Archivio Italiano di Urologia e Andrologia - Vol. 92 - n. 2 - 2020 by Edizioni Scripta Manent

ISSN 1124-3562

Vol. 92; n. 2, June 2020

Poste Italiane S.p.A. - Spedizione in abbonamento postale - D.L. 353/2003 (conv. in L. 27/02/2004 n. 46) Art. 1, comma 1 DCB Milano

Archivio Italiano di Urologia e Andrologia / Archives of Italian Urology and Andrology - Vol. 92; n. 2 June 2020

COVID-19 67

Hospital care in Departments defined as COVID-free: A proposal for a safe hospitalization protecting healthcare professionals and patients not affected by COVID-19 Rosario Leonardi, Piera Bellinzoni, Luigi Broglia, Renzo Colombo, Davide De Marchi, Lorenzo Falcone, Guido Giusti, Vincenzo Grasso, Guglielmo Mantica, Giovanni Passaretti, Silvia Proietti, Antonio Russo, Giuseppe Saitta, Salvatore Smelzo, Nazareno Suardi, Franco Gaboardi, UrOP Executive Committee

COVID-19 pandemic and its implications on sexual life: Recommendations from the Italian Society of Andrology Carlo Maretti, Salvatore Privitera, Davide Arcaniolo, Lorenzo Cirigliano, Adele Fabrizi, Michele Rizzo, Carlo Ceruti, Ilaria Ortensi, Stefano Lauretti, Tommaso Cai, Marco Bitelli, Fabrizio Palumbo, Alessandro Palmieri

COVID-19 pandemic and uro-oncology follow-up: A “virtual” multidisciplinary team strategy and patients’ satisfaction assessment Francesca Ambrosini, Andrea Di Stasio, Guglielmo Mantica, Barbara Cavallone, Armando Serao

Comment on Hospital care in Departments defined as COVID-free: A proposal for a safe hospitalization protecting healthcare professionals and patients not affected by COVID-19 Alessandro Tafuri, Andrea Minervini, Antonio Celia, Luca Cindolo, Riccardo Schiavina, Bernardo Rocco, Angelo Porreca, Alessandro Antonelli

ORIGINAL PAPERS 82

Holmium laser prostatectomy in a tertiary Italian center: A prospective cost analysis in comparison with bipolar TURP and open prostatectomy Riccardo Schiavina, Lorenzo Bianchi, Marco Giampaoli, Marco Borghesi, Hussam Dababneh, Francesco Chessa, Cristian Pultrone, Andrea Angiolini, Umberto Barbaresi, Matteo Cevenini, Fabio Manferrari, Alessandro Bertaccini, Angelo Porreca, Eugenio Brunocilla

Can multiparametric ultrasound improve cognitive MRI/TRUS fusion prostate biopsy Pietro Pepe, Ludovica Pepe, Paolo Panella, Michele Pennisi

Intensive simulation training on urological mini-invasive procedures using Thiel-embalmed cadavers: The IAMSurgery experience Guglielmo Mantica, Giovannalberto Pini, Davide De Marchi, Irene Paraboschi, Francesco Esperto, André Van der Merwe, Heidi Van Deventer, Massimo Garriboli, Nazareno Suardi, Carlo Terrone, Rosario Leonardi

Pediatric-adolescent andrology: Single centre experience Nicola Zampieri, Francesco Camoglio

102

The pathological and clinical features of anterior lesions of prostate cancer: Evaluation in a single cohort of patients Daniele D’Agostino, Paolo Corsi, Michele Colicchia, Daniele Romagnoli, Gian Maria Busetto, Matteo Ferro, Alessandro Tafuri, Matteo Cevenini, Federico Mineo Bianchi, Marco Giampaoli, Angelo Porreca

CASE REPORTS 107

Ureteral iliac artery fistula in idiopathic retroperitoneal fibrosis: A case report Eugenio Di Grazia, Tiziana La Malfa, Gherardo Gasso

109

Management of a kidney stone in ectopic pelvic kidney with Extracorporeal Shockwave Litothripsy: Description of a case and revision of literature Carmelo Agostino Di Franco, Maurizio Burrello, Francesco Guzzardi, Eva Intagliata, Irina Oxenius, Lavinia Galvagno, Calogero Cordaro

112

Thrombosis of the posterior scrotal vein associated with essential thrombocytemia: Report of a case Andrea Solinas

114 117

Penile verrucous squamous cell carcinoma: A rare case report

̧ ağatay Tosun, Levent Verim Omer Yuksel, Emre Karabay, Osman Bilen, C

Feasibility of a single session retrograde endoscopic laser lithotripsy of two large stones located in a bifid urinary tract. Presentation of a rare case Diomidis Kozyrakis, Anastasios Zarkadas, Ilias Katsaros, Vasileios Mourkas, Zisis Kratiras

119

Bilateral subcutaneous pyelovesical bypass in a Hautmann neobladder followed by a mononeuropathy multiplex and an underlying polyarteritis nodosa diagnosis Konstantina G. Yiannopoulou, Aikaterini I. Anastasiou, Ioannis Katafigiotis, Dimitrios Papadopoulos, Ioannis Anastasiou continued on page III

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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ONLINE ONLY http://www.edizioniscriptamanent.eu/2019/06/03/archivio-italiano-di-urologia-e-andrologia https://www.pagepressjournals.org/index.php/aiua

ORIGINAL PAPERS & CASE REPORTS 121

The impact of nutrition and lifestyle on male fertility Mahmoud Benatta, Redha Kettache, Noor Buchholz, Alberto Trinchieri

132

Percutaneous nephrolithotomy: Three-needle technique on two planes. Cury’s technique Carlos Abib Cury, Analaura de Oliveira Cury, Victoria Caroline Pagelkopf, Vinicius Ramos Bezerra de Morais, Vitor de Almeida Fernandes, Miguel Bonfitto

136

The importance of PSA-Density in active surveillance for prostate cancer

142

Short term effects of home-based bladder training and pelvic floor muscle training in symptoms of urinary incontinence

Caner Ediz, Serkan Akan, Muhammed Cihan Temel, Omer Yilmaz

Aybuke Ersin, Sule B. Demirbas, Fatih Tarhan

146

Microorganisms and antibiotic susceptibilities isolated from urine cultures

149

Comparison of the efficiency, safety and pain scores of holmium laser devices working with 20 watt and 30 watt using in retrograde intrarenal surgery: One center prospective study

Abdullah Gul, Esra Gurbuz Sercan Sari, Mehmet C¸ağlar C¸akici, ̇brahim I Güven Kartal, Volkan Selmœï, Harun Özdemïr, Hakkı Ugur Ozok, Ahmet Nihat Karakoyunlu, Serkan Yildiz, Emre Heps¸en, Serra Ozbal, Hamit Ersoy

153

Protective effect of chlorogenic acid on renal ischemia/reperfusion injury in rats Tuncay Toprak, Cagri Akin Sekerci, Hasan Riza Aydın, Mehmet Akif Ramazanoglu, Fatma Demet Arslan, Banu Isbilen Basok, Hatice Kucuk, Huseyin Kocakgol, Hamit Zafer Aksoy, Seyhan Sumeyra Asci, Yılören Tanıdır

158

Evaluation of the influence of subinguinal varicocelectomy procedure on seminal parameters, reproductive hormones and testosterone/estradiol ratio

162

Paraurethral cyst in a newborn

Ünal Öztekin, Mehmet Caniklioğlu, Sercan Sarı, Volkan Selmi, Abdullah Gürel, Mehmet S¸akir Tas¸pınar, Levent Is¸ıkay Raziye Ergun, Duran Yildiz, Cagri Akin Sekerci, Hasan Kahveci

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DOI: 10.4081/aiua.2020.2.67

ORIGINAL PAPER

Hospital care in Departments defined as COVID-free: A proposal for a safe hospitalization protecting healthcare professionals and patients not affected by COVID-19 Rosario Leonardi 1, Piera Bellinzoni 2, Luigi Broglia 2, Renzo Colombo 3, Davide De Marchi 2, Lorenzo Falcone 1, Guido Giusti 2, Vincenzo Grasso 1, Guglielmo Mantica 4, Giovanni Passaretti 2, Silvia Proietti 2, Antonio Russo 2, Giuseppe Saitta 2, Salvatore Smelzo 2, Nazareno Suardi 4, Franco Gaboardi 2, UrOP Executive Committee * 1 Musumeci

GECAS Clinic, Gravina di Catania, Catania, Italy; of Urology, San Raffaele Turro Hospital, Milan, Italy; 3 Department of Urology, San Raffaele Hospital, Milan, Italy; 4 Department of Urology, IRCCS Policlinico San Martino Hospital, University of Genova, Genova, Italy; 2 Department

Summary

The COVID-19 pandemic influenced the normal course of clinical practice leading to significant delays in the delivery of healthcare services for patients non affected by COVID-19. In the near future, it will be crucial to identify facilities capable of providing health care in compliance with the safety of healthcare professionals, administrative staff and patients. All the staff involved in the project of a Covid-free hospital should be subjected to a diagnostic swab for COVID-19 before the beginning of healthcare activity and then periodically in order to avoid the risk of contamination of patients during the process of care. The modifications of various activities involved in the process of care are described: outpatient care, reception of inpatients, inpatient ward and operating room. For outpatient care, modality of appointment procedure, characteristics of waiting room and personal protective equipment (PPE) for healthcare professionals and administrative staff are presented. Reception of inpatients shall be conditional on a negative swab for COVID-19 obtained with a drive-in procedure. The management of the operating room represents the most crucial step of the patient's care process. The surgical team should be restricted and monitored with periodic swabs; surgical procedures should be performed by experienced surgeons according to standard procedures; surgical training experimental treatments and research protocols should be suspended. Adequate personal protective equipment and measures to reduce aerosolization in the operating room (closed circuits, continuous cycle insufflators, fume extraction) should be adopted. Prevention of possible transmission of the virus during procedures in open, laparoscopic and endoscopic surgery is to use a multi-tactic approach, which includes correct filtration and ventilation of the operating room, the use of appropriate PPE (FFP3 plus surgical mask and protective visor for all the staff working in the operating room) and smoke evacuation devices with a suction and filter system.

KEY WORDS: COVID-19; Pandemy; Surgery; Endoscopy; Filtration. Submitted 20 April 2020; Accepted 21 April 2020

INTRODUCTION

This document was based on the review of information materials from AGENAS (Agenzia Nazionale per i Servizi Sanitari), SIU (Italian Society of Urology), SAGES (American

Society of Gastroenterology Endoscopic Surgery), EAES (European Society of Endoscopic Surgery) and Italian Society of Endoscopic Surgery. Prevention measures, personal protective equipment (PPE) and protocols for healthcare professional, administrative staff and patients have been included trying to implement the best prevention measures against COVID-19 infection in public or private healthcare facilities. The COVID-19 pandemic influenced the normal course of clinical practice through multiple mechanisms leading to significant delays in the delivery of healthcare services. The possibility of meeting the demand for healthcare in the near future will depend on the duration of the epidemic, its economic and social consequences, and also on changes of the population caused by the infection itself. In consideration of the awareness that for many months we will still have to live with the presence of the virus among the population, it becomes mandatory an immediate rationalization of resources in order to ensure continuity of healthcare for patients not affected by COVID-19. It is crucial to identify facilities capable of providing health care in compliance with the safety of healthcare professionals, administrative staff and patients who need medical treatment. The triage of medical and surgical procedures must take into account the heterogeneity of the pathologies to be treated, the variability of the timing useful for effective treatment, the different surgical approaches and non-surgical alternatives. It should not be forgotten that the epidemic has heterogeneous loco-regional outbreaks with differentiated measures from local government authorities. Although there is no official data, it has been reported that a new health migration is underway, with a flow of patients moving from high endemic areas to areas where they can obtain adequate care (AGENAS-SIU). This document aims to provide indications in the triage of patients and in the optimization of the resources available in this difficult moment. As a precondition, all the staff involved in the project of a Covid-free hospital should be subjected to a diagnostic swab for COVID-19 before the beginning of healthcare activity. The swab should be

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2020; 92, 2

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R. Leonardi, P. Bellinzoni, L. Broglia, et al.

repeated every two weeks in order to avoid the risk of contamination of patients during the process of care. If reliable tests will be validated, able to replace the swab in the diagnosis of COVID-19, these tests could be considered as faster and less expensive screening procedure to monitor the absence of infection in the medical staff and hospital nursing. We divided the text into several chapters concerning the various activities involved in the process of care: – Outpatient care – Reception of inpatients – Inpatient ward – Operating room. Outpatient visits Appointment procedure The outpatient visit should be booked through a telephone triage. Exclusion criteria: – Coming from high endemic areas (red areas) – Referred flu symptoms (sore throat, cough, rhinorrhea) – Temperature – State of quarantine or cohabitation with subjects in compulsory quarantine. Patients must be informed that they must access to the office equipped with a surgical mask. The patient can be accompanied by a person who however will not enter in the office at the time of the visit. If it is necessary to provide information to the companion, this will be convened separately so that the criteria for social distancing are respected within the office. Upon entering in the facility it would be useful to perform a body temperature measurement. Waiting room In relation to the size of the waiting room, one or more patients can be accepted. It is mandatory to maintain a distance between the patients and their companions of at least two meters. Healthcare professionals Healthcare professionals must be equipped with Personal Protective Equipment (PPE) including FFP3 mask and protective goggles or visors. Administrative staff (payment of outpatient service) Must be equipped with PPE (FFP2 mask). Note: It is important that the area of the consultations must be separated from the area of hospitalization. Hospitalization of the patient for surgery Indispensable condition for taking care of the patient (swab testing) An indispensable condition for the patient to be candidate for surgical treatment is that of being subjected to a swab for COVID-19 before entering the facility. How and how long before admission, it depends on the structural and organizational characteristics of the hospital and the time needed to obtain the result of the swab.

Archivio Italiano di Urologia e Andrologia 2020; 92, 2

Our suggested option is the drive-in swab. A protected area (parking) must be identified where the car with the patient on board can stop for the time necessary to perform the swab. The staff responsible for the procedure must be provided with the maximum individual protection (suit, FFP3 mask, protective visor and gloves). In the case that the Hospital could arrange a special area for pre-hospitalization the patient could be accepted after the swab in this area of the hospital to wait for the response. General criteria Protect the patient from potential Covid infections in the hospital setting. Protect staff and other patients from contamination, including mutual. The surgical team should be restricted and monitored with periodic swabs; surgical procedures should be performed by experienced surgeons according to standard procedures; surgical training experimental treatments and research protocols should be suspended. Admission of the patient to the hospital for elective surgery The call of patients for elective surgery must take place through a telephone interview to rule out a possible contagion from Coronavirus SARS-CoV-2: – clinical criteria: cough, rhinorrhea, body temperature rise, pharyngodynia, abdominal pain, conjunctivitis – epidemiological criteria: direct contact with positive COVID-19 patient (cohabitation/interview for more than 15 minutes in the same environment, attendance at hospital facilities); origin from high endemic geographic areas identified by current epidemiological data The patient must be informed that the following steps will be followed on the day of the call to enter the hospital: – arrival at the facility will take place starting at 7.30 with a staggering between one patient and the other of about 15 min – arrival by car and parking in the drive-in swab area. – return to his/her home where the patient must respect strict self-isolation until he/she receives the call from the triage staff who communicates the outcome of the swab – as an alternative (especially for patients domiciled far away from the hospital), the hospital could offer hospitality in a separate area with hotel service in individual rooms with private bathroom (nursing and service staff of this area must wear suitable personal protective equipment including gloves, FFP2 mask, plus surgical masks, if the former are equipped with an exhalation valve, waterproof gown for contacts, and protective visor) – any kind of personal contact of the patient with the other patients has to be avoided – in the case of a delayed result of the swab, food must be delivered out of the room in disposable tray with a sealable bag where the patient should pour food waste including the tray – food waste must be handled as special hazardous waste – room must undergo sanitization at the end of the stay – in the event of a negative outcome of the swab, the patient can be admitted to the ward, staying fasting, to start the acceptance and hospitalization procedure

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Hospitalization during Covid emergency

– in the event of a positive outcome, the patient is invited to inform the competent health authorities to arrange for self-isolation at home or hospitalization in the Covid ward. The patient can be accompanied by a family member or friend who will be able to assist him/her in the swab procedure and in the subsequent phase of hospitalization but who will not be admitted to the wards. Both the patient and the companion, in the various stages of the swab procedure and hospitalization must be equipped with a mask. Entry of the patient to the facility Waiting room Waiting room must be organized taking into account social distancing. Administrative staff appointed to accept the patient Front-office administrative staff must carry out their activity protected by a transparent glass barrier and equipped with PPE (FFP2 mask). Medical and nursing staff appointed to accept the patient Collection of clinical history, compilation of the clinical records and administration of the informed consent must be done with compliance of the distancing measures. Discussion of consent to surgery should include an illustration of the risk of COVID-19 exposure and its potential consequences on clinical outcomes. Personnel dedicated to blood sampling for blood chemistry and to cardiological and anesthesiological evaluation must be equipped with PPE (FFP2 masks with or without surgical mask based on the presence or absence of an exhalation valve, protective visor, gloves and waterproof gown). Everything can take place in a dedicated area where the rules of social distancing are respected or directly in the hospital room. Note: The attending physician and/or the patient's reference specialist should be invited to inform the head of the anesthesia department or his/her delegate, before the hospitalization phase, if there are, in his/her opinion, pathologies that may contraindicate the intervention or that could request diagnostic investigations before hospitalization. In this case, the patient should be booked for an anesthesiological outpatient visit in a reasonable time before admission. Entry of the patient into the ward After the acceptance phase and the first phase of evaluation in preparation for the surgical procedure, the patient is sent to the hospital ward and housed in a single room with personal bathroom. The medical and nursing staff, in this phase, must always wear suitable personal protective equipment (gloves, FFP2 mask, plus surgical masks, if the former are equipped with an exhalation valve, waterproof gown for contacts, protective visor). Management of the operating room General considerations Management of the operating room represents the most crucial step of the patient's care process. Even if the

patient underwent a swab the day before with a negative result, this is not sufficient to safely exclude a positivization in the following day. In the operating room for a whole series of conditions related to intubation and to the use of endoscopic and laparoscopic surgical instruments, the risk of transmission is maximum. For this reason, the most effective PPE systems must be adopted and it is necessary to implement well-coded behaviors that can be summarized as follows: – the surgical team should be restricted, monitored with periodic swabs and subjected to restrictive measures to limit the risk of infection – there should be no change of staff in the room – surgical procedures should be performed by experienced surgeons to reduce operating times and the risk of complications (therefore, the suspension of surgical training is recommended – the standard approach should be maintained, in order not to compromise the outcome and standardize the operating room times – surgical staff should not stay in the operating room during intubation maneuvers, waiting a few minutes from their conclusion before entering, leaving any infected droplets to settle – it would be desirable for intubation and extubation to take place inside a negative pressure room (https://www.asahq.org/in-the-spotlight/coronavirusCOVID-19-information) (1, 2) – all measures should be put in place to reduce the risk of contagion among healthcare professionals by adopting adequate personal protective equipment. All members of the operating room staff must use PPE (FFP3 mask). Appropriate clothing and face shields must be used. These measures should be used during all pandemic surgical procedures, regardless of known or suspected Covid status. The positioning and removal of PPE must be performed according to the World Health Organization (WHO) and Centre for Disease Control and Prevention (CDC) guidelines (https://www.cdc.gov) – measures to reduce aerosolization in the operating room should be considered (closed circuits, insufflators continuous cycle, fume extraction). Note: Remember that the virus has been isolated very frequently in respiratory secretions, saliva and feces, rarely in the blood, exceptionally in the urine. Specific technical considerations There is very little evidence regarding the risks of virus spread related to the use of the laparoscopic surgical technique compared to the open approach (3). Emerging evidence and regular updates are provided by the website https://siceitalia.com/covid19/ It is recommended, however, to seriously consider the possibility of viral contamination of operating room personnel during surgery, be it open, laparoscopic or robotic. It is advisable to actively monitor strict application of protective measures for the safety of the operating room staff. Although previous research has shown that the laparoscopic technique can favor the aerosolization of pathogens present in the blood (Corynebacteria, Papillomavirus and HIV) (4-6), there is no evidence to indicate that this effect Archivio Italiano di Urologia e Andrologia 2020; 92, 2

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is also possible for the coronavirus, nor that the risk can be confined exclusively to minimally invasive surgical procedures. However, as a precaution, coronavirus should potentially be considered capable of aerosolizing. For this reason, the use of devices to filter CO2 should be strongly considered. For further information https://eaes.eu/eaesand-sages-recommendations-regarding-surgical-response-to-covid-19-crisis/ The proven benefits of minimally invasive treatment in terms of reduced duration of hospitalization and reduction of complications, as well as the potential advantages in terms of ultrafiltration of most or all aerosol particles, must be strongly considered. In fact, the filtration of aerosolized particles can be more difficult during open surgery. There may be an increased risk of virus exposure for endoscopists during upper gastrointestinal tract and airway procedures. When these procedures are necessary, the rigorous use of PPE of greater protection is recommended. The complete mask with FFP 3 should be considered for the whole team, following the guidelines of CDC (https://www.cdc.gov) or WHO (https://www. who.int) (5, 6). Filtration The smaller droplets, in contact with the ambient air (aerosol) can transmit the infection from one individual to another via the respiratory tract (within a certain distance). Currently, the "droplet" diameter classification system (from 5 to 10 Îźm) represents the unit of measurement used to evaluate the transmission mode of an infectious disease. Filtration can be an effective means of protection from virus release during minimally invasive surgery and endoscopy. Masks such as N95 respirators are designed to filter 95% of 0.3 micron and larger particles. Respiratory masks of protection class FFP3 offer the maximum possible protection from the pollution of breathing air with a protection of at least 99% from particles up to 0.6 Îźm in size. Purified air respirators (PAPR) can be useful for intubation, extubation, bronchoscopy, endoscopy and tracheostomy. Intraoperatively, filters are used to remove smoke and particles including viruses. Air particulate filters (HEPA) have a minimum efficiency index of 99.97% for the removal of particles with a diameter greater than or equal to 0.3 microns (6). ULPA (Ultra-Low Particulate Air) filters can remove 99.999% of airborne particles with a minimum particle penetration size of 0.05 microns. The Association of periOperative Registered Nurses (AORN) guidelines define ULPA as filters capable of removing particles of 0.1 microns (7). Filtration is also essential on a large scale in positive pressure operating rooms. HEPA filters positioned in the ceiling provide terminal cleaning. Currently, the best practice to reduce the possible transmission of the virus during procedures in open, laparoscopic and endoscopic surgery is to use a multi-tactic approach, which includes correct filtration and ventilation of the operating room, the use of appropriate PPE (FFP3 plus surgical mask, plus protective visor for all staff working in the operating room) and smoke evacuation devices with a suction and filter system (8).

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Practical filtration measures during laparoscopic surgery 1. The pneumoperitoneum must always be safely evacuated from the trocar connected to the filtration device before removing the trocars, extracting the operating piece or converting by laparotomy. 2. Once the trocars are positioned, their valves should not be opened during surgery, if possible. If it is necessary to change the insufflation site on another trocar, the valve must be closed before disconnecting the tubing and the valve of the new trocar must remain closed until the insufflation tubing has been connected. The insufflator must be activated before the new insufflation valve is open. This is to prevent the backflow of gas into the insufflator itself. 3. During the desufflation phase, all gas and exhaust fumes must pass through an ultra-filtration system, possibly activating the desufflation mode on the insufflator, if this mode is available. 4. If the insufflator in use does not have a desufflation function, it must be ensured that the valve that is used for insufflation has been closed before the CO2 flow is deactivated (even if there is a filter in line with the tube). Without taking this precaution, contaminated intra-abdominal CO2 can be pushed into the insufflator when the intra-abdominal pressure is higher than the pressure inside the insufflator. 5. The patient must be on the level at the time of desufflation. 6. The workpiece(s) must be extracted once all the CO2 gas and smoke have been evacuated. 7. Drainage pipes should only be used if absolutely necessary. 8. The methods of closing the accesses of the trocars with the use of sutures that allow the escape of gas and residual fumes must be avoided. The fascial plane must be closed after complete desufflation. 9. Laparoscopic hand-assisted techniques can lead to significant CO2 and smoke losses and should therefore be avoided. A protection system can be positioned after complete desufflation to remove more voluminous operating pieces and protect the wound. The piece can then be removed and closed. Systems for the evacuation of smoke and gas Below is a list of commercially available products that could potentially be used to filter CO2 gas or smoke evacuated during surgical procedures (Table 1). The list was provided by SAGES and EAES that stated they do not promote any of the following products. SAGES and EAES specify that they have sought information by contacting the known manufacturers, but the possibility is recognized that there are many other companies that may have similar products on sale. Surgeons should be aware of the characteristics of the products used in their facility and contact the product representative or refer to the product instructions for their use. For a consultation of the smoke and gas evacuation systems currently on the market, refer to the links: https://www.sages.org/resources-smoke-gas-evacuation-duringopen-laparoscopic-endoscopicprocedures/https://www.sages. org/wp-content/uploads/2020/03/Summary-of-CommerciallyAvailablePneumoperitoneum-Smoke-Evacuation-Systems.pdf

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Table 1. Commercially available systems for the evacuation of smoke and gas. Company Commercial brand

ConMed

Cooper

Ethicon

Medtronic

Olympus

Stryker

Northgate

AirSeal® (lap)

SeeClear® Plume-Away

Megadyne

ValleyLab RapidVac™

UHI-4

Pneumoclear™

Nebulae™ I

PlumePen® (open)

Mega Vac Plus

Buffalo Filter®

Mega Vac™

Smoke Management Open

Yes

PureView™

Mini Vac™ No

In addition to the smoke evacuation products, the Ultravision system can minimize aerosolized particles inside the pneumoperitoneum (https://www.sages.org/ wpcontent/uploads/2020/03/Ultravision-as-an-adjunct. pdf). Electrosurgical and laser units The electrosurgical units and lasers must be programmed to the lowest possible settings for the desired effect and for the correct execution of the surgery. The use of monopolar electrosurgery, ultrasound dissectors and advanced bipolar devices and lasers can lead to aerosolization of the particles. If available, the use of monopolar electrosurgical units with integrated smoke aspirator is recommended (9-15). During their use, the rules of maximum protection of the medical nursing staff apply as required for all procedures in the operating room. Measures to be put into practice during laparoscopic surgery 1. The skin incisions should be as small as possible to allow trocars to pass and at the same time prevent CO2 losses around the trocars. 2. The CO2 insufflation pressure should be kept to a minimum and, if available, ultra-filtration (smoke evacuation or filtration system) should be used (https://www.sages.org/resources-smoke-gas-evacuationduring-open-laparoscopic-endoscopicprocedures/). 3. All pneumoperitoneum must be safely evacuated through a filtration system before removal of the trocars, extraction of the surgical piece, or conversion by open surgical procedure. Measures to be put into practice during digestive endoscopy procedures (https://www.asge.org/home/joint-gi-society-message-covid19) (16, 17). 1. In the absence of the ability to control the aerosolized virus during endoscopic procedures, all members of the endoscopy room or operating room must wear appropriate PPE (FFP3 mask, appropriate clothing and face shields). The positioning and removal of PPE must be carried out according to the CDC guidelines (https://www.cdc.gov). 2. Since patients can present with gastrointestinal manifestations of COVID-19, all endoscopic procedures in an emergency regime should be considered high risk. 3. Since the virus has been found in multiple cells of the gastrointestinal tract and in all fluids (saliva, enteric content, feces and blood) surgical energy must be minimized.

Yes

4. Endoscopic procedures that require additional insufflation of CO2 or ambient air should be avoided until we have a better understanding of the aerosolization properties of the virus. This includes many of the endoscopic mucosal resection procedures and endoluminal procedures. 5. Removing the caps on the endoscopes could release fluid and/or air and should be avoided.

REFERENCES 1. Wax RS, Christian MD. Practical recommendations for critical care and anesthesiology teams caring for novel coronavirus (2019nCoV) patients. Can J Anaesth. 2020 Feb 12 [Epub ahead of print]. 2. Zucco L, Levy N, Ketchandji D, et al. Anesthesia Patient Safety Foundation. https://www.apsf.org/news-updates/perioperativeconsiderations-for-the-2019-novel-coronavirus-covid-19/. Visited the 14th April 2020. 3. Zheng MH, Boni L, Fingerhut A. Minimally invasive surgery and the novel coronavirus outbreak: lessons learned from Italy. Annals of Surgery. 2020. [Accepted for Publication]. 4. Alp E, Bijl D, Bleichrodt RP, Hansson B, Voss A. Surgical smoke and infection control. J Hosp Infect. 2006; 62:1-5. 5. Kwak HD, Kim SH, Seo YS, et al. Detecting hepatitis B virus in surgical smoke emitted during laparoscopic surgery. Occup Environ Med. 2016; 73:857-863. 6. Choi SH, Kwon TG, Chung SK, Kim TH. Surgical smoke may be a biohazard to surgeons performing laparoscopic surgery. Surg Endosc. 2014; 28:2374-80. 7. Repici A, Maselli R, Colombo M, et al. Coronavirus (COVID-19) outbreak: what the department of endoscopy should know. Gastrointest Endosc. 2020; pii: S0016-5107(20)30245-5. 8. Zucco L, Levy N, Ketchandji D, et al. Perioperative Considerations for the 2019 Novel Coronavirus (COVID-19) https://www.apsf.org/ news-updates/perioperative-considerations-for-the-2019-novel-coronavirus-covid-19/. Visited the 15th April 2020. 9. Parsa RS, Dirig NF, Eck IN, Payne III WK. Surgical smoke and the orthopedic implications. The Internet Journal of Orthopedic Surgery 2015; Volume 24 Number 1. 10. Gloster HM Jr, Roenigk RK. Risk of acquiring human papillomavirus from the plume produced by the carbon dioxide laser in the treatment of warts. J Am Acad Dermatol. 1995, 32:436-41. 11. Garden JM, O‘Banion MK, Shelnitz LS, et al. Papillomavirus in the vapor of carbon dioxide laser-treated verrucae. JAMA. 1988; 259:1199-1202. 12. Ferenczy A, Bergeron C, Richart RM. Human papillomavirus Archivio Italiano di Urologia e Andrologia 2020; 92, 2

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DNA in CO2 laser-generated plume of smoke and its consequences to the surgeon. Obstet Gynecol. 1990; 75:114-118.

transmission of viral disease via the CO2 laser plume and ejecta. J Reprod Med. 1990; 35:1117-23.

13. Baggish MS, Poiesz BJ, Joret D, et al. Presence of human immunodeficiency virus DNA in laser smoke. Lasers Surg Med. 1991; 11:197-203.

16. Gu J, Han B, Wang J. COVID-19: Gastrointestinal manifestations and potential fecal-oral transmission. Gastroenterology. March 3 2020 [Epub ahead of print].

14. In SM, Park DY, Sohn IK, et al. Experimental study of the potential hazards of surgical smoke from powered instruments. Br J Surg. 2015; 102:1581-1586.

17. Joint GI Society message on COVID-19. Clinical insights for our community of gastroenterologists and gastroenterology care providers. https://www.asge.org/home/joint-gisociety-message-covid-1. Visited the 15th April 2020.

15. Wisniewski PM, Warhol MJ, Rando RF, et al. Studies on the

UrOP Executive Committee

Giuseppe Ludovico 1, Angelo Cafarelli 2, Ottavio De Cobelli 3, Ferdinando De Marco 4, Giovanni Ferrari 5, Stefano Pecoraro 6, Angelo Porreca 7, Domenico Tuzzolo 8 1 Department

of Urology, “F. Miulli” Hospital, Acquaviva delle Fonti (BA), Italy; of Urology, Villa Igea Clinic, Ancona, Italy; 3 Department of Urology, European Institute of Oncology, IRCCS - Department of Oncology and Hemato-0ncology, University of Milan, Milan, Italy; 4 Department of Urology, “INI” Italian Neurotraumatological Institute, Grottaferrata (Roma), Italy; 5 Department of Urology, CURE, Modena, Italy; 6 Department of Urology, Malzoni Clinic Neuromed, Avellino, Italy; 7 Department of Urology, Policlinico Abano Terme, Abano Terme (PD), Italy; 8 Department of Urology, “Casa del Sole” Clinic, Formia (LT), Italy. 2 Department

Correspondence Rosario Leonardi, MD (Corresponding Author) leonardi.r@tiscali.it Lorenzo Falcone, MD Vincenzo Grasso, MD Department of Urology and Andrological Surgery Musumeci GECAS Clinic Gravina of Catania, Catania (Italy) Piera Bellinzoni, MD Luigi Broglia, MD Davide De Marchi, MD Guido Giusti, MD Giovanni Passaretti, MD Silvia Proietti, MD Antonio Russo, MD Giuseppe Saitta, MD Salvatore Smelzo, MD Franco Gaboardi, MD Department of Urology, San Raffaele Turro Hospital, Milan (Italy) Renzo Colombo, MD Department of Urology, San Raffaele Hospital, Milan (Italy) Guglielmo Mantica, MD guglielmo.mantica@gmail.com Nazareno Suardi, MD Department of Urology, IRCCS Policlinico San Martino Hospital, University of Genova, Genova (Italy)

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DOI: 10.4081/aiua.2020.2.73

ORIGINAL PAPER

COVID-19 pandemic and its implications on sexual life: Recommendations from the Italian Society of Andrology Carlo Maretti 1, Salvatore Privitera 2, Davide Arcaniolo 3, Lorenzo Cirigliano 4, Adele Fabrizi 5, Michele Rizzo 6, Carlo Ceruti 7, Ilaria Ortensi 8, Stefano Lauretti 9, Tommaso Cai 10, Marco Bitelli 11, Fabrizio Palumbo 12, Alessandro Palmieri 4 1 Department

of Andrology , CIRM Medical Center , Piacenza, Italy; of Urology, University Hospital “G. Rodolico”, Catania, Italy; 3 Unit of Urology, University of Campania “Luigi Vanvitelli” , Naples, Italy; 4 Department of Urology, University “Federico II”, Naples, Italy; 5 Institute of Clinical Sexology, Rome, Italy; 6 Department of Urology, University of Trieste, Trieste, Italy; 7 Department of Urology, University of Turin, Turin, Italy; 8 Altamedica- Artemisia Center, Rome, Italy; 9 Department of Urology, “S. Caterina della Rosa” Clinic, Rome, Italy; 10 Department of Urology, “Santa Chiara Hospital”, Trento, Italy; 11 Department of Urology, “San Sebastiano Martire” Hospital, Frascati, Rome, Italy; 12 Department of Urology, “San Giacomo” Hospital, Monopoli, Bari, Italy. 2 Department

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the coronavirus that causes an infectious disease, called COVID-19, first detected in patients with pneumonia in Wuhan (People's Republic of China) on December 2019. Italy was the first European country to state the outbreak of the infection and its Council of Ministers declared the state of health emergency on 31.01.2020, then the World Health Organization ruled a global pandemic on 11.03.2020. The nasopharyngeal swab is based on the detection of virus RNA and is the only reliable one for declaring COVID-19 infection. The most common symptoms observed in COVID-19 patients before hospitalization may be fever, chills, cough, dyspnea, asthenia, myalgia and/or arthralgia. This symptomatology can be often complicated in a dramatically increasing manner such as to require hospitalization starting from the third-fourth week. COVID-19 outbreak has dramatically affected the quality of life by changing inter-personal relationships, community life and obviously sexual health. The purpose of this work, based on available evidence, is to provide recommendations to help the population to face their sexual life in this critical period.

Summary

KEY WORDS: COVID-19, Sexual-life; Outbreak; Recommendations; SIA (Italian Society of Andrology); SARS-CoV-2; Reproductive health; Sex; Pandemic. Submitted 14 May 2020; Accepted 15 May 2020

INTRODUCTION

Coronavirus 2019 (COVID-19) is an infectious disease caused by a virus first detected in patients with pneumonia in Wuhan, the extensive capital of Hubei province, China, at the end of December 2019. The Coronavirus Study Group (CSG) of the International Committee on Taxonomy of Viruses (ICTV), officially classified with the name of SARS-CoV-2 the virus provisionally called 2019-nCoV by the World Health Organization, after having evaluated the novelties of the "new" human pathogen

and on the basis of phylogeny, taxonomy and consolidated practice. The disease caused by the new Coronavirus has been named ‘COVID-19’ (where "CO" stands for corona, "VI" for virus, "D" for disease and "19" indicates the year in which it occurred). The Coronavirus Study Group formally associated this virus to the coronavirus that causes severe Acute Respiratory Syndrome Coronaviruses (SARS-CoVs), classifying it as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) (1-3). Italy was the first European country, to state the outbreak of the infection. The Italian Council of Ministers declared the state of health emergency on 31.01.2020. After the infection of 100.000 people in 100 countries the World Health Organization ruled a global pandemic on 11.03.2020 (4). On 13 March 2020 the Italian government’s “I Stay Home” decree suspended all non-urgent and non-essential services, blocking people’s movements unless proven needs or emergencies. These same restrictive measures were then adopted by many other European Countries with the aim of reducing the spread of the pandemic. Moreover, according to the “I Stay Home” decree issued by the Italian government people are forced stay home without outdoor activities or social contact with psychological implications and high impact on the quality of sexual life. Based on available evidences, the Italian Society of Andrology have tried to provide recommendations with the aim of helping people to face their sexual life in this peculiar period and healthcare professionals to establish an effective communication with their patients (5). Evidence acquisition We performed a systematic literature search of PubMed, Medline, Web of Science and Google Scholar using Medical Subject Headings (MeSH) indexes, keyword searches, and

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2020; 92, 2

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publication types until April 2020 for studies evaluating Corona Virus Disease 2019 (COVID-19) and its impact on population health and sexual and reproductive life. The search terms, limited to English language articles, included “COVID-19”, “COVID19”, “SARS-CoV-2”, “Corona Virus Disease 2019”, “coronavirus”, “sexual-life”, “outbreak”, “reproductive health”, “pandemic”, “quarantine”. We also searched reference lists of relevant articles. We have finally evaluated the non-indexed literature and what was published on the web by the World Health Organization and the most important institutions with particular reference to the Italian state. Virus pathogenesis SARS-CoV-2 is mainly transmitted via respiratory droplets, even if other extra-pulmonary transmissions has been suggested. Viral RNA has also been found, with variable frequency, in the feces and blood of COVID-19 patients. However, the possibility of infection from these materials is currently controversial (6). The pathogenesis of SARS-CoV-2 is complex and it is not fully defined because multiple factors can intervene and a wide range of clinical manifestations can be developed (7). The primary viral replication occurs in mucosal epithelium of upper respiratory tract. Then the virus proceeds with further multiplication in lower respiratory tract and gastrointestinal mucosa (8). At this stage it is possible to observe an initial low-grade viremia. It is also possible to develop extra respiratory symptoms, implying multiple organ involvement, such as acute pain in the liver and in the heart, kidney failure, diarrhoea (9). ACE2 receptors through which the virus enters the cells (10), is broadly expressed in nasal mucosa, bronchus, lungs, heart, oesophagus, kidneys, stomach, bladder, and ileum. These organs are vulnerable to SARS-CoV-2 (11, 12). ACE2 receptors are also expressed in many other tissues, such as the testicle. Clinicians are also studying the effects of SARS-CoV-2 on testicular tissues and potential consequences on fertility (13). A recent study suggests that the testis is a high-risk organ vulnerable to SARS-CoV-2 infection that may result in spermatogenic failure. These investigation states that the reproductive functions should be followed and evaluated in recovered COVID-2019 male patients (14). Another study, instead, does not reveal any influence of SARS-Cov-2 in the testis cells (e.g. germ cells, Leydig cells, Sertoli cells, etc). However, future studies are needed to evaluate the impact of COVID-19 on male reproduction and pregnancy rate. Furthermore, as more than 80% of those who are infected by the coronavirus are asymptomatic, the reproductive implications for these men would likely be favorable but they remain unknown right now (15). Around 7 to 14 days after onset, the virus then begins a second attack which can determine a clinical worsening in patients. Antibody production can be affected by a reduction in B lymphocyte that may occur early in the disease. Pneumonia appears to be the most frequent serious manifestation of infection. Pathological findings from severe COVID-19 show pulmonary bilateral diffuse alveolar damage with signs of acute respiratory distress syndrome (ARDS) and in both lungs can be observed interstitial mononuclear inflammatory infiltrates, domi-

Archivio Italiano di Urologia e Andrologia 2020; 92, 2

nated by lymphocytes. These pulmonary pathological findings extremely resemble those seen in SARS and MERS. ARDS is a life-threatening lung condition that prevents enough oxygen from getting to the lungs and into the circulation and can have fatal consequences. COVID-19 patients developing ARDS may require mechanical ventilation. ARDS development is due to an exuberant inflammatory response during SARS-CoV-2 infection. The pathological mechanism that causes pneumonia is still being studied but would seem to be linked to an excessive host immune reaction; the latter can be so massive that it is precisely labelled as a "cytokine storm". The cytokine storm determines the aggressive The protagonist of this “storm” is interleukin 6 (IL-6) (16). The cause of this production of exuberant proinflammatory cytokines (IFN-α, IFN-γ, IL-1β, IL-6, IL12, IL-18, IL-33, TNF-α, TGFγ, etc.) and chemokines (CCL2, CCL3, CCL5, CXCL8, CXCL9, CXCL10, etc.) is to be found in initial rapid viral replication, accompanied with massive epithelial cell death and an endothelial disfunction which generates an intravascular coagulation with generalized thrombotic phenomena. Additionally, several studies have reported that lymphopenia is a common feature of COVID-19, suggestive of a critical factor accounting for severity and mortality (9, 17, 18). Molecular and serological analysis of COVID-19 The nasopharyngeal swab is based on the detection of virus RNA and is the only reliable one for declaring COVID-19 infection. Extraction and purification of RNA is carried out by picking a little of biological material using a rapid molecular method named Reverse RealTime PCR (rRT-PCR), where the use of molecular probes makes this test extremely specific. The serological tests are still unreliable because they do not diagnose very recent infections and where the results must then be confirmed by the swabs. Even if the serological tests could be the winning key for people monitoring, there is still no evidence on their reliability. Serological tests are divided into two categories, quantitative and qualitative tests. Qualitative tests include rapid tests that produce a high percentage of false negatives and false positives and therefore they are unreliable for now. In quantitative serological tests, the kinetics of the IgM and IgG AntiSars-Cov-2 antibodies is different between patients under intensive or sub-intensive therapy and asymptomatic or pauci-symptomatic patients where the production of immunoglobulins (IgM and IgG) occurs with longer times. The quantitative tests are therefore unable to detect Cov-2 infections early, due to poor sensitivity and the need to confirm, in case of positivity, with a further molecular test. To conclude, serological tests do not replace molecular tests but are complementary, especially in the case of asymptomatic subjects (19). Moreover, serological tests seem interesting to collect epidemiological data and plan the future health-care strategies. COVID-19 clinical presentation The most common symptoms observed in COVID-19 patients before hospitalization may be fever, chills, cough, dyspnea, asthenia, myalgia and/or arthralgia. Less common signs are nausea and vomit, nasal congestion,

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COVID-19 and sex: Recommendations from SIA

hemoptysis, diarrhea, conjunctivitis (7). As recently reported by Guan et al. fever was present in 43.8% out of 109 patients with COVID-19, on admission, then it developed in 88.7% during hospitalization. The second most common symptom was dry cough (67.8%) while nausea or vomit (5.0%) and diarrhea (3.8%) were uncommon (20). This symptomatology can be often complicated in a dramatically increasing manner such as to require hospitalization starting from the third-fourth week. In severe cases, pneumonia, acute respiratory distress syndrome, sepsis, septic shock and endothelial dysfunction with diffuse thrombotic embolism can occur till to cause the patient's death especially for more fragile subjects or the presence of pre-existing comorbidities (21). It is important to remember that patients affected by COVID-19 can be also asymptomatic or who report mild symptoms, thus contributing considerably to the spread of the virus in the community (21, 22). The purpose of our recommendations is to provide some guidelines based on the available evidences for a safe sexual life during COVID-19 outbreak. Virus trasmission To prescribe the correct behaviors to adopt for a safe sexual life it is essential to know, in details, the virus transmission modalities. Regarding the human species, the transmission routes of the virus can be direct or indirect. The direct transmission of COVID-19 occurs mainly through the inhalation of droplets that are generated when an infected person speaks, coughs or sneezes; the transmission mode is therefore linked to short-distance interhuman contact. For this reason, it is recommended a two-meter distance at least. In closed environments where droplets can remain as aerosol in the air, it is recommended to ventilate three times a day for at least 15 minutes each time. Indirect infection can be transferred by animated vectors, such as animals (e.g. an infected person sneezing on the pet's fur) or inanimate (air, soil, food, personal effects, toys, paper sheets, money, plastic or metal surfaces, smart-phone, PC etc.) (23). SARSCoV-2 remains viable in aerosols for several hours and is more stable on plastic and stainless steel (72 h) than on copper and cardboard (3-4 h), and viable virus is detected after application to these surfaces (24). SARS-CoV-2 was found in the feces of infected people (8). In fact a transmission through anal intercourse cannot be excluded due to the possible presence of the virus on the penile glans mucosa. Some authors found the virus in the urine in 6.9% of the recovered patients (25, 26). Although there are not many available data, it would appear that the virus is not detectable in the vaginal fluid of women affected by COVID-19 (27). There is no evidence to demonstrate the presence of the virus in the female and male reproductive system. Infection implies the entry and possible multiplication in the organism of the virus that can lead to the latent (asymptomatic patients or who report mild symptoms) or full-blown state of the disease. During its course, infectious agents can infect other people. The infection index (R0) changes daily and in order to be safe R0 has to be below 1. In Italy, depending on the various geographical area, it varies from 2.4 to 4.0 at the moment.

Although the main methods of infection occur by air, they can also occur through sexual contact (28, 29). Psycho-sexuological implications of lockdown From a psychological point of view, the lockdown condition involves an increase in obsessive fear of contamination, feelings of uncertainty, dismay, worry, anxiety and depression. Many people have feelings of anger, irritability, insomnia, fear, boredom, anxiety related to the economic situation and, in some cases, a real risk of post-traumatic stress disorder (30). People with previous emotional and psychological fragility are at risk, as well as couples with disabled children or other health problems, conflictual couples and especially those where domestic violence is present. Social distancing slows down the spread of the virus, but it also forces us to repress or modify our need for closeness and relationship, leading us to reformulate our sexual life as well. According to the New York Department of Health Guidelines (29), it is reasonably safe to have sexual intercourse between cohabiting partners, unless one or both partner have professional risk of infection or they do present one or mere COVID-19 symptoms. Condoms can reduce contact with saliva or feces, especially during oral or anal sex. In a study by Hamermesh, it was found that the happiness of married individuals could have been slightly increased by isolation. This is not true for single people, where levels of happiness are diminished by losing their jobs and not being able to see other people (31). Married peopleâ&#x20AC;&#x2122;s happiness rises with additional time spent with a spouse, while singlesâ&#x20AC;&#x2122; happiness falls as they spend more time alone. This pandemic allows us to think of a new sexual intimacy also mediated by sex toys and technology. In conclusion, people who are experiencing the current social distancing are more likely to report discomfort due to fear and risk perceptions that may have an impact on their sex and couple life, but safe sex between intimate couples can be an activity to support psychologically fragile people living in restricted areas for longer quarantine periods. However, proper considerations of the risk can increase resilience. During lockdown, sex between habitual partners without symptoms, and cohabiting since the beginning of the restrictions is to be considered a real tool to stay connected and relieve anxiety during forced cohabitation. Finally, irritability, sadness, reduced or disturbed sleep, apathy, catastrophic thoughts that last a long time must warn us and eventually lead us to ask for help (32). Recovered patients A patient, who previously manifested any symptoms associated to the infection by COVID-19, is considered "clinically recovered" if clinical symptoms have been resolved. However, despite being clinically recovered, therefore asymptomatic, the patient can still present a positive oral swab at SARS-CoV-2. When a patient, in addition to symptoms of COVID-19 disappearance, shows two negative results to oral swabs carried out consecutively, 24 hours apart from each other, is then considered a "healed patient" (33). Patients that tested positive, if asymptomatic, have to repeat the test (two oral swabs 24 hours apart from each other) after 14 days from the first test. The same goes for the symptomatic Archivio Italiano di Urologia e Andrologia 2020; 92, 2

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C. Maretti, S. Privitera, D. Arcaniolo, et al.

patient after 14 days after the resolution of clinical symptoms, to verify that he/she has become negative(33, 34). In addition to the oral swab it could also be useful to perform an anal swab before discharging a patient, even if this is not routinely performed in clinical practice. Recommendations for sexual life and reproductive health during COVID-19 pandemic According to the previous discussed topics, these recommendations should be followed: • Regular de-facto couple, if negative and if it had not been infected, would not have any problem in lockdown time. • There is evidence of oral-fecal transmission of the SARS-CoV-2, that’s to say analingus could represent a theoretical risk for virus spreading. • Kissing can transmit the virus through saliva in case of an asymptomatic partner. • Indirect infection through hands contamination. Washing hands thoroughly is more important than ever. The necessary time for a good hand wash with soap have to be at least 40-60 seconds. You can also use an alcohol-based hand disinfectant (> 60% ethyl alcohol). • Independently from a sexual intercourse in a familiar environment disinfect keyboards and touch screens that are shared with others. Simple disinfectants containing 75% alcohol (ethanol) or 0.5% chlorine-based (bleach) can be used for the purpose. • Sex toys can be used safely if washed with water and soap or disinfected as before suggested. • Masturbation will not spread COVID-19, if hands and any sex toys are carefully washed. • Any close contact, including sex, with anyone outside family environment should be avoided. • Try to have close contacts only with your partner, follow the recommendations previously given and remember that the virus can also spread with an asymptomatic partner. • Avoid any other sex behaviors.. • It would be appropriate for the couple to discontinue temporarily any new Medically Assisted Procreation (PMA) treatments during outbreak as established by the ministerial decree and by the Italian Institute of Health (35). • There is no strong evidence of a risk of vertical maternal-fetal transmission, although it is a well-recognized risk (36, 37). Fetal distress and preterm delivery were reported in some other cases where infection occurred in the third trimester (38). Pregnancy women have not a higher risk to contracting the virus compared to general population, but pregnancy itself is a risk factor for morbidity and death in previous flu epidemic (39). Decision to become pregnant must be carefully considered in this period.

CONCLUSIONS

COVID-19 outbreak has dramatically affected the quality of life by changing inter-personal relationships, community life and obviously sexual health. The Italian Society of Andrology, based on available evidence, provided recommendations to help people to face their sexual life in this critical period.

Archivio Italiano di Urologia e Andrologia 2020; 92, 2

AUTHOR

CONTRIBUTIONS

CM conceived of the study and participated in its design and coordination and helped to draft the manuscript. SP, DA, LC, MB, AF drafting the manuscript. All authors read, contributed to the drafting and modification of the manuscript and approved the final work.

REFERENCES

1. Lefkowitz EJ, Dempsey DM, Hendrickson RC, et al. Virus taxonomy: the database of the International Committee on Taxonomy of Viruses (ICTV). Nucleic Acids Res. 2018; 46 (D1):D708-D717. 2. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol. 2020; 5:536-544. 3. Song Z, Xu Y, Bao L, et al. From SARS to MERS, thrusting coronaviruses into the spotlight. Viruses. 2019; 11(1). pii: E59. doi: 10.3390/v1101005. 4. WHO. What is a pandemic? February 2010 (https://www.who. int/csr/disease/swineflu/frequently_asked_questions/pandemic/en/) 5. Rizzo M, Liguori G, Verze P, et al. How the andrological sector suffered from the dramatic Covid 19 outbreak in Italy: supportive initiatives of the Italian Association of Andrology (SIA). Int J Impot Res. 2020 Apr 23. doi: 10.1038/s41443-020-0288-7. [Epub ahead of print] 6. Wölfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with COVID2019. Nature 2020 Apr 1. doi: 10.1038/s41586-020-2196-x. [Epub ahead of print] 7. Hui DSC, Zumla A. Severe acute respiratory syndrome: Historical, epidemiologic, and clinical features. Infect Dis Clin North Am. 2019; 33:869-889. 8. Gu J, Han B, Wang J. COVID-19: Gastrointestinal manifestations and potential fecal-oral transmission. Gastroenterology. 2020 Mar 3. doi: 10.1053/j.gastro.2020.02.054 9. Jin Y, Yang H, Ji W, et al. Virology, Epidemiology, Pathogenesis, and Control of COVID-19. Viruses. 2020 Mar 27; 12(4). pii: E372. doi: 10.3390/v12040372. 10. Cheng ZJ, Shan J. 2019 novel coronavirus: where we are and what we know. Infection. 2020; 48:155-163. 11. Zhang H, Kang Z, Gong H, et al. The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell transcriptomes. BioRxiv 2020; doi: https://doi.org/ 10.1101/2020.01.30.927806 12. Zou X, Chen K, Zou J, et al. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med. 2020; 14:185-192. doi: 10.1007/s11684-020-0754-0. Epub 2020 Mar 12. 13. Caibin F, Kai L, Yanhong D, Wei LL. ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection. MedRxiv 2020; doi: https://doi.org/10.1101/ 2020.02.12.20022418 14. Wang Z, Xu X. ScRNA-seq profiling of human testes reveals the presence of the ACE2 receptor, a target for SARS-CoV-2 infection in spermatogonia, Leydig and Sertoli cells. Cells. 2020; 9(4) pii: E920. doi: 10.3390/cells9040920. 15. Eisenberg ML. Coronavirus Disease 2019 (COVID-19) and men’s reproductive health. Fertility and Sterility. 2020 April 22. 16. Di Gennaro F, Pizzol D, Marotta C, et al. Coronavirus diseases

Maretti_Stesura Seveso 17/06/20 10:04 Pagina 77

COVID-19 and sex: Recommendations from SIA

(COVID-19) current status and future perspectives: a narrative review. Int J Environ Res Public Health. 2020 Apr 14; 17(8). pii: E2690. doi: 10.3390/ijerph17082690. 17. Li X, Geng M, Peng Y, Meng L, Lu S. Molecular immune pathogenesis and diagnosis of COVID-19. J Pharm Anal. 2020; 10:102-108. 18. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the `Cytokine Storm' in COVID-19. J Infect. 2020 Apr 10. pii: S01634453(20)30165-1. doi: 10.1016/j.jinf.2020.03.037. [Epub ahead of print] 19. Recommendations for collection, transport and storage of COVID-19 biological samples. ISS COVID-19 Translational Research Working Group 2020. Version of April 15, 2020. 19 p. Rapporti ISS COVID-19 n. 13/2020. 20. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395:497-506. 21. Borges do Nascimento IJ, Cacic N, Abdulazeem HM, et al. Novel Coronavirus infection (COVID-19) in humans: a scoping review and meta-Analysis. J Clin Med. 2020 Mar 30;9(4). pii: E941. doi: 10.3390/jcm9040941

tigation of 2019-nCoV infected patients: implication of multiple shedding routes. Emerg Microbes Infect. 2020; 9:386-389. 35. Position Paper Società Italiana Riproduzione Umana (SIRU) COVID-19. 10.03.2020. https://www.pmaumanizzata.com/ DASIRUUNATASKFORCE.pdf 36. Chen H, Guo J, Wang C, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet. 2020; 395:809-815. 37. Dong L, Tian J, He S, et al. Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn. JAMA. 2020 Mar 26. doi: 10.1001/jama.2020.4621. [Epub ahead of print] 38. Rasmussen SA, Smulian JC, Lednicky JA, et al. Coronavirus disease 2019 (COVID-19) and pregnancy: what obstetricians need to know. Am J Obstet Gynecol. 2020; 222:415-426. 39. Rasmussen SA, Jamieson DJ, Bresee JS. Pandemic influenza and pregnant women. Emerg Infect Dis. 2008; 14:95-100.

22. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel Coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020 Feb 7. doi: 10.1001/jama. 2020.1585. [Epub ahead of print] 23. Kampf G, Todt D, Pfaender S, Steinmann E. Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents. J Hosp Infect. 2020; 104:246-251. 24. Van Doremalen N, Bushmaker T, Morris DH, et al. Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1. N Engl J Med. 2020; 382:1564-1567. 25. Ling Y, Xu SB, Lin YX, et al. Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation patients. Chin Med J (Engl). 2020; 133:1039-1043. 26. Xie C, Jiang L, Huang G, et al. Comparison of different samples for 2019 novel coronavirus detection by nucleic acid amplification tests. Int J Infect Dis. 2020; 93:264-267. 27. Qiu L, Liu X, Xiao M, et al. SARS-CoV-2 is not detectable in the vaginal fluid of women with severe COVID-19 infection. Clin Infect Dis. 2020 Apr 2. pii: ciaa375. doi: 10.1093/cid/ciaa375. [Epub ahead of print] 28. Adhikari SP, Meng S, Wu YJ, et al. Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: a scoping review. Infect Dis Poverty. 2020; 9:29. 29. Sex and Covid - The NYC Health Department may change recommendations as the situation evolves from 24.03.2020. https://www1.nyc.gov/assets/doh/downloads/pdf/imm/covid-sex-guidance.pdf 30. Brooks SK, Webster RK, Smith LE, et al. The psychological impact of quarantine and how to reduce it: rapid review of the evidence, Lancet 2020; 395:912-20. 31. Hamermesh DS. Lockdowns, Loneliness and Life Satisfaction. Institute of Labor Economics, IZA. 2020. 32. Genadek KR, Flood SM, Moen P. For better or worse? Couples' time together in encore adulthood. J Gerontol B Psychol Sci Soc Sci. 2019; 74:329-338. 33. Italian Ministry of Health - C.S.S. - March 2020. 34. Zhang W, Du RH, Li B, et al. Molecular and serological inves-

Correspondence Carlo Maretti, MD Department of Andrology, CIRM Medical Center , Piacenza 29121 (Italy) Salvatore Privitera, MD - salvoprivi82@gmail.com Department of Urology, University Hospital “G. Rodolico”, Via Santa Sofia 78, 95123 Catania (Italy) Davide Arcaniolo, MD Unit of Urology, University of Campania “Luigi Vanvitelli” , Naples 80131 (Italy) Lorenzo Cirigliano, MD Alessandro Palmieri, MD Department of Urology, University “Federico II” , Naples 80138 (Italy) Adele Fabrizi, MD Institute of Clinical Sexology, Rome 00198 (Italy) Michele Rizzo, MD Department of Urology, University of Trieste, Trieste 34139 (Italy) Carlo Ceruti, MD Department of Urology, University of Turin, Turin 10126 (Italy) Ilaria Ortensi, MD Altamedica- Artemisia Center, Rome 00198 (Italy) Stefano Lauretti, MD Department of Urology, “S. Caterina della Rosa” Clinic, Rome 00176 (Italy) Tommaso Cai, MD Department of Urology, “Santa Chiara Hospital”, Trento 38122 (Italy) Marco Bitelli, MD Department of Urology, “San Sebastiano Martire” Hospital, Frascati, Rome 00044 (Italy) Fabrizio Palumbo, MD Department of Urology, “San Giacomo” Hospital, Monopoli, Bari 70043 (Italy)

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SHORT COMMUNICATION

DOI: 10.4081/aiua.2020.2.78

COVID-19 pandemic and uro-oncology follow-up: A “virtual” multidisciplinary team strategy and patients’ satisfaction assessment Francesca Ambrosini 1, 2, Andrea Di Stasio 2, Guglielmo Mantica 1, Barbara Cavallone 2, Armando Serao 2 1 Department 2 Department

of Urology, Policlinico San Martino Hospital, University of Genoa, Genoa, Italy; of Urology, Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.

Summary

COVID-19 pandemic strongly modified the organizations of our clinical practice. Strict containment measures have been adopted to limit the disease diffusion. In particular, hospital face-to-face post discharge and follow up visits have been reduced. Although cancelling or deferring appointments seems to be a pragmatic approach, this solution may have a devasting long-term impact on health medical care and on patients. In this context, telemedicine and remote consultations may have the potential to provide healthcare minimizing virus exposure. In this paper we describe how Multidisciplinary team (MDT) reorganized genitourinary cancer care delivery at our Institute (AO SS Antonio e Biagio e Cesare Arrigo, Alessandria), taking advantage of telematic means. Furthermore, we present our preliminary results regarding patients’ satisfaction.

KEY WORDS: COVID-19; Pandemy; Telemedicine. Submitted 24 April 2020; Accepted 28 April 2020

In the last few weeks our lives and the organization of our Departments have been completely turned upside down by the coronavirus novel SARS-Cov-2. The virus has rapidly spread all around the world and on the 11th March 2020 the World Health Organization declared the Coronavirus disease 2019 (COVID-19) a global pandemic. Strict containment measures have been taken by governments worldwide in attempt to curb the virus spread, ranging from school closures, social distancing to complete lockdown. As of the 24th April 2020 there have been 2.626.321 confirmed cases with 181.938 deaths and 213 countries involved (1). COVID-19 is, possibly, the greatest challenge healthcare systems around the world have seen for the last years, since drastic health resources reallocations have been necessary to face the pandemic. In this context, routine clinical and surgical activities, including urological practice, have been deeply reorganized prioritizing patients’ safety and well-being. Recommendations on the reorganization of urological activities have been provided by different scientific societies (2). In particular, all elective surgeries should be deferred, and surgical intervention

should be limited for high grade malignancies and unstable trauma patients. Hospital face-to-face post discharge and follow up visits should be reduced implementing telehealth strategies. We believe that oncological communications are by far the most delicate ones to share with the patient and that deserve particular attention. Before COVID-19 pandemic, weekly multidisciplinary hospital follow-up visits were carried out to patients treated for genitourinary cancers at our Institute. Our local Multidisciplinary Team (MDT) involves medical oncologists, radiotherapists, pathologists, clinical nurse specialists and urologists. In order to reduce home-hospital flow, all patients scheduled from March 9th 2020, first day of national lockdown, onwards have been phone called by the clinical nurse specialist and their email collected. They were asked to send the results of their instrumental and biochemical exams’ follow up by mail and to communicate any new clinical onset problem. The Patients’ documents and data were collected and then examined by MDT members on weekly videoconference meetings through the use of Zoom (Zoom Video Communications, Inc. San Jose, California, 2011). A clinical report containing oncological outcomes and the corresponding planning, with follow-up exam and visit, were sent to the patients via e- mail accompanied by a telephone call from the urologist. Face to face consultations were carried out only in case of disease progression or recurrence, onset of metastasis or severe clinical troubles. The follow-up of 56/60 (93.3%) scheduled patients were successfully managed by the “virtual” MDT, while only 4 patients required a conventional outpatient clinic setting. No complaints, objections or criticisms were recorded, regarding the proposed remote monitoring. At the end of the “virtual” consultations, the patients were asked to reply an anonymous online survey through Google Forms. With a response rate of 68.3% (41/60) most of the patients showed a high satisfaction (mean: 4.7/5) with no serious complaining about major technical issues. The smartness and convenience of the “virtual” visits were indicated as the most appreciated advantage by 10 No conflict of interest declared.

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Follow-up during COVID-19 pandemic

(24.4%) and 16 (39%) patients, respectively. The lack of Cliniciansâ&#x20AC;&#x2122; physical presence was perceived as the main limit of tele-visit by eleven patients (26.8%). Furthermore, 38/41 (92.7%) of the patients felt adequate sensitive data protection and no significant concerns about the privacy and security of remote visits. To date, while telemedicine is gaining popularity and numerous platforms and apps are available, it still poses some technical and practical problems. One of the main limits seems to be absence or unclearness of the legislation that still remains a common stumbling block for providers and patients (3). Telemedicine may increase clinical workflow efficiency in the coming years offering several benefits to the health system organization. SARS-Cov-2 pandemic is now driving the whole word transformation and could provide the decisive push

to make institutions, clinicians and, above all, patients familiar with telemedicine.

REFERENCES 1. Coronavirus [Internet]. World Health Organization. 2020 [cited 24th April 2020]. Available from: https://www.who.int/emergencies/ diseases/novel-coronavirus-2019. 2. Leonardi R, Bellinzoni P, Broglia L, et al. Hospital care in Departments defined as COVID-free: A proposal for a safe hospitalization protecting healthcare professionals and patients not affected by COVID-19. Arch Ital Urol Androl. 2020; 92(1). https://doi.org/ 10.4081/aiua.2020.2.67. 3. Castaneda P, Ellimoottil C. Current Use of Telehealth in Urology: A Review. World J Urol. 2019 Jul 27. doi: 10.1007/s00345-01902882-9. Online ahead of print.

Correspondence Francesca Ambrosini, MD (Corresponding Author) f.ambrosini1@gmail.com Department of Urology, Policlinico San Martino Hospital, University of Genoa Largo Rosanna Benzi, 10, 16132, Genoa, Italy Department of Urology, Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo Via Venezia 16, 15121, Alessandria, Italy ORCID 0000-0003-2160-763X Andrea Di Stasio, MD andrea.distasio@libero.it Barbara Cavallone, MD barbara.cavallone@ospedale.al.it Armando Serao, MD aserao@ospedale.al.it Department of Urology, Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo, Alessandria (Italy) Guglielmo Mantica, MD guglielmo.mantica@gmail.com Department of Urology, Policlinico San Martino Hospital, University of Genoa, Genoa, Italy

Archivio Italiano di Urologia e Andrologia 2020; 92, 2

DOI: 10.4081/aiua.2020.2.80

LETTER TO EDITOR

To the Editor The COVID-19 outbreak dramatically changed hospital everyday life, impairing the course of previous routine activity, also in urology (1, 2). In the next months, together with keeping the focus on the prevention of contagion recrudescence, the health care system will face another stringent issue, i.e. to restore all the services not COVID-related. Leonardi et al. in their paper (3) report an equilibrate overview on the incoming â&#x20AC;&#x153;Phase 2â&#x20AC;?, in order to set up so-called COVID-free hospitals and departments. The authors offer an insight from a practical point of view, detailing protocols for any of the steps of the path of care, from the outpatient visit to surgery. The aim is to ensure a safe healthcare flow, based on the early identification of the positive subjects and the rigorous protection of the negative ones. The cornerstones of this framework are: microbiological and instrumental COVID screening for patients but also for healthcare workers; furniture of personal protective equipment to the medical and administrative staff; re-definition of outpatient and inpatient scheduling to guarantee distancing; regulation of operating theaters by general protocols (as intubation in dedicated rooms, adoption of filters and smoke evacuation devices, etc), but also others dedicated to specific procedure (endoscopic, open, minimally-invasive). Although these actions will undoubtedly be pivotal to prevent virus contagion, to date no solid evidence is available on the safety of contemporarily hospitalization (4). Furthermore, the feasibility and sustainability of such measures have still to be established, first of all concerning economical resources. Secondly, many hospitals will be required to engage structural works in order to create appropriate spaces for distancing patients and personnel. Thirdly, the dilution of scheduling and increasing intervals between procedures will result in a significant extension of sessions and need for additional personnel, otherwise posing conflicts with the regulatory on shift and rest. Similarly, restricting surgical teams to a few operators periodically screened for COVID will result in the escalation of workload. Fourthly, academic institutions shall conjugate safety requirements with their educational mission; this objective will become even more challenging considering the emerging calls to increase the number of residency positions, already initiated before the COVID emergency. Besides these considerations there are several issues related to the patient side, mainly due to the withdrawal of procedures and consequent delay in execution of adequate new diagnostical examination (5) and in choice of best treatments occurred in this emergency period (6), with consequent repercussions on the quality of life of the patients (7). All these points should be read taking into account the peculiarities of Italian scenario, where marked differences in the epidemiology and effects of the pandemic have occurred (8). Additionally, our universalistic health systems, articulated in independent regional subsystems, count on institutions of various nature (academic, public, private), with different facilities, delivery capacity and attractiveness towards patients and investors. Such disparities have been already dramatically highlighted by the COVID emergency, but could be more and more emphasized if further phases will be managed on a local basis. Reasonably, supra-regional and, hopefully, supra-national coordination are needed to control such heterogeneity, sharing protocols and regulating funding allocation, in order to ensure that each institution could handle with both COVID and non-COVID patients.

REFERENCES 1. Puliatti S, Eissa A, Eissa R, et al. COVID-19 and Urology: a comprehensive review of the literature. BJU Int. 2020. 2. Rocco B, Sighinolfi MC, Sandri M, et al. The dramatic covid 19 outbreak in italy is responsible of a huge drop of urological surgical activity: a multicenter observational study. British Journal of Urology International. 2020; In Press. 3. Leonardi R, Bellinzoni P, Broglia L, et al. Hospital care in Departments defined as COVID-free: A proposal for a safe hospitalization protecting healthcare professionals and patients not affected by COVID-19. Archivio Italiano di Urologia e Andrologia. 2020; 92(1). 4. Maida FD, Antonelli A, Porreca A, et al. Letter to the Editor: "Clinical characteristics and outcomes of patients undergoing surgeries during the incubation period of COVID-19 infection". EClinicalMedicine. 2020:100362. 5. Vagnoni V, Brunocilla E, Bianchi L, et al. State of the art of PET/CT with 11-choline and 18F-fluorocholine in the diagnosis and follow-up of localized and locally advanced prostate cancer. Arch Esp Urol. 2015; 68:354-70.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2020; 92, 2

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Hospital care in Departments defined as Covid-free

6. Grasso AA, Cozzi G, DE Lorenzis E, et al. Multicenter analysis of pathological outcomes of patients eligible for active surveillance according to PRIAS criteria. Minerva Urol Nefrol. 2016;68:237-41. 7. Gacci M, Noale M, Artibani W, et al. Quality of Life After Prostate Cancer Diagnosis: Data from the Pros-IT CNR. Eur Urol Focus. 2017; 3:321-324. 8. Simonato A, Giannarini G, Abrate A, et al. Pathways for urology patients during the COVID-19 pandemic. Minerva Urol Nefrol. 2020 Mar 30.

Alessandro Tafuri 1, Andrea Minervini 2, Antonio Celia 3, Luca Cindolo 4, Riccardo Schiavina 5, Bernardo Rocco 6, Angelo Porreca 7, Alessandro Antonelli 1 1 Department

of Urology, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy; 2 Department of Urology, Careggi Hospital, University of Florence, Florence, Italy; 3 Department of Urology, St. Bassiano Hospital, Bassano del Grappa, Italy, 4 Department of Urology, "Villa Stuart" Private Hospital, Rome, Italy; 5 Department of Urology, University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy; 6 Department of Urology, University of Modena and Reggio Emilia, Modena, Italy; 7 Department of urology, Policlinico Abano Terme, Abano Terme, Italy.

Correspondence Alessandro Tafuri, MD Alessandro Antonelli, MD Department of Urology, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy Andrea Minervini, MD Department of Urology, Careggi Hospital, University of Florence, Florence, Italy. Antonio Celia, MD Department of Urology, St. Bassiano Hospital, Bassano del Grappa, Italy Luca Cindolo, MD Department of Urology, "Villa Stuart" Private Hospital, Rome, Italy Riccardo Schiavina, MD Department of Urology, University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy Bernardo Rocco, MD Department of Urology, University of Modena and Reggio Emilia, Modena, Italy Angelo Porreca, MD (Corresponding Author) angeloporreca@gmail.com Department of Urology, Policlinico Abano Terme, Abano Terme, Italy

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DOI: 10.4081/aiua.2020.2.82

ORIGINAL PAPER

Holmium laser prostatectomy in a tertiary Italian center: A prospective cost analysis in comparison with bipolar TURP and open prostatectomy Riccardo Schiavina 1, 2, Lorenzo Bianchi 1, 2, Marco Giampaoli 3, Marco Borghesi 1, 2, Hussam Dababneh 1, 2, Francesco Chessa 1, 2, Cristian Pultrone 1, 2, Andrea Angiolini 1, Umberto Barbaresi 1, Matteo Cevenini 1, Fabio Manferrari 1, 2, Alessandro Bertaccini 1, 2, Angelo Porreca 3, Eugenio Brunocilla 1, 2 1 Department

of Urology, University of Bologna, Bologna, Italy; of Experimental, Diagnostic and Specialty Medicine (DIMES), Cardio-Nephro-Thoracic Sciences Doctorate, University of Bologna, Bologna, Italy; 3 Department of Urology, Abano Terme Hospital, Padua, Italy. 2 Department

Summary

Objective: To assess the economic impact of Holmium laser enucleation of prostate (HoLEP) in comparison with transurethral resection of prostate (TURP) and open prostatectomy (OP). Methods: Between January 2017 and January 2018, we prospectively enrolled 151 men who underwent HoLEP, TURP or OP at tertiary Italian center, due to bladder outflow obstruction symptoms. Patients with prostate volume ≤ 70 cc and those with prostate volume > 70 cc were scheduled for TURP or HoLEP and OP or HoLEP, respectively. Intraoperative and early post-operative functional outcomes were recorded up to 6 months follow up. Cost analysis was carried out considering direct costs (operating room [OR] utilization costs, nurse, surgeons and anesthesiologists’ costs, OR disposable products costs and OR products sterilization costs), indirect costs (hospital stay costs and diagnostics costs) and global costs as sum of both direct and indirect plus general costs related to hospitalization. Cost analysis was performed comparing patients referred to TURP and HoLEP with prostate volume ≤ 70 cc and men underwent OP and HoLEP with prostate volume > 70 cc respectively. Results: Overall, 53 (35.1%), 51 (33.7%) and 47 (31.1%) were scheduled to HoLEP, TURP and OP, respectively. Both TURP, HoLEP and OP proved to effectively improve urinary symptoms related to BPE. Considering patients with prostate volume ≤ 70 cc, median global cost of HoLEP was similar to median global cost of TURP (2151.69 € vs. 2185.61 €, respectively; p = 0.61). Considering patients with prostate volume > 70 cc, median global cost of HoLEP was found to be significantly lower than median global cost of OP (2174.15 € vs. 4064.97 €, respectively; p ≤ 0.001). Conclusions: Global costs of HoLEP are comparable to those of TURP, offering a cost saving of only 11.4 € in favor of HoLEP. Conversely, HoLEP proved to be a strong competitor of OP because of significant global cost sparing amounting to 1890.82 € in favor of HoLEP.

KEY WORDS: HoLEP; Xost analysis; TURP; Open prostatectomy; Prostatic enlargement. Submitted 15 May 2019; Accepted 15 June 2019

INTRODUCTION

Benign prostatic enlargement (BPE) is one of the most common age-related medical disease in men, with troublesome impact on quality of life and a non-negligible social burden (1-3). The wide panorama of medical treatments developed over years has increasingly reduced the proportion of patients scheduled to surgical treatments (4). As a consequence, the economic impact of lower urinary tract symptoms (LUTS) is relevant, with costs exceeding 3 billion $ annually in US (5), 320 million € for pharmacological treatment and 74.834 days off work every year in Italy (6), and this trend is increasing over time (7). Surgical and endoscopic techniques, such as transurethral resection of prostate (TURP) and open prostatectomy (OP) have been the standard of care for many years in patients with drug-refractory disease. However, the surgical management of BPE has been changed in the last decade while laser prostatectomy increased in popularity (5). Although different laser techniques are available for surgical treatment of BPE, Holmium laser enucleation of prostate (HoLEP) has been the most rigorously studied (8) and has emerged as a viable minim-invasive option in patients with symptomatic BPE regardless prostate volume (9). Several studies including randomized controlled trials demonstrated equivalent early- and long-term functional outcomes as compared to TURP (10-13) and OP (14, 15), even in case of large prostate volume (16). Therefore, HoLEP is currently defined by International European Guidelines (17) as an effective alternative to TURP and OP, with several advantage of minim invasive approach including shorter catheterization time and hospital stay, reduced blood loss and lower blood transfusions (10, 11, 14, 15). Despite the initial non negligible costs, HoLEP could be less expensive by shortening the hospital stay and lowering the perioperative complications’ rate if compared to TURP (18, 19) and OP (2, 16). Since rigorous data on comparative costs of surgical treatments for BPE is limited in literature (20), we hereby aimed to assess the economic impact of HoLEP in comNo conflict of interest declared.

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parison with TURP and OP performed at single tertiary Italian center. Furthermore, we investigated and compared the surgical and early functional outcomes of the three surgical approaches.

MATERIAL

AND METHODS

Population Between January 2017 and January 2018, we prospectively enrolled 151 men who underwent surgical or endoscopic treatment for BPE at single tertiary Italian referral center (S. Orsola-Malpighi Hospital). Indications for surgical treatment consisted of persistent bladder outflow obstruction symptoms, International Prostatic Symptoms Score (IPSS) higher than 8, independent peak urinary flow rate (Qmax) ≤ 15 ml/s, or individuals non-responder to medical therapies including alfa blockers and 5α-reductase inhibitors (5-ARI). The baseline assessment of BPE consist of digital rectal examination (DRE), transrectal ultrasound of prostate (TRUS) reporting the overall prostate volume and prostatic adenoma's volume, IPSS score, Quality of Life score (QoL), Qmax, total PSA value and post void residual (PVR) measured with suprapubic ultrasound. Patients diagnosed with prostate cancer, those with history of previous prostatic or urethral surgery and with concomitant surgery needed (namely, bladder diverticulum excision and bladder stones removal) were excluded. Surgical techniques Patients with prostate volume ≤ 70 cc and those with prostate volume > 70 cc were scheduled for TURP or HoLEP and OP or HoLEP according to surgeon attitude and patient’s preference, respectively. TURP was carried out with a 26Fr continuous-flow Storz bipolar resectoscope, as previously described (21). All procedures were performed by 2 surgeons with more than ten years’ experience with endoscopic surgery of both lower and upper urinary collecting system. A 22 Fr three-way catheter was positioned at the end of the procedure with continuous irrigation. HoLEP was performed by using Lumenis Versa Pulse® Holmium laser at 2.0 J and 50 pulses per second with a maximum average power of 100 W and 26Fr continuous-flow Storz laser resectoscope. Laser energy was delivered with a 550-μm fiber. The enucleation of prostatic adenoma was performed according to Gilling's technique (22). The enucleated prostatic lobes were removed by using Lumenis VersaCut™ Morcellator System. All procedures were performed by a single surgeon at the end of learning curve with three years’ experience with HoLEP technique and more than 200 procedures performed. A 22 Fr three-way catheter was positioned at the end of the procedure with continuous irrigation. OP was performed though trans-vesical approach as previous described (23). All procedures were performed by 4 surgeons with more than ten years’ experience within OP techniques. A suprapubic drain and a 24Fr three-way catheter were positioned; the catheter was inflated in the prostatic fossa with a continuous irrigation. Collected data Each patient had complete preoperative data including

IPSS and QoL scores, Qmax and PSA values, prostate volume and PVR at TRUS and suprapubic ultrasound, respectively. Recorded intraoperative data were as follows: surgical time, anesthesia time, total operating room (OR) usage time and removed tissue weight. Moreover, we measured early post-operative outcomes: Hemoglobin (Hg) loss at 24 hours after surgery, catheterization time, hospital stay and early complications including re-catheterization, clot irrigation, transfusion and urinary tract infection according to Clavien-Dindo classification (24). After discharge, patients were scheduled to follow up examination at 3, 6 and 12 months including IPSS and QoL scores, PVR and Qmax. Moreover, urge and stress incontinence rates were recorded after discharge, at 3,6 and 12 months follow up. Urinary incontinence was defined as usage of ≥ 1 PAD per day. At time of analyses, all patients had complete follow up data up to 6 months after surgery. Cost analysis was carried out thought Delta analysis considering direct costs related to surgical procedure, indirect costs related to post-surgical hospitalizations and global costs as sum of both direct and indirect plus general costs related to hospitalization. Those data were obtained with the collaboration of the Finance Department with our center. Direct costs consist of OR utilization costs (2,01 €/minute) plus Nurse cost (0,5 €/minute, considering 3 nurses in OP and 2 nurses in HoLEP and TURP), O.R. personnel costs including surgeons (1,33 €/minute, considering 2 surgeons in OP and 1 Surgeon in HoLEP and TURP) and anesthesiologists (1,33 €/minute), O.R. disposable products costs and O.R. products sterilization costs. Indirect costs included hospital stay costs, diagnostics costs and costs of complications (including additional drugs, transfusions and medications). General costs included several costs of different services for each patient calculated by the hospital’s administration and related to the hospital stay (including insurance, water and electricity). Data analysis and statistical assessments First, preoperative patients’ characteristics and mildterm (≤ 6 months) postoperative data were compared between patients referred to the three surgical approaches (namely, OP, TURP and HoLEP): Anova test was used to compare continuous variables between the three groups. Second, postoperative stress and urge incontinence rates were reported at discharge, at 3 and 6 months after surgery and were compared between the three surgical techniques using chi-square test. Third, intraoperative and early postoperative data as well as intraoperative surgical times and surgical costs were analyzed comparing patients referred to HoLEP and TURP and those scheduled to HoLEP and OP, respectively. Since surgical indication to TURP or OP was respectively carried out in case of prostate volume ≤ 70 cc and > 70 cc at preoperative TRUS, while the indication to HoLEP was carried out regardless prostate volume, individuals referred to HoLEP with prostate volume ≤ 70 cc (HoLEP ≤ 70 cc) and those with prostate volume > 70 cc (HoLEP > 70 cc) were compared with men underwent TURP and OP, respectively, in order to assess whenever HoLEP technique could represent a direct competitor of both standard surgical procedures according to prostate volume. Archivio Italiano di Urologia e Andrologia 2020; 92, 2

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Statistical analysis was conducted with IBM SPSS 21 with a 2-sided significance level set at P < 0.05. The local institutional ethical committee approved the study (approval code STUD-OF by the S. Orsola-Malpighi Hospital, IRB September 11, 2012).

RESULTS

Table 1. Preoperative patients’ characteristics according to the surgical techniques (namely, OP, TURP and HoLEP). Number of patients (%) Age (years) Mean ± SD (range) Prostate Volume (cc) Mean ± SD (range) Qmax (mL/sec) Mean ± SD (range) IPSS Mean ± SD (range) QoL Mean ± SD (range) PVR (cc) Mean ± SD (range) PSA (ng/mL) Mean ± SD (range)

OP 47 (31.1)

TURP 5 1(33.7)

HoLEP 53 (35.1)

P value -

71.1 ± 7.3 (56-85)

69.0 ± 9.7 (46-86)

70.2 ± 6.8 (51-84)

0.4

109.8 ± 45.8 (75-280)

43.3 ± 13.1 (27-70)

75.4 ± 25.6 (32-140)

< 0.001

Preoperative data 8.5 ± 4.4 (2-15) 9.5 ± 4.9 (4-15) 9.1 ± 3.6 (4-15) 0.9 Overall, 151 patients were prospectively enrolled. Of them, 53 (35.1%), 15.6 ± 8.2 (8-33) 19.6 ± 7.7 (8-34) 17.2 ± 7.2 (8-30) 0.07 51 (33.7%) and 47 (31.1%) were 3.6 ± 1.5 (1-6) 4.1 ± 1.3 (1-6) 3.8 ± 1.4 (1-6) 0.2 scheduled to HoLEP, TURP and OP, respectively. Among patients submit96.7 ± 65.3 (10-300) 87.1 ± 55.8 (10-250) 88.7 ± 60.9 (10-220) 0.9 ted to HoLEP, 27 (50.1%) individuals had a preoperative prostatic volume ≤ 6.73 ± 3.29 (1.5-15.8) 2.55 ± 2.34 (0.5-11.0) 3.27 ± 2.46 (0.6-12.0) < 0.001 70 cc, while 26 (49.9%) had a preopOP: open prostatectomy; TURP: transuretral resection of prostate; HoLEP: Holmium Laser Enucleation erative prostatic volume > 70 cc. of Prostate; IPSS: international prostate symptoms score; PVR: post voided residual; QoL: Quality of life; SD: standard deviation. Between patients referred to OP, TURP and HoLEP, the preoperative clinical characteristics including age, IPSS and QoL scores, Qmax groups, except for prostate volume that was significantand PVR were found to be similar between the three ly higher in men treated with OP and HoLEP as comTable 2. Preoperative, surgical and early post-operative outcomes according to the surgical techniques (namely, TURP vs. HoLEP with preoperative prostatic volume ≤ 70 cc and OP vs HoLEP with preoperative prostatic volume >70 cc). Number of patients (%) Age (years) Mean ± SD (range) Prostate volume (cc) Mean ± SD (range) Qmax (mL/sec) Mean ± SD (range) IPSS Mean ± SD (range) QoL Mean ± SD (range) PVR (cc) Mean ± SD (range) PSA (ng/mL) Mean ± SD (range)

TURP 51(33.7)

OP 47 (31.1)

HoLEP > 70 cc 26 (17.2)

P value -

69.0 ± 9.7 (46-86)

70.9 ± 6.7 (51-83)

0.3

71.1 ± 7.3 (56-85)

69.5 ± 7.03 (57-84)

0.6

43.3 ± 13.1 (27-70)

47.8 ± 8.3 (32-70)

0.06

109.8 ± 45.8 (75-280)

96.8 ± 18.8 (75-140)

0.06

9.5 ± 4.9 (4-15)

8.7 ± 2.7 (5-15)

0.6

8.5 ± 4.4 (2-15)

9.7 ± 4.5 (3.7 – 15)

0.6

19.6 ± 7.7 (3-34)

16.1 ± 6.5 (3-27)

0.06

15.6 ± 8.2 (3-33)

18.3 ± 7.8 (3-30)

0.06

4.1 ± 1.3 (1-5)

3.8 ± 1.2 (1-5)

0.2

3.6 ± 1.5 (1-5)

4.3 ± 1.5 (1-5)

0.2

87.1 ± 55.8 (10-250)

95.4 ± 72.3 (15-220)

0.3

96.7 ± 65.3 (10-300)

96.6 ± 62.8 (10-220)

0.3

2.55 ± 2.34 (0.5-11.0)

2.50 ± 1.80 (0.6-7.6) 0.9 INTRAOPERATIVE DATA

6.73 ± 3.29 (1.5-15.8)

4.00 ± 2.80 (1.1-12.0)

0.9

26.4 ± 12.2 (20-55)

62.2 ± 32.7 (30-180)

50.2 ± 23.2 (31-90)

0.09

11 (23) 3 (6) 6 (13) 2 (4)

2 (8) 1 (4) 0 (0) 1 (4)

0.04*

Removed Tissue Weight (gr) Mean ± SD (range) 21.6 ± 11.1 (5-50) Intra-perioperative complications according to Clavien-Dindo classification (%) Overall 5 (10) Grade 1 3 (6) Grade 2 2 (4) Grade 3 0 (0) Hb loss at 24 hours (g/dL) Mean ± SD (range) Catheterization time (hr) Mean ± SD (range) Hospital stay (hr) Mean ± SD (range)

HoLEP ≤ 70 cc P value 27 (17.9) PREOPERATIVE CHARACTERISTICS

0.09

1 (4) 0.3 0 (0) 1 (4) 0 (0) EARLY POST-OPERATIVE OUTCOMES

1.1 ± 0.7 (0-3.9)

2.1 ± 3.4 (0.3-3.6)

0.1

2.1 ± 1.4 (0-6.2)

1.9 ± 1.2 (0-5.2)

0.2

74.4 ± 21.4 (48-144)

57.2 ± 43.9 (20-183)

0.003*

146.9 ± 55.6 (60-448)

68.1 ± 53.8 (20-200)

< 0.001*

84.4 ± 10.5 (60-104)

72.2 ± 37.4 (27-168)

0.01*

184.2 ± 78.7 (84-554)

83.9 ± 42.3 (47-192)

< 0.001*

OP: open prostatectomy; TURP: transuretral resection of prostate; HoLEP: Holmium Laser Enucleation of Prostate; Hb: hemoglobin; SD: standard deviation.

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pared to those referred to TURP (Table 1; p < 0.001). However, no significant differences were found between men referred to TURP and those underwent HoLEP with prostate volume ≤ 70 cc and between patients referred to OP as compared with those submitted to HoLEP with prostate volume > 70 cc, concerning preoperative characteristics (Table 2).

Table 3. Short-term functional outcomes of the three surgical techniques (namely, OP, TURP and HoLEP).

IPSS Mean ± SD Qmax (ml/s) Mean ± SD QoL Mean ± SD PVR (cc) Mean ± SD

OP (47)

3 months TURP (51) HoLEP (53) P value

7.6 ± 4.2

9.6 ± 7.0

23.8 ± 10.6 21.5 ± 8.5 1.2 ± 1.3

1.8 ± 1.6

9.5 ± 5.8

0.3

22.8 ± 10.5

0.7

1.5 ± 1.5

0.5

6 months OP (47) TURP (51) HoLEP (53) P value 7 ± 4.5

8.57 ± 5.7

8.3 ± 5.6

0.5

23.2 ± 10.8 22.8 ± 9.7

22.7 ± 9.6

0.2

1.4 ± 1.3

0.2

0.9 ± 1.0

1.4 ± 1.1

3.5 ± 2.1 10.9 ± 22.8 20.8 ± 12.1 0.4 4.1 ± 2.5 10.8 ± 25.3 24.5 ± 16.6 0.4 Perioperative data OP: open prostatectomy; TURP: transuretral resection of prostate; HoLEP: Holmium Laser Enucleation of Prostate; IPSS: international prostate Concerning mean removed tissue symptoms score; PVR: post voided residual; QoL: Quality of life; SD: standard deviation. weight, we found no significant difference between patients referred to TURP as compared with those submitted to HoLEP with Intraoperative times and costs analyses prostate volume ≤ 70 cc and between patients referred to O.R usage, anesthesiology and surgery time and disposOP as compared with those submitted to HoLEP with able products' costs revealed to be significantly higher in prostate volume > 70 cc (Table 2). Men in TURP group patients referred to HoLEP ≤ 70cc, as compared to those and those in OP group revealed higher catheterization and treated with TURP (all p ≤ 0.001). Accordingly, median hospital stay times as referred to individuals scheduled to direct costs of HoLEP in men with prostate volume ≤ 70 HoLEP regardless prostate volume (all p ≤ 0.01; Table 2). cc were significantly higher as compared to median direct In men with prostate volume ≤ 70 cc, both HoLEP and TURP Figure 1. revealed to be safety procedures Postoperative stress urinary incontinence rate according to the three surgical techniques with 4% and 10% overall compli- (namely, OP, TURP and HoLEP) at discharge, 3 and 6 months follow up. cations, respectively (p = 0.3). On the contrary, in men with prostate volume > 70 cc, those referred to OP experienced higher rates and higher grade of complications as referred to those underwent to HoLEP (p ≤ 0.04).

Postoperative functional outcomes Both TURP, HoLEP and OP proved to effectively improve urinary symptoms related to BPE at short term follow up, since no significant differences were found in term of IPSS score, Qmax, QoL score and PVR at time of discharge, at 3 and 6 months after surgery, between the three groups (Table 3). Patients in HoLEP group revealed higher stress incontinence rate at 3 months after surgery as compared to men in TURP and OP group, despite not significant difference (8% vs. 4% vs. 2%; Figure 1; p = 0.2); however, only 1 (2%) patients referred to HoLEP and 1 (2%) men underwent OP, experienced stress incontinence at 6 months follow up. Irritative symptoms were comparable between the three surgical approach and only 1 patient (2%) had urge incontinence at 6 months after HoLEP (Figure 2).

Figure 2. Postoperative urge urinary incontinence rate according to the three surgical techniques (namely, OP, TURP and HoLEP) at discharge, 3 and 6 months follow up.

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Table 4. Cost analysis including direct, indirect and total costs according to surgical procedure (namely, TURP vs. HoLEP with preoperative prostatic volume ≤ 70 cc and OP vs HoLEP with preoperative prostatic volume > 70 cc). Number of patients (%) O.R. usage time (min) Median (IQR) O.R usage cost (€) Median (IQR) Anesthesiology time (min) Median (IQR) Anestesiology cost (€) Median (IQR) Surgery time (min) Median (IQR) Surgeon cost (€) Median (IQR) Disposable products (€) Sterilization costs (€) Direct costs (€) Median (IQR) Indirect costs (€) Median (IQR) Direct + Indirect costs (€) Median (IQR) General costs (€) Median (IQR) Total cost (€) Median (IQR)

TURP 51 (33.7)

HoLEP ≤ 70 cc 27 (17.9)

P value -

OP 47 (31.1)

HoLEP > 70 cc 26 (17.2)

P value -

105 (89.75-125)

140 (113.25-176)

< 0.001*

110 (90-119)

140 (117-175)

< 0.001*

306.23 (270.14-376.25)

421.40 (332.61-535.78)

< 0.001*

386.10 (315.90-417.69)

421.40 (349.91-527.50)

0.04*

88 (74.5-111)

123 (103-161.5)

< 0.001*

93 (80-110)

117 (100-160)

< 0.001*

117.23 (99.09-147.63)

167.58 (129.01-214.13)

< 0.001*

123.69 (106.40-146.30)

154.94 (133.00-215.13)

< 0.001*

63 (47-85.25)

96 (70.5-123.25)

< 0.001*

68 (58-89)

96 (72-120)

0.001*

84.78 (62.51-113.38) 34.80 103.86

141.00 (89.76-161.60) 134.04 103.86

< 0.001* < 0.001*

180.88 (154.28-236.74) 34.8 103.86

114.38 (95.76-162.26) 134.04 103.86

< 0.001* < 0.001* 1.0

650.90 (559.46-760.41)

866.62 (717.94-1040.52)

< 0.001*

948.89 (813.15-1054.59)

803.31 (723.30-1074.98)

0.09

1218.29 (1214.36-1272.83)

889.13 (797.77-1433.61)

0.002*

2542.87 (2194.06-2885.68)

867.20 (794.12-1203.39)

< 0.001*

1868.19 (1771.48-2058.04)

1772.33 (1418.25-2234.13)

0.37

3507.33 (3205.78-3895.28)

1905.60 (1509.39-2132.37)

< 0.001*

317.42 (301.15-348.17)

301.29 (241.10-379.80)

0.38

596.24 (544.98-662.19)

323.95 (256.59-362.50)

< 0.001*

2185.61 (2072.64-2396.20) 2151.69 (1735.79-2618.85)

0.61

4064.97 (3636.36-4557.47) 2174.15 (1765.23-2465.19)

< 0.001*

OP: open prostatectomy; TURP: transuretral resection of prostate; HoLEP: Holmium Laser Enucleation of Prostate; OR: operating room; IQR: interquartile range.

costs of TURP (866.62 € vs. 650.90 €, respectively; p ≤ 0.001; Table 4). On the contrary, indirect costs were found to be inferior in HoLEP ≤ 70 cc group as compared to TURP group (all p ≤ 0.002), mainly due to lower hospitalization time. As a matter of fact, considering patients with prostate volume ≤ 70 cc, median global cost of HoLEP was similar to median global cost of TURP (2151.69 € vs. 2185.61 €, respectively; p = 0.61; Table 3). Despite significant difference in terms of O.R usage, anesthesiology and surgery time and disposable products' costs between patients referred to HoLEP > 70 cc and OP in favor of OP (all p < 0.001), median direct costs revealed to be similar between OP and HoLEP in men with prostate volume > 70 cc (948.89 € vs. 803.31 €; p = 0.09; Table 4). This could be explained with higher surgeon costs in OP which is related to the involvement of two surgeons per procedure, although the surgical time is lower in OP as referred to HoLEP which is a single surgeon procedure. On the other side, indirect costs were found to be significantly lower in HoLEP > 70 cc group as compared to OP group (p < 0.001), mainly due to lower hospitalization time and lower complications rates. Therefore, considering patients with prostate volume > 70 cc, median global cost of HoLEP was found to be significantly lower than median global cost of OP (2174.15 € vs. 4064.97 €, respectively; p ≤ 0.001; Table 4).

DISCUSSION

Thanks to unquestionable efficiency, early and long terms functional outcomes and safety profile, TURP represents

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nowadays the gold standard (17), (25) for surgical treatment of patients affected by BPE. On the other hand, laser technology has been worldwide increasingly diffused as safe minim invasive surgical treatment for BPE. Among different laser adopted in urology, Holmium laser has been the most rigorously studied (8) and HoLEP has passes the test of the time. On the other side, OP has been the first choice of surgical treatment in men with a substantially enlarged prostate (namely, prostate volume > 80 cc) in the last 50 years, despite more invasive approach and higher operative morbidity. However, contrarily to TURP, the rate of open procedures varies among different countries and cultures, because of different national health systems, variable economic pressure and available resources. In fact, analysis of direct and indirect costs suggests that OP is the most expensive surgical procedure for BPE (23). Taken together these considerations support that OP is a technique of the past which would be progressively abandoned. Contrarily, HoLEP proved to be a safe alternative to TURP (10-13) and OP (14, 15) with equivalent early and long term functional outcomes (10, 11, 14, 15), that render HoLEP an attractive competitor of both standard techniques. Despite such benefits, two main drawbacks including a steep learning curve and the costs related to initial laser equipment (Holmium laser, a dedicated laser resectoscope sheath, fibers and morcellator) could have limited diffusion of this technique. Nevertheless, it has been postulated that HoLEP is a cost-sparing procedure since fibers can be reused multiple times and holmium laser can be used for several other urological procedures (26). Moreover, previous authors showed that HoLEP is more

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Cost analysis of surgical approach for BPH

cost-effective as compared to TURP (18, 19) and OP (2, 16), giving a cost savings of 24.5% (18) and 9.6% (2), respectively. Our cost-analysis attempted to evaluate and compare the financial burden of different procedures for surgical treatment of BPE performed at single Italian institution, in order to define a future perspective concerning surgical management of patients with BPE. Indeed, several findings are noteworthy. First, HoLEP proved to be as efficient as TURP and OP in term of removed tissue weight. Second, our study provides further evidence to support optimal functional outcomes of HoLEP at short follow up. Moreover, HoLEP confirmed to be a safe procedure, since similar intraoperative and perioperative complications were found as compared to TURP. Conversely, HoLEP proved to be a safer approach than OP, considering lower complications rates compared to OP (8% vs. 23%; Table 2). Precisely, no men in HoLEP>70cc and 6 patients in OP group required blood transfusions; moreover, only 1 HoLEP > 70 cc and 2 OP needed re-intervention in order to achieve control of bleeding. Third, according to literature (25), patients submitted to HoLEP experienced faster recovery due to significantly lower catheterization time and hospital stay as compared to those underwent TURP and OP regardless prostate volume (Table 2). Fourth, direct costs, including OR surgical setup, disposables, fibers and surgical staff costs (namely, unitary cost of surgeon, anesthesiology and operating room nurses) of HoLEP ≤ 70 cc procedures, were found to be significantly higher as related to TURP's costs. A sub-analysis of direct costs shows as disposable costs and sterilization costs are similar between two techniques. Conversely, higher direct costs within HoLEP ≤ 70 cc group, seems to be related mainly to increased operating room usage time, that leads to augment costs of surgeon, anesthesiologists and all staff involved. However, indirect costs found to be significantly lower in patients referred to HoLEP ≤ 70 cc as compared to those treated with TURP, due to lower hospital stay. In fact, laser technology allows to spare almost 1 day of hospitalization, thanks to optimal hemostatic proprieties and earlier catheter removal. Therefore, global HoLEP’s costs found to be comparable to global TURP's costs considering patients with similar prostate volume (≤ 70 cc). This implies an overall cost saving of 11.4 € per procedure, in favor of HoLEP. Our findings differ from previous costeffectiveness analysis reported by Fraundorfer et al. (18) comparing Holmium laser prostatectomy (namely, Holmium laser resection of prostate) and TURP, by suggesting a net economic benefit of 24.5% (651 New Zeland dollars) in favor of laser. However, the authors did not include in their analysis the medical salary costs (urologist and anesthesiologist), that could reduce the cost-saving difference between two techniques. Fifth, our economic analysis shows that HoLEP could be an attractive competitor of OP. In fact, direct costs of HoLEP were found to be comparable to OP, considering patients with similar prostate volume (> 70 cc). Despite lower operating room usage time and related costs, in favor of OP, that would reduce surgeon cost, the median surgeon cost of OP (180.88 €) is significantly higher as compared with those of HoLEP (114.38 €) since it is

influenced by the number of surgeons involved in each procedure (namely, two surgeons in OP and one surgeon in HoLEP). Indeed, the higher costs of disposable products in HoLEP group, mainly related to the costs of fibers, can be amortized during time, since a single fiber can be re-used at least 10 times. Moreover, the main aspect that renders HoLEP an attractive and preferable procedure as referred to OP, consists of lower hospital stay and faster recovery to daily life. In fact, in our cohorts, patients treated with HoLEP > 70 cc have been discharged more than 4 days earlier than those referred to open surgery. It implies a significant reduction of indirect cost (867.20 € in HoLEP group vs. 2542.87€ in OP group; p < 0.001), due to lower hospitalization time and lower complications rates, that leads to spare 1661.05€ per patients, in favor of HoLEP. Indeed, considering the global cost of both procedures, HoLEP offers a net total cost saving of 1890.82 € per patient as compared to OP, that assumes an important economic impact in health systems. These findings are even more impressive than those reported by Salonia and colleagues (2), reporting a significant hospital net cost savings of 9.6% in favor of HoLEP as compared with OP. However, the medical salary costs (including urologist and anesthesiologist), that could increase the cost-saving difference between two techniques, has not been included in their analyses. Despite several strength, our study is not avoided from limitations. First, number of patients included in our analyses is limited and it could affect statistical strength. Second, our cohort consists of single Italian center population with BPE submitted to most common surgical procedures (namely, HoLEP, TURP and OP) recognized as standard procedures by international guidelines (17). However, we did not include patients referred to other diffused minim invasive techniques for surgical treatment of BPE. As consequence, our cohort could not be representative of the experience of other centers both in Italy and worldwide. Third, at baseline preoperative assessment of patients with BPE, we did not provide routine urodynamic study. Fourth, our cost effectiveness analysis did not include initial costs of laser equipment that may consist of main limitation to start the procedure: the initial global costs of Holmium laser and morcellator in our department was 150.000 € and 50.000 €, respectively. Of note, the economic impact of HoLEP could be overestimated, since the amount of initial financial charge, that would increase global cost of procedures, was not reported. Moreover, we did not consider how many cases are needed to amortize the initial costs of laser equipment.

CONCLUSIONS

HoLEP is a safe and valuable alternative to TURP and OP. Lower indirect costs and higher direct costs within patients treated with HoLEP, imply that global costs of HoLEP are comparable to global costs of TURP, offering a cost saving of only 11.4 € in favor of HoLEP. Conversely, HoLEP proved to be a strong competitor of OP because of consistent reduction of indirect cost, mainly due to lower hospitalization time, that leads to significant global cost sparing amounting to 1890.82 € in favor of HoLEP. However, further evaluations including Archivio Italiano di Urologia e Andrologia 2020; 92, 2

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the initial cost of laser equipment and multicentric experiences are needed to assess the real economic advantages of laser prostatectomy compared with standard surgical approaches.

REFERENCES

1. DerSarkissian M, Xiao Y, Duh MS, et al. Comparing Clinical and Economic Outcomes Associated with Early Initiation of Combination Therapy of an Alpha Blocker and Dutasteride or Finasteride in Men with Benign Prostatic Hyperplasia in the United States. Journal of managed care & specialty pharmacy. 2016; 22:1204-14. 2. Salonia A, Suardi N, Naspro R, et al. Holmium laser enucleation versus open prostatectomy for benign prostatic hyperplasia: an inpatient cost analysis. Urology. 2006; 68:302-6. 3. Cindolo L, Pirozzi L, Fanizza C, et al. Drug adherence and clinical outcomes for patients under pharmacological therapy for lower urinary tract symptoms related to benign prostatic hyperplasia: population-based cohort study. Eur Urol. 2015; 68:418-25. 4. Presicce F, C DEN, Gacci M, et al. The influence of the medical treatment of LUTS on benign prostatic hyperplasia surgery: do we operate too late? Minerva Urol Nefrol. 2017; 69:242-52. 5. Schroeck FR, Hollingsworth JM, Kaufman SR, et al. Population based trends in the surgical treatment of benign prostatic hyperplasia. J Urol. 2012; 188:1837-41. 6. Messina R, Mirone V. Benign Prostatic Hyperplasia - An economic assessment of fixed combination therapy based on a literature review. Arch Ital Urol Androl. 2015; 87:185-9. 7. Taub DA, Wei JT. The economics of benign prostatic hyperplasia and lower urinary tract symptoms in the United States. Curr Urol Rep. 2006; 7:272-81. 8. Krambeck AE, Handa SE, Lingeman JE. Experience with more than 1,000 holmium laser prostate enucleations for benign prostatic hyperplasia. J Urol. 2013; 189(1 Suppl):S141-5. 9. Tooher R, Sutherland P, Costello A, et al. A systematic review of holmium laser prostatectomy for benign prostatic hyperplasia. J Urol. 2004; 171:1773-81.

hyperplasia; is it a realistic endourologic alternative in developing country? World J Urol. 2016; 34:399-405. 17. 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. 18. Fraundorfer MR, Gilling PJ, Kennett KM, Dunton NG. Holmium laser resection of the prostate is more cost effective than transurethral resection of the prostate: results of a randomized prospective study. Urology. 2001; 57:454-8. 19. Fayad AS, Elsheikh MG, Zakaria T, et al. Holmium Laser Enucleation of the Prostate Versus Bipolar Resection of the Prostate: A Prospective Randomized Study. "Pros and Cons". Urology. 2015; 86:1037-41. 20. Mathieu R, Lebdai S, Cornu JN, et al. Perioperative and economic analysis of surgical treatments for benign prostatic hyperplasia: A study of the French committee on LUT. Prog Uro. 2017; 27:362-8. 21. Rassweiler J, Schulze M, Stock C, et al. Bipolar transurethral resection of the prostate--technical modifications and early clinical experience. Minim Invasive Ther Allied Technol. 2007; 16:11-21. 22. Gilling PJ, Kennett K, Das AK, et al. Holmium laser enucleation of the prostate (HoLEP) combined with transurethral tissue morcellation: an update on the early clinical experience. J Endourol. 1998; 12:457-9. 23. Tubaro A, de Nunzio C. The current role of open surgery in BPH. EAU-EBU Update Series. 2006;4:191-201. 24. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004; 240:205-13. 25. Cornu JN, Ahyai S, Bachmann A, et al. A systematic review and meta-analysis of functional outcomes and complications following transurethral procedures for lower urinary tract symptoms resulting from benign prostatic obstruction: an update. Eur Urol. 2015; 67:1066-96. 26. Vincent MW, Gilling PJ. HoLEP has come of age. World J Urol. 2015; 33:487-93.

10. Lourenco T, Pickard R, Vale L, et al. Alternative approaches to endoscopic ablation for benign enlargement of the prostate: systematic review of randomised controlled trials. BMJ. 2008; 337:a449. 11. Tan A, Liao C, Mo Z, Cao Y. Meta-analysis of holmium laser enucleation versus transurethral resection of the prostate for symptomatic prostatic obstruction. Br J Surg surgery. 2007; 94:1201-8. 12. Montorsi F, Naspro R, Salonia A, et al. Holmium laser enucleation versus transurethral resection of the prostate: results from a 2center prospective randomized trial in patients with obstructive benign prostatic hyperplasia. J Urol. 2008; 179(5 Suppl):S87-90. 13. Kuntz RM, Ahyai S, Lehrich K, Fayad A. Transurethral holmium laser enucleation of the prostate versus transurethral electrocautery resection of the prostate: a randomized prospective trial in 200 patients. J Urol. 2004; 172:1012-6. 14. Naspro R, Suardi N, Salonia A, et al. Holmium laser enucleation of the prostate versus open prostatectomy for prostates > 70 g: 24month follow-up. Eur Urol. 2006; 50:563-8. 15. Kuntz RM, Lehrich K, Ahyai SA. Holmium laser enucleation of the prostate versus open prostatectomy for prostates greater than 100 grams: 5-year follow-up results of a randomised clinical trial. Eur Urol. 2008; 53:160-6. 16. Elshal AM, Mekkawy R, Laymon M, et al. Holmium laser enucleation of the prostate for treatment for large-sized benign prostate

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Correspondence Riccardo Schiavina, MD - rschiavina@yahoo.it Lorenzo Bianchi, MD (Corresponding Author) lorenzo.bianchi3@gmail.com Marco Borghesi, MD - mark.borghesi1@gmail.com Hussam Dababneh, MD - drdababneh@gmail.com Francesco Chessa, MD - francesco.chessa@live.it Cristian Pultrone, MD - cristian28@libero.it Andrea Angiolini, MD - dr.angiolini@gmail.com Umberto Barbaresi, MD - ubarbaresi@libero.it Matteo Cevenini, MD - matteoceve@gmail.com Fabio Manferrari, MD - fabio.manferrari@unibo.it Eugenio Brunocilla, MD - eugenio.brunocilla@unibo.it Alessandro Bertaccini, MD - alessandro.bertaccini@gmail.com Department of Urology, University of Bologna, Bologna (Italy) Marco Giampaoli, MD - giampaoli.marco85@gmail.com Angelo Porreca, MD - angelo.porreca@gmail.com Department of Urology, Abano Terme Hospital, Padua (Italy)

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DOI: 10.4081/aiua.2020.2.89

ORIGINAL PAPER

Can multiparametric ultrasound improve cognitive MRI/TRUS fusion prostate biopsy Pietro Pepe, Ludovica Pepe, Paolo Panella, Michele Pennisi Urology Unit, Cannizzaro Hospital, Catania, Italy.

Summary

Objective: To evaluate the accuracy of multiparametric transrectal ultrasound (contrast-enhanced ultrasound plus elastosonography) in the detection of the suspicious area diagnosed by multiparametric magnetic resonance (mpMRI). Materials and methods: From June 2018 to June 2019 60 men (median age 63 years) with persistent suspicion of cancer underwent repeat saturation biopsy following pelvic mpMRI and the lesions characterized by a PI-RADS (Prostate Imaging Reporting and Data System) score ≥ 3 were submitted to 4 additional cores by transperineal cognitive fusion biopsy (TPBx). All patients, before prostate biopsy, underwent contrast-enhanced ultrasound (CEUS) following intravenous administration of a bolus of Sonovue® (2.4 mg of nonpyrogenic suspension of phospholipid/sulphur hexaphloride); in addition, a transrectal elastosonography (TRES) was done to evaluate prostate tissue elasticity. The accuracy of multiparametric ultrasound to detect the mpMRI lesions was evaluated. Results: In 27/60 (45%) of men a T1c prostate cancer (PCa) was diagnosed by TPBx and 21 (77.8%) of them were classified as clinically significant cancer (csPCa); in detail, 16/21 (76.2%) vs. 5/21 (23.8%) csPCa were located in the peripheric and anterior zone of the gland, respectively. Median total PSA was 10.3 ng/ml (range: 4.9-51 ng/ml). TRES and CEUS were positive for csPCa only in 6/21 (28.5%) and 13/21 (62%) of TPBx showing an increased accuracy directly related with the PI-RADS scores Conclusions: Multiparametric ultrasound using TRES and CEUS after Sonovue® administration did not improve the accuracy of TPBx in diagnosing csPCa.

KEY WORDS: Prostate cancer; Contrast-enhanced ultrasound; Multiparametric ultrasound; Fusion prostate biopsy. Submitted 11 October 2019; Accepted 23 December 2019

INTRODUCTION

Multiparametric magnetic resonance imaging (mpMRI) combined with transrectal ultrasound (TRUS) fusion targeted biopsy has improved the accuracy of standard biopsy schemes in detecting clinically significant prostate cancer (csPCa) (1-4). A lot of papers refer about the accuracy of mpMRI/TRUS targeted biopsy in the diagnosis of cancer but there are few data about the standardization of the procedure and/or the optimal technique of targeted biopsy (5-7). Although, the in-bore procedure seems to be more accurate to diagnose csPCa in comparion with MRI/TRUS fusion biopsy (61 vs. 47%) (8) no clinically significant difference has been reported in mul-

ticentric clinical trials comparing cognitive vs. fusion vs. in-bore targeted biopsy (5). In the last years, TRUS has been enriched by the introduction of tridimensional and computerized images and by the use of contrast media and transrectal elastosonography (TRES) (9, 10), which allow better characterization of intraparenchymal microvasculature. The use of microbubble ultrasound contrast agents (UCA: Sonovue®, Definity®, Imagent®) improve flow detection in small vessels distinguish the normal from pathological tissue (11-15). In addition, the elastosonography measures the degree of distortion of ultrasound beam under the application of an external force that is displayed and scored over the B-mode image in a colour scale that corresponds to tissue elasticity (16-19). In our series, the accuracy of multiparametric transrectal ultrasound (20) (CEUS plus TRES) in the detection of the suspicious area diagnosed by mpMRI and suitable of targeted transperineal prostate biopsy (TPBx) has been evaluated.

MATERIAL

AND METHODS

From June 2018 to June 2019 60 Caucasians men (median age 63 years; range: 47-75 years) with negative digital rectal examination and previous negative extended biopsy underwent repeat transperineal saturation biopsy (SPBx) for the suspicion of cancer (increasing or persistently elevated PSA values) (21). After institutional review board and ethical committee approval were granted the informed consent was obtained from all individual participants included in the study. Ten days before SPBx, all the patients underwent pelvic mpMRI. All mpMRI examinations were performed using a 3.0 Tesla scanner, (ACHIEVA 3T; Philips Healthcare Best, the Netherlands) equipped with surface 16 channels phased-array coil placed around the pelvic area with the patient in the supine position; multi-planar turbo spin-echo T2-weighted, axial diffusion weighted imaging, axial dynamic contrast enhanced MRI were performed for each patient. The mpMRI lesions characterized by a PI-RADS (Prostate Imaging Reporting and Data System) version 2 score ≥ 3 were considered suspicious for cancer. Two radiologists blinded to pre-imaging clinical parameters evaluated the mpMRI data separately and independently. SPBx (median of 28 cores; range: 26-30 cores) was per-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2020; 92, 2

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Table 1. formed transperineally by a Hitachi 70 Arietta ecograph Clinical and histological parameters in 21 patients with (Chiba, Japan) supplied with a bi-planar transrectal probe clinically significant prostate cancer (csPCa) diagnosed by (5-7.5 MHz) and using a tru-cut 18 gauge needle (Bard; cognitive targeted fusion biopsy. Covington, GA, USA) under sedation and antibiotic prophylaxis (intravenous administration of 1 gram of Biopsy histology and clinical parameters Number of cases Cefazolin before prostate biopsy). One urologist with Gleason score 3 + 4 (GG2) 10 cases more than 8 years of experience regarding MRI/TRUS PIRAD-S score (3 vs. 4 vs. 5)* 3 7 0 fusion targeted biopsy performed the procedure. In the Suspicious TRES 1 2 0 presence of mpMRI lesions suggestive of cancer a TPBx Suspicious CEUS 2 4 0 (four cores) was added to SPBx using the Hitachi 70 Gleason score 4 + 3 (GG3) 7 cases Arietta ecograph (10). The data have been collected folPIRAD-S score* 3 3 1 lowing the START criteria (22). Suspicious TRES 1 0 1 All patients, before prostate biopsy, underwent standard Suspicious CEUS 1 2 1 TRUS combined with administration of a bolus of Gleason score 4 + 4 (GG4) 3 cases Sonovue® (nonpyrogenic suspension of phospholipid/ PIRAD-S score* 0 2 1 sulphur hexaphloride) equal to 2.4 mg into a large periphSuspicious TRES 0 0 1 eral vein followed by a flush of saline (10 ml). Before scanSuspicious CEUS 0 1 1 ning with contrast-enhanced ultrasound (CEUS), an approGleason score 4 + 5 (GG5) 1 case priate setup that included low mechanical index (MI) and a PIRAD-S score* 0 0 1 Suspicious TRES 0 0 0 split-screen view to display the contrast and B-Mode Suspicious CEUS 0 0 1 images at the same time was selected on the Logiq E9 TRES: transrectal elastosonography; PI-RADS: Prostate Imaging Reporting and Data System; echograph (General Electric; Milwaukee, WI USA) provided CEUS: contrast-enhanced ultrasound; GG: Grade Groups ISUP (International Society of Urological of an end-fire transrectal probe. Pathology). A timer was activated after UCA injection and the investigation was performed for 200 seconds (median; range 180-240); at the end of the procedure microbubbles were bursted. diagnosed by targeted fusion biopsy and 21 (77.8%) of Post-contrast imaging began as soon as contrast medium them were classified as csPCa (Table 1); in detail, 16/21 was visible on gray scale continuous harmonic imaging (76.2%) vs. 5/21 (23.8%) csPCa were located in the (HI); the microbubbles normally were distributed peripheric (Figure 1) and anterior zone (Figure 2) of the throughout the prostate, that appeared contrastgland, respectively. Median total PSA was 10.3 ng/ml enhanced, and only areas characterized by the Sonovue® (range: 4.9-51 ng/ml); the PI-RADS scores, Sonovue® and enhancement (15) were considered suspicious for PCa. TRES results are listed in Table 1. No side-effects were The TRES evaluation was done before the execution of reported after Sonovue® administration; none had signifthe targeted cognitive biopsy performing a real-time tisicant complications (Clavien-Dindo grade I) from sue elastosonography of the gland by the Shear Wave prostate biopsy that needed hospital admission biopsyMeasurament (SWM) analysis of the prostate (Hitachi 70 related; moreover, the mpMRI procedure was well tolerArietta ecograph (Chiba, Japan). After multiparametric ated and successfully performed in all cases (men with ultrasound evaluation the patients were submitted to claustrophobia, cardiac pacemaker and hip replacement TPBx plus SPBx (1). The Clavien-Dindo grading system were not included in the study). for the classification of biopsy complications was used (23). Figure 1. The detection rate of TPBx in Sonovue® enhancement in correspondence of the left peripheric zone of the prostate the diagnosis of csPCa (Gleason (white arrow). score > 6 and/or greatest percentage of cancer > 50% and/or more than two positive cores) was evaluated (24); in addition, the accuracy of multiparametric ultrasound (elastosonography and/or Sonovue®) to detect the MRI lesions was evaluated.

RESULTS

The overall diagnosis of PCa vs. csPCa performing SPBx was equal to 32/60 (56.7%) vs. 25/60 (41.7%) cases, but the data will refer only to the TPBx detection rate for PCa. In 27/60 (45%) of men a T1c PCa was

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Multiparametric prostate ultrasound and fusion biopsy

In detail, TRES and CEUS were positive for csPCa only in 6/21 (28.5%) and 13/21 (62%) of cognitive fusion biopsies showing an increased accuracy directly correlated with the PI-RADS scores (Table 1); in addition, TRES analysis did not improve the CEUS accuracy.

DISCUSSION

The improvement of diagnostic imaging by mpMRI has allowed targeted biopsies of the suspicious area, increasing the diagnosis of csPCa (1, 2) and reducing the number of unnecessary systematic biopsies. Although mpMRI is strongly recommended in men candidate to prostate biopsy (3), still today, systematic biopsy should be always combined with mpMRI/TRUS fusion biopsy due to false negative rate of mpMRI (about 20% of the cases) (1) and the variable diagnostic accuracy of the different mpMRI/TRUS fusion biopsy platforms (25). On the other hand, an alternative clinical approach is to begin with mpMRI to determine which patients need a targeted biopsy (26). The detection rate of csPCa is directly related to the PI-RADS score (1, 2) and the results depend on clinical parameters, the number of previous negative biopsies and the quality of TPBx procedures. In the next future it would be good that the artificial intelligence for automatic delineation of the prostate on ultrasound could became reliable and applicable to different scanners to improve, guided prostate biopsies using magnetic resonance imaging-transrectal ultrasound fusion (27). Alternatively, the ideal approach to the diagnosis of PCa should be to detect significant disease performing a limited number of targeted biopsy cores improving the accuracy of standard TRUS by multiparametric ultrasound (28); in this respect, a lot of papers have been published on the use of UCA as an additional diagnostic tool for improving PCa diagnosis (2-4) showing a low detection rate included between 15.5 and 32% (14-20, 29). In addition, in recent years, elastosonography has improved by the introduction of Shear Wave Elastosonography (SWE) that is a quantitative method that evaluate local tissue elasticity resulting much less operator dependent; the sensitivity vs. specificity of TRES range from 71-82% vs. 60-95% (9) in definitive specimen of men who underwent radical prostatectomy. Recently, Micro-ultrasound (30) in preliminary studies has demonstrated similar sensitivity to clinically significant prostate cancer as mpMRI; unlike mpMRI, micro-ultrasound is performed in the office, in real-time during the biopsy procedure, and so is expected to maintain the cost-effectiveness of conventional ultrasound, but larger studies are needed before these results may be applied in a clinical setting. In our series, TRES and CEUS were positive for csPCa only in 6/21 (28.5%) and 13/21 (62%) of cognitive fusion biopsies showing an increased positive results directly related with the PI-RADS scores (Table 1); in addition, TRES analysis did not increased the CEUS accuracy. In definitive, the additional use of multiparametric ultrasound did not improve the accuracy of cognitive fusion biopsy in the diagnosis of csPCa resulting only in an increased cost of the procedure. Regarding our results some consideration should be

done. Firstly, non-targeted biopsies were performed in CEUS or TRES suspicious areas, therefore, it is unknown if multiparametric TRUS would have diagnosed csPCa missed by TPBx; secondly, CEUS was not performed during the execution of TPBx. Third, the false negative rate of mpMRI for csPCa (4/21 equal to 19% of the cases) has not been correlated to CEUS and TRES findings. Finally, a greater number of cases is needed to confirm the results.

CONCLUSIONS

Multiparametric ultrasound using TRES plus CEUS did not improved the accuracy of TPBx in diagnosing csPCa.

REFERENCES

1. Pepe P, Garufi A, Priolo GD, et al. Is it time to perform only MRI targeted biopsy? Ou experience in 1032 men submitted to prostate biopsy. J Urol 2018; 200:774-778. 2. Preisser F, Theissen L, Wenzel M, et al. Performance of combined magnetic resonance imaging/ultrasound fusion-guided and systematic biopsy of the prostate in biopsy-naĂŻve patients and patients with prior biopsies. Eur Urol Focus. 2019; pii: S2405-4569(19)30170-1. 3. Pepe P, Garufi A, Priolo G, et al. Can MRI/TRUS fusion targeted biopsy replace saturation prostate biopsy in the re-evaluation of men in active surveillance? World J Urol. 2016; 34:1249-1453. 4. Pepe P, Garufi A, Priolo G, et al. Transperineal versus transrectal MRI/TRUS fusion targeted biopsy: detection rate of clinically significant prostate cancer. Clin Genitourin Cancer. 2017; 15:e33-e36. 5. Wegelin O, Exterkate L, van der Leest M, et al. The FUTURE Trial: A Multicenter randomised controlled trial on target biopsy techniques based on magnetic resonance imaging in the diagnosis of prostate cancer in patients with prior negative biopsies. Eur Urol. 2019; 75: 582-590. 6. Galosi AB, Maselli G, Sbrollini G, et al. Cognitive zonal fusion biopsy of the prostate: Original technique between target and saturation: Arch Ital Urol Androl. 2016; 88:292-295. 7. Pepe P, Pennisi M, Fraggetta F. How many cores should be obtained during saturation biopsy in the era of multiparametric magnetic resonance? Experience in 875 patients submitted to repeat prostate biopsy. Urology. 2019; pii: S0090-4295(19)31022-2. 8. Costa DN, Goldberg K, Leon AD, et al. Magnetic resonance imaging-guided In-bore and magnetic resonance imaging-transrectal ultrasound fusion targeted prostate biopsies:an adjusted comparison of clinically significant prostate cancer detection rate. Eur Urol Oncol. 2019; 2:397-404. 9. Aboumarzouk OM, Ogston S, Huang Z, et al. Diagnostic accuracy of transrectal elastosonography (TRES) imaging for the diagnosis of prostate cancer: a systematic review and meta-analysis. BJU Int. 2012; 110:1414-1423. 10. Correas JM, Drakonakis E, Isidori AM, et al. Update on ultrasound elastography: miscellanea. Prostate, testicle, musculo-skeletal. Eur J Radiol. 2013; 82:1904-1912. 11. Mitterberger M, Horninger W, Pelzer A, et al: A prospective randomized trial comparing contrast-enhanced targeted versus systematic ultrasound guided biopsies: impact on prostate cancer detection. Prostate. 2007; 67:1537-1542. 12. Colleselli D, Bektic J, Schaefer G, et al. The influence of prostate volume on prostate cancer detection using a combined approach of Archivio Italiano di Urologia e Andrologia 2020; 92, 2

Pepe_Stesura Seveso 17/06/20 10:12 Pagina 92

P. Pepe, L. Pepe, P. Panella, M. Pennisi

contrast-enhanced ultrasonography-targeted and systematic grayscale biopsy. BJU Int. 2007; 100:1264.

cancer detection at initial and repeat evaluation. Urology. 2007; 70:1131-1135.

13. Linden RA, Trabulsi EJ, Forsberg F, et al. Contrast enhanced ultrasound flash replenishment method for directed prostate biopsies. J Urol. 2007; 178:2354-2358.

22. Moore CM1, Kasivisvanathan V, Eggener S, , et al. START Consortium: Standards of reporting for MRI-targeted biopsy studies (START) of the prostate: recommendations from an International Working Group. Eur Urol. 2013; 64:544-552.

14. Taymoorian K, Thomas A, Slowinski T, et al. Transrectal broadband-Doppler sonography with intravenous contrast medium administration for prostate imaging and biopsy in men with elevated PSA value and previous negative biopsies. Anticancer Res. 2007; 27:4315-4320. 15. Pepe P, Candiano G, Pennisi M, Aragona F. Can Sonovue targeted biopsy replace extended or saturation biopsy in prostate cancer diagnosis? Our experience at primary and repeat biopsy. Arch Ital Urol Androl. 2010; 82:155-159. 16. Nelson ED, Slotoroff CB, Gomella LG, Halpern EJ. Targeted biopsy of the prostate: the impact of color Doppler imaging and elastography on prostate cancer detection and Gleason score. Urology. 2007; 70:1136-1140. 17. Bercoff J, Tanter M, Fink M. Supersonic shear imaging: a new technique for soft tissue elasticity mapping. IEEE Trans Ultrason Ferroelectr Freq Control. 2004; 51:396-409. 18. Nguyen TM, Couade M, Bercoff J, Tanter M: Assessment of viscous and elastic properties of sub-wavelength layered soft tissues using shear wave spectroscopy: theoretical framework and in vitro experimental validation. IEEE Trans Ultrason Ferroelectr Freq Control. 2011; 58:2305-2315. 19. Tanter M, Bercoff J, Athanasiou A, et al. Quantitative assessment of breast lesion viscoelasticity: initial clinical results using supersonic shear imaging. Ultrasound Med Biol. 2008; 34:1373-1386. 20. Mannaerts CK, Wildeboer RR, Remmers S, et al. Multiparametric ultrasound for prostate cancer detection and localization: Correlation of B-mode, shearwave elastography and contrast-enhanced ultrasound with radical prostatectomy specimens. J Urol. 2019 202:11661173. 21. Pepe P, Aragona F. Saturation prostate needle biopsy and prostate

Correspondence Pietro Pepe, MD (Corresponding Author) piepepe@hotmail.com Ludovica Pepe, MD Paolo Panella, MD Michele Pennisi, MD Divisione di Urologia, Azienda Ospedaliera Cannizzaro, Via Messina, 829 - 95126 Catania (Italy)

Archivio Italiano di Urologia e Andrologia 2020; 92, 2

23. Dindo D, Clavien PA. Classification of surgical complications. A new proposal with evaluation in a Cohort of 6336 patients and results of survey. Annals of Surgery. 2004; 2:205-213. 24. Epstein J, Walsh P, Carmichael M. Pathological and clinical findings to predict tumor extent of non palpable (stage T1c) prostate cancer. JAMA. 1994; 271:368-374. 25. Kaufmann S, Russo GI, Bamberg F, et al. Prostate cancer detection in patients with prior negative biopsy undergoing cognitive, robotic or in-bore MRI target biopsy. World J Urol. 2018; 36:761-768. 26. Faria R, Soares MO, Spackman E, et al. optimising the diagnosis of prostate cancer in the era of multiparametric magnetic resonance imaging: a cost-effectiveness analysis based on the prostate MR imaging study (PROMIS). Eur Urol. 2018; 73:23-30. 27. van Sloun RJG, Wildeboer RR, Mannaerts CK, et al. Deep Learning for Real-time, Automatic, and Scanner-adapted Prostate (Zone) Segmentation of Transrectal Ultrasound, for Example, Magnetic Resonance Imaging-transrectal Ultrasound Fusion Prostate Biopsy. Eur Urol Focus. 2019; pii: S2405-4569(19)30125-7. 28. Grey A, Ahmed HU. Multiparametric ultrasound in the diagnosis of prostate cancer. Curr Opin Urol. 2016; 26:114-119. 29. Delgado Oliva F, Arlandis Guzman S, et al. Diagnostic performance of power doppler and ultrasound contrast agents in early imaging-based diagnosis of organ-confined prostate cancer: Is it possible to spare cores with contrast-guided biopsy? Eur J Radiol. 2016; 85:1778-1785. 30. Eure G, Fanney D, Lin J, et al. Comparison of conventional transrectal ultrasound, magnetic resonance imaging, and microultrasound for visualizing prostate cancer in an active surveillance population: A feasibility study. Can Urol Assoc J. 2019; 13:E70-E77.

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DOI: 10.4081/aiua.2020.2.93

ORIGINAL PAPER

Intensive simulation training on urological mini-invasive procedures using Thiel-embalmed cadavers: The IAMSurgery experience Guglielmo Mantica 1, 2, Giovannalberto Pini 2, 3, Davide De Marchi 2, 3, Irene Paraboschi 4, Francesco Esperto 5, André Van der Merwe 6, Heidi Van Deventer 6, Massimo Garriboli 7, Nazareno Suardi 1, Carlo Terrone 1, Rosario Leonardi 2, 3 1 Department

of Urology, Policlinico San Martino Hospital, University of Genova, Genova, Italy; International Accademy of Miniinvasive Surgery; 3 Department of Urology, San Raffaele Turro Hospital, Milan, Italy; 4 Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genova, Genova, Italy; 5 Department of Urology, Campus Bio-medico University of Rome, Rome, Italy; 6 Department of Urology, Stellenbosch University and Tygerberg Academic Hospital, Cape Town, South Africa; 7 Department of Pediatric Urology, Evelina Children Hospital, London, UK. 2 IAMSurgery,

Introduction: The objective of the study was to evaluate the benefits perceived by the use of cadaver models by IAMSurgery attendees and to define indications to standardize future similar training camps. Materials and methods: A 25-item survey was distributed via e-mail to all the participants of previous training courses named as “Urological Advanced Course on Laparoscopic Cadaver Lab" held at the anatomy department of the University of Malta, for anonymous reply. Participants were asked to rate the training course, the Thiel’s cadaveric model, and make comparison with other previously experienced simulation tools. Results: The survey link was sent to 84 attendees, with a response rate of 47.6% (40 replies). There was improvement in the median self-rating of the laparoscopic skills before and after the training camp with a mean difference of 0.55/5 points in the post-training skills compared to the basal (p < 0.0001). The 72.2% of the urologists interviewed considered Thiel's HCM better than other training methods previously tried, while five urologists (27.8%) considered it equal (p = 0.00077). Globally, 77.5% (31) of attendees found the training course useful, and 82.5% (33) would advise it to colleagues. Conclusions: Thiel’s fixed human cadaveric models seem to be ideal for training purposes, and their use within properly structured training camps could significantly improve the surgical skills of the trainees. An important future step could be standardization of the training courses using cadavers, and their introduction into the standardized European curriculum.

Summary

KEY WORDS: Training; Cadaver model; Urology; Thiel fixation; Simulation. Submitted 22 November 2019; Accepted 7 December 2019

INTRODUCTION Surgical ethics requires that surgical procedures should be performed on patients only after having reached adequate skills that ensure high standards in terms of quality and safety for the patient himself (1, 2). For this reason, in recent years, we have witnessed the multiplica-

tion of theoretical, technological, synthetic, and biological simulation/training models of varying utility for urologists and post-graduates (3-7). Although often useful, many of these models have significant limitations in terms of realism, accessibility, and ethics. As trivial as it sounds, nothing is more like the human body as the human body itself. For this reason, a solution in terms of education and pre-real patient surgical training could be provided by increased use of human cadaver models. Currently, there is little (but increasing) literature on the use of human cadaveric models (HCM) for training purposes, and there are a few experiences of training camps with a standardized format reported (8-14). The IAMSurgery has been organizing laparoscopic urological surgery training camps for several years using human cadaveric models. The objective of the study is, therefore, to evaluate the benefits perceived by the use of cadaver models by IAMSurgery attendees and to define indications to standardize future similar training camps.

MATERIALS

AND METHODS

From January 2016 to October 2019, the IAMSurgery (International Academy of Mini-invasive Surgery) organized six editions of a training camp called “Urological Advanced Course on Laparoscopic Cadaver Lab". The courses were held at the anatomy department of the University of Malta, an expert in the advanced preparation of the bodies following the Thiel’s soft-fix embalming method. Preparation of the Thiel’s cadaveric models The “Thiel method” 15 consists of the application of an intravascular injection formula, and submersion for a determinate time in a stainless steel tank in a particular solution that lacks toxic or irritating gases due to minimum formaldehyde concentrations. Thiel fixation provides “reusable” cadavers on which, in some cases, several proce-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2020; 92, 2

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G. Mantica, G. Pini, D. De Marchi, I. Paraboschi, F. Esperto, A. Van der Merwe, H. Van Deventer, M. Garriboli, N. Suardi, C. Terrone, R. Leonardi

dures might be performed, being more cost-effective than fresh and fresh frozen cadavers. Format of the course The course starts with six hours of face-to-face interactive lectures on embalming technique, preparation of the corpses, pelvic and retroperitoneal anatomy, patient positioning, followed by step-by-step modular videos on pelvic and kidney surgery. The hands-on practice began early on the second day. The course, supported by the expert faculty, allows practising simultaneously on three cadavers for a total time of 24 hours. Two four-hour modules were focused on laparoscopic radical prostatectomy, two four-hour modules on laparoscopic partial nephrectomy, and two four-hour modules on laparoscopic radical nephrectomy. The philosophy of the course was to maintain small groups for each procedure, favoring a modular rotation regulated by the tutor, to teach not only surgical technique but also non-technical skills and encouraging the team building, a fundamental requirement in the operating room and real life. Study design and data analysis A 25-item survey (Table 1) was designed by two of the course tutors (R.L. and G.P.) and checked by a third urologist (G.M.) not previously involved in the organization of the courses. The survey was designed following

the Checklist for Reporting Results of Internet E-Surveys (CHERRIES) guidelines, 16 uploaded on Google Form, and was distributed via e-mail to all the participants of the previous courses, for anonymous reply. The survey was distributed in November 2019. Before circulating, we tested the survey for usability and technical functionality. The survey consists of two parts: – Part one: General information of the responder (including age, trainee vs. specialist, nationality). – Part two: Ratings of the training course, the Thiel’s cadaveric model, and comparison with other previously experienced simulation tools. Some questions had a free answer option while others a ranking scale from 1 (very low) to 5 (very high). Only surveys with section one completed, and more than 90% completed in section two, were included in the analysis. Data were entered into a Microsoft Excel (version 14.0) database and transferred to SofastatsTM for Windows. A descriptive statistical analysis was performed. Variables are presented as median (1st-3rd interquartile range) or as a percentage (%). The statistical analysis of nominal variables was done using the T-Test Calculator and the Chi-Square Calculator for Goodness of Fit. The level of significance was set at p < 0.05.

Table 1. IAMSurgery - Malta - Training course on Thiel cadaver models. 1) 2) 3) 4) 5) 6) 7) 8) 9) 10) 11) 12) 13) 14) 15) 16) 17) 18) 19) 20) 21) 22) 23) 24) 25)

Age Working position at the time of the training course Nationality Were you already performing laparoscopy before the training camp? (YES/NO) If NO; Have you started to perform laparoscopy after the training camp? (YES/NO) Please give a mark to the team of Tutors (1 to 5) Please give a mark to the Course Concept (1 to 5) Please give a mark to the Time planning (was the training course too short/long?) (1 to 5) Usefulness of cadaver training model for radical nephrectomy (1 to 5) Realism of cadaver training model for radical nephrectomy (1 to 5) Usefulness of cadaver training model for partial nephrectomy (1 to 5) Realism of cadaver training model for partial nephrectomy (1 to 5) Usefulness of cadaver training model for prostatectomy (1 to 5) Realism of cadaver training model for prostatectomy (1 to 5) Do you have any experience with other training models (i.e. porcine, synthetic, etc)? (YES/NO) If YES; please state what other type of training model have you tried If YES; please explain the differences/advantages/disadvantages of the cadaveric model compared to the others that you have experienced (i.e. any difference in bleeding?) How would you rate the Thiel cadaveric model? (1 to 5) If you do have experiences with other training models, how do you consider Thiel cadaver model? (worse-equal-better) Please rate your laparoscopic skills confidence before the training (1 to 5) Please rate your laparoscopic skills confidence after the course (1 to 5) Were your couse expectations fullfilled? (YES/NO/NOT COMPLETELY) Have you found the training camp useful for your clinical and surgical practice? (YES/NO/NOT COMPLETELY) How would you rate the training course? (1 to 5) Would you advice it to a colleague? (YES/NO/I DON’T KNOW)

Archivio Italiano di Urologia e Andrologia 2020; 92, 2

RESULTS

The survey link was sent to 84 attendees, with a response rate of 47.6% (40 replies). All attendees were Italian, specialized in urology, and with a median age of 50 years (4357.5). Twenty-seven (67.5%) were already performing laparoscopy at their institution (either as first operator or assistant). Ten (76.9%) out of the 13 who were not performing laparoscopy started with this minimally invasive approach after the training course. The ratings given to the training course and the usefulness and realism of the HCM for training purposes are summarized in Table 2. There was improvement in the median selfrating of the laparoscopic skills before and after the training camp with a mean difference of 0.55/5 points in the post-training skills compared to the basal (p < 0.0001). Twenty-one (52.5%) attendees did not have experience with any other simulator models, while 18 (45%) had tried at least one other method (one surveyed colleague did not reply to this question). Porcine and virtual models were both tried by eight urologists while a synthetic model was tried by five urologists. The presence of bleeding was stated in favor of porcine models by seven urologists (87.5%) while the realism of anatomy 13 (72.2%) and better tissue consistency 8 (44.4%) was in favor of Thiel’s HCM. Thirteen (72.2%) urologists considered Thiel's HCM better than other training meth-

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Urological mini-invasive training using cadavers

Table 2. Overall and specific course rating.

training purposes (8). The Thiel method provides cadavers that can be re-used and on which many procedures can be Variable: respondent numbers (%) 1 2 3 4 5 performed. Tutors rating 1 (2.5%) 13 (32.5%) 26 (65%) The re-usability is of paramount imporCourse concept rating 1 (2.5%) 6 (15%) 33 (82.5%) tance, considering the scant supply of Time planning rating 8 (20%) 16 (40%) 16 (40%) human bodies available for research and Useful of HCM for RN 10 (25%) 30 (75%) training in some settings. The realism of HCM for RN 2 (5%) 19 (47.5%) 19 (47.5%) Moreover, from our survey, it emerges Useful of HCM for PN 2 (5%) 8 (20%) 20 (50%) 10 (25%) how most of the interviewees consider The realism of HCM for PN 4 (10%) 12 (30%) 18 (45%) 6 (15%) the cadaver model globally superior Useful of HCM for RP 7 (17.5%) 17 (42.5%) 16 (40%) compared to the other tested models 6 (15%) 17 (42.5%) 17 (42.5%) The realism of HCM for RP (porcine, synthetic, and virtual). Thiel HCM rating 3 (7.5%) 21 (52.5%) 16 (40%) The only flaw is the absence of bleedPre-course personal LAP skills 8 (20%) 6 (15%) 16 (40%) 10 (25%) ing, which compromises complete realPost-course personal LAP skills 8 (20%) 14 (35%) 18 (45%) ism in particular in some procedures Overall course rating 3 (7.5%) 16 (40%) 21 (52.5%) such as partial nephrectomy. Similarly, the Thiel method has already been tested in urology and showed to be Figure 1. suitable for training and testing purposWould you advice it to a colleague? Have you found the training camp useful for es within minimally-invasive approachyour clinical and surgical practice? es (19-20). Surgical training in adult cadaveric models may be useful also for pediatric urologists regarding some specific procedures such as nephrectomies (i.e., performed for Wilms 'tumors). The anatomy of an infant is different; however, a teenager often presents with an anatomy similar to an adult. Furthermore, while taking into account the limits as mentioned earlier, the ods previously tried, while five urologists (27.8%) conpediatric surgeon could benefit from confidence-buildsidered it equal (p = 0.00077). ing with tissue consistency and surgical planning. Globally, 77.5% (31) of attendees found the training From an educational point of view, Thielâ&#x20AC;&#x2122;s model might course useful, and 82.5% (33) would advise it to colbe a perfect tool to be introduced into standardized leagues (Figure 1). European curricula for urologists and pediatric urologists. DISCUSSION The future perspective of IAMS is to make the training Surgical training is very delicate and for ethical reasons even more realistic by mimicking a real surgical environcannot be performed directly on the patient but requires ment through a live cadaver model, and the anatomy a structured modular training first in the dry lab, then on department of the University of Malta is already at work animal or cadaveric models (17) to provide a cadaver perfusion system. The model will The "Urological Advanced Course on Laparoscopic Cadaver combine the realistic conditions of the living body with Lab" is a three-day training camp that combines theory, the real human anatomy in one model and is the only surgical practice, and team building. training model available that provides such a combinaThe cadaveric model is designed to bridge the gap tion (21, 22). between simulation and live surgery. In literature, there are other training camp reports on cadavers in different fields of urology with excellent feedback from the particCONCLUSIONS ipants who generally perceive an improvement in their Thielâ&#x20AC;&#x2122;s fixed human cadaveric models seem to be ideal operating skills at the end of the course itself (10-14). for training purposes, and their use within properly In such courses, the importance of the tutors is fundastructured training camps could significantly improve mental (18). the surgical skills of the trainees. An important future The preparation, the ability to teach, and the passion of step could be standardization of the training courses an excellent tutor can affect the quality of the contents. using cadavers, and their introduction into the standardThe quality of the cadaver models is also fundamental. ized European curriculum. Due to biological risk, human cadavers are often used after an embalming process (15). The most common method of embalming is formalin fixation. However, a ACKNOWLEDGEMENTS new method called "Thiel fixation" provides an alternative A kind and sincere thank you to Dr. Heidi Van Deventer to fresh or formalin-fixed specimens and can be ideal for for the English editing. Archivio Italiano di Urologia e Andrologia 2020; 92, 2

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G. Mantica, G. Pini, D. De Marchi, I. Paraboschi, F. Esperto, A. Van der Merwe, H. Van Deventer, M. Garriboli, N. Suardi, C. Terrone, R. Leonardi

REFERENCES 1. Carrion DM, Rodriguez-Socarrás ME, Mantica G, et al. Current status of urology surgical training in Europe: an ESRU-ESU-ESUT collaborative study. World J Urol. 2019 Apr 13. 2. de Oliveira TR, Cleynenbreugel BV, Pereira S, et al. Laparoscopic training in urology residency programs: a systematic review. Curr Urol. 2019; 12:121-126. 3. Tawfik AM, El-Abd AS, El-Enen MA, et al. Validity of a sponge trainer as a simple training model for percutaneous renal access. Arab J Urol. 2017; 15:204-210. 4. Monda SM, Weese JR, Anderson BG, et al. Development and validity of a silicone renal tumor model for robotic partial nephrectomy training. Urology. 2018; 114:114-120.

of Thiel embalmed cadavers for laparoscopic radical nephrectomy. J Endourol. 2015; 29:595-603. 20. Veys R, Verpoort P, Van Haute C, et al. Thiel-embalmed cadavers as a novel training model for ultrasound guided supine endoscopic combined intrarenal surgery. BJU Int. 2019 Nov 16. doi: 10.1111/bju.14954. [Epub ahead of print] 21. Aboud ET, Aboud G, Aboud T. "Live cadavers" for practicing airway management. Mil Med. 2015; 180 (3 Suppl):165-70. 22. Held JM, McLendon RB, McEvoy CS, Polk TM. A reusable perfused human cadaver model for surgical training: an initial proof of concept study. Mil Med. 2019;184(Suppl 1):43-47.

5. Mantica G, Pacchetti A, Aimar R, et al. Developing a five-step training model for transperineal prostate biopsies in a naïve residents' group: a prospective observational randomised study of two different techniques. World J Urol. 2019; 37:1845-1850. 6. Setia S, Feng C, Coogan C, et al. Urology residents' experience with simulation: initial evaluation of MRI/US fusion biopsy workshop. Urology 2019; pii: S0090-4295(19)30817-9. 7. Mantica G, Balzarini F, Dotta F, et al. Development of a photographic handbook to improve cystoscopy findings during resident's training: A randomised prospective study. Arab J Urol. 2019; 17:243-248. 8. Mantica G, Leonardi R, Pini G, et al. The current use of human cadaveric models in urology: a systematic review. Minerva Urol Nefrol. 2019 Nov 11. doi: 10.23736/S0393-2249.19.03558-6. 9. Healy SE, Rai BP, Biyani CS, et al. Thiel embalming method for cadaver preservation: a review of new training model for urologic skills training. Urology. 2015; 85:499-504. 10. Yiasemidou M, Roberts D, Glassman D, et al. A multispecialty evaluation of Thiel cadavers for surgical training. World J Surg. 2017; 41:1201-1207. 11. Mains E, Tang B, Golabek T, et al. Ureterorenoscopy training on cadavers embalmed by Thiel's method: simulation or a further step towards reality? Initial report. Cent European J Urol. 2017; 70:81-87. 12. Bele U, Kelc R. Upper and Lower Urinary Tract Endoscopy Training on Thiel-embalmed Cadavers. Urology. 2016; 93:27-32. 13. Özcan S, Huri E, Tatar I, et al. Impact of cadaveric surgical anatomy training on urology residents knowledge: a preliminary study. Turk J Urol. 2015; 41:83-7. 14. Ahmed K, Aydin A, Dasgupta P, et al. A novel cadaveric simulation program in urology. J Surg Educ. 2015; 72:556-65.

Guglielmo Mantica, MD (Corresponding Author) guglielmo.mantica@gmail.com Department of Urology, Policlinico San Martino Hospital, University of Genova Largo Rosanna Benzi 10, 16132, Genova (Italy) Giovannalberto Pini, MD Davide De Marchi, MD Rosario Leonardi, MD Department of Urology, San Raffaele Turro Hospital, Milan (Italy)

15. Thiel W. The preservation of the whole corpse with natural color. Ann Anat. 1992; 174:185-95.

Irene Paraboschi, MD Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genova, Genova (Italy)

16. 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.

Francesco Esperto, MD Department of Urology, Campus Bio-medico University of Rome, Rome (Italy)

17. Somani BK, Van Cleynenbreugel B, Gozen A, et al. The European Urology Residents Education Programme hands-on training format: 4 years of hands-on training improvements from the European School of Urology. Eur Urol Focus. 2019; 5:1152-1156. 18. Mantica G, Fransvea P, Virdis F, et al. Surgical training in South Africa: an overview and attempt to assess the training system from the perspective of foreign trainees. World J Surg. 2019; 43:2137-2142. 19. Rai BP, Stolzenburg JU, Healy S, et al. Preliminary validation

Correspondence

Archivio Italiano di Urologia e Andrologia 2020; 92, 2

André Van der Merwe, MD Department of Urology, Stellenbosch University and Tygerberg Academic Hospital, Cape Town (South Africa) Massimo Garriboli, MD Department of Pediatric Urology, Evelina Children Hospital, London (UK) Nazareno Suardi, MD Carlo Terrone, MD Department of Urology, Policlinico San Martino Hospital, University of Genova, Genova (Italy)

Zampieri_Stesura Seveso 17/06/20 10:13 Pagina 97

DOI: 10.4081/aiua.2020.2.97

ORIGINAL PAPER

Pediatric-adolescent andrology: Single centre experience Nicola Zampieri, Francesco Camoglio Woman & Child Hospital, Department of Surgery, Dentistry, Paediatrics and Gynecology; Division of Pediatric Surgery, University of Verona, Italy.

Summary

Introduction: Andrology is the medical specialty dealing with men’s health and reproductive system from birth to adulthood, including genital, hormonal, reproductive, sexual as well as psychological aspects; the aim of this study is to report our 10 year-experience Material and methods: In September 2009, a Pediatric Andrology Outpatient Clinic was opened at the Authors’ Institution. The continuous request for access to the service, together with an increasingly helpful collaboration with local clinicians, has led to an increase in the number of treated patients. At the Clinic, visits are performed for both surgical and medical consultations by the multidisciplinary medical group for the treatment of conditions in the adolescent patient. All patients are followed every 3, 6 and 12 months when indicated. Patients with undescended testes were excluded because managed into a specific protocol. Also patients with syndrome or metabolic diseases are excluded from the analysis. Results: During the study period, September 2009-September 2019, the following conditions were managed: varicocele 1436 patients; gynecomastia - 18 patients; penile curvature 89 patients; webbed penis - 132 patients; hypospadias-related diseases - 39 patients; erectile dysfunction - 14 patients; obesity and abnormal semen analysis - 47 patients. During the study period there was an increase for each category especially for medical reasons. Conclusions: Pediatric-adolescent andrology clinics should count on the expertise of different skilled professionals to cope with an ever-increasing number of requests and to offer the timely management of conditions that until very recently were considered social taboos or caused concern only in adulthood like the erectile dysfunction. The evolution of our society, which also means evolution of the mass media, should go hand in hand with the development of Medicine, which needs to adjust to and prevent new healthcare issues.

KEY WORDS: Pediatric andrology; Varicocele; Undescended testes; Adolescent. Submitted 7 January 2020; Accepted 28 January 2020

INTRODUCTION

Andrology is the medical specialty dealing with men’s health and reproductive system from birth to adulthood, including genital, hormonal, reproductive, sexual as well as psychological aspects (1). Regular andrological check-ups are essential to reveal possible problems and to receive thorough advice and information so that sexual and reproductive functions are well preserved. Estimates report that about one in three males suffers from andrological diseases with rates varying according

to the age: 27-30% of pediatric male subjects have reproductive and/or sexual conditions, especially cryptorchidism, varicocele, hypogonadism, congenital anomalies of the genitourinary tract and sexually transmitted diseases; in adulthood, 40% of men are affected by andrological diseases, in particular infertility and sexual problems. The main surgically correctable diseases to prevent hypofertility are varicocele (30%) and undescended testes (< 5%) (1-3). The origin of many of the andrological conditions appearing during adulthood is to be traced before the age of 18 years and sometimes even during gestation. The male gonad is extremely sensitive to external events even during gestation and soon after childbirth up until puberty (4-5). The andrological evaluation of pediatric patients is therefore extremely important for an early diagnosis of genital anomalies such as penile alterations or abnormal positions of the testis; early evaluation is helpful also to search for risk factors in terms of male general and sexual health. The aim of this study was to report the Authors’ 10-year experience at the Pediatric Andrology Outpatients clinic of their Institution, focusing on the different aspects of surgically treated andrological diseases and on the type of andrological requests.

MATERIALS

AND METHODS

In September 2009, a Pediatric Andrology Outpatients Clinic was opened at the Institution of Authors. The continuous request for access to the service, together with an increasingly helpful collaboration with local clinicians, has led to an increase in the number of treated patients. At the Clinic, visits are performed both for surgical conditions and for medical consultations when required by the multidisciplinary medical group for the treatment of conditions in the adolescent patient. Through the review of the cases, the aim was to focus on the type of conditions and the ever-increasing requests for advice and treatment. The study excluded the patients with phimosis, undescended testes and hypospadias, although it included penile complications such as residual penile curvatures or requests for penile lengthening. Upon specific request, some patients had hormonal tests and semen analysis performed. At the Authors’ Clinic, any patient who has accomplished his pubertal stage can perform semen analysis, even though he is a minor, provided that an informed consent has been signed by the patient together with his referring physician and his par-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2020; 92, 2

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N. Zampieri, F. Camoglio

ents. For undescended testes the Clinic adopts a specific follow-up procedure, which is not always performed by the same medical team (6). Other diseases, such as Klinefelter, metabolic diseases or oncologic conditions are managed with a multidisciplinary approach. Depending on the different conditions, patients are followed every 3, 6 or 12 months. The Clinic medical team includes 2 senior pediatric surgeons (1 with high specialty in andrology and urology), 2 registrars and 1 pediatric radiologist.

RESULTS

During the study period, September 2009-September 2019, the following conditions were managed: varicocele - 1436 patients; gynecomastia - 18 patients; penile curvature - 89 patients; webbed penis - 132 patients; hypospadias-related diseases - 39 patients; erectile dysfunction 14 patients; obesity and abnormal semen analysis - 47 patients. Patients data and distribution are showed into Table 1. Varicocele: 548 patients during the study period received surgery with different techniques depending on the type of reflux (7-8). Of these, 278 performed a spermiogram. Once the pubertal development was accomplished, non-surgical patients were always offered to perform a follow-up spermiogram. Gynecomastia: surgery was mainly requested for cosmetic reasons; only 18 cases out of the 69 managed at the Clinic showed concomitant hyperplasia of the gland. In 1 case, carcinoma was diagnosed in situ. Penile curvature: 89 patients; 27 had a lateral curvature between 60 and 90 degrees, 18 between 45 and 60 degrees and the remaining 44 had a curvature of less than 45 degrees. These included 15 ventral curvatures, 5 dorsal curvatures and 24 lateral curvatures. In 10 patients, exeresis of the traction plate with the addition of biological material resolved the penile curvature. Webbed penis: all patients received surgery after one year from birth; in 24 patients the suprapubic fat was removed in addition to the reconstruction of the penoscrotal and penopubic junctions. Hypospadias-related diseases: 39 patients; 15 had a residual ventral curvature between 15 and 30 degrees; the remaining patients required lengthening at puberty, with exeresis of the suspensory ligament. In two cases (pubertal patients) the diameter was increased with the addition of biological material. Table 1. Patient distribution. Disease varicocele Gynecomastia Penile curvature Webbed penis Hypospadias related disease E.R. Obesity

Number of pts 1436

Age range 13 ± 2.1

18 89 132 39 14 47

14 ± 0.9 14 ± 3.7 5 ± 1.8 13 ± 3.1 16 ± 2.1 17 ± 1.2

Erectile dysfunction: none of these patients had a concomitant surgical condition. 12 patients reported the problem after the age of 15 years, after the first sexual intercourse was reported as being unsatisfactory. Two patients over the age of 17 years made a continuous use of drugs. This group of patients included two male subjects over the age of 16 years who suffered from oncological conditions and had received a transplant. Obesity and abnormal semen analysis: all the patients accessed the Clinic mainly for the evaluation of the size of their external genitalia; all the patients were then offered to perform spermiogram.

Follow-up During the study period there was an increasing number of requests, with an increasing percentage of those patients requiring medical or aesthetic check. Focusing on each specific field, there was a statistical significance increasing percentage between the year 2009-2014 and 2015-2019 (p < 0.05). Excluding varicocele group where the percentage is stable during year (range between 475 and 576 visit per year with) the most significance differences were found into the penile curvature group (24 vs 65 cases), hypospadias related disease (12 vs 27 cases) and erectile dysfunction (1 vs 13 cases) (p < 0.05). About webbed penis there was an increasing demand but without statistical differences (59 vs 73 cases) probably because the main request was for phimosis and the final diagnosis for webbed penis. Obesity group increased after our National register study about bariatric surgery in adolescent and for this reason it was not possible to add any data about the increasing requests respect to other subgroups (9). In all cases of varicocele, testicular hypotrophy remains the main indication for surgery. As reported in previous studies, all these patients had spontaneous continuous spermatic vein reflux (10-11). They were corrected according to their pubertal stage and a correlation was found between high FSH level and small ipsilateral testicular volume with the controls. For this group motility, morphology and sperm count were significantly reduced than for the patients with the same grade of varicocele and spermatic vein reflux who were treated conservatively (normal testicular size). In terms of hormone levels, only FSH varied significantly in patients with different grades of testicular hypotrophy; it was not possible to observe the same for LH, testosterone (TT), estradiol or prolactin levels, which were not different between operated and non-operated patients. The patients who received post-op semen analysis after 1 year showed a statistically significant improvement in motility and morpholo2009-2014 2015-2019 727 1436 gy. Among non-operated patients, sperm 184 underwent surgery 364 underwent surgery morphology (head anomalies) was the 7 11 main abnormal parameter, followed by 24 65 motility and sperm count. These patients 59 73 with abnormal semen analysis underwent surgery. 12 27 None of the patients with gynecomastia 1 13 had abnormal hormone parameters, but 2 45 for all the operated patients the cumula-

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tive testicular volume was smaller than for controls (p < 0.05); also, the adolescents with gynecomastia had a testicular volume smaller than those with other andrological disease such as varicocele. Only 2 patients had semen analysis after surgery and the parameters were within the reference range. In the penile curvature group, 89 patients, 27 had a lateral curvature between 60 and 90 degrees, 18 between 45 and 60 degrees and the remaining 44 had a curvature of less than 45 degrees. These included 15 ventral curvatures, 5 dorsal curvatures and 24 lateral curvatures. In 10 patients, exeresis of the traction plate with the addition of biological material resolved the penile curvature. The increased request trough the period was probably related to a preventative campaign at school where our team each year performed 2-hour meetings with adolescents focusing about andrological disease. The same is done for female with the gynecologists. All the 132 patients with webbed penis had a surgical reconstruction of the penoscrotal junction and circumcision in case of tight phimosis; 24 patients had removal of suprapubic fat with a semi-circular incision in addition to the reconstruction of the penoscrotal and penopubic junctions. At the end of the follow-up period, 4 patients (aged between 12 and 15 years) underwent varicocelectomy. So far, no sexually active patient has reported any functional problems. Even if the main indication for the first visit by the general pediatricians was phimosis, in the first 5 year period, during the years it is was possible to establish an increased request for this specific disease and not only was phimosis, due to the well-known disease by the general pediatricians. The group of patients with complications related to the correction of hypospadias within 18 months from birth was certainly the most difficult to manage. As it is known, the possible complications related to urethroplasty include fistulas and their strictures/stenoses as well as any possible complications or discomfort later during adolescence. 39 patients are currently followed at the Clinic for residual ventral curvature between 15 and 30 degrees (15 patients) and for penile lengthening (5 patients aged between 15 and 18 years). 2 patients in this group also requested an increased penile diameter and were treated with a filler. The remaining 10 patients suffer from erection pain and 3 sexually active patients report pain during ejaculation. These last fields are treated and recognized especially in the second 5-year period, due to the multidisciplinary team approach. Another group of patients, new in terms of type of condition, is represented by adolescents with erection problems. 14 patients from this group are currently followed at the Clinic, all over 15 years of age and sexually active. None has been diagnosed with an organic disease, although most of the patients reported some discomfort during intercourse and a feeling of inadequacy with the partner. It is important to notice that no patient reported erectile dysfunction during masturbation. Two patients reported the use and abuse of drugs and alcohol. In general, about 90% of the patients reported difficulties in maintaining the erection but not in its induction. Two further patients accessed the Clinic after receiving a transplant following a hematological disease. As reported in a

previous study, after the clinical and radiological evaluation, they answered a questionnaire on the quality of their sexual life. Both were without relapses and reported a reduced quality of erection, especially regarding maintenance (12). This group of patients is the example of the transitional age defect: the age group 13-18 years in the past was never considered, while female are constantly followed by gynecologists. The andrological evaluation and obesity in the pediatric-adolescent age is of recent interest; although this relation is well established for the adults, little has been done for the pediatric age group. The patients who are currently cared for at the Authorsâ&#x20AC;&#x2122; Clinic mainly requested first access for a genital evaluation, especially for concealed penis. The hormonal and semen analysis tests (performed on 14 patients out of 47) showed that the testicular volume of overweight/obese adolescents (BMI > 25) was smaller than in patients with a normal weight (p < 0.05). These patients also had a delay in pubertal development and a reduced quality of their semen (mainly indicated by morphologic abnormalities and reduced motility). The study patients did not show abnormal hormone levels (FSH, LH, TT, Estradiol) even if the FSH level seems to be higher respect to normal weight patients.

DISCUSSION

Andrology greatly trusts primary prevention to reduce the incidence of andrological diseases and conditions. Clinical studies and primary prevention policies in andrology should be focused on the most vulnerable crucial phases of male gonad development that can be affected by a variety of external agents. The preservation of the genital and sexual health of young people also means protecting their fertility potential, a very important action within the broader scope of the interventions aimed at reducing the drop in the birth rate which is currently affecting modern society (13-15). It is therefore well established that most of the andrological problems have a prenatal origin and can be diagnosed, studied and treated before adulthood. As reported in a recent study, the prevalence of male adolescent that are followed by andrologists is very low, if compared to female; this could be a â&#x20AC;&#x153;genderâ&#x20AC;? discrimination (16). Although the development of the gonads is complex and not yet fully understood, there are some factors that could interfere with their correct anatomical development as well as with the successful pubertal development of the subject. A placental malfunction is associated with an abnormal andrological development: several studies described a relation between fetal growth restrictions and an increased risk of male reproductive problems, including hypospadias, cryptorchidism and testicular cancer (15-19). In addition, twin or triplet pregnancy and preterm birth were shown to be associated with non-gestational impaired reproductive development. Again, an increased birth weight in males was also positively correlated with adult serum testosterone levels, while adult men born with lower birth weights were found to display features of hypogonadism, with reduced testicular size, lower Archivio Italiano di Urologia e Andrologia 2020; 92, 2

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N. Zampieri, F. Camoglio

testosterone levels and higher LH values than controls born with weights within the reference range. Other maternal factors can affect fertility: abnormal maternal glucose metabolism in pregnancy may be associated with an increased risk for genital malformation as well as maternal obesity, smoking, maternal serum estrogens, and estrogenic endocrine disruptor exposure (20-24). This point in mind, in order to safeguard the reproductive and sexual health of young men, a synergic approach involving pediatricians, general practitioners, doctors at family planning clinics and andrologists for the adults plays a key role together with the implementation of territorial networks that may enhance the integration of the know-how and expertise of all these health professionals. This is especially true in the extremely vulnerable period of life generally ranging from 11 to 18 years of age, when young male patients experience the transition to adult life and maturity from a reproductive and sexual point of view. If we exclude the cases treated for varicocele, which has a more consolidated follow-up, what emerged from the analysis of the cases treated at the Authors’ Clinic was a progressive increase in some conditions which were not reported by patients until recent years. The problems related to urethroplasty, obesity, gynecomastia, webbed penis, and erectile dysfunction seem to be common causes of concern related more to the adolescents’ increased awareness and sexual maturity than to real healthcare issues suggested by a territorial primary prevention system. Two aspects deserve particular attention: the increase in obesity and in sexual dysfunctions in the adolescents can be considered important risk factors for the andrological health of adults. The merely functional aspect of the erectile dysfunction, if unrelated to conditions of surgical interest (outcome of penile surgery, bladder surgery, anorectal malformations, etc.), is complex to manage. Many adolescents experience pubertal development, relationship with their body and with their partners in an increasingly confused context, deeply affected by complex social stereotypes. A recent study pointed out that the main problems reported in addition to pain during intercourse were erectile dysfunction and premature ejaculation (25-27). This latter aspect is difficult to be properly evaluated, since very often it is not clear what teenagers mean by “premature” ejaculation and if the real situation clashes with their expectations, or with what is considered as acceptable by their friends, by their readings on the internet or on the social media, as reported by many patients who accessed the Authors’ Clinic. A different approach should be used in case of patients with erectile dysfunction associated with a history of cancer. In fact, despite being disease-free, these patients feel discomfort since they consider themselves as cancer patients, as being “different”. In the Authors’ experience, these patients are more easily treated because they have faster and more effective response mechanisms to the pathology and to their impaired physical condition than those young patients who have never experienced any pathological condition before (12). Obesity in relation to male reproductive health is well

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recognized, especially in adulthood. Obesity alters fertility and the fertility potential through various mechanisms, mainly the reduced quantity of testosterone used and converted into estrogen by the adipocytes and the reduced quality of the seminal fluid. Although most of the obese adolescents are monitored for weight reduction primarily to reduce diabetes, hypertension, cardiac risk and orthopedic diseases, little action is taken in terms of fertility potential; in fact, for the obese patients the primary aim is weight loss to improve self-image, while their overall health status is kept in the background. The experience on adult patients treated both clinically and surgically for obesity showed a significant improvement in hormone levels and semen quality in those patients who obtained correct weight control, and this proved to be true for male and female patients alike (27-30). The above considerations should drive patients towards weight control not only for esthetic and certainly important functional reasons, such as reducing hypertension, arthropathies and diabetes, but also to safeguard their fertility potential. Prevention policies should be gender specific, with the awareness that if many actions are currently implemented for the prevention of female conditions, little is done for male patients. For young male adults, an objective examination to the genitalia, comprehensive hormone panel tests and a spermiogram can help the diagnosis and early treatment of many conditions that may affect male fertility potential. Pediatric-adolescent andrology clinics should count on the expertise of different skilled professionals to cope with an ever-increasing number of requests and to offer the timely management of conditions that until very recently were considered social taboos or caused concern only in adulthood like the erectile dysfunction. The evolution of our society, which also means evolution of the mass media, should go hand in hand with the development of Medicine, which needs to adjust to and prevent new healthcare issues.

REFERENCES

1. Zampieri N, Bianchi F, Patanè S, Camoglio FS. Infertility worldwide: the lack of global pediatric andrologists and prevention. In Male Reproductive Health (Eds. Wei Wu, Francesco Ziglioli and Umberto Maestroni) doi: 10.5772/intechopen.88459. 2. Datta J, Palmer MJ, Tanton C, et al. Prevalence of infertility and help seeking among 15,000 women and men. Hum Reprod. 2016; 31: 2108-2118. 3. Agarwal A, Mulgund A, Hamada A, Chyatte MR. A unique view on male infertility around the globe. Reprod Biol Endocrinol. 2015; 13:37-46. 4. Juul A, Almstrup K, Andersson AM, et al. Possible fetal determinants of male infertility. Nat Rev Endocrinol 2014; 10:553-562. 5. Skakkebaek NE, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: An increasingly common development aspects.Hum Reprod. 2001; 16:972-978. 6. Zampieri N, Caridha D, Patanè S, et al. Elastonosographic evaluation of the post-operative morpho-volumetric recovery of the gonad in the cryptorchid patient. Am J Clin Exp Urol. 2019; 7:182-187.

Zampieri_Stesura Seveso 17/06/20 10:13 Pagina 101

Pediatric andrology follow-up

7. Camoglio FS, Zampieri N. Varicocele treatment in paediatric age:relationship between type of vein reflux, surgical technique used and outcomes Andrologia. 2016:; 48:389-392.

19. Nordenvall AS, Frisen L, Nordenstrom A, et al. Population based nationwide study of hypospadias in Sweden, 1973 to 2009: Incidence and risk factors. J Urol. 2014; 191:783-789.

8. Zampieri N, Zuin V, Corroppolo M, et al. relationship between varicocele grade, vein reflux and testicular growth arrest Pediatr Surg Int. 2008; 24:727-30..

20. Guerrero-Bosagna CM, Skinner MK. Epigenetic transgenerational effects of endocrine disruptors on male reproduction. Semin Reprod Med. 2009; 27:403-408.

9. Castellani R, Toppino M, Favretti F, et al. National survery fro bariatric procedures in adolescents:long time follow-up. J Pediatr Surg. 2017; 52:1602-1605.

21. Hart RJ, Doherty DA, Mori TA, et al. Features of the metabolic syndrome in late adolescence are associated with impaired testicular function at 20 years of age. Hum Reprod. 2019; 34:389-402.

10. Zampieri N, Corroppolo M, Zuin V, et al. longitudinal study of semen quality in adolescents with varicocele: to treat or not? Urology. 2007; 70:989-993.

22. Bonde JP, Flachs EM, Rimborg S, et al. The epidemiologic evidence linking prenatal and postnatal exposure to endocrine disrupting chemicals with male reproductive disorders: A systematic review and meta-analysis. Hum Reprod Update. 2016; 23:104-125.

11. Zampieri N, Zuin V, Corroppolo M, et al. Varicocele and adolescents: Semen quality after 2 different laparoscopic procedures. J Androl. 2007; 28:727-33. 12. Andreini A, Zampieri N, Costantini C, et al. Chronic graft versus host disease is associated with erectile dysfunction in allogenic hematopoietic stem cell transplant patients: a single center experience. Leuk Lymphoma. 2018; 21:1-4. 13. Brauner EV, Hansen AM, Doherty DA, et al. The association between in utero exposure to stressful life events during pregnancy and male reproductive function in a cohort of 20-year-old offspring: the Taine study. Hum Reprod. 2019; 34:1345-1355.

23. Anway MD, Cupp AS, Uzumcu M, Skinner MK. Epigenetic transgenerational actions of ndocrine disruptors and male fertility. Science. 2005; 308:1466-1469. 24. O'Sullivan LF, Byers ES, Brotto LA, et al. A Longitudinal study of problems in sexual functioning and related sexual distress among middle to late adolescents. J Adolesc Health. 2016; 59:318-324. 25. Wiggins A, Tsambarlis PN, Abdelsayed G, Levine LA. A treatment algorithm for healthy young men with erectile dysfunction. BJU Int. 2019; 123:173-179.

14. Bouty A, Ayers KL, Pask A, et al. The genetic and environmental factors underlying hypospadias. Sex Dev. 2015; 9:239-259.

26. O'Sullivan LF, Brotto LA, Byers ES, et al. Prevalence and characteristics of sexual functioning among sexually experienced middle to late adolescents. J Sex Med. 2014; 11:630-41.

15. Rae MT, Kyle CE, Miller DW, et al. The effects of undernutrition, in utero, on reproductive function in adult male and female sheep. Anim Reprod Sci. 2002; 72:63-71.

27. Wozniak SE, Gee LL,Wachtel MS, Frezza EE. Adipose tissue: The new endocrine organ? A review article. Dig Dis Sci. 2009; 54:1847-1856.

16. Olana S, Mazzilli R, Delfino M, et al. Adolescence and andrologist: An imperfect couple. Arch Ital Urol Androl. 2018; 90:208211.

28. Lima N, Cavaliere H, Knobel M, et al. Decreased androgen levels in massively obese men may be associated with impaired function of the gonadostat. Int J Obes Relat Metab Disord. 2000; 24:14331437.

17. Trabert B, Chodick G, Shalev V, et al. Gestational diabetes and the risk of cryptorchidism and hypospadias. Epidemiology. 2014; 25:152-153. 18. van der Zanden LF, van Rooij IA, Feitz WF, Fet al. Aetiology of hypospadias: A systematic review of genes and environment. Hum Reprod Update. 2012; 18:260-283.

29. Jensen TK, Andersson A-M, JĂ¸rgensen N, et al. Body mass index in relation to semen quality and reproductive hormones among 1,558 Danish men. Fertil Steril. 2004; 82:863-870. 30. Hammoud AO, Gibson M, Peterson CM, et al. Obesity and male reproductive potential. J Androl. 2006; 27:619-626.

Correspondence Nicola Zampieri, MD, PhD (Corresponding Author) nicola.zampieri@aovr.veneto.it Francesco Saverio Camoglio, MD, Prof francesco.camoglio@univr.it Pediatric Surgical Unit, Azienda Ospedaliera Universitaria Integrata Piazzale Aristide Stefani 1, 37100 - Verona (Italy)

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DOI: 10.4081/aiua.2020.2.102

ORIGINAL PAPER

The pathological and clinical features of anterior lesions of prostate cancer: Evaluation in a single cohort of patients Daniele D’Agostino 1, Paolo Corsi 1, Michele Colicchia 1, Daniele Romagnoli 1, Gian Maria Busetto 2, Matteo Ferro 3, Alessandro Tafuri 4, Matteo Cevenini 5, Federico Mineo Bianchi 5, Marco Giampaoli 5, Angelo Porreca 1 1 Department

of Urology, Abano Terme Hospital, Abano Terme (PD), Italy; of Urology, Università “la Sapienza”, Roma, Italy; 3 European Institute of Oncology, Milan, Italy; 4 Department of Urology, University of Verona, Italy; 5 Department of Urology, University of Bologna, Italy. 2 Department

Introduction. The aim of our work is to evaluate the principal differences of the pathological features in prostate cancer (PCa) lesions comparing those in the anterior region of the gland (APCa) to those in the posterior zone (PPCa) among patients who underwent to robotic-assisted radical prostatectomy (RP). Material and methods. A total of 85 consecutive patients (mean age 66; IQR 62-71) with clinically suspected PCa were studied with multiparametric magnetic resonance of prostate before prostate biopsies. The prostate biopsies were RM-guided (60 inbore biopsy (MR-GB) and 25 Fusion-biopsy (FB). A total of 72 cases were eligible for robotic RP. An experienced genitourinary pathologist reviewed the histopathology of the tissue specimens of the patients after RP. The exclusion criteria were as follows: previous hormonotherapy, radiotherapy and chemotherapy for others cancers. Results. Based on the histological diagnosis, after RP, 68 anterior prostate cancer, and 107 posterior lesions were found. We further subcategorized lesions into peripheral and central zones for each the anterior and posterior lesions. The specific distribution of lesions by pathologic stage was: T2 = 74 (42.3%), T3a = 87 (49.7%), T3b = 12 (6.9%), T4 = 2 (1.1%) cases. Tumor volume of posterior neoplasms ranged from 0.04 to 20.35 cm3, with a median of 3.39 cm3. Anterior tumor volume ranged from 0.17 to 15 cm3, with a median volume of 2.54 cm3: PPCa were larger than APCa but the difference in size was not significant. The prostate cancer grade group (GG) I was distributed as 16.6% and 36% in anterior and posterior lesions cases. GG II and III was 43.8% and 31.5% in anterior and posterior cases, respectively. Comparatively, GG IV-V showed 39.6% and 32.5% for anterior and posterior lesions respectively (p < 0.001). Extraprostatic extention of neoplasm (EPE) was found more frequently in anterior cases (31.4%) than in in posterior cases (25.1%), but without significant difference. Lymphovascular invasion was similar in both the groups: 24% and 28.6% in anterior and posterior group, respectively. Anterior lesions showed a significantly higher rate of lymph node metastasis (9.3%) than posterior lesions (3.4%) (p < 0.005). Conclusion. In our study, we have found EPE, often associated with worse prognosis, more frequently (but not significantly) present in anterior lesions among PCa patients. Although posterior lesions are often related to pT3b stage, in our findings, anterior lesions were more often associated with a more aggressive neoplasm with more frequent nodal involvements.

Summary

KEY WORDS: Prostate cancer; Anterior lesion; Multiparametric magnetic resonance. Submitted 7 May 2020; Accepted 13 May 2020

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INTRODUCTION

Prostate cancer (PCa) is the second most frequently diagnosed tumor in males globally (1). Many national and international efforts are ongoing to improve PCa diagnosis, treatment, and, ultimately, the quality of life of patients (2). The majority of tumors have an indolent clinical course, although some cancers have an aggressive and potentially lethal evolution, if they are not promptly treated. PCa is often found in the peripheral area of the prostate gland, although histopathological studies from radical prostatectomy (RP) samples have shown that up to 30% of clinically significant neoplasms (csPCa) can be located in the anterior portion of the gland (APCa), and these are increasing in prevalence (3, 4). Cancers that arise in the anterior zone may be difficult to palpate by digital rectal examination (DRE), and are often missed (5). Moreover, transrectal ultrasound (TRUS)-guided prostate biopsy fails to accurately assess the anterior zone of the prostate, where cancers may not be sampled. Various studies have shown that targeted MRI/ultrasound fusion biopsy (TB), compared with standard biopsy (SB), is associated with increased detection of high-risk prostate cancer and decreased detection of low-risk prostate cancer (6-8). Many authors (4, 5) report that there is no difference in terms of Gleason grade (GG) IV or V rate between patients with APCa or posterior (P)PCa, although APCa has smaller tumor volume and shows a higher rate of positive surgical margins after RP when compared with PPCa (5, 9). Additionally, anterior cancers tend to be more aggressive than posterior ones, so early detection of anterior prostate cancer is clinically important (9-11). The aim of the present study is to compare the detection of anterior and posterior PCa in a contemporary cohort of Caucasian patients, admitted to the hospital for suspected PCa diagnosis and to evaluate clinical and pathological features between APCa and PPCa. The investigation was prompted by the finding that, in our practice of RP specimens, tumor volume is lower and GG is higher in a majority of cases, when the index tumor is predominantly located in the anterior region of the gland, compared to the posterior zone. No conflict of interest declared.

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Anterior lesions of prostate cancer

MATERIALS

AND METHODS

A total of 85 consecutive patients (mean age 66; IQR 6271) with clinically suspected PCa were enrolled at our institution between January 2016 and January 2019. All enrolled patients had been studied with multiparametric magnetic resonance (mpMRI) of prostate before prostate biopsies. We identified 386 suspected lesions at mpMRI (excluding the lesion of transitional zone we included in the evaluation 229 lesions of posterior region and 157 in anterior region of prostate). The demografics and radiological details of cohort are summarized in Table 1. The prostate biopsies were all RM-guided, inbore biopsy (MR-GB) and Fusion-biopsy (FB). According to the risk category, patients were offered active surveillance (AS), robot assisted radical prostatectomy (RARP), or radiation therapy (RT). All details are clarified in Table 2 A total of 72 cases were eligible for robotic RP. The study was a retrospective analysis with the approval by the Ethics Committee Institutional Review Board of Abano Policlinic and signed informed consent was provided by all patients. An experienced genitourinary pathologist reviewed the histopathology of the tissue specimens of the patients after RP. The pathologist, reviewing all prostatectomy tissue sections, identified PCa foci larger than 5 mm in diameter. The exclusion criteria were as follows: previous hormonotherapy and radiotherapy, chemotherapy Table 1. Overall and stratified according to bioptic status clinical and radiologic features of patients undergoing target biopsy of prostatic anterior lesion identified at mpMRI.

Age Median IQR PSA (ng/ml) Median IQR Prostate volume (ml) Median IQR PSA density Median IQR DRE (%) Negative Positive Previous TRUS-GB (%) PiRADS score (%) 3 4 5 Index kesion diameter (mm) Median IQR Index kesion site (%) Peripheral Central

Overall (n = 386)

Posterior lesions (n = 229)

Anterior lesions (n = 157)

p-value

66 62-71

67 61-72

66 63-71

0.7

7 5-9.2

6.7 4.8-9.1

7.7 5.2-10.1

0.02

53.7 42-69.1

55 43-69.7

51.2 38.1-67.8

0.5

0.12 0.09-0.18

0.12 0.09-0.16

0.15 0.09-0.23

< 0.001

260 (67.4) 126 (32.6) 141 (36.6)

161 (70.3) 77 (33.6) 69 (30.1)

106 (67.5) 47 (29.9) 72 (45.9)

0.5

145 (37.6) 136 (35.2) 105 (27.2)

105 (45.9) 83 (36.2) 41 (17.9)

40 (25.5) 53 (33.8) 64 (40.8)

< 0.001

14 11-19

13 9-17

16 12-23

< 0.001

277 (71.8) 109 (28.2)

183 (79.9) 46 (20.1)

94 (59.9) 63 (40.1)

< 0.001

IQR: interquartile range; TRUS-GB: transrectal ultrasound-guided biopsy; PSA: prostatic specific antigen; DRE: digito-rectal examination.

0.002

Table 2. Overall and stratified according to Fusion and In-bore biopsy bioptic outcomes of patients undergoing target biopsy of prostatic anterior lesion identified at mpMRI. Overall (n = 386) Targeted biopsy technique (%) MR-GB 217 (56.2) Fusion 169 (43.8) Number of cores taken Median 12 IQR 2-14 Positive cores * Median 1 IQR 0-3 Gleason grade (%) Negative 138 (35.8) 1 64 (16.6) 2 90 (23.3) 3 65 (16.8) 4 26 (6.7) 5 3 (0.8) Indication (%) No treatment 138 (35.8) Active surveillance 43 (11.1) RP 175 (45.3) RT 23 (6) ADT 7 (1.8)

Posterior lesions (n = 229)

Anterior lesions (n = 157)

p-value

118 (51.5) 111 (49.5)

99 (63.1) 58 (36.9)

0.3

12 2-14

0.09

1 0-2

2 1-3

< 0.001

102 (44.5) 38 (16.6) 37 (16.2) 35 (15.3) 15 (6.6) 2 (0.9)

36 (22.9) 26 (16.6) 53 (33.8) 30 (19.1) 11 (7) 1 (0.6)

102 (44.5) 32 (14) 72 (31.4) 18 (7.9) 5 (2.2)

36 (22.9) 11 (7) 103 (65.6) 5 (3.2) 2 (1.3)

< 0.001

MR-GB: Magnetic Resonance-Guided Biopsy; ADT: androgen deprivation therapy; RT: radiotherapy; RP: radical prostatectomy.

for others cancers. Based on the histological diagnosis, 68 anterior and 107 posterior lesions were found. We also subcategorized the lesions into peripheral and central zones for each anterior and posterior group. The specific distribution of lesions by pathologic stage was: T2 = 74 (42.3%), T3a = 87 (49.7%), T3b = 12 (6.9%), T4 = 2 (1.1%) cases (ref Table 3). Pathology protocol The radical prostatectomy specimens were fixed in 10% formalin and cut into approximately 5 mm sections by hand as follows: apex and base in coronal plane, seminal vesicles in sagittal plane, and mid-gland in transverse plane, perpendicular to the long axis of the urethra. The 5-mm paraffin-embedded slices blocks were sectioned into 5- Îźm-thick sections and stained with hematoxylin and eosin (H&E). Dedicated pathologists examined surgical specimens, which were processed according to the Stanford protocol (30). ISUP grade group system was applied to classify tumors (31). Surgical margins were reported positive when cancer invaded the inked surface of the specimen. Lymph nodes were assessed for histopathology after hematoxylin and eosin staining. Immuno-histochemical staining was performed when appropriate. In each case, the number of removed lymph nodes and LNI was reported. Prostate and nodal specimens were then staged according to the 2010 AJCC staging system for PCa (18). Perioperative-features In each case, clinical pelvic lymph node staging (cN) was Archivio Italiano di Urologia e Andrologia 2020; 92, 2

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D. D’Agostino, P. Corsi, M. Colicchia, et al.

Table 3. Overall pathologic outcomes of patients who underwent radical prostatectomy (n = 72). Overall Pathologic stage (%) T2 T3a T3b T4 Pathologic ISUP grade (%) 1 2 3 4 5 Pathologic nodal status (%) N0 N1 Nx Positive surgical margins (%) Pathologic index lesion (%) Anterior Posterior

74 (42.3) 87 (49.7) 12 (6.9) 2 (1.1) 10 (5.7) 70 (40) 56 (32) 34 (19.4) 5 (2.9) 113 (64.6) 10 (5.7) 52 (29.7) 11 (6.3) 68 (39.9) 107 (61.1)

mpMRI: multiparametric Magnetic Resonance Imaging; ADT: androgen deprivation therapy; RT: radiotherapy; RP: radical prostatectomy; * among those with positive biopsies.

performed by axial imaging modalities (computed tomography CT or MRI). Enlarged pelvic nodes larger than one centimeter in diameter were staged as cN1 disease. The metastatic status was investigated by both axial imaging and total bone scan modalities. Patients were staged according to 2010 American Joint Committee on Cancer (AJCC) staging system for PCa (7th edition) (18). PCa patients were divided into low, intermediate and high risk, according to the D’Amico risk classification (19). In high risk patients in the RARP group, extend pelvic lymph node dissection (ePLND) was performed (20, 21). In intermediate risk patients, the decision to perform an extended lymph node dissection was mainly based on Table 4. Uni- and multivariate analysis model predicting features of patients who underwent. Univariate analysis Multi-variate analysis OR (95% CI) p-value OR (95% CI) p-value Age (yrs) 1.09 (1.05-1.12) < 0.001 1.07 (1.03-1.12) 0.002 PSA (ng/ml) 1.12 (1.06-1.17) < 0.001 1.15 (1.06-1.24) 0.001 Prostate volume (ml) 0.98 (0.97-0.99) < 0.001 0.97 (0.95-0.98) < 0.001 Digito-rectal examination 5.99 (3.69-9.71) < 0.001 7.03 (3.76-13.16) < 0.001 Previous TRUS-GB 1.55 (1.02-2.35) 0.04 1.03 (0.59-1-8) 0.9 N of bioptic cores 1.02 (0.99-1.06) 0.3 PIRADS score 3 Ref. Ref. 4 5.63 (3.27-9.68) < 0.001 4.08 (2.17-7.67) < 0.001 5 17.27 (9.17-32.53) < 0.001 9.6 (3.77-24.45) < 0.001 Index lesion diameter (mm) 1.08 (1.05-1.12) < 0.001 0.98 (0.92-1.03) 0.7 mpMRI index lesion location Posterior Ref. < 0.001 Ref. 0.01 Anterior 2.41 (1.59-3.65) 2.09 (1.19-3.68) targeted biopsy with clinical csPCa (GS ≥ 7) csPCa: clinically significant prostate cancer; PSA: prostate specific antigen; TRUS-GB: transrectal ultrasound-guided biopsy; mpMRI: multi-parametric magnetic resonance imaging.

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pre-operative nomograms showing a risk of lymph node invasion greater than 5% (22). In low risk patients, the decision to perform an ePLND was based on clinical factors indicating increased risk of tumor upgrading and lymph node invasion in the surgical specimen (23). Skilled and experienced surgeons performed RARP with ePLND using the da Vinci Robot Surgical System (Intuitive Surgical, Inc, Sunnyvale, CA, USA). All procedures were performed through a trans-peritoneal approach with anterograde prostatic dissection (24). Urethro-vesical anastomosis was performed using barbed sutures as previously described (25-26). The lymph node dissection template included bilateral external iliac lymph nodes until the crossing of the ureter and the external iliac artery. Statistical analysis Continuous variables were expressed as median and interquartile range (IQR) whereas categorical variables were expressed as frequencies with percentages. The independent-samples T-test and Chi-Square test were used to compare means and frequencies between the two groups, respectively. All data were statistically analyzed using SPSS v 21 for Macintosh.

RESULTS

Median age was 66 (IQR 63-71) and 67 (range 61-72) years among anterior and posterior lesions cases, respectively. Mean serum PSA level was 7.7 ng/mL (IQR 5.210.1) in anterior cases and 6.7 ng/mL (IQR 4.8-9.1) in posterior cases. Tumor volume of posterior neoplasms ranged from 0.04 to 20.35 cm3, with a median of 3.39 cm3.Tumor volume of anterior cases ranged from 0.17 to 15 cm3, with a median volume of 2.54 cm3. This difference in size was not statistically significant (p > 0.05). The GG I was distributed as 16.6% and 36% in anterior and posterior lesions cases, respectively. GGII and III was 43.8% and 31.5% in anterior and posterior cases, respectively. GG IV-V was 39.6% and 32.5% for anterior and posterior lesions, respectively (p < 0.001). Extraprostatic extension of neoplasm (EPE) was found more frequently in anterior cases (31.4%) than in in posterior cases (25.1%), but without significant difference (p > 0.05). Pathologic stages among patients with primary posterior lesions were as follows: 42.3% in pT2, 49.7% in pT3a, 6.9% in pT3b, and 1.1% in T4. Among patients with anterior primary lesions, in 38.0% were in pT2 stage, 5.3% were in pT3a, 5.6% were in pT3b, and 11.1% in T4. Lymphovascular invasion was similar in both the groups: 24% and 28.6% in anterior and posterior group respectively. Anterior lesions showed a significantly higher rate of lymph node metastasis (9.3%) than in posterior lesions (3.4%) (p < 0.005).

DISCUSSION

In the literature, the imaging techniques for prostate cancer are in constantly evolving, and several different examination techniques play a fundamental role in the diagnosis, staging (27), and choice of therapeutic approach (28). In particular, the localization of prostate cancer foci with

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Anterior lesions of prostate cancer

mpMRI is crucial in the planning the best diagnostic plane and surgical approach, for example, in robotic surgery (29-31). The pathological and biological features of prostate cancer lesion have been analyzed by numerous studies. The anatomical and biological behavior of APCa are unique, and the definition varies. In the study by Villers and colleagues, they defined the anterior borders of the prostate as the region of parenchyma at least 2.1 cm anterior to the posterior capsule which is an area that the transrectal biopsy needle characteristically fails to reach (32). Anatomically, this is a portion of the prostate anterior to the urethra which includes areas of McNeal’s transition zone, the anterior fibromuscular stroma and the anterior horns of the peripheral zone. These features make the use of MRI-guided prostate biopsy techniques indispensable to obtain a correct therapeutic approach; late identification of anterior lesions significantly affects disease prognosis and surgical outcomes (extra-prostatic extension and positive surgical margins). Here, we have studied the differences between neoplasms arising from anterior and posterior gland. In retrospective studies of RP, it is reported that over 50% of tumors are located in anterior prostate (33-34). In agreement with the literature, we found 40% of lesions were located in anterior gland. At the time of diagnosis, anterior lesions were bigger than posterior ones, because APCa are commonly more advanced and have positive surgical margins (PSM) on RP specimens so therefore they can carry more risk for the patient (35). However, the findings from the present investigation do not support the observed trend from the literature, that anterior lesions have a lover GG than posterior (36-37). We found that anterior lesions have a higher GG than posterior lesions (p < 0.005) and a more advanced local stage at the time of detection, even in presence of a smaller volume of neoplasm. Anatomy of the anterior extraprostatic space which spans across the apex through the base, is unique in that the capsule is vaguely defined and is covered with fibromuscular shielding (anterior fibromuscular stroma) AFMS (8). Not only does the lack of capsular structure makes it difficult to define EPE and PSM in these regions, but the particular histological structure may provide an alternative route through which malignant cells can spread and gain access to the lymphatic drainage system. In most studies in literature, APCa are reported to be associated with lower rate of EPE while PSM rate was higher compared to posterior cancers. Differences in EPE between anterior and posterior lesions result from mechanical/anatomical distinctions, rather than biological differences (38), thought we have found that EPE was slightly more common in anterior lesions, but not statistical so. To better clarify this discrepancy, further anatomopathological studies must be carried out. In accordance with the literature, the present study has found higher rates of seminal vesicles invasion (pT3b) in the posterior lesions than in the anterior lesions, probably correlated to the anatomical location of the seminal vesicle (39). Certainly, an interesting aspect is represented by lymph node diffusion. In our cohort, more lymph nodal involvement has been found in anterior lesions than in posterior ones.

This study has some limitations predominantly related to the retrospective design and the small size of the cohort. Additionally, selection bias may be due to patients who underwent MRI and fusion prostate biopsy were not all patients with a clinical suspect of PCa. Clinicians were used to suggest MRI (+/- biopsy) in more challenging clinical scenario. Moreover, the patients who underwent RP could be a selected subgroup of patients with a longer life expectancy and/or with a more aggressive PCa since lowrisk PCa might have been managed expectantly with active surveillance. Certainly, a prospective evaluation of pathological and clinical features and long term follow-up of APCa with a major number of cases will be useful to better investigate the real impact of PCa location within the gland.

CONCLUSIONS

Our anatomo-topographic study shows that the anterior prostatic lesions, although smaller than posterior tends to have a higher pathological grade. In contrast with others, we have found EPE, often associated at a worse prognosis, more likely present in anterior lesions. Although, posterior lesions are often related to pT3b stage, in our findings, anterior lesions are associated to a more aggressive neoplasm with more frequent nodal involvements.

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. Noale M, Maggi S, Artibani W, et al. Pros-IT CNR: an Italian prostate cancer monitoring project. Aging Clin Exp Res. 2017; 29:165-72. 3. Sahu M, Wijesekera N, Donohue JF. Anterior prostate cancer: Current perspectives and diagnostic dilemmas. J Clin Urol. 2017; 10:49-55. 4. Wright JL, Ellis WJ. Improved prostate cancer detection with anterior apical prostate biopsies. Urol Oncol. 2006; 24:492-495. 5. Mygatt J, Sesterhenn I, Rosner I, et al. Anterior tumors of the prostate: clinicopathological features and outcomes. Prostate Cancer Prostatic Dis. 2014; 17:75-80. 6. Kasivisvanathan V, et al. MRI-targeted or standard biopsy for prostate-cancer diagnosis. N Engl J Med. 2018; 378:1767-1777. 7. Siddiqui MM, Rais-Bahrami S, Turkbey B, et al. Comparison of MR/ultrasound fusion-guided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. JAMA. 2015; 313:390-397. 8. Kasivisvanathan V, Rannikko AS, Borghi M, et al. MRI-targeted or standard biopsy for prostate-cancer diagnosis. New Engl J Med. 2018; 378:1767-779. 9. Koppie TM, Bianco Jr FJ, Kuroiwa K, et al. The clinical features of anterior prostate cancers. BJU Int. 2006; 98:1167-71. 10. Lawrentschuk N, Haider MA, Daljeet N, et al. “Prostatic evasive anterior tumours”: the role of magnetic resonance imaging. BJU Int. 2010; 105:1231e6. 11. Mai KT, Moazin M, Morash C, et al. Transitional zone and anterior peripheral zone of the prostate. A correlation of small-volume cancer in the biopsy cores and high psa with positive anterior margins in radical prostatectomy specimens. Urol Int. 2001; 66:191e6.

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12. Cerantola Y, Haberer E, Torres J, et al. Accuracy of cognitive MRI-targeted biopsy in hitting prostate cancer-positive regions of interest. World J Urol. 2016; 34:75-82. 13. Gayet M, van der Aa A, Beerlage HP, et al. The value of magnetic resonance imaging and ultrasonography (MRI/US)-fusion biopsy platforms in prostate cancer detection: a systematic review. BJU Int. 2016; 117:392-400. 14. Tan N, Lin W-C, Khoshnoodi P, et al. In-bore 3-T MR-guided transrectal targeted prostate biopsy: Prostate Imaging Reporting and Data System version 2-based diagnostic performance for detection of prostate cancer. Radiology. 2016; 283:130-9. 15. Schiavina R, Vagnoni V, D'Agostino D, et al. "In-bore" MRIguided prostate biopsy using an endorectal nonmagnetic device: a prospective study of 70 consecutive patients. Clin Genitourin Cancer. 2017; 15:417-27. 16. Barentsz JO, Richenberg J, Clements R, et al. ESUR prostate MR guidelines 2012. Eur Radiol. 2012; 22:746-57. 17. 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.

30. D'Agostino D, Bianchi FM, Romagnoli D, et al. Comparison between “In-bore” MRI guided prostate biopsy and standard ultrasound guided biopsy in the patient with suspicious prostate cancer: Preliminary results. Arch Ital Urol Androl. 2019; 91:87-92. 31. Porreca A, D'Agostino D, Vigo M., et al. "in-bore" MRI prostate biopsy is a safe preoperative clinical tool to exclude significant prostate cancer in symptomatic patients with benign prostatic obstruction before transurethral laser enucleation Arch Ital Urol Androl. 2020; 91:224-229. 32. Villers A, Puech P, Flamand V, et al. Partial prostatectomy for anterior Cancer: short-term oncologic and functional outcomes. Eur Urol. 2017; 72:333-342. 33. Koppie TM, Bianco FJ Jr, Kuroiwa K, et al. The clinical features of anterior prostate cancers. BJU Int. 2006; 98:1167-1171. 34. Takahashi H, Epstein JI, Wakui S, et al. Difference in prostate cancer grade, stage, and ocation in radical prostatectomy specimens from United States and Japan. Prostate 2014; 74:321-5.

18. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010; 17:1471-4.

35. Volkin D, Turkbey B, Hoang AN, et al. Multiparametric magnetic resonance imaging (MRI) and subsequent MRI/ultrasonographyfusion-guided biopsy increase the detection of anteriorly located prostate cancers. BJU Int. 2014; 114:E43-E49.

19. D'Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998; 280:969-74.

36. Hossac T, Patel MI, Huo A, et al. Location and pathological characteristics of cancers in radical prostatectomy specimens identified by transperineal biopsy compared to transrectal biopsy. J Urol. 2012; 188:781-5.

20. Porcaro AB, De Luyk N, Corsi P, et al. Clinical factors predicting bilateral lymph node invasion in high-risk prostate cancer. Urol Intern. 2017; 99:392-9.

37. Mygatt J, Sesterhenn I, Ronser I, et al. Anterior tumors of the prostate: Clinicopathological features and outcomes. Prostate Cancer Prostatic Dis. 2014; 17:75-80.

21. Mottet N, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol. 2017; 71:618-29.

38. Al-Ahmadie HA, Tickoo SK, Olgac S, et al. Anterior-predominant prostatic tumors: zone of origin and pathologic outcomes at radical prostatectomy. Am J Surg Pathol. 2008; 32:229-35.

22. Briganti A, Larcher A, Abdollah F, et al. Updated nomogram predicting lymph node invasion in patients with prostate cancer undergoing extended pelvic lymph node dissection: the essential importance of percentage of positive cores. Eur Urol. 2012; 61:480-7.

39. Hossac T, Patel MI, Huo A, et al. Location and pathological characteristics of cancers in radical prostatectomy specimens identified by transperineal biopsy compared to transrectal biopsy. J Urol. 2012; 188:781-5.

23. Grasso AA, Cozzi G, E. Del, et al. Multicenter analysis of pathological outcomes of patients eligible for active surveillance according to PRIAS criteria. Minerva Urol Nefrol. 2016; 68:237-41. 24. Menon M, Tewari A, Peabody J. Vattikuti Institute prostatectomy: technique. J Urol. 2003; 169:2289-92. 25. Porreca A, Salvaggio A, Dandrea M, et al. Robotic-assisted radical prostatectomy with the use of barbed sutures. Surg Technol Intern. 2017; 30:39-43. 26. Bianchi FM, Romagnoli D, D'Agostino D, et al. Posterior muscle-fascial reconstruction and knotless urethro-neo bladder anastomosis during robot-assisted radical cystectomy: Description of the technique and its impact on urinary continence Arch Ital Urol Androl. 2019: 91:5-10. 27. Vagnoni V, Brunocilla E, Bianchi L, et al. State of the art of PET/CT with 11-choline and 18F-fluorocholine in the diagnosis and follow-up of localized and locally advanced prostate cancer. Arch Esp Urol. 2015; 68:354-70.

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Correspondence Daniele D’Agostino, MD (Corresponding Author) dott.dagostino@gmail.com Paolo Corsi, MD - pcorsi@casacura.it Michele Colicchia, MD - mcolicchia@casacura.it Daniele Romagnoli, MD - dromagnoli@casacura.it Angelo Porreca, MD Department of Urology, Abano Terme Hospital Piazza Cristoforo Colombo 1, 35031, Abano Terme (PD) (Italy) Gian Maria Busetto, MD - gianmaria.busetto@uniroma1.it Department of Urology, Università “la Sapienza”, Roma Matteo Ferro, MD - matteo.ferro@ieo.it European Institute of Oncology, Milan

28. Gacci M, Noale M, Artibani W, et al. Quality of Life After Prostate Cancer Diagnosis: Data from the Pros-IT CNR. Eur Urol Focus. 2017; 3:321-324.

Alessandro Tafuri, MD - aletaf@hotmail.it Matteo Cevenini, MD - matteoceve@gmail.com Federico Mineo Bianchi, MD - federico.mineobianchi@gmail.com Department of Urology, University of Verona

29. D'Agostino D, Bianchi FM, Romagnoli D, et al. MRI/TRUS FUSION guided biopsy as first approach in ambulatory setting:

Marco Giampaoli, MD - mgiampaoli@casacura.it Department of Urology, University of Bologna

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DOI: 10.4081/aiua.2020.2.107

CASE REPORT

Ureteral iliac artery fistula in idiopathic retroperitoneal fibrosis: A case report Eugenio Di Grazia 1, Tiziana La Malfa 2, Gherardo Gasso 3 1 U.O.C.

di Urologia - ARNAS Garibaldi-Nesima, Catania, Italy; Analisi - Casa di Cura Mater Dei, Catania, Italy; 3 U.O.C. di Chirurgia Vascolare - ARNAS Garibaldi-Nesima, Catania, Italy. 2 Laboratorio

Summary

Ureter-arterial fistula (UAF) is an uncommon condition. The presentation is usually a life-threatening intermittent massive gross hematuria and the diagnosis is still a challenge for urologist. Idiopathic Retroperitoneal fibrosis (IRF) is a condition of unknown etiology characterized by a highly fibrotic retroperitoneal mass that frequently causes ureteral obstruction. To our knowledge we report the first case describing the UAF in a patient suffering from IRF. We hypothesize that inflammation and fibrosis resulted in fixation of the ureter to the adjacent artery causing a fistulous path. UAF was managed by deploying a 10 x 59 mm endo-graft at the intersection of common iliac artery bifurcation with the right ureter. Post treatment course was uneventful.

KEY WORDS: Idiopathic retroperitoneal fibrosis; Stent; Ureter; Uretero-arterial fistula. Submitted 25 August 2019; Accepted 21 September 2019

INTRODUCTION

Ureter arterial fistula (UAF) is an uncommon condition and about 150 cases are described in the literature. UAF can develop with aorta, common iliac artery, external iliac artery and hypogastric artery. Fistulas between ureter and common or external iliac artery are usually associated with a history of pelvic surgery, pelvic irradiation, chronic ureteral stenting and vascular disease (1, 2). The presentation is usually a lifethreatening massive gross hematuria with acute anemia and the diagnosis is still a challenge for urologist, because of misleading cross-sectional imaging, ureteral contrast-enhanced studies and endoscopy to assess the fistula. Digital subtracted angiography and vascular treatment are considered to be the best tools for the ureteric-arterial fistula assessment and management (2). Retroperitoneal fibrosis (RPF) is a condition of variable etiology characterized by a highly fibrotic retroperitoneal mass that frequently causes ureteral obstruction. RPF encompasses the idiopathic form (IRF) (> 75% of the cases) and secondary forms, which include cases secondary to malignancies, infections, drugs, radiotherapy, or other conditions. To our knowledge we report the first case describing the UAF in a patient with IRF.

CASE

REPORTS

A 73-year-old male patient with gross hematuria was admitted to the emergency room. Anamnestic evaluation revealed a history of multiple aortocoronary bypass, bilateral inguinal hernioplastic, hypertension treated with antihypertensives and anticoagulants and idiopathic retroperitoneal fibrosis assessed one year earlier for obstructive renal failure. The patient was on treatment with Prednisone and bilateral ureteral stents. Patient was clinically stable, hemoglobin was 10 mg/dl and other blood chemistry parameters were normal. CT scan showed slight enlargement of the aorta associated with retroperitoneal fibrosis involving the abdominal aorta and the common iliac arteries. Blood clots were present in the right pyelocaliceal system, along the right ureter and in the bladder. Ureteral stents were in place. Cystoscopy and a thorough endoscopic evaluation of the right upper urinary tract revealed no existing disease. The following days new episodes of gross-hematuria with right flank pain requiring blood transfusions occurred. After hemodynamic stabilization the patient was urgently subjected to digital angiography. After removal of the double J stent that was replaced by a guidewire, selective arteriography of the common iliac artery and its branches did not show any fistulous tract with the right ureter. It was therefore decided to place a 10 x 59 mm endovascular prosthesis at the intersection of common iliac artery bifurcation with the right ureter on the basis of previous CT scan evaluation of iliac artery ureteral crossing (Figure 1). Ureteral 6 x 26 stents were deployed again bilaterally in the upper urinary tract. The procedure was uneventful and the patient was discharged five days later without presenting new episodes of blood loss. One month later duplex sonographic evaluation of common iliac and external arteries showed normal blood flow and normal flowmetric indices. UAF is classified into primary (15%) and secondary (85%) type on the basis of its cause. Primary causes are natural disease processes of the arterial system such as aneurysms, vascular malformations, or aberrant vessels that erode into the ureter. Secondary causes are pelvic surgery (89%) combined with radiation (43%) and with ureteral stent placement (67%) leading to inflammation and fibrosis that, in turn, result in fixation of the ureter to the adjacent artery. High arterial pressure is transmit-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2020; 92, 2

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E. Di Grazia, T. La Malfa, G. Gasso

Figure 1.

CT scan showing the intersection of common iliac artery bifurcation with the right ureter where the fistula path is supposed to be.

Digital arteriography showing a guidewire in the ureter crossing the common iliac artery.

The fibrous tissue comprises an extracellular matrix composed of type I collagen fibers organized in thick irregular bundles. Plasma cells account for a significant proportion of the inflammatory cells. Angiographic findings of UAF can vary from dramatic extravasation or a pseudoaneurysm to a subtle irregularity or intimal defect. In approximately one third of the patients with UAF angiography may not reveal abnormal findings, making UAF challenging to observe. Another important issue is that the onset of hematuria is usually spontaneous but can be incited by initiation of anticoagulation or ureteral stent manipulation. Multiple options exist to treat UAF using the endovascular approach including stent-graft exclusion of the fistula and coil embolization of the affected artery. If stent-graft placement involves the iliac artery bifurcation, embolization of the ipsilateral internal iliac artery with coils or a vascular plug is considered to prevent retrograde feeding of the fistula.

CONCLUSIONS

Endovascular prosthesis deployment at the intersection of common iliac artery bifurcation with the right ureter.

Post endograft deployment evaluation showing the prostheris and the patency of iliac arteries.

ted to the juxtaposed arterial and ureteral walls and supposed to determine pressure necrosis and fistula formation. The pressure head of arterial pulsion on a weakened arterial wall against a scarred and fibrotic stented ureter may facilitate fistula formation. Idiopathic RPF is a rare disease, with an estimated incidence of 0.1-1.3 cases/100,000 persons per year, and a prevalence of 1.4 cases/100,000 inhabitants (3). Idiopathic RPF disease usually involves the adventitia of the abdominal aorta and the iliac arteries and the surrounding retroperitoneum, and histologically shows a mixture of fibrous tissue and chronic inflammation involving the ureters. Correspondence Eugenio Di Grazia, MD (Corresponding Author) e.digrazia@ao-garibaldi.ct.it U.O.C. di Urologia - ARNAS Garibaldi-Nesima, Catania (Italy) Tiziana La Malfa, MD Laboratorio Analisi - Casa di Cura Mater Dei, Catania (Italy) Gherardo Gasso, MD U.O.C. di Chirurgia Vascolare - ARNAS Garibaldi-Nesima, Catania (Italy)

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IRF and chronic ureteral stenting may determine a UAF with life-threatning severe bleeding. Diagnosis is a challenge for Urologist and Radiologist. Minimally invasive angiographic management is recommended for high success and low complication rates.

REFERENCES

1. Pillai AK, Anderson ME, Reddick MA, et al. Ureteroarterial fistula: diagnosis and and management. AJR Am J Roentgenol. 2015; 204:W592-W598. 2. Mahlknecht A, Bizzotto L, Gamper C, Wieser A. A rare complication of ureteral stenting: Case report of a uretero-arterial fistula and revision of the literature. Arch Ital Urol Androl. 2018; 90:215-21. 3. Rafiei A, Weber TA, Kongnyuy M, Ordorica R. Bilateral ureteraliliac artery fistula in a patient with chronic indwelling ureteral stents: a case report and review. Case Rep Urol. 2015; 826760. 4. Vaglio A, Maritati F. Idiopathic Retroperitoneal Fibrosis J Am Soc Nephrol. 2016; 27:1880-1889.

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DOI: 10.4081/aiua.2020.2.109

CASE REPORT

Management of a kidney stone in ectopic pelvic kidney with Extracorporeal Shockwave Litothripsy: Description of a case and revision of literature Carmelo Agostino Di Franco 1, Maurizio Burrello 1, Francesco Guzzardi 1, Eva Intagliata 1, Irina Oxenius 1, Lavinia Galvagno 2, Calogero Cordaro 1 1 Department 2 Translation

of Urology, S. Elia Emergency Hospital, Caltanissetta, Italy; and Language Revision Service, Enna, Italy.

Summary

Urolithiasis is one of the most frequent disease in the population and it represents one of the most frequent causes of access to emergency department. In addition. congenital anomalies occur more often in the kidney than in any other organ and the association of both renal abnormalities and stones is of clinical relevance. In this report, we discuss a case of a women with pelvic ectopic kidney affected by a large pyelic stone treated with ESWL (Extracorporeal Shockwave Lithotripsy).

KEY WORDS: Pelvic ectopic kidney; Urinary calculi; Extracorporeal Shockwave Lithotripsy. Submitted 24 November 2019; Accepted 3 January 2020

INTRODUCTION

Urolithiasis is one of the most frequent diseases in the population and it represents one of the most frequent causes of access to the emergency department. For patients affected by kidney anomalies, stone treatment could be a strong challenge for the Urologist. In addition, Extracorporeal Shockwave Lithotripsy (ESWL), is considered one of the first-line option treatment for kidney stones. In particular, Retrograde Intrarenal Surgery (RIRS) is not always available in all departments and it is associated to a higher complication rate than ESWL. However, urinary stasis that usually is associated with kidney anomalies, could interfere with clearance of stone fragments after shockwave lithotripsy. In this report, we discuss a case of a woman with pelvic ectopic kidney affected by a large pyelic stone treated with ESWL.

CASE

REPORT

We describe the case of a 63-years woman who presented to our emergency department with fever 39Â°C and abdominal pain. Blood samples showed leukocytosis (WBC 21000) and increased C-reactive protein, normal kidney function. Computed tomography (CT)-scan showed a right pelvic ectopic kidney with hydronephrosis and a large pyelic stone around 19 millimeters (Figure 1). Radiologist described increased peripyelic fat density secondary to phlogistic process. The patient was

subjected to ureteral double J stenting into the ectopic kidney and bladder catheter with emission of pyuria. We treated the septic status with antibiotic (piperacillin/ tazobactam) and parenteral hydration. The patient was monitored with blood samples that showed a rapid improvement. In the first post-operative day the patient was afebrile. The patient was affected by diabetes mellitus type II controlled with diet and she did not take any drug. After one month, the patient was subjected to first ESWL treatment on the ectopic kidney stone; ureteral double J stent was maintained inside. In total, we performed two ESWL treatments. We monitored stone changes after the first ESWL with radiographic scans (Figure 2). The position on the treatment-table was prone and we performed fluoroscopic control during the procedure. The shockwave lithotripsy was performed with a SonolithÂŽ device using electro-conductive shock head module. In both the procedures, we administered 3000 shocks, middle energy was 657 J, frequency 2 Hz. Fluoroscopy time was 02 minutes and 25 seconds with X-ray dose 3687 mGy/cm2 in first treatment and 02 minutes and 48 seconds with X-ray dose 3702 mGy/cm2 in second treatment. Procedures were well tolerated; the patient did not need any antalgic drug during or after the procedure. No immediate complications were reported. We reported macrohaematuria during the first operative day in both procedures with spontaneous resolution and occasional dysuria during the two months with ureteral stent. After the second treatment, we performed outpatient ultrasound check and abdominal CT-scan. CT-scan showed complete stone free ectopic kidney as shown in Figure 3. We removed ureteral stent after CT-scan check, two weeks from latest ESWL treatment. The patient was enrolled to our outpatient service and metabolic study.

DISCUSSION

The introduction of ESWL in 1980 revolutionized the treatment of kidney stones. It is a less invasive treatment for kidney stones, with low rate of complications and well accepted by patients. Therefore, it is now used for almost 80% of patients with urinary stones. However,

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2020; 92, 2

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C. Agostino Di Franco, M. Burrello, F. Guzzardi, E. Intagliata, I. Oxenius, L. Galvagno, C. Cordaro

Figure 1. Preoperative CT-scan showing stone in ectopic pelvic kidney.

Figure 2. Rx- check showing stone modification after the 1st ESWL treatment.

Figure 3. CT-scan after the 2nd ESWL treatment showing 100% stonefree rate with ureteral JJ stent inside.

today other minimally invasive techniques such as RIRS or mini-PERC (Percutaneous Stone Surgery) represent good solutions for kidney stone treatment although they are not always available in all centers especially in secondary hospitals. As reported in literature, ESWL can obtain good results in patients with malformed kidney, with an overall stonefree rate of 71.77% (1). For stones smaller than 1 cm, the stone-free rate was higher (up to 96.1%) demonstrating the importance of stone size for a successful treatment. Brad et al. (2) reported retrospectively ESWL results in a population with renal malformations; in their study average stone size was 10.23 mm and stone free-rate was 71.7%. They reported two cases of subcapsular hematoma (1.7%), two cases of acute pyelonephritis (1.69%) and two cases of haematuria which needed bladder washout and catheterization. Overall complication rate in their report was 13.56%. In addition, the most severe complication is renal haematoma: it seems to be favoured in patients suffering of hypertension, liver diseases or anticoagulation drug use (2). In literature we found some studies related to the use of the ureteral stent in association with ESWL. Common idea is that ureteral stents compromise the results of ESWL with a difference of around 22% in the stone-free rate in favour of non-stented patients as ureteral stents interfere with stone clearance because the presence of stent hinders the passage of fragments after ESWL. In particular, a recent paper by Ahmad et al. (3) reports that stone-free rate within patient without double J stent was 81,8% and within patients with JJ stent was 16.7% (p < 0.05). Regarding stone-free rate in the management of stones in anomalous kidneys with ESWL, in literature some studies are reported, with a range from 31% to 100%. Brad et al. (2) reported stone-free rate of 71.7% in 118 patients with kidney abnormalities and a medium stone size of 10.2 mm. The study of Al-Tawheed et al. (4) reported stone-free rate 83,9% with 9 patients with ectopic kidney an average stone-size of 1.5 cm. In Ahmad et al. study (3) 50 patients with kidney malformations were evaluated and 22% of patients had ectopic kidney. In ectopic kidney group, stone-free rate was 100% with ectopic abdominal kidney, 75% with ectopic lumbar kidney and 0% with ectopic pelvic kidney. Stone size was relevant, in particular stone-free rate was 74%; in patients with stone size below 1 cm, stone-free rate rose up to 91,6% demonstrating the importance of stone size for a successful ESWL treatment. In our report, we describe a successful ESWL treatment in a large stone (19 mm) in ectopic pelvic kidney. In our case patient had ureteral stent because she was first treated for septic status. However, in our routine we usually place the stent to patients with kidney calculi greater than 1.5 cm.

CONCLUSIONS

ESWL is a good treatment for kidney stones also in malformed kidneys achieving a good stone-free rate.

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Stone in ectopic pelvic kidney treated with SWL

However, the success of ESWL depend on many factors, in particular stone size, stone density and kidney position. The stone-free rate is related to patient compliance: in our case the patient was very collaborative and she did not need any analgesic drug. In addition, ESWL treatment in selected cases could be an alternative to other stone treatments such us RIRS or percutaneous nephrolithotomy (PCNL).

REFERENCES 1. Tunc L, Tokgoz H, Tan MO, et al. Stones in anomalous kidneys:

results of treatment by shock wave lithotripsy in 150 patients. Int J Urol. 2004; 11:831-6. 2. Brad A, et al. The place of ESWL in the treatment of urinary stones in patients with renal malformations." Romanian Journal of Urology. 2016; 15:28-32 3. Ahmad MNA, Hussein Abdallah Galal HA, Ayman Kotb Koritinah AK. Outcome of extracorporeal shockwave lithotripsy in congenital malformed kidneys. The Egyptian Journal of Hospital Medicine 2019; 76:3963-3967. 4. Al-Tawheed, AR, Al-Awadi KA., Kehinde EO, et al Treatment of calculi in kidneys with congenital anomalies: an assessment of the efficacy of lithotripsy. Urol Res. 2006; 34:291-298.

Correspondence Carmelo Agostino Di Franco, MD (Corresponding Author) carmelo_difranco@tiscali.it Maurizio Burrello Francesco Guzzardi Eva Intagliata Irina Oxenius Calogero Cordaro donc86@tiscali.it Department of Urology, S.Elia Emergency Hospital, Caltanissetta (Italy) Lavinia Galvagno Translation and Language Revision Service, Enna (Italy)

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DOI: 10.4081/aiua.2020.2.112

CASE REPORT

Thrombosis of the posterior scrotal vein associated with essential thrombocytemia: Report of a case Andrea Solinas Department of Surgery, Unit of Urology, ATS Sardegna - ASSL Carbonia, Ospedale Sirai, Carbonia, Italy.

Summary

Mondor’s disease is a rare superficial thrombophlebitis of subcutaneous vein and usually occurs in the anterior and lateral chest. Penile Mondor’s disease is a rare condition characterized by superficial thrombophlebitis of the dorsal vein of the penis. We report a rare case of atypical penile Mondor’s disease involved the right posterior scrotal vein, in a patient affected by essential thrombocythemia. A 50-years old man presented with thrombosis of right posterior scrotal vein. He presented with an indurated subcutaneous and painful cord, palpable along the length of the involved vein and located parallel to the urethra in the posterior aspect of the scrotum. It was treated with lowmolecular-weight heparin and resolves without sequelae. The scrotal vein thrombosis is a fairly rare disease.

KEY WORDS: Mondor’s disease; Superficial thrombophlebitis; Tender cord; Scrotal vein thrombosis. Submitted 3 December 2019; Accepted 16 January 2020

INTRODUCTION

Mondor’s disease is a rare superficial thrombophlebitis of subcutaneous vein and was first described by Henry Mondor in the superficial veins of the chest wall in 1939 (1). In 1955 Braun- Falco defined dorsal phlebitis of the penis in the context of generalized phlebitis while the first isolated penile Mondor’s disease was defined by Helm and Hodge in 1958 (2). Penile Mondor’s disease is rarer, arising out of thrombophlebitis of the penile veins. It has been reported after genital trauma such as stretching and torsion of the veins and can cause endothelial necrosis and thrombosis. It typically involves the dorsal vein of the penis and presents with a cord-like indurated lesion with a beaded feel, palpable along the length of the involved vein. The causes of the disease include frequent and prolonged sexual intercourse, prolonged sexual abstinence, infections, thrombophilia, repair of inguinal or umbilical hernia (3), orchiopexy, varicocelectomy, use of intracavernous drugs, use of vacuum, Behçet’s disease, body building exercises, cancer in the pelvic region, metastatic pancreas cancer and migratory phlebitis due to paraneoplastic syndromes and tendency to thrombosis (4). Thrombosis occur as a consequence of intravascular coagulation due to injury to vessel wall, stasis, and hypercoagulation known as Virchow’s triad. Though penile Mondor’s disease involving the dorsal vein of the penis has been reported by many authors, atypical localization involved the circumflex vein (5) or

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the superficial scrotal veins (3-6) are also described. We report a rare case, involved the right posterior scrotal vein, in a patient affected by essential thrombocythemia.

CASE

REPORT

A 50-years old man presented with a thrombosis of right posterior scrotal vein. He had a cord-like indurated lesion, palpable along the length of the involved vein and located parallel to the urethra in the posterior aspect of the scrotum associated with a feeling of heaviness. There was no fever, hematuria, dysuria. He gave a history of essential thrombocythemia for six months treated by interferon. Examination of genito-urinary system was normal. Standard investigations (blood and urine) requested were normal, while a blood cell count revealed 800 x 103 platelets. Diagnosis was confirmed on Doppler ultrasonography of the scrotal superficial venous system. It was treated with low-molecular-weight heparin for eight week and subsequently received aspirin (100 mg once daily) for prophylaxis of recurrences. He resolves without sequelae in eight weeks with recanalization of the vein and remained well three years after therapy.

DISCUSSION

Mondor’s disease is a rare superficial thrombophlebitis, historically involving the thoracic venous system. However, it can occur all over the skin. In 1955, the first reported case of Mondor’s disease (superficial thrombophlebitis) of the penis was published (2). Since then there have been described reports of penile Mondor’s disease in the literature. Most studies suggest neoplasm, sexual trauma, sickle cell anemia, excessive sexual activity or abstinence as the most frequent etiology and diabetes as predisposing factor due to its frequent pelvic problems leading to a potential venous inflammatory trigger. The application of immunohistochemical markers revealed that almost all Mondor’s diseases appeared to be thrombophlebitis of the superficial vein. The progression of phlebitis includes some pathophysiological steps in developing Mondor’s disease. At the initial stages, thrombotic events occur in the affected veins. As a result the lumen often becomes occluded with fibrin and inflammatory cells (7). Subsequently, the connective tissue gathering in the vessel forms a hard, cord-like No conflict of interest declared.

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Thrombosis of the posterior scrotal vein

induration. Thereafter, recanalization proceeds for several weeks until establishment. Mondor’s disease can occur without a clearly determined aetiology but In our case, thrombocytemia was identified as a main risk factor. Diagnosis of Mondor’s disease is usually made on clinical findings, thorough taking of the medical history and a correct physical examination are essential for diagnosing. The thrombosed superficial veins should first be detected with Doppler ultrasonography. Doppler ultrasonography can be also used in follow-up, showing the recanalization of the endoluminal thrombosis vein (8-9). The standard treatment strategy for Mondor’s disease has not yet been established because of the paucity of clear evidence. Most cases resolve within 4 to 6 week with re-permeabilization. Currently treatment is palliative for most patients with anti-inflammatory drugs and local heparin containing creams but in our patient with thrombophilia we preferred anticoagulation with low-molecularweight heparin and subsequently with aspirin to prevent additional thrombosis. However, antibiotic therapy should be administered when cellulitis is suspected and vein stripping may be necessary for severe, persistent cases. In secondary Mondor’s disease, treating the underlying disease is of the highest priority because Mondor’s disease itself is not life-threatening, while the underlying diseases may lead to a lethal outcome.

CONCLUSIONS

Mondor’s disease is a rare self-limiting benign process with acute presentation characterized by a cord-like induration in several parts of the body. Although its physiopathology is not exactly known, transection of the vessel during surgery or any type of trauma such as external compression may trigger its possible development. The patient usually feel the superficial vein like a hard cord and present with complaint of pain around this hardness. Diagnosis is usually easy with medical history and physical examination. Color Doppler ultrasound examination is important for differential diagnosis. The relationship between Mondor’s disease and other sites of superficial thrombophlebitis remains unclear, but such lesions are considered an initial manifestation of generalized throm-

bophlebitis. Some cases of Mondor disease may occur secondary to an underlying disease, such us vasculitis, a hypercoagulative state, or malignancy. The prognosis of secondary Mondor’s disease therefore depends on the prognosis of the underlying disease. Physicians should correctly identify Mondor’s disease, evaluate the possible presence of an underlying disease and avoid performing unnecessary invasive tests or treatment.

ACKNOWLEDGMENTS The article is dedicated to my son Lorenzo.

REFERENCES

1. Nazir SS, Khan M. Thrombosis of the dorsal vein of the penis (Mondor’s Disease): A case report and review of the literature. Indian J Urol. 2010; 26:431-3. 2. Helm JD Jr, Hodge IG. Thrombophlebitis of dorsal vein of the penis: report of a case treated by phenylbutazone (Butazolidin). J Urol. 1958; 79:306-7. 3. Mendez Rubio S, Menéndez Sánchez P, et al. Idiopathic thrombosis of the superficial scrotal veins (Mondor’s disease) during the postoperative period of an umbilical herniorraphy. Arch Esp Urol. 2012; 65:903-7. 4. Öztürk H, Penile Mondor’s disease. Basic Clin Androl 2014; 3:24:5. 5. Arora R, Sonthalia S, Gera T, Sarkar R. Atypical penile Mondor’s disease-involvement of the circumflex vein. Int J STD AIDS. 2015; 26:360-3. 6. Fujii Y, Arisawa C, Horiuchi S, et al. Thrombosis of the posterior scrotal vein: report of two cases. Hinyokika Kiyo. 1992; 38:1417-19. 7. Amano M, Shimizu T. Mondor’s disease: a review of the literature. Intern Med. 2018; 57:2607-12. 8. Ouattara A, Karim Parè A, Kaborè AF, et al. Subcutaneous dorsal penile vein thrombosis or penile Mondor’s disease: a case report and literature review. Case Rep Urol. 2019; 2019:1297048. 9. Dicuio M, Pomara G, Ales V, et al. Doppler ultrasonography in a young patient penile Mondor’s disease. Arch Ital Urol Androl. 2005; 77:58-9.

Correspondence Andrea Solinas, MD (Corresponding Author) sol.andrea@tiscali.it S.C. Urologia, ATS Sardegna -ASSL Carbonia, Ospedale Sirai Via Ospedale, 09013 Carbonia (Italy)

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DOI: 10.4081/aiua.2020.2.114

CASE REPORT

Penile verrucous squamous cell carcinoma: A rare case report Omer Yuksel, Emre Karabay, Osman Bilen, Ă&#x2021;agĚ&#x2020;atay Tosun, Levent Verim Haydarpasa Numune Training and Research Hospital, University of Health Sciences, Department of Urology, Uskudar/Istanbul Turkey.

Summary

Penile cancer is a rare type of urological cancer. Predisposing factors include phimosis, poor hygiene, and smoking. Circumcision in early childhood has been shown to be protective against penile cancer. About 95% of penile cancers are squamous cell carcinomas, while verrucous type is a rare variant with frequent recurrences, but with a favorable prognosis. The majority of patients are asymptomatic; however, patients may present with pain, discharge, and bad odor depending on the severity of the disease. Although hospital admission is often late due to psychosocial factors, cancer is often localized. Herein, we report a 61-year-old circumcised patient presenting with painful penile mass who was diagnosed with a penile verrucous squamous cell carcinoma in the light of literature data.

KEY WORDS: Penile cancer; Verrucous cancer; Penectomy. Submitted 17 November 2019; Accepted 12 December 2019

INTRODUCTION

Penile cancer is the rarest of urological malignancies in male. Its annual incidence is 1/100,000 in the United States (US) and Europe. As it is more common in many countries worldwide, it is considered a global health problem (1). According to the American Cancer Society, 2,080 newly diagnosed penile cancer patients and 410 penile cancer-related death have been estimated in the US in 2019 (2). Its incidence is the highest in Brazil, Uganda, and India and the lowest in the Jewish and Muslim communities in which male infants and children are mostly circumcised. Male circumcision in early childhood has been shown to reduce the risk for penile cancer by three to five-fold, probably as it prevents chronic irritation (3). Predisposing factors being uncircumcised, balanoposthitis, balanitis xerotica obliterans (BXO), ultraviolet phototherapy, sexual promiscuity, sexual intercourse in early adolescence, history of condyloma, tobacco smoking, and sexual intercourse with a partner infected with Human Papillomavirus (HPV) (4). In addition, a high-risk HPV-DNA positivity has been associated with reduced survival (5). The most common type of penile cancer is squamous cell carcinoma (SCC). Penile SCC can be divided into several subtypes. The most common subtypes include usual SCC (48 to 65%), basaloid carcinoma (4 to 10%), warty carcinoma (7 to 10%), verrucous carcinoma (3 to 8%), papillary carcinoma (5 to 15%), and mixed carcinomas (9 to 10%). Verrucous carcinoma is a rare variant of well-

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differentiated SCC with low malignancy potential. Premalignant lesions include penile cutaneous horn, Bowenoid papulosis, and BXO, while potential risk factors for the development of penile cancer are penile intraepithelial neoplasms, erythroplasia of Queyrat, and Bowen disease (3). Of these lesions, about 30% result in invasive cancer. Penile cancer, which is mostly seen in individuals aged 50 to 70 years, affects glans of penis (48%), prepuce (21%), both glans and prepuce (15%), coronal sulcus (6%), and penile shaft (< 2%). Initial physical examination manifestations may widely vary from a small redness to a large ulcer or infiltrative lesion. Patients may present with itching, pain, bleeding, discharge, and bad odor depending on the severity of the disease. Hospital admission is often late due to psychosocial factors; 15 to 60% of patients seek a medical diagnosis and treatment at least one year after the symptom onset. Nonetheless, the disease is localized in 66% of patients. In the initial admission, inguinal lymph nodes must be evaluated. Penile cancer metastasizes in a predictable pattern with superficial and deep inguinal lymph nodes occurring first, followed by pelvic and periaortic lymph nodes. Distant metastasis is very rare (1 to 10%) and mostly occurs in the late stages of the disease (6). Disease staging is based on the American Joint Committee on Cancer TNM Staging System depending on the depth of invasion, lymph node invasion, and distant metastases (6, 7). Herein, we report a 61-year-old circumcised patient presenting with painful penile mass who was diagnosed with a penile verrucous SCC in the light of literature data.

CASE

REPORT

A 61-year-old male patient who was circumcised at the age of 13 years was admitted to our outpatient clinic with a painful penile mass. Although his complaints were present for two years, he did not seek a medical treatment due to psychosocial factors. Upon increased penile pain, he applied to our clinic. His medical history revealed no smoking history, except being a social smoker, dysuria, having multiple sexual partners or sexually transmitted disease, or previous surgery. He was on regular medical treatment for hypertension and diabetes mellitus. His familial medical history revealed rectal cancer in his father. Physical examination revealed a 2-cm No conflict of interest declared.

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Verrucous carcinoma of penis

Figure 1. Penile mass on physical examination.

Figure 2. Partial penectomy material.

ulcerative mass with bleeding and itching advancing toward the coronal sulcus from the dorsal layer of the glans without urethral meatus involvement (Figure 1). Poor penile hygiene was observed. Inguinal region examination showed no palpable lymphadenopathy. Skin biopsy of the penile ulcer was performed. Pathological examination result reported a well-differentiated penile verrucous SCC. Magnetic resonance imaging and positron emission tomography-computed tomography revealed TaNoMo clinical stage and partial penectomy was performed (Figure 2). Partial penectomy pathology was reported T3NxMx. No recurrence or metastasis was observed in the postoperative six months of follow-up.

DISCUSSION

Penile cancer is a rare type of cancer which accounts for less than 1% of cancers in men (8). Its prevalence is higher in developing countries. It more frequently affects uncircumcised, white men with low income (9). Squamous cell carcinoma is the most common type and 33% of SCCs originate from premalignant lesions. Possible mechanisms which stimulate malignant transformation include chronic irritation, tobacco smoking, and poor penile hygiene which induce chronic inflammation, metaplasia, and differentiation (10). Certain types of viral infections such as HPV may also lead to penile cancer through DNA damage. In addition, damages in tumor suppressor genes such as p53 disrupt the cell cycle, resulting in DNA damage and malignant transformation (4, 5). Verrucous SCC of the oral cavity was first defined by Ackerman in 1948. It accounts for 3 to 8% of penile cancers and 20% of verruciform lesions. It is a rare variant of exophytic, papillomatous, low-grade, and well-differentiated SCC. As verrucous SCCs mostly present with squamous epithelial hyperplasia and keratinization, misdiagnosis is common, when diagnostic biopsy fails.

Therefore, biopsy is strongly recommended for definitive diagnosis. Its etiology has not been fully understood, yet (11). Earlier studies have demonstrated that verrucous SCCs are associated with low-risk HPV infection (12). However, later studies using broad-spectrum HPV polymerase chain reaction testing have revealed controversial results. In a study, Rubin et al. (12) reported that basaloid and warty SCCs were associated with HPV, while the HPV positivity rate was 33.3% and 34.9% for verrucous and usual SCCs, respectively. In another study, Stankiewicz et al. (13) reported an HPV-DNA positivity of 23% and 59% for verrucous and usual SCCs, respectively. These findings indicate a low-degree association between penile verrucous SCC and HPV. Although most of the current data regarding verrucous SCCs are based on case reports and case series, surgery is the mainstay of the treatment. The main strategy is wide excision of the mass or partial penectomy. Radical penectomy can be performed in rare cases. Recurrence of penile verrucous SCCs is high; one case with recurrence after 30 years has been reported in the literature (14). In early recurrence, additional resection and even radical penectomy can be performed. Distant metastasis is extremely rare and is not seen in almost none of patients with penile verrucous SCC. Therefore, inguinal lymphadenectomy is reserved for only very few patients. Hatzichristou et al. (15) performed inguinal lymphadenectomy in selected patients with penile verrucous SCC; however, no specific lesion could be detected. Thus, prophylactic inguinal lymphadenectomy is not recommended for this patient population. Early diagnosis and prevention are of utmost importance for the management of penile cancer. Neonatal circumcision, smoking cessation, and HPV vaccination have been suggested to decrease the incidence of penile cancer.

REFERENCES

1. Parkin DM, Whelan SL, Ferlay J, et al. Cancer Incidence in Five Continents. Vol. VIII. http://www.iarc.fr/en/Publicaions/PDFsonline/Cancer-Epidemiology/IARC-Scientific Publication-No.155.Accessed March 12,2014. 2. American Cancer Society. Cancer Facts & Figures 2019. Atlanta: American Cancer Society; 2019. 3. Barnholtz-Sloan JS, Maldonado JL, Pow-Sang J, Guliano AR. Incidence trends in primary malignant penile cancer. Urol Oncol. 2007; 25:361-367. 4. Pizzocaro G, Algaba F, Horenblas S, et al. EAU penile cancer guidelines 2009. Eur Urol. 2010; 57:1002-1012. 5. Bezerra AL, Lopes A, Santiago GH, et al. Human papillomavirus as a prognostic factor in carcinoma of the penis: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. Cancer. 2001; 91:2315-2321. 6. Marchionne E, Perez C, Hui A, Khachemoune A. Penile squamous cell carcinoma: a review of the literature and case report treated with Mohs micrographic surgery. An Bras Dermatol. 2017; 92:95-99. 7. Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manuel. (7th edn), New York, NY: Springer. 2010. 8. Wilson CN, Sathiyasusuman A. Associated risk factors of STIs Archivio Italiano di Urologia e Andrologia 2020; 92, 2

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and multipl sexual relationships among youths in Malawi. PLoS One. 2015; 10:e0134286.

tiple independent pathways of penile carcinogenesis. Am J Pathol. 2001; 159:1211-1218.

9. Morrison BF. Risk factors and prevalence of penile cancer. West Indian Medical Journal. 2014; 63:559-560.

13. Stankiewicz E, Kudahetti SC, Proxse DM, et al. HPV infection and immunochemical detection of cell-cycle markers in verrucous carcinoma of the penis. Mod Pathol. 2009; 22:1160-1168.

10. Velazquez EF, Cubilla AL. Lichen sclerosus in 68 patients with squmous cell carcinoma of the penis: frequent atypias and correlation with special carcinoma variants suggest a precancerous role. Am Surg Patol. 2003; 27:1448-1453. 11. Schwartz RA. Verrucous carcinoma of the skin and the mucosa. J Am Acad Dermatol. 1995; 32:1-21. 12. Rubin MA, Kleter B, Zhou M, et al. Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for mul-

Correspondence Omer Yuksel, MD dr_omer_yuksel@hotmail.com Emre Karabay, MD (Corresponding Author) emrekarabay@gmail.com Osman Bilen, MD osmanbilen1212@gmail.com Çağatay Tosun, MD cagataytosun@hotmail.com Levent Verim, MD leventverim@hotmail.com Haydarpasa Numune Training and Research Hospital, University of Health Sciences, Dept. Urology Tibbiye Street. No: 23 34668 Uskudar/Istanbul (Turkey)

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14. Alouani I, Barki A, Zizi N, Dikhaye S. Penile verrucous carcinoma: a new case report in a circumcised man. Clin Oncol. 2019; 4:1594. 15. Hatzichristou DG, Apostolidis A, Tzortzis V, et al. Glansectomy: an alternative surgical treatment for Buschke-Löwenstein tumors of the penis. Urology 2001; 57:966-969.

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CASE REPORT

Feasibility of a single session retrograde endoscopic laser lithotripsy of two large stones located in a bifid urinary tract. Presentation of a rare case Diomidis Kozyrakis 1, 2, Anastasios Zarkadas 1, Ilias Katsaros 1, Vasileios Mourkas 3, Zisis Kratiras 1 1 “Achillopoulio”

General Hospital of Volos, Department of Urology, Volos, Greece; General” Health Clinic, Department of Urology, Athens, Greece; 3 “Achillopoulio” General Hospital of Volos, Department of Anesthesiology, Volos, Greece. 2 “Metropolitan

A 76 year-old male presented with urosepsis and acute renal injury secondary to obstruction by a 13 mm stone located in the common segment of a bifid left ureter. A second 10 mm stone was detected in the mid calyx of the lower moiety of the kidney. Drainage of both moieties with two double-J stents was initially performed. Following recovery from urosepsis a retrograde endoscopic semirigid and flexible laser lithotripsy of the distal and proximal stone respectively was performed resulting in stone clearance. Although retrograde ureterolithotripsy has been presented in the past, to the best of the authors’ knowledge, this is the first description of flexible retrograde intrarenal lithotripsy performed through a bifid ureter.

tion of the second limb of the bifid ureter was made under direct vision of the joint by the ureteroscope (Figure 3). Then retrograde intrarenal surgery (RIRS) of the 10 mm intrarenal stone was performed using a 7.5F flexible scope and 200 micron fiber for stone fragmentation facilitated by a 45 cm long, 10/12 F access sheath (Figure 4). Two stents were postoperatively placed in each ureter. Surgical time was 67 minutes. After 36 hours of hospital staying, the patient was discharged. Postoperative recovery was uneventful. The stents were left in place for 14 days. Three months after lithotripsy the patient was stone free having normal renal function.

KEY WORDS: Bifid ureter; Lithiasis; Lithotripsy; RIRS; Ureteroscopy; Duplication.

DISCUSSION

Summary

Submitted 11 February 2020; Accepted 2 March 2020

CASE

REPORT

A 76 year-old male presented in the emergencies due to fever (up to 39° C), chills, mild hematuria and cloudy urine that lasted for 48 hours and also dyspnea of 24 hours duration. He had a history of non-insulin dependent diabetes mellitus, hyper-lipidemia and arterial hypertension; all of them under control with oral treatment. The diagnostic work-up revealed urosepsis due to E. Coli with acute renal injury due to obstruction by a 13 mm stone in the common segment of an incomplete duplicated left ureter. Another 10 mm stone was detected in the mid calyx of the lower moiety of the ipsilateral kidney. Incidentally, an atrophic contralateral kidney was detected. Intravenous administration of antibiotics and drainage of both moieties was performed using two double-J stents (Figure 1). Recovery from urosepsis and renal injury was quick and uneventful. Fifty days later the patient was readmitted for lithotripsy. Prior to treatment he signed informed consent and also gave a written permission to record the procedure and to use the material for scientific presentations. The procedure and the conduct of the study were approved by the Institution’s Scientific Committee. Fragmentation of the proximal stone was performed using a 8/9.5F semirigid scope with a 30W Ho:YAG laser and a 325 micron laser fiber (Figure 2). The catheteriza-

Complete and incomplete (bifid) ureteral duplication (UD) represent different clinical manifestations of the same embryologic disorder. During the 4th-5th gestation week, the mesenchymal ureteral bud starts its development to form the ureter. If two buds arise separately from the mesenchyme, two different ureters are developed and complete ureteral duplication is encountered. If a single bud splits later during various stages of metanephric tissue development a bifid collecting system is generated (1). UD usually has an uneventful clinical course, though obstruction of a bifid ureter by stones has been reported in the literature. A recent case report underscored the role of the contrast enhanced computed tomography (CT) imaging in the correct diagnosis of ureteral duplication. Plain kidney ureter bladder (KUB) X-ray is unreliable in detecting this anatomical disorder. Only in CT scan images the bifid ureter can be recognized, and the size and location of stones if any, can be clearly determined contributing to the appropriate delivery of treatment (2). In our case, due to the patient’s critical condition, the CT scan was performed in emergency settings. Although a contrast agent was not administered due to renal dysfunction, the anatomy of the dilated collecting system was adequately delineated and the presence of ureteral duplication was identified. Bhatia and Biyani reported on 8 lithiasic cases in UD, five of which were located in a bifid ureter. All of them were treated with shock wave lithotripsy (SWL) with excellent

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2020; 92, 2

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Figure 1. Preoperative KUB X-ray of stented ureters. The intrarenal stone is not clearly shown.

Figure 2. A 13 mm hard stone (mean 970 Hounsfield units) located in the common segment of the bifid ureter.

Figure 3. Appearance of joint of the bifid ureter under endoscopic vision with the semirigid ureteroscope. The arrow shows the entrance to the other limb of the ureter. The asterisk shows lithiasic dust. Figure 4. An intrarenal 10 mm stone (mean Hounsfield units 785).

results (2). Migliari and Usai were the first to perform endoscopic treatment in incomplete UD in 1991. They used a semirigid scope to gain access to a 1 cm stone located in the pelvic portion of the lower limb of a bifid ureter. Fragmentation was performed using an ultrasonic lithotripter with optimal stone clearance (3). To the best of our knowledge, the present study is the first to report on flexible retrograde intrarenal surgery (RIRS) and laser lithotripsy with the scope inserted into the kidney through the joint of a bifid ureter. Initially, to ensure adequate drainage, both moieties of the kidney had to be decompressed with stents. The presence of a double-J stent also facilitated the retrograde endoscopic treatment. Intraoperatively, a safety guidewire was inserted in each limb of the ureter and after the disintegration of the distal stone, an access sheath was advanced up to the ureteropelvic junction of the moiety hosting the stone. The use of the sheath allowed an easy detection of the stone and a safe and quick operation under low intrarenal pressure. The sheath also facilitated the immediate removal of stone fragments. Despite the large lithiasic burden, the duration of the procedure was approximately one hour. This brief operation time eliminates the risks of surgical complications, particularly postoperative sepsis, and shortens the duration of hospital staying. In conclusion, the present study is the first to report the performance of flexible RIRS in a bifid collecting system. Preoperative CT scan, stenting of both limbs, use of safety guidewires and placement of ureteral access sheath under fluoroscopic guidance were crucial for a successful outcome. With the use of semirigid and flexible ureteroscopy the disintegration of a large lithiasic burden in the ureter and in the pyelo-calyceal system is feasible to be performed in one session, within a reasonable operation time and a minimum risk of complications.

REFERENCES

1. Xiao N, Ge B, Wang J, Zhao H. Obstruction of bifid ureter by two calculi: A case report. Medicine (Baltimore). 2018; 97. 2. Bhatia V, Biyani CS. Calculus disease in duplex dystem - role of extracorporeal shockwave lithotripsy. Urol Int. 1993; 50:164-169. 3. Migliari R, Usai E. Ureteroscopic removal of ureteral calculi in bilateral ureteral duplications. Urol Int. 1991; 46:79-81.

Correspondence Diomidis Kozyrakis, MD (Corresponding Author) dkozirakis@yahoo.gr Anastasios Zarkadas, MD Ilias Katsaros, MD Zisis Kratiras, MD “Achillopoulio” General Hospital of Volos, Department of Urology 134 Polymeri Str., Volos, GR 38222 (Greece) Vasileios Mourkas, MD “Achillopoulio” General Hospital of Volos, Department of Anesthesiology, Volos, Greece

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DOI: 10.4081/aiua.2020.2.119

CASE REPORT

Bilateral subcutaneous pyelovesical bypass in a Hautmann neobladder followed by a mononeuropathy multiplex and an underlying polyarteritis nodosa diagnosis Konstantina G. Yiannopoulou 1, Aikaterini I. Anastasiou 2, Ioannis Katafigiotis 2, Dimitrios Papadopoulos 3, Ioannis Anastasiou 2 1 Neurology

Department, Henry Dunant Hospital Center, Athens, Greece; University Urology Clinic, Laiko Hospital, Athens Greece; 3 Athens Medical Centre-Paleo Phaliro Clinic, Athens, Greece. 2 1st

Summary

Subcutaneous pyelovesical bypasses are the best choice for the long-term palliative treatment of ureteral obstructions. In rare cases this obstruction is due to polyarteritis nodosa. We present the only reported patient with a bilateral Detour bypass in a Hautmannâ&#x20AC;&#x2122;s neobladder. The patient also suffers from polyarteritis nodosa.

KEY WORDS: Bilateral; Detour bypass; Hautmann neobladder; polyarteritis nodosa. Submitted 10 August 2019; Accepted 1 September 2019

INTRODUCTION

Subcutaneous pyelovesical bypasses or Detour bypass is the safest and most effective method for the long-term palliative treatment of ureteral obstructions (1). Ureteral obstruction can be caused from either benign or malignant disease (1). We present a rare case of bilateral subcutaneous pyelovesical bypass in a Hautmann neobladder in a 66-year-old man. To our knowledge this is the first case ever reported. Three months after the second bypass, a mononeuropathy multiplex appeared and polyarteritis nodosa (PON) was diagnosed in the same patient. To our knowledge, five cases of bilateral ureteral stenosis and 16 of unilateral ones due to (PON) have been reported in the literature so far (2). None of them has been occurred in a patient with a neobladder.

CASE

PRESENTATION

A 66-year-old man was presented to our Urology Department (1st University Urology Clinic, Laiko hospital, Athens, Greece), with a bladder carcinoma. We performed an endoscopic bladder resection and the final histology revealed a pT2 muscle invasive bladder tumour. A radical cyctectomy was performed with Hautmann neobladder as diversion. Six months later an obstructed uropathy manifested due to left ureter stenosis and thus we placed a nephrostomy for temporary management. The final treatment was achieved with the placement of a left subcutaneous pyelovesical bypass. Three years later the patientâ&#x20AC;&#x2122;s right ureter presented also stenosis. Initially we placed a double J stent which how-

ever did not achieve a final solution of the obstruction. Consequently, we performed a second subcutaneous pyelovesical bypass in the right ureter (Figure 1). Three months later, the patient was admitted with right foot and left wrist drop, fever and myalgias. A neurophysiologic evaluation revealed a mononeuropathy multiplex affecting peroneal and radial nerves with both motor and sensory deficits. A mild proximal muscle weakness and a severe muscle tenderness were present. The diagnosis of PON was based upon muscle biopsy from right quadriceps which revealed typical necrotizing vasculitis in medium size arteries in conjunction with elevated sedimentation rate (107 mm/h) and rheumatoid factor (73 IU/ml). The patient was managed with oral prednisolone (1mg/kg), which resulted in gradual resolution of his symptoms.

DISCUSSION

Bladder cancer is more common in men than in women and usually does not involve the muscle wall. For this reason it is mainly treated by endoscopic transurethral resection of the bladder tumor (TURBT). In our male patient the first surgery was a TURBT, which demonstrated cancer infiltrating the bladder muscle wall. Those patients are at higher risk and therefore are treated with major surgery to remove the bladder. Subcutaneous pyelovesical bypasses are considered to be the best choice for ureteric obstruction, in comparison to other methods, such as the J stent. It is not associated with septicemia and irritative bladder symptoms or frequent infections (1). The fact that there is no participation of the impaired ureter is the main difference between pyelovesical bypasses and other methods (1). Ureteral obstruction may be caused by benign as well as malignant disease, but is also an important complication of modern surgeries (1, 3). In fact, uretero-ileal anastomotic stricture (UIAS) in orthotopic ileal neobladder can develop in 4-10% of cases during a follow-up time of 636 months (3). In our case it was caused by fibrosis in the site of the anastomosis of the ureter with the neobladder. Other methods, which have been used to treat this complication, are percutaneous nephrostomy

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2020; 92, 2

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Figure 1. Placement of the second subcutaneous pyelovesical bypass in the right kidney.

vasculitis of periureteral vessels. To our knowledge, five cases of bilateral ureteral stenosis and 16 of unilateral ones due to (PON) have been reported in the literature so far (2), two of them as the first manifestation of the disease (4). We suggest that the vasculitic background in our patient due to his underlying polyarteritis pathology in conjunction with the major surgical procedure in his bladder contributed to the unprecedented occurrence of such a severe bilateral ureteral obstruction after Hartmann neobladder surgical construction that only Detour intervention could resolve.

CONCLUSIONS

Although UIAS in orthotopic ileal neobladder may develop in 4-10% of cases in the follow-up period of 6-36 months, bilateral UIAS can also occur. Subcutaneous pyelovesical bypasses (Detour bypass) can be applied bilaterally with safety and long-term efficacy. Furthermore, additional underlying causes of the obstructive process, like systematic vasculitis. should be suspected in these extremely rare cases.

and double J stents. In our patient both methods where applied before the use of subcutaneous pyelovesical bypasses, however their efficiency was poor and the Detour was the final treatment. Nevertheless, this is the first case in the literature where a bilateral ureteric obstruction after Hautmann neobladder was managed succesfully with a bilateral pyelovesical bypass. Several months after the second Detour procedure, patient presented with multiple mononeuropathies and symptoms of systemic inflammation. He was finally diagnosed with PON, an entity that did not show previous clinical or laboratory signs of its existence in our patient. However, ureteral obstruction has been described as a manifestation of PON (2). It is supposed to result from

Correspondence Konstantina G. Yiannopoulou, MD k.giannopoulou.14@hotmail.com Neurology Department, Henry Dunant Hospital Center, Athens (Greece) Aikaterini I. Anastasiou, MD (Corresponding Author) ekati2@otenet.gr Ioannis Katafigiotis, MD katafigiotis.giannis@gmail.com Ioannis Anastasiou, MD aikatianast@gmail.com 1st University Urology Clinic, Laiko Hospital Ag.Thoma 17, Athens 11527 (Greece) Dimitrios Papadopoulos, MD dimipapuro@yahoo.gr Athens Medical Centre-Paleo Phaliro Clinic, Athens (Greece)

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REFERENCES

1. Wrona AJ, Zgajewski J, KopecĚ N, Chodor D, Kopcza P, Klekot S. Subcutaneous pyelovesical bypass - Detour bypass - as a solution for ureteric obstruction. Cent European J Urol. 2017; 70:429-433. 2. Bolat D, Zumrutbas AE, Baser A, Tuncay L. Spontaneous ureteral rupture in a patient with polyarteritis nodosa. Int Urol Nephrol. 2016; 48:223-4. 3. Mohamed Wishahi, Hossam Elganzoury, Amr Elkhouly. Detour technique, dipping technique, or iIeal bladder flap technique for surgical correction of uretero-ileal anastomotic stricture in orthotopic ileal neobladder. Int Braz J Urol. 2015; 41:796-803. 4. Jois R, Gupta A, Krishnamurthy S. Ureteric vasculitis, an unusual presentation of polyarteritis nodosa: a case report. Int J Rheum Dis. 2015; 18:577-9.

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DOI: 10.4081/aiua.2020.2.121

ORIGINAL PAPER

The impact of nutrition and lifestyle on male fertility Mahmoud Benatta 1, 2, Redha Kettache 1, 3, Noor Buchholz 1, Alberto Trinchieri 1 1 U-merge

Ltd. (Urology for Emerging Countries), London, UK. of Urology, Djilali Lyabes University Hospital, Sidi Bel Abbes, Algeria; 3 Department of Urology, EPH Bachir Bennacer, Biskra, Algeria. 2 Department

Background and aims: Male unexplained infertility has long been suspected to result from environmental, lifestyle and nutritional factors. However, the literature on the subject is still scarce, and clinical studies providing robust evidence are even scarcer. In addition, some similar studies come to different conclusions. Dietary pattern can influence spermatogenesis by its content of fatty acids and antioxidants. Yet, in an age of industrialized mass food production, human bodies become more exposed to the ingestion of xenobiotics, as well as chemicals used for production, preservation, transportation and taste enhancement of foods. We attempted in this paper to collect the available evidence to date on the effect of nutritional components on male fertility. Material and methods: A systematic search of the relevant literature published in PubMed, ScienceDirect and Cochrane Central Register of Controlled Trials Database was conducted. Literature was evaluated according to the Newcastle-OttawaScale. Results: Epidemiological observations are concordant in demonstrating an association of low-quality sperm parameters with higher intake of red meat, processed and organ meat and fullfat dairy. On the contrary, better semen parameters were observed in subjects consuming a healthy diet, rich in fruit, vegetables, whole grains and fish. Evidences of the negative impact on male fertility of by-products of water disinfection, accumulation in food chain of persistent organochlorine pollutants, pesticides, phthalates from food and water containers and hormones used in breeding cattle have been reported. Clinical trials of the effects of micronutrients on semen parameters and outcomes of assisted fertilization are encouraging, although optimal modality of treatment should be established. Conclusions: Although quality of evidence should be ameliorated, it emerges that environmental factors can influence male fertility. Some nutrients may enhance fertility whereas others will worsen it. With diagnostic analysis on a molecular or even sub-molecular level, new interactions with micronutrients or molecular components of our daily ingested foods and leisure drugs may lead to a better understanding of so far suspected but as yet unexplained effects on male spermatogenesis and fertility.

Summary

KEY WORDS: Male fertility; Nutrients; Micronutrients; Dietary supplements; Lifestyle; Xenobiotics. Submitted 13 April 2020; Accepted 20 April 2020

INTRODUCTION Male infertility is attracting increasing interest due to its worldwide prevalence and the evidence of decline in semen quality of young health men (1). Prevalence of

reported male infertility ranges from 2.5% to 12% with highest rates in Africa and Central/Eastern Europe (2). Rates of male infertility in North America, Australia, and Central and Eastern Europe varied from 4.5-6%, 9%, and 8-12%, respectively. Male infertility is defined as the failure to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourse as reported by couples or female partners of a couple. Seminal quality is a prognostic factor of fertility which can be considered a proxy of male infertility although fecundity also depends from other couple-based covariates (3). Along the last 50 years a progressive decrease of the quality of the seminal parameters has been observed. A recent systematic review of 185 studies involving more than 40.000 men who provided semen analysis in the period 1973-2011 demonstrated a significant decline between 1973 and 2011 (4). This trend may arise from genetic, developmental and lifestyle factors. Particularly, involvement of nutritional factors has been highlighted by many studies. Cross-sectional population studies or case-control studies using food questionnaires evaluated the association of dietary patterns or quality of foods with seminal parameters (count, concentration, motility, morphology, DNA fragmentation) or with testis volume or sex hormone levels. In addition, some studies from fertility clinics considered more robust outcomes such as implantation rate, rate of clinical pregnancy and of live birth. Most of studies focused on the content of saturated fats that could have a negative impact on fertility or on the content of antioxidants and folates that could improve fertility. Molecular pathways of the effects of these nutrients in male fertility have been studied but they are not yet fully explained (Figure 1) (5-7). Saturated fats are prevalent in animal-derived foods as red meat, processed meat and full-fat dairy product while fats from vegetable foods and fishes are polyunsaturated. Sperm cell are characterized by a high content of polyunsaturated fatty acids, as docosahexaenoic acid (DHA). Concentrations of DHA with respect to saturated or trans fatty acids influence the melting point of plasmatic membrane, regulate the expression of peroxisome proliferatoractivated receptor gamma (PPARG), anti-apoptosis and hormone activity. Particularly, omega-3 PUFAs in fish are precursors of eicosanoids, which contribute to sperm

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2020; 92, 2

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Figure 1. Molecular pathways of the effects of fatty acids and antioxidants in sperm cell (negative effect in red, positive in green).

structure) and have a positive impact on testicular function. On the contrary, trans saturated fats interfere with the incorporation of long-chain polyunsaturated fatty acids into sperm membranes during epididymal maturation, and have a negative impact on testicular function, with reduction in total and free testosterone. Antioxidants molecules, that are abundant in fruits and vegetables, have a positive effect on male fertility and in general on health conditions, by contrasting the activity of reactive oxygen species (ROS). ROS (reactive oxygen species) show a biphasic effect on sperm cell function, because at physiological concentrations ROS from mitochondria have an important role in capacitation by activation of different intracellular mechanisms (high levels of cAMP, activating the PKA pathway, and leading to tyrosine phosphorylation). On the contrary, oxidative stress from excess ROS production causes peroxidation of lipids in the plasmatic membrane together with a damage of spermatic DNA. ROS have a negative effect on sperm motility by damaging plasmatic membrane and mitochondrial function. Folates are involved in DNA synthesis and in methylation processes connected with protein synthesis. Folate deficiency causes instability and fragility of DNA by reducing availability of methylic groups that are a protection factor of DNA. Other micronutrients are involved in the development of male infertility, as divalent cations such selenium, zinc or manganese that have a role in oxidative stress being incorporated in enzymes such as glutathione peroxidase or superoxide dismutase (8). Optimal levels are requested for spermiogenesis, whereas both deficiency and excess intake are associated with alterations of seminal parameters and serum testosterone levels. In addition to the effects of nutrients, food intake can be associated to exposure to food-contaminating toxic substances or hormones that can have a relevant impact on male fertility. In an age of progressive industrialization, and moreover industrial mass food production using herbicides, pesticides, antibiotics, hormones, and chemicals to preserve and enhance the taste of heavily processed foods, these components can be absorbed into the human body. Evaluation of the effects of toxic contamination of

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foods is difficult by using dietary questionnaires whereas more reliable results can be obtained by using biological markers to evaluate exposure to toxic substances. The effects of the intake of some foods on seminal parameters can be biased by the concomitant effect of contamination. By example, it is difficult to differentiate the impact of consumption of vegetables from that of pesticides that are used in agriculture or the effect of red meat from that of residual hormones that could have been used in breeding or that of fish consumption by the risk of contamination from sea water pollution. Finally, other information can be derived from the evaluation of the effect of the administration of dietary supplements to ameliorate seminal parameters of subfertile men attending fertility centres. In this paper, we tried to review and summarize the available evidence on the topic. Our results are subdivided in two chapters describing review of epidemiological observations and clinical studies respectively.

METHODS

A systematic search of the relevant literature published in PubMed, ScienceDirect and Cochrane Central Register of Controlled Trials Database was conducted. We reviewed separately epidemiological observations as reported in the literature and clinical trials with various nutritional components and their influence on male fertility. For this reason, two separate searches (up to December 2018) were done using a combination of terms as both, Medical Subject Headings (MeSH) and keywords. In the first search, male fertility-related keywords (“male fertility” OR “male infertility” OR “semen quality” OR “oligoasthenozoospermia” OR “sperm DNA fragmentation” OR “sperm DNA damage” OR “sperm aneuploidy” OR “Y chromosome”) were used in combination with key words relating to food or nutrient (“food” OR “diet” OR “nutrition” OR “meat” OR “fish” OR “sugar” OR “vegetables” OR “fruits” OR “dairy” OR “genetically modified food” OR “alcohol” OR “pesticides” Figure 2. Systematic literature search 1.

Figure 3. Systematic literature search 2.

Male fertility and nutrition

OR “hormone food contaminated” OR “tobacco” OR “cannabis”) and combined with ‘questionnaire’ (Limit: Human, English). Reviews, clinical trials and case reports were excluded (Figure 2). In the second search the same male fertility-related keywords were used in combination with key words relating to vitamin or micronutrient or herbal treatments (“selenium” OR “vitamin E” OR “coenzyme Q10” OR “zinc” OR “LCarnitine” OR “folic acid” OR “L Arginine” OR “herbal”). (Limit: Human, English). Only clinical trials were included (Figure 3). The first search screened 103 studies, that were reduced to 38 after evaluation by title and abstract; 29 studies were retrieved by references of the selected studies; a total of 67 studies was assessed and 50 were included in the review. In the second search, the number of study screened, selected by title/abstract, retrieved by references, assessed and included were 79, 43, 14, 57 and 19 respectively. Information extracted from each study was charted

including: first author's last name; year of publication; number of subjects; food or nutrients or dietary pattern studied. Literature was evaluated using the NewcastleOttawa-Scale and evaluation forms. A narrative review of the data from the included studies was done.

RESULTS Epidemiological observations Nutrition and lifestyle are considered by several authors as main factors in reproduction and fertility (9-11). Recent studies indicate that male obesity (12), as well as lifestyle factors as smoking and alcohol intake affect negatively the sperm quality (13). Diet plays a key role in the improvement of sperm parameters, particularly the Mediterranean diet which is rich in omega 3 fatty acids, antioxidants and vitamins (vitamin E, vitamin C, beta-carotene, lycopene, cryptoxanthin, lutein) that all are associated with better semen

Table 1. Vitamin, mineral and antioxidant intake and sperm quality.

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Table 2. Dietary patterns and sperm quality.

quality parameters (Table 1) (14-18). A better compliance with Mediterranean diet was found to be associated with better semen quality parameters (sperm concentration, count, and motility) (19). Similarly, in non-Mediterranean Countries, the so called “Prudent” or “Health Conscious” diets, involving high intakes of fruits, vegetables, legumes, fish and whole grains, were related to better sperm quality than “Western” diet that is rich in red and processed meat, refined grains, high-energy drinks and sweets (Table 2) (20-24). Higher intakes of seafood, poultry, whole grains, fruits and vegetables have been consistently associated with better semen parameters in a wide range of studies in North America, Europe, the Middle East and East Asia. (Table 3) (10, 19-27). A recent review concluded that diets rich in red and processed

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meats, potatoes, sweets and sweetened beverages were associated with decreased quality of semen parameters whereas higher intakes of fruits and vegetables, whole grains, seafood and poultry had the opposite effect (34). Soy foods have been inversely associated with the quality of semen in some studies (35) although soy food intake in men was not related to outcomes of in vitro fertilization in couples undergoing infertility treatment (36). The intake of trans and saturated fats has been related to poor semen quality. Trans-saturated fat intake has also been related to other markers of poor testicular function, such as lower testosterone and lower testicular volume (37-40) (Table 4). On the contrary, omega-3 polyunsaturated fats were associated with better seminal parameters and testicular volume (37, 40).

Male fertility and nutrition

Table 3. Foods and sperm quality.

Critical appraisal of this evidence highlights some possible limitations. In most cross-sectional studies populations were numerically limited and not always representative of the general population. Many studies were performed on volunteers recruited among university students aged 18 to 23 years, whereas other studies considered men from couples who attended fertility clinics. Translation of these results to the general population might be questionable. Only a few studies have been carried out in numerically consistent populations representing the general population (23, 38). Similarly, case-con-

trol studies were performed by comparing the dietary intakes of men from couples attending fertility clinics with and without alterations of seminal parameters. Alcohol and caffeine Alcohol induces testicular atrophy and alterations of Leydig and Sertoli cells and decrease luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels (41). Daily consumption of alcohol affects sperm quality and decreases ejaculate volume, sperm counts, and sperm motility. Comparing the sperms of 66 "alcoholic" men to Archivio Italiano di Urologia e Andrologia 2020; 92, 2

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Table 4. Dietary fats and semen quality.

those of 30 "non-alcoholic" men, there was a significant decrease in sperm count, progressive mobility, and vitality (42). Chronic high consumption of alcohol (more than 60 g per day or 6 glasses of wine) can lead to azoospermia (43). There is a significant inverse relationship between alcohol consumption and sperm concentration, sperm count and percentage of typical spermatozoids. Stopping consumption would restore normal spermatogenesis and azoospermia secondary to alcohol (44). A meta-analysis confirmed that alcohol has a detrimental effect on semen parameters although spermatogenesis seemed to be not affected by a moderate consumption (45). Another meta-analysis of the effects of alcohol on in vitro fertilization (IVF) showed that live birth rates are significantly reduced when humans consume alcohol even in Table 5. Water and food contaminants and male infertility.

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lower doses in the month or even the week before attempted fertilization. Excessive consumption of alcohol must be avoided in humans during the attempted medical assisted fertilization, but a moderate consumption (one or two glasses of wine per day) might also have an opposite effect on the spermatic characteristics and the results of the medical assisted procreation attempt (46). A systematic review of the effects of coffee and caffeine intake on semen parameters found inconsistent evidences and conflicting results, although some studies showed a possible association with sperm DNA damage (47). Food and water contamination Most of the literature on the effect of water and food contaminants on male infertility is derived from experimental

Male fertility and nutrition

animal studies or studies of acute occupational exposure. Evidence of the effects in the general population of chronic low-dose exposures is limited because of the complexity of the design of the studies. Levels of biological markers of exposure have been correlated with seminal and hormone parameters in general population. Available data has been reviewed by Gabrielsen and Tanrikut (8). In Table 5 we summarized evidences about water and food contaminants that could affect male fertility. Food contaminants often induce endocrine disorders, as in the case of commonly used glyphosate-based herbicides that act as a disruptor of mammalian cytochrome P450 aromatase activity from concentrations 100 times lower than the recommended use in agriculture and can also affect aromatase gene expression (48). Endocrine disorders can also be induced by the presence of residual hormones in red meat and processed meat. In some countries anabolic sex steroids are administered to cattle for growth promotion resulting hormone residues in beef. Although the possible biological significance of very low levels of estradiol is neglected, residual hormones are one possible explanation of lower semen quality parameters observed in consumers of processed or red meat (49). On the other hand, maternal beef consumption, and possibly xenobiotics in beef may alter testicular development in utero and adversely affect offspring reproductive capacity (50). Despite a lack of human studies, a link between infertility and genetically modified foods (GMF) has been postulated although GMF-related infertility seems to affect women more than men (51). Tobacco Smokers have an unusually high concentration of heavy metals in the seminal fluid, such lead and cadmium that are negatively correlated with sperm concentration, mobility and morphology (52). On the other hand, high levels of trans-3â&#x20AC;&#x2122;-hydroxycotinine (3HC), a metabolite of nicotine, in seminal fluid are correlated with a decreased sperm mobility (53). The seminal plasma analysis of smokers shows a significantly higher proportion of inflammatory proteins. In fact, smoking seems associated with an inflammatory state of the accessory glands, which would eventually cause an alteration of the functional quality of spermatozoids, a decrease of acrosome integrity and mitochondrial activity, and an increased DNA fragmentation (54). Sperm concentration, total motility, and the number of typical spermatozoids is reduced in smokers (55). Tobacco also affects the intrinsic quality of spermatozoids. The analysis of the degree of fragmentation of sperm DNA showed a significantly higher fragmentation of DNA in smokers than in non-smokers (32% against 25.9%) (56). In an in-vitro fertilization trial, smoking among men was significantly and positively correlated with an increased risk of early spontaneous abortion (OR = 2.2) (57). Paternal smoking can also influence the health of newborns by transmission of DNA damaged by oxidative stress. Alterations of the methylation of sperm DNA in male smokers are compatible with alterations observed in their offspring (58). In addition, de-novo mutations in paternal spermatozoids induced by smoking can be transmitted (59).

Cannabis After consumption of cannabis, its metabolites are found in the seminal fluid, and spermatozoa are thus exposed during their passage through the epididymis (60). Cannabis interferes with spermatogenesis by central and peripheral mechanisms. The stimulation of receptors coupled to G protein inhibits adenylate cyclase levels decreasing cAMP levels in testicular tissue, spermatozoa, and hypothalamus. Cannabis blocks the hypothalamic release of GnRH and the anterior pituitary production of LH. Furthermore, it reduces the release of testosterone from Leydig cells via specific receptors (61). In a large sample of the general male population of Denmark, there was a significant negative correlation between cannabis consumption and sperm concentration, count, and mobility. In case of regular exposure to cannabis (9 to 18 cannabis joints a week) a decrease in sperm concentration was observed with a significant negative correlation between the amount of cannabis consumed and the sperm count. Chronic and intensive use of cannabis (more than 10 cannabis joints per week) was also associated with an alteration of Leydig cell function resulting in a significant dose-dependent decrease in testosterone serum levels (62). In conclusion, cannabis use should be considered as a potential cause of alteration of spermatogenesis or a co-factor aggravating preexisting spermatogenesis disorders. Obesity Obesity is related to excessive intake of food and reduced physical activity. Oligospermia is more frequent in obese men and in obesity an increase in DNA fragmentation was also described (63). Multiple interdependent mechanisms contribute to the negative effect of obesity on male fertility (64). Obesity is associated to alterations of the hypothalamic-pituitary axis because of various endocrine mechanisms such as production of estrogens by aromatization of testicular and adrenal androgens in excess adipose tissue, leptin resistance at kisspeptin neurons, and excessive production of endogenous opioids, leading to hypogonadotropic hyper-estrogenic hypogonadism. A significant decrease in free and total testosterone levels and a significant increase in estrogen levels are resulting, both contributing to alteration of spermatogenesis. The decrease in serum testosterone concentration is significantly associated with insulin resistance and a lower volume of ejaculate (65). Furthermore, obesity may directly alter spermatogenesis by its action on Sertoli cells, as suggested by the more severe decrease in inhibin B levels compared with the decrease in FSH. Finally, an increase in scrotal temperature caused by excessive testicular warming in the seated position may negatively affect spermatogenesis. Clinical trials Several interventional studies evaluated the effect of dietary supplementation on semen parameters of subfertile men or outcomes of assisted fertilization. Oral supplements include coenzyme Q10, L-Carnitine, vitamins, zinc and other antioxidants. Coenzyme Q10 A significant improvement of spermatogenesis was eviArchivio Italiano di Urologia e Andrologia 2020; 92, 2

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dent with coenzyme Q10 therapy. Mean sperm concentration, sperm progressive motility, and rate of sperm with normal morphology improved significantly after 12 month of coenzyme Q10 therapy (66). A positive correlation was found between duration of Q10 treatment duration and sperm count, motility and morphology (67). Even the reduced form of coenzyme Q10 (ubiquinol) was significantly effective in men with unexplained oligoasthenoteratozoospermia (68). L-Carnitine L-Carnitine (LC) together with acetyl-L-Carnitine (LAC) are commonly used because of their ability to improve sperm quality and pregnancy rate in males suffering from asthenoteratozoospermia (69). LC and LAC improve the total oxyradical scavenging capacity of the seminal fluid (70) and prevent DNA oxidation of human spermatozoa (71). Treatment with LC increased the success rate of intracytoplasmic sperm injection (ICSI) (72). In a doubleblind randomized controlled trial, a combination of LC and coenzyme Q10 increased sperm motility and rate of progressively motile sperm more than LC or coenzyme Q10 alone or than In the control group. The percentage of sperm DNA fragments was markedly low and the rate of clinical pregnancy was remarkably higher in the combination group than in controls (73). Vitamin E Levels of vitamin E in seminal plasma are related to sperm motility (74). Accordingly, lower levels of vitamin E were observed in the semen of infertile men (75). A prospective, multi-centered, randomized controlled study reported that vitamin E can improve sperm concentration, percentage of progressively motile sperm, and rate of natural pregnancies (76). Zinc and folic acid The zinc concentration of seminal plasma is significantly higher in fertile men in comparison to subfertile men (77). In a study, supplementation with zinc sulphate and folic acid did not ameliorate sperm functional parameters in oligoasthenoteratozoospermic men (78), whilst in another double-blind, placebo-controlled interventional study the total normal sperm count increased after a combined zinc sulfate and folic acid treatment in both subfertile and fertile men (79). Combination treatment A double-blind placebo-controlled study (80) using supplementation of L-carnitine, fumarate, acetyl-L-carnitine, Fructose, CoQ10, vitamin C, zinc, folic acid and vitamin B12 reported an increase of sperm concentration, total motility and pregnancy rate in couples whose males had varicocele or not. No difference of semen volume and not significant improvement of progressive motility were observed. Another double-blind, multi-center, randomized controlled trial showed that a combination of antioxidants and vitamins (vitamin C, vitamin D3, vitamin E, folic acid, zinc, selenium, L-carnitine) did not improve semen parameters or DNA fragmentation in infertile men (81). An evidence-based review of randomized trials concluded that antioxidant supplements are beneficial in

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improving semen quality and clinical pregnancy rates for men from couples undergoing infertility treatment (82). More recent meta-analyses confirmed the positive results of the administration of antioxidants in subfertile men, although the poor quality of the studies considered in their analyses was highlighted. A Cochrane meta-analysis considered 61 randomized clinical trials (RCTs) with a total population of 6000 subfertile men of couples attending a reproductive clinic to evaluate the effect of the oral administration of a wide range of 18 antioxidants on assisted reproductive techniques outcomes pregnancy or live birth rate (83). Only few small studies reported on pregnancy or live birth rate. Use of antioxidants increased, the chance of clinical pregnancy from an estimated baseline of 7% following placebo or no treatment to a 12% to 26% rate after antioxidants (OR = 2.97). Live birth rate after antioxidants ranged between 14 and 26% whereas a 12% rate was observed after placebo or no treatment (OR = 1.79). Most studies were rated as 'low' to 'very low' quality with high heterogeneity and serious risk of bias (poor reporting of methods of randomisation, unclear or high attrition, low event rates and small sample sizes). In another meta-analysis of 7 studies (84) a significant improvement of semen parameters (count, motility, morphology) was shown after administration of selenium (200 Âľg/day and 100 Âľg/day), combination of ), L-carnitine (2 g/day) and acetyl-L-carnitine (LAC; 1 g/day) and co-enzyme Q10 (200 and 300 mg/day). Information of the effect on pregnancy rate was not obtained because it was evaluated in a limited number of trials. The systematic review of other trials identified promising results for supplementation with zinc combined with folic acid, eicosapentaenoic acid and docosahexaenoic acid. Phytotherapeutica A poly-herbal formulation (a combination of the roots of Chlorophytum borivilianum, seeds of Mimosa pudica, sap of Acacia Senegal, root of Astragalus membranaceus, seed coat of Plantago ovate, sap of Bombax ceiba, root of Eurycoma longifolia and rocky candy) was tested for its effect on the spermatogenic potential in oligospermic patients. After 90 days, there was a 256% increase in sperm concentration, a 154% increase in semen volume and a 215% increase in sperm motility, respectively (85).

REFERENCES

1. Winters BR, Walsh TJ. The epidemiology of male infertility. Urol Clin North Am. 2014; 41:195-204. 2. Agarwal A, Mulgund A, Hamada A, Chyatte MR. A unique view on male infertility around the globe. Reprod Biol Endocrinol. 2015; 13:37. 3. Levine H, Jergensen N, Martino-Andrade A, et al. Temporal trends in sperm count: a systematic review and meta-regression analysis. Hum Reprod Update. 2017; 23:646-659. 4. Buck Louis GM, et al. Semen quality and time to pregnancy: the Longitudinal Investigation of Fertility and the Environment Study. Fertil Steril. 2014; 101:453-62. 5. Aksoy Y, Aksoy H, Altinkaynak K, et al. Sperm fatty acid compo-

Male fertility and nutrition

sition in subfertile men Prostaglandins Leukot Essent Fatty Acids. 2006; 75:75-9.

their relationship with semen quality. Am J Mens Health. 2016; 93:86-91.

6. Esmaeili V, Shahverdi AH, Moghadasian MH, Alizadeh AR. Dietary fatty acids affect semen quality a review Andrology. 2015; 3:450-461.

25. Mendiola J, Torres-Cantero AM, Moreno-Grau JM, et al. Food intake and its relationship with semen quality: a case-control study. Fertil Steril. 2009; 91:812-818.

7. Martin-Hidalgo D, Bragado MJ, Batista AR, et al. Antioxidants and male fertility: from molecular studies to clinical evidence. Antioxidants (Basel) 2019; 8(4). pii: E89. 8. Gabrielsen JS, Tanrikut C. Chronic exposures and male fertility: the impacts of environment, diet, and drug use on spermatogenesis. Andrology. 2016; 4:648-61. 9. Giahi L, Mohammadmoradi S, Javidan A, Sadeghi MR. Nutritional modifications in male infertility: a systematic review covering 2 decades. Nutr Rev. 2016; 74:118-30. 10. Braga DP, Halpern G, Figueira RC, et al. Food intake and social habits in male patients and its relationship to intracytoplasmic sperm injection outcomes. Fertil Steril. 2012; 97:53-59. 11. Salas-Huetos A, Bulló M, Salas-Salvadó J. Dietary patterns, foods and nutrients in male fertility parameters and fecundability: a systematic review of observational studies. Hum Reprod Update. 2017; 23:371-389. 12. Kahn BE, Brannigan RE Obesity and male infertility Curr Opin Urol. 2017; 27:441-445. 13. Bendayan M, Alter L, Swierkowski-Blanchard N, et al. Environment and lifestyle: Impacts on male fertility? Gynecol Obstet Fertil Senol. 2018; 46:47-56. 14. Eskenazi B, Kidd SA, Marks AR, et al. Antioxidant intake is associated with semen quality in healthy men. Hum Reprod 2005; 20:1006-1012. 15. Mendiola J, Torres-Cantero AM, Vioque J, et al. A low intake of antioxidant nutrients is associated with poor semen quality in patients attending Fertility Clinics.Fertil Steril 2010; 93:1128-1133. 16. Mínguez-Alarcón L, Mendiola J, López-Espín JJ, et al. Dietary intake of antioxidant nutrients is associated with semen quality in young university students. Hum Reprod 2012; 27:2807-2814. 17. Zareba P, Colaci DS, Afeiche M, et al. Semen quality in relation to antioxidant intake in a healthy male population. Fertil Steril. 2013; 100:1572-1579. 18. Valk E, Hornstra G. Relationship between vitamin E requirement and polyunsaturated fatty acid intake in man: a review. Int J Vitam Nutr Res. 2000; 70:31-42. 19. Karayiannis D, Kontogianni MD, Mendorou C, et al. Association between adherence to the Mediterranean diet and semen quality parameters in male partners of couples attempting fertility.Hum Reprod. 2017; 32:215-222. 20. Vujkovic M, de Vries JH, Dohle GR, et al. Associations between dietary patterns and semen quality in men undergoing IVF/ICSI treatment. Hum Reprod. 2009; 24:1304-1312. 21. Gaskins AJ, Colaci DS, Mendiola J, et al. Dietary patterns and semen quality in young men. Hum Reprod. 2012; 27:2899-2907.

26. Maldonado-Carceles AB, Minguez-Alarcon L, Mendiola J, et al. Meat intake in relation to semen quality and reproductive hormone levels among young men in Spain. Br J Nutr. 2019; 121:451-460. 27. Eslamian G, Amirjannati N, Rashidkhani B, et al. Intake of food groups and idiopathic asthenozoospermia: a case-control study. Hum Reprod. 2012; 27:3328-3336. 28. Afeiche M, Williams PL, Mendiola J, et al. Dairy food intake in relation to semen quality and reproductive hormone levels among physically active young men. Hum Reprod. 2013; 28:2265-2275. 29. Afeiche MC, Bridges ND, Williams PL, et al. Dairy intake and semen quality among men attending a Fertility Clinic. Fertil Steril. 2014; 101:1280-1287. 30. Afeiche MC, Williams PL, Gaskins AJ, et al. Meat intake and reproductive parameters among young men. Epidemiology. 2014; 25:323-30. 31. Afeiche MC, Gaskins AJ, Williams PL, et al. Processed meat intake is unfavorably and fish intake favorably associated with semen quality indicators among men attending a Fertility Clinic. J Nutr. 2014; 144:1091-1098. 32. Chiu YH, Afeiche MC, Gaskins AJ, et al. Sugar-sweetened beverage intake in relation to semen quality and reproductive hormone levels in young men. Hum Reprod. 2014; 29:1575-1584. 33. Chiu YH, Afeiche MC, Gaskins AJ, et al. Fruit and vegetable intake and their pesticide residues in relation to semen quality among men from a Fertility Clinic. Hum Reprod. 2015; 30:1342-1351. 34. Gaskins AJ, Chavarro JE. Diet and fertility: a review. Am J Obstet Gynecol. 2018; 218:379-389. 35. Chavarro JE, Toth TL, Sadio SM, Hauser R. Soy food and isoflavone intake in relation to semen quality parameters among men from an inFertility Clinic. Hum Reprod. 2008; 23:2584-2590. 36. Mínguez-Alarcón L, Afeiche MC, Chiu YH, et al. Male soy food intake was not associated with in vitro fertilization outcomes among couples attending a fertility center. Andrology. 2015; 3:702-708. 37. Attaman JA, Toth TL, Furtado J, et al. Dietary fat and semen quality among men attending a fertility clinic. Hum Reprod. 2012; 27:1466-74. 38. Jensen TK, Heitmann BL, Blomberg Jensen M,, et al. High dietary intake of saturated fat is associated with reduced semen quality among 701 young Danish men from the general population. Am J Clin Nutr. 2013; 97:411-418. 39. Chavarro JE, Mínguez-Alarcón L, Mendiola J, et al. Trans fatty acid intake is inversely related to total sperm count in young healthy men. Hum Reprod 2014; 29:429-440. 40. Minguez-Alarcón L, Chavarro JE, Mendiola J, et al. Fatty acid intake in relation to reproductive hormones and testicular volume among young healthy men. Asian J Androl. 2017; 19:184-190.

22. Cutillas-Tolín A, Mínguez-Alarcón L, Mendiola J, et al. Mediterranean and western dietary patterns are related to markers of testicular function among healthy men. Hum Reprod. 2015; 30:2945-2955.

41. Emanuele MA, Emanuele MV. Alcohol’s effect on male reproduction Alcohol Health Res World. 1998; 22:195-201.

23. Liu CY, Chou YC, Chao J, et al. The association between dietary patterns and semen quality in a general sian population of 7282 males. PLoS ONE 2015; 10:e0134224.

42. Muthusami KR, Chinnaswamy P. Effect of chronic alcoholism on male fertility hormones and semen quality. Fertil Steril. 2005; 84:919-24.

24. Jurewicz J, Radwan M, Sobala W, et al. Dietary patterns and

43. Guthauser B, Boitrelle F, Plat A, et al. Chronic excessive alcohol

Archivio Italiano di Urologia e Andrologia 2020; 92, 2

129

M. Benatta, R. Kettache, N. Buchholz, A.Trinchieri

consumption and male fertility: a case report on reversible azoospermia and a literature review.Alcohol Alcohol. 2014; 49:42-4. 44. Jensen TK, Gottschau M, Madsen JO, et al. Habitual alcohol consumption associated with reduced semen quality and changes in reproductive hormones; a cross-sectional study among 1221 young Danish men. BMJ Open. 2014; 4:e005462.

63. Dupont C, Faure C, Sermondade N, et al. Obesity leads to higher risk of sperm DNA damage in infertile patients. Asian J Androl. 2013; 15:622-5.

45. Ricci E, Al Beitawi S, Cipriani S, et al. Semen quality and alcohol intake: a systematic review and meta-analysis. Reprod Biomed Online. 2017; 34:38-47.

64. Kahn BE, Brannigan RE Obesity and male infertility Curr Opin Urol. 2017; 27:441-445.

46. Nicolau P, Miralpeix E, Solà I, et al. Alcohol consumption and in vitro fertilization: a review of the literature. Gynecol Endocrinol. 2014; 30:759-63.

65. Calderón B, Gómez-Martín JM, Vega-Piñero B, et al. Prevalence of male secondary hypogonadism in moderate to severe obesity and its relationship with insulin resistance and excess body weight. Andrology. 2016; 4:62-7.

47. Ricci E, Viganò P, Cipriani S, et al. Coffee and caffein intake and male infertility: a systematic review. Nutr J. 2017; 16:37. 48. Richard S, Moslemi S, Sipahutar H, et al. Differential effects of glyphosate and roundup on human placental cells and aromatase. Environ Health Perspect. 2005; 113:716-20. 49. Andersson AM, Skakkebaek NE. Exposure to exogenous estrogen in food: possible impact on human development and health. Eur J Endocrinol. 1999; 140:477-85.

66. Safarinejad MR. The effect of coenzyme Q10 supplementation on partner pregnancy rate in infertile men with idiopathic oligoasthenoteratozoospermia: An open-label prospective study. Int Urol Nephrol. 2012; 44:689-700. 67. Safarinejad MR. Efficacy of coenzyme Q10 on semen parameters, sperm function and reproductive hormones in infertile men. J Urol. 2009; 182:237-48.

50. Swan SH, Liu F, Overstreet JW, et al. Semen quality of fertile US males in relation to their mothers' beef consumption during pregnancy. Hum Reprod. 2007; 22:1497-502.

68. Safarinejad MR, Safarinejad S, Shafiei N, Safarinejad S. Effects of the reduced form of coenzyme Q10 (ubiquinol) on semen parameters in men with idiopathic infertility: a double-blind, placebo controlled, randomized study. J Urol. 2012; 188:526-31.

51. Gao M, Li B, Yuan W, et al. Hypothetical link between infertility and genetically modified food. Recent Pat Food Nutr Agric. 2014; 6:16-22.

69. Wang YX, Yang SW, Qu CB,, et al. L-carnitine: safe and effective for asthenozoospermia. Zhonghua Nan Ke Xue. 2010; 16:420-2.

52. Kiziler AR, Aydemir B, Onaran I, et al. High levels of cadmium and lead in seminal fluid and blood of smoking men are associated with high oxidative stress and damage in infertile subjects. Biol Trace Elem Res. 2007; 120:82-91. 53. Abu-Awwad A, Arafat T, Schmitz OJ. Simultaneous determination of nicotine, cotinine, and nicotine N-oxide in human plasma, semen, and sperm by LC-Orbitrap MS. Anal Bioanal Chem. 2016; 408:6473-81. 54. Antoniassi MP, Intasqui P, Camargo M, et al. Analysis of the functional aspects and seminal plasma proteomic profile of sperm from smokers. BJU Int. 2016; 118:814-822. 55. Künzle R, Mueller MD, Hänggi W, et al. Semen quality of male smokers and nonsmokers in infertile couples. Fertil Steril. 2003; 79:287-91. 56. Sepaniak S, Forges T, Gerard H, et al. The influence of cigarette smoking on human sperm quality and DNA fragmentation. Toxicology. 2006; 223:54-60. 57. Zitzmann M, Rolf C, Nordhoff V, et al. Male smokers have a decreased success rate for in vitro fertilization and intracytoplasmic sperm injection.Fertil Steril. 2003; 79 (Suppl 3):1550-4. 58. Jenkins TG, James ER, Alonso DF, et al. Cigarette smoking significantly alters sperm DNA methylation patterns. Andrology. 2017; 5:1089-1099. 59. Linschooten JO, Verhofstad N, Gutzkow K, et al. Paternal lifestyle as a potential source of germline mutations transmitted to offspring. FASEB J. 2013; 27:2873-9. 60. Nahas GG, Frick HC, Lattimer JK, et al. Pharmacokinetics of THC in brain and testis, male gametotoxicity and premature apoptosis of spermatozoa. Hum Psychopharmacol. 2002; 17:103-13. 61. du Plessis SS, Agarwal A, Syriac A. Marijuana, phytocannabinoids, the endocannabinoid system, and male fertility. J Assist Reprod Genet. 2015; 32:1575-88.

130

62. Gundersen TD, Jørgensen N, Andersson AM, et al. Association between use of marijuana and male reproductive hormones and semen quality: a study among 1,215 healthy young men. Am J Epidemiol. 2015; 182:473-81.

Archivio Italiano di Urologia e Andrologia 2020; 92, 2

70. Balercia G, Regoli F, Armeni T, et al. Placebo-controlled doubleblind randomized trial on the use of L-carnitine, L-acetylcarnitine, or combined L-carnitine and L-acetylcarnitine in men with idiopathic asthenozoospermia. Fertil Steril. 2005; 84:662-71. 71. Banihani S, Agarwal A, Sharma R, Bayachou M. Cryoprotective effect of L-carnitine on motility, vitality and DNA oxidation of human spermatozoa. Andrologia. 2014; 46:637-41. 72. Wu ZM, Lu X, Wang YW, et al. Short-term medication of L-carnitine before intracytoplasmic sperm injection for infertile men with oligoasthenozoospermia. Zhonghua Nan Ke Xue. 2012; 18:253-6. 73. Cheng JB, Zhu J, Ni F, Jiang H. L-carnitine combined with coenzyme Q10 for idiopathic oligoasthenozoospermia: A doubleblind randomized controlled trial. Zhonghua Nan Ke Xue. 2018; 24:33-38. 74. Thérond P, Auger J, Legrand A, Jouannet P. alpha-Tocopherol in human spermatozoa and seminal plasma: Relationships with motility, antioxidant enzymes and leukocytes. Mol Hum Reprod. 1996; 2:739-44. 75. Omu AE, Fatinikun T, Mannazhath N, Abraham S. Significance of simultaneous determination of serum and seminal plasma alphatocopherol and retinol in infertile men by high-performance liquid chromatography. Andrologia. 1999; 31:347-54. 76. Chen XF, Li Z, Ping P, et al. Efficacy of natural vitamin E on oligospermia and asthenospermia: a prospective multi-centered randomized controlled study of 106 cases. Zhonghua Nan Ke Xue. 2012; 18:428-31. 77. Chia SE, Ong CN, Chua LH, et al. Comparison of zinc concentrations in blood and seminal plasma and the various sperm parameters between fertile and infertile men. J Androl. 2000; 21:53-7. 78. Raigani M, Yaghmaei B, Amirjannti N, et al. The micronutrient supplements, zinc sulphate and folic acid, did not ameliorate sperm functional parameters in oligoasthenoteratozoospermic men. Andrologia. 2014; 46:956-62.

Male fertility and nutrition

79. Wong WY, Merkus HM, Thomas CM, et al. Effects of folic acid and zinc sulfate on male factor subfertility: a double-blind, randomized, placebo-controlled trial. Fertil Steril. 2002; 77:491-8.

82. Ahmadi S, Bashiri R, Nadjarzadeh A. Antioxidant supplements and semen parameters:an evidence based review Int J Reprod Biomed 2016; 14:629-736.

80. Busetto GM, Agarwal A, Virmani A, et al. Effect of metabolic and antioxidant supplementation on sperm parameters in oligoastheno-teratozoospermia, with and without varicocele: A doubleblind placebo-controlled study. Andrologia. 2018; 50.

83. Smits RM, Mackenzie-Proctor R, Yazdani A, et al. Antioxidants for male subfertility. Cochrane Database Syst Rev. 2019; 3:CD007411.

81. Steiner A, Hansen K, Diamond MP, et al. Antioxidants in the treatment of male factor infertility: Results from the double blind, multicenter, randomized controlled Males, Antioxidants, and Infertility (MOXI) trial. Abstract Book of 34th Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE), 1-4 July 2018 Barcelona; Human Reproduction 2018; 33 (Suppl 1):i30.

84. Buhling K, Schumacher A, Eulenburg CZ, Laakmann E. Influence of oral vitamin and mineral supplementation on male infertility: a meta-analysis and systematic review. Reprod Biomed Online. 2019; 39:269-279. 85. Hussain SA, Hameed A, Nasir F, et al. Evaluation of the spermatogenic activity of polyherbal formulation in oligospermic males. BioMed Research International 2018; 2018:2070895.

. .

Correspondence Mahmoud Benatta benatta.mahmoud@gmail.com Dept. of Urology, Djilali Lyabes University Hospital, Sidi Bel Abbes/Algeria Redha Kettache kettacher@gmail.com Dept. of Urology, EPH Bachir Bennacer, Biskra/Algeria Noor Buchholz (Corresponding Author) scientific-office@u-merge.com noor.buchholz@gmail.com U-merge Scientific Office 21 Athens/Greece Alberto Trinchieri alberto.trinchieri@gmail.com U-merge Scientific Office

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DOI: 10.4081/aiua.2020.2.132

ORIGINAL PAPER

Percutaneous nephrolithotomy: Three-needle technique on two planes. Cury’s technique Carlos Abib Cury 1, Analaura de Oliveira Cury 2, Victoria Caroline Pagelkopf 3, Vinicius Ramos Bezerra de Morais 3, Vitor de Almeida Fernandes 4, Miguel Bonfitto 4 1 Professor,

Urology Sector, São José do Rio Preto School of Medicine (Famerp), Brazil; Student, Votuporanga University Center (Unifev), Brazil; 3 Medical Student, São José do Rio Preto School of Medicine (Famerp), Brazil; 4 Resident in Urology, São José do Rio Preto Base Hospital/Famerp, Brazil. 2 Medical

Summary

Introduction: Percutaneous nephrolithotomy is the main type of surgery indicated for kidney stones larger than 2 cm. The present study describes a three-needle technique for percutaneous nephrolithotomy on two planes. Surgical technique: The patient is first placed in the lithotomy position for cystoscopy, which guides the ureteral and urethral catheter. Next, the patient is placed in ventral decubitus for the three-needle technique. With the aid of the nephroscope, the first needle is positioned in the projection of the renal pelvis, the second needle is placed in the most posterior of the inferior calyces and the third needle is aligned with the other two at the most depressible point determined by the surgeon’s index finger. After alignment in the topography of the third needle, an incision is made with the scalpel 1-2 cm perpendicular to the aponeurosis of the latissimus dorsi muscle. The second needle is replaced with a peridural needle, which is used to confirm the location of the inferior renal calyx and limit the depth of the Chiba needle inserted in the topography of the third needle, forming a 90° angle with the peridural needle. The Chiba needle enables the passage of the guidewire and subsequent dilatation until the 30F caliber for the passage of the Amplatz dilator, initiating the conventional procedure. Comments: The technique described has been used at our service for 15 years and has the advantages of less morbidity, fewer complications and less use of the nephrostomy tube. The technique is also easy to learn and highly reproducible.

KEY WORDS: Urology; Nephrolithiasis; Percutaneous nephrolithotomy. Submitted 27 August 2019; Accepted 1 September 2019

INTRODUCTION

Lithiasis of the urinary tract is a common cause of urological morbidity, affecting approximately 12% of the population and with recurrences in approximately 50% of cases (1-4). For kidney stones larger than 2 cm in diameter, percutaneous nephrolithotomy had been the main treatment method since the first successful surgery described by Fernström and Johansson in 1976 (2-4). Percutaneous nephrolithotomy replaced open surgery for the treatment of these calculi, as the reduction in morbidity and improvement in the experience of surgeons led to the increased indication for this procedure (5, 6). According to the guidelines of the European

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Association of Urology and American Urological Association, the percutaneous approach is indicated for renal calculi larger than 2 cm in diameter or calculi located in the inferior pole larger than 1.0 cm in diameter (2, 3). This paper describes a novel three-needle technique for percutaneous nephrolithotomy on two planes. Surgical technique The patient is first placed in the lithotomy position. Cystoscopy is performed, followed by insertion of the ureteral and urethral catheter. The patient is then placed in ventral decubitus with the lower limbs slightly flexed for the onset of the three-needle technique. 1. With the aid of the fluoroscope, the projection of the renal pelvis is determined through cutaneous demarcation with Kelly forceps (Figures 1, 2) in order to not expose the surgeon’s hand to radiation. 2. The first needle (21 G) is positioned in the projection of the renal pelvis previously demarcated by the Kelly forceps (Figure 3). 3. Next, the inferior calyces are located and reached through the injection of contrast through the ureteral catheter (Figure 4). The most posterior calyx is preferable due to its proximity to the puncture site. 4. The second needle is inserted in the calyx located in Item 3, obeying the same location steps using the Kelly forceps (Figure 5). 5. The two needles positioned in the pelvis and inferior calyx will serve as reference for the alignment of the third needle (Figure 6). 6. The third needle is positioned in the most depressible point between the 12th rib and superior iliac crest determined by the surgeon’s index finger on the axis of the first two aligned needles. The point is near the lumbar triangle and posterior axillary line (Figure 7). 7. In the topography of the 3rd needle, an incision is made 1-2 cm perpendicular to the axis of the needles in the skin until reaching the thoracolumbar aponeurosis of the latissimus dorsi, which is also incised (Figure 8). 8. Next, the second needle in the projection of the inferior calyx is replaced with a peridural needle until reaching the lumen of the calyx, determined by urinary flow, thereby establishing the distance from the No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2020; 92, 2

Percutaneous nephrolithotomy: Three-needle technique on two planes

Figure 1. X-ray showing location of calculus and catheter.

Figure 2. (A) X-ray showing Kelly forceps in center of calculus with aid of fluoroscopy to demarcate projection of first needle to be inserted. (B) Cutaneous demarcation with Kelly forceps.

Figure 6. (A) X-ray showing alignment guided by needles, establishing axis for puncture of third needle (B).

Figure 7. (A) Most depressible point identified by index finger located between 12th rib and upper iliac crest. (B) Third needle inserted. (C) X-ray showing three needles and (D) respective alignment.

Figure 3. (A) First needle positioned. (B) Confirmation of site through fluoroscopy.

Figure 8. Incision in topography of third needle. Figure 4. Ascending pyelography showing first needle (arrow).

Figure 5. (A) X-ray showing demarcation of puncture site for second needle in inferior calyces, opting for posterior calyx (B).

skin to the calyx, enabling the definition of the superficial and deep axes (Figure 9). 9. With the incision in the muscular and aponeurotic plane, the Kelly forceps are placed in the direction of the inferior pole of the kidney, opening the space in which the puncture and dilation of the percutaneous path will be performed (Figure 10). 10. In the opening achieved with the Kelly forceps, the surgeon’s index finger verifies the path to toward the inferior pole of the kidney, which is easily moved (Figure 11). 11. The definitive puncture is initiated with the Chiba needle running the previously established path at an initial angle close to 45° (individualized based on body mass and the orientation given by the surgeon’s index finger). The Chiba needle should reach the depth determined by the peridural needle (Figure 12). Archivio Italiano di Urologia e Andrologia 2020; 92, 2

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C. Abib Cury, A. de Oliveira Cury, V.Caroline Pagelkopf, V. Ramos Bezerra de Morais, V. de Almeida Fernandes, M. Bonfitto

Figure 9. (A) Replacement of second needle (21 G) with peridural needle to reach calyx, determining puncture depth. (B) Peridural needle positioned. (C) X-ray showing locations of first needle and peridural needle (arrows).

Figure 10. (A) Insertion of Kelly forceps in direction of inferior renal pole, confirmed by X-ray (B).

Figure 13. Urine flow through lumen of Chiba needle.

Figure 14. (A) X-ray showing insertion of guidewire in calyx system. (B) Dilation of path directed by guideline by telescopic route and initial and subsequent rigid instruments (C). (D) Introduction of Alken’s rod in dilator sleeve enveloping guidewire, which will be starting point for progressive dilation. (E) X-ray confirming location of Alken’s rod. (F) Introduction of last dilator with coupled Amplatz® 30F dilator. (G) X-ray showing Amplatz® dilator positioned for continuity of procedure.

Figure 11. X-ray showing index finger in direction of inferior renal pole.

Figure 12. (A) Insertion of Chiba needle, traveling incision path. (B) X-ray showing Chiba needle in inferior extremity of peridural needle.

ventional standard for percutaneous nephrolithotomy, with the advantage that this slanted puncture enables better navigation of the nephroscope through the pelvis as well as the middle and upper calyces, thereby avoiding multiple punctures.

12. Upon reaching the extremity of the peridural needle, the Chiba needle is in the interior of the selected calyx, confirmed by the flow of urine (Figure 13). 13. Accessing the inferior calyx, the procedure is initiated by introducing the guidewire, followed by progressive dilation through a telescopic pathway with rigid instruments or individualized dilation to the 30F caliber, replaced by the Amplatz® dilator (Figure 14). 14. At this point, the entire procedure follows the con-

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Comments This technique have been used and improved over the course of 15 years at our service and has the advantage of a single access throughout the entire calyx system, thereby minimizing trauma to the parenchymatous tissue in comparison to a direct puncture, in which there is substantial parenchymatous injury when attempting to reach a neighboring calyx. In most cases, this technique avoids the use of a nephrostomy tube. The three-needle technique is an alternative to conventional percutaneous nephrolithotomy. It is a novel treatment strategy for kidney stones that enables an approach on two planes in the prone position with the aid of a fluoroscope during the procedure.

Percutaneous nephrolithotomy: Three-needle technique on two planes

The technique obeys the Pythagorean theorem, which states that the sum of the squares of the catheti is equal to the square of the hypothenuse: a² + b² = c². Cathetus “a” is the linear distance on the surface of the skin determined by the second needle to the third needle. The hypothenuse “c” is defined by the surface of the third needle to the point of cathetus “b”, determined by the second needle positioned in the inferior calyx. By obeying the theorem, the surgeon has greater control over the depth to which he/she wishes to insert the needle. As kidneys are in an inclined position in relation to the spinal column at an angle of approximately 30°, the puncture in the inferior pole enables access to all calyces and the pelvis of the kidney, enabling the surgeon to navigate with the nephroscope through the renal excretory pathway, thereby avoiding further punctures. Access through the inferior pole diminishes the risk of injury to the renal vessels. In summation, the technique described herein diminishes the use of the nephrostomy tube at the end of the procedure, leading to less postoperative pain and a shorter hospital stay.

REFERENCES

1. Teichman JM. Acute renal colic from ureteral calculus. New England Journal of Medicine. 2004; 350:684-93. 2. Guideline E.S. (2016). American Urological Association (AUA) Endourological Society Guideline SURGICAL MANAGEMENT OF STONES: AMERICAN UROLOGICAL ASSOCIATION/American Urological Association (AUA) Endourological Society Guideline Surgical Management of Stones, (April), 1-50. 3. Türk C, Skolarikos A, Neisius A, et al. Guidelines Associates: Donaldson JF, Drake T, Grivas N, Ruhayel Y. EAU guidelines on interventional treatment for urolithiasis. EAU Guidelines. Edn. presented at the EAU Annual Congress Barcelona 2019. ISBN 978-9492671-04-2. 4. Fernström I, Johansson B. Percutaneous pyelolithotomy: a new extraction technique. Scandinavian journal of urology and nephrology. 1976; 10:257-9. 5. Lee JY, Jeh SU, Kim MD, et al. Intraoperative and postoperative feasibility and safety of total tubeless, tubeless, small-bore tube, and standard percutaneous nephrolithotomy: a systematic review and network meta-analysis of 16 randomized controlled trials. BMC urology. 2017; 17:48. 6. Warmerdam GJ, De Laet K, Wijn RP, Wijn PF. Treatment options for active removal of renal stones. Journal of medical engineering engineering & technology. 2012; 36:147-55.

Correspondence Carlos Abib Cury Professor, Urology Sector, São José do Rio Preto School of Medicine (Famerp), Brazil Analaura de Oliveira Cury Medical Student, Votuporanga University Center (Unifev), Brazil Victoria Caroline Pagelkopf Vinicius Ramos Bezerra de Morais Medical Student, São José do Rio Preto School of Medicine (Famerp), Brazil Vitor de Almeida Fernandes Miguel Bonfitto miguelbonfitto@gmail.com Resident in Urology, São José do Rio Preto Base Hospital/Famerp, Brazil

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DOI: 10.4081/aiua.2020.2.136

ORIGINAL PAPER

The importance of PSA-Density in active surveillance for prostate cancer Caner Ediz, Serkan Akan, Muhammed Cihan Temel, Omer Yilmaz Department of Urology, Sultan Abdulhamid Han Education and Research Hospital, Istanbul, Turkey.

Summary

Objective: In this study, we aimed to determine the predictive factor for additional treatment requirement in active surveillance (AS) for patients with low or very low-risk prostate cancer (PCa) and we investigated the effect of tumor burden by total core involvement rate in biopsy to predict of need for additional treatment. Material and methods: 107 patients with PCa in AS between 2005 and 2018 have been evaluated retrospectively. Groups were divided into two groups according to the need for additional treatment. Group 1 received additional treatment, group 2 did not receive additional treatments and active surveillance was continued. Patient’s total prostate-specific antigen (tPSA), prostate-specific antigen density (PSA-D), total core involvement count, quantity and rate at biopsy pathology results and follow-up period were recorded and compared in the two groups. Results: The current cohort includes 107 patients. Mean age at diagnosis was 63.01years. Mean tPSA values at diagnosis were 6.09 ng/mL and 5.2 ng/mL in the group 1 and group 2, respectively. Mean follow-up period was 38.1 months (range, 12 to 134 months). Only PSA-D measurement significantly predicted need for additional treatment (p = 0.017). ROC analysis showed that the optimal threshold was 0.13 ng/mL/cc (sensitivity: 70.8%; specificity: 57.1%). Additional treatment requirement was not detected in patients with PSA-D cut-off level less than 0.07 ng/mL/cc. Conclusions: Total tumor burden of less than 5% is safe for patients with low or very low-risk PCa in AS. A 0.13 ng/mL/cc cut-off level of PSA-D can predict to need for additional treatment in patients managed by AS.

KEY WORDS: Prostate cancer; Active surveillance; Prostate specific antigen density; Definitive treatment. Submitted 12 December 2019;Accepted 3 January 2020

INTRODUCTION

Prostate cancer (PCa) is the most common cancer in men (1) and has a high mortality rate like lung cancer. PSA screening and early diagnosis have led to a decrease in the mortality rates (2). There are many changes in the treatment of prostate cancer over the years and one of the most significant changes is active surveillance (AS) protocol. The time from the diagnosis of low-risk disease to the clinical progression is generally long and progression signs are detectable during the follow-up period. For this reason, AS is applied at low-risk PCa because definitive treatment can be offered when needed. Another reason for choosing AS, is to prevent overtreatment by selecting patients with

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low-risk prostate cancer in order to preclude possible side effects of the definitive treatment. In 2003, this point was emphasized to avoid or delay definitive treatment and its associated morbidity without compromising survival (35). AS provides these benefits to patients and it is extremely cost effective compared to definitive treatment (6). Active surveillance has been used for many years in the follow-up of PCa. Unfortunately, we do not know the answer to questions such as “which patients will need additional treatment?” or “when the definitive treatment should be started?” We aimed to evaluate whether total core involvement count, quantity and rate were the correct parameter and we analyzed the efficacy of prostate-specific antigen density or total core involvement rate to predict tumor burden and possible additional treatment needs. We reported outcomes of AS in patients with very low and low-risk PCa.

MATERIALS

AND METHODS

Study population and design 1695 patients with prostate biopsy performed due to high prostate-specific antigen (PSA) or significant digital rectal examination findings in our clinics between June 2005 and June 2018 were enrolled. The data were collected retrospectively. No ethical committee approval was required owing to the retrospective nature of our study. A total of 117 patients with PCa were managed by AS. The current cohort with available data includes 107 patients. Patient’s age, digital rectal examination (DRE) findings, prostate volumes (PV), total PSA (tPSA), PSADensity (PSA-D), in biopsy; total core involvement count (TCIC), quantity (TCIQ) and rate (TCIR), pathology results and follow-up period were recorded. The criteria for inclusion in the study was as follows: patients with the low risk of cancer progression: > ten years life expectancy, cT1/2, PSA ≤ 10 ng/mL, biopsy Gleason score of </= 6, ≤ 2 positive biopsies, minimal biopsy core involvement (≤ 50% cancer per biopsy). The criteria for exclusion in the study were: patients who started follow-up before 2003 and patients whose data could not be reached. Patients who voluntarily opted to leave the active surveillance protocol were not included in this study. The patient's medical records were reviewed. Patients’ age, grading and findings of digital rectal examination, No conflict of interest declared.

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prostate volumes (PVs) calculated by transrectal ultrasound RESULTS (TRUS) with the ellipse method (length X depth X width For the 107 patients included in analyses, the mean age X π/6) by using height obtained by transaxial scanning, at diagnosis was 63.01 years (range, 47 to 74 years). The tPSA, PSA-D that was calculated as tPSA (ng/mL) dividdistributions of all patients by age, PV, tPSA and PSA-D ed by PV, were eveluated in all patients. In each biopsy. were shown in Table 1 and by TCIC, TCIQ and TCIR in TCIC, TCIQ and TCIR were calculated by total core Table 2. An abnormal DRE findings were found in 32 of number (n), total tumor length in all cores (mm) and 107 patients (such as asymmetric growth of lateral lobes, ratio of total tumor length to total length of biopsy tisnodule or stiffness). Mean follow up period was 38.1 sues detected within the tumor (%), respectively. Recurrent pathology results and follow-up time were Table 1. eveluated. Pathological specimens were reviewed by a Evaluation of descriptive characteristics in patients single genitourinary pathologist based on the 2005 and with PCa were managed by AS. 2014 International Society of Urological Pathology (ISUP) Variable Mean ± SD (min-max) Consensus Conference grading of prostate cancer (7, 8). The patients who were diagnosed with prostate cancer Age (years) 63.01 ± 5.85 (47-74) before 2014 were evaluated using 2005 ISUP grading Prostate Volume (ml) 43.47 ± 17.92 (10-114) criteria and patients who were followed-up after 2014 tPSA (ng/mL) 5.35 ± 1.96 (1.24-10) were classified using the 2014 ISUP new grading system. PSA density (ng/mL/cc) 0.14 ± 0.09 (0.02-0.83) The follow-up protocol included a minimum of four reSD: standard deviation. AS: active surveillance. examinations per year. tPSA measurement was performed every 3 months for 2 years and then every 6 months in suitable patients. DRE were routinely performed in all patients. Possible tPSA Table 2. changes were confirmed at least two Total core involvement count. quantity and rate of patients according times. A confirmation biopsy was recom- to number of biopsy procedures. mended for all patients within the first First biopsy n = 107 Second biopsy n = 68 Third biopsy n = 23 year after diagnosis. Mean ± SD (min-max) Mean ± SD (min-max) Mean ± SD (min-max) Confirmation biopsies generally involve TCIC (n) 1.18 ± 0.39 (1-2) 2.2 ± 1.06 (1-5) 2.3 ± 1.84 (1-7) more core assessment than standard TCIQ (mm) 1.89 ± 1.25 (0.1-7) 5.31 ± 4.22 (1-18) 6.31 ± 7.2 (1-20) biopsies. Multiparametric magnetic resoTCIR (%) 14.78 ± 11.24 (0.55-50) 26.23 ± 19.19 (2.5-90) 20.59 ± 25.8 (1-85.8) nance imaging of the prostate (mpMRI) SD: standard deviation. TCIC: Total Core Involvement Count. TCIQ: Total Core Involvement Quantity. TCIR: Total Core Involvement Rate. was performed in patients who do not want to have a second biopsy or before recurrent biopsies. Patient-based modalities are preferred in the definitive treat- Table 3. 5-year average of PCa patients who underwent PSA follow-up with active ment decision. Definitve treatment was surveillance. planned primarily in patients who were found to be unsuitable for AS. However, Follow-up period n (Overall) tPSA (ng/mL) (min-max) androgen deprivation treatment was First year (initial) 107 5.35 (1.24-10) prefered in patients who did not accept Second year (confirmation) 100 5.88 (0.43-28.1) surgical treatment or radiotherapy. Statistical analysis In the analysis of the data, PSPP and Microsoft Excel computer programs were used. As a statistical method in the analysis of data in the research, descriptive analyzes (mean and standard deviation) were applied. In the analysis of the data, the normality hypothesis was first investigated using the Kolmogorov-Smirnov test and Mann Whitney U test was used for data analysis after the normal distribution test. The statistically significant parameters were analyzed by the Receiver Operating Characteristic (ROC) that allowed for the determination of the cutoff value by the combination of the greater specificity and sensitivity by the definition of the area under the curve. The results were evaluated at 95% confidence interval and p < 0.05 significance level.

Third year

Fourth year

5.86 (1.04-12.2) 6.88 (0.84-22)

Fifth year

6.56 (1.64-19.08)

Table 4. Evaluation of descriptive characteristics according to the patients with or without additional treatment requirement (surgical or medical). Additional treatment (-) n = 24 Mean ± SD (min-max)

Additional treatment (+) n = 83 Mean ± SD (min-max)

Age (years)

63.92 ± 5.79 (57-74)

62.76 ± 5.84 (47-74)

0.74

Prostate Volume (ml)

40.5 ± 12.16 (15-70)

43.95 ± 19.45 (10-114)

0.72

tPSA (ng/mL)

6.09 ± 1.83 (3.36-9.47)

5.2 ± 2.02 (1.24-10)

0.7

PSA density (ng/mL/cc)

0.16 ± 0.06 (0.07-0.28)

0.14 ± 0.12 (0.03-0.83)

0.017*

TCIC (n)

1.16 ± 0.38 (1-2)

1.19 ± 0.39 (1-2)

0.79

TCIQ (mm)

1.88 ± 1.36 (1-6)

1.96 ± 1.34 (0.1-7)

0.64

15.56 ± 11.93 (5-50)

15.31 ± 12.81 (0.55-50)

0.75

TCIR (%)

SD: standard deviation. TCIC: Total Core Involvement Count. TCIQ: Total Core Involvement Quantity. TCIR: Total Core Involvement Rate. * < 0.05.

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al treatment; in 49/107 patients PSA-D was more than 0.13 ng/mL/cc and 17 (34.69%) of them required additional treatment (Table 5). When the cut-off PSA-D ≤ 0.13* (n = 58) PSA-D > 0.13* (n = 49) level of PSA-D was based on 0.13 Mean ± SD Mean ± SD ng/mL/cc, the follow-up period until the Age (years) 63.06 ± 5.41 62.93 ± 6.39 decision to start additional treatment ATR ATR was 26.14 months for PSA-D ≤ 0.13 and n = 7 (%) n = 17 (%) 25.4 months for PSA-D > 0.13) months, Treated with radical prostatectomy ISUP 1 6 (85.71) 6 (35.29) respectively. ISUP 2 0 5 (29.41) Two patients with PSA-D > 0.13 ISUP 3 0 1 (5.88) ng/mL/cc lost their chance of definitive ISUP 4 0 0 treatment. PSA-D was associated with ISUP 5 1 (14.28) 0 predicting of additional treatment pT0** 0 1 (5.88) requirement for active surveillance (p = Treated with RT 0 2 (11.76) 0.017) and ROC analysis showed that Treated with ADT 0 2 (11.76) the optimal threshold was 0.13 ng/mL/cc PSA-D: PSA-Density. ATR: Additional Treatment Requirement. ISUP: International Society of Urological Pathology. (sensitivity: 70.8%; specificity: 57.1%). RT: Radiotherapy. ADT: Androgen-Deprivation Therapy. Twenty patients underwent radical *: ng/mL/cc. **: tumor tissue was not detected in pathology specimen after radical prostatectomy. prostatectomy (RP) as additional treatment in follow-up. Average follow-up Table 6. time until RP was 25.47 months (range, 12 to 60 months). Number of PCa patients managed with active surveillance In patients with prostate cancer managed by active suraccording to ISUP grades. veillance, annual changes of tPSA levels in follow-up according to patients with PSA-D > 0.13 or 0.13 ≤ ISUP Grades (PCa in RP) n (Overall) % ng/mL/cc are shown in Figure 1. ISUP 1 12 60 Pathology results of radical prostatectomy specimens ISUP 2 5 25 according to the ISUP classification are reported in ISUP 3 1 5 Table 6. Twelve out of 20 (60%) radical prostatectomy ISUP 5 1 5 specimens were graded ISUP 1. Two patients preferred radiotherapy (RT) and another two received androgenpT0* 1 5 deprivation therapy (RT not approved by radiation *: tumor tissue was not detected in pathology specimen after radical prostatectomy. oncologist) as additional treatment (Figure 2). ISUP: International Society of Urologic Pathologists. PCa: Prostate cancer. Additional treatments were offered to other two patients, but the patients refused to additional treatments and months (range, 12 to 134 months); tPSA changes in the were removed from the treatment protocol of their own following years after diagnosis were shown in Table 3. volition. Additional cancers were observed in 3 of 107 There was no difference in TCIC, TCIQ and TCIR levels patients under follow-up, one patient was diagnosed between the 2 groups as reported in Table 4 (p > 0.05). with bladder cancer and two patient diagnosed with The PSA-D was less than 0.13 ng/mL/cc in 58/107 renal cell cancer. Two patients died due to non-cancerpatients and only 7 (12.06%) of them required additionous causes (chronic heart failure and lymphoma). Table 5. Number of patients managed with additional treatments in different PSA-density levels and grouping of patients with radical prostatectomy by ISUP grade.

Figure 1. In patients with prostate cancer managed by active surveillance. annual changes of PSA levels in follow-up according to patients with PSA-Density > 0.13 or 0.13 ≤ ng/mL/cc.

PSA: prostate specific antigen. PSAD: prostate-specific antigen density. TPSA1.2.3.4.5: First, second, third, fourth and fifth year total prostate specific antigen levels in follow-up.

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the patients needed additional treatment and follow-up period until the decision to start surgical or hormonal theraphy was shortened when the PSA-D was increased. In patients with PSA-D greater than 0.13 ng/mL/cc, high Gleason scores (from 3+4 to 4+5) were detected when radical prostatectomy was performed as definitive treatment. In a study by Camur et al., upgrading was seen in 35 (44.8%) of 78 patients included in the study, but PV had no significant effect on upgrading in AS appropriate patients (16). Although PV is ineffective, AS criterias may include PSA-D. Patients with PSA-D levels < 0.07 ng/mL/cc were not upgraded and needed no additional treatment. Especially very low PSA-D levels (< 0.07) are extremely safe. We think that risk classifications according to PSA-D levels will contribute to the determination of secondary or tertiary biopsy requirements in follow-up protocols of patients and believe that the cutoff value of the recommended PSA-D in the guidelines should be updated to below 0.15 ng/mL/cc. The number of positive cores is limited by two according to many authors. In California University, this value should not exceed 33% of the total number of cores taken (17). Many guidelines and Authors have suggested that involvement rate in cores should be limited to 50%. Soloway et al. suggested a rate of 20% (18) and Porten et al. of 33% (19). We think that 50% is an optimal value, but this rate cannot be evaluated in inadequate biopsy samples. The ideal core length should be more than 1.5 cm. Tumor measurements such as number of positive cores, fraction of positive cores, linear percentage of carcinoma in each core or across all sites and linear millimeters of carcinoma in each core or across all sites are used for patient selection in AS (20). The actual area of the tumor in millimeters is used to calculate percentage (21). The percent of needle biopsy cores and surface area are the strongest predictors of tumor volume and pathological stage (22). In the literature, many articles found that maximum percent core involvement at diagnosis was associated with progression (23-26). Sternberg et al. (27) and Iremashvili et al. (28) created nomograms that include number of positive cores and percent of positive cores at diagnosis. However, disease progression and extent of cancer on biopsy are not associated significantly in some studies (29, 30). In this area; open to different interpretations, TCIC, TCIQ and TCIR measurements are optional and we thought that the TCIC, TCIQ and TCIR would be more significant than the amount of tumor rate in each core. Quintal et al found that TCIC and TCIR were significantly stronger than linear percentage of cancer or greatest millimeter length in each core to predict biochemical recurrence (31). Brimo et al. found that TCIR is closely associated with stage and biochemical failure (32). However, Park et al. found that

Figure 2. The flowchart includes patients who remained on surveillance or moved to active treatment (RP, RT or ADT) and annual change of tPSA for 5-year in the study population.

DISCUSSION

Active Surveillance is a well-recognized option in patients with low (clinical stage T1-T2a and tPSA < 10 ng/mL and Grade Group 1) and very low-risk (clinical stage T1-T2a and tPSA < 10 ng/mL and Grade Group 1 and PSA-Density < 0.15 ng/mL/cc and < 34% of biopsy cores positive and no core with > 50% involved) PCa (9). There are different protocols and selection criterias to select the appropriate patient. tPSA, clinical stage, and number of positive cores, each core involvement, PSA-D and a life expectancy of at least 10 yr are the basis of different protocols. Prostate specific antigen threshold values in AS are variable, but generally less than 10 ng/mL, in a study conducted by Royal Marsden Clinic in 2008, tPSA threshold was determined â&#x2030;¤ 15 ng/mL (10). Clinical stage T1c or T2a is accepted as eligible for AS guidelines. The tPSA threshold values for AS suggested by the guidelines have a low risk potential. However, we think that the low Gleason score is more valuable than the low PSA, and the threshold value of high PSA values (above 10 ng/mL) should be preferred in appropriate patients. In our clinical practice, we apply AS more flexibly in informed patients (information including detailed explanations about their condition and the likely outcomes of treatment) than the guidelines suggest. PSA-Density is a predictor of upgrading of ISUP degree after radical prostatectomy and it is used safely in AS (11-13). The threshold value of PSA-D is 0.15 ng/mL/cc in current guidelines, but nowadays, in some studies, the cut-off value of PSA-D of 0.08 ng/mL/cc indicates significant risk for disease progression (14). Jin et al. found that optimal cut-off level of PSA-D was 0.13 ng/mL/cc (11). Barayan et al. found that a PSA-D > 0.15 ng/ml/cc is an important predictor for disease progression (15). In our cohort, PSA-D was the only factor that was statistically significant in predicting the need for additional treatment and optimal cut-off level was 0.13 ng/mL/cc. In patients with PSA-D > 0.13 ng/mL/cc, a larger part of

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these paramaters were not significant in predicting pT3 disease (33). Russo et al. found a cut-off value of 0.4 mm for each core (34). Today, clearly defined and accepted values are still not available to predict total tumor burden. In this study, we found that the measurements except than PSA-D were insufficient in predicting the need for additional treatment. One of the most important points in AS is patient compliance to follow-up periods. Patients may want to withdraw from the AS protocol because they can not accept living with recurrent PSA measurements, examinations, biopsies and diagnosis of tumor. For this reason, followup of this protocol with non-invasive methods such as mpMRI is extremely valuable. Alberts et al found that Prostate Imaging Reporting and Data System score of 13 and PSA-D of < 0.15 ng/mL/cc did not show Gleason score upgrading in biopsies at each time point of surveillance (35). AS may be more preferable to patients with low risk PCa due to reduced biopsy requirements in the future. Especially combination of PSA-D and mpMRI may be the future of this therapy management. The limitations of the study are the evaluation of data retrospectively, the relatively patientsâ&#x20AC;&#x2122; low compliance with the follow-up protocol, the comparatively short mean follow-up period and the lack of multiparametric MRI findings. More studies are needed to predict total tumor burden at diagnosis and additional treatment requirement over time.

CONCLUSIONS

Active surveillance in the treatment of prostate cancer is a proven protocol and there is a high degree of consensus on its criterias. Although TCIC, TCIQ and TCIR measurements are thought to help us to have an idea about the total tumor burden and progression, there is no contribution to predict the need for additional treatment. Therefore, we don't think they need to be measured routinely. Cut-off value of PSA-D as a 0.13 ng/mL/cc may be effective in determining the risk group and may be predictive of the need for additional treatment in the follow-up.

ACKNOWLEDGEMENTS

OF FINANCIAL SUPPORT

The authors would like to thank the entire staff of the Department of Urology, Sultan Abdulhamid Han Education and Research Hospital and certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.

REFERENCES

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018; 68:7-30. 2. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin. 2007; 57:43-66. 3. Klotz L. Active surveillance with selective delayed intervention: a biologically nuanced approach to favorable-risk prostate cancer. Clin Prostate Cancer. 2003; 2:106-110. 4. Koo KC, Lee KS, Jeong JY, et al. Pathological and oncological fea-

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tures of Korean prostate cancer patients eligible for active surveillance: analysis from the K-CaP registry. Jpn J Clin Oncol. 2017; 47:981-985. 5. Lee DH, Koo KC, Lee SH, et al. Low-risk prostate cancer patients without visible tumor (T1c) on multiparametric MRI could qualify for active surveillance candidate even if they did not meet inclusion criteria of active surveillance protocol. Jpn J Clin Oncol. 2013; 43:553-558. 6. Corcoran AT, Peele PB, Benoit RM. Cost comparison between watchful waiting with active surveillance and active treatment of clinically localized prostate cancer. Urology. 2010; 76:703-707. 7. Egevad L, Delahunt B, Srigley JR, et al. International Society of Urological Pathology (ISUP) grading of prostate cancer - An ISUP consensus on contemporary grading. APMIS. 2016; 124:433-435. 8. Epstein JI, Allsbrook WC Jr., Amin MB, et al. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol. 2005; 29:1228-1242. 9. Thostrup M, Thomsen FB, Iversen P, et al. Active surveillance for localized prostate cancer: update of a prospective single-center cohort. Scand J Urol. 2018; 52:14-19. 10. van As NJ, Norman AR, Thomas K, et al. Predicting the probability of deferred radical treatment for localised prostate cancer managed by active surveillance. Eur Urol. 2008; 54:1297-1305. 11. Jin BS, Kang SH, Kim DY, et al. Pathological upgrading in prostate cancer patients eligible for active surveillance: Does prostate-specific antigen density matter? Korean J Urol. 2015; 56:624-629. 12. Kotb AF, Tanguay S, Luz MA, et al. Relationship between initial PSA density with future PSA kinetics and repeat biopsies in men with prostate cancer on active surveillance. Prostate Cancer Prostatic Dis. 2011; 14:53-57. 13. Loeb S, Bruinsma SM, Nicholson J, et al. Active surveillance for prostate cancer: a systematic review of clinicopathologic variables and biomarkers for risk stratification. Eur Urol. 2015; 67:619-626. 14. San Francisco IF, Werner L, Regan MM, et al. Risk stratification and validation of prostate specific antigen density as independent predictor of progression in men with low risk prostate cancer during active surveillance. J Urol. 2011; 185:471-476. 15. Barayan GA, Brimo F, Begin LR, et al. Factors influencing disease progression of prostate cancer under active surveillance: a McGill University Health Center cohort. BJU Int. 2014; 114:E99-E104. 16. Camur E, Coskun A, Kavukoglu, et al. Prostate volume effect on Gleason score upgrading in active surveillance appropriate patients. Arch Ital Urol Androl. 2019; 91:93-96 17. Cooperberg MR, Cowan JE, Hilton JF, et al. Outcomes of active surveillance for men with intermediate-risk prostate cancer. J Clin Oncol. 2011; 29:228-234. 18. Soloway MS, Soloway CT, Eldefrawy A, et al. Careful selection and close monitoring of low-risk prostate cancer patients on active surveillance minimizes the need for treatment. Eur Urol. 2010; 58:831-835. 19. Porten SP, Whitson JM, Cowan JE, et al. Changes in prostate cancer grade on serial biopsy in men undergoing active surveillance. J Clin Oncol. 2011; 29:2795-2800. 20. Amin MB, Lin DW, Gore JL, et al. The critical role of the pathologist in determining eligibility for active surveillance as a management option in patients with prostate cancer: consensus statement with recommendations supported by the College of American Pathologists, International Society of Urological Pathology, Association of Directors

PSA-Density and active surveillance

of Anatomic and Surgical Pathology, the New Zealand Society of Pathologists, and the Prostate Cancer Foundation. Arch Pathol Lab Med. 2014; 138:1387-1405. 21. Draisma G, Boer R, Otto SJ, et al. Lead times and overdetection due to prostate-specific antigen screening: estimates from the European Randomized Study of Screening for Prostate Cancer. J Natl Cancer Inst. 2003; 95:868-878. 22. Sebo TJ, Bock BJ, Cheville JC, et al. The percent of cores positive for cancer in prostate needle biopsy specimens is strongly predictive of tumor stage and volume at radical prostatectomy. J Urol. 2000; 163:174-178. 23. Tseng KS, Landis P, Epstein JI, et al. Risk stratification of men choosing surveillance for low risk prostate cancer. J Urol. 2010; 183:1779-1785. 24. Bul M, Zhu X, Valdagni R, et al. Active surveillance for low-risk prostate cancer worldwide: the PRIAS study. Eur Urol. 2013; 63:597-603. 25. Eggener SE, Mueller A, Berglund RK, et al. A multi-institutional evaluation of active surveillance for low risk prostate cancer. J Urol. 2013; 189:S19-25. 26. Venkitaraman R, Norman A, Woode-Amissah R, et al. Predictors of histological disease progression in untreated, localized prostate cancer. J Urol. 2007; 178:833-837. 27. Sternberg IA, Yu C, Keren Paz GE, et al. Predicting progression in patients followed with active surveillance for low-risk prostate cancer. American Society of Clinical Oncology; 2014. 28. Iremashvili V, Burdick-Will J, Soloway MS. Improving risk stratification in patients with prostate cancer managed by active surveillance: a nomogram predicting the risk of biopsy progression. BJU Int. 2013; 112:39-44.

29. Cary KC, Cowan JE, Sanford M, et al. Predictors of pathologic progression on biopsy among men on active surveillance for localized prostate cancer: the value of the pattern of surveillance biopsies. Eur Urol. 2014; 66:337-342. 30. Adamy A, Yee DS, Matsushita K, et al. Role of prostate specific antigen and immediate confirmatory biopsy in predicting progression during active surveillance for low risk prostate cancer. J Urol. 2011; 185:477-482. 31. Quintal MM, Meirelles LR, Freitas LL, et al. Various morphometric measurements of cancer extent on needle prostatic biopsies: which is predictive of pathologic stage and biochemical recurrence following radical prostatectomy? Int Urol Nephrol. 2011; 43:697-705. 32. Brimo F, Vollmer RT, Corcos J, et al. Prognostic value of various morphometric measurements of tumour extent in prostate needle core tissue. Histopathology. 2008; 53:177-183. 33. Park EA, Lee HJ, Kim KG, et al. Prediction of pathological stages before prostatectomy in prostate cancer patients: analysis of 12 systematic prostate needle biopsy specimens. Int J Urol. 2007; 14:704-708. 34. Russo GI, Cimino S, Castelli T, et al. Percentage of cancer involvement in positive cores can predict unfavorable disease in men with low-risk prostate cancer but eligible for the prostate cancer international: active surveillance criteria. Urol Oncol. 2014; 32:291-296. 35. Alberts AR, Roobol MJ, Drost FH, et al. Risk-stratification based on magnetic resonance imaging and prostate-specific antigen density may reduce unnecessary follow-up biopsy procedures in men on active surveillance for low-risk prostate cancer. BJU Int. 2017; 120:511-519.

Correspondence Caner Ediz, MD (Corresponding Author) drcanerediz@gmail.com Serkan Akan, MD drserkanakan@hotmail.com Muhammed Cihan Temel, MD dr.cihantemel@gmail.com Omer Yilmaz, MD dr_omeryilmaz@yahoo.com Department of Urology, Sultan Abdulhamid Han Education and Research Hospital, Istanbul, Turkey Tibbiye Street. Selimiye neighborhood. Uskudar/Istanbul

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DOI: 10.4081/aiua.2020.2.142

ORIGINAL PAPER

Short term effects of home-based bladder training and pelvic floor muscle training in symptoms of urinary incontinence Aybuke Ersin 1, Sule B. Demirbas 2, Fatih Tarhan 3 1 Istanbul

Medipol University, Institute of Health Sciences, Department of Physiotherapy and Rehabilitation, Istanbul, Turkey; University, Faculty of Health Sciences, Department of Physiotherapy and Rehabilitation, Istanbul, Turkey; 3 Health Sciences University, Dr. Lutfi Kirdar Training and Research Hospital, Urology Clinic, Istanbul, Turkey. 2 Yeditepe

Summary

Aim: The aim of this non-controlled trial was to investigate the effects of a homebased pelvic floor muscle training (PFMT) and bladder training (BT) in urinary incontinence (UI) among women. Patients and methods: The study included 25 individuals who were diagnosed with UI. PFMT which strengthens pelvic floor muscles was described to patients in litotomy position with using digital palpation method. PFMT was given as homebased exercise program for six weeks, 7 days a week and ten times a day. BT was planned according to the symptoms of the patients. Assessments were done at the beginning and at the end of the six weeks exercise program. The outcome measures were UI severity measured by pad test and QoL measured by Kingâ&#x20AC;&#x2122;s Health Questionnaire. The secondary outcome measure was lower urinary tract symptoms and sexual health measured by Bristol Female Lower Urinary Tract Symptoms Index. Results: Pre- and post-treatment assessments done with pad test showed that there was a statistically significant decrease in the severity of UI (p = 0.002). The difference between preand post-treatment QoL scores (p = 0.001) and lower tract symptom scores were also statistically significant (p = 0.000). Conclusions: When PFMT and BT were given together there was a decrease in the symptoms and increases the QoL.

KEY WORDS: Urinary incontinence; Pelvic floor muscle training; Bladder training; Physiotherapy. Submitted 25 October 2019; Accepted 12 December 2019

INTRODUCTION

International Urogynecological Association and the International Continence Society (IUGA/ICS) defined urinary incontinence (UI) as the complaint of involuntary loss of urine. There are three main types of UI in women: stress urinary incontinence (SUI), urgency urinary incontinence (UUI), and mixed urinary incontinence (MUI). SUI is defined as the involuntary loss of urine during sneezing, coughing, or other types of physical effort; UUI is characterized by involuntary loss of urine related with urgent conditions; MUI is the mixture of stress and urge UI (1). Although UI is not a life-threatening problem among women, it effects the physical and psychological aspects of social life. Because of these reasons the problem should be handled meticulously (2). UI is more common in women than in men. Studies

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from different countries report a prevalence of UI in the range of 25% to 45% in adult women (3). UI was reported as 38.7% of women and 9.9% of men in Turkey (4). Although many conservative approaches are available for treating female UI, pelvic floor muscle training (PFMT) and bladder training (BT) are the most popular, of which PFMT is recommended as the first-line therapy. Numerous studies have reported the effectiveness of either BT or PFMT singly for treating the female UI. At present, only one randomized clinical trial and one pragmatic non-randomized controlled trial have been conducted regarding the efficacy of adding PFMT to BT for treating UI (5, 6). In this study, we aimed to investigate the effects of a six week home based PFMT and BT program in women with UI.

MATERIALS

AND METHODS

Design The study was approved by the local ethics committee of Health Sciences University Dr. Lutfi Kirdar Training and Research Hospital (Istanbul, Turkey; approval no: 2014/05, 514/43/6), and all participants submitted written informed consent. Our study started with thirty-six patients and ended up with twenty five patients who completed the 6-week program (Figure 1). The UI was diagnosed by the urologist and the assessment and the therapy were done by the physiotherapist. Patients Women in the 25-75 age range, with UI diagnoses were included in the study. Those who had cancer, neurological disorders, pregnancy, pelvic organ prolapse, mental retardation or uro-gynecologic operation in the last six months were excluded. Evaluation Patients age as year and body mass index (BMI) as kg/cm2 were recorded. Patients were questioned about their education, profession and smoking habits. Their obstetric histories were also recorded. Quality of life (QoL) and No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2020; 92, 2

Short term effects of home-based bladder training and pelvic floor muscle training in symptoms of urinary incontinence

Figure 1. Flow of participants.

UI effects were tested by King’s Health Questionnaire (KHQ), severity of incontinence by pad test, lower urinary tract symptoms and sexual health conditions by Bristol Female Lower Urinary Tract Symptoms Index (B-FLUTS). The patients were assessed in the beginning and at the end of the program. They filled out an exercise follow up chart during home exercises and these charts were examined at the end of the 6-week program. KHQ consists of 8 sections. These are role limitation, physical limitation, social limitation, personal relationship, emotions, sleep, energy and incontinence severity (5). B-FLUTS is a questionnaire used for the assessment of lower track urinary system symptoms, sexual health and QoL (7). Pad test is one of the most objective tests which shows the existence of UI and its severity. It is used extensively in the diagnosis of incontinence and in the evaluation of the therapy. The 1-hour pad test which was standardized by ICS in 1983 is the most frequently used test (8). The patients, after taking 500 cc water, were asked to use pre-weighed pads during the test period. During the test period the patients were asked to cough, sit to stand and climb stairs several times which increase the abdominal pressure or stimulate detrusor contractions. At the end of the test, if the weight difference of the pad was less than 2 grams it was rated as normal; if it was between 2-10 grams as mild, 10-50 grams as moderate, over 50 grams as severe incontinence (9). Treatment The patients were informed about the structure and function of the lower urinary system. PFMT which

strengthens pelvic floor muscles was described to patients in lithotomy position by using digital palpation method. Patients completed a home-based exercise program consisting of strength and endurance training. They were taught both fast (5-s) and slow voluntary pelvic floor muscle contractions (VPFMCs). One slow contraction took 15 s (5-s contraction, 5-s hold, 5-s relaxation). One set of exercises involved ten fast and ten slow VPFMCs. During the program, patients were instructed to perform ten sets of exercises per day. The patients were asked to do the exercise in the supine, seated, and upright positions. They were supposed to integrate these exercises into their daily living activities. PFMT chart was given to every patient to remind them of exercise and to discipline them. The aim was to decrease the frequency of urination and to increase the capacity of the bladder. Special BT was planned according to the patients’ urgency symptoms. In BT the patients were asked to keep away from bladder irritant fluids (coffee, tea, coke, lemonade etc.) and not to limit the water intake. Extension of the urination intervals were done gradually during the six weeks period. In order to help increase the intervals, the patients were taught some control techniques for urgencies. In these techniques the patients were asked to contract the pelvic floor, to take deep and slow breaths and to think of something different in order to repress the feeling of urgency. Statistical analyses Statistical analyses were performed using SPSS software (Statistical Package for Social Sciences) version 21.0. During the evaluation of the data Student’s t-test, Paired sample t-test, Wilcoxon signed-rank test were used for comparison of quantitative data along with descriptive statistical methods (mean, standard deviation, frequency). McNemar’s test was used for comparison of qualitative data. Multiple regression analysis was used to determine risk factors. Confidence interval which was 95% and p < 0.05 were considered significant.

RESULTS

Mean age, BMI, number of births, abortions and miscarriage were respectively: 47.6 ± 10.12 years (min 28 - max 73); 30,8 ± 5,88 kg/m2 (min 20.2 - max 42.97); 3 ± 2.1 (0-10); 1.04 ± 1.24 (0-4); 0.2 ± 0.64 (0-3). 92% gave birth at least one child with 76% giving natural birth and 16% with sectio. 8% did not give birth (Table 1). 15 women had SUI, 7 women UUI, 8 women MUI. Pre- and post-treatment assessments with pad test showed that the incontinence severity decreased statistically and KHQ showed significant increase in the QoL (Table 2). The difference between pre- and post-treatment scores of UI was statistically significant. Statistical analyses Archivio Italiano di Urologia e Andrologia 2020; 92, 2

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A. Ersin, Sule B. Demirbas, F. Tarhan

Table 1. Characteristics of individuals. Characteristic Age (years) BMI (kg/m2) Parity Abortion Misscarriage

Mean 47.6 30.8 3 1.04 0.2

SD* 10.12 5.88 2.1 1.24 0.64

*Standard deviation.

Table 2. Outcomes of pre&post treatment on incontinence severity, Quality of life and lower urinary tract symptom. Before treatment Mean S.D. Min Max Pad Test (g) 36.24 46.19 0 213 KHQ scores 544.26 185.14 150 888.8 B-FLUTS scores 51.04 13.3 18 72

After treatment Mean S.D. Min Max P* 13.28 16.65 0 70 0.002 361.31 237.73 0 900 0.001 37.04 14.2 11 72 0.000

*Comparison between pre and post treatment. S.D: Standard deviation. KHQ: King’s Health Question. B-FLUTS: Bristol Female Lower Urinary Tract Symptoms Index.

showed us that an increase in BMI can cause increased of incontinence severity. Participants reported that their urination frequency had decreased and sexual health had improved as well.

DISCUSSION

The aim of the study was to investigate the effects of a home-based PFMT and BT in UI among women. It was found that 6-week PFMT and BT was effective in the decrease of UI symptoms and increase in QoL. In a study by Fan et al. the mean of age was 52.3 years and they found that age did not have any influence on the effectiveness of PFMT. Our mean age was 47.6 years and we found similar results as far as the mean age and the effectiveness were concerned (10). In their study Kaya et al. compared BT with the BT+ PFMT complex and showed that a short term (6 weeks) complex approach was more effective, which was also supported by our results (5). Ahlund et al. chose digital palpation technique in order the teach their patients to contract their pelvic floor muscle in the most accurate way. In their study they also gave information about anatomy and physiology of the pelvic floor and UI to their patients. They informed that they achieved accurate muscle contraction in 66% of their patient (11). Moen et al. informed that they achieved accurate muscle contraction in 70% of their patients by digital palpation (12). In our study we used digital palpation in order to teach pelvic floor muscle contraction. We gave information about anatomy and physiology of the pelvic floor. Even though it was not evaluated statistically, we observed that our patients learned accurate contraction of pelvic floor muscle. Mommsen et al. showed that BMI was related to UI values (13). Our study showed that BMI increases severity of UI and supported the literature.

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Archivio Italiano di Urologia e Andrologia 2020; 92, 2

Kaya et al. reported an increase in the QoL of the patients (5) and our study showed the same result. Vaz et al. conducted a combined PFMT and CT program in the same manner as us and reported positive results in the quality of life and incontinence in 6 weeks. They also stated that there was no difference in efficacy between home-based program and health center treatment. Our study similarly demonstrated the success of the 6-weeks home-based program (6). In our study, we used the KHQ to evaluate the symptomspecific QoL. The validity and reliability of the Turkish version of this questionnaire, which was first developed in urinary incontinence, had been proved by Akkoç et al. (7). The KHQ was used in studies in pelvic floor muscle strengthening exercises designed similarly to our study. Neumann et al. used the KHQ to determine changes in the QoL before and after treatment (14). B-FLUTS, which we used to evaluate filling, voiding and incontinence symptoms and sexual functions, was found to be valid and reliable by Gökkaya et al. It is an effective index to determine the success of the treatment (8). Bø et al. used BFLUTS to investigate the effects of pelvic floor muscle exercises in QoL and sexual problems (15). Also Ahlund et al. used BFLUTS to evaluate urinary incontinence symptoms and sexual functions (10). In our study, BFLUTS was used to evaluate the symptoms of lower urinary tract before and after treatment and a statistically significant difference was observed which also supported by the literature. Ahlund et al. reported that their patients had decreased UI symptoms based on their feedback Based on their patients’ feedbacks Ahlund et al. reported that the UI symptoms had reduced (10). We also had the same results from the feedbacks of our participants that reported that they were feeling better. When we overviewed the limitations of our study, one of them was that the patients were not statistically classified and evaluated according to their incontinence type. If we had greater number of patients we would have stronger statistical results. The other limitation of our therapy program was that long-term results were not evaluated along with the short-term results. In order to reach a definitive conclusion, randomized controlled trials with larger sample numbers are needed.

CONCLUSIONS

To sum up, pelvic floor muscle training and bladder training, together result in reducing the symptoms and in increasing the quality of life. By combining these two approaches a home based exercise program, the therapy becomes more effective, cheaper, safer and quicker in achieving the result.

ACKNOWLEDGMENTS

The authors would like to thank Ayse Ardali and Burcu Ardali Gurcay for editing the English translation of this article. Funding: The authors declare no funding about this project.

Short term effects of home-based bladder training and pelvic floor muscle training in symptoms of urinary incontinence

Conference presentation: part of this paper was presented at the IUGA (International Urogynecological Association) 40th Annual Scientific Meeting 9-13 June 2015, Nice, France.

7. Akkoc Y, Karapolat H, Eyigor S, et al. Quality of life in multiple sclerosis patients with urinary disorders: reliability and validity of the Turkish version of King’s Health Questionnaire. Neurol Sci 2011; 32:417-421.

REFERENCES

8. Gokkaya CS, Öztekin CV, Doluoglu OG, et al. Index validation of Turkish version of Bristol Female Lower Urinary Tract Symptom Index. J Clin Anal Med. 2012; 3:415-8.

1. Haylen BT, De Ridder D, Freeman RM, et al. International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Neurourol Urodyn. 2010; 29:4-20. 2. Can T, Yagci N, Cavlak U. Effects of urinary incontinence on depressive symptoms and quality of life in women with reproductive age. Fizyoter Rehabil. 2012; 23:83-89. 3. Milsom I, Altman D, Cartwright R, et al. Epidemiology of urinary incontinence (UI) and other lower urinary tract symptoms (LUTS), pelvic organ prolapse (POP) and anal (AI) incontinence. In: Abrams P, Cardozo L, Wagg A, Wein, A. (Eds) Incontinence 6th Edition. ICIICS. International Continence Society, Bristol UK, ISBN: 978 0956960733; 2017. 4. Zumrutbas AE, Bozkurt AI, Tas E, et al. Prevalence of lower urinary tract symptoms, overactive bladder and urinary incontinence in western Turkey: Results of a population-based survey. Int J Urol. 2014; 21:1027-1033.

9. Kaya S. Comparison of different treatment modalities in patients with idiopathic detrusor overactivity: physical therapy and rehabilitation, medical treatment. Degree MSc., Hacettepe University, Ankara, Turkey; 2008. 10. Fan HL, Chan SSC, Law TSM, et al. Pelvic floor muscle training improves quality of life of women with urinary incontinence: a prospective study. Aust N Z J Obstet Gynaecol. 2013; 53:298-304. 11. Ahlund S, Nordgren B, Wılander E, et al. Is home-based pelvic floor muscle training effective in treatment of urinary incontinence after birth in primiparous women? A randomized controlled trial. Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstet Gynecol Scand. 2013; 92:909-915. 12. Moen MD, Noone MB, Vassallo BJ, Elser DM. Pelvic floor muscle function in women presenting with pelvic floor disorders. Int Urogynecol J Pelvic Floor Dysfunct 2009; 22:654-8. 13. Mommsen S, Foldspang, A. Body Mass Index and Adult Female Urinary Incontinence. World J Urol 1994; 12:319-322.

5. Kaya S, Akbayrak T, Gürsen C, Beksac S. Short-term effect of adding pelvic floor muscle training to bladder training for female urinary incontinence: a randomized controlled trial. Int Urogynecol J. 2015; 26:285-93.

14. Neumann PB, Grımmer AK, Grant RE, Gill VA. Physiotherapy for female stress urinary incontinence: a multicentre observational study. Aust N Z J Obstet Gynaecol. 2005; 45:226-232.

6. Vaz CT, Sampaio RF, Saltiel F, Figueiredo EM. Effectiveness of pelvic floor muscle training and bladder training for women with urinary incontinence in primary care: a pragmatic controlled trial. Braz J Phys Ther. 2019; 23:116-24.

15. Bø K, Talseth T, Vınsnes A. Randomized controlled trial on the effect of pelvic floor muscle training on quality of life and sexual problems in genuine stress incontinent women. Acta Obstet Gynecol Scand 2000; 79:598-603.

Correspondence Aybuke Ersin, MD Istanbul Medipol University Göztepe Mah. Atatürk Cad. No: 40/16, 34815 Beykoz, !stanbul aybukeu2011@gmail.com Sule B. Demirbas, MD Yeditepe University, Faculty of Health Sciences, Department of Physiotherapy and Rehabilitation, Istanbul, Turkey Fatih Tarhan, MD Health Sciences University, Dr. Lutfi Kirdar Training and Research Hospital, Urology Clinic, Istanbul, Turkey

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DOI: 10.4081/aiua.2020.2.146

ORIGINAL PAPER

Microorganisms and antibiotic susceptibilities isolated from urine cultures Abdullah Gul 1, Esra Gurbuz 2 1 University 2 Kelkit

of Health Sciences, Bursa Yuksek Ihtisas Training and Research Hospital, Department of Urology, Bursa, Turkey; State Hospital, Department of Infectious Diseases and Clinical Microbiology, Gumushane, Turkey.

Summary

Objectives: Urinary tract infection (UTI) is the second most common cause of infection among all infectious diseases at hospitals. Antibiogram results are needed to maintain treatment in patients with suspected UTI. However, empirical antibiotic treatment is initiated in patients since it takes time to obtain the results of antibiograms. The aim of this study was to evaluate the urine culture and antibiogram results of patients who were admitted to our hospital with suspected UTI and compare the results with other studies. Methods: Urine cultures requested from the hospital information system database between January of 2018 and 2019 were analyzed. Microorganism-positive urine samples and antibiogram results were evaluated and included in the study. Results: Of the patients, 748 (61.8%) were female and 463 (38.2%) were male. The average age of all patients was 44.9 years. Escherichia coli was the most frequently isolated microorganisms from urine cultures (n = 828, 68.4%). Among all microorganism-positive urine samples, antibiotic resistance against Cefalexin, Fusidic acid, Ampicillin, Erythromycin, Levofloxacin, Cefuroxime Axetil, Trimethoprim/ Sulfamethoxazole, Ceftriaxone and Ciprofloxacin was 83.9%, 68.4%, 61.8%, 44.7%, 42.7%, 36.4%, 30%, 28.6% and 26.7%, respectively. Conclusions: High resistance to Cefalexin, Ampicillin, Cefuroxime, Axetil, Trimethoprim/ Sulfamethoxazole, Ceftriaxone and Ciprofloxacin, which are often preferred in empirical antibiotic selection, has been found. We believe that empirical antibiotic selection should not be overlooked in cases of UTI. Our study may help clinicians use appropriate antibiotics for the clinical management of UTIs.

KEY WORDS: Antibiotic resistance; Microorganisms; Urine culture. Submitted 18 November 2019; Accepted 19 January 2020

INTRODUCTION

Antibiotic-resistant microorganisms are becoming widespread and the emergence of bacteria causing multidrugresistant (MDR) urinary tract infection (UTI) has become a major public health problem (1, 2). UTIs are the second most common cause of infection among all infectious diseases at hospitals (3). Around 150 million new UTI cases develop worldwide each year, with an estimated treatment cost of $ 150 billion (4). The urethra is a portal for urine output, but it also allows pathogenic microorganisms to enter the urinary tract. Bacteria live in the vicinity of the urethral opening in both men and women and routinely colonize urine, but women are more likely to develop UTIs resulting from anatomical

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differences, hormonal effects and behavior (5, 6). Antibiograms are used to maintain treatment in patients with suspected UTIs. However, empirical antibiotic treatment is initiated in patients since it takes time to obtain the results of antibiograms. The causative agent and the selected antibiotic affect the success of the treatment. The choice of drug for empirical antibiotic treatment is very important because of antibiotic resistance. Empirical antibiotic selection should be followed at regular intervals for the sensitivity results of the hospital and the region studied (7). Because the prevalence of UTI pathogens and their resistance to different antibiotics may have changed over the years (8). Antimicrobial resistance is increasing worldwide, leading to infections that are difficult to treat and are associated with high mortality, morbidity and cost (9, 10). The aim of this study was to evaluate the urine culture and antibiogram results of patients who were admitted to our hospital with suspected UTI and compare the results with other studies. We believe that our study will help physicians select appropriate empirical antibiotics for the clinical management of UTIs. Morever, it may serve as data source for reviews and meta-analysis in future.

MATERIALS

AND METHODS

In this study, both urine cultures and antibiogram results of 1211 patients who were admitted to urology outpatients clinic of Van Regional Training and Research Hospital between 2018-2019 and who were positive for urine culture were analyzed retrospectively. In the microbiology laboratory urine samples obtained for culture from mid stream by sterile urine containers were evaluated as standard with 0.01 milliliter calibrated flasks with 5% sheep blood and eosin methylene blue (EMB) agar and incubated at 37Ë&#x161;C for 18-24 hours. Isolated bacteria were identified by fully automated identification with antibiogram device (VITEK 2 Compact BioMerieux, France) and antibiotic susceptibility results were determined. Antibiogram results were given in three groups as less sensitive, sensitive and resistant. Data were expressed as mean Âą standard deviation and percentage.

RESULTS

Of the patients, 748 (61.8%) were female and 463 (38.2%) were male. The average age of all patients was 44.9 years. No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2020; 92, 2

Epidemiology of urinary tract infections

It was 38.2 years in female patients whilst 55.8 years in male patients. Escherichia coli (E. coli) was the most frequently isolated microorganisms (n = 828, 68.4%) from urine cultures. Isolated microorganisms are shown in Table 1 as number and percentage. When all samples were examined, antibiotic resistance against to Cefalexin, Fusidic acid, Ampicillin, Erythromycin, Netilmicin, Levofloxacin was 83.9%, 68.4%, 61.8%, 44.7%, 43.8%, 42.7%, respectively. Also, antibiotic resistance to Cefuroxime Axetil, Cefuroxime, Cefixime, Trimethoprim/Sulfamethoxazole, Ceftriaxone,

Ciprofloxacin was found to be 36.4%, 36%, 34.3%, 30%, 28.6% and 26.7%, respectively. No microorganisms were found to be resistant to Amphotericin B, Chloramphenicol, Colistin, Flucytosine and Rifampicin. However, antibiotic resistance to Meropenem, Ertapenem, Imipenem and Amikacin was found to be 0.88%, 1.14%, 1.5% and 1.6%, respectively. The data on the resistance status of antibiotics are given in Table 2 as number and percentage. Table 2. Antibiotic resistance rates. Sensitive

Antibiotic

Table 1. Microorganisms isolated from urine cultures. Isolated microorganisms Acinetobacter spp Acinetobacter baumannii Alcaligenes faecalis Burkholderia cepacia Candida albicans Candida famata Candida kefyr Candida krusei Candida spherica Candida tropicalis Citrobacter freundii Citrobacter koseri Enterobacter aerogenes Enterobacter cloacae complex Enterococcus spp Enterococcus faecalis Enterococcus faecium Escherichia coli Klebsiella spp Klebsiella oxytoca Klebsiella pneumoniae Morganella morganii Proteus spp. Proteus mirabilis Providencia rettgeri Pseudomonas aeruginosa Salmonella spp Serratia fonticola Serratia liquefaciens group Serratia marcescens Shigella sonnei Staphylococcus aureus Staphylococcus epidermidis Staphylococcus haemolyticus Staphylococcus hominis Staphylococcus saprophyticus Staphylococcus warneri Stteptococcus spp Streptococcus agalactiae Streptococcus constellatus ssp pharyngis Streptococcus dysgalactiae ssp equisimilis Streptococcus mitis Streptococcus salivarius ssp salivarius Streptococcus sanguinis Total

Number 2 7 1 1 15 1 2 1 3 3 2 3 1 9 4 55 9 828 34 6 87 3 4 21 4 24 1 2 2 1 1 4 23 3 1 6 1 2 26 1 2 3 1 1 1211

Percent (%) 0.17 0.58 0.08 0.08 1.24 0.08 0.17 0.08 0.25 0.25 0.17 0.25 0.08 0.74 0.33 4.5 0.74 68.4 2.8 0.5 7.2 0.25 0.33 1.73 0.33 1.2 0.08 0.17 0.17 0.08 0.08 0.33 1.9 0.25 0.08 0.5 0.08 0.17 2.15 0.08 0.17 0.25 0.08 0.08 100

Amikacin Amoxicillin/Clavulanic Acid Amphotericin B Ampicillin Ampicillin/Sulbactam Aztreonam Benzylpenicillin Caspofungin Cefalexin Cefepime Cefixime Cefotaxime Cefoxitin Ceftazidime Ceftriaxone Cefuroxime Cefuroxime Axetil Chloramphenicol Ciprofloxacin Clindamycin Colistin Daptomycin Ertapenem Erythromycin Fluconazole Flucytosine Fosfomycin Fusidic Acid Gentamicin Imipenem Levofloxacin Linezolid Meropenem Micafungin Moxifloxacin Netilmicin Nitrofurantoin Oxacillin Piperacillin Piperacillin/Tazobactam Rifampicin Teicoplanin Tetracycline Tigecycline Tobramycin Trimethoprim/Sulfamethoxazole Vancomycin Vorikonazol

719 13 15 362 69 5 29 17 5 25 574 14 24 625 609 561 557 4 698 35 37 53 865 21 17 17 847 12 835 873 46 130 891 17 17 18 798 23 15 682 0 92 28 113 26 677 128 16

Low Resistant Total Percent sensitive (%) 178 15 912 1.6 1 7 21 33.3 0 0 15 0 2 588 952 61.8 0 15 84 17.9 18 4 27 14.8 5 3 37 8.1 0 1 15 5.6 0 26 31 83.9 1 3 29 10.3 0 300 874 34.3 0 1 5 6.7 769 82 875 9.4 68 218 911 23.9 26 254 889 28.6 0 316 877 36 0 319 876 36.4 0 0 4 0 46 271 1015 26.7 0 10 45 22.2 0 0 37 0 0 3 56 5.4 2 10 877 1.14 0 17 38 44.7 0 1 18 5.6 1 18 36 0 0 59 906 6.5 0 26 38 68.4 5 111 951 11.7 24 14 911 1.5 1 35 82 42.7 0 2 132 1.5 14 8 913 0.88 0 1 18 5.6 0 4 21 19 0 14 32 43.8 1 75 874 8.6 0 15 38 39.5 2 10 27 37 96 124 902 13.7 4 0 4 0 0 8 100 8 0 13 41 31.7 4 0 117 0 0 16 42 18.8 35 310 1022 30.3 0 4 132 3 0 0 16 0

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DISCUSSION

Bacteria are the most common etiology of UTIs, accounting for more than 95% of cases. E. coli is the most common causal organism of UTIs and is responsible for more than 80% of them (11). Wright et al. reported that the rate of E. coli in urine cultures was 67% (12). Another study conducted by Akbas et al. revealed that the rate of E. coli in urine cultures was 35-80% (13). In our study, we found the rate of E. coli to be 68.4% and this rate is consistent with other studies. Microorganisms and antibiotic susceptibilities isolated from urine cultures may differ among countries due to usage of different agents and multifactorial causes. In our study, a serious resistance to Cefalexin, which is one of the most common antibiotics used for the treatment of UTIs, is observed. In a study published in 2019, Shrestha et al. reported a 60% resistance to Cefalexin (14). Ganesh and colleagues also reported 94.1% resistance to Cefalexin in their study in the same year (15). In our study, antibiotic resistance rate to Cefalexin was found to be 83.9%. All three studies point out that the rate of antibiotic resistance to Cefalexin is high. Zhanel et al. reported a resistance rate of Ampicillin to 37.7% in 2006 (16). Bryce et al. found the resistance rate to Ampicillin as 60.3% in 2016 (17). In our study, the resistance rate to Ampicillin was found to be 61.8%. Antibiotics prescribed for UTIs, most of which are caused by E. coli, have a high prevalence of resistance. When we look at the studies conducted worldwide, we found that Ampicillin resistance rate is the highest and Nitrofurantoin resistance rate is at very low levels. In our study, we found the Nitrofurantoin resistance rate to be 8.6%.

CONCLUSIONS

Empirical antibiotic selection against E. coli, which is the most frequently isolated microorganism in urine cultures of patients with suspected UTI, was highly resistant to most of the antibiotics that are frequently preferred. We think that empirical antibiotic selection in cases of UTI should not be overlooked and that such studies should be repeated frequently to carry out current antibiotic susceptibilities.

7. Sucu N, Aktoz-Boz G, Bayraktar Ö, et al. Üropatojen Escherichia coli suslarının antibiyotik duyarlılıklarının yıllar içerisindeki degisimi. Klimik Dergisi. 2004; 17:128. 8. Kehinde A, Adedapo K, Aimakhu C, et al. Urinary pathogens and drug susceptibility patterns of urinary tract infections among antenatal clinic attendees in Ibadan, Nigeria. J Obstet Gynaecol Res. 2012; 38:280. 9. Gardiner BJ, Stewardson AJ, Abbott IJ, Peleg AY. Nitrofurantoin and fosfomycin for resistant urinary tract infections: old drugs for emerging problems. Aust Prescr. 2019; 42:14. 10. Perletti G, Magri V, Cai T, et al. Resistance of uropathogens to antibacterial agents: Emerging threats, trends and treatments. Arch Ital Urol Androl. 2018; 90:85. 11. Nachimuthu R, Chettipalayam S, Velramar B, et al. Urinary tract infection and antimicrobial susceptibility pattern of extended spectrum beta lactamase producing clinical isolates. Adv Biol Res. 2008; 2:78. 12. Wright SW, Wrenn KD, Haynes ML. Trimethoprim-sulfamethoxazole resistance among urinary coliform isolates. Int J Gen Med. 1999; 14:606. 13. Akbas E, Zarakolu P, Aktepe OC, et al. !drar yolu enfeksiyonu ön tanısı ile basvuran olgularda idrar örneklerinin mikrobiyolojik olarak degerlendirilmesi: !ki yıllık bir çalısma. Mikrobiyoloji Bülteni. 1997; 31:351. 14. Shrestha LB, Baral R, Poudel P, Khanal B. Clinical, etiological and antimicrobial susceptibility profile of pediatric urinary tract infections in a tertiary care hospital of Nepal. BMC Pediatr. 2019; 19:36. 15. Ganesh R, Shrestha D, Bhattachan B, Rai G. Epidemiology of urinary tract infection and antimicrobial resistance in a pediatric hospital in Nepal. BMC Infect Dis. 2019; 19:420. 16. Zhanel GG, Hisanaga TL, Laing NM, et al. Antibiotic resistance in Escherichia coli outpatient urinary isolates: final results from the North American Urinary Tract Infection Collaborative Alliance (NAUTICA). Int J Antimicrob Agents. 2006; 27:468. 17. Bryce A, Hay AD, Lane IF, et al. Global prevalence of antibiotic resistance in paediatric urinary tract infections caused by Escherichia coli and association with routine use of antibiotics in primary care: systematic review and meta-analysis. BMJ. 2016; 352; i939.

REFERENCES

1. Ibrahim ME, Bilal NE, Hamid ME. Increased multi-drug resistant Escherichia coli from hospitals in Khartoum state, Sudan. Afr Health Sci. 2012; 12:368. 2. Tiruneh M, Yifru S, Gizachew M, et al. Changing trends in prevalence and antibiotics resistance of uropathogens in patients attending the Gondar University Hospital, Northwest Ethiopia. Int J Bacteriol. 2014; 2014:629424. 3. Saraçoglu KT, Fidan V, Pekel Ö, et al. !drar kültürlerinde izole edilen bakterilerin antibiyotik duyarlılıkları. J of Clin and Exp Inv. 2013; 4:356. 4. Kadanalı A. Üriner sistem infeksiyonları. Eurasian J Med. 2006; 38:119. 5. Foxman, B. The epidemiology of urinary tract infection. Nat Rev Urol. 2010; 7:653. 6. Minardi D, d’Anzeo G, Cantoro D, et al. Urinary tract infections in women: etiology and treatment options. Int J Gen Med. 2011; 4:333.

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Correspondence Abdullah Gul, MD dr_abdullahgul@hotmail.com Bursa Training and Research Hospital Floor 2, 16310 Bursa (Turkey) ORCID 0000-0003-4002-4659 Esra Gurbuz, MD dr.inanhazan@gmail.com Kelkit State Hospital, Department of Infectious Diseases and Clinical Microbiology, Gumushane (Turkey)

DOI: 10.4081/aiua.2020.2.149

ORIGINAL PAPER

Comparison of the efficiency, safety and pain scores of holmium laser devices working with 20 watt and 30 watt using in retrograde intrarenal surgery: One center prospective study Sercan Sari 1, Mehmet Çağlar Çakici 2, İbrahim Güven Kartal 2, Volkan Selmï 1, Harun Özdemïr 3, Hakkı Ugur Ozok 4, Ahmet Nihat Karakoyunlu 2, Serkan Yildiz 5, Emre Hepşen 6, Serra Ozbal 7, Hamit Ersoy 2 1 Bozok

University, Department of Urology,Yozgat, Turkey; of Health Sciences, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Department of Urology, Ankara, Turkey; 3 University of Health Sciences, Haseki Training and Research Hospital, Istanbul, Turkey; 4 Karabuk Unıversity, Department of Urology, Karabuk, Turkey; 5 Siirt State Hospital, Department of Urology, Siirt, Turkey; 6 Çubuk State Hospital,Department of Urology, Ankara,Turkey; 7 University of Health Sciences, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Department of Radiology, Ankara, Turkey. 2 University

Summary

Objectives: Holmium:Yttrium Aluminum Garnet laser lithotripsy is used in Retrograde Intrarenal Surgery. Fragmentation is made with a certain value of pulse energy (Joule) and frequency (Hertz) in Holmium laser lithotripsy and the multiplication of these values gives us total power (Watt). Devices with maximum power of 20 Watt and 30 Watt are used in clinical practice. We want to compare the efficiency, safety and pain scores of the lithotripsy made below 20 Watt and over 30 Watt with 30 Watt laser device. Materials and methods: 60 patients who had 2-3 cm sized kidney stones and operation planned were prospectively divided into three groups. Groups were random identified. In the first group, fragmentation was performed below 20 Watt power with 20 Watt laser device. In the second group, fragmentation was performed below 20 Watt power with 30 Watt laser device. In the third group, fragmentation was performed over 20 Watt power with 30 Watt laser device. Demographic, stone, intraoperative and postoperative data were recorded. We compared these groups regarding efficiency, safety and pain score. Results: For demographic and stone data, there was a statistically significant difference only for stone number. For intraoperative and postoperative data, there was a statistically significant difference only for ureteral access sheath usage between the groups. Success was lower than the other groups in Group 1. Conclusions: Success was higher in groups using 30 Watt laser device. There was not statistically significantly difference between complications and pain. 30 Watt laser device is safe and efficient in Retrograde Intrarenal Surgery.

KEY WORDS: Comparison; Efficiency; Kidney stone; Pain; Safety; Watt. Submitted 16 December 2019; Accepted 23 Decembe 2019

INTRODUCTION

The increasing incidence of kidney stone disease caused the increasing number of lithotripsy in urology clinics (1). Retrograde intrarenal surgery (RIRS) is a new method. Its usage recently widened with advances of technology (2). Holmium:Yttrium Aluminum Garnet

149

(Ho:YAG) laser lithotripsy is a lithotripsy method used in RIRS. Ho:YAG laser lithotripsy fragments stone with the photothermal mechanism (3). In Ho:YAG laser lithotripsy fragmentation is made with a certain value of pulse energy (Joule/J) and frequency (Hertz/Hz.). The multiplication of these values gives us total power (Watt/W). In clinical practice, the device with the maximum power of 20 W was at first available. Recently the device with maximum power of 30 W has been used. In our study, we used these two devices. We want to compare efficiency, safety and pain scores of the lithotripsy made below 20 W and over 30 W with 30 W laser device.

MATERIALS

AND METHODS

After receiving local ethical board approval, a randomized prospective study was planned. Study was recorded into National Clinical Trials (NCT) and NCT code was taken (NCT 02443909). Sixty patients who had 2-3 cm sized kidney stones and for whom RIRS was planned were divided into three groups. Groups were random identified. Informed consent was obtained from all individual participants included in the study. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Blood count, biochemical tests, coagulation tests, urine analysis, urine culture, kidney ureter bladder Xgraphy (KUBG), urinary system ultrasonography (US), computerized tomography (CT) were preoperatively performed. Patients age, gender, body mass index (BMI), history of shock wave lithotripsy (SWL), American Society of Anesthesiologists (ASA) score, previous stone surgery history, preoperative double J stent (JJ) history, anticoagulant usage, kidney anomaly, stone laterality, stone number, stone size and stone localization were recorded. No conflict of interest declared.

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Preoperative urine culture was sterile ative controls, were evaluated as successful. We comPatients were taken Dexketoprofen Trometamol twice a pared groups regarding efficiency, safety and pain score. day as the analgesic and anti-inflammatory treatment after the operation. Visual analogue scale (VAS) was filled Statistical analysis at postoperative eighth hours by patients. Patients Analysis was made with SPSS for Windows 16.0 package marked the value equal to his/her pain in the VAS. The program. Normality of numerical measurement values marked value was recorded. Intraoperative operation distributions was at first researched. One-Sample time, scopy time, postoperative JJ stent rate, ureteral Kolmogorov-Smirnov test was used to determine the disaccess sheath (UAS) usage, hospitalization time and comtributions of parameters except for age, BMI and operaplications were recorded. Complications were evaluated tion time. The distributions were not normal (p < 0.05). according to modified Clavien and Dindo classification. Kruskal Wallis test was used to determine whether there The patients who had kidney anomalies, were < 18 years was difference between two groups for gender, ASA old, had urinary system infections in the preoperative score, stone laterality, stone localization, stone number, evaluations were excluded from the study. The patients stone size, UAS usage, postoperative JJ stent usage, residwere divided into three groups. In the first group, fragual stone, scopy time, previous stone surgery history, mentation was performed below 20 W power with 20 W SWL history, intraoperative and postoperative complicalaser device. In the second group, fragmentation was tions, anticoagulant usage and VAS score. In the patients performed below 20 W power with 30 W laser device. In with statistically significant differences in Kruskal Wallis the third group, fragmentation was performed over 20 W test, to determine from which group the difference origpower with 30 W laser device. We used dusting and inated in the analyze, Mann-Whitney U test was used to fragmentation methods in our study. perform dual comparisons. One-Way Anova test was Preoperative antibiotic was administered to all patients. performed to determine whether there was a statistical RIRS was performed under general anesthesia with 7.5 difference between the groups for age, BMI and operaFrench (Fr) flexible renoscope (Flex-X2; Karl Storz, tion time. P < 0.05 value was accepted as statistically sigTutlingen, Germany). After general anesthesia in modified nificant for results. supine position, the patient was taken to modified dorsal lithotomy position. Semi-rigid ureterorenoscope was applied into the ureter under fluoroscopic control and RESULTS 0.035/0.038 inch hydrophilic safety wire was placed into When we look at demographic and stone data, there was the ureter under fluoroscopic control. Semi-rigid no statistically significant difference for the parameters ureterorenoscopy was performed. In case of semirigid age, gender, BMI, ASA, SWL history, previous stone surureterorenoscopy failure due to ureteral stricture, JJ stent gery history, anticoagulant usage, preoperative JJ stent, was placed and the operation ended. After semirigid stone laterality, stone size and stone localization between ureterorenoscopy, 9.5-11.5 Fr or 11-13 Fr access sheath the groups. There was a statistically significant difference (Elit Flex, Ankara, Turkey) was placed into the ureter up for stone number (p = 0.036) (Table 1). to the ureteropelvic junction under fluoroscopic control. When we evaluate intraoperative and postoperative data, Then flexible renoscope was placed through the UAS to there was no statistically significant difference for operaprovide access to the kidney. When access sheath was tion time, scopy time, postoperative JJ stent usage and not placed, flexible renoscope was moved via safety wire hospitalization time. There was a statistically significant to access the kidney. Fragmentation was performed via 200 mm: Yttrium Table 1. Aluminum Garnet laser probe (Dornier Demographic and stone characteristics. Medilas H20 and HSolvo; Medtech, Group 1 (n = 20) Group 2 (n = 20) Group 3 (n = 20) p Munich, Germany) after the stone had Age (years) ( ± SD) 51.15 ± 12.58 47.75 ± 14.26 54.45 ± 14.45 0.315 been reached. In Group 1 and 2, 8-10 Gender (M/F) (n) 8/12 14/6 12/8 0.154 Hz. frequency and 1.2-1.8 J pulse enerBMI (kg/m2) ( ± SD) 28.57 ± 4.43 28.12 ± 4.60 26.42 ± 3.97 0.265 gy were used. In Group 3, 10-12 Hz. ASA mean (n) 1.551 1.3525 1.671 0.409 frequency and 2-3 J pulse energy were SWL history (n, %) 5 (25) 2 (10) 3 (15) 0.438 used. We used dusting and fragmentaPrevious surgery history (n, %) 9 (45) 5 (25) 5 (25) 0.298 tion methods. All calices were explored Anticoagulant usage (n, %) 1 (5) 0 0 0.368 with flexible renoscope at the end of Preoperative JJ stent (n, %) 8 (40) 2 (10) 5 (25) 0.094 operation under fluoroscopic control. Stone laterality (R/L) (n) 9/11 7/13 7/13 0.758 JJ stent was placed into the ureter due Stone number (n) ( ± SD) 1.85 ± 0.48 2.20 ± 0.89 1.75 ± 1.41 0.036 to intraoperative conditions. JJ stent Stone size (mm) (± SD) 22.30 ± 3.21 22.60 ± 3.33 23.90 ± 4.09 0.56 was taken three weeks later with an Stone localization (n, %) 0.55 outpatient procedure. Upper calyx (n, %) 1 (5) 1 (5) 1 (5) KUBG and US were performed on postLower calyx (n, %) 6 (30) 6 (30) 5 (25) operative first day. CT was performed Mid calyx (n, %) 0 0 2 (10) at postoperative third month. Patients Pelvis (n, %) 2 (10) 3 (15) 8 (40) who were stone free or had clinically Multicaliceal (n, %) 11 (55) 10 (50) 4 (20) insignificant residual fragment (< 2 M/F: Male/female; BMI: Body Mass Index; ASA: American Society of Anesthesiologists; JJ: Double J; SWL: Shock Wave Lithotripsy. mm) after intraoperative and postoperArchivio Italiano di Urologia e Andrologia 2020; 92, 2

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S. Sari, M. Çağlar Çakici, İ. Güven Kartal, V. Selmï, H. Özdemïr, H. Ugur Ozok, A. Nihat Karakoyunlu, S. Yildiz, E. Hepşen, S. Ozbal, H. Ersoy

Table 1. !ntraoperative and Postoperative Data.

(5-7). These are in vitro studies. Human stones or stone-like material were used in these studies. In the same power setGroup 1 (n = 20) Group 2 (n = 20) Group 3 (n = 20) p tings, low frequency/high pulse energy Average Operation Time (min.) ( ± SD) 52.40 ± 21.29 61.45 ± 21.60 52 ± 18.23 0.263 and high frequency/low pulse energy Average Scopy Time (Sc.) (± SD) 57.05 ± 74.40 35.85 ± 24.13 32.50 ± 21.13 0.57 were compared in these studies. In the Postoperative JJ stent, n (%) 19 (95) 20 (100) 19 (95) 0.368 same power settings, the low-frequency Uretheral Access Sheath Usage, n (%) 14 (70) 20 (100) 19 (95) 0.007 high pulse energy is more effective. Average Hospitalisation Time (± SD) (day) 1 1 1 1 There are studies that report pulse enerSuccess, (n) (%) 7 (35) 16 (80) 15 (75) 0.006 gy is the major variable affecting fragStone-free 7 (35) 16 (80) 15 (75) mentation efficiency (6). Total fragmenResidual fragment (< 3 mm) 0 0 0 tation increases as pulse energy increase 13 (65) 4 (20) 5 (25) Residual fragment (≥ 3 mm) (6). The increase of pulse energy proVAS Score (point) (± SD) 3.30 ± 2.15 2.20 ± 1.61 2.60 ± 1.23 0.409 vides fast fragmentation but produces Complication rate, n (%) 5 (25) 8 (40) 4 (20) 0.35 larger fragments (6). Retropulsion Intraoperative complication 3 (15) 5 (25) 1 (5) 0.214 increases due to the increase of pulse Mucosal Injury, n (%) 1 (5) 1(5) 0 energy (7-10). As retropulsion increases, Bleeding, n (%) 1 (5) 3 (15) 0 the distance between fiber tip and stone Malfunctioning or breakage of instruments, n(%) 1 (5) 1(5) 0 decreases (7) and the energy applied to Perforation, n (%) 0 0 1 (5) the stone decreases (11), so retropulsion Postoperative complication 2 (10) 6 (30) 3 (15) decreases fragmentation efficiency (9). Fever (Clavien I), n (%) 1 (5) 2 (10) 2 (10) Also, the high pulse energy is associated Bleeding (Clavien I), n (%) 0 3 (15) 0 with fiber tip malfunctioning and this Urinary Tract Infection (Clavien II), n (%) 1 (5) 1(5) 0 causes low efficiency (6, 12). Steinstrasse (Clavien IIIb), n (%) 0 0 1 (5) When we look at literature, fragmentaMin: Minutes; Sec: Seconds; JJ: Double J ; VAS: Visuel Analog Scale. tion speed increases as total power increases. There are studies about low difference for UAS usage between the groups. There was power settings (13). In a study, shorter lithotripsy time no statistically insignificant difference between the was reported by high power settings (2.8 J and 15 Hz.), groups for VAS score (Table 2). but there was not a comparison (14). In our study, we When we look at success, in Group 1 seven patients, in aimed to compare the efficiency, safety and pain score of Group 2 sixteen patients, and in Group 3 fifteen patients the lithotripsy under 20 W and over 20 W power with two were stone free. The difference was statistically significant different laser devices in the same sized stones. (p = 0.006). In Group 1 the operation was unsuccessful in When we look at demographic and stone characteristics, one patient due to malfunctioning of the device, in four there was no statistically significant difference between patients due to ureteral stricture and in eight patients due the groups except the stone number. When we look at to inability to reach the stone. In Group 2, the operation the operation data, there was statistically significant difwas unsuccessful in one patient due to the malfunctioning ference between the groups for UAS usage rate and sucof the device, in three patients due to inability to reach the cess. In group 1, UAS usage rate was lower than the stone. In Group 3, the operation was unsuccessful due to other groups, that may explaun the higher number of ureteral stricture in one patient, in two patients due to ureteral stricture observed in Group 1. inability to reach the stone and in two patients due to When success was evaluated, it was lower than the other stone burden. There was not clinically insignificant residgroups in Group 1. The inability to reach the stone was ual fragment in any group (Table 2). seen in 8 patients for group 1, three patients for group 2 Complications were seen in five patients for Group 1, and two patients for group 3. The lower caliceal stone eight patients for Group 2 and four patients for Group 3 rates were similar between the groups. Multicaliceal stones (p = 0.35). Intraoperative complications were seen in rate was higher in group 1 and 2 than group 3. Failure due three patients for Group 1, five patients for Group 2 and to ureter stricture was higher in group 1 than the other one patient for Group 3 (p = 0.214). Postoperative comgroups. This result can explain the lower success rate in plications were seen in two patients for Group 1, six group 1. Success was higher in the group in which 30 W patients for Group 2 and three patients for Group 3. laser device was used. The success rate was similar with Bleeding was the intraoperative and postoperative assoliterature except for group 1. In group 1, due to ureter ciated complication in Group 2 (Table 2). stricture and multicaliceal stones, success was lower. In our study, first operation success was evaluated. Success reached 90-95% after repeating operations in all DISCUSSION groups. RIRS is a method of increasing use in kidney stone treatThere was no statistically significant difference between ment (4). Ho:YAG laser is used in RIRS. A certain value of the groups for complications. The increasing pulse energy frequency (Hz.) and pulse energy (J) are used in Ho:YAG produces larger fragments (6), so larger residual fragments laser lithotripsy. The multiplication of these values give us were seen in group 3. Also, steinstrasse was seen in one power (W). There are studies to determine optimum patient of group 3. Operation time was lower in group 3 power settings in Ho:YAG laser lithotripsy in the literature than group 2 due to increasing pulse energy. Operation

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time was similar between group 1 and 3. Due to the high number of unsuccessful patients in group 1, operation time was lower in group 1. The complication rate is higher in our study when we compared it with literature data. The fewer patient number may explain this result, therefore studies with larger patient number are needed. There was not a statistically significant difference between the groups for VAS score. There are few studies evaluating pain in the literature. Shoshtari et al. reported the main cause of admission to the hospital was pain (15). Singh et al. reported that patients undergoing RIRS had more pain than patients undergoing SWL at postoperative first and second day (16). Oguz et al. reported that female gender, stone size and UAS duration time in ureter were statistically significant factors affecting pain (17). In a review researching the effect of female gender on pain scores, Tighe et al. observed that postoperative pain scores at first day were higher in females (18). Although there are studies that report postoperative JJ stent decreases postoperative pain significantly, other studies report that JJ stent increases postoperative pain (19). In our study, postoperative JJ stent rate was similar between the groups. A limitation of our study was the absence of stone analysis. In a study, comparing Ho:YAG laser settings, different types stones or stone-like materials were used in vitro (5-7). Another limiting factor was the type of laser fiber used. A study reported that fragmentation changed due to use of different laser fiber types (6). The same laser fiber was used in three groups. Patient number is another limiting factor because larger patient number studies are needed.

CONCLUSIONS

For Ho:YAG laser lithotripsy in RIRS, success was higher in groups using 30 W laser device. There was not statistically significantly difference between complication and pain rates. 30 W laser device is safe and efficient in RIRS.

REFERENCES

1. Scales CD, Smith AC, Hanley JM, Saigal CS. Prevalence of kidney stones in the United States. Eur Urol. 2012; 62:160-165. 2. Wendt NG, Mut T, Krombach P, et al. Do new generation flexible ureterorenoscopes offer a higher treatment success than their predecessors? Urol Res. 2011; 39:185-8. 3-Vassar GJ, Chan KF, Teichman JMH, et al. Holmium:YAG lithotripsy:Photothermal mechanism. J Endourol. 1999; 13:181-190. 4. Schoenthaler M, Wilhelm K, Katzenwadel A, et al. Retrograde intrarenal surgery in treatment of nephrolithiasis: is a 100% stonefree rate achievable? J Endourol. 2012; 26:489-93. 5. Kronenberg P, Traxer O. In vitro fragmentation efficiency of holmium: yttrium-aluminum-garnet (YAG) laser lithotripsy – a comprehensive study encompassing different frequencies, pulse energies, total power levels and laser fibre diameters. BJU Int. 2014; 114:261-267. 6. Spore SS, Teichman JM, Corbin NS, et al. Holmium:YAG lithotripsy:optimal power settings. J Endourol. 1999; 13:559.12. 7. Sea J, Jonat LM, Chew BH, et al. Optimal Power Settings for Holmium:YAG Lithotripsy. J Urol. 2012; 187:914-9.

8. Lee H, Ryan RT, Teichman JM, et al. Stone retropulsion during holmium:YAG lithotripsy. J Urol. 2003; 169:881. 9. Finley DS, Petersen J, Abdelshehid C, et al. Effect of holmium:YAG laser pulse width on lithotripsy retropulsion in vitro. J Endourol. 2005; 19:1041. 10. Kang HW, Lee H, Teichman JM, et al. Dependence of calculus retropulsion on pulse duration during Ho:YAG laser lithotripsy. Lasers Surg Med. 2006; 38:762. 11. Jansen ED, van Leeuwen TG, Motamedi M, et al. Temperature dependency of the absorption coefficient of water for mid-infrared laser irradiation. Laser Surg Med. 1994; 14:258. 12.Vassar GJ, Teichman JMH, Glickman RD. Holmium:YAG lithotripsy efficiency varies with energy density. J Urol. 1998; 160:471. 13. Razvi HA, Densted JD, Chun SS, Sales SL. Intracorporeal lithotripsy with the holmium:YAG laser. J Urol. 1996; 156:912-914. 14. Gould DL. Holmium:YAG laser and its use in the treatment of urolithiasis: Our first 160 cases. J Endourol. 1998; 12:23-26. 15. Zargar SK, Anderson W, Rice M. Role of emergency ureteroscopy in the management of ureteric stones: analysis of 394 cases. BJU Int. 2015; 115:946-50. 16. Singh BP, Prakash J, Sankhwar SN, et al. Retrograde intrarenal surgery vs extracorporeal shock wave lithotripsy for intermediate size inferior pole calculi: a prospective assessment of objective and subjective outcomes. Urology. 2014; 83:1016-22. 17. Oguz U, Sahin T, Senocak Ç, et al. Factors associated with postoperative pain after retrograde intrarenal surgery for kidney stones.Turk J Urol. 2017; 43:303-308. 18. Tighe PJ, Riley JL, 3rd, Fillingim RB. Sex differences in the incidence of severe pain events following surgery: a review of 333,000 pain scores. Pain Med. 2014; 15:1390-404. 19. Mustafa M. The role of stenting in relieving loin pain following ureteroscopic stone therapy for persisting renal colic with hydronephrosis. Int Urol Nephrol. 2007; 39:91-4. Correspondence Sercan Sari, MD - sercansari92@hotmail.com Volkan Selmi, MD - volkanselmi@hotmail.com Bozok University, Department of Urology, Yozgat (Turkey) Mehmet Caglar Cakici, MD - mcaglarcakici@hotmail.com ! brahim Güven Kartal, MD - igk84@hotmail.com Ahmet Nihat Karakoyunlu, MD - nkarakoyunlu@gmail.com Hamit Ersoy, MD - hamitersoy@gmail.com University of Health Sciences, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Department of Urology, Ankara (Turkey) Harun Özdemir, MD - dr.harun-17@hotmail.com University of Health Sciences, Haseki Training and Research Hospital, Istanbul (Turkey) Hakkı Ugur Ozok, MD - drozok@gmail.com Karabuk Unıversity, Department of Urology, Karabuk (Turkey) Serkan Yildiz, MD - s_yildiz55@yahoo.com Siirt State Hospital, Department of Urology, Siirt (Turkey) Emre Hepsen, MD - emreepsen@hotmail.com Çubuk State Hospital,Department of Urology, Ankara (Turkey) Serra Ozbal, MD - sozbal@gmail.com University of Health Sciences, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Department of Radiology, Ankara (Turkey)

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DOI: 10.4081/aiua.2020.2.153

ORIGINAL PAPER

Protective effect of chlorogenic acid on renal ischemia/reperfusion injury in rats Tuncay Toprak 1, Cagri Akin Sekerci 2, Hasan Riza Aydın 3, Mehmet Akif Ramazanoglu 4, Fatma Demet Arslan 5, Banu Isbilen Basok 5, Hatice Kucuk 6, Huseyin Kocakgol 3, Hamit Zafer Aksoy 3, Seyhan Sumeyra Asci 7, Yılören Tanıdır 8 1 Fatih

Sultan Mehmet Training and Research Hospital, Urology, Istanbul; University Pendik Training and Research Hospital, Pediatric Urology, Istanbul; 3 Kanuni Training and Research Hospital, Urology, Trabzon; 4 Rize State Hospital, Urology, Rize; 5 Tepecik Training and Research Hospital, Biochemistry, Izmir; 6 Kanuni Training and Research Hospital, Pathology, Trabzon; 7 Kanuni Training and Research Hospital, Anesthesiology and Reanimation, Trabzon, Turkey; 8 Marmara University, School of Medicine, Urology Istanbul, Turkey. 2 Marmara

Summary

Objectives: Ischemia/reperfusion (I/R) injury is a common cause of renal injury and to date, many pharmacological agents have been identified to decrease I/R injury. One of the potential compound that can target I/R injury is chlorogenic acid (CGA). It has potent antiinflammatory, antibacterial, anti-oxidant, analgesic and antipyretic activities in in vitro experiments and in vivo animal models. The aim of the study was to investigate the protective characteristic of CGA on renal I/R injury. Material and Methods: 24 rats were randomly allocated to three groups (n = 8): Sham, I/R+CGA and I/R groups. CGA was administered intraperitoneally at a dose of 20 mg/kg, 10 min before reperfusion. I/R injury was achieved by clamping the left renal artery for 45 minutes, followed by reperfusion for 4 hours. The left kidneys of the rats were examined for tissue damage by histopathological and biochemical examination. For histological evaluation, EGTI scoring system was used. For biochemical examination total oxidant status, total antioxidant status and oxidative stress index were used. The power analysis indicated that 8 subjects per group would be required to produce 80% chance of achieving statistical significance at p < 0.05 level. The results are expressed as mean ± SD. MannWhitney U was performed for statistical analysis. Results: Histopathological examination of the tissue damage revealed that all kidneys in the sham group were normal. I-R group had significantly higher histopathological scores than other groups. Histopathological improvement was seen after CGA treatment. TAS, TOS and OSI values of I-R group were significantly higher than sham group (0.88 vs 0.76 (p: 0.004), 13.8 vs 7.04 (p: 0.021) and 0.15 vs 0.09 (p: 0.034), respectively). In CGA treated group TAS, TOS and OSI levels were 0.84, 6.47 and 0.07, respectively. CGA treatment resulted in significant improvement in TOS and OSI parameters. Conclusions: CGA treatment provided marked improvement in renal histology and suppressed oxidative stress. Thus, CGA may have a protective effect in renal tissue against I/R injury.

KEY WORDS: Renal ischemia; Oxidative stress; Chlorogenic acid; Rat. Submitted 29 November 2019; Accepted 12 December 2019

INTRODUCTION

Ischemia/reperfusion (I/R) injury is a common cause of renal injury arising from a variety of clinical circumstances, including partial nephrectomy, renal transplan-

tation, iatrogenic trauma, sepsis and shock (1, 2). It is characterized by restriction of the blood flow, followed by restoring the blood flow and oxygenation. Cessation of blood flow causes ischemia and tissue damage. Restoration of blood flow during reperfusion period, often leads to exacerbation of these harmful events instead of improving (3). The pathologic processes underlying this injury are complex and include interactions between the endothelium, cell death programs and immune system (4). Reactive oxygen radicals (ROR), necrosis, apoptosis, and inflammation plays a role in this process but the exact mechanisms remain unclear (5, 6). The production of ROR is considered a key reason for oxidative stress during the reperfusion period (6). Thus, targeting oxidative stress’ processes is an ideal therapeutic approach. I/R injury in renal transplantation often leads to allograft dysfunction and increased rejection (7). In partial nephrectomy, renal tissue damage may occur due to clamping of renal arteries (8). In the clinical scenario, renal I/R models generated in animals are important to understand the pathophysiology of renal injury and the potential treatment options. To date, many pharmacological agents such as N-acetylcysteine (9), Allopurinol (10) or Mannitol (11) have been identified to decrease I/R injury after nephron sparing surgery. To prevent the kidney damage due to I/R injury, several anti-inflammatories and antioxidants have been used in experimental studies (12-14). Another potential compound that can target I/R injury is chlorogenic acid (CGA). It is formed by esterification of quinic and caffeic acids and it is one of the polyphenols abundant in the human diet (15). It has potent anti-inflammatory, antibacterial, anti-oxidant, analgesic and antipyretic activities in in vitro experiments and in vivo animal models (16-18). Thus, we investigate protective effects of CGA against renal I/R injury in an in vivo rat model which may potentially help us in urological surgeries such as partial nephrectomy and renal transplantation where clamping is required. To examine this, we evaluated histopathological findings and biochemical analyses (including

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total oxidant (TOS) status, total antioxidant (TAS) assays). In our knowledge, there have been no studies concerning the protective effect of CGA against renal I/R injury.

were sutured. The rats were sacrificed 4 h after completion of the reperfusion and the left kidneys were removed and stored for biochemical and histopathological examination under favorable conditions.

MATERIALS

Histological analysis Removed kidney was fixed with 10% formalin and embedded in paraffin. 5 μm tissue sections obtained for Hematoxylin and Eosin staining. An experienced, independent pathologist, who was blinded to the groups, analyzed three different tissue sections in each group, using a Zeiss Axio Imager A2 microscope (Carl Zeiss AG, Germany). The histological evaluations of the renal tissue were graded as described in the study of Medeiros et al. (20) (Table 1). The scores were applied to microscopic changes consistent with tubular necrosis: vacuolization of tubular cells, tubular lumen dilation, intra-tubular cylinders, interstitial fibrosis and tubular cell necrosis. For histological evaluation, EGTI scoring system, which was developed especially for animal studies in kidney tissues in the context of injury, was also used (21), (Table 2). This system consists of histological damage in 4 separate components: Endothelial, Glomerular, Tubular, and Interstitial.

AND METHODS

The experimental and surgical procedures were conducted according to routine animal care guidelines, and the Guide for the Care and Use of Laboratory Animals (19). The approval was obtained from Institutional Animal Care and Use Committee of Karadeniz Technical University (Trabzon, Turkey) (Approval Number/ID: 2019/5). 24 male Sprague-Dawley rats (8 weeks old, weight 230-300 g) were purchased from the Karadeniz Technical University Laboratory Animals Research Centre (Trabzon, Turkey). All animals were kept in captivity under the same nutritional and environmental conditions. Rats were entrained under a 12:12 h dark: light cycle (lights on 6 am-6 pm) with stable temperature (21 ± 2°C) and humidity (60 ± 5%). The rats had sterile water and food available ad libitum. Experimental design Rats were randomly and equally divided into 3 groups; 1. Vehicle- treated ischemic (I/R): After sterile conditions were obtained, a midline laparotomy was performed. Isotonic saline (1 mg/kg) was applied intraperitoneally 10 min before the beginning of reperfusion. The left kidney pedicle was clamped with an artery clamp for 45 minutes. After 45 minutes of left renal ischemia, the occlusion clamp was removed for reperfusion for 4 hours and the incision was closed. 2. Vehicle- treated sham (Sham): Rats underwent the same surgical procedures except unilateral renal occlusion. During the experiment, they were kept under anesthesia with gauze, soaked in saline in the abdominal cavities. 3. CGA-treated ischemic (I/R+CGA): After sterile conditions were obtained, a midline laparotomy was performed. CGA (Sigma-Aldrich) (20 mg/kg) was applied intraperitoneally 10 min before the beginning of reperfusion. The left kidney pedicle was clamped with an artery clamp for 45 minutes. After 45 minutes of left renal ischemia, the occlusion clamp was removed and the incision was closed. Administration of CGA CGA was dissolved in saline (vehicle) and administered intraperitoneally at a total dose of 20 mg/kg 10 minutes before reperfusion. Surgical procedure For anesthetic ketamine hydrochloride (100 mg/kg, Ketalar, Eczacıbasi, Turkey) and xylazine (10 mg/kg) were used intraperitoneally. Following fluid replacement with 3 mL·kg-1·h-1 lactated Ringer’s solution, the surgical area was prepared for sterilization. Then a midline laparotomy incision was performed and the left kidney pedicle was dissected. Left renal ischemia was induced by clamping the left renal artery for 45 min for the I/R and I/R-CGA groups. For reperfusion the clamp was removed and the pulsation of renal artery was verified visually. After controlling the bleeding, the skin layers

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TAS and TOS assays The serum TAS and TOS levels were determined with a Table 1. Scoring system for renal histopathology. Score 0 0.5 1 2 3 4

Histopathological pattern Normal Small focal damaged areas < 10% Cortical damaged zone 10–25% Cortical damaged zone 25–75% Cortical damaged zone > 75% Cortical damaged zone

Table 2. The EGTI histology scoring system. Tissue type Tubular

Endothelial

Glomerular

Tubulo/Interstitial

Damage Score No damage 0 Loss of Brush Border (BB) in less than 25% of tubular cells. Integrity of basal membrane 1 Loss of BB in more than 25% of tubular cells, Thickened basal membrane 2 (Plus) Inflammation, cast formation, necrosis up to 60% of tubular cells 3 (Plus) Necrosis in more than 60% of tubular cells 4 No damage 0 Endothelial swelling 1 Endothelial disruption 2 Endothelial loss 3 No damage 0 Thickening of Bowman capsule 1 Retraction of glomerular tuft 2 Glomerular fibrosis 3 No damage 0 Inflammation, haemorrhage in less than 25% of tissue 1 (Plus) necrosis in less than 25% of tissue 2 Necrosis up to 60% 3 Necrosis more than 60% 4

Chlorogenic acid and renal injury

novel automatic method, developed by Erel (22, 23). The ratio of TAS to TOS is defined as oxidative stress index (OSI), expressed as percentage. Statistical analysis IBM SPSS 22 version (SPSS IBM, Turkey) program was used for analysis. Before starting to study, we performed power analysis. The power analysis indicated that 8 subjects per group would be required to produce 80% chance of achieving statistical significance at p < 0.05 level. The Kolmogorov-Smirnov test was performed to determine the normality of data. The results are expressed as mean ± SD. Mann-Whitney U was performed for statistical analysis, as appropriate. A p value below 0.05 was considered statistically significant. Table 3. Histopathology scoring of cortical damage of the groups. Rats 1 2 3 4 5 6 7 8

Sham group 0 0 0 0 0 0 0 0

I/R group 0.5 1 1 1 0.5 0.5 1 0.5

I/R + CGA group 0.5 0 1 0.5 0.5 0.5 1 0.5

Table 4. Comparison of rats in terms of EGTI scoring. Rats 1 2 3 4 5 6 7 8

Sham group 0 0 0 0 0 0 0 0

I/R group 8 7 8 8 5 5 8 4

I/R + CGA group 5 3 6 3 3 4 7 6

Figure 1. Histological images of rat renal cortex sections. a; Normal renal cortex (sham group), b; tubular necrosis (I/R), c; tubular injury (I/R+CGA group. a b c

RESULTS

CGA showed histopathologic improvement in ischemia reperfusion injury as shown in Tables 3 and 4. All rats in the sham group had normal histopathological findings. By contrast, as shown in table 3, 4 (50%) rats in the I/R group had small focal damaged areas and 4 (50%) had < 10% cortical damage. In I/R+CGA group, 1 (12.5%) rat had normal kidney, 5 (62.5%) had small focal damaged areas and 2 (25%) had < 10% cortical damage. EGTI scores of the rats in each group are shown in Table 4, separately. The pathological figures were shown in Figure 1. As shown in Table 5, CGA improved biochemical values. TAS, TOS and OSI values of the sham group was significantly lower than I/R group (P: 0.004, 0.021, 0.034, respectively). There was no significant difference between the sham and I/R + CGA groups in terms of TOS and OSI values (P: 0.83, 0.52, respectively). TOS and OSI values of the I/R group were significantly higher than the other groups (P: 0.021, 0.034, respectively for comparison of sham and I/R groups and P: 0.046, 0.040, respectively for comparison of I/R+CGA and I/R groups).

DISCUSSION

Renal I/R injury is a major reason for renal dysfunction. It induces an inflammatory response and oxidative stress. At the site of inflammation, leukocytes infiltration occurs and results in the secretion of pro-inflammatory cytokines, including TNF-α, HMGB1, IL-6, and IL-1β (24). ROR, produced during reperfusion is considered to play a central role in I/R injury by direct attack on multiple molecule sequences. In living organisms, ROR arise as a result of normal biological metabolism and they can distort the structures of DNA, fats, proteins and carbohydrates. To ensure I/R experimentally, the left renal artery was occluded for 45 min. It was shown that the 45 min model of IR injury used here provides reproducible and robust assessment of treatment effects against IR injury (25, 26). Oxidative stress and antioxidant status can be assessed by several markers and various methods. However, it is both time-consuming and costly to measure these markers separately (27). For this reason, in this study we used TOS, TAS and OSI levels to measure the oxidative stress status. In recent years it has become more common to measure these values (23, 28, 29). In this study TAS, TOS and OSI levels were found to be significantly higher in I/R group compared to sham group and CGA alleviated these parameters. The histopathological classification system presented in Table 1 was used for histological diagnosis. However, since this system shows only cortical damage. Renal IR injury is a complex process which effects the glomerular, tubulo-interstitial and endothelial cells. Acute tubular necrosis, loss of endothelial cell integrity, glomerular

Table 5. Comparison of groups in terms of biochemical parameters. Group 1-2 Group 2-3 Group 1-3

TAS median (min-max) 0.84 (0.76-1)-0.76 (0.66-0.80) 0.76 (0.66-0.80)-0.88 (0.75-0.98) 0.84 (0.76-1)-0.88 (0.75-0.98)

P 0.021 0.0048 0.49

TOS median (min-max) 6.47 (2.1-23.7)-7.04 (4.7-13.9) 7.04 (4.7-13.9)-13.8 (6.4-18.5) 6.47 (2.1-23.7)-13.8 (6.4-18.5)

P 0.83 0.021 0.046

OSI median (min-max) 0.07 (0.03-0.26)-0.09 (0.06-0.21) 0.09 (0.06-0.21)-0.15 (0.09-0.19) 0.07 (0.03-0.26)-0.15 (0.09-0.19)

P 0.52 0.034 0.040

(1) I-R +CGA, (2) sham, (3) I-R. Mann Whitney U test

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ischemic damage and tubulo-interstitial damage are the hallmarks of renal IR injury which is important for complete and comprehensive documentation. For this reason, EGTI scoring system was used together with other system. Because it is reliable, simple, more informative and more detailed scoring system about the degree of tissue damage of the kidney (21). The histological study showed tubular dilation, tubular necrosis, cellular edema and inflammatory cell infiltration in the tubular interstitium. These lesions were less intense in CGA treated rats compared to untreated animals. In order to block inflammatory response and oxidative stress, several drugs have been used to prevent renal I/R injury in several experimental studies (13, 14). However, the new experimental studies will help us to find the most appropriate feasible treatment. In the present study, CGA was examined for its potential effects on regulating renal I/R injury. CGA is a polyphenol, which is abundantly found in coffee, fruits and vegetables. It has been used as an antioxidant, analgesic and anti-inflammatory. It has a certain number of R-OH radicals that are capable of forming the hydrogen free radical, thereby protecting tissue cells from oxidative damage (30). It has been shown to act as a scavenger of hydroxyl radicals, peroxynitrite and superoxide radicals in a concentrationdependent manner in vitro (31). In the study of Yun et al. (32) CGA given at 10 mg/kg intraperitoneally, 10 min before ischemia and reperfusion was chosen as the most effective dose for histology evaluation for I/R- induced hepatic injury. In our study, it was administered intraperitoneally at a total dose of 20 mg/kg 10 minutes before reperfusion. Previous studies in rat models have shown that CGA is protective against hepatic and focal cerebral I/R injury (32, 33). We have observed that CGA has a protective effect against renal I/R injury in our study. We considered that CGA may serve a protective role in the rat model of renal I/R injury. To the best of our knowledge, there is no data showing the effect of CGA on I/R kidney injury and evaluating TAS, TOS levels and histopathology together. As a limitation of our study, since we did not perform a right nephrectomy, we did not measure plasma creatinine, the most commonly used marker as a measure of renal excretory function (34).

CONCLUSIONS

4. Eltzschig HK. Eckle T Ischemia and reperfusionâ&#x20AC;&#x201D;from mechanism to translation. Nat Med. 2011; 17:1391. 5. Zhang J, et al. Erythropoietin pretreatment ameliorates renal ischaemia-reperfusion injury by activating PI3K/Akt signalling. Nephrology (Carlton). 2015; 20:266-72. 6. Wang L, et al. Effect of picroside II on apoptosis induced by renal ischemia/reperfusion injury in rats. Exp Ther Med. 2015; 9:817-822. 7. Fadili W, Allah MH, Laouad I. Chronic renal allograft dysfunction: risk factors, immunology and prevention. Arab J Nephrol Transplant. 2013; 6:45-50. 8. Martin GL, et al. Comparison of total, selective, and nonarterial clamping techniques during laparoscopic and robot-assisted partial nephrectomy. J Endourol. 2012; 26:152-156. 9. Conesa EL, et al. N-acetyl-L-cysteine improves renal medullary hypoperfusion in acute renal failure. Am J Physiol Regul Integr Comp Physiol, 2001; 281: R730-7. 10. Rhoden E et al., Protective effect of allopurinol in the renal ischemia--reperfusion in uninephrectomized rats. Gen Pharmacol. 2000; 35:189-93. 11. Feitoza CQ, et al. Cyclooxygenase 1 and/or 2 blockade ameliorates the renal tissue damage triggered by ischemia and reperfusion injury. Int Immunopharmacol. 2005; 5:79-84. 12. Sahna E, et al. The protective effects of physiological and pharmacological concentrations of melatonin on renal ischemia-reperfusion injury in rats. Urol Res. 2003; 31:188-193. 13. Hosseini F, et al. Effect of beta carotene on lipid peroxidation and antioxidant status following renal ischemia/reperfusion injury in rat. Scand J Clin Lab Invest. 2010; 70:259-263. 14. Kizilgun M, et al. Beneficial effects of N-acetylcysteine and ebselen on renal ischemia/reperfusion injury. Ren Fail. 2011; 33:512-517. 15. Suzuki A, et al. Chlorogenic acid attenuates hypertension and improves endothelial function in spontaneously hypertensive rats. J Hypertens. 2006; 24:1065-1073. 16. Dos Santos MD, et al. Evaluation of the anti-inflammatory, analgesic and antipyretic activities of the natural polyphenol chlorogenic acid. Biol Pharm Bull. 2006; 29:2236-2240. 17. Almeida AAP, et al. Antibacterial activity of coffee extracts and selected coffee chemical compounds against enterobacteria. J Agricol Food Chem. 2006; 54:8738-8743. 18. Kono Y, et al. Iron chelation by chlorogenic acid as a natural antioxidant. Biosci Biotechnol Biochem. 1998; 62:22-27. 19. Council NR. Guide for the Care and Use of Laboratory Animals. 1996, Washington, DC: The National Academies Press. 140.

CGA treatment provided marked improvement in renal histology and suppressed oxidative stress. Thus, CGA may have a protective effect in renal tissue against I/R injury.

20. Medeiros PJD, et al. Effect of sildenafil in renal ischemia/reperfusion injury in rats. Acta Cir Bras. 2010; 25:490-495.

REFERENCES

21. Chavez R, et al. Kidney ischaemia reperfusion injury in the rat: the EGTI scoring system as a valid and reliable tool for histological assessment. Journal of Histology and Histopathology. 2016; 3.

1. Sagiroglu T, et al. Effects of apelin and leptin on renal functions following renal ischemia/reperfusion: An experimental study. Exp Ther Med. 2012; 3: 08-914.

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resilience to warm ischemia in a solitary porcine kidney model. Urology. 2007; 69:984-987.

22. Erel O. A novel automated method to measure total antioxidant response against potent free radical reactions. Clin Biochem. 2004; 37:112-119.

2. Snoeijs MG, et al. Acute ischemic injury to the renal microvasculature in human kidney transplantation. Am J Physiol Renal Physiol. 2010; 299:F1134-40.

23. Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem. 2005; 38:1103-1111.

3. Orvieto MA, et al. Ischemia preconditioning does not confer

24. Ysebaert DK, et al. Identification and kinetics of leukocytes after

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Chlorogenic acid and renal injury

severe ischaemia/reperfusion renal injury. Nephrol Dial Transplant. 2000; 15:1562-74. 25. Delbridge M, et al. The effect of body temperature in a rat model of renal ischemia-reperfusion injury. in Transplantation proceedings. 2007. Elsevier. 26. Wystrychowski W, et al. Nephroprotective Effect of Pentoxifylline in Renal Ischemia–Reperfusion in Rat Depends on the Timing of Its Administration. in Transplantation proceedings. 2014. Elsevier. 27. Tarpey MM, Wink DA, Grisham MB. Methods for detection of reactive metabolites of oxygen and nitrogen: in vitro and in vivo considerations. Am J Physiol Regul Integr Comp Physiol. 2004; 286:R431R444. 28. Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem. 2004; 37:277-285. 29. Harma M, Erel O. Increased oxidative stress in patients with hydatidiform mole. Swiss Med Wkly. 2003; 133:563-6.

30. Zhang J, et al. Liquid chromatograph/tandem mass spectrometry assay for the simultaneous determination of chlorogenic acid and cinnamic acid in plasma and its application to a pharmacokinetic study. J Pharm Biomed Anal .2010; 51:685-690. 31. Graziani G, et al. Apple polyphenol extracts prevent damage to human gastric epithelial cells in vitro and to rat gastric mucosa in vivo. Gut. 2005; 54:193-200. 32. Yun N, Kang J-W, Lee S-M. Protective effects of chlorogenic acid against ischemia/reperfusion injury in rat liver: molecular evidence of its antioxidant and anti-inflammatory properties. J Nutr Biochem. 2012; 23:1249-1255. 33. Miao M, et al. Protective effect of chlorogenic acid on the focal cerebral ischemia reperfusion rat models. Saudi Pharm J. 2017; 25:556-563. 34. Suzuki Y, et al. Clinical validity of renal function markers including serum cystatin C on chronic kidney disease classification. Rinsho Byori. 2011; 59:345-351.

Correspondence Tuncay Toprak, MD (Corresponding Author) drtuncay55@hotmail.com Fatih Sultan Mehmet Training and Research Hospital, Urology, Istanbul, Turkey E5 karayolu üzeri Fatih Sultan Mehmet Hastanesi C Blok Kat 3 icerenkoy Atasehir/Istanbul Çagrı Akın Sekerci, MD cagri_sekerci@hotmail.com Marmara University Pendik Training and Research Hospital, Pediatric Urology, Istanbul, Turkey Hasan Riza Aydın, Assoc. Prof. hrizaaydin@gmail.com Huseyin Kocakgol, MD hsynkocakgl@gmail.com Hamit Zafer Aksoy, Ass. Prof. hamitzaferaksoy@hotmail.com Kanuni Training and Research Hospital, Urology, Trabzon, Turkey Mehmet Akif Ramazanoglu, MD maramazanoglu@hotmail.com Rize State Hospital, Urology, Rize, Turkey Fatma Demet Arslan, Assoc. Prof. fatmademet.arslan@gmail.com Tepecik Training and Research Hospital, Biochemistry, Izmir, Turkey Banu Isbilen Basok, Assoc. Prof. drisbilen@yahoo.com Tepecik Training and Research Hospital, Biochemistry, Izmir, Turkey Hatice Kucuk, Ass. Prof. dr.hatice.kucuk@hotmail.com Kanuni Training and Research Hospital, Pathology, Trabzon, Turkey Seyhan Sumeyra Asci, MD seyransumeyra@hotmail.com Kanuni Training and Research Hospital, Anesthesiology and Reanimation, Trabzon, Turkey Yılören Tanıdır, Assoc. Prof. yiloren@yahoo.com Marmara University, School of Medicine, Urology Istanbul, Turkey

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DOI: 10.4081/aiua.2020.2.158

ORIGINAL PAPER

Evaluation of the influence of subinguinal varicocelectomy procedure on seminal parameters, reproductive hormones and testosterone/estradiol ratio Ünal Öztekin, Mehmet Caniklioğlu, Sercan Sarı, Volkan Selmi, Abdullah Gürel, Mehmet Şakir Taşpınar, Levent Işıkay Bozok Unıversıty Faculty of Medicine, Department of Urology, Yozgat, Turkey.

Summary

Objective: Varicocele is the most commonly surgically curable cause of male infertility. However, the mechanisms related to the effect of reducing fertility potential have not been clearly identified. The aim of this study was to investigate the effects of varicocelectomy on semen parameters, reproductive hormones and testosterone / estradiol ratio. Matherial and methods: Fifty seven patients outcomes were evaluated before and 6 months after subinguinal microsurgical varicocelectomy. Semen parameters, reproductice hormones and testosteron/estradiol ratio results of patients were compared retrospectively. Results: The mean age was 26.8 years. Fifty four (94.7%) patients had grade 3 and 3 (5.3%) patients had grade 2 varicocele. There was a significant increase in semen parameters except semen volume. There was a statistically significant increase in serum testosterone levels, but not on testosterone/ estradiol ratio. Conclusions: According to our results, microsurgical subinguinal varicocelectomy can be recommended for both improving semen parameters and hormonal recovery.

KEY WORDS: Varicocele; Testosterone; Testosterone/Estradiol ratio; Semen parameters; Reproductive hormones. Submitted 14 September 2019; Accepted 23 December 2019

INTRODUCTION

Varicocele is a genital abnormality that disrupts the growth and development of the ipsilateral testis and can also reduce the quality of life due to pain symptoms. It is seen in 11.7% of adult males and 25.4% of whose with abnormal sperm parameters. It is thought to cause hypogonadism and to be associated with male subfertility (1). Varicocele is the most commonly surgically curable cause of male infertility (2). Pain and feeling of scrotal fullness are also indications for surgical treatment (3). Factors such as reflux of kidney and adrenal metabolites, hypoxia, endocrine disorders, increased sperm DNA fragmentation, oxidative stress, increased intratesticular apoptosis, and disruption of intratesticular enzymes due to temperature increase have been implicated in the etiology (4). However, the mechanisms related to the effect of reducing fertility potential have not been clear-

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ly identified (1). There is also limited evidence of how Leyding cells and testosterone production are affected after varicocelectomy and how much it changes testosterone production (5). In the literature, it is generally indicated that Leydig cell function is negatively affected in varicocele patients with decreased testosterone production and that also hormone level is improved by varicocelectomy (4, 6, 7). Studies on rats have shown pathological changes such as increased apoptosis of Leydig and Sertoli cells causing decreased viability and testosterone synthesis due to varicocele (8, 9). However, there are studies advocating that varicocelectomy has no effect on serum testosterone levels in human studies (3, 10, 11). Local hormonal balance between testicular testosterone and estradiol ratio is effective on spermatogenesis. Impairment of this balance in semen and serum can cause infertility by disrupting normal spermatogenesis. Varicocelectomy can positively affect the balance between testosterone and testosterone/estradiol ratio (T/E) (4). Therefore, evaluating T/E ratio changes may provide more useful information (12). The aim of this study was to investigate the effects of varicocelectomy on sperm parameters, reproductive hormones and T/E ratio.

MATERIALS

AND METHODS

Data of patients who presented with infertility and/or pain and then underwent microsurgical subinguinal varicocelectomy between November 2017 and July 2019 were evaluated retrospectively. After approval from the local ethics committee, patients aged 18 and over were included in the study and the study was conducted in accordance with the Declaration of Helsinki. Fifty seven patients who met the study criteria were evaluated. All patients were examined while standing and evaluated with Valsalva maneuver and then color flow doppler ultrasonography (CFDU) was performed. Patients were classified according to clinical grading system. Grade 0 (subclinical): cannot be detected by inspection or palpation but can only be detected by CFDU. Grade I: only palpable on Valsalva maneuver. No conflict of interest declared.

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Table 1. Grade II: palpable without Valsalva maneuver. Grade III: Overall and specific course rating. visible with no need for palpation. Patients with known or detected hormonal pathology (hypo/hypergonadism, Age (mean) (min-max) 26.8 (18-41) hypo/hyperthyroidism, hyperprolactinemia), azoospermia 2 (mean)(min-max) BMI kg/m 24.77 (18.31-29.41) and cryptozoospermia (≤ 1 million/mL), body mass index 2 (BMI) ≥ 30 kg/m , genital tract infection (orchitis, epiTestosterone change didymitis, urethritis) and patients who had used No increase (n) 21 (36.8%) chemotherapeutic drugs were excluded from the study. 0-50% increase (n) 31 (54.3%) Semen analyses were performed after 3-7 days of absti50-100% increase (n) 5 (8.7%) nence using the 2010 criteria of the World Health BMI: Body Mass Index. Organization (13). Semen volume, sperm concentration, total sperm count, progressive motility and total motility data were recorded as semen parameters before and 6 months after varicoc- Table 2. Comparison of semen parameters before and after varicocelectomy. electomy. Age, body mass index, hormone profiles including follicle stimulating hormone Preoperative Postoperative P value (FSH), luteinizing hormone (LH), prolactin Semen volume, ml (mean ± SD) 3.12 ± 1.39 3.33 ± 1.56 0.105b (PRL), estradiol (E2) and total testosterone (T) Sperm concentration (mil/ml) (mean ± SD) 35.54 ± 24.76 45.13 ± 23.76 0.001a results and T/E ratios were recorded. Total sperm count, (mil) (mean ± SD) 113.44 ± 98.54 153.84 ± 115.98 < 0.001b Subinguinal incision was performed and Progressive motility (Type A) (%) 24.71 ± 10.57 28.95 ± 9.95 0.001a microsurgical varicocelectomy procedure was performed by defining spermatic cord Total motility (Type A+B) (%) 41.96 ± 16.00 45.14 ± 14.63 0.011b a b from external inguinal ring in all patients. Calculated using Paired-sample T-test. Calculated using Wilcoxon Signed Ranks Tests. SD: standard deviation. Preoperative and postoperative results of patients were compared retrospectively.

Statistical analysis All statistical tests were performed using the Statistics Package for Social Sciences version 25 (IBM SPSS®, Chicago, IL). KolmogorovSmirnov test was used to determine the normal distribution of data. Paired-sample T-test was used for pre-postoperative comparison of parametric data and Wilcoxon Signed Ranks Test was used for pre-postoperative comparison of non-parametric data. A value p < 0.05 was considered statistically significant.

RESULTS

Table 3. Comparison of hormonal data before and after varicocelectomy. Preoperative

Postoperative

P valueb

3.69 ± 2.69

3.73 ± 2.50

0.689

Serum LH, mIU/ml (mean ± SD)

3.33 ± 1.51

3.32 ± 1.68

0.161

Serum PRL, ng/ml (mean ± SD)

10.20 ± 3.96

9.86 ± 3.35

0.609

Serum E2, ng/L (mean ± SD)

24.88 ± 8.78

26.48 ± 9.02

0.445

Serum T, ng/dl (mean ± SD)

507.63 ± 174.27

547.01 ± 184.59

0.003

22.36 ± 9.46

22.87 ± 11.10

0.978

Serum FSH, mIU/ml (mean ± SD)

T/E2 (mean ± SD)

b Wilcoxon Signed Ranks Tests. SD: Standard deviation. FSH: Follicle stimulating hormone. LH: Luteinizing hormone. PRL: Prolactin.

E2: Estradiol and T: Total testosterone T/E2: Testosterone/Estradiol ratio.

A total of 57 patients aged 18-41 (mean: 26.8) were included in the study. The mean BMI value was 24.77 (18.31-29.41) kg/m2. The varicocele grade was grade 2 in 3 (5.3%) patients who underwent varicocelectomy. Fifty four (94.7%) patients had grade 3 varicocele. In 21 (36.8%) of the patients, no increase was observed according to the preoperative testosterone values, while 31 (54.3%) had less than 50% and 5 (8.7%) had more than 50% change (Table 1). There was no significant difference between preoperative and postoperative semen volumes. There was a statistically significant improvement in sperm concentration, total sperm count, progressive and total sperm motility compared to preoperative period (p < 0.05) (Table 2). There were no significant changes in serum FSH, LH, E2, PRL values compared to preoperative values. There was a statistically significant increase in serum testosterone levels 507.63 ± 174.27, 547.01 ± 184.59 ng/dl preoperatively and postoperatively, respectively (p = 0.003). However, T/E ratios (preoperative and postoperative 22.36 ± 9.46, 22.87 ± 11.10, respectively) were not significantly changed (p = 0.978) (Table 3).

DISCUSSION

Varicocele is an abnormal dilation of the plexus pampiniformis and testicular spermatic veins in the spermatic cord (14). It is often caused by left side veins and is a venous dilatation disorder characterized by increased pressure within the internal spermatic vein (6). It affects male fertility by creating anatomical and functional damage within the testis (15). It has been reported that patients with varicocele have higher degree of sperm DNA fragmentation when compared to healthy individuals. Also, varicocele patients with abnormal sperm parameters have higher fragmentation levels than those with normal sperm parameters (16). More severe damage to the testicle has been reported as the degree of varicocele increases (17). Increased venous pressure in the varicocele, which is a dilated venous disease, can cause venous stasis by delaying vascular washout, resulting in impaired thermal regulation leading to hyperthermia and accumulation of toxins (18). As a result of hyperthermia, it has been suggested that after germ cell apoptosis, inhibition of enzymes involved in spermatogenesis (19) and steroid biosynthesis decreases converArchivio Italiano di Urologia e Andrologia 2020; 92, 2

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sion to intratesticular testosterone and synthesis (20). In support of this theory, studies advocating increased testosterone levels after varicocelectomy are presented. In the study of Tanrıkut et al. (6), they reported the results of testosterone before and after varicocelectomy as 416 ng/dL and 469 ng/dL respectively in their series of 325 patients with palpable varicocele. They showed a significant increase in testosterone level in two thirds of patients after varicocelectomy. The results of our study were 507.63 ± 174.27 and 547.01 ± 184.59 ng/dl before and after surgery respectively and there was a significant increase (p = 0.003). Similarly, two-thirds of our patients had increased testosterone. In the study by Sathya S. et al, testosterone levels increased from 1.77 ± 0.18 ng/ml to 3.01 ± 0.43 ng/ml after varicocelectomy (21). Hsiao et al. likewise stressed that there was a significant increase in testosterone level and sperm concentration and total sperm count in all varicocelectomy patients, including the 5th and 6th decade age group (22). In a meta-analysis evaluating 814 patients, it was concluded that surgical treatment of varicocele significantly increased Leyding cell function and testosterone production (23). Numerous studies have shown that testosterone levels are elevated after varicocelectomy, but there are also studies advocating that it does not cause any changes. In the study by Rodriguez et al., there was no relationship between varicocele and low testosterone. It was also argued that there was no improvement in semen profile in treated varicoceles (10). Similarly, Panach-Navarrete et al. showed that there was no correlation between the presence of varicocele and decreased serum testosterone level (11). Zheng et al. detected that there is not significant change in testosterone levels compared to preoperative values in 104 infertile patients after left or bilateral varicocelectomy procedure (24). Although the prevalence of varicocele is widespread worldwide and associated with low testosterone levels, this relationship has not been clearly demonstrated. In this context, it is considered that T/E ratio evaluation can provide more useful information (12). Simorangkir et al. concluded that the T/E2 ratio in pampiniform plexus was significantly lower than in the control group in their study by creating varicocele in a rabbit model (25). Although there are limited studies on this subject in the literature, the pre and postoperative T/E ratio was found to be 19 ± 7.7 and 27.5 ± 1.2 in the prospective study conducted by Gomaa et al. (4). They emphasized that there was a significant postoperative decrease in E2 level (26.9 ± 3.2 and 22.9 ± 3.1 pg/ml p < 0.001, respectively). In our study, T/E2 ratios were 22.36 ± 9.46 and 22.87 ± 11.10, before and after surgery, respectively (p = 0.978). There was an increase in postoperative serum E2 values but it was not statistically significant (p = 0.445). When we evaluated only 36 patients with increased testosterone levels, the mean preoperative and postoperative E2 levels were 23.85 ± 9.17 and 26.92 ± 9.57 ng/L (p = 0.104), respectively. There was an increase in E2 values with increasing T levels. However, it was not statistically significant. In addition, there was no significant increase in T/E ratios in this patient group (p = 0.470). No significant difference was found between the two groups whose T level increased and showed no change

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(p = 0.212). Therefore, it is suggested that these changes may be in the testicular cells regardless of peripheral aromatase activity. Although these results suggest that improvement in Leydig cell functions after varicocelectomy may increase estradiol production, further prospective randomized studies with more patients and longterm follow-up are needed. A meta-analysis of 548 patients evaluating seven studies emphasized that varicocelectomy provided significant improvement, particularly on progressive sperm motility (26). In another meta-analysis, the varicocelectomy group was compared to the untreated group in terms of semen parameters in adolescents, but no difference was observed between the two groups (27). In general, it is seen that microsurgical varicocelectomy increases sperm concentration and motility (28). Also, there was a significant increase in semen volume, sperm concentration and total number, progressive and total motility after varicocelectomy in our study. Retrospective design of our study is a limitation. Other limitations include low number of study population and short follow-up, collection of single-centered data, and failure to evaluate pregnancy outcomes.

CONCLUSIONS

When the data of our study were evaluated, we concluded that subinguinal varicocelectomy procedure with microsurgical method provided significant improvement on semen parameters and testosterone levels. However, we did not find a significant relationship between T/E2 ratio and surgery. According to our results, microsurgical subinguinal varicocelectomy can be recommended for both improving semen parameters and hormonal recovery. However, multicenter prospective randomized studies are needed to clarify relationship with reproductive hormones and semen parameters, including more patients with long-term follow-up and pregnancy rate evaluation.

REFERENCES

1. Jungwirth A, Diemer T, Kopa Z, et al. EAU Guidelines on Male Infertility. In: Jungwirth A, editor. EAU Guidelines 2018. Arnhem: EAU Guidelines Office. 2018; pp. 734-5. 2. Sabanegh E, Agarwal A. Male Infertility. Tenth Edition. ed. Kavoussi L, Partin A, Novick A, Peters C, editors: Campbell Walsh Urology. 2012; pp 617-42. 3. Resorlu B, Kara C, Sahin E, Unsal A. The significance of age on success of surgery for patients with varicocele. Int Urol Nephrol. 2010; 42:351-6. 4. Gomaa MD, Motawaa MA, Al-Nashar AM, El-Sakka AI. Impact of subinguinal varicocelectomy on serum testosterone to estradiol ratio in male patients with infertility. Urology. 2018; 117:70-7. 5. Tanrikut C, Goldstein M. Varicocele repair for treatment of androgen deficiency. Curr Opin Urol. 2010; 20:500-2. 6. Tanrikut C, Goldstein M, Rosoff JS, et al. Varicocele as a risk factor for androgen deficiency and effect of repair. BJU Int. 2011; 108:1480-4. 7. Ando S, Giacchetto C, Colpi G, et al. Physiopathologic aspects of Leydig cell function in varicocele patients. J Androl. 1984; 5:163-70.

Varicocelectomy and hormones

8. Oh YS, Jo NH, Park JK, Gye MC. Changes in inflammatory cytokines accompany deregulation of claudin-11, resulting in interSertoli tight junctions in varicocele rat testes. J Urol. 2016; 196:1303-12.

19. Wang C, Cui YG, Wang XH, et al. transient scrotal hyperthermia and levonorgestrel enhance testosterone-induced spermatogenesis suppression in men through increased germ cell apoptosis. J Clin Endocrinol Metab. 2007; 92:3292-304.

9. Luo DY, Yang G, Liu JJ, et al. Effects of varicocele on testosterone, apoptosis and expression of StAR mRNA in rat Leydig cells. Asian J Androl. 2011; 13:287-91.

20. Rajfer J, Turner TT, Rivera F, et al. Inhibition of testicular testosterone biosynthesis following experimental varicocele in rats. Biol Reprod. 1987; 36:933-7.

10. Rodriguez Pena M, Alescio L, Russell A, et al. Predictors of improved seminal parameters and fertility after varicocele repair in young adults. Andrologia. 2009; 41:277-81. 11. Panach-Navarrete J, Morales-Giraldo A, Ferrandis-Cortes C, et al. Is there a relationship between varicocele and testosterone levels? Aging Male. 2019:1-7. 12. Parekattil SJ, Agarwal A. Male Infertility: Contemporary Clinical Approaches, Andrology, ART & Antioxidants. Male Infertility: Springer Science & Business Media. 2012; pp. 247-59. 13. World Healt Organization: Laboratory manual for the examination and processing of human semen, 5th ed. Geneva: WHO press; 2010. 14. Lomboy JR, Coward RM. The Varicocele: Clinical Presentation, Evaluation, and Surgical Management. Semin Intervent Radiol. 2016; 33:163-9. 15. Yildiz O, Gul H, Ozgok Y, et al. Increased vasoconstrictor reactivity and decreased endothelial function in high grade varicocele; functional and morphological study. Urol Res. 2003; 31:323-8. 16. Alargkof V, Kersten L, Stanislavov R, et al. Relationships between sperm DNA integrity and bulk semen parameters in Bulgarian patients with varicocele. Arch Ital Urol Androl. 2019; 91:2.

21. Sathya Srini V, Belur Veerachari S. Does varicocelectomy improve gonadal function in men with hypogonadism and infertility? Analysis of a prospective study. Int J Endocrinol. 2011; 2011:916380. 22. Hsiao W, Rosoff JS, Pale JR, et al. Older age is associated with similar improvements in semen parameters and testosterone after subinguinal microsurgical varicocelectomy. J Urol. 2011; 185:620-5. 23. Li F, Yue H, Yamaguchi K, et al. Effect of surgical repair on testosterone production in infertile men with varicocele: a metaanalysis. Int J Urol. 2012; 19:149-54. 24. Zheng YQ, Gao X, Li ZJ, et al. Efficacy of bilateral and left varicocelectomy in infertile men with left clinical and right subclinical varicoceles: a comparative study. Urology. 2009; 73:1236-40. 25. Simorangkir L, Sihombing AT, Noegroho BS. Estrogen-testosterone ratio in plexus pampiniform of normal rabbits and rabbits with left artificial varicocele. Indonesian Journal of Urology. 2013; 20:1-4. 26. Kim HJ, Seo JT, Kim KJ, et al. Clinical significance of subclinical varicocelectomy in male infertility: systematic review and metaanalysis. Andrologia. 2016; 48:654-61.

17. Steckel J, Dicker AP, Goldstein M. Relationship between varicocele size and response to varicocelectomy. J Urol. 1993; 149:769-71.

27. Zhou T, Zhang W, Chen Q, et al. Effect of varicocelectomy on testis volume and semen parameters in adolescents: a meta-analysis. Asian J Androl. 2015; 17:1012-6.

18. Eisenberg ML, Lipshultz LI. Varicocele-induced infertility: Newer insights into its pathophysiology. Indian J Urol. 2011; 27:58-64.

28. Yuan R, Zhuo H, Cao D, Wei Q. Efficacy and safety of varicocelectomies: A meta-analysis. Syst Biol Reprod Med. 2017; 63:120-9.

Correspondence Ünal Öztekin, MD (Corresponding Author) dr_unal@hotmail.com Mehmet Caniklioğlu, MD dr.mehmetcaniklioglu@gmail.com Sercan Sarı, MD sercansari92@hotmail.com Volkan Selmi, MD volkanselmi@hotmail.com Abdullah Gürel, MD abdullahgurel@hotmail.com Mehmet Şakir Taşpınar mehmetsakirtaspinar@hotmail.com Levent Işıkay, MD isikay@gmail.com Yozgat Bozok University, Research and Application Hospital, Urology Department, Yozgat, Turkey

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DOI: 10.4081/aiua.2020.2.162

CASE REPORT

Paraurethral cyst in a newborn Raziye Ergun 1, Duran Yildiz 2, Cagri Akin Sekerci 3, Hasan Kahveci 2 1 Erzurum

Regional Training and Research Hospital, Pediatric Urology, Erzurum, Turkey; Regional Training and Research Hospital, Neonatology, Erzurum, Turkey; 3 Marmara University Pendik Training and Research Hospital, Pediatric Urology, Istanbul, Turkey. 2 Erzurum

Paraurethral cysts are rare and occur with obstruction of the Skene duct. In this case, we aimed to present a paraurethral cyst in a baby girl. A 4-day-old newborn was consulted for pediatric urology because of an interlabial mass. In genital examination, a noninvasive mass measuring 2 × 1.5 cm was observed in the interlabial region, and the introitus was completely closed. Ultrasonography showed a cystic lesion localized on the right side of the urethra with a smoothly contoured, thin-walled, hypoechoic structure. The patient underwent puncture under sterile conditions. The content of the mass was mucoid and clear fluid. Paraurethral cysts are often asymptomatic and benign. There is no definitive consensus on treatment.

Summary

KEY WORDS: Newborn; Paraurethral cyst. Submitted 26 July 2019; Accepted 31 January 2020

Complete blood count (CBC), C-reactive protein, and other biochemical tests were normal. Ultrasonography (US) showed a cystic lesion localized on the right side of the urethra with a smoothly contoured, thin-walled, hypoechoic structure that was unrelated to the surrounding tissues. Abdominopelvic US was normal. The patient’s oxygen saturation values returned to normal after cleaning nasal secretions with saline. Following the evaluation of pediatric urology, the mass was thought to be a paraurethral cyst. After written informed consent was obtained from the family, the patient underwent puncture under sterile conditions. The content of the mass was mucoid and clear fluid. After the procedure, the urethra and vagina were normal. It was observed that the cyst did not recur during follow up at the neonatal unit or after the patient’s discharge.

INTRODUCTION Paraurethral cysts are a rare cause of intralabial mass in neonatal period. They develop due to congenital obstruction of the ducts of the paraurethral glands. The incidence of paraurethral cysts has been reported as 1.038 to 7.246 live births (1). Paraurethral cysts are usually asymptomatic, 6-10 mm in size, cystic and soft masses in the physical examination. Most of them spontaneously resolve. In this article, we aimed to present a case of paraurethral cyst which was treated by needle aspiration in early neonatal period.

CASE

REPORT

On the fourth day after birth, a baby girl was admitted to the neonatal intensive care unit with cyanosis. She was born from non-consanguineous parents, following an uneventful second pregnancy for her 40-year-old mother, by the normal spontaneous vaginal route at a private center. She was born at 37 weeks of gestation, with a weight of 2.200 grams (3rd-10th percentile) a height of 45 cm (25-50th percentile). In the systemic examination, the patient's general status was good. The neonatal reflexes were active and alive, and her vital signs were normal. Moreover, the results of her respiratory, cardiovascular, neurological, and abdominal examinations were normal. In genital examination, a noninvasive mass measuring 2 × 1.5 cm was observed in the interlabial region, and the introitus was completely closed. The patient had spontaneous urine output.

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DISCUSSION Paraurethral glands were first described by Alexander Johnston Chalmers Skene in 1880 (2). They are located in the distal part of the urethra and considered to be homologues of the prostate in females; they generate mucoid secretion with sexual stimulation (3). The distal urethra of an adult woman has between 6 and 30 ducts in the paraurethral glands, the largest of which is called the Skene duct. Paraurethral cysts are rare and occur with obstruction of the Skene duct. Although the etiology is not clear, it is thought that dislocation of the epithelium and inflammation may cause obstruction (4). The diagnosis of paraurethral cyst in newborns is based on the localization of the cyst and relationship with the urethra. In paraurethral cysts, the urethra is free, and the urethral meatus can displace with the mass effect. Perineal ultrasound shows a smooth contoured simple cyst filled with mucoid fluid. On pathological examination, the internal surface of the cyst wall comprises transitional or squamous epithelium. Differential diagnoses of paraurethral cysts in newborns include imperforate hymen, Gardner canal cyst, Muller canal cyst, urethral prolapse, vaginal rhabdomyosarcoma, ectopic ureterocele, condyloma, urethral polyp, congenital lipoma, and vaginal prolapse. If paraurethral cysts are accompanied by lower urinary tract obstruction, further urological evaluation should also be performed. There is no consensus about the treatment for paraurethral cysts because they are benign and often asymptoNo conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2020; 92, 2

Paraurethral cyst in a newborn

Figure 1. View of the paraurethral cyst and aspirated fluid with the naked eye.

Fujimoto et al. reported that the five neonates with paraurethral cysts who were followed conservatively showed spontaneous recovery after 150 days on average (5). The most common method for surgical procedures is needle aspiration, which can often be applied at the bedside with a local anesthetic cream without the need for general anesthesia.

REFERENCES

1.Phupong V, Aribarg A. Management of Skene's duct cysts in newborn girls. BJU Int. 2000; 86:562.

1A: Image of interlabial mass in vulva before operation. The mass was approximately 2 x 3 cm in size, covered with genital mucosa, ovoid, soft/elastic, and partially reddish but also generally creamy. 1B: Content of the aspirated cyst during operation. 1C: Image of vulva after operation (fifth day).

matic. Cyst excision, marsupialization, and needle aspiration, as in our case, are among the surgical methods that can be used in the treatment. Because of spontaneous resolution in neonates, a conservative approach is another alternative to surgery.

2. Skene AJ. The anatomy and pathology of two important glands of the female urethra. The American Journal of Obstetrics and Diseases of Women and Children (18691919). 1880; 13:265. 3. Costantino E, Ganesan GS. Paraurethral cysts in newborn girls. BMJ case reports. 2016; 2016:bcr2016216689.

4. Merlob P, Bahari C, Liban E, Reisner S. Cysts of the female external genitalia in the newborn infant. Am J Obstet Gynecol. 1978; 132:607-10. 5. Fujimoto T, Suwa T, Ishii N, Kabe K. Paraurethral cyst in female newborn: is surgery always advocated? J Pediatr Surg. 2007; 42:400-3.

Correspondence Raziye Ergun, MD raziye_ergun@hotmail.com Erzurum Regional Training and Research Hospital, Pediatric Urology, Erzurum (Turkey) Duran Yildiz, MD doktorduranyildiz@hotmail.com Erzurum Regional Training and Research Hospital, Neonatology, Erzurum (Turkey) Cagri Akin Sekerci, FEBU, Assoc. Prof. (Corresponding Author) cagri_sekerci@hotmail.com Marmara University Pendik Training and Research Hospital, Pediatric Urology, Istanbul (Turkey) Hasan Kahveci, Assoc. Prof. drhasankahveci@hotmail.com Erzurum Regional Training and Research Hospital, Neonatology, Erzurum (Turkey)

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