TURP is the possibility of incontinence or inability to void despite surgical intervention. Tyson et al. demonstrated in their study that the use of the temporary prostatic urethral stent provided a good provocative test that enabled patients to experience what their voiding status would be if they were to undergo definitive surgical management (84). Doxazosin resulted in the improvement of LUTS and the maximum flow rate and was well tolerated in men with PD. The response to treatment is dependent on the severity of neurological disability (85). Recently the a1 adrenergic receptor antagonist terazosin was shown to activate PGK1, a possible target for the mitochondrial deficits in PD related to its function as the initial enzyme in ATP synthesis during glycolysis. It has been shown that terazosin had neuroprotective effects in neurotoxin models of nigrostriatal degeneration in invertebrates and rodents, including after delayed administration. Additionally, tera-

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zosin reduced a-synuclein levels in transgenic mice and neurons derived from patients with LRRK2 mutationassociated (44). An epidemiologic study was performed by Sasane et al. to test the PD occurrence rate in 113,450 individuals from the United States with 5 or more years of follow-up. Patients were classified as tamsulosin users (n = 45,380), terazosin/alfuzosin/doxazosin users (n = 22,690), or controls matched for age, sex, and Charlson comorbidity index score (n = 45,380). Terazosin/alfuzosin/doxazosin users did not differ in PD risk from matched controls (P = 0.29) but rather that tamsulosin may in some way potentiate PD progression (86). In case of significant and symptomatic PVR, a specific treatment is necessary in order to empty the bladder. The gold standard therapy in PD patients with neurogenic bladder still the self-intermittent-catheterizations (87). Managing Nocturia in PD Managing nocturia in PD patients necessitates managing reduced functional bladder capacity and nocturnal polyuria. The use of antimuscarinics, detrusor injection of BT, neuromodulation, and CIC could be useful to manage reduced bladder capacity. Desmopressin and late-afternoon diuretic could help in the management of nocturnal polyuria (60). Managing incontinence in PD In a systemic review of 3 studies with a total sample size of n = 1077, 25 percent of the women with PD suffer from urgency incontinence compared to seven percent of the women without Parkinson's disease (p < 0.01). Men with PD were affected with a 28% rate in comparison of 6% of men without Parkinson's disease (p < 0.01). With pelvic floor muscle exercises and accompanying measures as well as with injections of botulinum toxin A a reduction of urinary incontinence seems to be possible (88). Artificial urinary sphincter implantation shows significantly worse continence rates for patients with PD, even though it is considered as a safe procedure (89). Management of the sexual dysfunction in PD patients Impulse control disorders (ICDs) affect up to 40% of patients with PD using dopamine agonists and about 15% of patients with PD overall. The mainstay of medical management for ICD is reducing or discontinuing dopamine agonists. Cognitive-behavioral therapy was found to be useful for the treatment of ICD in patients with PD (90). Sildenafil citrate may be considered to treat ED in patients with PD as concluded in multiple studies. The benefit of apomorphine on sexual function in some patients suggests a possible role in the treatment of impotence in PD but its role is not validated. A daily dose of transdermal testosterone gel improved testosterone deficiency symptoms in men with PD (91). Pergolide substantially improved sexual function in the younger male patients who were still interested in sexual activities (92).

CONCLUSIONS

Urinary symptoms and sexual dysfunctions are common in PD patients, occurring in any stage of the disease. PD patients experience both storage and voiding difficulties.

Urological care in Parkinson’s disease patients

Storage symptoms, specifically OAB are markedly common in those patients. Anticholinergics and mirabegron remain potential treatment options. DBS, intradetrusor botulinum toxin injections can be used to treat intractable OAB symptoms in PD. TURP could be performed safely in PD patients with BPH if MSA is excluded. Other supportive non-pharmacological therapies such as behavioral therapy are used in early and advanced PD patients. Phosphodiesterase-5 inhibitors are essential to treat sexual dysfunction. Treatment of all urologic dysfunction in PD is optimal with a multidisciplinary approach to improve the quality of life of these patients.

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Correspondence Mohamad Moussa, MD mohamadamoussa@hotmail.com Head of Urology Department, Zahraa Hospital, University Medical Center, Beirut (Lebanon) Mohamed Abou Chakra, MD (Corresponding Author) mohamedabouchakra@hotmail.com Department of Urology, Faculty of Medical Sciences, Lebanese University, Beirut (Lebanon) Athanasios G. Papatsoris, MD agpapatsoris@yahoo.gr 2nd Department of Urology, School of Medicine, Sismanoglio Hospital, National and Kapodistrian University of Athens, Athens (Greece) Athanasios Dellis, MD aedellis@gmail.com Department of Urology/General Surgery, Areteion Hospital, Athens (Greece) Baraa Dabboucy, MD baraa.dabboucy@gmail.com Department of Neurosurgery, Faculty of Medical Sciences, Lebanese University, Beirut (Lebanon) Michael Peyromaure, MD michael.peyromaure@aphp.fr Nicolas Barry Delongchamps, MD nicolas.barry-delongchamps@aphp.fr Hugo Bailly, MD h.bailly.md@gmail.com Igor Duquesne, MD igor.duquesne@aphp.fr Department of Urology, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris Descartes University, Paris (France)

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LETTER TO EDITOR

DOI: 10.4081/aiua.2022.1.118

Core urological surgical training: The pivotal role of feminizing genital reconstruction for gender dysphoria Gianmartin Cito 1*, Elena Rovero 1*, Francesco Sessa 1, Simone Sforza 1, Girolamo Morelli 2, Arturo Lo Giudice 3, Lorenzo Masieri 1, Andrea Minervini 1, Riccardo Bartoletti 2, Giorgio Ivan Russo 3, Andrea Cocci 1 1 Department

of Urology, Careggi Hospital, University of Florence, Florence, Italy; of Urology, Cisanello Hospital, University of Pisa, Pisa, Italy; 3 Department of Urology, University of Catania, Catania, Italy. 2 Department * These

authors contributed equally to the work.

KEY WORDS: Sex reassignment; Male to female; Surgery; Urology; Gender. Submitted 25 November 2021; Accepted 3 December 2021

INTRODUCTION

In recent years, the surgical techniques for sex reassignment surgery in male-to-female (MtoF) transsexualism have been standardized and improved with better functional and aesthetic results, therefore increasing patients’ satisfaction. Feminizing genital reconstruction is a complex surgical procedure that can be performed by using several skills such as penile skin inversion, penoscrotal flap, enterovaginoplasty. This challenging surgery is done by specific steps that could be related to other procedures in uro-andrological field, especially for benign conditions. In this context, MtoF reassignment surgery could represent a complete training model for future urologists. Here, we aim to describe all surgical steps of feminizing genital reconstruction as a core urological surgical training for young urologists.

MTOF

REASSIGNMENT SURGERY

From November 2016 to December 2019, all resident doctors in urology training were involved in MtoF reassignment surgery. The basic steps of the feminizing genital reconstruction for gender dysphoria were described as follow: 1. Orchiectomy After anesthesia is induced, the patient is placed in the lithotomic position. An inverted U-shaped incision on the posterior surface of the scrotum is performed, the incision is extended through subcutaneous tissue so that the urethral corpus spongiosum and corpora cavernosa are bilaterally exposed (Figure 1). Subsequently, bilateral orchiectomy is performed by dissecting and suturing both spermatic cords at the level of external inguinal rings (Figure 2). Once this is done, the proximal end of these structures will retract into the inguinal canal, in order to close bilaterally external inguinal ring to avoid future weakness that can lead to inguinal hernia (1). 2. Penile degloving A circumferential subcoronal incision is made, allowing outwards folding of the penile skin downward to the base in order to expose the corpora. The penile skin is transected from the corpus spongiosum and the corpora cavernosa. A cylindrical penile skin flap is created and dissected from the albuginea, being careful to preserve the vitality of the skin, this flap will provide the anterior wall of the neovagina (Figure 3). 3. Penectomy The corpus spongiosum is isolated starting from the crura up to the penile glans. Through a bilateral incision of the Buck’s fascia, a plane is created between the tunica albuginea and the dorsal neurovascular bundle, whose connection to the glans is meticulously preserved. The glans is detached from the corpora cavernosa without danger and neurovascular bundle isolation is held in a retrograde fashion (Figure 4). The corpora are then excised as proximally as possible (1). 4. Creation of a prostatorectal space Fibers of bulbocavernosus muscles are divaricated on the midline and the bulbar urethra is completely freed. The central tendon of the perineum is incised, and an accurate, blunt dissection is performed in order to create a wide space between

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No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 1

Sex reassignment training surgical model

Figure 1. Inverted U-shape incision on the posterior aspect of the scrotum, centrally prolonged on the penis.

Figure 2. Isolation of the testis and spermatic cord, before the ligature at the external inguinal ring.

Figure 3. Penile degloving.

the rectum and the prostate, where the neovagina will be placed. The Denonvillier’s fascia is identified, and the blunt dissection continues through this avascular plane, transecting the medial fibers of the elevator ani muscles (Figure 5). The penile-scrotal cylinder of skin is placed into the neo-cavity, forming the neovagina and sutured to the Denonvillier’s fascia (1). 5. Creation of the neourethra After the bulb of penis is completely excised, the distal urethra is reduced at the pubic symphysis and passed through a second incision, more ventrally, so as to obtain a Y-shaped. The distal part of the urethral stump is spatulated and the urethro-cutaneous anastomosis is performed, with the apex fixed to the anterior portion of pubis. This becomes the reference point for positioning the neoclitoris, which will be framed by urethral mucosa. The urethral bulb is carefully removed in order to avoid its bulging during sexual arousal and dyspareunia (Figure 6). The creation of the urethra-clitoris complex gives to the neoclitoris a mucosal environment providing adequate lubrication; furthermore, the two layers suture permits a reciprocal vascular support, useful in case of urethral or clitoral ischemia (2).

MAIN Figure 4. Asportation of corpora cavernosa after isolation of neurovascular bundle.

Figure 5. Creation of a prostatorectal space or neovaginal cavity, we can appreciate the prostate with Denonvillier’s fascia.

Figure 6. Conservation of bulbar urethra and reduction urethral bulb.

Procedure Circumcision Orchiopexy Varicocelectomy Radical orchifunicolectomy Hydrocelectomy Corporoplasty Penile prosthesis implantation Meatoplasty Radical or partial penectomy

Total 25 10 10 5 5 2 3 2 2

FINDINGS

We analyzed how the learning curve of MtoF reassignment surgery could influence the skills of the same resident in practicing simpler andrological procedures as lead surgeon, assisted by his tutor. After performing 10 feminizing genital reconstructions as assistant surgeon, the resident performed 64 andrological procedures as lead surgeon, at the end of his training period with the tutor in the operating room (Table 1). No postoperative complications occurred. Operating times, as well as hospitalization times were comparable to those performed by the tutor. After the first 10 procedures, the mean operating time decreased of 20 minutes (SD ± 5; p < 0.05) and the mean blood loss decreased of 80 ml (SD ± 15; p < 0.05). The perineal approach using the inverted U-shaped incision on the posterior surface of the scrotum, the dissection and suture of spermatic cords at the external inguinal rings and the bilateral orchiectomy helped the learning curve of the resident for the radical orchiectomy to treat testicular torsion (n = 5). Likewise, it helped to practice bilateral orchiopexy for testicular retraction (n = 10), that is generally performed with vertical perineal incision or homolateral transversal incision; by the way it was possible to facilitate to learn the inguinal approach, the exteriorization and asportation of the spermatic cord and testicle, that must be preferred in case of testicular cancer. The acquired expertise in gonadic surgery helped also to learn the procedure of hydrocelectomy in case of tense and large hydrocele (n = 5). Once a scrotal median incision is performed, the fluid is aspirated, the testicle exposed, and the sac everted to avoid a recurrence. The process of penile degloving in MtoF reassignment surgery facilitated the performance for the treatment of congenital or acquired penile curvature (Nesbit’s corporoplasty, n = 2). In this

Table 1. Andrological procedures performed by resident, as lead surgeon, at the end of his training period with the tutor in the operating room. Archivio Italiano di Urologia e Andrologia 2022; 94, 1

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case, the best approach for penile skin degloving is a circumcisional incision 0,5-1 cm below the coronal sulcus deepened until the whitish Buck’s fascia, continued by blunt and sharp dissection (3). Circumcision and dissection with Dartos fascia preservation, to obtain a complete penile degloving, is normally performed during feminizing genital reconstruction for gender dysphoria. This training simplifies the learning ability of other surgical steps such as circumcision (n = 25), in case of severe phimosis or the preservation of the dorsal neurovascular bundle, required during corporoplasty. Moreover, the penoscrotal approach is widely used to implant penile prosthesis for the treatment of erectile dysfunction (n = 3) (4). The feminizing genital reconstruction helped also to get skills concerning functional anatomy of the penis, that allowed the resident to practice in radical penectomy for penile cancer (n = 2) (5). The preparation of the urethral stump before the urethrocutaneous anastomosis for the creation of the neourethra in feminizing genital reconstruction was useful to learn procedures of meatoplasty, performed in case of urethral strictures (n = 2) (6). Lastly, sex reassignment surgery requires expertise of the inguinal canal anatomy, that is conductive in varicocele treatment (n = 10). The inguinal approach involves a 3-5 cm incision over the inguinal canal, the opening of the external oblique aponeurosis and the delivery of the spermatic cord. All internal spermatic veins are identified and dissected under microscopy and then ligated with sutures or surgical clips. The vas deferens, vasal vessels, testicular artery and as many lymphatic channels as possible are preserved. In conclusion, assisting to complex andrological procedures, as MtoF reassignment surgery, seems to have a positive influence in facilitating the learning curve of other simpler procedures in young urologists. Thus, the challenging steps of feminizing genital reconstruction could be a core urological training in performing surgery for andrology conditions.

REFERENCES

1. Mirone V, Imbimbo C, Verze P, Arcaniolo D. Transgender rencostructive surgery. In: Austoni E (ed). Atlas of reconstructive penile surgery. 1st edn. (Pacini Editore Medicina, 2010) pp.419-432. 2. Trombetta C, Liguori G, Bertolotto M (eds). Management of Gender Dysphoria: A Multidisciplinary Approach. (Springer, Milan, Heidelberg, New York, Dordrecht London, 2015). 3. Fabiani A, Fioretti F, Pavia MP, et al. Buccal mucosa graft in surgical management of Peyronie's disease: Ultrasound features and clinical outcomes. Arch Ital Urol Androl. 2021;93:107-110. 4. Bayrak O, Erturhan S, Seckiner I, et al. Comparison of the patient's satisfaction underwent penile prosthesis; Malleable versus Ambicor: Single center experience. Arch Ital Urol Androl. 2020; 92:25-29. 5. Moulavasilis N, Yiannopoulou K, Frangoulis M, et al. A surgical approach to squamous cell carcinoma of penis that also resolved the psychological dysfunction of the patient. Arch Ital Urol Androl. 2020; 92:58-60. 6. Gentile G, Martino A, Nadalin D, et al. Penile-scrotal flap vaginoplasty versus inverted penile skin flap expanded with spatulated urethra: A multidisciplinary single-centre analysis. Arch Ital Urol Androl. 2020; 92:186-191. Correspondence Gianmartin Cito, MD gianmartin.cito@gmail.com Elena Rovero, MD elena.rovero@stud.unifi.it Francesco Sessa, MD francesco_sessa@hotmail.it Simone Sforza, MD simone.sforza1988@gmail.com Lorenzo Masieri, MD lorenzo.masieri@meyer.it Andrea Minervini, MD andreamine@libero.it Andrea Cocci, MD, PhD (Corresponding Author) cocci.andrea@gmail.com Department of Urology, Careggi Hospital, University of Florence, Largo Brambilla 3, 50134, Florence (Italy) Girolamo Morelli, MD girolamomorelli@gmail.com Riccardo Bartoletti, MD riccardo.bartoletti@hotmail.com Department of Urology, Cisanello Hospital, University of Pisa, Via Piero Trivella, 56124, Pisa (Italy) Arturo Lo Giudice, MD arturologiudice@gmail.com Giorgio Ivan Russo, MD giorgioivan1987@gmail.com Department of Urology, University of Catania, Via Plebiscito, 628, 95124, Catania (Italy)

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DOI: 10.4081/aiua.2022.1.121

LETTER TO EDITOR

COVID-19 vaccination and penile Mondor disease. There is any relationship? Andrea Fabiani 1, Alessandra Filosa 2, Daniele Maglia 1, Emanuele Principi 1, Silvia Stramucci 3 1 Urology

Unit, Surgery Department, Macerata Civic Hospital, Area Vasta 3 ASUR Marche, Italy; Unit, ASUR Marche Area Vasta 5, Ascoli Piceno, Italy; 3 Urologic Clinic, Marche Polytechnic University, Ancona, Italy. 2 Pathology

KEY WORDS: Covid-19; Vaccination; Penile Mondor; Phlebitis. Submitted 9 January 2022; Accepted 16 January 2022

Dear Editor, the pandemic spread of Coronavirus 2 infection (SARS-CoV-2), determining the coronavirus disease 2019 (Covid-19), had devastating consequences globally with several waves affecting social and economic life. The use of masks, physical distancing, testing of exposed or symptomatic persons, contact tracing and isolation have helped limit the transmission where they have been rigorously applied; however, these actions have proved not sufficient to limit the virus spread. The vaccinations are needed to reduce the morbidity and mortality of Covid-19 (1). Two vaccine types have been developed using two different technologies: viral vectors (Vaxzevria; AstraZeneca) and mRNA (Comirnaty-Pfizer and mRNA-1273Moderna). Aside from transient local and systemic reactions, no safety concerns were identified from vaccination. Nevertheless, there are several concern in the public opinion about the possible consequences on uro-genital system, both in men and women. We know that exist evidence suggesting no embryo and gametes infections by SARS-CoV-2 and no consequences on fertility potential after vaccination (2). Thrombosis is the most severe and nontypical adverse effects of vaccine. Similarly to Covid-19 infection, in which we recognized a predisposition to both venous and arterial thromboembolism due to excessive vascular and systemic inflammation, endothelial dysfunction, cytokine storm, hypoxia and immobilization, after vaccination there is a growing evidence of thrombotic vaccine-related events (2). During the first wave in 2020, we had already reported an increase in outpatient evaluations of patients complaining of a vascular andrological disease, known as penile Mondor disease (PMD) (1). The PMD occurs with palpable subcutaneous cord-like indurations beneath the penile skin (Figure 1). Usually, PMD is an under-reported benign, self-limited disease that resolves spontaneously in four to eight weeks. The PMD under reporting may be because the lesion is often non painful and self-resolving. Most patients refrain from seeking medical attention, and when they do, sometimes even physicians pay little attention to the lesion. The PMD pathogenesis can be demonstrated by Virchow’s triad. Triggering factors for endothelial damage intersect with underlying risk of blood stasis and hypercoagulability. For example, PMD may occur after frequent, vigorous, prolonged sexual activity, prolonged erection, urogenital infection and sexually transmitted diseases, pelvic surgery, penile trauma, prolonged sitting position, hematologic disease or thrombophilia. The intersection between the three Virchow’s factors allows for blood clot formation in PMD typically isolated to the superficial dorsal vein with associated phlebitis (3, 4). Covid-19 infection is also related to PMD, based on several cases report published in the last years (5). Nothing is reported in the literature regarding the possible relationship between vaccination against Covid-19 and PMD. However, in our daily clinical practice, in the last three months, we have recorded an increase in outpatient assessments of PMD. We refer to 5 cases whose clinical data are reported in Table 1. Table 1. Clinical data of 5 cases. Patient 1 2 3 4 5

Age 25 37 21 24 28

Vaccine type Pfizer Moderna Moderna Pfizer Pfizer

No conflict of interest declared.

Vaccination month July September August August July

Outpatient evaluation month October December November December October

Coagulation Normal Normal Normal Normal Normal

Abnormal sex activity No No No No No

Hystory clinic Silent Silent Silent Silent Silent

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Anamnesis and physical examinations were conducted to evaluate any possible cause of PMD. All patients underwent fast abdominal ultrasound and penile ecocolorDoppler in flaccidity. Laboratory tests with particular interest on coagulation state were performed. Only the symptomatic patients (2/5) were treated with analgesic. Only one case (1/5) received low molecular weight heparin for 15 days. All patient reported complete recovery from symptoms and subcutaneous cord-like indurations complained at the presentation. PMD usually affect men at 20 to 40 years of age and in our little case series age ranged between 24 and 37 years. All performed vaccination 4 or 5 months before with mRNA-ComirnatyPfizer (3 cases) and mRNA-1273-Moderna (2 cases). No patients declared prolonged or unusual sexual activity. The clinical histories were silent for any possible hypercoagulability status. Vaccinations were the only possible pathogenetic factors linking the 5 young patients. The questions arising from this real-life experience are basically two. Is it therefore possible that there is a pathogenetic link between PMD and vaccination anti Covid-19? Is there any possibility of identifying subjects predisposed to the onset of this vascular disease after vaccination? Although the PMD clinical course is very often self-limiting, in a scenario characterized by an annual anti-Covid vaccination, may be important to always inform young male about the eventuality of developing PMD and alert general practitioners and referral specialists about the possible increase in the PMD response. From a diagnostic or therapeutic point of view, we don’t identify the need to change the usual attitude. We must continue to reassure the patient and to treat symptomatic cases since PMD can cause significant patient anxiety and embarrassment and may be easily confused with more concerning conditions. Our aim is to urge the andrological scientific community to perform a large-scale data collection that allows us to define a correct answer to our questions.

Figure 1. Clinical appearance (left, thin arrow) and ultrasound feature (right, arrow) of Penile Mondor disease.

REFERENCES

1. Maretti C, Fabiani A, Colombo F, et al. Italian experiences in the management of andrological patients at the time of Coronavirus pandemic. Arch Ital Urol Androl. 2021; 93:111-114. 2. Ruan Y, Hu B, Liu Z, et al. No detection of SARS-CoV-2 from urine, expressed prostatic secretions, and semen in 74 recovered COVID-19 male patients: A perspective and urogenital evaluation. Andrology. 2021; 9:99-106. 3. Manimala NJ, Parker J. Evaluation and treatment of penile thrombophlebitis (Mondor's Disease). Curr Urol Rep. 2015; 16:39. 4. Solinas A. Thrombosis of the posterior scrotal vein associated with essential thrombocytemia: Report of a case. Arch Ital Urol Androl. 2020; 92:112-113 5. Lessiani G, Boccatonda A, D'Ardes D, et al. Mondor's Disease in SARS-CoV-2 Infection: A Case of Superficial Vein Thrombosis in the Era of COVID-19. Eur J Case Rep Intern Med. 2020; 7:001803.

Correspondence Andrea Fabiani, MD (Corresponding Author) andreadoc1@libero.it Surgery Dpt, Section of Urology, ASUR Marche Area Vasta 3 Macerata Hospital, Via Santa Lucia, 60100, Macerata (Italy) Alessandra Filosa, MD PhD alessandra.filosa@sanita.marche.it Pathology Unit, ASUR MARCHE Area Vasta 5, Ascoli Piceno (Italy) Daniele Maglia, MD emanuele.principi@sanita.marche.it Emanuele Principi, MD emanuele.principi@sanita.marche.it Surgery Dpt, Section of Urology ASUR Marche Area Vasta 3, Macerata Hospital, Macerata (Italy) Stramucci Silvia, MD silvia.stramucci@gmail.com Urologic Clinic, Marche Polytechnic University, Ancona (Italy)

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LETTER TO EDITOR

DOI: 10.4081/aiua.2022.1.123

Aristolochic acid: What urologists should know Mohanarangam Thangavelu, Asmaa Ismail, Ahmed Zakaria, Hazem Elmansy, Walid Shahrour, Owen Prowse, Ahmed Kotb Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada.

KEY WORDS: Aristolochic; TCC; Herbal; Balkan nephropathy. Submitted 3 January 2022; Accepted 19 January 2022

To the Editor, Aristolochic acid is one of major causes for upper tract urothelial carcinoma, especially in younger population. While it is mentioned as a cause in guidelines, little is actually known about the toxin by urologists. We are aiming in our letter to provide some direct and clear information to ourselves that would help us to know more about that toxin and how it can adversely affect our patients. What is Aristolochic acid? Aristolochic acid is an acid obtained from a plant that grows in several areas of the world. Its use was started in China as an herbal medicine that was used to treat many diseases, then was advanced to be used in many herbal medications sold over the shelf worldwide (1). Why people use that herbal drug? This herbal supplement was long used as a miracle supplement for weight loss. Other less common uses were arthritis and menstrual problems (1). In Balkan areas; that herb was mixed with wheat used for home baked bread. Importance to urologists Aristolochic acid were found to be significantly associated with interstitial nephritis, end stage renal disease. This is currently known as a major cause of Balkan nephropathy (2). This was also proved to be a carcinogenic causing upper urinary tract urothelial carcinoma (3). A recent study (2017) looked for the oncological outcomes of patients with upper tract urothelial carcinoma exposed to Aristolochic acid. This was found to be significantly associated with higher rate of local and contralateral upper tract recurrence, as well as higher rate for intravesical recurrence (4). A recent meta-analysis and systematic review (2021) confirmed the same findings of higher rate of intravesical and contralateral recurrence for patients exposed to Aristolochic acid, as well as worse overall and disease specific survival (5). Authorities’ action and obstacles The toxic and carcinogenic effect of Aristolochic acid was raising concerns since 1999. Food and drug administration (FDA) released warning in 2001 about the use of that herbal supplement and started to recall products from the market containing the acid. This was followed in 2004 by a warning from health Canada regarding the use of the supplement with an alert to the Canadian border to prevent importing the drug in any form (6, 7). Why Aristolochic acid is a concern 20 years following authorities’ action? The concerns for Aristolochic acid are still existent for three important reasons. First; unlike other known factors as smoking, studies did show that patients that stopped the use of Aristolochic acid for more than 5 years were still at the same risk and worse oncological outcomes for upper tract urothelial carcinoma, similar to patients with recent exposure. It seems that exposure produces a permanent genetic alteration that keeps risking the patients’ cancer development despite of cessation of exposure (4). The second problem is the natural growth of the plant in many areas of the world. While the plant may be avoided because of the known risks, studies have confirmed that the toxins of the plant can spread through the soil and affect other vegetables and fruits that can become contaminated by the toxins. That soil contamination leaching into rivers raised some concerns about water contamination in endemic areas where just drinking water may be imposing a risk for Aristolochic acid exposure. Another natural risk is through butterflies that can act as an intermediate host for the herbal contamination (8, 9). Chan et al. could recently (2016) identify Aristolochic acid in corn, wheat grains and soil samples taken from Balkan areas (10). More recent studies confirmed the same findings as the root vegetables in Balkan areas were found to be extensively contaminated with Aristolochic acid (11, 12). The last risk is through No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 1

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Table 1. Plants containing Aristolochic acid (From FDA 2020). Plant name Aristolochia spp. Aristolochia acuminata Lam. Syn. Aristolochia tagalaChamp. Aristolochia argentina Griseb. Aristolochia baetica Linn. Syn. Aristolochia bracteolataLam. Aristolochia bracteata Retz. Aristolochia chilensis Bridges in Lindl. Aristolochia cinnabarina C.Y. Cheng & J.L. Wu Aristolochia clematitis L. Aristolochia contorta Bunge Aristolochia cymbifera Mart. & Zucc. Aristolochia debilis Siebold & Zucc. Syn. Aristolochia longa Thunb. Syn. Aristolochia recurvilabraHance Syn. Aristolochia sinarumLindl. Aristolochia elegans Mast. Syn. Aristolochia hasslerianaChodat Aristolochia esperanzaeKuntze Aristolochia fangchi Y.C. Wu ex L.D. Chow & S.M. Hwang

Aristolochia fimbriata Cham. Aristolochia indica L. Aristolochia kaempferi Willd. Syn. Aristolochia chrysops(Stapf) E.H. Wilson ex Rehder Syn. Aristolochia feddei H. Lév. Syn. Aristolochia heterophyllaHemsl. Syn. Aristolochia mollis Dunn Syn. Aristolochia setchuenensisFranch. Syn. Aristolochia shimadaiHayata Syn. Aristolochia thibeticaFranch. Syn. Isotrema chrysops Stapf Syn. Isotrema heterophylla(Hemsl.) Stapf Syn. Isotrema lasiops Stapf Aristolochia kwangsiensisChun & F.C. How Syn. Aristolochia austroszechuanica C. B. Chien & C. Y. Cheng Aristolochia macrophylla Lam. Syn. Aristolochia sipho L'Hér. Aristolochia manshuriensisKom. Syn. Hocquartia manshuriensis(Kom.) Nakai Syn. Isotrema manshuriensis(Kom.) H. Huber

Common/alternative name Aristolochia Guan Mu Tong Guang Mu Tong Oval leaf Dutchman's pipe

Plant name Aristolochia maurorum L. ristolochia mollissima Hance Aristolochia pistolochia L. Aristolochia rigida Duch. Aristolochia rotunda Linn. Aristolochia serpentaria L. Syn. Aristolochia serpentariavar. hastata (Nutt.) Duch.

Ukulwe

Aristolochia serpentaria L. Syn. Aristolochia serpentariavar. hastata (Nutt.) Duch.

Birthwort Ma Dou Ling Tian Xian Teng Mil homens Ma Dou Ling Tian Xian Teng Qing Mu Xiang Sei-mokkou (Japanese) Birthwort Long birthwort

Aristolochia watsoni Wooton & Standley or Aristolochia watsonii Wooton & Standley Syn. Aristolochia porphyrophylla Pfeifer Aristolochia westlandii Hemsl. or Aristolochia westlandi Hemsl. Aristolochia zollingerianaMiq. Syn. Aristolochia kankauensisSasaki Syn. Aristolochia roxburghianasubsp. kankauensis (Sasaki) Kitam. Syn. Hocquartia kankauensis(Sasaki) Nakai ex Masam. Syn. Aristolochia tagala var. kankauensis (Sasaki) T. Yamaz. Asarum canadense Linn. Syn. Asarum acuminatum(Ashe) E.P. Bicknell Syn. Asarum ambiguum (E.P. Bicknell) Daniels Syn. Asarum canadense var. ambiguum (E.P. Bicknell) Farw. Syn. Asarum canadense var.reflexum (E.P. Bicknell) B.L. Rob. Syn. Asarum furcatum Raf. Syn. Asarum medium Raf. Syn. Asarum parvifolium Raf. Syn. Asarum reflexum E.P. Bicknell Syn. Asarum rubrocinctumPeattie Asarum canadense Linn. Syn. Asarum acuminatum(Ashe) E.P. Bicknell Syn. Asarum ambiguum (E.P. Bicknell) Daniels Syn. Asarum canadense var. ambiguum (E.P. Bicknell) Farw. Syn. Asarum canadense var.reflexum (E.P. Bicknell) B.L. Rob. Syn. Asarum furcatum Raf. Syn. Asarum medium Raf. Syn. Asarum parvifolium Raf. Syn. Asarum reflexum E.P. Bicknell Syn. Asarum rubrocinctumPeattie Asarum himalaicum Hook. f. & Thomson ex Klotzsch or Asarum himalaycum Hook. f. & Thomson ex Klotzsch Asarum splendens (F. Maek.) C.Y. Cheng & C.S. Yang Bragantia wallichii R.Br. Specimen exists at New York Botanical Gardens. Tropicos does not list this species as a synonym for any Thotteaspecies. Kew Gardens Herbarium does not recognize the genera Bragantia. Until additional information is obtained the name used is as cited in J. Nat. Products 45:657–666 (1982)

Guang Fang Ji Fang Ji Mokuboi (Japanese) Kwangbanggi (Korean) Fang Chi Kou-boui (Japanese) Indian birthwort Yellowmouth Dutchman's pipe

Dutchman's pipe Manchurian birthwort Manchurian Dutchman's pipe Guang Mu Tong Kan-Mokutsu (Japanese) Mokuboi (Japanese) Kwangbanggi (Korean)

Common/alternative name

Virginia snakeroot Serpentaria Virginia serpentary Virginia snakeroot Serpentaria Virginia serpentary

Wild ginger Indian ginger Canada snakeroot False coltsfoot Colic root Heart snakeroot Vermont snakeroot Southern snakeroot Wild ginger Indian ginger Canada snakeroot False coltsfoot Colic root Heart snakeroot Vermont snakeroot Southern snakeroot Tanyou-saishin (Japanese) Do-saishin (Japanese)

currently existing other herbal supplements widely used worldwide. While the intentional inclusion of Aristolochic acid is currently not allowed, contamination of the available herbal supplement with Aristolochic acid is a continuous risk. Abdullah et al. (2017) examined 573 different samples lacking Aristolochic acid as one of the ingredients. They could identify the substance in 206 samples (36%). This was a surprising fact that 1/3 of herbal supplements in market could be contaminated with Aristolochic acid (13). What are the herbs that can possibly contain Aristolochic acid? There were many plants reported in a monograph published in 2018 that can possibly contain Aristolochic acid. Most of these herbs have common names that are far away from the original toxin name including Dutchman’s pipe, Virginia snakeroot, Canada snakeroot, wild ginger and Indian ginger (14). More recently, FDA updated its plant lists providing warning to the manufacturers and the public against the use of large numbers of herbs that can potentially harbour the toxin (15). Table 1 illustrate the plants having the toxin.

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Aristolochic acid

Are there ongoing ways for population protection against the toxin exposure? Herbal medicine is being used worldwide as an alternative medicine that can augment the traditional medicine. The main issues are the large number of plants that can be harbouring the toxin together with possible language barriers and the use of English names to some herbs that can be completely different and not presenting the herb containing the toxin. There is no guaranteed current way to confirm the absence of toxin from available herbal medicine. In 2018; four DNA sequences were identified in a large study as possible target areas to detect the toxin out of eleven different plants. These DNA sequences were bcL, matK, ITS2 and trnH-psbA (16). DNA barcoding is promising and ongoing way to detect most of the herbs that can be having the toxin, although it may still miss some uncommon herbs.

CONCLUSIONS

Aristolochic acid is a currently existing possible risk factor for the development of nephropathy and upper tract urothelial carcinoma. Its actual contribution to new cases diagnosed with upper tract urothelial carcinoma may be underestimated. Awareness programs to the public for possible herbal supplements contamination with Aristolochic acid as well as testing all herbal supplements for possible contamination should be implemented. DNA barcoding is able to identify most common herbs containing Aristolochic acid but may be still missing uncommon herbs.

REFERENCES

1. Luciano RL, Perazella MA. Aristolochic acid nephropathy: epidemiology, clinical presentation, and treatment. Drug Saf. 2015; 38:55-64. 2. Jelakovic B, Dika Ž, Arlt VM, et al. Balkan endemic nephropathy and the causative role of aristolochic acid. Semin Nephrol. 2019; 39:284-296. 3. Rouprêt M, Babjuk M, Burger M, et al. European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2020 Update. Eur Urol. 2021; 79:62-79. 4. Zhong W, Zhang L, Ma J, et al. Impact of aristolochic acid exposure on oncologic outcomes of upper tract urothelial carcinoma after radical nephroureterectomy. Onco Targets Ther. 2017; 10:5775-5782. 5. Kang YC, Chen MH, Lin CY, et al. Aristolochic acid-associated urinary tract cancers: an updated meta-analysis of risk and oncologic outcomes after surgery and systematic review of molecular alterations observed in human studies. Ther Adv Drug Saf. 2021; 12:2042098621997727 6. http://wayback.archive-it.org/7993/20171114232638/https://www.fda.gov/Food/RecallsOutbreaksEmergencies/SafetyAlertsAdvisories/ ucm095272.htm. Accessed online on December 29, 2021. 7. https://www.canada.ca/en/news/archive/2004/07/health-canada-advises-consumers-not-use-products-containing-aristolochic-acid.html. Accessed online on December 29, 2021. 8. Chan CK, Liu Y, Pavlovic NM, Chan W. Aristolochic acids: newly identified exposure pathways of this class of environmental and food-borne contaminants and its potential link to chronic kidney diseases. Toxics. 2019; 7:14. 9. Li W, Chan CK, Liu Y, et al. Aristolochic acids as persistent soil pollutants: determination of risk for human exposure and nephropathy from plant uptake. J Agric Food Chem. 2018; 66:11468-11476. 10. Chan W, Pavlovic NM, Li W, et al. Quantitation of aristolochic acids in corn, wheat grain, and soil samples collected in Serbia: identifying a novel exposure pathway in the etiology of Balkan endemic nephropathy. J Agric Food Chem. 2016; 64:5928-34. 11. Au CK, Zhang J, Chan CK, et al. Determination of aristolochic acids in vegetables: nephrotoxic and carcinogenic environmental pollutants contaminating a broad swath of the food supply and driving incidence of Balkan endemic nephropathy. Chem Res Toxicol. 2020; 33:2446-2454. 12. Draghia LP, Lukinich-Gruia AT, Oprean C, et al. Aristolochic acid I: an investigation into the role of food crops contamination, as a potential natural exposure pathway. Environ Geochem Health. 2021; 43:4163-4178. 13. Abdullah R, Diaz LN, Wesseling S, Rietjens IM. Risk assessment of plant food supplements and other herbal products containing aristolochic acids using the margin of exposure (MOE) approach. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2017; 34:135-144. 14. https://monographs.iarc.who.int/wp-content/uploads/2018/06/mono100A-23.pdf. Accessed online on January 17, 2022. 15. https://www.accessdata.fda.gov/cms_ia/importalert_141.html. Accessed online on January 18, 2022. 16. Dechbumroong P, Aumnouypol S, Denduangboripant J, Sukrong S. DNA barcoding of Aristolochia plants and development of species-specific multiplex PCR to aid HPTLC in ascertainment of Aristolochia herbal materials. PLoS One. 2018; 13:e0202625. Correspondence Mohanarangam Thangavelu, MD - drtmohan@googlemail.com Asmaa Ismail, MD - asmaaismail0782@gmail.com Ahmed Zakaria, MD - aszakaria81@yahoo.com Hazem Elmansy, MD - hazemuro100@yahoo.com Walid Shahrour, MD - walid.shahrour@gmail.com Owen Prowse, MD - owenprowse@rogers.ca Ahmed Kotb, MD (Corresponding Author) - drahmedfali@gmail.com Urology Department, Northern Ontario School of medicine, 146 Court Street South, Thunder Bay, ON P7B 2X6, Canada.

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LETTER TO EDITOR

DOI: 10.4081/aiua.2022.1.126

Overweight and obesity: The allies of prostate inflammation Juan Sebastián Moncada López, Jenniffer Puerta Suárez, Walter Darío Cardona Maya Grupo Reproducción, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.

KEY WORDS: Obesity; Prostate; Fertility; Antioxidants; Semen. Submitted 14 February 2022; Accepted 17 February 2022

To the Editor, World Health Organization (WHO) defines infertility as the inability of a sexually active partner to achieve a clinically confirmed pregnancy after at least one year of intercourse without contraceptive protection on fertile days (1). As women are primarily responsible for the conception, childbirth, and postpartum, fertility problems have been related to fertile female capacity. However, men play an essential role, being responsible for about 50% of alterations in fertility due to dysfunctions in the male reproductive tract, including varicocele, hypogonadism, poorly descended testicles, testicular tumors, and even anti-sperm autoantibodies (2-4). However, a high percentage of cases of male infertility is still of idiopathic cause. Male infertility has also been associated with aging and unhealthy lifestyles, such as cigarette smoking, recreational drug use, alcohol, sedentary lifestyle, psychological stress, as well as environmental factors such as pollution and heat exposure (5, 6). Additionally, there is a relationship between infertility and non-contagious diseases or chronic diseases, including cancer, chronic respiratory diseases, cardiovascular diseases, diabetes mellitus, obesity, and prostatitis (7-10) producing stress and general deterioration of health, including seminal parameters and fertile male capacity. Prostatitis and obesity Prostatitis is a common urogenital disease with a worldwide prevalence between 2.2 and 9.7% and an average of 8.2% (11), and has been directly related to seminal parameters alteration and male fertility (8). On the other hand, the increasing trend of obesity is associated to the decline of male fertility (20). In fact, it has been reported that men with a high BMI tend to be infertile more often than men with adequate body weight (12). Several studies have been reported in which an alteration of seminal quality and male fertility is found, along with an increase in the incidence of obesity. Furthermore, in the United States, it has been found that sperm counts decrease by 1.5% annually, and obesity has been considered as a possible etiological agent of infertility and reduced fertility (13). To the best of our knowledge, there is insufficient evidence to link obesity and prostatitis. Some studies have tried to relate these two pathologies, as Wallner et al. (14), who found that having a high BMI acts as a protective factor for prostatitis. Although this finding elucidates the relationship between prostatitis and obesity, future studies are necessary. While the relationship between prostatitis and obesity is still unknown, the latter has been involved with the risk of suffering from other prostate diseases, such as benign prostatic hyperplasia and prostate cancer (15, 16). Inflammatory status and antioxidants: A threat to fertility with a therapeutic alternative Obesity implies an increase in abdominal or visceral adipose tissue, which leads to rise in hormone levels in addition to a chronic inflammatory process (18), which is precisely due to abundant white adipose tissue in obese men, where increased aromatase activity has been found (13, 17). Adipose white tissue is considered an endocrine organ, responsible for producing around 30 biologically active peptides, such as leptin and adiponectin, and can even secrete adipokines (as modulating agents) (13). Leptin, a hormone derived from adipose tissue, known as the regulator of food intake and body energy expenditure, is mediated by hypothalamus (18, 19) and is necessary for proper functioning of reproductive system (20). This hormone is generated in excess in obese people, contributing to a decrease in androgens and altering male fertility (20). It should be mentioned that obesity is positively associated with a hyperinsulinemic state, which suppresses the production of androgen transporting proteins, such as sex hormone-binding globulin (SHBG) and decreases circulating testosterone levels (21). The main component of adipose tissue are adipocytes, specialized cells that can secrete various adipokines, such as tumor necrosis factor a (TNF-a), interleukin 6 (IL-6), and tissue factor (18). Some of these adipokines have been linked to infertility, testicular cancer, and chronic inflammatory conditions (22). Constant inflammation leads to a release of reactive oxy-

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gen species (ROS) and reactive nitrogen species (RNS) (23), which generate direct toxic effects (oxidative stress) on sperm, altering conventional seminal parameters such as concentration, motility, and morphology (24) and increases DNA damage to sperm and its membrane (25), composed mostly of polyunsaturated fatty acids, which give it fluidity, but also high susceptibility to oxidative stress, due to production of reactive aldehydes, which react with aminoacids, and can even alter mitochondrial function (26). As therapy against oxidative stress, there are antioxidants, which normalize spermatozoa's functioning altered by ROS and RNS, becoming used as therapy in cases of chronic prostatitis and male infertility (27, 28). There is scientific evidence that supports the hypothesis that sperm are protected from oxidative stress thanks to antioxidants present in seminal plasma (29). Some examples of these therapeutic alternatives are superoxide dismutase, catalase, coenzyme Q10, carnitine/L-carnitine, vitamin E, isoflavones and green tea (30). Analysis of our data To analyze the relationship between prostatitis, obesity, and oxidative stress, a geometric representation of the information obtained from 40 volunteers with a BMI greater than 25 was made through principal component analysis (PCA) using Prism 9.0 statistical software (GraphPad Software, San Diego, CA, USA) (Figure 1). The group included fourteen men with chronic prostatitis symptoms and twenty-six men asymptomatic for urogenital infections. The variables were the ones related to oxidative stress, including sperm membrane lipid peroxidation, antioxidant capacity in serum and semen, production of reactive oxygen species and body mass index.

Figure 1. Principal component analysis. The principal component 1, X-axis in figure 1, is considered as the principal axis, because it presented the highest coefficient of variability within the system, with a value of 32.4%, while the principal component 2, collected 24.2% of the variability of the data.

CONCLUSIONS

This analysis showed that 73.1% of controls were located on the lower side, and 64.3% of the patients were located on the top of the graph. Indicating that subjects with chronic prostatitis symptoms present a particular distribution of semen parameters compared to asymptomatic controls, which supports the relationship of oxidative stress with prostatitis. In conclusion, prostatitis and obesity are pathologies that are entirely related to male fertile state, and in cases of infertility they should be considered as etiological factors. Both coincide in the production of an inflammatory condition, altering sperm function. This damage can be lessened with antioxidant supplementation, an option that should not be ruled out as a therapeutic alternative. Finally, future studies that link prostatitis, obesity, and antioxidants may help developing strategies that could allow us to continue assessing importance of male sexual and reproductive health.

ACKNOWLEDGMENTS

JSML and JPS were supported by a fellowship from Minciencias.

REFERENCES

1. Zegers-Hochschild F, Adamson GD, de Mouzon J, et al. The International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) Revised Glossary on ART Terminology, 2009. Hum Reprod. 2009; 24:2683. 2. Jungwirth A, Giwercman A, Tournaye H, et al. European Association of Urology Guidelines on Male Infertility: The 2012 Update. Eur Urol. 2012; 62:324. 3. Restrepo B, Cardona Maya W. Anticuerpos antiespermatozoides y su asociación con la fertilidad. Actas Urol Esp 2013; 37:571. 4. Mayorga-Torres BJ, Camargo M, Agarwal A, et al. Influence of ejaculation frequency on seminal parameters. Reprod Biol Endocrinol. 2015; 13:47. 5. Barazani Y, Katz BF, Nagler HM, Stember DS. Lifestyle, environment, and male reproductive health. Urol Clin North Am. 2014; 41:55. 6. Wise LA, Cramer DW, Hornstein MD, et al. Physical activity and semen quality among men attending an infertility clinic. Fertil Steril. 2011; 95:1025.

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7. Carlsen E, Giwercman A, Keiding N, Skakkebaek NE. Evidence for decreasing quality of semen during past 50 years. BMJ. 1992; 305:609. 8. Condorelli RA, Russo GI, Calogero AE, et al. Chronic prostatitis and its detrimental impact on sperm parameters: a systematic review and meta-analysis. J Endocrinol Invest. 2017; 40:1209. 9. Williams DHt, Karpman E, Sander JC, et al. Pretreatment semen parameters in men with cancer. J Urol. 2009; 181:736. 10. Chavarro JE, Toth TL, Wright DL, et al. Body mass index in relation to semen quality, sperm DNA integrity, and serum reproductive hormone levels among men attending an infertility clinic. Fertil Steril. 2010; 93:2222. 11. Krieger JN, Lee SW, Jeon J, et al. Epidemiology of prostatitis. Int J Antimicrob Agents. 2008; 31 Suppl 1:S85. 12. Sallmen M, Sandler DP, Hoppin JA, Blair A, Baird DD. Reduced fertility among overweight and obese men. Epidemiology. 2006; 17:520. 13. Cabler S, Agarwal A, Flint M, du Plessis SS. Obesity: modern man's fertility nemesis. Asian J Androl. 2010; 12:480. 14. Wallner LP, Clemens JQ, Sarma AV. Prevalence of and risk factors for prostatitis in African American men: The Flint Men's Health Study. Prostate. 2009; 69:24-32. 15. Parikesit D, Mochtar CA, Umbas R, Hamid AR. The impact of obesity towards prostate diseases. Prostate Int. 2016; 4:1. 16. Parazzini F, Artibani W, Carrieri G, 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 2019; 91:245. 17. Roth MY, Amory JK, Page ST. Treatment of male infertility secondary to morbid obesity. Nat Clin Pract Endocrinol Metab. 2008; 4:415. 18. Trayhurn P, Beattie JH. Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc Nutr Soc. 2001; 60:329. 19. Bhat GK, Sea TL, Olatinwo MO, et al. Influence of a leptin deficiency on testicular morphology, germ cell apoptosis, and expression levels of apoptosis-related genes in the mouse. J Androl. 2006; 27:302. 20. Isidori AM, Caprio M, Strollo F, et al. Leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels. J Clin Endocrinol Metab. 1999; 84:3673. 21. Tewari R, Rajender S, Natu SM, et al. Diet, obesity, and prostate health: are we missing the link? J Androl. 2012; 33:763. 22. Bialas M, Fiszer D, Rozwadowska N, et al. The role of IL-6, IL-10, TNF-alpha and its receptors TNFR1 and TNFR2 in the local regulatory system of normal and impaired human spermatogenesis. Am J Reprod Immunol. 2009; 62:51. 23. Fraczek M, Kurpisz M. Inflammatory mediators exert toxic effects of oxidative stress on human spermatozoa. J Androl. 2007; 28:325-33. 24. Agarwal A, Sharma RK, Nallella KP, et al. Reactive oxygen species as an independent marker of male factor infertility. Fertil Steril. 2006; 86:878. 25. Mayorga-Torres BJM, Camargo M, Cadavid AP, et al. Are oxidative stress markers associated with unexplained male infertility? Andrologia. 2017; 49. 26. Agarwal A, Rana M, Qiu E, et al. Role of oxidative stress, infection and inflammation in male infertility. Andrologia. 2018; 50:e13126. 27. Ross C, Morriss A, Khairy M, et al. A systematic review of the effect of oral antioxidants on male infertility. Reproductive BioMedicine Online. 2010; 20:711. 28. Benatta M, Kettache R, Buchholz N, Trinchieri A. The impact of nutrition and lifestyle on male fertility. Arch Ital Urol Androl 2020; 92:121. 29. Agarwal A, Saleh RA, Bedaiwy MA. Role of reactive oxygen species in the pathophysiology of human reproduction. Fertil Steril. 2003; 79:829. 30. Ihsan AU, Khan FU, Khongorzul P, et al. Role of oxidative stress in pathology of chronic prostatitis/chronic pelvic pain syndrome and male infertility and antioxidants function in ameliorating oxidative stress. Biomed Pharmacother. 2018; 106:714.

Correspondence Juan Sebastián Moncada López, Microbiol. jsebastian.moncada@udea.edu.co Jenniffer Puerta Suárez, PhD jenniffer.puerta@udea.edu.co Walter Darío Cardona Maya, PhD (Corresponding Author) wdario.cardona@udea.edu.co Grupo Reproducción, Facultad de Medicina, Universidad de Antioquia, Medellin (Colombia)

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Infectious complications of endourological treatment of kidney stones: A 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, Panagiotis Mourmouris 7, 13, Adama Ouattara 8, 13, Gianpaolo Perletti 9, 10, 13, Joseph Philipraj 11, 13, Alberto Trinchieri 12, 13, Noor Buchholz 13 1 Smart

* 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

LIST

OF SELECTED PAPERS AND

PICO

TABLES

RIRS vs PCNL 1. Agrawal MS, Mishra D. Minimally-invasive percutaneous nephrolithotomy versus retrograde intrarenal surgery for treatment of medium sized (10-20 mm) renal calculi-a prospective study Journal of Endourology. 2016; 30(Suppl2):A204-A205. 2. Fayad AS, Elsheikh MG, Ghoneima W. Tubeless mini-percutaneous nephrolithotomy versus retrograde intrarenal surgery for lower calyceal stones of ≤ 2 cm: A prospective randomised controlled study. Arab Journal of Urology. 2017; 15:36-41. 3. Gu XJ, Lu JL, Xu Y. Treatment of large impacted proximal ureteral stones: randomized comparison of minimally invasive percutaneous antegrade ureterolithotripsy versus retrograde ureterolithotripsy. World J Urol. 2013; 31:1605-1610. 4. Jain M, Manohar C, Nagabhushan M, Keshavamurthy R. A comparative study of minimally invasive percutaneous nephrolithotomy and retrograde intrarenal surgery for solitary renal stone of 1-2 cm Urology Annals. 2021; 13:226-231. 5. Jiang K, Chen H, Yu X, Chen Z, et al. The “all-seeing needle” micro-PCNL versus flexible ureterorenoscopy for lower calyceal stones of ≤ 2 cm. Urolithiasis. 2019; 47:201-206. 6. Jin L, Yang B, Zhou Z, Li N. Comparative Efficacy on Flexible Ureteroscopy Lithotripsy and Miniaturized Percutaneous Nephrolithotomy for the Treatment of Medium-Sized Lower-Pole Renal Calculi. J Endourol. 2019; 33:914-919. 7. Kumar A, Kumar N, Vasudeva P, et al. A prospective, randomized comparison of shock wave lithotripsy, retrograde intrarenal surgery and miniperc for treatment of 1 to 2 cm radiolucent lower calyceal renal calculi: a single center experience. J Urol. 2015; 193:160-164. 8. Lee JW, Park J, Lee SB, et al. Mini-percutaneous Nephrolithotomy vs Retrograde Intrarenal Surgery for Renal Stones Larger Than 10 mm: A Prospective Randomized Controlled Trial. Urology 2015; 86:873-877. 9. Li JW, Wang F, Cai FZ, Gao HZ. [Staged retrograde flexible ureteroscopic lithotripsy versus miniaturized percutaneous nephrolithotomy for renal stones of 2-4 cm in diameter: a randomized controlled trial]. Nan Fang Yi Ke Da Xue Xue Bao. 2016; 36:1672-1676. Chinese. 10. Mhaske S, Singh M, Mulay A, et al. Miniaturized percutaneous nephrolithotomy versus retrograde intrarenal surgery in the treatment of renal stones with a diameter &lt;15 mm: A 3-year open-label prospective study. Urology Annals. 2018; 10:165-169. 11. Oo SM. Outcomes of minipercutaneous nephrolithotomy versus retrograde intrarenal surgery in lower pole renal stone. International Journal of Urology. 2020; 27(Suppl1):40. 12. Sabnis RB, Ganesamoni R, Doshi A, et al. Micropercutaneous nephrolithotomy (microperc) vs retrograde intrarenal surgery for the management of small renal calculi: a randomized controlled trial. BJU Int. 2013; 112:355-61. No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2022; 94, 1

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13. Wen J, Xu G, Du C, Wang B. Minimally invasive percutaneous nephrolithotomy versus endoscopic combined intrarenal surgery with flexible ureteroscope for partial staghorn calculi: A randomised controlled trial. International Journal of Surgery. 2016; 28:22-27. 14. Zeng G, Zhang T, Agrawal M, et al. Super-mini percutaneous nephrolithotomy (SMP) vs retrograde intrarenal surgery for the treatment of 1-2 cm lower-pole renal calculi: an international multicentre randomised controlled trial. BJU International. 2018; 122:1034-1040. 15. Zhang H, Hong TY, Li G, et al. Comparison of the Efficacy of Ultra-Mini PCNL, Flexible Ureteroscopy, and Shock Wave Lithotripsy on the Treatment of 1-2 cm Lower Pole Renal Calculi. Urol Int. 2019; 102:153-159.

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MINI vs PCNL 1. Agrawal M, Mishra D. Minimally-invasive percutaneous nephrolithotomy versus conventional percutaneous nephrolithotomy for treatment of large sized (20-30 mm) renal calculi-a prospective study. J Endourol. 2018; 32(Suppl2):A59-A60. 2. Bozzini G, Aydogan TB, Müller A, et al. A comparison among PCNL, Miniperc and Ultraminiperc for lower calyceal stones between 1 and 2 cm: A prospective, comparative, multicenter and randomised study. BMC Urology. 2020; 20:1. 3. Cheng F, Yu W, Zhang X, et al. Minimally invasive tract in percutaneous nephrolithotomy for renal stones. J Endourol. 2010; 24:1579-82. 4. Guddeti RS, Hegde P, Chawla A, et al. Super-mini percutaneous nephrolithotomy (PCNL) vs standard PCNL for the management of renal calculi of < 2 cm: a randomised controlled study. BJU Int. 2020; 126:273-279. 5. Güler A, Erbin A, Ucpinar B, et al. Comparison of miniaturized percutaneous nephrolithotomy and standard percutaneous nephrolithotomy for the treatment of large kidney stones: a randomized prospective study. Urolithiasis. 2019; 47:289-295. 6. Sakr A, Salem E, Kamel M, et al. Minimally invasive percutaneous nephrolithotomy vs standard PCNL for management of renal stones in the flank-free modified supine position: single-center experience. Urolithiasis. 2017; 45:585-589. 7. Tepeler A, Akman T, Silay MS, et al. Comparison of intrarenal pelvic pressure during micro-percutaneous nephrolithotomy and conventional percutaneous nephrolithotomy. Urolithiasis. 2014; 42:275-279. 8. Zeng G, Cai C, Duan X, et al. Mini Percutaneous Nephrolithotomy Is a Noninferior Modality to Standard Percutaneous Nephrolithotomy for the Management of 20-40 mm Renal Calculi: A Multicenter Randomized Controlled Trial. Eur Urol. 2021; 79:114-121. 9. Sabnis R, Ganpule A, Desai M. Is there any rationale of preferring ultraminiperc (MIP S) over miniperc(MIP M)?Prospective randomized study. J Endourol. 2016; 30(Suppl2):A376-A377.

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Paper considered for qualitative analysis

Tubeless vs non tubeless List of papers

1. Agrawal MS, Agrawal M, Gupta A, et al. A randomized comparison of tubeless and standard percutaneous nephrolithotomy. J Endourol. 2008; 22:439-442. 2. Bhat S, Lal J, Paul F. A randomized controlled study comparing the standard, tubeless, and totally tubeless percutaneous nephrolithotomy procedures for renal stones from a tertiary care hospital Indian J Urol. 2017; 33:310-314. 3. Istanbulluoglu MO, Ozturk B, Gonen M, et al. Effectiveness of totally tubeless percutaneous nephrolithotomy in selected patients: A prospective randomized study. International Urol Nephrol. 2009; 41:541-545. 4. Lu Y, Ping J-G, Zhao X-J, et al. Randomized prospective trial of tubeless versus conventional minimally invasive percutaneous nephrolithotomy. World J Urol. 2013; 31:1303-1307. 5. Mishra S, Sabnis RB, Kurien A, et al. Questioning the wisdom of tubeless percutaneous nephrolithotomy (PCNL): a prospective randomized controlled study of early tube removal vs tubeless PCNL. BJU Int. 2010; 106:1045-8. 6. Moosanejad N, Firouzian A, Hashemi SA, et al. Comparison of totally tubeless percutaneous nephrolithotomy and standard percutaneous nephrolithotomy for kidney stones: A randomized, clinical trial. Braz J Med Biol Res. 2016; 49:e4878.

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Tubeless vs tubeless with sealant/infiltration with bupivacaine 1. Shah HN, Hegde S, Shah JN, et al. A Prospective, Randomized Trial Evaluating the Safety and Efficacy of Fibrin Sealant in Tubeless Percutaneous Nephrolithotomy. J Urol. 2006; 176:2488-2493. 2. Titaram S, Nualyong C, Taweemonkongsap T, et al. The impact of gelatin-sealant in the access tract after tubeless percutaneous nephrolithotomy: A randomized controlled trial. J Med Ass Thai. 2017; 100(Suppl2):S132-S137. 3. Mankongsrisuk T, Nualyong C, Tantiwong A, et al. Efficacy of nephrostomy tract infiltration with bupivacaine before and after tubeless percutaneous nephrolithotomy: A randomized control study. J Med Ass Thai. 2017; 100(Suppl2):S138-S143.

Suctioning sheath 1. Huang J, Song L, Xie D, et al. A Randomized Study of Minimally Invasive Percutaneous Nephrolithotomy (MPCNL) with the aid of a patented suctioning sheath in the treatment of renal calculus complicated by pyonephrosis by one surgery BMC Urology. 2016; 16:1 Article Number 71. 2. Lai D, Xu W, Chen M, et al. Minimally Invasive Percutaneous Nephrolithotomy with a Novel Vacuum-assisted Access Sheath for obstructive calculous pyonephrosis: A Randomized Study. Urol J. 2020; 17:474-479. 3. Zhong W, Wen J, Peng L, Zeng G. Enhanced super-mini-PCNL (eSMP): low renal pelvic pressure and high stone removal efficiency in a prospective randomized controlled trial. World J Urol. 2021; 39:929-934. 4. Eisner B, Agrawal S, Desai M, et al. Initial human experience with a novel stone aspiration device used during ureteroscopic lithotripsy for renal stones. J Urol. 2020; 203(Suppl4):e211.

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Comparison of perioperative prophylaxis with/without short oral antibiotic course in patients with higher risk of infectious complications 1. Sur RL, Krambeck AE, Large T, et al. A Randomized Controlled Trial of Preoperative Prophylactic Antibiotics for Percutaneous Nephrolithotomy in Moderate to High Infectious Risk Population: A Report from the EDGE Consortium. J Urol. 2021; 205:1379-1386.

Comparison of perioperative prophylaxis with/without short oral antibiotic course 1. Bag S, Kumar S, Taneja N, et al. One week of nitrofurantoin before percutaneous nephrolithotomy significantly reduces upper tract infection and urosepsis: A prospective controlled study. Urology. 2011; 77:45-49. 2. Chew BH, Miller NL, Abbott JE, et al. A Randomized Controlled Trial of Preoperative Prophylactic Antibiotics Prior to Percutaneous Nephrolithotomy in a Low Infectious Risk Population: A Report from the EDGE Consortium. J Urol. 2018; 200:801-808. 3. Demirtas A, Yildirim YE, Sofikerim M, et al. Comparison of infection and urosepsis rates of ciprofloxacin and ceftriaxone prophylaxis before percutaneous nephrolithotomy: a prospective and randomised study. Scientific World Journal. 2012; 2012:916381. 4. Dogan HS, Sahin A, Cetinkaya Y, et al. Antibiotic prophylaxis in percutaneous nephrolithotomy: prospective study in 81 patients. J Endourol. 2002; 16:649-653. 5. Mariappan P, Smith G, Moussa SA, Tolley DA. One week of ciprofloxacin before percutaneous nephrolithotomy significantly reduces upper tract infection and urosepsis: a prospective controlled study. BJU Int. 2006; 98:1075-9. 6. Seyrek M, Binbay M, Yuruk E, et al. Perioperative prophylaxis for percutaneous nephrolithotomy: randomized study concerning the drug and dosage. J Endourol. 2012; 26:1431-6. 7. Tuzel E, Aktepe OC, Akdogan B. Prospective comparative study of two protocols of antibiotic prophylaxis in percutaneous nephrolithotomy. J Endourol. 2013; 27:172-6.

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Antibiotic prophylaxis for PCNL (comparison of antibiotics)

1. Song F, Liu C, Zhang J, et al. Antibacterial effect of Fosfomycin tromethamine on the bacteria inside urinary infection stones. Int Urol Nephrol. 2020; 52:645-654. 2. Taken K, Asik A, Eryilmaz R, et al. Comparison of ceftriaxone and cefazolin sodium antibiotic prophylaxis in terms of SIRS/urosepsis rates in patients undergoing percutaneous nephrolithotomy, Journal of Urological Surgery 2019; 6:2(111-117). Plus, two studies included in the previous section (Demirtas 2012, Seyrek 2012)

Antibiotic prophylaxis for PCNL (vs placebo)

1. Fourcade RO. Antibiotic prophylaxis with cefotaxime in endoscopic extraction of upper urinary tract stones: a randomized study. The Cefotaxime Cooperative Group. J Antimicrob Chemother. 1990; 26(supplA):77-83.

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Infectious complications of endourology for kidney stones

Antibiotic prophylaxis for RIRS (vs placebo)

1. Zhao Z, Fan J, Sun H, et al. Recommended antibiotic prophylaxis regimen in retrograde intrarenal surgery: evidence from a randomised controlled trial. BJU Int. 2019; 124:496-503.

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RISK RIRS vs PCNL

Mini vs standard PCNL

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Archivio Italiano di Urologia e Andrologia 2022; 94, 1

BIAS

Infectious complications of endourology for kidney stones

Tubeless vs standard - tubeless vs tubeless with sealant/bupivacaine infiltration

Suctioning sheath

Antibiotic prophylaxis

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

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R. Bapir, K. Hassan Bhatti, A. Eliwa, et al.

SUMMARY

FINDINGS

Table 1a. Post-operative complications of retrograde intrarenal surgery (RIRS) vs. percutaneous nephrolithotomy (PCNL).

Table 1b. Post-operative complications of miniaturized percutaneous nephrolithotomy (mini-PCNL) vs. standard PCNL.

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Archivio Italiano di Urologia e Andrologia 2022; 94, 1

Infectious complications of endourology for kidney stones

Table 1c. Post-operative complications of tubeless percutaneous nephrolithotomy (PCNL) vs. standard percutaneous nephrolithotomy (PCNL).

Table 1d. Post-operative percutaneous nephrolithotomy (PCNL) with suctioning sheath vs. standard PCNL.

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

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R. Bapir, K. Hassan Bhatti, A. Eliwa, et al.

Table 1e. Post-operative complications of percutaneous nephrolithotomy (PCNL) with simple perioperative antibiotic prophylaxis (PAP) plus a short oral antibiotic course vs. PCNL with simple PAP.

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Infectious complications of endourology for kidney stones

PUBLICATION BIAS

Archivio Italiano di Urologia e Andrologia 2022; 94, 1

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Archivio Italiano di Urologia e Andrologia 2022; 94, 1

Infectious complications of endourology for kidney stones

Table 2. 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.

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