Archivio Italiano di Urologia e Andrologia - Vol. 93 - n. 3 - 2021 by Edizioni Scripta Manent

ISSN 1124-3562

Vol. 93; n. 3, September 2021

ORIGINAL PAPERS 251

Prediction of post radical nephrectomy complications based on patient comorbidity preoperatively Evangelos Fragkiadis, Christos Alamanis, Constantinos A. Constantinides, Dionysios Mitropoulos

255

The impact of orthotopic reconstruction on female sexuality and quality of life after radical cystectomy for non-malignant bladder conditions Chiara Borghi, Margherita Manservigi, Elena Sofia Milandri, Carmelo Ippolito, Pantaleo Greco, Lucio Dell’Atti

262

268

Oncological and functional outcomes of extraperitoneal laparoscopic radical prostatectomy: An 18-years, single-center experience Francesco Saverio Grossi, Emanuele Utano, Paolo Minafra, Pier Paolo Prontera, Francesco Schiralli, Antonio De Cillis, Evangelista Martinelli, Marco Lattarulo, Meri Luka, Antonio Carrieri, Angelo D’Elia

274

Reconstruction of the Denonvillier's fascia and posterior ligament of the external urethral sphincter: Assessment of its effect on urinary continence after laparoscopic radical prostatectomy Pedro Sousa Passos, Sara Teixeira Anacleto, Rui Simeão Versos, Mário Cerqueira Alves, Paulo Oliveira Mota

280

The presence of chronic inflammation in positive prostate biopsy is associated with upgrading in radical prostatectomy Ekrem Guner, Yavuz Onur Danacioglu, Yusuf Arikan, Kamil Gokhan Seker, Salih Polat, Halil Firat Baytekin, Abdulmuttalip Simsek

285

Visceral adiposity is associated with worse urinary and sexual function recovery after radical prostatectomy: Results from a longitudinal cohort study Tommaso Cai, Andrea Cocci, Fabrizio Di Maida, Stefano Chiodini, Francesco Ciarleglio, Lorenzo Giuseppe Luciani, Giovanni Pedrotti, Alessandro Palmieri, Gianni Malossini, Michele Rizzo, Giovanni Liguori, Truls E. Bjerklund Johansen

291

Association of metabolic syndrome with prostate cancer diagnosis and aggressiveness in patients undergoing transrectal prostate biopsy Charalampos Fragkoulis, Ioannis Glykas, Lazaros Tzelves, Konstantinos Stasinopoulos, Lazaros Lazarou, Andreas Kaoukis, Athanasios Dellis, Georgios Stathouros, Georgios Papadopoulos, Konstantinos Ntoumas

296

Incidental testicular masses and the role of organ-sparing approach Yash Narayan, Dominic Brown, Stella Ivaz, Krishanu Das, Mohamad Moussa, Georgios Tsampoukas, Athanasios Papatsoris, Noor Bucholz

301

Testicular germ cells tumors in adolescents and young adults: Management and outcomes from a single-center experience Claudio Spinelli, Gianmartin Cito, Girolamo Morelli, Marco Ghionzoli, Alessia Bertocchini, Beatrice Sanna, Luca Galli, Andrea Antonuzzo, Riccardo Morganti, Silvia Strambi

307

Stone composition of renal stone formers from different global regions Adam Haliński, Kamran Hassan Bhatti, Luca Boeri, Jonathan Cloutier, Kaloyan Davidoff, Ayman Elqady, Goran Fryad, Mohamed Gadelmoula, Hongyi Hui, Kremena Petkova, Elenko Popov, Bapir Rawa, Iliya Saltirov, Francisco R. Spivacow, Belthangady Monu Zeeshan Hameed, Alberto Trinchieri, Noor Buchholz

313

Stone free rate and clinical complications in patients submitted to retrograde intrarenal surgery (RIRS): Our experience in 571 consecutive cases Orazio Maugeri, Ettore Dalmasso, Dario Peretti, Fabio Venzano, Germano Chiapello, Carlo Ambruosi, Claudio Dadone, Astrid Bonaccorsi, Pietro Pepe, Letterio D’Arrigo, Michele Pennisi

318

Do we have a limit for retrograde intrarenal surgery for solitary kidney stone? Bulent Kati, Eyyup Sabri Pelit, Mehmet Demir, Ismail Yagmur, Adem Tuncekin, Halil Ciftci continued on page III

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Official Journal of SIEUN, UrOP, SSCU and GUN

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

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

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

ORIGINAL PAPERS 323

Predicting negative ureteroscopy for stone disease – Minimizing risk and cost Miguel Eliseu, Roberto Jarimba, Pedro Moreira, Pedro Simões, Paulo Temido, Arnaldo Figueiredo

326

Comparison of a single-use, digital flexible ureteroscope with a reusable, fiberoptic ureteroscope for management of patients with urolithiasis Panagiotis Mourmouris, Lazaros Tzelves, Grigorios Raptidis, Marinos Berdempes, Titos Markopoulos, Grigorios Dellis, Ioannis Siafakas, Andreas Skolarikos

330

Outcome of Transperitoneal Laparoscopic Ureterolithotomy (TPLU) for proximal ureteral stone > 15 mm: Our experience with 60 cases Ali Eslahi, Faisal Ahmed, Mohammad Rahimi, Seyed Hamed Jafari, Seyyed Hossein Hosseini, Saleh Al-wageeh, Pegah Mohammad Zadeh Shirazi, Khalil Al-naggar, Ebrahim Al-shami, Mohammad Hossein Taghrir

336

Effect of bladder dysfunction on development of depression and anxiety in Parkinson’s disease Erdal Benli, Fahriye Feriha Ozer, Nesrin Helvaci Yilmaz, Ozge Arici Duz, Ahmet Yuce, Abdullah Cirakoglu, Tuba Saziye Ozcan

341

Male sexual functions and behaviors in the age of COVID-19: Evaluation of mid-term effects with online cross-sectional survey study Erhan Ates, Hakan Gorkem Kazici, Ahmet Emre Yildiz, Saparali Sulaimanov, Arif Kol, Haluk Erol

348

Urologists’ knowledge base and practice patterns in Peyronie’s disease. A national survey of members of the italian andrology society Gianni Paulis, Francesca Pisano, Alessandro Palmieri, Tommaso Cai, Fabrizio Palumbo, Bruno Giammusso

356

Immediate insertion of a soft penile prosthesis as a new option for a safe and cost-effective treatment of refractory ischemic priapism Franco Palmisano, Valerio Vagnoni, Alessandro Franceschelli, Giorgio Gentile, Fulvio Colombo

361

Erectile dysfunction treatment with Phosphodiesterase-5 Inhibitors: Google trends analysis of last 10 years and COVID-19 pandemic Müslim Doğan Değer, Serdar Madendere

LETTERS TO EDITOR 366

Digital informed consent on radical prostatectomy surgery – A turning point on patient communication means Pedro Sousa Passos, Nuno Carvalho, Sara Teixeira Anacleto, Mário Cerqueira Alves, Paulo Oliveira Mota

370

Stereotactic Body Radiation Therapy (SBRT) for prostate cancer: Preliminary results of toxicity Asmâa Naim, Safae Mansouri, Kamal Saidi, Abdeljalil Heddat, Younes Elhoury, Redouane Rabii

373

Potential prognostic value of miR-132 and miR-212 expression in mCRPC patients Mariano Pontico, Viviana Frantellizzi, Luca Cindolo, Giuseppe De Vincentis

375

Studying the electrolyte changes in ileal urine at the time of radical cystectomy and ileal conduit diversion Mohamed Adel Atta, Tamer Abou Youssif, Ahmed Kotb

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GENERAL INFORMATION AIMS AND SCOPE “Archivio Italiano di Urologia e Andrologia” publishes papers dealing with the urological, nephrological and andrological sciences. Original articles on both clinical and research fields, reviews, editorials, case reports, abstracts from papers published elsewhere, book rewiews, congress proceedings can be published. Archivio Italiano di Urologia e Andrologia 2021, 93, 3

III

DOI: 10.4081/aiua.2021.3.251

ORIGINAL PAPER

Prediction of post radical nephrectomy complications based on patient comorbidity preoperatively Evangelos Fragkiadis, Christos Alamanis, Constantinos A. Constantinides, Dionysios Mitropoulos 1st Urology Department Univesity of Athens Laiko Hospital, Athens, Greece.

Summary

Objectives: Comorbidity along with tumor and patient characteristics is taken into account when deciding for the surgical treatment of renal cell carcinoma (RCC). Comorbidity has also been used as an independent predictive factor for postoperative complications of several major urological procedures including radical nephrectomy for RCC. The aim of the present study was to objectively evaluate the association between comorbidity and postoperative complications after radical nephrectomy for RCC, using standardized systems to grade both comorbidity and severity of postoperative complications. Materials and methods: Clinicopathological data of 171 patients undergoing open radical nephrectomy for lesions suspected of RCC were prospectively recorded for a period of 3 years. Comorbidity was scored using the Charlson Comorbidity Index (CCI) while postoperative complications were graded according to the Clavien-Dindo system. Results: Patients were predominantly males (59.1%); their age ranged from 35 to 88 years (mean ± SD: 63.6 ± 11.9 yrs) with 50.8% of them being ≤ 65 yrs. CCI ranged from 0 to 8 with the majority (85.3%) scoring ≤ 2. The procedure was uncomplicated in 57.3% cases; 10 patients suffered major (grade III/IV) complications and 4 patients died within the 40 days postoperative period. CCI correlated with the manifestation of any postoperative complication, Clavien ≥ 1, OR (95% CI): 1.47 (1.09-1.96), p = 0.011 and the occurrence of severe complications, Clavien > 2. OR (95% CI): 1.29 (1.01-1.63), p = 0.038. Conclusions: The present prospective study showed that considerable complications occur in patients with major comorbidities. CCI is easily calculated and should be incorporated in preoperative consultation especially in cases of elder patients with severe comorbidity and favorable tumor characteristics where less invasive interventions or even active surveillance could be applied.

KEY WORDS: Nephrectomy; Complications; Comorbidity; Clavien Dindo; Charlson. Submitted 29 July 2021; Accepted 22 August 2021

INTRODUCTION

Surgery (radical or partial nephrectomy using an open, laparoscopic or robotic-assisted approach) is traditionally the preferred treatment for renal cell carcinoma (RCC) (1). Both tumor- (i.e., clinical stage) and patient-related (i.e., physical status and comorbidities) characteristics evaluated preoperatively are important prognosticators of treat-

ment outcome and survival (2, 3). It is possible therefore that age and comorbidities rather than the tumor itself may be the primary cause of death (3, 4). Comorbidity is defined as “any co-existing disease or condition that can affect the diagnosis, treatment, and prognosis for an index disease under study” and is used for assessing fitness for surgery (5). Furthermore, its prognostic effect has been present in various cancers including urological cancers such as prostate, bladder and renal cancer (6-8), the effect being more prominent in indolent tumors. Comorbidity should not be confused with quality-of-life scales such as the Karnofsky and Eastern Cooperative Oncology group scales, or functionality scales. Comorbidity can be represented by a mathematical index; one of them is the Charlson Comorbidity Index (CCI) that was developed in 1987 as a prognostic taxonomy for 19 medical conditions, each with its own associated weight, which singly or in combination might alter the risk of short-term mortality for patients enrolled in longitudinal studies. The total score ranges from 0-37 and reflects the cumulative likelihood of one-year mortality (9). The CCI was further adapted to include increasing age (Age-adjusted Charlson Comorbidity Index-ACCI) (8, 10). Both indices are easy to use and have shown good reliability (11), while Kutikov et al. (12) recently incorporated patient comorbidity, as measured by CCI, into a nomogram in addition to age, race, gender, and tumor size. This instrument calculates the probability of kidney cancer death compared to death from other causes and helps in selecting those who could really benefited from surgical intervention. Complication rates have been mainly used in comparing surgical techniques as well as surrogate markers of health care quality. However, this is hampered by the lack of standardized methodology in reports of surgical complications. In 2012 an ad hoc European Association of Urology (EAU) Guidelines panel (13) recommended the preferential use of the Clavien-Dindo system that classifies complications assigning a severity grade according to the type of the intervention needed to resolve them (14). This system has been developed for use in general surgery but has also been validated to be used in urological procedures (15). While preoperative nomograms and comorbidity indices have been widely used to assess short-and long-term mortality following surgical interventions for kidney tumors, there are only scares reports of objective predic-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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E. Fragkiadis, C. Alamanis, C.A. Constantinides, D. Mitropoulos

tion of postoperative morbidity using standardized comorbidity assessment and complication grading (1619), often with contradicting results. We present a singlecenter experience of open radical nephrectomies for RCC evaluating the association between preoperative comorbidity and the severity of postoperative complications using standardized systems (CCI and Clavien-Dindo, respectively).

MATERIALS

AND METHODS

This was an analysis of data gathered prospectively over a period of 3 years. We included all patients undergoing radical nephrectomy for suspected RCC. Our study was approved by the Scientific and Ethics Committee of our Hospital. Cases of nonmalignant final pathology such as oncocytoma, mimicking renal tumors and treated by radical nephrectomy, were also included in the study. Patients treated with partial nephrectomy and patients with vena cava infiltration were excluded, due to different surgical approach. All operations were performed under general anesthesia with standard retroperitoneal open approach, by experienced surgeons. Data included gender, age, clinical tumor size (largest diameter at computed tomography or magnetic resonance imaging), pathological stage (TNM-UICC 2002), comorbidity (CCI) and postoperative complications within 40 postoperative days. Complications were graded according to Clavien-Dindo by an independent researcher not involved in medical decisions. A drainage was left indwelling in all cases, typically removed on 3rd postoperative day and patients were discharged on 5th postoperative day. Patients hospitalized more than the 6th postoperative day were considered as having a prolonged hospital stay. Complications with a severity grade of > 2 were considered as “major”. In case of multiple complications in the same patient, only the highest grade was used for the analysis. The prognostic value of each variable for Clavien, was primarily assessed by univariate logistic regression analysis. Variables that exhibit significant association with the outcome were included in the multivariate logistic regression model in a stepwise method (p for entry 0.05, p for removal 0.10), in order to identify independent factors, associated with Clavien results.

RESULTS

Table 1 shows the characteristics of the 171 patients included in the study. Of the total group, 10 patients (5.8%) present with nodal disease and 17 (9.9%) with metastases at time of diagnosis. CCI ranged from 0 to 8. Eighty seven patients (50.8%) had no comorbidities at all, while 59 patients (34.5%) had mild (CCI 1 or 2) comorbidities and only 25 patients (14.6%) had considerable (CCI ≥ 3) comorbidities. No notable complications were recorded in most of the cohort (98 patients, 57.3%); the overall postoperative complication rate was 42.6% (73 of 171 patients). Most patients suffered minor complication of Clavien I (35 pts 20.5%) and Clavien II (14pts 8.2%). Major complications (grade ≥ III) occurred in 14 patients (postoperative ileus,

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Archivio Italiano di Urologia e Andrologia 2021; 93, 3

Table 1. Characteristics of the study population. Patients, n (%) Age, years ≤ 65 years > 65 years Gender Female Male Tumor size Tumor stage T1a T1b T2a T2b T3a T3b T4 N+ M+ CCI O 1 2 3 4 5 6 7 8 ≤2 Complications None Minor (Grade ≤ II) Major (Grade ≥ III) Grade I Grade II Grade III Grade IV Grade V

171 (%) 63.6 ± 11.7 yrs (35-88) 87 (50.8) 84 (49.2) 70 (40.9) 101 (59.1) 5.8 ± 3.2 cm (4.4-8.2 cm) 21 (12.2) 38 (22.2) 24 (14.0) 4 (2.3) 57 (33.3) 3 (1.7) 12 (7.0) 10 (5.8) 17 (9.9) 87 (50.8) 38 (22.2) 21 (12.2) 8 (4.6) 4 (2.3) 1 (0.5) 8 (4.6) 2 (1.2) 2 (1.2) 86 (47.3) 98 (57.3) 49 (28.6) 14 (8.2) 35 (20.4) 14 (8.1) 4 (2.3) 6 (3.5) 4 (2.3)

pneumonia, respiratory insufficiency after pneumonia, postoperative bleeding requiring intervention; of which 4 cases were fatal (grade V). Univariate logistic regression analyses for the occurrence of any complication (Clavien ≥ I) showed that: increased CCI was associated with increased likelihood for the manifestation of Clavien ≥ I with an OR (95% CI) of 1.45 (1.18-1.79), p < 0.001. Univariate logistic regression analyses for major complication (Clavien ≥ III) indicated that increased CCI was associated with increased odds for the occurrence of Clavien ≥ III with an OR (95% CI) of 1.35 (1.08-1.7) and p = 0.01. When multiple logistic regression analysis was applied for any complication (Clavien ≥ I) in a stepwise method, it was found that CCI was independently associated with complications. Specifically for one unit increase of CCI the likelihood for Clavien ≥ I increases 47% with a p value of 0.011. Multiple logistic regression analysis for major complications of Clavien ≥ III showed that CCI was also an independent predictor and for one unit increase of CCI the likelihood for Clavien ≥ III increases 29% with a p value of 0.038.

Radical nephrectomy complications and preoperative comorbidity

DISCUSSION

Treatment decisions in oncology patients are based on cancer type and stage, the assessment of life-expectancy and the treatment benefits against treatment-related adverse events. While age is the main determinant of lifeexpectancy, comorbidity, physical and mental functioning may also play a critical role. RCC patients may have significant comorbidities at diagnosis. An analysis of 47 studies where CCI was used (references on demand) revealed that at least 20% of the patients had significant comorbidity at diagnosis. In our cohort of patients, considerable (CCI ≥ 3) comorbidity was observed in 14.6% of them. Several studies have shown a significant correlation of CCI with cancer-specific and overall survival (3, 19, 20) this demonstrates that survival in RCC is dependent on not only tumor-related variables but also patient-related variables. Recording comorbidity with a validated instrument like CCI may even be incorporated into nomograms (11) to provide useful prognostic information. In cases of competing causes of death, a more conservative management (i.e., active surveillance) could be advocated, especially for T1a renal masses. The relationship between comorbidity and postoperative complications using standardized indices (CCI) and systems (Clavien-Dindo), accordingly, has not been studied appropriately. Hennus et al. (8) studied 198 patients with lesions suspected of RCC who underwent partial or radical nephrectomy. The complication rate was 34% while preoperative comorbidities were present in 51% of all patients. There were significantly more major complications (> grade II) in patients with major comorbidities (CCI > 2). Watanabe et al. (17) studied 62 patients ≥ 65 years old who underwent open partial or radical nephrectomy. Significant comorbidity (CCI ≥ 3) and grade ≥ II complications was observed in 9.7% and 17.7% of patients, respectively. The relationship between comorbidity and postoperative complications was statistically insignificant. Lue et al. (18) studied 144 patient who underwent nephrectomy along with excision of vena cava thrombus. The complication rate was 50% and comorbidity was significantly correlated with complication rate in multivariate analysis. Trudeau et al. (19) studied patients who underwent percutaneous or laparoscopic tumor ablation (289 and 227 patients, respectively). While median CCI was significantly different (2.1 vs 2.7, p = 0.03), postoperative complication rates were similar (21% vs 25%, p = 0.3). In both groups the complication rate was independent of comorbidity in multivariate analysis. In our study the overall postoperative complication rate was 24.2% and CCI was significantly correlated to the severity of postoperative complications.

CONCLUSIONS

Although no definite conclusions can be drawn, our results along with those of Hennus and Lue are useful in considering how to prevent complications or take proactive action, when possible, in patients with considerable comorbidity and RCC. For example, in patients with

chronic obstructive pulmonary disease postponing surgery to give time for pulmonary rehabilitation and systematic postoperative physiotherapy may help to avoid postoperative pneumonia or respiratory distress that could require admission to intensive care. Moreover, complication rate reports should be adjusted for comorbidity to allow fair comparisons of quality of care and performance among individual surgeons, different techniques, urology departments and hospitals.

REFERENCES

1. Ljungberg B, Albiges L, Abu-Ghanem Y, et al. European Association of Urology Guidelines on Renal Cell Carcinoma: The 2019 Update. Eur Urol. 2019; 75:799-810. 2. Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009; 27:5794-9. 3. Santos Arrontes D, Fernandez Acenero MJ, Garcia Gonzalez JI, et al. Survival analysis of clear cell renal carcinoma according to the Charlson comorbidity index. J Urol. 2008; 179:857-61. 4. Kutikov A, Egleston BL, Wong YN, Uzzo RG. Evaluating overall survival and competing risks of death in patients with localized renal cell carcinoma using a comprehensive nomogram. J Clin Oncol. 2010; 28:311-7. 5. Thomas M, George NA, Gowri BP, et al. Comparative evaluation of ASA classification and ACE-27 index as morbidity scoring systems in oncosurgeries. Indian J Anaesth. 2010; 54:219-25. 6. Post PN, Hansen BE, Kil PJ et al. The independent prognostic value of comorbidity among men aged < 75 years with localized prostate cancer: a population-based study. BJU Int. 2001; 87:821826. 7. Svatek RS, Fisher MB, Matin SF, et al. Risk factor analysis in a contemporary cystectomy cohort using standardized reporting methodology and adverse event criteria. J Urol. 2010; 183:929-34. 8. Hennus PML, Kroeze SGC, Bosch JLHR, Jans JJM. Impact of comorbidity on complications after nephrectomy: use of the Clavien classification of surgical complications. BJU Int. 2012; 110:682-687. 9. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis. 1987; 40:373-383. 10. Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidem. 1994; 47:1245-1251. 11. de Groot V, Beckerman H, Lankhorst G, Bouter L. How to measure comorbidity: a critical review of available methods. J Clin Epidemiol. 2003; 56:221-229. 12. Kutikov A, Egleston BL, Canter D, et al. Competing risks of death in patients with localized renal cell carcinoma: a comorbidity based model. J Urol. 2012; 188:2077-2083. 13. Mitropoulos D, Artibani W, Graefen M, et al. European Association of Urology Guidelines Panel. Reporting and grading of complications after urologic surgical procedures: an ad hoc EAU guidelines panel assessment and recommendations. Eur Urol. 2012; 61:341-9. 14. Clavien PA, Barkun J, de Oliveira ML, et al. The ClavienDindoclassification of surgical complications: five-year experience. Ann Surg. 2009; 250:187-196. 15. Mitropoulos D, Artibani W, Biyani CS, et al. Validation of the Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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Clavien-Dindo grading system in Urology by the EAU guidelines ad hoc panel. European Urology Focus. 2018; 4:608-613.

IVC Thrombectomy: A Large Contemporary Tertiary Center Analysis. Clinical Genitourinary Cancer. 2016; 14:89-95.

16. Watanabe D, Miura K, Yamashita A, et al. A Comparison of the Predictive Role of the Geriatric Nutritional Risk Index and Immunonutritional Parameters for Postoperative Complications in Elderly Patients with Renal Cell Carcinoma. J Invest Surg. 2020; 1-6.

18. Trudeau V, Larcher A, Boehm K, et al. Comparison of postoperative complications and mortality between laparoscopic and percutaneous local tumor ablation for T1a renal cell carcinoma: a population-based study. Urology. 2016; 89:63-7.

17. Lue K, Russell CM, Fisher J, et al. Predictors of Postoperative Complications in Patients Who Undergo Radical Nephrectomy and

Correspondence Evangelos Fragkiadis, MD (Corresponding Author) e.fragkiadis@gmail.com Christos Alamanis, MD Constantinos A Constantinides, MD Dionysios Mitropoulos, MD 1st Urology Department Univesity of Athens Laiko Hospital Athens Greece

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19. Lund L, Jacobsen J, Norgaard M, et al. The prognostic impact of comorbidities on renal cancer, 1995 to 2006: a Danish population based study. J Urol. 2006; 182:35-40.

DOI: 10.4081/aiua.2021.3.255

ORIGINAL PAPER

The impact of orthotopic reconstruction on female sexuality and quality of life after radical cystectomy for non-malignant bladder conditions Chiara Borghi 1, Margherita Manservigi 1, Elena Sofia Milandri 1, Carmelo Ippolito 3, Pantaleo Greco 1, Lucio Dell’Atti 2 1 Department

of Surgical Sciences, Section of Obstetrics and Gynecology, Azienda Ospedaliero-Universitaria Sant’Anna, University of Ferrara, Cona (Ferrara), Italy; 2 Division of Urology, Department of Clinical, Special and Dental Sciences, University Hospital "Ospedali Riuniti" School of Medicine, Marche Polytechnic University, Ancona, Italy; 3 Department of Surgical Sciences, Section of Urology, Azienda Ospedaliero-Universitaria Sant’Anna, University of Ferrara, Cona (Ferrara), Italy.

Summary

Objective: To review the literature on the impact on female quality of life and sexual function of orthotopic reconstruction after radical cystectomy for non-malignant bladder conditions. Radical cystectomy is commonly required to treat malignant conditions but may also be considered for the treatment of non-malignant diseases. These heterogeneous group of disorders includes interstitial cystitis, painful bladder syndrome, neurogenic bladder, haemorrhagic/radiation cystitis, endometriosis and refractory genitourinary fistula. Treatment begins with non-invasive medical therapies but, in non-responder cases, a surgical solution should be considered. Such invasive techniques include urinary diversion and reconstructive procedures that have an impact on healthrelated quality of life, physical, social, and mental status. Materials and methods: This narrative review research was done using the PubMed database up until 2020, July. All papers referring to cystectomy for benign indication were considered. Results: In comparison to other reconstructive options, orthotopic neobladder allows the restoration of a normal self-image and consequently it is the most suitable procedure when a surgical reconstruction is necessary for non-malignant conditions. However, women can face many disorders that impact on everyday life, such as voiding dysfunction or sexual activity problems. Conclusions: Scant data is available about quality of life, sexual life and self-perception in women treated by cystectomy for benign conditions and most literature is dedicated to those indicators in cancer patients. More research is needed to understand the tolerability and the quality of life results of the female population affected by benign conditions undergoing this kind of surgical approach.

KEY WORDS: Orthotopic bladder; Cystectomy; Quality of life; Woman; Benign conditions; Non malignant conditions; Endometriosis; Interstitial cystitis; Neurological bladder; Sexuality; Urinary symptoms. Submitted 25 January 2021; Accepted 23 April 2021

INTRODUCTION

Cystectomy is commonly required to treat malignant conditions such as urothelial carcinoma of the bladder. Cystectomy with urinary diversion may also be considered

for the treatment of non-malignant conditions in patients who have failed previous conservative therapies. These benign conditions represent a heterogeneous group of disorders including interstitial cystitis, painful bladder syndrome, neurogenic bladder, hemorrhagic/radiation cystitis, endometriosis and refractory genitourinary fistula. Treatment begins with non invasive medical therapies but, in refractory cases, a surgical solution should be considered. After cystectomy, a urinary diversion and reconstructive procedures are needed. Over the past decades, orthotopic neobladder became a widely accepted technique for urinary diversion and the preferred method after removal of the bladder. Initially, it was limited just to men; women were considered ineligible for this procedure because urethra-sparing orthotopic substitution was thought to be associated with an increased risk of local recurrence and voiding dysfunction. With the improved understanding of the female sphincter mechanism, however, this approach has become technically accepted in selected cases (1). An important issue in the decision-making process, prior to urinary diversion in females, is health related quality of life, including the effects of reconstruction of neobladder on physical, social and mental status. Comparing the orthotopic neobladder to the other reconstructive options, this approach allows the restoration of a normal self-image and then it is the most suitable procedure when a surgical reconstruction is necessary for non-malignant conditions. However, women undergoing cystectomy for benign bladder conditions can face many disorders that can impact on everyday life, such as voiding dysfunction or sexual activity problems. These symptoms and complications can be temporary or permanent. Voiding often has a major impact on quality of life and an improved quality of life after urinary diversion fails to be realized when voiding dysfunction arises (2). Voiding dysfunction following the orthotopic neobladder can be divided into failure to store urine, during daytime, nighttime or both, and failure to empty, requiring intermittent self-catheterization (3). This paper reviews the literature on the impact of ortho-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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topic reconstruction on female quality of life and sexual function after radical cystectomy for non-malignant bladder conditions.

MATERIALS

RESULTS AND METHODS

Research was done using the PUBMED database up until 2021, January. All papers referring to cystectomy for benign indication were considered. A combination of Medical Subject Headings (MeSH) terms was used. The keywords were: orthotopic bladder, cystectomy, quality of life, sexuality, woman, benign, endometriosis, interstitial cystitis, radiation cystitis and neurogenic bladder. All titles and abstracts published in English were evaluated. Each article was evaluated according to the inclusion criteria: studies reporting any surgical intervention to treat benign bladder conditions, orthotopic neobladder for benign condition, quality of life after cystectomy and reconstructive surgery with particular attention to female population. All studies were considered, with the exception of those performed on animals, comments, letters, editorials and case reports. Due to the high heterogeneity regarding the indication for surgery, surgical approach, anesthesia procedures and complications, only a non-systematic Figure 1. Flow chart for paper selection.

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review of literature and a critical synthesis of clinical experiences was performed.

Archivio Italiano di Urologia e Andrologia 2021; 93, 3

AND DISCUSSION

The initial search yielded a total of 47 articles. Forty articles were excluded after title/abstract screening for not meeting inclusion criteria. A total of seven articles strictly related to our issue were finally evaluated and reviewed by the authors. The selection of papers is reported in Figure 1. Other papers were included because of the topic relevance. Non-malignant indications for cystectomy Few benign diseases include cystectomy with urinary diversion among the treatment options. All of them have behavioral and medical first line therapies but, when patients are refractory to these less invasive ones, they can be considered for surgery. These conditions are included in the present review’s purpose and here shortly described. - Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS): a chronic debilitating inflammatory disease of the bladder that mainly affects women, most often in the fourth decade or later. It is defined as an unpleasant sensation characterized by suprapubic pain and lower urinary

Bladder orthotopic reconstruction in women

tract symptoms lasting more than six weeks, in absence of infection or other identifiable causes (4, 5). Neurogenic bladder: a condition that can be caused by congenital anomalies such as meningomyelocele and spina bifida or by acquired central nervous system diseases, such as spinal cord injury, multiple sclerosis, stroke, and parkinsonism (6). If left untreated, these pathological conditions can lead to a progression of urinary dysfunction. The diagnosis is based on clinical evaluation. Biological, radiological, and urodynamic investigations are indicated to plan the best management (6-8). Hemorrhagic cystitis is a condition characterized by hematuria and lower urinary tract symptoms. It can be acute or chronic, caused by trauma, infections, chemotherapy, and radiation (9-11). The diagnosis of hemorrhagic/radiation cystitis is based on past medical history, signs, symptoms, urine tests and cystoscopy (12). Genitourinary tuberculosis and schistosomiasis are infectious diseases endemic in developing countries that can cause severe urinary damage such as bladder fibrosis. About 30% of extra-pulmonary tuberculosis interest the genitourinary system. The most common symptoms of bladder tuberculosis are flank pain, dysuria, hematuria and frequency (13). The diagnosis is based on clinics, urine testing with sterile pyuria, histopathological examination and radiological exam (caverns of kidney) (14). All patients are treated with antibiotics, but in case of severe retracted bladder or serious reflux that damages the upper urinary tract, a surgical treatment could be necessary (13, 15). In schistosomiasis, the host immune reaction to the bilharzial eggs results in healing by fibrosis and may progress to mucosal, submucosal, or muscular lesions, up to squamous cell carcinoma (16-18). Bladder endometriosis is defined as the infiltration of the endometrial tissue into the detrusor muscle. Characteristic symptoms include dysuria, frequency, hematuria, urgency and bladder pain, symptoms that may worsen during menstruation. Vaginal and physical examinations allow the identification of palpable nodules. Trans-vaginal ultrasonography should be regarded as a first line radiological test for the assessment of bladder endometriosis, while Magnetic Resonance is considered a second-line technique. Cystoscopy is used to assess the interior lining of the urethra and bladder (19). Conservative approaches can be used, such as the simple resection of endometriotic nodules, however, in selected cases, partial cystectomy is needed (20).

Orthotopic neobladder - Surgical principles Orthotopic neobladder is one of the reconstructive urinary diversion procedures after cystectomy. Technique of orthotopic bladder aim to build a high capacity and low pressure reservoir and to connect it to the native urethra, proximally to the external striated sphincter. The neobladder reservoir is made of de-tubularized gastric, ileum, ileocolonic or colonic segments. Maximal neobladder capacity depends on the choice and configuration of bowel segments harvested. In general, pressures are lower and capacities are greater in ileal segments. This procedure allows the patient to void volitionally through the urethra, restoring a more natural voiding pattern (21).

Long-Term Quality of Life following cystectomy and urinary diversion with orthotopic bladder In the World Health Organization (WHO) concept of health and quality of life (QoL), the latter is defined as “an individual’s perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations and standards and concerns” (22). Health-related quality of life after surgery appears to be an important issue in the decision-making process prior to urinary diversion. Although disease or anatomic considerations may limit neobladder use in some patients, orthotopic bladder is commonly suitable to many of those undergoing cystectomy. This procedure is associated with significant changes in urinary and sexual function, relationships, and psychosocial habits (23). All these changes impact patients’ perceived quality of life. Several groups analyzed QoL after radical cystectomy and reconstruction of neobladder for malignant conditions, comparing it with other types of urinary diversion, to clarify the effects on physical, social, and mental status. Some proponents of continent orthotopic diversion have used general quality of life instruments (i.e. 36-Item Short Form SF36) (24) to study patient outcomes and have cited incontinence bother, sexual function, and social comfort as possible reasons to use neobladder diversion (25, 26). Most investigators, however, have been unable to demonstrate significant differences in quality of life parameters among diversion groups. For example, Hobisch at al. compared subjective morbidity of ileal neobladder versus ileal conduit urinary diversion to elucidate its influence on quality of life. Using the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC-QLQC30 (27) they found that patients with a neobladder needed a shorter period of rehabilitation, 92.8% of them did not feel handicapped at all and 87% had no feelings of sickness or illness. They also demonstrated that urinary leakage, odor, and wet clothing were much more common in patients with the stomal appliance of conduit than in the continent reservoir and neobladder patients (28). On the other hand, Hedgepeth at al. studied the body image and quality of life, evaluating urinary, sexual and bowel domains, and they did not find any difference between patients undergoing urostomy and those who had neobladder reconstruction (29). There is a paucity of outcome data regarding quality of life after urinary diversion with orthotopic bladder for benign conditions in literature. In a study about bladder substitution by ileal neobladder in women with IC/PBS, authors found that all patients presented good treatment outcomes and quality of life by using SF36 questionnaire. They showed significant improvement of both physical and mental health (30). Moreover, the main factors affecting General Health QoL (GH-QoL) after neobladder substitution were voiding dysfunctions. In fact, patients with daytime incontinence or requiring clean intermittent catheterization (CIC), had lower SF36 scores than those without these symptoms (2, 30). However, Cody and colleagues, in a Cochrane collaboration review, analyzed the different types of urinary diversion and the review did not find any significant evidence Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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as to the superiority of continent vs incontinent diversion after cystectomy for malignant as well as non-malignant indications (31). Voiding dysfunctions in the orthotopic neobladder Voiding dysfunctions following orthotopic neobladder can be divided into urinary incontinence during the daytime, night-time or both, or the inability to empty the bladder (“hyper-continence”) requiring CIC (32). Voiding disorders are frequent findings in female patients after orthotopic neobladder and can arise both from physiological and anatomical defects. Risk factors for the development of the daytime urinary incontinence include advanced age, inadequate storage reservoir and alteration of the sphincteric mechanism (3). Nerve sparing cystectomy is another factor believed to provide early continence in female patients, along with the preservation of the trigone with no damage to the autonomic nervous system. However, with the preservation of the trigone, a significant portion of patients develop urinary retention, which worsens over time. The highest rates of urinary retentionists are found where nerve-sparing technique is performed (30, 33). Another common effect of neobladder is night-time incontinence. It results from the overdistension of the neobladder and lack of voiding sensation. The patient fails to wake up during the night to empty the bladder, allowing excessive urinary volume to overcome the urethral closure mechanism. The use of cystectomy with a neobladder for treatment of patients with bladder carcinoma has been reported with long term follow up, demonstrating that this operation is safe for female patients (34). However, care must be taken at the time of surgery to prevent future voiding problems. In fact, the post-operative reduction in terms of QoL is substantial when voiding dysfunctions occur

following the neobladder. Patients with daytime incontinence or requiring CIC had lower SF36 scores than those without incontinence or CIC. However, General healthQuality of Life (GH-QoL) score in patients with enuresis was the same as that without enuresis, regardless of the degree of enuresis and urination QoL was not as high as surgeons expected (2). On the other hand, it was found that, even if the patient is incontinent and requires 5 to 6 sanitary pads daily, neobladder was preferable to maintain body image (1). Sexual function following cystectomy and urinary diversion with orthotopic bladder During radical cystectomy in women, the neurovascular bundles, placed on the lateral walls of the vagina, are usually removed or damaged by removal of the bladder, urethra, and anterior vaginal wall. Therefore, anterior exenteration may result in diminished ability or inability to achieve orgasm, decreased lubrication, decreased sexual desire and dyspareunia (35). Sexual dysfunction is a prevalent problem after female radical cystectomy and many of bladder cancer specific questionnaires, such as the Bladder Cancer Index (BCI), Vanderbilt Cystectomy Index (VCI), Functional Assessment of Cancer Therapy – Bladder (FACT-B) and EORTC-QOL-B20, include sexual function and dysfunction items. For women, the most commonly used questionnaire is the Female Sexual Function Index (FSFI), that analyzes specific domains including the degree of vaginal lubrication, ability to achieve orgasm, degree of pain during intercourse, overall sexual desire and interest, and overall sexual satisfaction. Craig et al. conducted a clinical study to address sexual dysfunction in a subset of sexually active women undergoing radical cystectomy (RC) using a modified Index of Female Sexual Function questionnaire and strat-

Table 1. Studies about orthotopic neobladder for benign conditions, extraction of women population. Authors, year

Type of study

Disease

Number of benign cases

Gross et al., 2015 (37) Cohn et al., 2014 (38)

Observational Observational

Gobeaux et al., 2011 (39)

Observational

Post-radiation cystitis Infection, fistula, bleeding, neurogenic bladder or pain Neurogenic detrusor overactivity

4 2 (not clear if men or women) 31

Takenaka et al., 2010 (2) Observational

Contracted bladder

Kochakarn et al., 2007 (30) Observational Observational

Interstitial cystitis neobladder (modified Sturder) Not specified

Shimogaki et al., 1999 (1) Observational

Contracted bladder

Studer et al., 2005 (40)

Type of orthotopic neobladder after RC or SC RC with ileal orthotopic neobladder RC with ileal orthotopic neobladder

Mean age (years)

SC with ileal orthotopic neobladder (modified Hautmann)

34.7

1 (not clear if man or woman) 35

RC with ileum or colon as neobladder reservoirs

RC with ileal orthotopic (SF-36 questionnaire)

17 (not clear if men or women) 2

QoL = Quality of Life.

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61.7 57.8

QoL (evaluated yes/no instrument if yes) No No

LUTS Sexual function (evaluated (evaluated yes/no) yes/no) Yes No Yes No

Yes (voiding diary, radiological, laboratory, endoscopic and urodynamic assessment) Yes (SF-36 questionnaire)

Yes

No (only in male)

45.9

Yes

RC with ileal orthotopic neobladder

Yes

No (only in male)

SC with ileal orthotopic neobladder

45.5

Yes (questionnaire about voiding status, continence and QoL)

Yes

Bladder orthotopic reconstruction in women

ifying the sexual response by the type of urinary diversion to determine whether vaginal sparing (as performed in the orthotopic diversion) influenced the sexual response. No statistically significant difference was found between the Indiana external diversion stoma and the Studer orthotopic in women after RC (35). When performed for benign conditions, cystectomy frequently does not need anterior pelvic exenteration. Nevertheless, sexual dysfunction may be related to neural injury and changes in pelvic anatomy. Other factors that may impact sexual satisfaction and libido include body alterations associated with urinary diversion, resulting in changes in body images, emotional and psychological responses of both patients and their partners, and the age-related changes in libido and sexual interest. Patients with orthotopic neobladder do not undergo the same degree of body alteration as others urinary diversion techniques, but the poor urine control and incontinence can be significant stressors that may limit interest in sexual activity (36). Moreover, preservation of normal sexual function in women has not been the main goal in most studies of neobladders in women. In conclusion, orthotopic neobladder technique, used for the treatment of benign diseases, allows the improvement of both physical and mental health. Urinary symptoms remain the most frequently reported problems affecting general health and sexual function in operated women. Sexual function and quality of life in women after radical cystectomy for non-malignant bladder conditions In Table 1 we listed the few articles taking into account the population of interest. Gross et al. in 2015 evaluated how hysterectomy and nerve sparing affected functional outcomes after ileal orthotopic bladder substitution in 73 women. Four of them underwent cystectomy for postradiation cystitis, the other 69 for invasive urothelial cancer. The results showed a strong correlation between postoperative urinary incontinence and pre- or perioperative hysterectomy. These findings suggest that voiding disorders are related to the damage of autonomic nerves, which run along the lateral aspect of cervix uteri (37). Cohn et al. (2014) investigated perioperative outcomes after cystectomy and urinary diversion for the treatment of refractory benign urological diseases, like infection, fistula, bleeding, incontinence, neurogenic bladder or pain. The study group included 8 males and 18 females; 22 patients underwent ileal conduit, 2 underwent ileal neobladder and 2 underwent Indiana pouch diversion. The authors demonstrated that cystectomy and urinary diversion resulted in resolution of urological symptoms in 73% of patients but the procedure was morbid for many, in fact 73% of patients experienced a complication within 30 days of surgery (urinary tract infection, abscess, urine leak etc) (38). Gobeaux et al. (2011) evaluated continence status, urodynamic changes and long-term sequelae of Hautmann pouch following supratrigonal cystectomy in a population of 61 patients, 30 males and 31 females, with neurogenic detrusor overactivity. They found that this surgical technique achieved complete continence in 75% of cases, reduced rates of infection and dependency on pharmaco-

logical agents. All these factors contributed to the improvement of QoL (39). Takenaka et al. (2010) analyzed the general health QoL, urinary QoL, and sexual QoL in 78 males and 8 females five years after orthotopic neobladder substitution. Most of the population had bladder cancer or malignancies of other organs that had invaded the bladder. Only one patient, whose gender isn’t specified, had a benign pathology. The authors found that although the general health QoL was generally well maintained, the presence of intermittent CIC or daytime incontinence impaired the QoL. Regarding sexual satisfaction and female sexual function, authors didn’t examine these items (2). Kochakarn et al. in 2007 reported their experience with cystectomy and ileal neobladder in 35 female patients with interstitial cystitis, in particular they assessed general QoL, voiding disorders and sexual life. They showed that QoL improved in both physical and mental health components; after 6 months diurnal and nocturnal continence were achieved in 100% of patients, spontaneous voiding was noted in 33 cases, the other 2 cases voided spontaneously with residual urine and used intermittent catheterization. Among 30 cases of sexually active patients, 12 had mild degree of dyspareunia during the first year, no patient had problems in sexuality after 1 year (30). Studer et al. in 2005 presented long-term results of a large series of patients after ileal orthotopic bladder substitution. The study considered 482 patients including 40 women; cystectomy was performed for cancer in 465 cases and for other reasons in only 17 cases (not clear if males or females). The authors demonstrated that the bladder capacity was increased rapidly after surgery, daytime and nighttime frequency decreased during the first year then remained unchanged for 5 years and urinary infections occurred in 10% of patients, in association with residual urine. The sexual function was considered only in men (40). Shimogaki et al. (1999) investigated the long-term outcome of orthotopic neobladders in 8 women, 6 of whom were treated for invasive bladder cancer and 2 for contracted bladder. In particular, they focused on QoL and voiding dysfunction. They found that patients’ satisfaction was excellent, daytime and nighttime continence was achieved in 88% of the patients, although half of the women required intermittent catheterization (1). In cases of failure of all conservative treatments, cystectomy with enterocystoplasty is used in many institutions for treating IC/PBS. At the beginning of bladder reconstruction in female patients, supratrigonal cystectomy has been used to avoid urinary incontinence. However, even leaving only vestigial bladder muscle, persistent painful bladder was still present. Webster et al. reported complete painful relief after additional removal of the trigone in patients submitted to supratrigonal cystectomy and enterocystoplasty for treating IC/PBS (41-43). In fact, urinary incontinence after a neobladder operation depends on creating adequate storage reservoir and preserving the sphincteric mechanism. Sectioning the urethra below bladder neck in female patients can maintain the continence mechanism with better emptying than in the case of bladder neck preservation (44). Nerve sparing cystecArchivio Italiano di Urologia e Andrologia 2021; 93, 3

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tomy is another factor believed to provide early continence in women. Sparing of autonomic nerve fibers provide beneath the urethra was found to provide early urinary control in derived patients. Keeping endopelvic fascia intact not only preserves the nerve but also keeps urethra-pelvic ligament, enhancing urinary control (45).

CONCLUSIONS

Orthotopic neobladder is a complex surgical technique used for reconstruction of lower urinary tract after cystectomy. Such procedure is used for benign conditions only in cases of lack of response to conservative treatments. It allows preservation of normal body perception but, on the other hand, it is related to several possible adverse conditions and complications. Scant data is available about quality of daily life, sexual life and self-perception in women treated for benign conditions and most literature is dedicated to QoL indicators in cancer patients (46). More research is still needed to better understand the tolerability and the Quality of Life results in the female population affected by benign conditions undergoing this kind of surgical approach.

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29. Hedgepeth RC, Gilbert SM, He C, et al. Body image and bladder cancer specific quality of life in patients with ileal conduit and neobladder urinary diversions. Urology. 2010; 76:671-675.

10. Dropulic LK, Jones RJ. Polyomavirus BK infection in blood and marrow transplant recipients. Bone Marrow Transplant. 2008; 41:11-18.

30. Kochakarn W, Lertsithichai P, Pummangura W. Bladder substitution by ileal neobladder for women with interstitial cystitis. Int Braz J Urol. 2007; 33:486-492.

11. Stillwell TJ, Benson RC. Cyclophosphamide induced hemorrhagic cystitis: A review of 100 patients. Cancer 1988; 61:451-457.

31. Cody JD, Nabi G, Dublin N, et al. Urinary diversion and bladder reconstruction/replacement using intestinal segments for intractable incontinence or following cystectomy. Cochrane Database Syst Rev. 2012; 2012:CD003306

12. Okaneya T, Kontani K, Komiyama I, Takezaki T. Severe cyclophosphamide-induced hemorrhagic cystitis successfully treated by total cystectomy with ileal neobladder substitution: A case report. J Urol. 1993; 150:1909-1910.

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13. Gokce G, Kilicarslan H, Ayan S, et al. Genitourinary tuberculosis: A review of 174 cases. Scand J Infect Dis. 2002; 34:338-340.

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32. Park JM, Montie JE. Mechanisms of incontinence and retention after orthotopic neobladder diversion. Urology. 1998; 51:601-609.

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33. Chiang PH, Huang YS, Wu WJ, et al. Orthotopic bladder substitution in women using the ileal neobladder. J Formos Med Assoc. 2000; 99:348-351.

40. Studer UE, Burkhard FC, Schumacher M, et al. Twenty years experience with an ileal orthotopic low pressure bladder substitutelessons to be learned. J Urol. 2006; 176:161-166.

34. Hautmann RE, Volkmer BG, Schumacher MC, et al. Long-term results of standard procedures in urology: The ileal neobladder. World J Urol. 2006; 24:305-314.

41. Webster GD, Maggio MI. The management of chronic interstitial cystitis by substitution cystoplasty. J Urol. 1989; 141:287-91.

35. Zippe CD, Raina R, Shah AD, et al. Female sexual dysfunction after radical cystectomy: A new outcome measure. Urology. 2004; 63:1153-1157. 36. Modh RA, Mulhall JP, Gilbert SM. Sexual dysfunction after cystectomy and urinary diversion. Nat Rev Urol. 2014; 11:445-453. 37. Gross T, Meierhans Ruf SD, Meissner C, et al. Orthotopic ileal bladder substitution in women: Factors influencing urinary incontinence and hypercontinence. Eur Urol. 2015; 68:664-671. 38. Cohn JA, Large MC, Richards KA, et al. Cystectomy and urinary diversion as management of treatment-refractory benign disease: The impact of preoperative urological conditions on perioperative outcomes. Int J Urol. 2014; 21:382-386. 39. Gobeaux N, Yates DR, Denys P, et al. Supratrigonal cystectomy with Hautmann pouch as treatment for neurogenic bladder in spinal cord injury patients: Long-term functional results. Neurourol Urodyn. 2012; 31:672-676.

42. Peeker R, Aldenborg F, Fall M. The treatment of interstitial cystitis with supratrigonal cystectomy and ileocystoplasty: difference in outcome between classic and nonulcer disease. J Urol. 1998; 159:1479-82. 43. Osman NI, Bratt DG, Downey AP, et al. A systematic review of surgical interventions for the treatment of bladder pain syndrome/interstitial cystitis. Eur Urol Focus. 2020; S24054569(20)30071-7. 44. Venn SN, Mundy AR. 'Nerve-sparing' cystectomy in women. Int Urogynecol J Pelvic Floor Dysfunct. 2000; 11:237-40. 45. Chiang PH, Huang YS, Wu WJ, Chiang CP. Orthotopic bladder substitution in women using the ileal neobladder. J Formos Med Assoc. 2000; 99:348-51. 46. Chong JT, Dolat MT, Klausner AP, et al. The role of cystectomy for non-malignant bladder conditions: a review. Can J Urol. 2014; 21:7433-41.

Correspondence Chiara Borghi, MD (Corresponding Author) borghi.chr@gmail.com Margherita Manservigi, MD mnsmgh@unife.it Elena Sofia Milandri, MD elenasofia.milandri@gmail.com Pantaleo Greco, MD, Prof. pantaleo.greco@unife.it Department of Surgical Sciences, Section of Obstetrics and Gynecology, Azienda Ospedaliero-Universitaria Sant' Anna, University of Ferrara, via Aldo Moro 8, 44124 Cona (Ferrara), Italy Carmelo Ippolito, MD c.ippolito@ospfe.it Department of Surgical Sciences, Section of Urology, Azienda Ospedaliero-Universitaria Sant' Anna, University of Ferrara, via Aldo Moro 8, 44124 Cona (Ferrara), Italy Dell’Atti, MD, PhD dellatti@hotmail.com Division of Urology, Department of Clinical, Special and Dental Sciences, University Hospital "Ospedali Riuniti" School of Medicine, Marche Polytechnic University via Conca 71, 60126 Ancona (Italy)

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DOI: 10.4081/aiua.2021.3.262

ORIGINAL PAPER

Technique selection of ureteroileal anastomosis in hautmann ileal neobladder with chimney modification: Reliability of patient-based selection strategy and its impact on ureteroentric stricture rate Dejan Djordjevic 1, Svetomir Dragicevic 1, Marko Vukovic 2 1 Urology Clinic, Euromedik General Hospital, Belgrade, Serbia; ² Urology clinic, Clinical centre of Montenegro, Podgorica, Montenegro.

Summary

Objective: We aimed to establish the reliability of technique selection strategy for ureteroileal anastomosis (Bricker vs. Wallace) by comparing perioperative outcomes, complications, and anastomotic stricture rate in a contemporary series of patients who underwent open radical cystectomy followed by reconstruction of modified Hautmann neobladder. Materials and methods: A total of 60 patients underwent radical cystectomy and modified Hautmann neobladder, of whom 30 patients (group I) with Bricker anastomotic technique were compared to 30 matched paired patients with end-to-end ureteroileal anastomosis (group II). Long-term results, including ureteroileal stricture (UIS) and postoperative complication rate at two year follow up were available. The choice of anastomosis type was successively based on chimney size, ureteral length after retro-sigmoidal tunneling and diameter of distal ureter. Postoperative complications were graded according to the Clavien-Dindo system. Results: Ureteroileal stricture rate was 6.6% in group I vs. 0% in group II, after three months (p < 0.05), while anastomotic leakage rate was 6.6% vs. 3.3% (group I vs group II) between the two groups for the same follow up period (p > 0.05). High-grade complications (Clavien III-V) were more in Bricker group as compared to Wallace group and the difference was significant (20% vs 10.3%, p = 0.03). Conclusion: Our preliminary outcomes demonstrate that this selection strategy seems to be clinically reliable, with lower incidence of postoperative complications in Wallace group.

KEY WORDS: Orthotopic bladder substitution; Urinary diversion; Reconstructive urology; Selection strategy; Surgical technique. Submitted 25 May 2021; Accepted 25 June 2021

INTRODUCTION

In both male and female patients, orthotopic bladder substitution has become the preferred method of urinary diversion post radical cystectomy (RC) for malignant disease (1). Among different reconstructive modalities, ileal neobladder with Hautmann or Studer reservoir is a frequent orthotopic diversion and several modified techniques have been described (2-6). The standard technique for uretero-enteric anastomosis is

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No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

the Bricker ureteral implantation in an end-to-side fashion using running sutures (7). According to the literature, the ureteroileal stricture (UIS) rate using this technique ranges between 3%-20% (7-10). A frequently used anastomotic technique in urinary diversions is that described by Wallace, in which the end of the intestine is sutured to the end of the ureter (11). It is already known that this technique has the lowest complication rate comparing to other ureterointestinal anastomosis (12), including its usage in orthotopic bladder reservoirs (13, 14). Nevertheless, only a few studies favour this technique in orthotopic neobladder (5, 6, 15). The objective of this study was to establish the reliability of technique selection strategy for ureteroileal anastomosis, based upon patients characteristics; additionally, we aimed to compare perioperative outcomes and ureteroileal anastomotic stricture rate in a contemporary series of patients who underwent open RC followed by reconstruction of modified Hautmann neobladder.

MATERIALS

AND METHODS

Study design and patients We compared 30 matched paired patients who underwent Hautmann neobladder with single chimney and Bricker anastomotic technique (2, 3) with 30 matched paired patients who underwent Hautmann neobladder with chimney modification consisting of a longer ureteral spatulation (3-4 cm) combined with end-to-end ureteroileal anastomosis (Wallace type I) and 6-8 cm long isoperistaltic tubularised chimney (16). Long-term results, including uretero-ileal stenosis (UIS) and postoperative complications rate (graded according to Clavien-Dindo system) at 2-year follow-up, were available for analysis. The main differences between techniques were the length of the ureteral spatulation, the chimney size and the endto-end running suture ureteroileal anastomosis (Figure 1). Patient characteristics included three aspects: ureteral length after retro-sigmoidal tunneling, chimney size and diameter of distal ureter after dissection and preparation for anastomosis. When the ureteral length was similar on

Technique selection for ureteroileal anastomosis in orthotopic diversion

Clinical Centre of Serbia and conducted in accordance with the principles of the Declaration of Helsinki from the World Medical Association. The surgery comprised RC with standard pelvic lymph node dissection (PLND), which was followed by reconstruction of Hautmann neobladder with chimney modification. Eligible patients were aged ≥ 30 yr and had BCa clinical stage T2-T3/N0/M0. Patients were excluded if they had previous pelvic radiation, clinical stage T4 or N1-N3/M1, positive frozen-section urethral biopsy, extensive prior abdominal surgery, serum creatinine level of > 2.0 ng/mL and any history of upper urinary tract malignancy (4). Complications were reported according to the modified Clavien-Dindo classification system (18). Reservoir-related complications included obstructive or non-obstructive hydronephrosis, UIS, both sides, Wallace was preferred; when disparate, pyelonephritis, anastomotic leakage, metabolic acidosis Bricker was performed (12, 17). Moreover, if the ureters and vesicoureteral reflux (VUR). UIS was diagnosed when were transected at the level of common iliac vessels [difthere was evidence of obstruction on imaging (symptofuse carcinoma in situ (CIS)], chimney length was 10-12 matic hydronephrosis), worsening renal function or cm and Bricker anastomosis was performed (2, 3); if infection (18). Non-obstructive hydronephrosis was ureters were divided more distally, as close to the bladder defined as a distended intrarenal collecting system on as possible, Wallace anastomosis on 6-8 cm long chimney imaging without evidence of UIS or other mechanical was preferred (16). The third decision was based on the obstruction and was confirmed by intravenous urography diameter of distal ureteral end, after the ureter has been (IVU) or computed tomography (CT). divided and prepared for anastomosis. When distal Of note, pyelonephritis was designated as a positive urine ureteral end was more than double size of normal diamculture in association with foul smelling urine and fever eter (long-standing hydronephrosis), Wallace was pre(19). Perioperative outcomes were systematically and ferred. If distal end was of a normal caliber, the choice of prospectively collected at surgery and during hospitalizaanastomotic technique was based upon other two varition and each complication classified as early (< 3 ables. The inclusion and exclusion criteria are presented months) or late (> 3 months after surgery). Patient interin the patient flowchart (Figure 2). views were conducted by medical doctors and according Bladder cancer (BCa) patients scheduled for definitive to European Association of Urology (EAU) guidelines on treatment were recruited from the Urology Clinic at the reporting and grading of complications (20). Clinical Centre of Serbia. The surgical protocol had been In this study we aimed to establish an optimal technique approved by the University of Belgrade Institutional review selection strategy for ureteroenteric anastomosis (Bricker board and registered with the Ethical committee of vs. Wallace) based on patient characteristics and evaluated according to difference in early Figure 2. and late perioperative complicaPatient flowchart describes selection criteria for surgical approach. tions and postoperative healthrelated quality of life (HRQOL). Figure 1. Differences between two techniques: a) modified Hautmann neobladder with long chimney and Bricker ureteroileal anastomosis (group I); b) our modified a. b. technique with short afferent limb, similar ureteral length on both sides and Wallace anastomotic type (group II).

Outcomes measures and follow up Postoperatively, all patients were placed on the identical treatment pathway and follow-ups were scheduled every 3-4 months during the first year and semi-annually in the second (19). Renal function was measured by serum creatinine, hydronephrosis was examined by abdominal ultrasound or computed tomography, and VUR was assessed by voiding cystography (6). Diagnostic imaging (kidney ultrasound, CT abdomen/pelvis and chest radiography) was performed annually or when clinically indicated. Abdominal ultrasound (US) was performed immediately before discharge of patients to deterArchivio Italiano di Urologia e Andrologia 2021; 93, 3

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Table 1. Clinicopathological features and perioperative outcomes between group I and II. Clinicopathological characteristics Age (years) BMI, kg/m2, mean (SD) Male, n (%) Female, n (%) ASA score, n (%) 2 ≥3 Pathologic stage, n (%) T2 T3 LNP patients, n (%) Operative time (min), SD Estimated blood loss (ml), SD Hospital stay (days), SD Transfusion rate, n (%)

Mean (SD)/Percentage (%) Group I (n = 30) Group II (n = 30) 63 (7.2) 68 (6.6) 27.2 (2.6) 26.1 (3.2) 22 (73.3) 24 (80.0) 8 (26.6) 6 (20)

P value 0.6 0.8 0.2 0.1

17 (56.6) 13 (43.3)

18 (62) 11 (38)

0.3 0.09

23 (76.6) 7 (23.4) * 4 (13.3) 270 (42.3) 340 (150) 18 (4.6) 7 (23.3)

25 (83.3) 4 (13.3) 5 (16.6) 240 (33.6) 400 (210) 19 (3.4) 5 (16.6)

0.1 0.03 0.7 0.3 0.06 0.6 0.08

* Statistically significant difference between two groups (p < 0.05). BMI: Body mass index; ASA: American Society of Anaesthesiologists; LPN: Lymph node positive.

The mean operative time was 270 ± 42.3 min and 240 ± 33.6 min in the first and second group respectively (p = 0.3). The distribution of postoperative complications is shown in table 2. A total of 135 complications were recorded in 40/60 (66.6%) patients. 105 complications (77.7%) occurred in the first 90 days, with the remaining 30 complications (22.2%) occurring between 90 days and one year postoperatively. The majority of complications (44/60, 73.3%) were classified as low-grade with 41.6% in Grade I and 31.6% in Grade II. High-grade (ClavienDindo Grade III-V) complications were seen in 10/60 (16.6%) patients. Grade III, IV and V complications were observed in 11.6%, 1.6% and 3.3% of the patients, respectively (Table 3). The overall mortality rate was 3.3% (2/60). High-grade complications were less in Wallace group as compared to Bricker group, and the difference was significant (3/30, 10% vs. 6/30, 20%, p = 0.03). Following 3 months, hydronephrosis was observed in eight patients (26.6%) in group I and six (20%) in group II, (p = 0.2) (grade I-III Clavien). Consequent to hydronephrosis, UIS was seen in two ureters (6.6%) in group I but none in group II (grade III Clavien). Moreover, one out of two patients with UIS required surgical treatment (grade IIIb Clavien). These differences were statistically significant (p = 0.0063). Additionally, the anastomotic leakage rate was higher in the first group, although not significantly (6.6% vs. 3.3%, p = 0.06) (grade I/IIIa Clavien).

mine the pouch capacity and post voiding residue (PVR). The acidosis was monitored using the base excess by venous blood gas analysis, initially every three days followed by weekly, depending on the blood gas values. The European Organization for the Research and Treatment of Cancer (EORTC) Quality-of-Life Core Questionnaire (QLQ-C30) version 3 was Table 2. Postoperative complications of 60 patients with muscle invasive bladder cancer used to measure HRQOL (21, 22). who underwent radical cystectomy and modified Hautmann neobladder Continence rates and time intervals with Bricker (group I) or Wallace (group II) ureteroileal anastomosis. between clear intermittent catheterizations (CICs) obtained at the end of 2-year follow Mean (SD)/Percentage (%) up were recorded. CIC was recommended Clinicopathological characteristics Group I (n = 30) Group II (n = 30) P value for patients with a postvoid residual volume Early Late Early Late (PVR) of >150 mL. Statistical analysis Statistical analysis was performed with SPPS v16.0 (SPPS, Chicago, IL, USA). Blood loss, operative time, and time to discharge (hospital stay) were assessed as continuous variables and tested for normality using the Kolmogorov test. The Student T test and Mann Whitney U test were used to determine statistical significance. The difference between obtained values was considered significant when p < 0.05. Descriptive statistics such as mean (SD) values and percentages, generated with SPSS, were also included.

RESULTS

Clinicopathological features and perioperative outcomes are summarized in Table 1. The two groups were similar for gender, age, ASA class and BMI. All patients had transitional cell carcinoma and the tumor stage ranged from T2 to T3 N0-3/M0. The followup time for the entire cohort was 2 years.

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Paralitic ileus, n (%) Wound infections, n (%) Blood transfusions for anemia, n (%) Pelvic hematoma, n (%) Lymphorrhea, n (%)

8 (26.6) 2 (6.6) 9 (30) 2 (6.6) 6 (20)

0 1 (3.3) 0 0 1 (3.3)

9 (30) 1 (3.3) 10 (33.3) 1 (3.3) 4 (13.3)

0 3 (10) 0 0 2 (6.6)

0.7 0.4 0.5 0.1 0.08

Pneumonia, n (%) Reservoir related complications Renal insufficiency, n (%) Vesicoureteral reflux (VUR), n (%) - Grade I - Grade II - Grade III - Grade IV Hydronephrosis, n (%) - Unilateral - Bilateral Pyelonephritis, n (%) - i.v antibiotics only - Oral antibiotics only Anastomotic leakage rate, n (%) Anastomotic stricture rate (UIS), n (%) Metabolic acidosis, n (%)

0 Early 0 4 (13.3) 2 1 1 0 8 (26.6) 8 0 4 (13.3) 1 3 2 (6.6) 2 (6.6) * 6 (20)

4 (13.3) Late 1 (3.3) 3 (10) * 2 1 0 0 1 (3.3) 1 0 0 0 0 0 1 (3.3) 1 (3.3)

1 (3.3) Early 0 3 (10) 2 1 0 0 6 (20) 0 6 5 (16.6) 2 3 1 (3.3) 0 5 (16.6)

3 (10) Late 0 1 (3.3) 1 0 0 0 3 (10) * 2 2 0 0 0 0 0 2 (6.6) *

0.1

* Statistically significant difference between two groups (p < 0.05).

0.07 0.03

0.02

0.4

0.09 0.04 0.04

Technique selection for ureteroileal anastomosis in orthotopic diversion

end-to-side ureteroileal anastomosis. The study included three patients with short follow-up; no postoperative complications were reported, demonstrating that the technique employed was a promising modification to the original Hautmann neobladder. In 2000, P value a more comprehensive study was performed on 50 patients with invasive BCa (3), using 0.03 8-12 cm tubularised isoperistaltic ileal chimney. This technique proved to be safe and feasible, easy to perform and created a reliable ureterointestinal anastomosis (Bricker) without tension, which resulted in a relatively low UIS rate (6%). On the other hand, 0.01 Hautmann et al. (23) reported that freely refluxing Wallace anastomosis to the afferent limb of the orthotopic reservoir has the lowest non-tumor related anastomotic stricture rate (5.4% compared to 16.3% using Bricker technique). Furthermore, Kouba et al. (12) revealed a statistically significant difference in UIS rate between Bricker and Wallace anastomotic techniques (3.7% vs. 0), in favour with the latter. Despite these results, the success and complications of two techniques are still debatable and no definite conclusion regarding the optimal anastomotic technique for orthotopic diversion has been made. The reason for this may be the lack of clear selection criteria for each anastomotic technique, instead of simple surgeon preference (12, 24). A recent study (17), suggesting an individualized selection strategy for deciding upon the type of uretero-ileal anastomosis (Bricker vs. Wallace), showed acceptable low rate of ureteral strictures (3.1%) and confirmed clinical reliability of research. The technique selection was based on several individual patient factors, including tumor characteristics, ureteral anomalies and ureteral length. In our study, however, chimney size and diameter of distal ureter, together with ureteral length after retro-sigmoidal tunneling were considered as selection criteria to decide upon the type of ureteroileal anastomosis. The results we reported here revealed higher incidence of UIS using Bricker technique (6.6%), after three months follow-up; on the other hand, this complication was not detected using Wallace anastomosis on shortened tubularised isoperistaltic chimney. Since this type of stricture remains the most challenging and difficult of all ureteral strictures to treat (25, 26), any technical modification that aims to decrease or prevent UIS is recommended (17). Our modified Wallace technique consisted of longer ureteral spatulation and short Chimney, seemed to be effective in reducing the occurrence of both UIS and anastomotic leakage during followup period. Moreover, a shorter chimney may also play a role in reflux prevention, due to the fact that a shorter limb allows the use of longer segments of the lower ureters that participate in reflux prevention (27). All these findings together bolster the assertion that proper patient selection and meticulous ureteral handling of distal ureter, as well as a shorter intestinal chimney with end-to-end running suture ureteroileal anastomosis, may be essential to minimize the risk of postoperative reservoir-related complications.

Table 3. Classification of postoperative complications and treatment options for reservoir-related complications after radical cystectomy and construction of modified Hautmann reservoir with Bricker (group I) or Wallace (group II) ureteroileal anastomosis. Postoperative complications & treatment Clavien-Dindo classification Grade I Grade II Grade III (IIIa/IIIb) Grade IV (IVa/IVb) Grade V (death) Treatment, n (%) Antegrade stent placement Percutaneus nephrostomy (PCN) Balloon dilatation of strictures Surgical repair of strictures Intraabdominal drainage Intermitent catheterization (CICs)

Group I (n = 30) Early Late 19 (63.3) * 9 (30) 8 (26.6) 4 (13.3) 7 (23.3) 2 (6.6) 4 (13.3) * 1 (3.3) 0 1 (3.3) 0 1 (3.3) 15 (50) * 7 (23.3) * 1 0 1 1 2 0 1 0 2 0 8 6

Group II (n = 30) Early Late 16 (53.3) 10 (33.3) 9 (30) 4 (13.3) 5 (16.6) 5 (16.6) * 2 (6.6) 0 0 0 0 1 (3.3) 6 (20) 4 (13.3) 0 0 1 0 0 0 0 0 0 0 5 4

* Statistically significant difference between two groups (p < 0.05).

Nine patients (15%) required interventions under general or local anesthesia for the management of high-grade (≥ III) complications. Four patients from the first group required invasive treatment of early reservoir-related complications (13.3%), which was significantly higher compared to the Wallace group (3.3%; p = 0.01). Three patients underwent percutaneous nephrostomy for ureteroileal anastomotic stricture or anastomotic leak in both groups, whereas two patients from the first group had percutaneous drainage for lymphocele or pelvic collection. Only one patient from the Bricker group developed local tumor recurrence (3.3%) (grade IIIa), which was treated endoscopically (Table 3). Neoadjuvant chemotherapy was performed in 16 patients (27.1%), while adjuvant treatment received only one examinee (1.7%). At the end of the 2-year follow-up, two patients with VUR in group I had improved after CICs (grade I Clavien). In addition, five out of six patients with hydronephrosis had improved with or without treatment. However, one case with UIS - related unilateral hydronephrosis resulted in a non-functional kidney despite the treatment for the stricture (grade IV Clavien). Serum creatinine was less than 1.4 mg/dl preoperatively in all patients and it remained within the normal ranges, during the follow-up in both groups, except in the patient with kidney failure. Complete daytime continence at one year was achieved in 28 patients (93.3%) in the first group and 26 patients (89.6%) in the second group, with no statistical differences however (p > 0.05). Complete night time continence was achieved in 24 (80%) and 25 patients (86.2%), respectively (p > 0.05). Patient self-rated emotional and social functional scales were similar between groups.

DISCUSSION

The first description of Hautmann neobladder with chimney modification was published by Lipper and Theodorescu (2) consisting of a 5-10 cm isoperistaltic chimney with an

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Oncologic factors were an important consideration in our series. Although the Wallace technique has the lowest rate of UIS, it not recommended for patients with increased risk of recurrent tumors (bladder CIS) (4,11). In our study, however, patients with multifocal bladder CIS were selected exclusively for Bricker anastomotic technique, after obtaining negative frozen-section urethral biopsy. Therefore, oncologic limitations of direct end-to-end ureteroileal anastomosis were clinically insignificant in our cohort with conclusion that Wallace technique may become the preferred anastomotic approach, in properly selected patients. It is questionable, however, why the Bricker group was associated with high postoperative complications rate (Clavien-Dindo grade III-13.3%), where incidence of UIS was higher than expected (1, 3, 23). Since the obesity may impair the outcome of ureteroileal anastomosis after RC (17), we assumed that higher BMI of patients within Bricker group, associated with short mesentery and extensive dissection of the distal left ureter, led to significantly higher rate of UIS, comparing to Wallace group. Incidence of CICs after neobladder construction is generally 4-25% in males and up to 53% in females (28, 29). In our study, however, 16.9% of patients still required CICs at the end of first year. Nevertheless, during the initial three months post-surgery, hydronephrosis had improved after CICs in 50% of patients within the second group, whereas only one patient required an invasive procedure for the treatment of hydronephrosis (PCN). The limitations of this study are the small size of groups of patients and the short follow-up periods. Despite that, we found an acceptable rate of ureteroenteric strictures, VUR and anastomotic leakage, lower than that found in the conventional technique. Furthermore, our research was conducted with no clear protocol for administration of neoadjuvant or adjuvant chemotherapy, as this was left to the discretion of the uro-oncologist board. In addition, the unusually high rate of anastomotic leakage in patients within the first group could lead to research bias regarding effectiveness of our modified Hautmann neobladder with Wallace anastomotic technique. Single surgeon experience could be the major reason for this bias, which should be addressed by involving other highly trained surgeons.

CONCLUSIONS

Our preliminary outcomes demonstrated that this patient-based selection strategy for ureteroileal anastomosis in orthotopic urinary diversion after RC seems to be clinically reliable and favors Wallace anastomotic technique over the Bricker approach.

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1. Hautmann RE, Abol-Enein H, Davidsson T, et al. ICUD-EAU International Consultation on Bladder Cancer 2012: urinary diversion. Eur Urol. 2013; 63:67-80.

19. Al Hussein Al Awamlh B, Wang LC, et al. Is continent cutaneous urinary diversion a suitable alternative to orthotopic bladder substitute and ileal conduit after cystectomy. BJU Int. 2015; 116:805-14.

2. Lippert MC, Theodorescu D. The Hautmann neobladder with a chimney: a versatile modification. J Urol. 1997; 158:1510-2.

20. Mitropoulos D, Artibani W, Graefen M, et al. Reporting and grading of complications after urologic surgical procedures: an ad hoc EAU guidelines panel assessment and recommendations. Eur Urol. 2012; 61:341-9.

3. Hollowell CM, Christiano AP, Steinberg GD. Technique of

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Technique selection for ureteroileal anastomosis in orthotopic diversion

21. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993; 85:365-376. 22. Singh V, Yadav R, Sinha RJ, Gupta DK. Prospective comparison of quality of life outcomes between ileal conduit urinary diversion and orthotopic neobladder reconstruction after radical cystectomy: a statistical model. BJU Int. 2014; 113:726-732. 23. Hautmann RE, Volkmer BG, Schumacher MC, et al. Long-term results of standard procedures in urology: the ileal neobladder. World J Urol. 2006; 24:305-314. 24. Evangelidis A, Lee EK, Karellas ME, et al. Evaluation of ureterointestinal anastomosis: Wallace vs. Bricker. J Urol. 2006; 175:1755-8.

25. Kurzer E, Leveillee RJ. Endoscopic management of ureterointestinal strictures after radical cystectomy. J Endourol. 2005; 19:677-82. 26. Farnham SB, Cookson MS. Surgical complications of urinary diversion. World J Urol. 2004; 22:157-67. 27. Hassan Abol-Enein, Nuzhat Faruqui, Nashwa Barakat, Shokeir AA. Does the afferent tubular segment in an orthotopic bladder substitution compromise ureteric antireflux properties? An experimental study in dogs. Arab J Urol. 2012; 10:125-30. 28. Hautmann RE, Paiss T, de Petriconi R. The ileal neobladder in women: 9 years of experience with 18 patients. J Urol. 1996;155:76-81. 29. Ali-el-Dein B, el-Sobky E, Hohenfellner M, Ghoneim MA. Orthotopic bladder substitution in women: functional evaluation. J Urol. 1999; 161:1875-80.

Correspondence Dejan Djordjevic, MD, PhD, Urologist dejanurl@gmail.com Svetomir Dragicevic, MD, Urologist dejanurl@gmail.com Urology Clinic, Euromedic General Hospital Bulevar Umetnosti 29, 11000 Belgrade (Serbia) Marko Vukovic, MD (Corresponding Author) marko.vukovic09@gmail.com Department of Urology, Clinical centre of Montenegro Ljubljanska bb, 81000 Podgorica (Montenegro)

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DOI: 10.4081/aiua.2021.3.268

ORIGINAL PAPER

Summary

Objective: To present a retrospective analysis on the oncological and functional outcomes of a single-center experience on a large series of extraperitoneal laparoscopic radical prostatectomies (eLRP) with an extended follow-up. Materials and methods: Herein we present a retrospective review of patients who underwent eLRP. Oncological and functional follow-up data were collected by means of outpatient visits and telephone interviews, assessing overall mortality and biochemical recurrence-free survival. Patients with clinical T4 stage prostate cancer (PCa), previous surgery for benign prostatic hyperplasia (BPH), previous androgen deprivation, radiotherapy, concomitant chemotherapy and/or experimental therapies, and with insufficient follow-up data were excluded. Preoperative data recorded were age, body mass index, ultrasound prostate volume, preoperative PSA and clinical stage of PCa. Operative data (operative time, nerve sparing technique and any perioperative complication) and pathological findings were obtained by consulting the surgical and pathological reports. Oncological and functional follow-up were collected during follow-up visits and telephone interview. Results: Between January 2001 and December 2019, overall 938 eLRP were performed at our Institution. The median follow-up was 132 months. 69.7% of the patients had complete dataset. The estimated overall biochemical recurrence (BCR)-free survival was 71.4% at 5 years and 58.9% at 10 years. Cancer specific survival was 84,5%. Erectile function was preserved in the most of patients as postoperative IIEF-5 score within 12 months after surgery was > 12 in the 82.1%. About the urinary incontinence, 0.76% of the patients presented severe incontinence (continued and persistent loss of urine) and 7.0% were mildly incontinent (using up to one pad per day). Conclusions; eLRP has shown oncological and functional results comparable to other minimally invasive techniques and to open radical prostatectomy (ORP), with favorable perioperative outcomes than the open technique and a reduced complication rate.

KEY WORDS: Prostate cancer; Radical prostatectomy; Laparoscopic prostatectomy; Laparoscopy; Extraperitoneal prostatectomy. Submitted 27 May 2021; Accepted 27 June 2021

INTRODUCTION

Prostate cancer (PCa) represents the most commonly diagnosed cancer in men (1). Radical prostatectomy (RP) rep-

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No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

resents a first-line option for the treatment of localized PCa (2). Open RP is the traditional approach, but it is burdened by higher perioperative morbidity, greater blood loss and longer hospitalization (3). Over the last three decades, mini-invasive techniques have increasingly gained popularity owing to their advantages on perioperative outcomes over open RP. At present, about two every three RPs are laparoscopic or robotassisted (4, 5). Laparoscopic radical prostatectomy (LRP) could be performed in either transperitoneal or extraperitoneal route. Both these approaches have pros and cons: the transperitoneal LRP (tLRP) provides a broader surgical space with full exposure of all the anatomical landmarks of the pelvis; on the other hand, the extraperitoneal laparoscopic radical prostatectomy (eLRP) resembles more the open retropubic RP (6). It also decreases the risk of anesthetic and surgical complications, since it avoids the exposure of intraperitoneal structures and requires less steep Trendelenburg tilt. eLRP was first described by Raboy in 1997(7). Since then, no clear evidence of the superiority of one approach to LRP over the other has been highlighted. Nevertheless, data on very large series of eLRP with long follow-up are still missing. This work presents a retrospective, long-term follow-up analysis of a single-center experience on a large series of eLRP, over an 18-years period.

MATERIAL

AND METHODS

In this retrospective cohort study, we retrospectively reviewed data of 938 patients who underwent eLRP at our Institution between January 2001 and December 2019. Among these, 168 presented exclusion factors and were removed from the analysis while 113 were excluded because of insufficient follow-up or incomplete dataset available. All the procedures were performed by three different surgeons (FSG, DB, and AD), using a standardized technique, as described below. All of them were already skilled in laparoscopic surgery, since they had already performed at least 20 laparoscopic procedures at the starting point of the analysis. Exclusion criteria were: Clinical T4 stage prostate cancers, history of benign prostatic surgery, patient previously

Results of eLRP with long-term follow-up

treated with androgen deprivation and/or radiotherapy, previous or concomitant chemotherapy and/or experimental therapies. Additionally, men with less than 6months follow-up and with largely incomplete dataset were excluded. Preoperative data recorded were age, body mass index (BMI), ultrasound prostate volume, preoperative PSA, Gleason score, and clinical stage. Patients were classified in risk groups by considering preoperative clinical stage. Operative data (operative time, nerve sparing technique and any perioperative complication) and pathological findings were obtained by consulting the surgical and pathological reports. Oncological and functional followup data were collected by means of outpatient visits and telephone interviews, assessing overall mortality and biochemical recurrence-free survival (BRFS). Oncological management of patients after RP In most of the cases, men with pT2 or pT3 tumors or men with positive surgical margins followed a “wait and see” strategy with eventual subsequent salvage radiotherapy at PSA recurrence. Biochemical recurrence (BCR) was defined as two consecutive values of PSA ≥ 0.2 ng/mL at least 6 weeks after surgery. This threshold matches the classical EAU definition of BCR after RP (8), even though this definition has recently changed (9). Patients having persistent PSA levels > 0.2 ng/mL were considered as having BCR, as well. Neither this group of patients, nor men who received adjuvant radiation therapy for locally advanced disease were excluded from the analysis. Functional outcomes Urinary incontinence (UI) was evaluated by the number of pads needed per 24 h and stratified as follows: 0 pad (no incontinence), 1 pad (mild incontinence), and ≥ 2 pads (severe incontinence). International Index of Erectile Function-5 (IIEF-5) questionnaire were administered to evaluate the 12-month erectile function, as well as to assess pre-existing erectile dysfunction (10). Statistical analysis Statistical analysis was carried out with the software Stata MP15 (StataCorp LLC, College Station, TX, USA). Baseline data were analyzed using descriptive statistics: frequencies were expressed as percentages while continuous variablse were presented as medians and interquartile ranges. We considered a two-tailed p-value of < 0.05 as statistically significant. We present the following article in accordance with the STROBE reporting checklist. Surgical technique The eLRP technique adopted in our Urology department was already presented in another work (11). A laparoscopic radical prostatectomy with bilateral pelvic lymph node dissection was performed with an extraperitoneal laparoscopic approach, regardless Gleason score and clinical T-stage. The patient was placed in supine position, the table hyperextended at the pubic symphysis level. A 20° Trendelenburg tilt was given. The initial incision was medial, 1 cm below the umbilicus. After rectus fascia

identification and incision, a blunt dissection was performed under direct vision with a round shape balloon to develop the extraperitoneal space of Retzius. Four trocars were then placed under direct control of the surgeon’s index finger: two pararectal 10 mm trocars and two 5 mm trocars, 2 cm cranially and medially from the anterior superior iliac spine. A 10 mm structural balloon trocar served as the optical trocar in the median sub umbilical incision. Bilateral extended pelvic lymph node dissection was first performed. The template for lymphadenectomy included common, internal and external iliac and obturator lymph nodes. The bladder was divided from the prostatic base in a bladder neck-sparing fashion whenever it was possible. This step was completed using blunt dissection as much as possible. Seminal vesicles and deferent ducts were dissected and freed. The dissection of the posterior surface of the prostate could be made along an intra-, inter-, or extrafascial plane according to risk stratification and preoperative erectile function. When a nerve-sparing procedure was planned, the Denonvilliers’ fascia was incised in the midline and the dissection along the intrafascial plane was carried on towards the lateral surface of the prostate, strictly avoiding cautery and limiting stretching of the neurovascular bundles. The prostatic pedicles were controlled using endoscopic Hem-o-Lok clips and cut. The dorsal venous complex (DVC) was divided using an ultrasonic energy scalpel or a combined bipolar/ultrasonic energy device. This is usually sufficient to control any bleeding from DVC and no stitch was usually required. Then the prostate apex was carefully divided from the membranous urethra to obtain the longest possible urethral stump. Thereafter, the urethra was cut with cold scissors. The specimen was placed in a laparoscopic bag and removed through the sub umbilical incision. The incision was extended if needed. A classical double-running VLock 3-0 suture was adopted during the vesico-prostatic anastomosis. Antibiotics, intravenous fluids, and prophylaxis for deep vein thrombosis were given per institutional protocol. Blood parameters, diuresis and drainage were monitored and the drain tube removed as soon as possible. The ambulation was encouraged, and diet was started on the first postoperative day. The urethral catheter was removed after ten days, always after performing cystogram. All patients were followed with standardized protocol. Outpatient visits were scheduled every 3-month for the first year. At each visit, a physical examination and PSA were routinely performed. The clinical history about continence and erectile function was collected. Sexual function was measured using the IIEF-5 questionnaire. Men reporting a daily use of no pad were considered as completely continent, whereas the use of one pad per day was considered as mild incontinence. Patients were addressed to continence ad sexual rehabilitation with postoperative pelvic floor muscle training and PDE5 Inhibitors and/or intracavernous injections with customized protocol. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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F.S. Grossi, E. Utano, P. Minafra, P.P. Prontera, F. Schiralli, A. De Cillis, E. Martinelli, M. Lattarulo, M. Luka, A. Carrieri, A. D’Elia

Table 1. Demographic and perioperative characteristics. N = 657 Age (y), median (IQR) BMI (kg/m2), median (IQR) Prostate volume (ml), median (IQR) PSA (ng/ml), median (IQR) Preoperative potency (IIEF-5 > 12), n (%) Preoperative urinary continence, n (%) Operative time (m), median (IQR) Postoperative LOS (d), median (IQR) Overall NS procedures, n (%) Yes Bilateral Monolateral No

Results 67 (62-73) 28.3 (26.7-29.5) 52.2 (45.5-61.3) 10.5 (6.4-14.2) 513 (78.1) 657 (100) 115 (85-184) 3.5 (2.5-4) 408 (62.1) 243 (37.0) 165 (25.1) 249 (37.9)

BMI: Body Mass; PSA: Prostate-Specific Antigen; IIEF-5: International Index of Erectile Function-5; LOS: length of stay; NS: nerve-sparing; IQR: Interquartile range.

Table 2. Intraoperative and perioperative complications. Blood transfusion Bladder neck contracture Anastomotic leak Ochiepididimitis Symptomatic lymphocele Rectal injury Ileus Deep vein thrombosis Total adverse events Clavien Dindo I-II Clavien Dindo III-IV

N 21 6 9 3 12 3 8 4 66 53 10

RESULTS

(%) 3.2 0.9 1.4 0.5 1.8 0.5 1.2 0.6 8.1 25

Between 2001 and 2019, 938 patients with median age of 67 years (IQR: 62-73) years underwent eLRP at our Urology department and were followed with a median follow-up time of 132 months (IQR: 63-173 mo). Within the total population, 657 (69.7%) have no exclusion criteria and had complete oncological and functional data. The median BMI of the patients was 28.3 kg/m2 (IQR: 26.7-29.5). The median ultrasound prostate volume was 52.2 cc (IQR: 45.5-61.3). Preoperative median PSA value was 10.5 ng/mL (IQR: 6.4-14.2). Complete demographic and operative features are reported in Table 1. The median operative time was 115 minutes (IQR: 85184 minutes), whereas the median length of postoperative hospitalization was 3.5 days (IQR: 2.5-4). The posterolateral dissection of the prostate was carried out using a nerve-sparing technique in 408/657 patients (62.1%), in 37.0% on both sides while in 25.1% monolaterally. The 37.9% of men did not receive a nerve-sparing surgery. Overall, 66 perioperative complications occurred in 51 men (7.8%). All complications with Clavien-Dindo classification are listed in Table 2. At definitive histology, pathological stage was T2 in 535 (81.4%), T3 in 117 (17.8%) and T4 in 5 cases (0.8%).

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Lymph nodes invasion was observed in 57 men (8.7%). Positive surgical margins (PSM) were found in 87 (13.2%). Among men with T2 prostate cancer, 52 had PSM (9.7%). 156 patients (23.7 %) received immediate adjuvant radiation therapy for locally advanced disease (Table 3). During the observation period, a total of 58 patients died. In nine of them, the cause of death was linked to PCa. The estimated overall BCR-free survival was 71.4% at 5 years and 58.9% at 10 years. In organ-confined prostate cancer the BCR-free survival was 77.2% at 5 years and 65.2% at 10 years. In pT3 stage the BCR-free survival was 47.9% at 5 years and 32.5% at 10 years (Table 3). Preoperative IIEF-5 questionnaire showed a good erectile function or at most a mild-moderate erectile dysfunction in 78.1% of the cases (513/657). All these men were interested in postoperative resumption of sexual activity. Among these patients, respectively 56.9% and 28.4% underwent nerve-sparing prostatectomy. Postoperative IIEF-5 score within 12 months after surgery was > 12 in the 82.1% (421/513). As for urinary incontinence, after a minimum of 12 months after the surgery, the great majority of patients experimented a complete recovery of the urinary continence (no needing for pad). On the other hand, 5 patients (0.76%) presented severe incontinence (continued and persistent loss of urine) and 46 (7.0%) were mildly incontinent (using one pad per day) (Table 4). Table 3. Pathological and oncological outcomes. N = 657 pT2 pT3 pT4 pN+ Overall PSM pT2 pT3 pT4 Immediate adjuvant RT Overall mortality Overall pT2 pT3

5 years 71.4 77.2 47.9

N (%) 535 (81.4) 117 (17.8) 5 (0.8) 57 (8.7) 87 (13.2) 52 (9.7) 32 (27.4) 3 (60) 156 (23.7) 58 (8.9) BCR free survival

Table 4. Functional outcomes 12 months after surgery. Postoperative recovery EF, n (%) Surgical technique *, n (%) Bilateral NS Monolateral NS Non-NS Complete continence **, n (%) Mild incontinence **, n (%) Severe incontinence **, n (%)

421/513 (82.1) 292 (56.9) 146 (28.5) 75 (14.6) 606 (92.2) 46 (7) 5 (0.8)

BEF: erectile function; IIEF-5: International Index of Erectile Function-5; NS: nerve-sparing technique. * In men with preoperative IIEF-5 ≥ 12. ** Continence: no pad; mild incontinence: 1 pad; severe incontinence ≥ 2 pad.

10 years 58.9 65.2 32.5

Results of eLRP with long-term follow-up

DISCUSSION

There is an ongoing debate about the worthiness of eLRP versus tLRP. Both the approaches share the main advantages of laparoscopy over open surgery, such as a better visualization of the surgical field, lower blood loss, a more precise and watertight anastomosis that allows early catheter removal, and a shorter hospital stay. For this reason, the widespread diffusion of minimally invasive prostatectomy have led to a significant reduction of the surgical burden, while ensuring similar oncological results and complication rates compare to open RP (1214, 34). However, no evidence still exists about the superiority of one laparoscopic approach over the other in terms of perioperative outcomes and incidence of complications (15). The transperitoneal approach offers the best visibility and workspace for pelvic surgery. However, the extraperitoneal route reduces potential complications linked to the peritoneum opening, such as bowel injury, ileus, intraperitoneal bleeding or urinary leakage, and formation of intraperitoneal adhesions. Moreover, eLRP have gained popularity among urologists, since it seems a more straightforward procedure (16, 17). Some authors also suggests that this approach may shorten the learning curve, but this point remains controversial (18). The rapidly increasing application of the mini-invasive techniques makes long-term data essential for a proper counselling of the patients. Many studies have been directed to show the results of laparoscopic radical extraperitoneal prostatectomy, some even with very large sample size (19). Nevertheless, insufficient data on large series of eLRP with long-term follow-up are available. With this study, we filled this gap by presenting the results of a large cohort of extraperitoneal laparoscopic radical prostatectomy with extended follow-up. Oncological outcomes The complete resection of the tumor is a primary goal of radical prostatectomy and the presence of PSM after RP is predictor of PSA recurrence and is considered a negative prognostic factor. In our population, the overall rate of PSM was 13.2%, while it was 9.7% in the subgroup of T2 tumors. Such findings are consistent with those previously reported. The overall rate of positive surgical margins after laparoscopic prostatectomy varies from 19.2% to 38.6% (20-23). Very large series of eLRP reported PSM rates of 10.8-16.1% and 31.2-34.6% in pT2 and pT3 cancers, respectively (19, 24). However, comparative data between extraperitoneal and intraperitoneal LRP show no differences in terms of PSM (25, 26), as well as no significant difference exist between open and laparoscopic RP (27). Regardless of the surgical technique, one of the most relevant predictors for PSM is tumor stage. However, analyzing data by groups, no difference are shown between open prostatectomy and mini-invasive techniques in PSM rate for T2 and T3 tumors (27). Another important indicator of the oncological safety of a surgical approach is biochemical recurrence (BCR), which has been associated with increased mortality (28). In the present investigation, the overall BCR-free survival was 71.4% at 5 years and 58.9% at 10 years. Stratifying our

population by tumor stage, it was 77.2% at 5 years and 65.2% at 10 years for T2 stage and 47.9% at 5 years and 32.5% at 10 years for T3 stage tumors (Table 3). Of note, these results are slightly below those already presented in other studies. Indeed, after ORP, the 10years BCR-free survival rate is 80 % for T2 prostate cancer (29) and 54% for pT3 tumors (30); on the other hand, the overall 10-year BCR-free survival was 75.6% after LRP (31). Our results probably represent the result of the lack of patient selection and, above all, of the “wait and see” strategy adopted in the majority of cases instead of a more aggressive attitude with early initiation of adjuvant therapies. Many papers have directly compared the incidence of BCR between LRP to ORP. To date, the oncological data with the largest follow-up (49 months) were provided in the work of Martínez-Holguín et al. (32). This work did not highlight any difference in the incidence of BCR between the two techniques. No long-term data on BCR exist on te direct comparison between tLRP and eLRP. Functional outcomes We classified patients in three groups: full continence (no need for diapers), mild incontinence (1 per day) and severe incontinence (more than 2 per day). After a twelve-month postoperative follow-up, 92.2% (n = 606) of 657 patients were completely continent, 7% (n = 46) had mild incontinence, and 0.76% (n = 5) needed more than 2 pads per day. These data are consistent with previously published results for LRP (19, 31, 35). Stolzenburg et al. presented continence results for the extraperitoneal approach reporting a 12-months continence rate of 92%. Overall, we offered a nerve-sparing eLRP to 408 patients (62.1%), while, among patients who presented good preoperative erectile function, the 85.4% underwent nervesparing prostatectomy. In this subgroup, 82.1% of men preserved the erectile function 12 month after surgery. Our findings on erectile function recovery are in line with some data reported in other series of nerve-sparing prostatectomy, though potency rates after open nervesparing ORP vary considerably across studies, reaching up to 86% at 12 months in selected patients (33). In our work, patients are not the result of meticulous selection, except for the identification of the necessary requirements to indicate a nerve-sparing prostatectomy. However, a similar rate of continence recovery partly depends also on our definition of erection recovery, that includes men with mild-moderate erectile dysfunction (IIEF-5 score higher than 12). Perioperative outcomes In our series, eLRP was shown to be a procedure with short operative times, and a reduced incidence of intra and perioperative complications. Different comparative cohort studies have reported that the extraperitoneal approach needs shorter times (16, 17), but data of a meta-analysis comparing perioperative results and complications of intraperitoneal and extraperitoneal RP show that eLRP and tLRP have similar operative times. Moreover, blood loss and rate of transfusion of the two techniques are comparable. No significant differences were observed for the rate of intraoperative Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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complications and the rate of open conversion, whereas a higher rate of postoperative complications was reported in the tLRP group (25). Several limitations of the present study have to be addressed: the single-centre retrospective design of the present analysis potentially represents a bias. Moreover, this a consecutive series of 657 patients who underwent eLRP over a period of 18 years by three different surgeons. In that way, this series reflects the evolution of this technique and of the surgeons’ learning curve along such a long time. Moreover, the lack of a standardized protocol for the oncological management and the functional rehabilitation represents a limitation.

CONCLUSIONS

Extraperitoneal RP brings considerable advantages in terms of perioperative outcomes (short duration of surgery, reduced blood losses, low risk of complications) compared to other laparoscopic techniques and ORP. It also presents similar results in the main oncological objectives and with optimal recovery of continence and erectile function.

12. Schuessler WW, Schulam PG, Clayman RV, Kavoussi LR. Laparoscopic radical prostatectomy: initial short-term experience. Urology. 1997; 50:854-7. 13. Türk I, Deger S, Winkelmann B, et al. Laparoscopic radical prostatectomy. Technical aspects and experience with 125 cases. Eur Urol. 2001;40:46-52. 14. Guillonneau B, Vallancien G. Laparoscopic radical prostatectomy: the Montsouris technique. J Urol. 2000;163:1643-9. 15. van Velthoven RFP. Laparoscopic radical prostatectomy: transperitoneal versus retroperitoneal approach: is there an advantage for the patient?. Curr Opin Urol. 2005; 15: 83-8. 16. Porpiglia F, Terrone C, Tarabuzzi R, et al. Transperitoneal versus extraperitoneal laparoscopic radical prostatectomy: experience of a single center. Urology. 2006; 68:376-80. 17. Eden C, King D, Kooiman G,, et al. Transperitoneal or extraperitoneal laparoscopic radical prostatectomy: does the approach matter? J Urol. 2004; 172:2218-23. 18. Stolzenburg J, Truss M, Bekos A, et al. Does the extraperitoneal laparoscopic approach improve the outcome of radical prostatectomy? Curr Urol Rep. 2004; 5:115-22.

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11. Grossi FS, Di Lena S, Barnaba D, et al. Laparoscopic versus open radical retropubic prostatectomy: a case-control study at a single institution. Arch Ital Urol Androl. 2010; 82:109-12.

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21. Dahl D, Barry M, McGovern F, et al. A prospective study of symptom distress and return to baseline function after open versus laparoscopic radical prostatectomy. J Urol. 2009; 182:956-65. 22. Jurczok A, Zacharias M, Wagner S, et al. Prospective non-randomized evaluation of four mediators of the systemic response after extraperitoneal laparoscopic and open retropubic radical prostatectomy. BJU Int. 2007; 99:1461-6. 23. Jacobsen N, Moore K, Estey E, Voaklander D. Open versus laparoscopic radical prostatectomy: a prospective comparison of postoperative urinary incontinence rates. J Urol. 2007; 177:615-9. 24. Paul A, Ploussard G, Nicolaiew N, et al. Oncologic outcome after extraperitoneal laparoscopic radical prostatectomy: midterm followup of 1115 procedures. Eur Urol. 2010; 57:267-72. 25. Wang K, Zhuang Q, Xu R, et al. Transperitoneal versus extraperitoneal approach in laparoscopic radical prostatectomy: A meta-analysis. Medicine (Baltimore). 2018; 97:e11176. 26. Kallidonis, Panagiotis P, Rai, Bhavan PB, et al. Critical appraisal of literature comparing minimally invasive extraperitoneal and transperitoneal radical prostatectomy: A systematic review and meta-analysis. Arab J Urol. 2017; 15:267-279. 27. Cao L, Yang Z, Qi L, Chen C. Robot-assisted and laparoscopic vs open radical prostatectomy in clinically localized prostate cancer: perioperative, functional, and oncological outcomes: A Systematic review and meta-analysis. Medicine (Baltimore). 2019; 98:e15770. 28. Uchio E, Aslan M, Wells C, et al. Impact of biochemical recurrence in prostate cancer among US veterans. Arch Intern Med. 2010; 170:1390-5.

Results of eLRP with long-term follow-up

29. Chun F, Graefen M, Zacharias M, et al. Anatomic radical retropubic prostatectomy-long-term recurrence-free survival rates for localized prostate cancer World J Urol. 2006; 24:273-80. 30. Hruza M, Bermejo J, Flinspach B, et al. Long-term oncological outcomes after laparoscopic radical prostatectomy. BJU Int. 2013; 111:271-80. 31. Busch J, Stephan C, Herold A, et al. Long-term oncological and continence outcomes after laparoscopic radical prostatectomy: a single-centre experience BJU Int. 2012; 110:E985-90. 32. Martínez-Holguín E, Herranz-Amo F, Mayor de Castro J, et al. Comparison between laparoscopic and open prostatectomy:

Oncological progression analysis. Actas Urol Esp. 2021; 45:139145. 33. Walsh. Radical prostatectomy for localized prostate cancer provides durable cancer control with excellent quality of life: a structured debate. J Urol. 2000; 163:1802-7. 34. Abboudi H, Doyle P, Winkler M. Day case laparoscopic radical prostatectomy. Arch Ital Urol Androl. 2017 ;89:182-185. 35. Gozen AS, Akin Y, Ates M, et al. The impact of bladder neck sparing on urinary continence during laparoscopic radical prostatectomy; Results from a high volume centre. Arch Ital Urol Androl. 2017; 89:186-191.

Correspondence Francesco Saverio Grossi, MD (Corresponding Author) grossifs@libero.it Emanuele Utano Paolo Minafra Pier Paolo Prontera Francesco Schiralli Antonio De Cillis Evangelista Martinelli Marco Lattarulo Meri Luka Antonio Carrieri Angelo D’Elia Department of Urology, SS Annunziata Hospital Via Francesco Bruno 1, 74121, Taranto (Italy)

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273

ORIGINAL PAPER

DOI: 10.4081/aiua.2021.3.274

Reconstruction of the Denonvillier's fascia and posterior ligament of the external urethral sphincter: Assessment of its effect on urinary continence after laparoscopic radical prostatectomy Pedro Sousa Passos 1, 2, Sara Teixeira Anacleto 1, Rui Simeão Versos 2, Mário Cerqueira Alves 1, Paulo Oliveira Mota 1, 3 1 Department

of Urology, Hospital de Braga, Portugal; of Urology, Hospital de Guimarães, Portugal; 3 Institute of Life and Health Sciences, University of Minho, Portugal. 2 Department

Summary

Objectives: Some studies have shown that rhabdosphincter reconstruction provides an earlier return to continence after radical prostatectomy. We aim to study the impact of this procedure in urinary continence along with comparing two specific surgical techniques for posterior reconstruction. Materials and methods: We studied a group of patients who were submitted to LRP with No Rhabdosphincter Reconstruction (NRR) and another group with Posterior Reconstruction of the Rhabdosphincter (PRR). The latter was further divided into two groups: "Rocco type stitch" group and "Bollens type stitch" group. We used three questionnaires (IIEF-5, ICIQ-SF and IPSS) to assess urinary continence and erectile function 90 days after surgery. Results: Patients of PRR group had a better full continence rate than patients of NRR group at 90 days (96.6% vs 33.3%, p < 0.001). Concerning urinary incontinence (p = 0.116), lower urinary tract symptoms (p = 0.543) and postoperative complication rates (p = 0.738), our results suggested that there were no differences between the techniques studied. Conclusions: Posterior reconstruction of the rhabdosphincter has significant benefits for urinary continence recovery on patients undergoing radical prostatectomy. No differences were observed in continence recovery between the two techniques analyzed. Additionally, reconstruction of the rhabdosphincter appears to be a safe procedure with no increased risk of postoperative complications.

KEY WORDS: Radical prostatectomy; Prostate cancer; Rhabdosphincter reconstruction; Postoperative complications; Erectile dysfunction; Urinary continence. Submitted 11 June 2021; Accepted 9 July 2021

INTRODUCTION

One of the most common and effective treatments for localized Prostate Cancer (PCa) is the radical prostatectomy (RP) (1, 2). However, this procedure has shown to have a significantly negative impact on multiple quality-of-life domains due to its adverse effects such as urinary incontinence and erectile dysfunction (3, 4).

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No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

Previous studies show that urinary incontinence's prevalence widely varies from 2% to 65.5% and sexual dysfunction up to 87% (5, 6). Laparoscopic radical prostatectomy (LRP) has become a frequent treatment on local control of prostate cancer (8). Bollens et al. described an extraperitoneal laparoscopic surgical approach that combines the usual advantages of a laparoscopic procedure (less painful, reduced morbidity, earlier recovery) and the benefits of the open retropubic approach (avoid intraperitoneal organs injuries, potential risk of cancer spillage in the peritoneal cavity, intraperitoneal bleeding or urine leakage and allows possible later adjuvant radiotherapy) with results in terms of erectile function and continence equivalent to other techniques (9). Prostate removal causes the destruction of the supporting system that anatomically and functionally separates the urethral sphincter complex from the prostatic apex and Denonvilliers' fascia, resulting in postoperative incontinence (6). The avoidance of these major complications after RP depends mainly on a high-quality surgical technique based on preservation, reconstruction, and reinforcement of the pelvis's anatomical structures, which will make a new supporting system after RP. Surgical techniques for posterior reconstruction of the rhabdosphincter were developed, namely Rocco Stitch (RS) and Bollens Stitch (BS) (6, 7, 14). A recent systematic review suggests that the rhabdosphincter's reconstruction could offer a significantly earlier return to continence in the first 30 days after RP still; its effect at 90 days remains controversial (10, 11). Salazar et al. (2019) concluded as well that the reconstruction of the rhabdosphincter is the only technique that has shown improved functional results through randomized trials (12). This study compares the impact of posterior reconstruction of the rhabdosphincter on urinary continence recovery with no rhabdosphincter reconstruction after LRP procedure; while assessing, prospectively, two types of posterior reconstruction of the rhabdosphincter, namely RS or BS.

Rhabdosphincter reconstruction after laparoscopic radical prostatectomy

MATERIALS

AND METHODS

General We performed an observational and prospective nonrandomized study. The data was collected from the Braga's Hospital information system, Glintt®, and via in-person interviews with patients, at the time of their postoperative appointment (90 days after LRP). All collected data were kept confidential. The research protocol was submitted and approved by the Ethics Commission for Health of Braga's Hospital (CESHB) and by the Ethics Commission for Sciences of Life and Health of Minho's University (CEICVS). There were no potential conflicts of interest. Patient population The selected patients were older than 18 years old who attended Braga's Hospital consultations and submitted to LRP between January 2018 and November 2019. The inclusion criteria were histological confirmation of PCa and localized PCa. The exclusion criteria included the presence of urinary incontinence before the procedure, previous radiation therapy of the prostate or pelvis, presence of prostatic surgery prior to the procedure, prior medical history of psychiatric disorder or drug addiction, and any other condition that contraindicated LRP. Patients with a history of urethral surgery, urethral stenosis or artificial urinary sphincter were also excluded. According to these criteria, we selected a sample of 63 patients that had been submitted to LRP. Two different surgeons had performed the surgery in this group of patients, which was divided into two major groups: NRR: retrospective group, whose patients have been submitted to LRP between January 2018 and December 2018 and had No Reconstruction of the Rhabdosphincter. PRR: a group of patients who have been submitted to LRP, followed by Posterior Reconstruction of the Rhabdosphincter, between January 2019 and November 2019. According to the technique used for posterior rhabdosphincter reconstruction, this group was further divided into two sub-groups - RS and BS groups. Each technique was performed solemnly by a different surgeon (surgeon 1 - RS and surgeon 2 - BS). Patients undergoing postoperative radiotherapy or major Clavien Dindo complications in the postoperative period were not included for the urinary continence assessment. Clinical data collection The demographic characteristics (age and sex), alcohol consumption, smoking habits, lower urinary tract symptoms, familiarity with PCa, previous procedures of the urologic tract and number of pads used daily since LRP were asked to the patients under consultation. The following data were collected by analyzing clinical reports: rhabdosphincter reconstruction (and type of stitch) or no reconstruction, patient's usual medication, metabolic disorders (hypertension, dyslipidemia, Diabetes mellitus, increased waist circumference), PSA (ng/mL) previous to LRP, the result of digital rectal examination (normal or suspicious), prostate biopsy mode realization (aleatory, cognitive fusion or ultrasonography fusion) and associated complications, hospitalization duration and urinary catheter duration (days) after LRP and PSA value (ng/mL) one

month after surgery (PSA T0). Clavien-Dindo Classification was usd to classify the complications rate after surgery. In this study, the pelvic floor rehabilitation protocols assessed were the Pelvic Floor Muscle Training (PFMT) in combination with behavioral therapy. Outcome measures The following outcome data were collected 90 days after the procedure by the healthcare provider: - Urinary continence: Declared urinary continence (defined by 0/1 safety pad per day) after physician evaluation on both the NRR and PRR groups, 90 days after LRP (33) Number of pads/day used after LRP (RS vs BS) International Consultation on Incontinence QuestionnaireShort Form (ICIQ-SF) assessment (RS vs BS) International Prostatic Symptoms Score (IPSS) assessment (RS vs BS). - Erectile function: Erectile function using International Index of Erectile Function (IIEF-5) assessment (RS vs BS). - Morbidity associated to the surgical techniques: Peri and postoperative complication rates (NRR vs PRR and RS vs BS). Clavien-Dindo Classification (NRR vs PRR and RS vs BS). Questionnaires ICIQ-SF, validated in Portuguese (Cronbach's alpha coefficient of 0.88) to assess the patient's urinary continence (13). IPSS, validated in Portuguese (Cronbach's alpha coefficient of 0.80) to assess LUTS (13, 14). IIEF-5, validated in Portuguese (Cronbach's alpha coefficient of 0.89) to assess erectile function (16). Statistical analysis The statistical analysis was performed with IBM SPSS® Statistics for Windows, Version 26.0. Data normality was assessed through the Shapiro-Wilk test, skewness, kurtosis and visual evaluation of the histograms (17, 18). To characterize the study's variables, we performed a descriptive analysis. Categorical variables were presented as frequencies (n) and proportions (%). Numerical variables were presented as means (M) and standard deviations (SD) for symmetrically distributed variables, and medians (Mdn) and interquartile ranges (IQR) for non-symmetrically distributed variables. The comparison of numerical variables between groups was performed with Student's T-test. The applied effect size measure was Cohen's d (19). A Mann-Whitney U test was performed when variables were not normally distributed. The effect size measure of this test was r = Z/√n, where 'n' is the total number of cases related to the study variable (20). The Chi-Square test was used to compare proportions across qualitative variables. Fisher's exact test was used alternatively when the expected frequency was lower than 5 in more than 20% of the contingency table cells (21). The applied effect size measure was phi (ϕ) or Crammer's V, since the cross-tables were two by two or three by two, respectively. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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To compare the urinary continence Table 1. Baseline characteristics of NRR and PRR groups. between-group NRR and PRR, we used a Chi-Square test (χ2), and the effect size measure used was phi (ϕ), since the cross-table was two by two. The Clavien-Dindo score was converted to a categorical variable: no complication (0), minor complication (I+II) and major complication (III+IV). A Fisher's exact test was used to compare these variables between groups NRR and PRR and to compare them between groups RS and BS. The effect size measure used was Cramer's V Table 2. since the cross-tables were three by two. Gleason Score and TNM of included patients. For numerical variables, such as the number of pads/day used after LRP and the IIEF assessment results, ICIQ-SF assessment and IPSS assessment, we applied a MannWhitney U Test. This test was also used to compare these numerical variables between group RS and BS. The effect size measure used was r. A p-value of less than 0.05 was considered statistically significant, and the confidence interval was 95%.

RESULTS

From the total sample population of 63 patients, 28 were not submitted to the posterior reconstruction of the rhabdosphincter (NRR), and 35 patients were (PRR). The mean value for age was 64 years for both NRR and PRR group. ed physical therapy (p = 0.648) (n = 1 in both RS and BS Table 1 shows the baseline characteristics between NRR groups) 90 days after surgery. and PRR groups, in which there were no differences. Table 4 shows that the PRR group patients had a better Table 2 shows the Gleason score and TNM staging of the urinary continence rate than patients of the NRR group included patients. (96% vs 33,3%; p < 0.001), 90 days after surgery. Regarding intraoperative complications, minor complicaAccording to the posterior rhabdosphincter reconstructions were reported in n = 3 (10.7%) from the NRR group tion techniques, 25 patients (71.4%) were submitted to and n = 6 (17.2%) from the PRR group; and major comRS and ten patients (28.6%) to BS. The baseline characplications occurred in n = 3 (10.7%) and n = 5 (14.3%), teristics of both groups are presented in Table 5. There in the NRR and PRR groups, respectively. were no differences between them. Complications were observed in both groups within days Regarding intraoperative complications, minor complicaafter surgery. However, after the mean (SD) follow-up tions were reported in n = 5 (20%) from the RS group and period of 90 days, there were no complications in group n = 1 (10%) from the BS group, and major complications PRR, and two patients from group NRR had complicaoccurred in n = 3 (12%) and n = 2 (20%) in the BS and tions. Regarding the Clavien Dindo classification, most RS groups, respectively. patients did not present complications. Table 6 compares the outcomes: number of pads/day Table 3 compares postoperative medication and pelvic used after LRP and ICIQ-SF, IPSS and IIEF assessments floor rehabilitation between NRR and PRR, and it shows between RS and BS. One patient (5.6%) from RS used no statistically significant differences. The table also more than one safety pad/day, while no patient from BS shows that, at 90 days after surgery, 17 patients from NRR group and 14 from PRR group (n = 4 (28.5%) and Table 3. Comparison of postoperative erectile dysfunction medication and pelvic floor n = 10 (71.5%) from RS and BS rehabilitation between groups NRR and PRR. groups, respectively) had already initiated PDH5 inhibitor (p = 0.131); five patients from NRR and three from PRR had started PGE1 (p = 0.449) (n = 3 (100%), from the RS group, and n = 0 from the BS group). Regarding pelvic floor rehabilitation, three patients (10.7%) from NRR and two (5,7%) from PRR had start-

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Rhabdosphincter reconstruction after laparoscopic radical prostatectomy

Table 4. Comparison of urinary continence between groups NRR and PRR.

Table 5. Baseline characteristics of RS and BS groups.

used more than one safety pad/day, but a significant difference was not found. The median score on ICIQ-SF was higher on RS than on BS (with no statistically significant differences, p = 0.116), and the median score on IIEF-5 assessment was 5 (0) in both groups. Table 7 presents the impact of posterior rabdosphincter in both groups, RS and BS. After 90 days from LRP, no complications were observed in either group. Regarding Clavien Dindo classification, there were no complications in most of the subjects in both RS and BS group (68% vs 70%; p = 0.738).

DISCUSSION

The results of this study suggest that posterior reconstruction of the rhabdosphincter improves the early continence of patients undergoing LRP, as it is described in Table 6. Comparison of the outcomes between RS and BS groups.

Table 7. Impact of posterior rabdosphincter in both groups, RS and BS.

several studies (11, 22-24). Rocco et al. (2007) conducted a prospective study on patients undergoing LRP, defining continence as no pads or one diaper/day. At 90 days after catheter removal, the continence rates were 92.3% on patients with posterior musculofascial plate reconstruction versus 76.9% on patients with no reconstruction (25). Rocco's study corroborates our results where patients of the PRR group had a better full continence rate than patients of the NRR group at 90 days. Our study also showed no differences between the complication rates in the posterior rhabdosphincter reconstruction group and the non-reconstruction group and similar Clavien Dindo classification of complications. Coelho et al. (2011) related that overall complication rate and postoperative acute urinary retention rates at 30 days were similar between both groups (24). Grasso et al. (2016) have also shown no association between rhabdosphincter reconstruction and postoperative complications in a review and meta-analysis (11). Regarding posterior rhabdosphincter reconstruction techniques (RS and BS), the current study found that both groups reported similar urinary continence rate and that one patient from RS group used more than one safety pad per day. In contrast, no pads were used in the BS group. For measuring urinary function, two questionnaires were applied to the reconstruction group: ICIQ-SF and IPSS, in which the median scores were similar in both groups. Machioka et al. (2019) demonstrated that the ICIQ-SF questionnaire was effective and convenient for evaluating urinary incontinence, including in patients after RP (26). However, this questionnaire is a subjective measure of the severity of urinary loss and the impact of urinary incontinence on quality-of-life (13), as its results depend on the patient's perspective. Since the results on IPSS are between 1 and 7, lower urinary tract symptoms have a mild severity in these patients (27). Assessing erectile function after 90 days from posterior rhabdosphincter reconstruction, the median score on IIEF5 assessment was the same in both groups. However, most patients were not on medication for erectile dysfunction at the time of the interview. Rocco et al. have described that erectile function was similar in reconstruction and nonreconstruction groups (28). Further literature corroborates that rhabdosphincter reconstruction techniques have no benefit for erectile function recovery (29). The complication rates were similar in both RS and BS groups and, considering Clavien Dindo classification of complications, both groups had similar results. According to a meta-analysis stratified by surgical approaches, no association has been found between rhabdosphincter reconstruction and postoperative complications (11), suggesting that it is a safe procedure. Moreover, we measured selected demographic variables that are described in previous literature to have a great influence on postoperative urinary incontinence and erectile function (such as age, prostate size, PSA score, metabolic disorders, Gleason score, urinary catheter duration and surgical complications.) and Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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found that there were no statistically significant differences between the groups NRR and PRR (3, 25, 30-32). This study has some limitations. The low sample size of the prospective part of the study (n = 35) limits possible extrapolation. Additionally, the follow-up period (90days) was short for evaluating urinary continence, and the reference used for its definition in the PRR groups (number of pads/day) was a biased and subjective outcome, as opposed to a pad weight test. Furthermore, the non-reconstruction group is retrospective, and, therefore, the data were based on the physician interview and could have been affected by subjectivity. Finally, several surgeons were responsible for performing the surgeries, which means that this was a non-controlled variable in this study. More extensive research on surgical techniques for earlier urinary continence in LRP is required to allow more robust conclusions. Therefore, we recommend further studies on the current topic.

CONCLUSIONS

This study shows that the rhabdosphincter's posterior reconstruction has significant benefits for urinary continence recovery in the first 90 days on patients undergoing LRP. Additionally, reconstruction of the rhabdosphincter appears to be a safe procedure with no increased risk of postoperative complications. Concerning urinary continence and postoperative complication rates after LRP and postoperative complication rates, the results suggest that there are no statistically significant differences between Rocco Stitch and Bollens Stitch. Still, a system of support appears to play an essential role in urinary continence after surgery. Further work is required to establish this.

REFERENCES

10. Rocco B, Cozzi G, Spinelli MG, et al. Posterior musculofascial reconstruction after radical prostatectomy: A systematic review of the literature. Eur Urol. 2012; 62:779-90. 11. Grasso AAC, Mistretta FA, Sandri M, et al. Posterior musculofascial reconstruction after radical prostatectomy: an updated systematic review and a meta-analysis. BJU Int. 2016; 118:20-34. 12. Salazar A, Regis L, Planas J, et al. Early continence after radical prostatectomy: A systematic review. Actas Urologicas Espanolas. 2019;43:526-535. 13. Tamanini TNJ, Dambros M, Levi ACD, et al. Validation of the “International Consultation on Incontinence Questionnaire-Short Form” (ICIQ-SF) for Portuguese. Rev Saude Publica. 2004; 38:438-44. 14. Mineo Bianchi F, Romagnoli D, D’Agostino D, et al. Posterior muscle-fascial reconstruction and knotless urethro-neo bladder anastomosis during robot-assisted radical cystectomy: Description of technique and its impacto n urinary continence. Arch Ital Urol Androl. 2019; 91:5-10. 15. Berger M, Luz Junior PN, Brasil SN, Koff WJ. Statistical validation of the international prostatic symptom score (I-PSS) in portuguese. J Bras Urol. 1999; 25:225-34. 16. Pechorro PS, Calvinho AM, Pereira NM, Vieira RX. Validação da versão portuguesa do Índice Internacional de Função Eréctil-5 (IIEF-5). Rev Int Andrología. 2011; 9:3-9. 17. Razali NM, Wah YB. Power comparisons of Shapiro-Wilk, Kolmogorov-Smirnov, Lilliefors and Anderson-Darling tests. J Stat Model Anal. 2011; 2:21-33. 18. Kim HY. Statistical notes for clinical researchers: assessing normal distribution using skewness and kurtosis. Restor Dent Endod. 2013; 38:52. 19. Cohen J. Statistical power analysis for the behavioral sciences. 2nd edition. New York: Lawrence Erlbaum Associates; 1988, Chapt 2, pp 20-52. 20. Chan YH. Biostatistics 102: Quantitative data-parametric & non-parametric tests. Singapore Med J. 2003; 44:391-396.

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21. Chan YH. Biostatistics 103: Qualitative data-tests of independence. Singapore Med J. 2003; 44:498-503.

2. Cao L, Yang Z, Qi L, Chen M. Robot-assisted and laparoscopic vs open radical prostatectomy in clinically localised prostate cancer. Medicine (Baltimore). 2019; 98:e15770.

22. Liao X, Qiao P, Tan Z, et al. "Total reconstruction" of the urethrovesical anastomosis contributes to early urinary continence in laparoscopic radical prostatectomy. Int Braz J Urol. 2016; 42:215-22.

3. Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med. 2008; 358:1250-61.

23. Wu YP, Xu N, Wang ST, et al. The efficacy and feasibility of total reconstruction versus non total reconstruction of the pelvic floor on short-term and long-term urinary continence rates after radical prostatectomy: a meta-analysis. World J Surg Oncol. 2017; 20;15:228.

4. Miller DC, Saigal CS, Litwin MS. The demographic burden of urologic diseases in America. Urol Clin North Am. 2009; 36:11-27. 5. Trost L, Elliott DS. Male stress urinary incontinence: A review of surgical treatment options and outcomes. Adv Urol. 2012; 8:1-13. 6. Alivizatos G, Skolarikos A. Incontinence and erectile dysfunction following radical prostatectomy: a review. Scientific World Journal. 2005; 5:747-58. 7. Topaktas R, Urkmez A, Kutluhan MA, et al. Vesicourethral anastomosis including rhabdosphincter in retropubic radical prostatectomy: Technique and results. Arch Ital Urol Androl. 2019; 90:249-253. 8. 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.

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24. Coelho RF, Chauhan S, Orvieto MA, et al. Influence of modified posterior reconstruction of the rhabdosphincter on early recovery of continence and anastomotic leakage rates after robot-assisted radical prostatectomy. Eur Urol. 2011; 59:72-80. 25. Rocco B, Gregori A, Stener S, et al. Posterior Reconstruction of the rhabdosphincter allows a rapid recovery of continence after transperitoneal videolaparoscopic radical prostatectomy. Eur Urol. 2007; 51:996-1003. 26. Machioka K, Kadono Y, Naito R, et al. Evaluating urinary incontinence before and after radical prostatectomy using the international consultation on incontinence questionnaire-short form. Neurourol Urodyn. 2019; 38:726-33.

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27. Barry MJ, Fowler FJ, O'Leary MP, et al. The American urological association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol. 1992; 148:1549-57. 28. Rocco F, Carmignani L, Acquati P, et al. Restoration of Posterior aspect of rhabdosphincter shortens continence time after radical retropubic prostatectomy. J Urol. 2006; 175:2201-6. 29. Tewari A, Jhaveri J, Rao S, et al. Total reconstruction of the vesicourethral junction. BJU Int. 2008; 101:871-7. 30. Gershman B, Psutka SP, McGovern FJ, et al. Patient- reported functional outcomes following open, laparoscopic, and robotic assist-

ed radical prostatectomy performed by high-volume surgeons at high-volume hospitals. Eur Urol Focus. 2016; 2:172-179. 31. Fujimoto M, Higuchi T, Kouichi H, Takada M. Association of statin use with storage lower urinary tract symptoms: Data mining of claims database. J Pharmacovigil. 2014; 2:5. 32. Heesakkers J, Farag F, Bauer RM, et al. Pathophysiology and contributing factors in postprostatectomy incontinence: A review. Eur Urol. 2017; 71: 936-44. 33. Kretschmer A, Hübner W, Sandhu JS, Bauer RM. Evaluation and management of postprostatectomy incontinence: a systematic review of current literature. Eur Urol Focus. 2016; 2:245-59.

Correspondence Pedro Sousa Passos, MD (Corresponding Author) pedrosousapassos@gmail.com Department of Urology, Hospital de Braga Largo Bairro do Jardim 3, 4900-467 Viana do Castelo (Portugal) Sara Teixeira Anacleto, MD sara.anacleto241@gmail.com Mário Cerqueira Alves, MD mcerqueiraalves@gmail.com Paulo Oliveira Mota, MD damota.paulo@gmail.com Department of Urology, Hospital de Braga (Portugal) Rui Simeão Versos, MD rui.1971.versos@gmail.com Department of Urology, Hospital de Guimarães (Portugal)

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DOI: 10.4081/aiua.2021.3.280

ORIGINAL PAPER

The presence of chronic inflammation in positive prostate biopsy is associated with upgrading in radical prostatectomy Ekrem Guner 1, Yavuz Onur Danacioglu 1, Yusuf Arikan 1, Kamil Gokhan Seker 1, Salih Polat 2, Halil Firat Baytekin 3, Abdulmuttalip Simsek 1 1 University

of Health Sciences, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Department of Urology, Istanbul, Turkey; University Medical Faculty, Department of Urology, Amasya, Turkey; 3 University of Health Sciences, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Department of Pathology, Istanbul, Turkey. 2 Amasya

Summary

Objective: This study aimed to determine the predictive effect of the presence of chronic prostatitis associated with prostate cancer (PCa) in prostate biopsy on Gleason score upgrade (GSU) in radical prostatectomy (RP) specimens. Materials and methods: The data of 295 patients who underwent open or robotic RP with a diagnosis of localized PCa following biopsy were retrospectively analyzed. Patients were divided into two groups with and without GSU following RP. Predictive factors affecting GSU on biopsy were determined. The impact of chronic prostatitis associated with prostate cancer on GSU was examined via logistic regression analysis. Results: Out of 224 patients with Gleason 3+3 scores on biopsy, 145 (64.7%) had Gleason upgrade, and 79 (35.2%) had no upgrade. Whilst comparing the two groups with and without Gleason upgrade in terms of patient age, prostate-specific antigen (PSA) value, PSA density (PSAD), prostate volume (PV), neutrophil/lymphocyte (N/L) ratio, number of positive cores, percentage of positive cores, and Prostate Imaging Reporting and Data System version 2 score, no statistically significant difference was detected. The presence of chronic prostatitis associated with PCa was higher in the patient cohort with GSU in contrast to the other group (p < 0.001). According to the univariate logistic regression analysis, the presence of chronic prostatitis was identified to be an independent marker for GSU. Conclusions: Pathologists and urologists should be careful regarding the possibility of a more aggressive tumor in the presence of chronic inflammation associated with PCa because inflammation within PCa was revealed to be linked with GSU after RP.

KEY WORDS: Prostate cancer; Prostate biopsy; Chronic prostatitis; Prostate inflammation. Submitted 16 March 2021; Accepted 7 May 2021

INTRODUCTION

Inflammation may play a role in the development and progression of many cancers (1). In various epidemiologic studies, it is noted that ulcerative colitis, esophagitis, and hepatitis cause an increased risk for the development of malignant neoplasm and that chronic inflammation accompanies 17% of all cancers (2). After Rudolf Virchow identified the relationship between inflammation and cancer in

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No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

1863, several biological and epidemiological studies were conducted to demonstrate this. As a result of these studies, although contradictory opinions are present, it is stated that development of prostate cancer (PCa) is associated with chronic prostatitis (1, 3). Prostatitis, defined as inflammation of the prostate gland, is classified by the National Institutes of Health (NIH) as acute bacterial prostatitis, chronic bacterial prostatitis, inflammatory prostatitis, noninflammatory prostatitis, and asymptomatic prostatitis (4). In a study of 68.675 male patients, the risk of developing PCa was found to be increased in patients with a history of prostatitis and prolonged prostatitis symptoms (5). These findings show that chronic inflammation plays an important role in PCa carcinogenesis (6). Via altering tumor microenvironment, interleukins (IL-8, IL-6) released as a result of inflammation may lead to an increase in angiogenesis, broadening of tumor size, build-up of invasive characteristics, progression of PCa, and cancer becoming more resistant to androgen blockade or chemotherapy (7, 8). There is no evidence that inflammation is related to tumor aggressive PCa. Because of the discrepancy between Gleason score (GS) detected in prostate biopsy and GS of radical prostatectomy (RP) specimen, it is difficult to predict tumor aggressiveness, and this may change the appropriate treatment options for patients. In the literature, advanced age, serum prostate-specific antigen (PSA) elevation, PSA density (PSAD), and multi-parametric magnetic resonance imaging (mp-MRI) have been reported to be predictors of GS upgrade (GSU) in various studies (9, 10). The increase in tumor aggressiveness resulting from chronic inflammation suggests that it may be a predictor for GSU. In the published literature, no study has examined the relationship between the presence of chronic inflammation associated with PCa and GSU. The aims of this study was to determine the predictive effect of coexisting chronic prostatitis in PCa diagnosed by prostate biopsy on GSU in RP specimen.

MATERIALS

AND METHODS

Patient selection After obtaining Institutional Review Board approval (2018/267)

Chronic inflammation and upgrading in radical prostatectomy

for the study, the data of 295 patients who underwent prostate biopsy due to high PSA levels after antibiotic therapy, PSA elevation together with suspicious digital rectal examination (DRE) or PSA elevation together with mpMRI findings and whose results showed prostate cancer and underwent radical prostatectomy from May 2012 to December 2018 were reviewed, retrospectively. Patients receiving anti-androgen therapy, those with history of radiotherapy, patients with a previous biopsy history, those included in active surveillance (AS), patients with primary metastatic PCa, and subjects with incomplete data were excluded. Transrectal ultrasound (TRUS)-guided (GE Logic 9; General Electric, Milwaukee, WI, USA) prostate biopsy (TRUS-Bx) was performed through an E8C 7.5-MHz transrectal linear array transducer placed in an automatic biopsy gun (ACECUT; TAF, Tochigi, Japan) equipped with an 18-gauge biopsy needle (Magnum; Bard, Covington, GA, USA). Regions suspicious for malignancy on mpMRI (targeted lesions) were sampled with two cores. This was followed by standard 10-core systemic biopsies that were taken from patients dependent on prostate volume. All MRI target TRUS-Bx and RP specimens were collected at our institution, and we obtained actual pathologic tissue slides for examination by two pathologists. The clinical and pathologic data included preoperative PSA measured prior to DRE and TRUS, PSAD, prostate volume (assessed by TRUS), GS of TRUS-Bx and RP specimens, evidence of histologic chronic prostatitis on biopsy, number and percentages of positive cores in biopsy samples, the final (pathologic) GS of RP specimens, and Prostate Imaging Reporting and Data System version 2 (PIRADS) scores in mpMRI. Pathologic assessment All pathology specimens were evaluated by two experienced uropathologists. TRUS-Bx specimens were analyzed in terms of the following: tumor type, GS, number of tumor localizations and positive core ratios, presence of perineural invasion, evidence of high-grade prostatic intraepithelial neoplasia (PIN) in tumor-free areas, presence of atypical small acinar proliferation (ASAP), evidence of atrophy, and presence of chronic or active prostatitis along with its extent. RP specimens were assessed more thoroughly; the factors taken into consideration in addition to the parameters described above for TRUS-Bx were as follows: intraductal component, predominant tumor localization and diameter, the status of surgical margins, seminal vesicle involvement, and bladder neck invasion. Histopathologic diagnosis of chronic inflammation in the prostate was made by the presence of primarily lymphocytes (predominantly T lymphocytes) infiltrating the stromal and/or glandular component; neutrophils infiltrating the glands in some cases, even playing a role in development of luminal micro-abscesses or larger prostatic abscesses; macrophages to a lesser extent; plasma cells; and eosinophil leukocytes. The diagnosis of prostatitis was defined as chronic active prostatitis via the detection of neutrophils infiltrating the glandular epithelium within more than one gland and more than one core, or as chronic prostatitis in cases of uncertain neutrophilic infiltration by identification of increased number of lympho-

cytes (with or without histiocytes) forming aggregates in parenchyma, as well as infiltrating the glands. In our study, GS in acinar adenocarcinoma were compared between TRUS-Bx and RP specimens for the same patient. In RP specimens, an increase in numerical value of GS or a change from a total score in TRUS-Bx of 3+4 = 7 to a score of 4+3 = 7, was acknowledged as GSU (11). Statistical analysis Statistical analysis was performed using the Statistical Package of Social Sciences version 21 software package (IBM SPSS Statistics; IBM Corp., Armonk, NY). The Shapiro-Wilk test was used to determine whether distributions of continuous variables were normal. The mean differences between two related groups of normally distributed data were compared by independent ttest, and the Mann-Whitney U test was used to compare non-normally distributed data. The effect of the presence of prostatitis on biopsy upon Gleason score upgrade was examined using logistic regression analysis. The Chisquare (χ2) test was used for comparison of qualitative independent variables within groups. A P value ≤ 0.05 was considered statistically significant.

RESULTS

A total of 295 patients with complete clinical and pathologic data who underwent open or robotic RP with the diagnosis of localized PCa after biopsy were included in the study for analysis. Overall, the mean age, PSA, PSAD, and PV were respectively 61.4 ± 6 years, 9.5 ± 6 ng/mL, 23 ± 17.2 and 45.5 ± 17.3 cm3. Histopathologic analysis following TRUS-Bx revealed 224 (75.9%) patients with GS 3+3, 52 (17.6%) patients with GS 3+4, 15 (5%) patients Table 1. Patient characteristics. Age (years, mean ± SD) PSA value (ng/mL, mean ± SD) PSA density (ng/mL2, mean ± SD) Prostate volume, n (%) ≤ 35 35-65 ≥ 65 Neutrophil/lymphocyte ratio (N/L) (mean ± SD) Biopsy Gleason score, n (%) 3+3 3+4 4+3 8 9-10 No. of positive cores, n (%) Percentages of positive cores, n (%) MR PI-RADS category, n (%) ≤2 3 4 5 Prostatectomy Gleason score, n (%) 3+3 3+4 4+3 8 9-10

61.4 ± 6.0 9.5 (6.0) 23.0 (17.2) 83 173 39 5.2 (3.3) 224 (75.9) 52 (17.6) 15 (5) 3 (1) 1 (0.3) 3.73 (2.1) 35.9 (21.5) 53 (17.9) 50 (16.9) 179 (60.6) 13 (4.4) 79 (26.7) 131 (44.4) 47 (15.9) 21 (7.1) 17 (5.7)

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Table 2. Radical prostatectomy grades stratified by biopsy Gleason scores. Biopsy GS Radical prostatectomy GS 3+3 3+4 4+3 8 9-10 Total

5-6

3+4

4+3

9-10

Total

79 106 29 7 3 224

0 25 17 3 7 52

0 0 1 10 4 15

0 0 0 1 2 3

0 0 0 0 1 1

79 131 47 21 17 295

Table 3. Clinical and pathologic parameters with Gleason score (GS) group: upgrading from biopsy GS 5-6 to GS > 6 at radical prostatectomy. Variables Age Mean (SD) Median (range) PSA Mean Median PSA density Mean Median Prostate volume ≤ 35 35-65 ≥ 65 NL ratio Mean Median No. of positive cores Mean Median Percentages of positive cores Mean Median MR PI-RADS category ≤2 3 ≥4 Bx result PCa with chronic prostatitis Pure PCa

Upgrade (n = 145)

No upgrade (n = 79)

61.5 (5.7) 61.0 (46-78)

60.3 (6.4) 60.0 (47-74)

9.8 (6.3) 8.0 (1.8-43.0)

9.0 (4.5) 7.5 (3.3-27.0)

22.3 (17.1) 16.0 (4.8-122.8)

22.2 (13.1) 19.6 (5.3-67.5)

31 91 23

26 39 14

5.4 (3.4) 4.9 (1.1-20.8)

4.7 (2.7) 4.3 (1.1-15.0)

3.75 (2.3) 3.0 (1-12)

3.1 (1.6) 3.0 (1-8)

36.1 (22.5) 30.0 (6-100)

30.4 (16.8) 30.0 (8-83)

34 21 90

15 16 48

82 63

24 55

P value 0.099 0.902

DISCUSSION

0.285 0.282

0.148 0.141 0.166 0.729

< 0.001

with GS 4+3, 3 (1%) patients with a total GS of 8, and 1 (0.3%) patient with a total GS of 9-10. The median number of positive cores detected as cancer on biopsy was 3 (range, 1-12), and the mean percentage of positive cores was 30% (range, 6-100%). In mpMRI performed prior to biopsy, the results indicated the following: 53 (17.9%) patients with a PIRADS 2, 50 (16.9%) patients with a Table 4. Univariate logistic regression model to prediction of upgrading from biopsy GS 5-6 to GS > 6 at RP. Variable Bx result Pure PCa PCa with chronic prostatitis

282

OR (95% CI)

p value

ref 2.983 (1.668-5.333)

< 0.001

Archivio Italiano di Urologia e Andrologia 2021; 93, 3

PIRADS 3, 179 (60.6%) patients with a PIRADS 4, and 13 (4.4%) patients with a PIRADS 5 lesion. On histopathologic examination of RP specimens, 79 (26.7%) patients had GS of 3+3, 131 (44.4%) patients had GS of 3+4, 47 (15.9%) patients had GS of 4+3, 21 (7.1%) patients had GS of 8, and 17 (5.7%) patients had GS of 9-10 (Table 1). Based on these findings, 145 (64.7%) of the total 224 patients with a GS of 3+3 on TRUS-Bx were identified as having GSU, and 79 (35.2%) had no upgrade (Table 2). There was no statistically significant difference observed between the two groups with and without GSU in terms of patient age, PSA value, PSAD, prostate volume, neutrophil/lymphocyte (N/L) ratio, number of positive cores, percentage of positive cores, and PIRADS score (Table 3). The presence of chronic prostatitis associated with PCa was higher in the GSU group in comparison with the other group (p < 0.001). According to the univariate logistic regression analysis, the presence of chronic prostatitis was found to be an independent predictor for GSU (OR: 2.98, 95% CI, p < 0.001) (Table 4).

Ethnic origin, age, and family history are amongst the known risk factors of PCa, yet there are many other probable risk factors currently being researched. Epidemiologic, genetic, and experimental studies have suggested that chronic inflammation may be associated with PCa, though this is unclear (12). Although prostatitis is defined as inflammation of the prostate gland in terms of pathologic description, it has traditionally been used to express the clinical picture of urinary tract symptoms, inflammation, pain of prostate origin, and not fully understood etiopathogenesis. Pathologically, evidence of neutrophils, eosinophils, lymphocytes, macrophages, and plasma cells in the parenchyma is presented as prostatitis (13). The incidence of prostatitis in the male population is 4.5-9%; it is as common as ischemic heart disease and diabetes in the population (14, 15). Chronic asymptomatic inflammatory prostatitis is described as category IV according to the NIH classification and as the presence of inflammatory cells in biopsy specimens of asymptomatic patients with high PSA values (16). In patients with a PSA value of > 4 ng/mL, the incidence of chronic prostatitis is reported as 42% (17). Although no verifiable infectious agent has been identified, an increase in PSA values may be present in cases where the rate of inflammation within the prostate is above 20% (18). Inflammatory infiltrates include T lymphocytes, macrophages, plasma cells, and eosinophils. The presence of CD-204 macrophages and CD-3 T lymphocytes play a role in tumor development. The pro-carcinogenic inflammatory process leads to cell transformation by activation of transcription factor NF-kB and a consequent increase of tumor necrosis factor (TNF)-a and IL-6 (19). In addition, IL-30 has been shown to take part in PCa stem-like cell regulation and is proven to be responsible for onset, vascularization, and increased tumor proliferation (20). In recent years, Vav3 oncogene has been documented to cause both chronic prostatitis and PCa (21). Studies in the literature indicate that the presence of chronic prostatitis increases the risk of PCa by

Chronic inflammation and upgrading in radical prostatectomy

1.83-fold (22). Some authors state that the use of aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) decreases the risk of PCa (23). Apart from the chemokines and cytokines produced in chronic prostatitis, inflammatory cells provide a microenvironment favorable to tumor progression by increasing production of oxygen species, which induce oxidative DNA damage, reducing DNA repair, stimulating tumor growth and angiogenesis (12). In patients with PCa not detected on the first biopsy, the incidence of PCa was found to be higher in patients with histologically demonstrated chronic inflammation after the 5-year follow-up in comparison with patients without chronic inflammation (20% vs. 6%) (24). Furthermore, evidence of chronic inflammation along with PCa results in patients having a more aggressive and advanced disease. Patients with high-grade inflammation surrounding malignant glands had significantly more advanced disease and higher postoperative biochemical recurrence (BCR) rates than patients with low-grade inflammation (25, 26). Considering the current studies, it is thought that cooccurrence of PCa and chronic inflammation might also be associated with the possibility of GSU, which is encountered in clinical practice with a 44% probability. In different studies, several markers such as higher PSA, older age, higher percentage of positive cores, lower prostate volume, PSAD, and mp-MRI findings have been identified as important indicators for upgrading and upstaging (9, 10). GSU may be associated with outcomes of RP including extra prostatic extension, positive surgical margin, and seminal vesicle invasion. This may lead us to be more selective in determining AS patients and may result in BCR during follow-up of these patients (9). In our study, factors described in previous studies for GSU were also reviewed, yet the presence of chronic prostatitis on biopsy accompanying PCa was the only significant marker for GSU according to logistic regression analysis. There are several studies in the literature in relation to the prediction of GSU using the N/L ratio prior to surgery. Although caution is advised regarding GSU in patients with N/L ≥ 3, some studies reveal no relationship between this finding and GSU (27). The N/L ratio was not classified as a predictive factor for GSU in our study. The intraobserver match was 41-43% in the histopathologic assessment of TRUS-Bx and RP specimens, but in our study, the possibility of misevaluation was eliminated via analysis of biopsy and RP specimens by two uropathologists. The point, as identified in our study, that the presence of chronic inflammation is a significant marker for GSU, is important for clinical practice and future studies. Porcaro et al. (28) showed that patients diagnosed with low-risk PCa in biopsy are a heterogeneous group, in fact, these patients may represent a higher disease than their PSA and positive cores. On the other hand, Gurel et al. (29) found that men with more intraprostatic inflammation in patients with prostate cancer had a higher risk of poor outcomes. AS which is the first-line treatment plan for patients in the low risk group, is not a suitable treatment option in terms of GSU risk for patients with evidence of chronic inflammation. With the support of these studies in the future, we argue that one of the AS exclusion criteria should be the presence of prostatitis in the biopsy.

Our study has some limitations that should be taken into consideration. First, this was designed as a retrospective study. We did not quantify the extent of inflammation within each prostate specimen. They could not determine the relationship between the degree of inflammation and tumor aggressiveness. We did not report the presence of other prostatic lesions such as high grade PIN, postatrophic hyperplasia or proliferative inflammatory atrophy. Due to the design of our study, it was not possible to assess the association of chronic inflammation presence with more aggressive outcomes. Our findings should be confirmed using more distant end points such as metastasis and survival.

CONCLUSIONS

The present study showed that inflammation within PCa was associated with GSU after RP. Hence, pathologists and urologists should be cautious about the possibility of a more aggressive tumor in the presence of chronic inflammation associated with PCa. This may be due to inflammatory mediators promoting development of aggressive PCa. Our study is the only study to demonstrate the relationship between chronic inflammation and GSU. However, prospective studies are required in order to examine clinical reflection and the long-term outcomes of our study.

REFERENCES

1. Cai T, Santi R, Tamanini I, et al. Current knowledge of the potential links between inflammation and prostate cancer. Int J Mol Sci. 2019; 20:3833. 2. Jiang J, Li J, Yunxia Z, et al. The role of prostatitis in prostate cancer: meta-analysis. PloS one. 2013; 8:e85179. 3. Sfanos KS, Yegnasubramanian S, Nelson WG, De Marzo AM. The inflammatory microenvironment and microbiome in prostate cancer development. Nat Rev Urol. 2018; 15:11-24. 4. Puhr M, De Marzo A, Isaacs W, et al. Inflammation, microbiota, and prostate cancer. Eur Urol Focus. 2016; 2:374-82. 5. Cheng I, Witte JS, Jacobsen SJ, et al. Prostatitis, sexually transmitted diseases, and prostate cancer: the California Men's Health Study. PLoS One. 2010; 5:e8736. 6. Neveu B, Moreel X, Deschênes-Rompré M-P, et al. IL-8 secretion in primary cultures of prostate cells is associated with prostate cancer aggressiveness. Res Rep Urol. 2014; 6:27. 7. Araki S, Omori Y, Lyn D, et al. Interleukin-8 is a molecular determinant of androgen independence and progression in prostate cancer. Cancer Res. 2007; 67:6854-62. 8. Nguyen DP, Li J, Tewari AK. Inflammation and prostate cancer: the role of interleukin 6 (IL-6). BJU International. 2014; 113:986-92. 9. Alchin DR, Murphy D, Lawrentschuk N. Risk factors for Gleason Score upgrading following radical prostatectomy. Minerva Urol Nefrol. 2017; 69:459-65. 10. Dinh KT, Mahal BA, Ziehr DR, et al. Incidence and predictors of upgrading and up staging among 10,000 contemporary patients with low risk prostate cancer. J Urol. 2014; 194:343-9. 11. Moussa AS, Li J, Soriano M, et al. Prostate biopsy clinical and pathological variables that predict significant grading changes in Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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patients with intermediate and high grade prostate cancer. BJU international. 2009; 103:43-8. 12. Doat S, Cénée S, Trétarre B, et al. Nonsteroidal anti-inflammatory drugs (NSAID s) and prostate cancer risk: results from the EPICAP study. Cancer Med. 2017; 6:2461-70. 13. Nickel JC, True LD, Krieger JN, et al. Consensus development of a histopathological classification system for chronic prostatic inflammation. BJU International. 2001; 87:797-805. 14. Clemens JQ, Meenan RT, Rosetti MCK, Kimes T, Calhoun EA. Prevalence of and risk factors for prostatitis: population based assessment using physician assigned diagnoses. J Urol. 2007; 178:1333-7. 15. Teke K, Danacıoglu YO, Polat S. Predictive parameters on the effect of ofloxacin treatment on the reduction of PSA in patients with elevated PSA level. Yeni Üroloji Dergisi - The New Journal of Urology. 2019; 14:166-75. 16. Polackwich A, Shoskes D. Chronic prostatitis/chronic pelvic pain syndrome: a review of evaluation and therapy. Prostate Cancer Prostatic Dis. 2016; 19:132. 17. Potts JM. Prospective identification of National Institutes of Health category IV prostatitis in men with elevated prostate specific antigen. J Urol. 2000; 164:1550-3. 18. Carver BS, Bozeman CB, Williams B, Venable DD. The prevalence of men with National Institutes of Health category IV prostatitis and association with serum prostate specific antigen. J Urol. 2003; 169:589-91. 19. Nguyen DP, Li J, Yadav SS, Tewari AK. Recent insights into NFκB signalling pathways and the link between inflammation and prostate cancer. BJU International. 2014; 114:168-76. 20. Sorrentino C, Ciummo SL, Cipollone G, et al. Interleukin30/IL27p28 shapes prostate cancer stem-like cell behavior and is critical for tumor onset and metastasization. Cancer Res. 2018; 78:2654-68.

Correspondence Ekrem Guner, MD (Corresponding Author) ekremguner@yahoo.com Yavuz Onur Danacioglu, MD dr_yonur@gmail.com Yusuf Arikan, MD dryusufarikan@gmail.com Kamil Gokhan Seker, MD gkhnseker@hotmail.com Abdulmuttalip Simsek, MD simsek76@yahoo.com University of Health Sciences, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Department of Urology, Istanbul (Turkey) Zuhuratbaba Mh. Tevfik Saglam Cd. No:11 Bakirkoy, Istanbul (Turkey) Salih Polat, MD salihpolat@gmail.com Amasya University Medical Faculty, Department of Urology, Amasya (Turkey) Akbilek Mah. Muhsin Yazıcıoglu Cad. No:7, Amasya (Turkey) ORCID:0000-0002-7580-6872 Halil Firat Baytekin, MD baytekin2001@yahoo.com University of Health Sciences, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Department of Pathology, Istanbul (Turkey) Zuhuratbaba Mh. Tevfik Saglam Cd. No:11 Bakirkoy, Istanbul (Turkey)

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21. Liu Y, Mo JQ, Hu Q, et al. Targeted overexpression of vav3 oncogene in prostatic epithelium induces nonbacterial prostatitis and prostate cancer. Cancer Res 2008; 68:6396-406. 22. Perletti G, Monti E, Magri V, et al. The association between prostatitis and prostate cancer. Systematic review and meta-analysis. Arch Ital Urol Androl. 2017; 89:259-65. 23. Jafari S, Etminan M, Afshar K. Nonsteroidal anti-inflammatory drugs and prostate cancer: a systematic review of the literature and meta-analysis. Can Urol Ass J. 2009; 3:323. 24. Delongchamps NB, De La Roza G, Chandan V, et al. Evaluation of prostatitis in autopsied prostates—is chronic inflammation more associated with benign prostatic hyperplasia or cancer? J Urol. 2008; 179:1736-40. 25. Klink JC, Bañez LL, Gerber L, et al. Intratumoral inflammation is associated with more aggressive prostate cancer. World J Urol. 2013; 31:1497-503. 26. McArdle P, Canna K, McMillan D, et al. The relationship between T-lymphocyte subset infiltration and survival in patients with prostate cancer. Br J Cancer. 2004; 91:541. 27. Özsoy M, Moschini M, Fajkovic H, et al. Elevated preoperative neutrophil-lymphocyte ratio predicts upgrading at radical prostatectomy. Prostate Cancer Prostatic Dis. 2018; 21:100. 28. Porcaro AB, Siracusano S, de Luyk N, et al. Low-risk prostate cancer and tumor upgrading in the surgical specimen: analysis of clinical factors predicting tumor upgrading in a contemporary series of patients who were evaluated according to the modified Gleason score grading system. Curr Urol. 2017; 10:118-125. 29. Gurel B, Lucia MS, Thompson IM Jr, et al. Chronic inflammation in benign prostate tissue is associated with high-grade prostate cancer in the placebo arm of the prostate cancer prevention trial. Cancer Epidemiol Biomarkers Prev. 2014; 23:847-56.

DOI: 10.4081/aiua.2021.3.285

ORIGINAL PAPER

Visceral adiposity is associated with worse urinary and sexual function recovery after radical prostatectomy: Results from a longitudinal cohort study Tommaso Cai 1, 2, Andrea Cocci 3, Fabrizio Di Maida 3, Stefano Chiodini 1, Francesco Ciarleglio 4, Lorenzo Giuseppe Luciani 1, Giovanni Pedrotti 5, Alessandro Palmieri 6, Gianni Malossini 1, Michele Rizzo 7, Giovanni Liguori 7, Truls E. Bjerklund Johansen 2, 8, 9 1 Department

of Urology, Santa Chiara Regional Hospital, Trento, Italy; of Clinical Medicine, University of Oslo, Oslo, Norway; 3 Department of Urology, University of Florence, Florence, Italy; 4 Department of Surgery, Santa Chiara Regional Hospital, Trento, Italy; 5 Department of Anesthesiology, Santa Maria del Carmine Hospital, Rovereto, Italy; 6 Department of Urology, University Federico II, Naples, Italy; 7 Department of Urology, University of Trieste, Trieste, Italy; 8 Department of Urology, Oslo University Hospital, Oslo, Norway; 9 Institute of Clinical Medicine, University of Aarhus, Denmark. 2 Institute

Summary

Objective: A prospective longitudinal cohort study on the impact of anthropometric measures on the sexual function and continence recovery in patients treated with laparoscopic radical prostatectomy (LRP) is presented. Material and methods: Anthropometric measures, International Index of Erectile Function (IIEF-5) and International Prostatic Symptoms Score questionnaires, were collected before surgery and at the end of follow-up period. All patients were assigned into the following groups: A) non-obese; B) non-obese with central adiposity; C) obese without central adiposity; D) obese with central adiposity. Urinary and sexual functions were the outcome measures. Results: At the end of follow-up, in 29 patients with visceral adiposity (VA) the median IIEF-5 was 14 (IQR 7-18) while in 49 non-VA patients (62.8%) was 22 (IQR 17-24) (p < 0.001). Twenty-three patients (79.3%) with VA reported complete continence, while 6 (20.7%) used ≥ 2 pads per day. Forty-eight patients (97.9%) without VA reported complete continence. VA was confirmed as a strong independent predictor for worse continence (HR 3.67; 2.75-4.51 CI95% p = 0.003) and sexual function recovery (HR: 4.51; 3.09-5.63 CI95% p < 0.001). Conclusion: We truly believe obese with visceral adiposity patients with prostate cancer should receive detailed preoperative counseling before surgery, including higher risk of suboptimal functional outcomes.

KEY WORDS: Prostate cancer; Adiposity; Metabolic syndrome; Body mass index; Quality of life. Submitted 17 May 2021; Accepted 3 July 2021

INTRODUCTION

Several treatment options are available for the management of localized prostate cancer (PCa). To date, more than 40% of PCa patients have radical prostatectomy (RP) for their definitive treatment (1-2). Quality of life after

surgery is strictly related to continence and potency sphere (3). As such, apart from cancer control, functional outcomes have been widely explored in an endeavor to timely predict which patients may experience worse sexual and continence recovery (4-5). In the last few years, obesity has emerged has a clinical factor potentially influencing perioperative features. Indeed, several studies have reported evidence for obesity being independently associated with higher complication rates (6), as well as worse oncologic (7) and functional outcomes after surgery (8). However, we are still far from drawing definitive conclusions. To date, current literature on this issue has been critically influenced by several features: 1) most studies have defined body habitus using body mass index (BMI), whilst data on district adiposity parameters such as waist circumference (WC), subcutaneous and abdominal fat were poorly investigated; 2) a significant body of evidence still derives from open RP series. As such, reported findings may be not completely contemporary, being RP increasingly performed nowadays by laparoscopic or robot-assisted approach. To address this unmet need, we designed this longitudinal cohort study with a long-term follow-up period to better understand the impact of abdominal visceral adiposity (VA), WC and BMI on the recovery of sexual function and continence in patients with PCa treated with laparoscopic RP (LRP).

MATERIALS

AND METHODS

Patients, dataset and study schedule All patients affected by localized intermediate-risk prostate cancer and treated with laparoscopy radical prostatectomy at our Centre between January and December 2012, have been enrolled in this longitudinal cohort study. Clinical (including BMI and WC), instrumental, surgical, and

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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pathological features were recorded before enrolment. All surgical procedures were performed by a single highly trained laparoscopic surgeon (GM). In brief, all procedures have been performed by using an extraperitoneal 5trocar approach (9). The vesico-urethral anastomosis was made via 2 running sutures with 2-0 Monocryl according to the technique described by Van Velthoven (10). All patients underwent oncological follow-up evaluations, in line with International Guidelines, for prostate cancer and with our previous studies (9, 11). After six months, one year after surgery and at each year follow-up evaluation, additionally to the standard biochemical and instrumental evaluations, all patients underwent specific questionnaires about quality of life and sexual function. The Figure 1 shows the study schedule. The median follow-up period was 86 months (82-95). The study was conducted in line with the STROBE statement (http://www.strobestatement.org) and in line with the Good Clinical Practice guidelines and the ethical principles laid down in the latest version of the Declaration of Helsinki. Inclusion and exclusion criteria We consider all patients affected by localized intermediate-risk prostate cancer, in line with the definition and criteria of D’Amico (12), and candidates for laparoscopy radical prostatectomy. We excluded from the study patients who had a history of erectile disfunction, patients on PDE-5 or 5a-reductase inhibitors, patients with penile prosthesis implants. Patients affected by hypotestosteronemia and with other concomitant major diseases were excluded. Finally, all patients who require adjuvant hormonal therapy after surgery were also excluded. Body mass index and anthropometric measures At the enrolling time, the following anthropometric measures have been collected: height (cm), weight (kg), and waist circumference (cm) measurement. BMI was calculated as weight in kg divided by squared height in meters (kg/m2). The waist circumference was measured using a standard measurement strip with the patients standing and breathing normally, at the midway between the lowest rib margin and iliac crest. In line with the National Cholesterol Educational Program Adult Treatment Panel III (NCEP: ATP III) (13), a cut-off of 102 cm for the waist circumference and of 30 kg/m2 for the BMI has been considered. In line with De Nunzio et al. (14). patients were then categorized in 4 body habitus groups: Figure 1. Follow-up schedule.

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a) non-obese (BMI < 30 kg/m2 and WC < 102 cm) b) non-obese with central adiposity (BMI < 30 kg/m2 and WC ≥ 102 cm) c) obese without central adiposity (BMI > 30 kg/m2 and < WC 102 cm) d) obese with central adiposity (BMI ≥ 30 kg/m2 and WC ≥ 102 cm) Even if some authors stated that visceral adiposity index was shown to be a better surrogate index than these single anthropometric indices to use in clinical practice, we decided to not use it due to the complexity of its calculation (15, 16). In fact, visceral adiposity index is comprised of anthropometric measures like BMI, WC and clinical measures of serum triglycerides and high-density lipoprotein-cholesterol levels (15). Data collection and urological evaluations at each follow-up visit At the time of surgery, in addition to all anthropometric measures, the following parameters were recorded: the patient’s and partner’s age, the Charlson comorbidity index, preoperative prostate-specific antigen levels, Gleason score, clinical prostate cancer stage (through an abdominal computed tomography (CT) scan and skeletal scintigraphy), duration of hospital stay and surgical complications. All patients underwent a standard follow-up schedule (Figure 1) depending on individual tumors and characteristics, in line with International Guidelines and in line with our everyday clinical practice (1, 17). In brief, clinical evaluation with DRE, prostate-specific antigen level and instrumental evaluation. Moreover, after six months, one year after surgery and at each year follow-up evaluation all patients underwent the following questionnaires: International Index of Erectile Function (IIEF-5) (18) and International Prostatic Symptoms Score (IPSS) (19) questionnaires, in line with previous study (20). Continent patients were defined by use of 0 or 1 safety pad/day (11). Outcome measures The main outcome measures were change in questionnaire score, the urinary and sexual function recovery at the end of the follow-up evaluation in each body habitus groups. Statistical analysis For statistical purposes, independent variables included all patient- and tumor-related data available in our institutional database. First, descriptive statistics were obtained reporting medians and interquartile range (IQR, 25th and 75th percentiles) for continuous variables, and frequencies and proportions for categorical variables, as appropriate. Continuous variables were compared using the Student t test. Categorical variables were tested with the chi-square test. BMI and waist circumference were examined as continuous variables using crude and adjusted logistic regressions to evaluate their association with the recov-

Visceral adiposity and functional outcomes

ery of sexual function and continence. Multivariable Cox regression analysis to evaluate clinical and surgical predictors for continence and sexual recovery was performed. Statistical analyses were performed using SPSS v. 24 (IBM SPSS Statistics for Mac, Armonk, NY, IBM Corp). A significance level of p < 0.05 was set for all tests. According to the nature of the study, we consider the following sample size to enroll: all patients attending a single Centre in the same period between January and December 2012 represent our patients’ population.

RESULTS

Overall, 78 patients were considered for this study. Median age was 68 (IQR: 62-77) and median pre-operative PSA was 9.9 ng/ml (IQR: 3.2-14.7). Nerve sparing RP was performed in 36 (46.1%) patients. At final histopathological examination pT2a, pT2b and pT2c were assessed in 26 (33.3%), 15 (19.2%) and 37 (47.5%) patients, respectively. Table 1. Demographic, clinical and pathological patients’ data at the enrolment time. Patients (n°) Age (median; IQR*) Educational qualification Primary school High school University Pre-operative evaluation PSA (median; IQR*) Clinical stage cT2 cT3 Prostate volume, ml (median; IQR*) DRE# - positive BMI§ (median; IQR*) Waist circumference, cm IPSS$ IIEF-5’ Surgical approach Nerve-sparing Unilateral Bilateral Pathological findings pT2a pT2b pT2c Gleason score 3+3 3+4 4+3 Positive margins NCEP: ATP III” Group A Group B Group C Group D

78 68 (62-77) 55 (70.5) 21 (26.9) 2 (2.6) 9.9 (3.2-14.7) 74 (94.9) 4 (5.1) 48 (32–78) 19 (24.3) 26.3 (20.8-34.3) 91 (89-105) 13 (12-14) 25 (24-26) 36(46.1%) 21 (58.3) 15 (41.7)

Anthropometric measures and questionnaires results at baseline Baseline median BMI was 26.3 (IQR: 20.8-34.3), while median WC was 91.6 cm (IQR: 89.3-105.4). Pre-operative IPSS and IIEF-5 were 13 (IQR: 12-14) and 25 (IQR: 24-26), respectively. In line with the NCEP: ATP III, 23 patients were included in the Group A, 9 in the Group B, 26 in the Group C and 20 in the Group D. No differences among the four groups have been showed in terms of preoperative IIEF-5, IPSS scores or pathological data. All clinical, demographic, instrumental and pathological data have been showed in Table 1. Operative and peri-operative complications Only two patients required conversion to open surgery due to intraoperative bleeding, that, however, did not require other emergent managements or intensive care. In 76 cases (97.4%) no complications occurred that required an emergent return to the operating room. Even if an increased blood loss has been observed in Group B and D when compared with Group A and C, there was not statistically significant difference. No statistically significant difference has been showed among the Groups in terms of operative median time or hospital stay. No statistically significant differences have been reported among the Groups in terms of peri-operative complications (such as thrombosis, prolonged compression nerve injury or bladder neck disruptions). Follow-up data Survival outcome At a median follow up of 86 months (82-95), 12 patients reported a biochemical recurrence showing a biochemical-recurrence free survival of 84.7%. The overall survival rate at the end of follow-up period was 96.1%. No difference has been reported among the Groups in terms of cancer-specific survival and overall survival, according to the baseline model with adjustments for age and year at cancer diagnosis. The Figure 2 shows the Kaplan-Meier curve analysis on the survival probability of patients with prostate cancer by Group. Figure 2. Kaplan-Meier curve analysis on the survival probability of patients with prostate cancer by body habitus.

26 (33.3) 15 (19.2) 37 (47.5) 10 (12.8) 35 (44.9) 33 (42.3) 15 (19.2) 23 (29.4) 9 (11.5) 26 (33.4) 20 (25.7)

The table shows all baseline characteristics, clinical and pathological parameters. n°= number; IQR* = Interquartile range; DRE# = Digital rectal examination; BMI§ = Body Mass Index; IPSS$ = International Prostatic Symptoms Score; IIEF-5’ = International Index of Erectile Function; NCEP: ATP III” = National Cholesterol Education Program Adult Treatment Panel III.

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Table 2. Functional findings at the follow-up evaluation according to the body habitus. Patients (n°) NCEP: ATP III# (body habitus) Patients (n°) Urinary continence No pad/die No or 1 pad/die 2 or more pads/die IIEF-5§ (median; IQR*) IPSS’

78 Group A 23 (29.4)

Group B 9 (11.5)

Group C 26 (33.4)

Group D 20 (25.7)

19 4 0 22 (18-23) 11 (6-14)

7 1 1 14 (7-16) 12 (7-13)

20 5 1 22 (17-24) 10 (6-11)

12 3 5 14 (8-18) 11 (6-13)

The table shows all follow up data according to the body habitus. n° = number; NCEP: ATP III# = National Cholesterol Education Program Adult Treatment Panel III; IIEF-5§ = International Index of Erectile Function; IQR* = interquartile range; IPSS’ = International Prostatic Symptoms Score.

reported spontaneous erection without any pharmacological support. Conversely, 38 (48.7%) and 10 (12.8%) reported sexual function recovery with the use of oral support and/or PGE1 administration, respectively, while 18 patients (23.1%) reported complete absence of erections. The median IIEF-5 in 29 patients with VA (Group B+D) was 14 (IQR 7-18) while was 22 (IQR 17-24) in 49 nonVA patients (Group A+C) (62.8%), with a statistically significant difference between the two groups (p < 0.001) (Figure 3). Twenty-three patients (79.3%) with VA reported complete continence, while 6 (20.7%) used ≥ 2 pads per day. On the other hand, 48 patients (97.9%) without VA reported complete continence. All follow-up data stratified for body habitus groups have been showed in Table 2.

Multivariate analysis findings At multivariable analysis, visceral adiposity was confirmed as a strong independent predictor for worse continence (Group B: HR 3.67; 2.75-4.51 CI 95%; p = 0.003; Group D: HR 2.03; 1.81-3.14 CI 95%; p = 0.04) and sexual function recovery (Group B: HR 4.51; 3.09-5.63 CI 95%; Figure 3. a) Median IIEF-5 in patients by body habitus at baseline and at the end of the study. p = 0.001; Group D: HR 3.33; b) Median IIEF-5 in patients with and without visceral adiposity at baseline 3.04-5.09 CI 95%; p = 0.001) and at the end of the study. (Table 3). Functional outcomes Overall, 71 (91%) patients reported complete continence, while 7 (8.9%) used ≥ 2 pads per day. Median postoperative IIEF-5 was 18 (IQR: 7-24). Twelve patients (15.4%)

DISCUSSION Main findings It is widely known that functional outcomes have a non-negligible impact on health-related quality of life after RP. The impact of obesity on the outcomes of RP, irrespective of surgical approach, has been extensively investigated but we are still far from drawing definitive conclusions (7). Yet there is a strong need for further investigation to explore association between continence and sexual recovery and obesity, assessed not only by BMI but also evaluating district adiposity parameters such as WC, subcutaneous and abdominal fat volume. To address this unmet need, we conducted the current longitudinal, cohort study to further pose a little cornerstone towards an in-depth knowledge of this critical issue. On the basis of this background, we demonstrated that obesity with central adiposity was associated with worse continence and sexual function recovery after laparoscopic RP.

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Visceral adiposity and functional outcomes

Table 3. Multivariate analysis results of factors associated with worse functional outcome (urinary and sexual function). Categories (variables) Urinary function Age (< 65, ≥ 65 years) Body Mass Index (kg/m2, continuous) Waist (cm, continuous) Body habitus Non-obese Non-obese with central adiposity Obese without central adiposity Obese with central adiposity Charlson Comorbidity Index (0-1, > 2) American Society of Anesthesiologists Score (≤ 2, ≥ 3) Sexual function Age (< 65, ≥ 65 years) Body Mass Index (kg/m2, continuous) Waist (cm, continuous) Body habitus Non-obese Non-obese with central adiposity Obese without central adiposity Obese with central adiposity Charlson Comorbidity Index (0-1, > 2) American Society of Anesthesiologists Score (≤ 2, ≥ 3)

Multivariate analysis (p) (HR; 95% CI) (0.57) (HR 1.01; 0.75-1.34) (0.07) (HR 1.62; 0.91-1.92) (0.32) (HR 1.13; 0.55-1.87) (0.08) (HR 0.95; 0.63-0.99) (0.04) (HR 2.03; 1.81-3.14) (0.09) (HR 1.19; 0.69-1.90) (0.003) (HR 3.67; 2.75-4.51) (0.89) (HR 1.12; 0.70-1.56) (0.09) (HR 1.33; 0.90-1.60) (0.63) (HR 1.07; 0.43-1.65) (0.11) (HR 1.82; 0.90-1.96) (0.28) (HR 0.91; 0.34-1.23) (0.12) (HR 0.80; 0.58-1.12) (0.001) (HR 3.33; 3.04-5.09) (0.08) (HR 1.20; 0.71-1.87) (0.001) (HR 4.51; 3.09-5.63) (0.77) (HR 1.93; 0.77-1.60) (0.93) (HR 1.42; 0.84-1.79)

The table shows the multivariate analysis results of factors associated with worse functional outcome (urinary and sexual function) in all enrolled patients. HR = Hazard risk; CI = Confidence interval.

Results in the context of previous studies First key point of our study is that visceral obesity was confirmed to be independently associated with worse sexual function recovery. Of course, the presence of a greater amount of periprostatic adipose tissue may be associated with a higher risk of injury to the neurovascular bundle. Moreover, metabolic syndrome itself is linked with worse potency and higher rates of endothelial disfunction (21). Actually, several previous studies showed no impact of obesity on sexual domain after open and/or robotic RP (22-24), while other series reported adverse effects (25) or impact with the metabolic and systemic disease (26, 27). However, we would like to point out that in all the above-mentioned health-related quality of life studies, the definition of potency and its measurement was mostly subjective, meaningfully undermining reliability of reported finding. In our study, we tried to overcome this limit by objectively defining pre- and postoperative erectile function with IIEF-5 questionnaire. Second, visceral obesity resulted an independent predictor also of delayed continence recovery. Consistently with our findings, Wiltz et al. (25) published one of the largest series, with 945 patients stratified according to BMI, reporting that obesity was associated with worse continence recovery at 12 and 24 months (25). Moreover, a systematic review and metanalysis by Xu et al. confirmed that obese patients are at higher risk of experiencing worse functional outcomes after RP (28). Of course, obesity might also bring about additional physical strain on the bladder, ultimately resulting in more preoperative urinary problems and a prolonged duration of return to continence. Considering these underlying issues unrelat-

ed to surgical expertise, suboptimal functional outcomes should be discussed with obese patients during preoperative counseling. Strengths and limitations of this study The present study was not devoid of limitations. First, this was a retrospective review of a prospectively collected database. Second, the relatively small sample size together might have undermined the evaluation of potential predictors of functional outcomes in our series. Even if all cases were performed by a single surgeon with extensive experience in LRP, our findings could not be applicable to all surgeon- or center-related scenarios. Acknowledged these limitations, our study represents the largest series so far exploring association between continence and sexual recovery and obesity, assessed not only by BMI but also evaluating district adiposity parameters such as WC, subcutaneous and abdominal fat volume. Further multi-institutional series are warranted to confirm our preliminary findings.

CONCLUSIONS

In our experience, visceral adiposity was associated with worse continence and sexual function recovery after laparoscopic RP, highlighting the need for an accurate pre-surgical evaluation of the body habitus and a detailed preoperative counselling before surgery. REFERENCES

1. Mottet N, van den Bergh RCN, Briers E, et al. EAU-EANMESTRO-ESUR-SIOG Guidelines on prostate cancer-2020 Update. Part 1: Screening, diagnosis, and local treatment with curative intent. Eur Urol. 2021; 79:243-262. 2. Perletti G, Magri V, Vral A, et al. Green tea catechins for chemoprevention of prostate cancer in patients with histologically-proven HG-PIN or ASAP. Concise review and meta-analysis. Arch Ital Urol Androl. 2019; 91:153-156 3. Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med. 2008; 358:1250-61. 4. Neumaier MF, Segall Júnior CH, Hisano M, et al. Factors affecting urinary continence and sexual potency recovery after roboticassisted radical prostatectomy. Int Braz J Urol. 2019; 45:703-712. 5. Briganti A, Gallina A, Suardi N, et al. Predicting erectile function recovery after bilateral nerve sparing radical prostatectomy: a proposal of a novel preoperative risk stratification. J Sex Med. 2010; 7:2521-31. 6. Lindner U, Lawrentschuk N, Abouassaly R, et al. Radical prostatectomy in obese patients: Improved surgical outcomes in recent years. Int J Urol. 2010; 17:727-32. 7. Yu YD, Byun SS, Lee SE, et al. Impact of body mass index on oncological outcomes of prostate cancer patients after radical prostatectomy. Sci Rep. 2018; 8:11962. 8. Khoder WY, Trottmann M, Stuber A, et al. Early incontinence after radical prostatectomy: A community based retrospective analysis in 911 men and implications for preoperative counseling. Urol Oncol. 2013; 31:1006-11. 9. Luciani LG, Mattevi D, Mantovani W, et al. Retropubic, laparoArchivio Italiano di Urologia e Andrologia 2021; 93, 3

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scopic, and robot-assisted radical prostatectomy: a comparative analysis of the surgical outcomes in a single regional center. Curr Urol. 2017; 11:36-41. 10. Van Velthoven RF, Ahlering TE, Skarecky DW, et al. Technique for laparoscopic running urethrovesical anastomosis: the single knot method. Urology. 2003; 61: 699-702. 11. Ludovico GM, Dachille G, Pagliarulo G, et al. Bilateral nerve sparing robotic-assisted radical prostatectomy is associated with faster continence recovery but not with erectile function recovery compared with retropubic open prostatectomy: the need for accurate selection of patients. Oncol Rep. 2013; 29:2445-50. 12. 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. 13. Kassi E, Pervanidou P, Kaltsas G, et al. Metabolic syndrome: Definitions and controversies. BMC Med. 2011; 9:48.

19. Badia X, Garcia-Losa M, Dal-Re R. Ten-language translation and harmonization of the International Prostate Symptom Score: developing a methodology for multinational clinical trials. Eur Urol. 1997; 31:129-40. 20. Palmieri A, Arcaniolo D, Palumbo F, et al. SIA-Low intensity shock wave for Erectile Dysfunction (LED) Study Group. Low intensity shockwave therapy in combination with phosphodiesterase-5 inhibitors is an effective and safe treatment option in patients with vasculogenic ED who are PDE5i non-responders: a multicenter single-arm clinical trial. Int J Impot Res. 2020 Jul 18. doi: 10.1038/s41443-020-0332-7. Epub ahead of print. 21. Otunctemur A, Ozbek E, Cakir SS, et al. Association of erectile dysfunction and urolithiasis. Arch Ital Urol Androl. 2014; 86:215-6. 22. Freedland SJ, Haffner MC, Landis PK, et al. Obesity does not adversely affect health-related quality-of-life outcomes after anatomic retropubic radical prostatectomy. Urology. 2005; 65:1131-6. 23. Uffort EE, Jensen JC. Impact of obesity on early erectile function recovery after robotic radical prostatectomy. JSLS. 2011; 15:32-7.

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24. Garg T, Young AJ, Kost KA, et al. Patient-reported quality of life recovery curves after robotic prostatectomy are similar across body mass index categories. Investig Clin Urol. 2017; 58:331-338.

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27. Parazzini F, Artibani W, Carrieri G, et al. Effect of body mass and physical activity at younger age on the risk of prostatic enlargement and erectile dysfunction: Results from the 2018 #Controllati survey. Arch Ital Urol Androl. 2020; 91:245-250.

18. Cappelleri JC, Rosen RC, Smith MD, et al. Diagnostic evaluation of the erectile function domain of the International Index of Erectile Function. Urology 2009; 54:346-351.

28. Xu T, Wang X, Xia L, et al. Robot-assisted prostatectomy in obese patients: How influential is obesity on operative outcomes? J Endourol. 2015; 29:198-208.

Correspondence Tommaso Cai, MD ktommy@libero.it Stefano Chiodini, MD Lorenzo Giuseppe Luciani, MD Gianni Malossini, MD Department of Urology, Santa Chiara Regional Hospital Largo Medaglie d'Oro, 9, Trento (Italy) Andrea Cocci, MD Fabrizio Di Maida, MD Department of Urology, University of Florence, Florence (Italy) Francesco Ciarleglio, MD Department of Surgery, Santa Chiara Regional Hospital, Trento, Italy Giovanni Pedrotti, MD Department of Anesthesiology, Santa Maria del Carmine Hospital, Rovereto (Italy) Alessandro Palmieri, MD Department of Urology, University Federico II, Naples (Italy) Michele Rizzo, MD Giovanni Liguori, MD Department of Urology, University of Trieste, Trieste (Italy) Truls E. Bjerklund Johansen, MD Department of Urology, Oslo University Hospital, Oslo (Norway)

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DOI: 10.4081/aiua.2021.3.291

ORIGINAL PAPER

Association of metabolic syndrome with prostate cancer diagnosis and aggressiveness in patients undergoing transrectal prostate biopsy Charalampos Fragkoulis 1, Ioannis Glykas 1, Lazaros Tzelves 2, Konstantinos Stasinopoulos 3, Lazaros Lazarou 2, Andreas Kaoukis 4, Athanasios Dellis 5, Georgios Stathouros 1, Georgios Papadopoulos 1, Konstantinos Ntoumas 1 1 Department

of Urology, General Hospital of Athens ‘’G. Gennimatas’’, Athens, Greece; of Urology, National and Kapodistrian University of Athens, School of Medicine, Sismanoglio Hospital, Athens, Greece; 3 Department of Urology, General Hospital of Lakonia, Sparta, Greece; 4 Department of Cardiology, General Hospital of Athens ‘’G. Gennimatas’’, Athens, Greece; 5 2nd Department of Surgery, Aretaieion Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. 2 2nd Department

Summary

Introduction and objective: Even though the only established risk factors for prostate cancer (PCa) are age, ethnic origin and family history, there are data suggesting that environmental factors, such as the presence of metabolic syndrome (MetS), may also play a role in the etiology of the disease. The aim of this study is to correlate MetS with PCa diagnosis and Gleason score (GS) in patients undergoing transrectal ultrasound guided prostate biopsy. Materials and methods: This is a prospective, single-center study including 378 patients who underwent transrectal ultrasound guided prostate biopsy in our department during the years from 2018 to 2019. Patients were divided into two groups according to the presence of PCa. Group A included 197 patients diagnosed with PCa while Group B consisted of 181 patients without PCa in their biopsy result. Multiple variables such as the presence of MetS and its components were evaluated in correlation to the presence of PCa and PCa characteristics. Statistical analysis was performed using the IBM SPSS Statistics v.23 program. Results: Mean PSA value was 8.7 ng/dl in the PCa group and 7.1 ng/dl in the non PCa group, respectively. MetS was diagnosed in 108 patients (54.8%) with PCa and 80 patients (44.2%) without PCa and the difference was statistically significant. Hypertriglyceridemia was the MetS component with statistically higher frequency in PCa patients. Furthermore, the prevalence of MetS was higher in higher Gleason score PCa (GS ≥ 4+3) patients vs lower Gleason score PCa (GS ≤ 3+4) patients. More specifically, MetS, hypertriglyceridemia, and low HDL levels were independent factors associated with higher Gleason score PCa (GS ≥ 4+3). Conclusions: Patients suffering from MetS who undergo prostate biopsy present with higher rates of PCa diagnosis and higher GS in comparison with patients with a normal metabolic profile.

KEY WORDS: Metabolic syndrome; Prostate cancer; Association of metabolic syndrome with prostate cancer; Metabolic syndrome and prostate cancer characteristics; Metabolic syndrome and high Gleason score prostate cancer. Submitted 17 June 2021; Accepted 10 July 2021

INTRODUCTION

Metabolic syndrome (MetS) is a clinical entity consisting of a cluster of hyperglycemia/insulin resistance, obesity, dyslipidemia and hypertension (1). MetS is documented as a traditional risk factor for atherosclerotic cardiovascular disease (1, 2) and has become a global health problem with increasing prevalence, paralleling the increasing incidence of obesity and poor eating habits (3). It is well known that overweight and obese men are at increased risk of prostate enlargement and erectile dysfunction (4). Furthermore, there is accumulating evidence that metabolic syndrome is associated with some common forms of cancer, as well as it poses a negative impact on cancer morbidity and mortality (5). This association sounds reasonable, since obesity, diabetes, and dyslipidemia have already been shown to be interrelated with some forms of cancer (6-8). Nowadays, prostate cancer (PCa) is the second most common male malignancy worldwide with established risk factors being increasing age, ethnic origin, and heredity (9). Association between PCa and MetS comprise a matter of debate among published literature. Data suggest that single components of MetS, such as hypertension and central obesity, are related with a significantly greater risk of PCa (10). In contrast, patients suffering from > 3 components of MetS are found to have a reduced risk for PCa (11). The purpose of this study is to evaluate whether MetS correlates with PCa diagnosis and Gleason score (GS), in a sample of Greek patients who underwent prostate biopsy in a tertiary, high volume, PCa center.

MATERIALS

AND METHODS

Study design Clinical data were collected from a prospective database in a tertiary PCa center, from consecutive patients who underwent transrectal, ultrasound-guided prostate biopsy between 2018-2019. Patients were eligible for inclusion

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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when there was a clinical suspicion for PCa, based on elevated total PSA values (> 4 ng/ml) or increasing trends of PSA values compared to previous results. A multiparametric magnetic resonance imaging (mpMRI) was not an essential component of our diagnostic algorithm, but when performed, reports indicating PIRADS 4 or 5 lesions, were an absolute indication to perform a biopsy. Patients presenting with PSA values > 20 ng/ml or signs suggestive of metastatic disease, were excluded. Biopsy technique The protocol for transrectal biopsy in our center uses the systematic approach, with 6 cores from each prostatic lobe in biopsy-naïve patients. In case images from a mpMRI were available, we also targeted suspicious lesions (cognitive biopsy), but no fusion protocol was followed. Patients received orally antibiotic prophylaxis two days before and two days after biopsy. Assessment of metabolic syndrome parameters Diagnosis of metabolic syndrome was based on the American Heart Association criteria (1). A patient suffering from metabolic syndrome should present with three or more of the following five criteria: a) fasting glucose level ≥ 100 mg/dl (or prescription for treatment of diabetes mellitus), b) blood pressure ≥ 130/85 mmHg (or prescription for treatment of hypertension), c) triglycerides levels ≥ 150 mg/dl (or prescription for treatment of hypertriglyceridemia), d) HDL cholesterol level < 40 mg/dl and e) central obesity, defined as a waist circumference ≥ 102 cm (Table 1). Patients were asked regarding the use of drug regimen for management of diabetes, hypertension, and hypertriglyceridemia and in those patients, who did not follow any prescription, we measured fasting blood glucose levels and triglyceride levels. To assess hypertension, we performed blood pressure measurements at least on three occasions and also asked patients to present with a diary of measurements (three times daily for a week). In case abnormal blood pressure measurements were noted, a cardiology referral was made, and patient was considered to suffer from hypertension. We measured the waist circumference at our center using a scaled tape at the level above umbilicus, taking care to avoid skin compression and after patients exhaled. All patients underwent a measurement of HDL levels. Other variables collected were age, PSA value, BMI, and Gleason score according to biopsy results. Patients were divided in two groups according to PCa diagnosis: Group A included patients with a positive biopsy and Group B those without malignant disease. Table 1. American Heart Association criteria for diagnosis of Metabolic Syndrome. 1. Fasting glucose ≥ 100 mg/dL (or drug therapy for hyperglycemia) 2. Blood pressure ≥ 130/85 mmHg (or drug therapy for hypertension) 3. Triglycerides ≥ 150 mg/dL (or drug therapy for hypertriglyceridemia) 4. HDL cholesterol < 40 mg/dL (or drug therapy for reduced HDL) 5. Waist circumference ≥ 102 cm

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All patients were informed regarding the aims and design of the study and were included after signing an informed consent. The institutional review board of the hospital approved study protocol before initiation and all patients were managed according to the principles of Helsinki Declaration. Statistical analysis Continuous variables are described as means ± SDs or medians depending on whether there was normal distribution or not, while categorical variables are described with proportions. We performed independent sample ttest for comparing continuous variables when assumption for normality was met, as indicated by Shapiro- Wilk test. If normality assumption was not met, comparison of continuous variables was performed using MannWhitney U test. Comparison of categorical variables was performed either with chi-square or Fisher’s exact test, depending on the number of observations in each cell of the variable. Binary logistic regression was performed to detect the effect of age, MetS and each one of the five components (central obesity, triglycerides > 150 mg/dl, HDL < 40 mg/dl, diabetes mellitus, and hypertension) on occurrence of prostate cancer. Linearity of the continuous variables used in the regression model regarding the logit of dependent variable was assessed with the Box- Tidwell procedure. A Bonferroni correction was applied using all terms in the model created. Based on this test, all continuous independent variables were linearly associated to the logit of the dependent variable. No significant outliers were detected during performance of the binomial regression model. All analyses were performed using IBM SPSS Statistics v. 23 (IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp.).

RESULTS

Prospective data collection was performed for 378 patients within the two-year period of the study (20182019). Mean patient age, body mass index and waist circumference did not differ significantly between the two groups (Table 2). Mean PSA value was 8.7 ng/dl in the PCa group and 7.1 ng/dl in the non PCa group, respectively (p < 0.001). Besides PSA value, both triglycerides (166 vs 146 mg/dl, p < 0.001) and HDL cholesterol (46 vs 44.4 mg/dl, p < 0.001) were higher in patients diagnosed with prostate cancer (Table 2). Table 2. Baseline patient characteristics. No patients, n (%) Age (years) PSA (ng/ml) BMI (kg/m2) Waist circumference (cm) Triglycerides (mg/dl) HDL (mg/dl)

Patients with PCa 197 (52.1) 64.6 (8) 8.7 (3.2) 28.6 (3) 108 (8.6) 166 (50) 46 (8.3)

Patients without PCa 181 (47.9) 65 (7.2) 7.1 (2.4) 27.9 (2.7) 104.3 (7.7) 146 (39) 44.4 (6.7)

PCa = Prostate cancer. * Numbers are presented as means (± SD).

p-value 0.620 < 0.001 0.178 0.233 < 0.001 < 0.001

Association between metabolic syndrome and prostate cancer diagnosis

Table 3. Comparison of metabolic syndrome components between patients with and without prostate cancer (PCa).

MetS Central obesity High triglycerides Low HDL Diabetes mellitus Hypertension

Patients with PCa n (%) 108 (54.8) 139 (70.6) 118 (59.9) 45 (22.8) 81 (41.1) 125 (63.5)

Patients without PCa n (%) 80 (44.2) 110 (60.8) 77 (42.5) 45 (24.9) 75 (41.4) 111 (61.3)

p-value * 0.039 0.061 0.001 0.645 0.950 0.670

Supplementary Table 1. Variables associated with PCa.

Age Metabolic syndrome Central obesity Triglycerides > 150 mg/dl HDL < 40 mg/dl Diabetes mellitus HTN

p value

Odds ratio (OR)

0.579 0.552 0.551 0.012 0.935 0.570 0.957

0.992 0.780 1.195 2.310 1.022 0.870 1.013

95% C.I. Lower Higher 0.965 1.020 0.343 1.772 0.666 2.144 1.201 4.446 0.611 1.708 0.539 1.405 0.631 1.627

MetS = Metabolic Syndrome. * Comparisons between groups were performed using Chi-square test.

Table 4. Chi-square for metabolic syndrome components on higher Gleason score PCa vs lower Gleason score prostate cancer (PCa).

MetS Central obesity High triglycerides Low HDL Diabetes mellitus Hypertension

Patients with higher Gleason score PCa (GS ≥ 4+3) n (%) 42 (65.6) 50 (78.1) 40 (62.5) 10 (15.6) 23 (35.9) 43 (67.2)

Patients with lower Gleason score PCa (GS ≤ 3+4) n (%) 66 (49.6) 88 (66.2) 78 (58.6) 35 (26.3) 58 (43.6) 82 (61.7)

p-value 0.035 0.086 0.605 0.096 0.305 0.450

MetS = Metabolic Syndrome; PCa = Prostate cancer; GS = Gleason score. * Comparisons between groups were performed using Chi-square test.

MetS was diagnosed in 108 patients (54.8%) with and 80 patients (44.2%) without PCa (p = 0.039). Patients with PCa more frequently suffered from abnormal levels of triglycerides, compared to healthy patients (59.9% vs 42.5% respectively, p = 0.001), as shown in Table 3. MetS was diagnosed in 42 patients (65.6%) with higher Gleason score PCa (GS ≥ 4+3) and in 66 patients (49.6%) with lower Gleason score PCa (≤ 3+4), p = 0.035. (Table 4). Individual components of metabolic syndrome did not differ significantly in patients with higher Gleason score PCa, compared to those with lower Gleason score PCa disease (Table 4). Age (OR 1.061, 95% C.I.: 1.0161.107, p = 0.007) and presence of metabolic syndrome (OR 5.949, 95% C.I.: 1.503-23.543, p = 0.011) seem to increase the risk for higher Gleason score PCa occurTable 5. Variables associated with higher Gleason score prostate cancer (PCa) (GS ≥ 4+3).

Age Metabolic syndrome Central obesity Triglycerides > 150 mg/dl HDL < 40 mg/dl Diabetes mellitus Hypertension

p value

Odds ratio (OR)

0.007 0.011 0.912 0.034 0.005 0.102 0.685

1.061 5.949 1.059 0.309 0.260 0.531 0.844

95% C.I. Lower Higher 1.016 1.107 1.503 23.543 0.381 2.943 0.104 0.916 0.102 0.659 0.249 1.134 0.373 1.913

Supplementary Table 2. Variables associated with high grade PCa (GS ≥ 4+4).

Age Metabolic syndrome Central obesity Triglycerides > 150 mg/dl HDL < 40 mg/dl Diabetes mellitus Hypertension

p value

Odds ratio (OR)

0.007 0.348 0.459 0.294 0.147 0.663 0.841

1.090 2.464 1.738 0.450 0.371 0.789 0.887

95% C.I. Lower Higher 1.024 1.161 0.375 16.179 0.402 7.512 0.102 1.997 0.097 1.416 0.271 2.295 0.275 2.863

rence, while hypertriglyceridemia (OR 0.309, 95% C.I.:0.104-0.916, p = 0.034) and low HDL (OR 0.260, 95% C.I.: 0.102-0.659, p = 0.005) seem to be protective factors according to logistic regression analysis (Table 5). Further analysis was implemented regarding the associations between age and MetS and its components with PCa (Supplementary Table 1). Triglycerides > 150 mg/dl were associated with PCa (p = 0.012). Additional analysis was conducted regarding the associations between age and MetS and its components and highest Gleason score PCa (GS ≥ 4+4) (Supplementary Table 2). Age was significantly associated with high Gleason score PCa in the study population (p = 0.007).

DISCUSSION

MetS is described as a multi-level risk factor combining insulin resistance, abnormal adipose fat deposition, hypertension, increased levels of triglycerides and low levels of HDL cholesterol. As a risk factor, it is associated with a high risk of atherosclerotic cardiovascular disease and type 2 diabetes (1, 2). Additionally, MetS is associated with some common forms of cancer, with existing data suggesting that it can negatively affect cancer mortality (5). Although the only established risk factors for PCa development include age, ethnic origin, and family history there are data suggesting that environmental factors, such as eating habits or physical activity, may also play a role in the etiology of the disease. The adoption of poor eating habits combined with reduced physical activity may be an explanation for the rising rates of PCa in Asian populations living in the United States, compared to lower incidence of PCa in Asia (12). Nevertheless, there is no curArchivio Italiano di Urologia e Andrologia 2021; 93, 3

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rent evidence suggesting that dietary preventing measures may reduce the risk of PCa development, since the outcomes of the selenium and vitamin E cancer prevention trial (SELECT) failed to show significant results (13). Existing evidence about the association of PCa with MetS is conflicting (14). A series of meta-analyses have demonstrated contradictory results regarding the presence of a significant association between MetS and PCa incidence. Esposito et al. in their meta-analysis, reported that metabolic syndrome was associated with a 12% increase in prostate cancer risk (10). In this metanalysis the association between MetS and PCa was significant in the European studies, but not in the U.S. and Asian studies included. Risk estimations of PCa for higher values of body mass index, dysglycemia or dyslipidemia were not significant, while on the contrary the remaining two components of MetS, namely hypertension and waist circumference > 102 cm, were associated with a significantly greater risk of prostate cancer. Therefore, MetS is weakly associated with the risk of PCa with different results reported from several geographical locations (10). Furthermore, in a Canadian population-based, case-control study by Blanc-Lapierre et al., the association between MetS and PCa was also investigated (11). Nearly 2000 men (1937) with incidental prostate cancer, aged ≤ 75 years and diagnosed between 2005 and 2009 were evaluated and their detailed lifestyle, medical history, and anthropometric measures, were collected. A history of MetS (≥ 3 components) was associated with a reduced risk of prostate cancer, suggesting a synergistic interaction of the components. Findings from this study were consistent with a reverse association between MetS and prostate cancer risk (11). Moreover, the meta-analysis performed by Xiang et al. failed to detect any association between the two entities, a result probably originating both from the heterogeneity of included studies and the fact that the individual components of the metabolic syndrome might exert antagonistic actions between them. However, it was demonstrated that the metabolic syndrome is related to prostate cancer of higher Gleason score or advanced clinical stage or even increased prostate cancer-specific mortality (15). On the other hand, a non-systematic review by De Nunzio et al., suggests an association between MetS and its mediators which affect the prostate microenvironment with the initiation and clinical progression of benign prostate hyperplasia and PCa, although these molecular pathways remain incompletely described (16). More recently, in a study by Bhindi et al, including 2.235 patients with prostate cancer, of whom 22.1% had metabolic syndrome, it was demonstrated that although no individual component of metabolic syndrome was independently associated with cancer, there was an increasing association between the number of metabolic abnormalities and both the diagnosis and grade of cancer (17). As far as it concerns the pathophysiology of MetS, central obesity is considered to be the initial step for the development and the progression of the disease. As a result of dysfunctional adipose fat deposition, proinflammatory cytokines and other molecules are released leading to insulin resistance (18). These proinflammatory substances, triggered by central obesity and resulting into

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insulin resistance, include resistin, leptin, interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-a), fibrinogen, plasminogen, and c-reactive protein (CRP) (2). A potential molecular mechanism explaining the correlation of MetS and PCa is based on insulin resistance. Insulin-growth-factor 1 (IGF-1) levels are increased in patients presenting with insulin resistance. IGF-1 may stimulate growth of both androgen sensitive and androgen independent human PCa cell lines in vitro (19). Moreover, a polymorphism within the leptin genetic sequence leading to increased leptin production, was associated with higher risk of advanced PCa disease (19). On a population level, metformin users were found to be at a decreased risk of PCa diagnosis compared to nonusers (20). On the other hand, in 540 diabetic participants of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study, metformin use was not significantly associated with PCa and therefore not advised as a preventive measure (21). A meta-analysis of 14 large prospective studies did not show any association between blood total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol levels and the risk of either overall PCa or high-grade PCa (22). Results from the REDUCE study also did not show a preventive effect of statins on PCa risk (21). Within the REDUCE study, obesity was associated with lower risk of low-grade PCa in multivariable analyses, but increased risk of high-grade PCa (23). In addition, obesity is characterized by low serum levels of adiponectin, which is believed to have anti-angiogenetic and possible antitumor properties, but its role has not been fully understood yet (24). The findings of our study agree with those of similar studies, as that of De Nunzio, which also implies an association between metabolic syndrome and high-grade prostate cancer (25). More specifically, among Italian men with elevated PSA level or abnormal digital rectal examination, MetS was present in 44% of all patients. Although MetS was not associated with more frequent diagnosis of PCa overall, it was associated with an increased risk of Gleason score 7 or higher disease (25). Although the exact molecular pathways remain incompletely described, a possible association with PCa may be present, triggered by proinflammatory cytokines, chronic prostate inflammation, and hormones such as leptin and adiponectin. Western culture and way of life is often characterized by poor dietary habits and less physical exercise and is commonly adopted in Greece. The present study presents data suggesting that Greek patients presenting with elevated levels of PSA or abnormal digital rectal examination have an increased risk of PCa detection after a prostate biopsy when they fulfill the criteria for MetS diagnosis. Moreover, these patients have a trend to present with a worse Gleason score when compared to patients not suffering from MetS. A potential limitation is that patients were recruited only at one large, Metropolitan center with no patients from remote areas included. Another possible limitation is the relatively small sample size of 378 patients. To our knowledge this is the first Greek study correlating MetS with PCa cancer diagnosis and GS in patients undergoing transrectal ultrasound guided prostate biopsy.

Association between metabolic syndrome and prostate cancer diagnosis

CONCLUSIONS

MetS is a complex disorder with multiple organ targets and severe effects on public health. Thus, it is quite important for urologists to be familiar with MetS, to recognize it and consult their patients accordingly as simple alterations in lifestyle habits may prevent or delay the occurrence high Gleason score PCa development. It is mandatory to further investigate the correlation of MetS with PCa with studies involving higher numbers of patients.

REFERENCES

1. Huang PL. A comprehensive definition for metabolic syndrome. Dis Model Nech. 2009; 2:231-237.

16. De Nunzio C, Aronson W, Freedland SJ, et al. The correlation between metabolic syndrome and prostatic diseases. Eur Urol 2012; 61:560-570. 17. Bhindi B, Locke J, Alibhai SM, et al. Dissecting the association between metabolic syndrome and prostate cancer risk: analysis of a large clinical cohort. Eur Urol. 2015; 67:64-70. 18. Gustafson B, Hammarstedt A, Andersson CX, et al. Inflamed adipose tissue: a culprit underlying the metabolic syndrome and atherosclerosis. Arterioscler Thromb Vasc Biol. 2007; 27:2276-2283. 19. Buschemeyer III WC, Freedland SJ. Obesity and prostate cancer: epidemiology and clinical implications. Eur Urol. 2007; 52:331-343. 20. Preston MA, Riis AH, Ehrenstein V, et al. Metformin use and prostate cancer risk. Eur Urol. 2014; 66:1012-20.

2. Grundy SM. Metabolic syndrome: a multiplex cardiovascular risk factor. J Clin Endocrinol Metab. 2007; 92:399-404.

21. Freedland SJ, Hamilton RJ, Gerber L, et al. Statin use and risk of prostate cancer and high-grade prostate cancer: results from the REDUCE study. Prostate Cancer Prostatic Dis. 2013; 16:254-9.

3. Ford ES, Giles WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among U.S. adults. Diabetes Care. 2004; 27:2444-2449.

22. YuPeng L, YuXue Z, PengFei L, et al. Cholesterol levels in blood and the risk of prostate cancer: a meta-analysis of 14 prospective studies. Cancer Epidemiol Biomarkers Prev. 2015; 24:1086-93.

4. Parazzini F, Artibani W, Carrieri G, et al. Effect of body mass and physical activity at younger age on the risk of prostatic enlargement and erectile dysfunction: Results from the 2018 #Controllati survey. Arch Ital Urol Androl. 2020; 91:245-250.

23. Vidal AC, Howard LE, Moreira DM, et al. Obesity increases the risk for high-grade prostate cancer: results from the REDUCE study. Cancer Epidemiol Biomarkers Prev. 2014; 23:2936-42.

5. Zhou JR, Blackburn GL, Walker WA. Symposium introduction: metabolic syndrome and the onset of cancer. Am J Clin Nutr. 2007; 86:s817-s819.

24. Brakenhielm E, Veitonmaki N, Cao R, et al. Adiponectin induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc Natl Acad Sci USA 2004; 101:24762481.

6. Renehan AG, Tyson M, Egger M, et al. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008; 371:569-578.

25. De Nunzio C, Freedland SJ, Miano R, et al. Metabolic syndrome is associated with high grade gleason score when prostate cancer is diagnosed on biopsy. Prostate 2011; 71:1492-1498.

7. Nicolucci A. Epidemiological aspects of neoplasms in diabetes. Acta Diabetol. 2010; 47:87-95.

Correspondence

8. Jafri H, Alsheikh-Ali AA, Karas RH. Baseline and on-treatment high-density lipoprotein cholesterol and the risk of cancer in randomized controlled trials of lipid altering therapy. J Am Coll Cardiol. 2010; 55:2846-2854. 9. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015; 1; 136:E359-86. 10. Esposito K, Chiodini P, Capuano A, et al. Effect of metabolic syndrome and its components on prostate cancer risk: meta-analysis. J Endocrinol Invest. 2013; 36:132-139. 11. Blanc-Lapierre A, Spence A, Karakiewicz PI, et al. Metabolic syndrome and prostate cancer risk in a population-based case-control study in Montreal, Canada. BMC Public Health. 2015; 18; 15:913. 12. Hsing AW, Sakoda LC, Chua Jr S. Obesity, metabolic syndrome and prostate cancer. Am J Clin Nutr. 2007; 86:843-857. 13. Lippman SM, Klein EA, Goodman PJ, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2009; 301:39-51. 14. Fragkoulis C, Glykas I, Gkialas I, et al. The role of nutrition in the prevention of prostatic adenocarcinoma. J BUON. 2017; 22:1085-1086. 15. Xiang YZ, Xiong H, Cui ZL, et al. The association between metabolic syndrome and the risk of prostate cancer, high-grade prostate cancer, advanced prostate cancer, prostate cancer-specific mortality and biochemical recurrence. J Exp Clin Cancer Res. 2013; 13; 32:9.

Charalampos Fragkoulis, MD harisfrag@yahoo.gr Georgios Stathouros, MD gstathouros@yahoo.gr Georgios Papadopoulos, MD gipapadopoulos@yahoo.gr Konstantinos Ntoumas, MD ntoumask@yahoo.com Ioannis Glykas, MD (Corresponding Author) giannis.glykas@gmail.com Department of Urology, General Hospital of Athens G. Gennimatas Leof. Mesogeion 154 Athens (Greece) Lazaros Tzelves, MD lazarostzelves@gmail.com Lazaros Lazarou, MD lazarou_laz@hotmail.com 2nd Department of Urology, National and Kapodistrian University of Athens, School of Medicine, Sismanoglio Hospital, Athens (Greece) Konstantinos Stasinopoulos, MD konstasinopoulos@gmail.com Department of Urology, General Hospital of Lakonia, Sparta (Greece) Andreas Kaoukis, MD andreaskaoukis@yahoo.gr Department of Cardiology, General Hospital of Athens ‘’G. Gennimatas’’, Athens (Greece) Athanasios Dellis, MD aedellis@gmail.com 2nd Department of Surgery, Aretaieion Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens (Greece)

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DOI: 10.4081/aiua.2021.3.296

ORIGINAL PAPER

Incidental testicular masses and the role of organ-sparing approach Yash Narayan 1, Dominic Brown 1, Stella Ivaz 1, Krishanu Das 2, 3, Mohamad Moussa 4, Georgios Tsampoukas 1, 2, Athanasios Papatsoris 2, 3, Noor Bucholz 2 1 Department

of Urology, Princess Alexandra Hospital, Harlow, UK; Ltd.* (Urology for emerging countries), London, UK; 3 Consultant Urologist, Bahrain Specialist Hospital, Bahrain; 4 Al Zahraa Hospital, University Medical Center, Lebanese University, Beirut, Lebanon. 2 U-merge

* U-merge

Ltd. (Urology for Emerging Countries) is an academic urological platform dedicated to facilitate knowledge transfer in urology on all levels from developed to emerging countries. U-merge Ltd. is registered with the Companies House in London/ UK. www.U-merge.com

Summary

Objectives: The widespread use of ultrasonography for the investigation of common urological conditions, such as infertility or pain, has resulted in an increased incidence of incidental non-palpable testicular masses. The majority of these are expected to be benign therefore a conservative approach, either active monitoring or organsparing approach, is recommended. However, there are no clinical or radiological parameters which define the exact nature of such lesions and optimal patient selection criteria are lacking. In this comprehensive review we discuss the significance of incidental, small testicular masses (STMs) and the role of organ-sparing approach in the management of these lesions. Materials and methods: A non-systematic search was performed using PubMed to identify articles that covered the following topics; clinical implications at diagnosis, role of imaging in identifying the malignant capabilities of a lesion, role of surgery and the final pathology. Results: Incidental STMs are routinely identified following ultrasound examination of infertile men. STMs usually measure a few millimeters in size and the majority of these are benign. Therefore, strict follow up or an organ-sparing approach, with utilisation of frozen section analysis (FSA), is favored for STMs. FSA has a high correlation with final pathology and prevents unnecessary orchidectomies. Advances in imaging, namely ultrasound and magnetic resonance imaging may provide enhanced assessment of STMs and guidance intraoperatively. Conclusions: The optimal approach is not well defined and there is no specific clinical parameter that can predict the nature of STMs. The increasing incidence of small, benign testicular masses has resulted in the development of organ-sparing surgery to investigate and manage these lesions. Organ-sparing surgery has been shown to be practical and carries excellent oncological outcomes.

per 100000 men (1). The traditional treatment for suspected tumors is radical orchidectomy and organ-sparing surgery is considered primarily in cases of bilateral tumors or monorchid patients (2). In recent years the widespread use of ultrasound for noncancerous indications has resulted in an increase in incidental, small testicular masses (STMs) of questionable significance (3, 4). STMs are most efficiently characterized as non-palpable testicular lesions measuring < 25 mm in diameter. However, a specific size cutoff is difficult to define and the exact dimensions are still debated in the literature (5, 6). In this size though, the probability of benign pathology is regarded as significantly high, and thus, a stepwise approach of inguinal surgical exploration, delivery of the organ and frozen section examination is recommended. Organ-preserving surgery is preferred if the diagnosis is benign while radical orchidectomy is usually preserved if there is evidence of malignancy (5, 7, 8). The most common scenario on routine ultrasound is the finding of a non-palpable lesion during workup for infertility or scrotal pain, where the majority of these patients have benign lesions and a conservative approach is strongly indicated (9). Nevertheless, the management of incidental STMs warrants a critical review of the literature as there are no patient selection criteria for an organ-sparing approach, and a strict diagnostic algorithm is lacking. In this review we discuss the significance of STMs and the role of organ-sparing approach in the management of the condition.

KEY WORDS: Incidental testicular masses; Non-palpable; Testissparing surgery; Surveillance; ultrasound.

We performed a non-systematic search in PubMed with the terms ‘small testicular masses’, ‘incidental testicular masses’, ‘testicular sparing approach’ and ‘partial orchidectomy’. Only studies in English were included. Case reports were excluded and literature reviews were used to identify additional articles. After screening the abstracts, full-text articles were evaluated in an attempt to identify studies engaging with relevant clinical topics.

Submitted 25 February 2021; Accepted 5 July 2021

INTRODUCTION

Testicular germ-cell tumors (GCT) are the most common solid neoplasms in young men with an incidence of 10

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MATERIAL

AND METHODS

Incidental testicular masses

RESULTS

Clinical implications at time of discovery of incidental mass STMs can be found at any age, ranging from childhood to adolescence and up to middle aged men (10-12). Male infertility presenting as dyspermia or the more severe azoospermia, are amongst the most frequently reported indications for ultrasound examination which results in the diagnosis of an incidental STM (13-19). Unspecified testicular or epididymal pain, an acute inflammation in the genital area, scrotal swelling, a history of trauma, varicocele, abdominal pain, hydrocele, suspicion of nephrolithiasis, gynecomastia, and follow up of cryptorchidism are also reported as indications (8, 11, 12, 2025). Of note small masses might be discovered during the follow up of patients with previous treatment of GCT or other testicular tumors (26-28), and a prior history of cryptorchidism might unmask an undetected testicular mass during follow up (12, 15, 23, 29). In the same vein, extra attention should be given to patients with suspected retroperitoneal, extragonadal GCT as STMs might indicate a burned out primary testicular tumor (30). Role of imaging in the assessment of the malignant potential of the lesion The size of STMs on ultrasound usually ranges from 3 mm up to 25 mm (4, 31), and the majority of these lesions will be found to be benign however malignancy cannot be excluded even in the smallest lesions (7, 17). In spite of this, size and risk of malignancy are strongly correlated (5, 32); large lesions seem to carry a greater risk of malignancy and the smaller the nodule, the less likely it is to be malignant (5, 8, 33). Using a cutoff of 5 mm in infertile patients with STMs, Bieniek et al. reported that the majority of these masses did not show significant growth during follow up and could be safely surveilled (19). In such cases Toren et al. observed that initial larger size and vascular flow, as identified on ultrasound, were factors associated with intervention during follow up (14). Similarly Scandura et al. reported that lesions smaller than 5 mm are always benign whereas malignancy can be found in one third of cases in lesions measuring 5-10 mm (29). In another study, Gentile and colleagues stated that the malignant probability of STMs, measuring less than 10mm, is smaller than 10% whilst the risk increases sevenfold with each millimeter (5). However other authors have advised that inguinal exploration and frozen section analysis (FSA) are essential even in small masses, less than 5 mm, as malignancy cannot be excluded definitely (11). This is because the most common ultrasonographic appearance is of an hypoechoic lesion, a finding which should be regarded as non-specific (33, 34). However Dell’Atti et al. reported that malignant and benign lesions differ significantly as cancerous lesions were strongly hypoechoic, in appearance, in comparison to benign lesions (89.8% vs 39.3%, p > 0.001) and calcified lesions were strongly associated with benign tumors (25). Others have suggested that extra attention should be given to echogenic foci as these might represent burned out tumors and in such cases, the retroperitoneal space should be evaluated (30, 35). The presence of vascularization on Color Doppler Ultrasound is also strongly

associated with malignancy whereas small, inflammatory lesions usually do not exhibit any flow (28). Contrastenhanced testicular ultrasound, if available, is a costeffective imaging method for the characterization of nonpalpable testicular lesions (36). With the enhancement of diagnostic performance, some authors have reported that the combination of different ultrasonographic techniques in a multiparametric fashion offers excellent sensitivity and specificity in the assessment of STMs. The combination of elastography with contrast-enhanced scrotal ultrasound demonstrated a sensitivity of 100%, a specificity of 93%, and a positive likelihood ratio of 14.3 for malignancy (37). Magnetic Resonance Imaging (MRI) might also increase the diagnostic accuracy in its ability to distinguish between fat, fluid, fibrosis, cystic and solid lesions; gadolinium contrast enhancement technique may also be able to differentiate between benign and malignant lesions (6, 20). Thus, MRI can assist the decision making in cases of diagnostic uncertainty favoring a testicular sparing approach in patients with low suspicion of malignancy (6, 38, 39). The operative technique If an intervention is scheduled, the procedure follows the same principles as for radical orchidectomy. The testis is exposed, mobilized and exteriorized through an inguinal incision. The clamping of the spermatic cord is controversial as seeding of malignant cells is mostly related to the nature of the tumor and not with the manipulation alone (40). If cross-clamping is performed before delivery, the testis should be protected from warm ischemia, with an iced pack, as warm ischemia may cause irreversible damage of the testicular parenchyma thus impairing both the endocrine and exocrine functions of the organ (15). There are two possible approaches; one in an avascular plane on the anterior aspect of the organ exposing the whole parenchyma or alternatively a smaller incision directly onto the tumor (40). Intraoperatively the use of a linear ultrasound transducer (7.5-15 MHz) can guide the excision and also ensure adequate preservation of testicular parenchyma. Some authors perform real-time ultrasonography to facilitate the placement of a stereotaxic hook-shaped needle which can guide the resection (15, 20). Either way the tumor is excised and sent for FSA leaving 2-3 mm safe surgical margins (15, 41). Frozen-section biopsies should be taken from the borders of the lesion to ensure adequate resection and as a rule, if there is not enough parenchyma for frozen-section biopsies then preservation of the organ is not recommended (40). If the benign nature of a lesion is confirmed or the removal of a malignant tumor is completed, the testicle is placed back into the scrotum otherwise a radical orchidectomy is performed for all other indications (42). Significance of frozen section analysis, testis-sparing surgery and random biopsies FSA is regarded as indispensable during organ-sparing surgery in patients with indeterminate STMs or if the diagnosis of malignancy is in doubt, regardless of size (8, 43). The correlation of FSA with the final pathology is high, the procedure is dependable, and FSA is not limitArchivio Italiano di Urologia e Andrologia 2021; 93, 3

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ed by size (5, 31, 44, 45). It could be stated that FSA prevents unnecessary orchidectomies and enables preservation of the testicular parenchyma (5, 46). Therefore, the optimal treatment of STMs should include FSA to guide management of the extricated tumour, in the form of testis-sparing surgery (TSS) or radical orchidectomy. If a GCT is identified on FSA, TSS should be considered if imperative indications are met (synchronous bilateral tumours, metachronous tumours in solitary testicle) in order to attempt preservation of fertility and hormonal function (5, 8). In that scenario, field biopsies in a systematic and random manner are also mandatory as in situ germ cell neoplasia may be present elsewhere, even a long distance from the initial tumor. This finding reflects the malignant spread of the tumor and warrants treatment with adjuvant radiotherapy (12, 33). The final pathology In the final specimen, benign lesions are found in most patients and in some studies the incidence is as high as 80% (5, 21, 34, 47). Leydig cell tumor is the most frequently reported pathology in non-malignant cases (5, 11, 15, 21, 27, 48). Other diagnoses include fibrosis, epidermoid cysts, granulomatous orchitis (25), ectopic nodule of adrenal cortex, adenomatous tumour and fibrous pseudotumor (29). Sertoli tumor and hemorrhagic infiltration with no evidence of tumor have also been reported (49). Of the malignant lesions, pure seminoma along with the presence of distant carcinoma in situ is the most commonly reported finding (11, 23, 28, 49). Leiomyoma, mixed germ cell tumours including embryonal carcinoma, mature teratoma, and liposarcoma have also been reported in the final specimen (27, 50, 51).

DISCUSSION

Although there is no specific clinical parameter that can predict the exact nature of STMs, those that are non-palpable are usually benign (24). Palpability, raised testicular markers, hypoechoicity on ultrasound images, and larger size are considered risk factors for malignancy (52). Specific patient groups such as infertile patients seem to enjoy a favorable prognosis thus justifying the avoidance of unnecessary surgery. Eifler et al. and Lagabrielle et al. found that patients with small, incidental masses identified during work-up for infertility, can usually be monitored with repeat ultrasound and additionally surgical intervention can be performed safely should the clinical need arise (13, 16). In such cases, where intervention is required, the simultaneous performance of TSS and microscopic testicular tissue extraction has been proposed by some authors, without causing any significant complication or compromising the remaining testicular volume (15). With regards to the development of secondary hypogonadism, no significant change in plasma testosterone has been reported and secondary hypogonadism should not be expected in patients with bilateral testis undergoing TSS for STMs (11, 51). However it seems that patients undergoing TSS for malignant lesions are at higher risk of secondary hypogonadism as this may be found in up to 15% of cases (42). Similarly the effect on endocrine function is comparative even when a radi-

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cal approach is performed and it increases significantly as the treatment is escalated (53). In this regard, it seems that the approach alone is not entirely responsible, rather it is the relative risk of malignancy that affects the outcome. Importantly the oncological prognosis in patients with malignancy is regarded to be excellent (54). Therefore, it seems apparent that an organ sparing approach or a surveillance protocol is optimal for patients with incidental testicular masses. Some authors have attempted to provide specific recommendations regarding the management of STMs such as the diagnostic algorithm proposed by Scandura et al. in patients with STMs less that 10 mm. They state that if tumor markers are negative an ultrasound should be repeated in 3 months, and if there is no change then the patient can be discharged from further follow up with the recommendation of selfexamination. If there is an increase in size, of less than 20% of the original, an ultrasound is repeated in 3 months and if no change is identified the patient is discharged as previously. Alternatively if there is a greater than 20% increase in size then FSA is advised (29).

CONCLUSIONS

The increasing incidence of small, non-palpable and benign testicular masses has resulted in the development of organ sparing surgery to investigate and treat these lesions. The optimal approach is not well defined however patients who present for routine investigation of infertility or scrotal pain who have no palpable nodules, negative testicular markers, and lesions only a few millimeters in size are likely to have benign pathology. In such cases options include either an active monitoring program or an organ sparing approach. The latter has been shown to be practicable and reproducible and carries excellent oncological and functional outcomes.

REFERENCES

1. Heidenreich A, Paffenholz P, Nestler T, Pfister D. European Association of Urology guidelines on testis cancer: important take home messages. Eur Urol Focus. 2019; 5:742-4. 2. La Rocca R, Capece M, Spirito L, et al. Testis-sparing surgery for testicular masses: current perspectives. Minerva Urol Nefrol. 2019; 71:359-64. 3. Corrie D, Mueller EJ, Thompson IM. Management of ultrasonically detected nonpalpable testis masses. Urology. 1991; 38:429-31. 4. Buckspan MB, Klotz PG, Goldfinger M, et al. Intraoperative ultrasound in the conservative resection of testicular neoplasms. J Urol. 1989; 141:326-7. 5. Gentile G, Rizzo M, Bianchi L, et al. Testis sparing surgery of small testicular masses: retrospective analysis of a multicenter cohort. J Urol. 2020; 203:760-766. 6. Brown D, Tsampoukas G, Popov EP, et al. The role of radiological surveillance in the conservative management of incidental small testicular masses: A systematic review. Arab J Urol. 19:179-185, 7. Horstman WG, Haluszka MM, Burkhard TK. Management of testicular masses incidentally discovered by ultrasound. J Urol. 1994; 151:1263-5. 8. Khan MJ, Bedi N, Rahimi MNC, Kalsi J. Testis sparing surgery for

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small testicular masses and frozen section assessment. Cent Eur J Urol. 2018; 71:304-9. 9. Paffenholz P, Held L, Loosen SH, et al. Testis sparing surgery for benign testicular masses: diagnostics and therapeutic approaches. J Urol. 2018; 200:353-60. 10. Caldwell BT, Saltzman AF, Maccini MA, Cost NG. Appropriateness for testis-sparing surgery based on the testicular tumor size in a pediatric and adolescent population. J Pediatr Urol. 2019; 15:70.e1-70.e6.

27. De Stefani S, Isgro G, Varca V, et al. Microsurgical testis-sparing surgery in small testicular masses: seven years retrospective management and results. Urology. 2012; 79:858-62. 28. Drudi FM, Maghella F, Martino G, et al. Detection of small testicular masses in monorchid patients using US, CPDUS, CEUS and US-guided biopsy. J Ultrasound. 2016; 19:25-8. 29. Scandura G, Verrill C, Protheroe A, et al. Incidentally detected testicular lesions < 10 mm in diameter: can orchidectomy be avoided? BJU Int. 2018; 121:575-82.

11. Müller T, Gozzi C, Akkad T, et al. Management of incidental impalpable intratesticular masses of ≤ 5 mm in diameter. BJU Int. 2006; 98:1001-4.

30. Comiter C V, Renshaw AA, Benson CB, Loughlin KR. Burned-out primary testicular cancer: sonographic and pathological characteristics. J Urol. 1996; 156:85-8.

12. Pierconti F, Martini M, Grande G, et al. Germ cell neoplasia in situ (GCNIS) in testis-sparing surgery (TSS) for small testicular masses (STMs). Front Endocrinol (Lausanne). 2019; 10:512.

31. Shilo Y, Zisman A, Raz O, et al. Testicular sparing surgery for small masses. Urol Oncol. 2012; 30:188-91.

13. Eifler JBJ, King P, Schlegel PN. Incidental testicular lesions found during infertility evaluation are usually benign and may be managed conservatively. J Urol. 2008; 180:261-4 14. Toren PJ, Roberts M, Lecker I, et al. Small incidentally discovered testicular masses in infertile men--is active surveillance the new standard of care? J Urol. 2010; 183:1373-7. 15. Hallak J, Cocuzza M, Sarkis AS, et al. Organ-sparing microsurgical resection of incidental testicular tumors plus microdissection for sperm extraction and cryopreservation in azoospermic patients: surgical aspects and technical refinements. Urology. 2009; 73:887-91.

32. Connolly SS, D’Arcy FT, Bredin HC, et al. Value of frozen section analysis with suspected testicular malignancy. Urology. 2006; 67:162-5. 33. Hopps C V, Goldstein M. Ultrasound guided needle localization and microsurgical exploration for incidental nonpalpable testicular tumors. J Urol. 2002; 168:1084-7. 34. Rolle L, Tamagnone A, Destefanis P, et al. Microsurgical “testissparing” surgery for nonpalpable hypoechoic testicular lesions. Urology. 2006; 68:381-5. 35. Sheynkin YR, Sukkarieh T, Lipke M, et al. Management of nonpalpable testicular tumors. Urology. 2004; 63:1163-7.

16. Lagabrielle S, Durand X, Droupy S, et al. Testicular tumours discovered during infertility workup are predominantly benign and could initially be managed by sparing surgery. J Surg Oncol. 2018; 118:630-5.

36. Rübenthaler J, Kim SH, Kunz WG, et al. Should we use contrastenhanced ultrasound (CEUS) for the characterization of nonpalpable testicular lesions? An analysis from a cost-effectiveness perspective. Ultraschall Med. 2020; 41:668-674.

17. Colpi GM, Carmignani L, Nerva F, et al. Testicular-sparing microsurgery for suspected testicular masses. BJU Int. 2005; 96:67-9.

37. Auer T, De Zordo T, Dejaco C, et al. Value of multiparametric US in the assessment of intratesticular lesions. Radiology. 2017; 285:640-9.

18. Carmignani L, Gadda F, Mancini M, et al. Detection of testicular ultrasonographic lesions in severe male infertility. J Urol. 2004; 172:1045-7. 19. Bieniek JM, Juvet T, Margolis M, et al. Prevalence and management of incidental small testicular masses discovered on ultrasonographic evaluation of male infertility. J Urol 2018; 199:481-6. 20. Avci A, Erol B, Eken C, Ozgok Y. Nine cases of nonpalpable testicular mass: An incidental finding in a large scale ultrasonography survey. Int J Urol. 2008; 15:833-6. 21. Shilo Y, Zisman A, Lindner A, et al. The predominance of benign histology in small testicular masses. Urol Oncol. 2012; 30:719-22. 22. Brunocilla E, Gentile G, Schiavina R, et al. Testis-sparing surgery for the conservative management of small testicular masses: an update. Anticancer Res. 2013; 33:5205-10. 23. Fabiani A, Filosa A, Fioretti F, et al. Diagnostic ultrasound-guided excisional testicular biopsy for small (< 1 cm) incidental nodules. A single institution experience. Arch Ital di Urol Androl. 2014; 86:373-7. 24. Carmignani L, Gadda F, Gazzano G, et al. High incidence of benign testicular neoplasms diagnosed by ultrasound. J Urol. 2003; 170:1783-6. 25. Dell’Atti L, Fulvi P, Benedetto Galosi A, Galosi AB. Are ultrasonographic measurements a reliable parameter to choose non-palpable testicular masses amenable to treatment with sparing surgery? J BUON. 2018; 23:439-43. 26. Assaf GJ. Non-palpable testicular lesion: the case for testicular preservation. Can J Urol. 2006; 13:3034-8.

38. Obembe OO, Patel MD. Value of dynamic, contrast-enhanced MRI and intraoperative ultrasound for management of a nonpalpable, incidental, testicular Leydig-cell tumor. Radiol Case Reports. 2010; 5:432. 39. Thomas LJ, Brooks MA, Stephenson AJ. The role of imaging in the diagnosis, staging, response to treatment, and surveillance of patients with germ cell tumors of the testis. Urol Clin North Am. 2019; 46:315-31. 40. Heidenreich A, Angerer-Shpilenya M. Organ-preserving surgery for testicular tumours. BJU Int. 2012; 109:474-90. 41. Powell TM, Tarter TH. Management of nonpalpable incidental testicular masses. J Urol. 2006; 176:96-8. 42. Heidenreich A, Weissbach L, Holtl W, et al. Organ sparing surgery for malignant germ cell tumor of the testis. J Urol. 2001; 166:2161-5. 43. Tuygun C, Ozturk U, Goktug HNG, et al. Evaluation of frozen section results in patients who have suspected testicular masses: a preliminary report. Urol J. 2014; 11:1253-7. 44. Benelli A, Varca V, Derchi L, et al. Evaluation of the decisionmaking process in the conservative approach to small testicular masses. Urologia. 2017; 84:83-7. 45. Matei DV, Vartolomei MD, Renne G, et al. Reliability of frozen section examination in a large cohort of testicular masses: what did we learn? Clin Genitourin Cancer. 2017; 15:e689-96. 46. Subik MK, Gordetsky J, Yao JL, et al. Frozen section assessment

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in testicular and paratesticular lesions suspicious for malignancy: its role in preventing unnecessary orchiectomy. Hum Pathol. 2012; 43:1514-9. 47. Giannarini G, Dieckmann K-PP, Albers P, et al. Organ-sparing surgery for adult testicular tumours: a systematic review of the literature. Eur Urol. 2010; 57:780-90. 48. Steiner H, Holtl L, Maneschg C, et al. Frozen section analysisguided organ-sparing approach in testicular tumors: technique, feasibility, and long-term results. Urology. 2003; 62:508-13. 49. Galosi AB, Fulvi P, Fabiani A, et al. Testicular sparing surgery in small testis masses: A multinstitutional experience. Arch Ital di Urol Androl. 2016; 88:320-4. 50. Ayati M, Ariafar A, Jamshidian H, et al. Management of non-

palpable incidental testicular masses: Experience with 10 cases. Urol J. 2013; 11:1892-5. 51. Gentile G, Brunocilla E, Franceschelli A, et al. Can testis-sparing surgery for small testicular masses be considered a valid alternative to radical orchiectomy? A prospective single-center study. Clin Genitourin Cancer. 2013; 11:522-6. 52. Esen B, Yaman MO, Baltaci S. Should we rely on Doppler ultrasound for evaluation of testicular solid lesions? World J Urol. 2018; 36:1263-6. 53. Jacobs LA, Vaughn DJ. Hypogonadism and infertility in testicular cancer survivors. J Natl Compr Canc Netw. 2012; 10:558-63. 54. Pfister D, Paffenholz P, Haidl F. Testis-sparing surgery in patients with germ cell cancer: indications and clinical outcome. Oncol Res Treat. 2018; 41:356-8.

Correspondence Yash Narayan, MD y.narayan@nhs.net Dominic Brown, MD dominic.brown5@nhs.net Stella Ivaz, MD stellaivaz@hotmail.com Georgios Tsampoukas, MD tsampoukasg@gmail.com Department of Urology, Princess Alexandra Hospital, Harlow (UK) Hamstel Road, Harlow, United Kingdom, CM20 1QX Krishanu Das, MD Consultant Urologist, Bahrain Specialist Hospital, Bahrain Mohamad Moussa, MD mohamad.moussa@zhumc.org.lb Al Zahraa Hospital, University Medical Center, Lebanese University, Beirut (Lebanon) Athanasios Papatsoris, MD agpapatsoris@yahoo.gr U-merge Ltd., London (UK) Noor Bucholz, MD noor.buchholz@gmail.com U-merge Ltd., London (UK)

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DOI: 10.4081/aiua.2021.3.301

ORIGINAL PAPER

Testicular germ cells tumors in adolescents and young adults: Management and outcomes from a single-center experience Claudio Spinelli 1, Gianmartin Cito 2, Girolamo Morelli 3, Marco Ghionzoli 1, Alessia Bertocchini 1, Beatrice Sanna 1, Luca Galli 4, Andrea Antonuzzo 5, Riccardo Morganti 6, Silvia Strambi 1 1 Division

of Pediatric, Adolescents and Young Adults Surgery, Department of Surgical Pathology, Medical, Molecular and Critical Area, University of Pisa, Pisa, Italy; 2 Department of Urology and Andrology Surgery, Careggi Hospital, University of Florence, Florence, Italy; 3 Department of Urology and Andrology Surgery, University of Pisa, Pisa, Italy; 4 Medical Oncology II, University of Pisa, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy; 5 Medical Oncology I, National Health Service Department of Translational Medicine Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy; 6 Section of Statistics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Summary

Objective: To investigate and compare the effectiveness of active surveillance versus post-surgical active treatment, in patients with testicular germ cells tumor (TGCT). Materials and methods: We retrospectively analyzed 52 patients who underwent surgery for TGCT from January 2009 to December 2014. All the patients were divided into two age groups: the Group A included children-adolescents from 18 months to 21 years old, while the Group B comprised young adults from 22 to 39 years old. Clinical, histopathological, therapeutic and follow-up data were collected. Results: Overall, 22 patients (42,3%) were enrolled in the Group A and 30 patients (57.7%) were categorized in the Group B. Inguinal orchiectomy was performed in all patients. Retroperitoneal lymphadenectomy was performed in 4 patients (7.7%). Post-surgical management differed based on clinical stage, resulting in active surveillance or adjuvant therapy. After an average 7 years follow-up period (range: 3.5-9.0 years), the overall survival rate is 100%. The relapse risk is significantly higher for the patients in the Group B, displaying a recurrence free-survival rate of 72% versus 95% (Group A); 11 relapses (21.1%) were recorded 2 years after surgery. Of these, 3 recurrences (12.0%) occurred in patients undergoing an active surveillance approach, while 8 (29.6%) in patients subjected to an active treatment. Conclusions: The excellent prognosis in both age groups confirms the high curability of this neoplasia. The active surveillance could represent an optimal option for low recurrence risk tumors. However, post-surgical treatments should be taken into consideration for TGCT with high risk factors, including tumor size, lymphovascular and rete testis invasion.

KEY WORDS: Testicular germ cell tumors; Surgery; Children; Young adults; Active surveillance. Submitted 10 March 2021; Accepted 7 May 2021

INTRODUCTION

Testicular germ cell tumor (TGCT) is a rare form of cancer in childhood, adolescence and young adulthood. Despite

its infrequency (only 1% of male frequencies in the United States), TGCT represents the most common malignancy in young men between 20-39 years old in Northern and Southern Europe (the peak age of incidence is 30 years) (1). The incidence of TGCT has been increasing in the developed countries for at least four decades (2-4). Rates vary by ethnic group: white men are at a higher risk for TGCT, with an annual incidence of 6.6/100,000, compared to 1.4/100.000 in black men and 1.9/100.000 in Asians/Pacific Islanders (5, 6). The pathogenesis of TGCT is multifactorial, including both genetic and environmental factors (7-9). A relationship between cryptorchidism and testicular cancer is well known (10). However, the risk factors for testicular cancer are not well characterized. A previous unilateral testicular cancer and a family history of testicular tumor are the only other factors clearly associated with increased risk. So far, studies have estimated an increased risk of TGCT 8-10 times fold and 4-6 times fold in brothers and sons respectively (7). Nonetheless, mortality rates have dropped significantly over the past 3 decades owing to the development of more effective treatments (2). The aim of this study was to investigate the clinical outcomes of TGCT in two different age groups treated with active surveillance (AS) or active treatment (AT), according to the histopathological findings and the stage of disease.

MATERIALS

AND METHODS

We retrospectively analyzed 52 patients who underwent surgery for TGCT from January 2009 to December 2014. All the patients were divided into two age groups: the Group A included children-adolescents from 18 months to 21 years old, while the Group B comprised young adults from 22 to 39 years old. Clinical, histopathological, therapeutic and follow-up data were collected. For

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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the guidance during diagnostic assessment, tumor markers levels were recorded, including human chorionic gonadotropin (HCG), alpha-fetoprotein (AFP) and lactate dehydrogenase (LDH). Total testosterone, estradiol, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were collected pre-operatively. In order to define the pre-surgical tumor stage, all patients underwent thorax and abdomen imaging scans, including contrast-enhancement computed tomography (CT) or magnetic resonance (MR). We selected the treatments for patients according to the European Association of Urology (EAU) guidelines. AS is considered a feasible approach in clinical stage (CS) I seminoma testis patients. The AS protocol after surgery has involved the evaluation of tumor marker levels every 2 months in the first two years, every 4 months during the third year, every 6 months during the fourth year, and then yearly from the fifth year onwards. Chest radiography or abdominal/pelvic CT/MRI, color doppler ultrasonography (US) of testicles, abdomen and pelvis were performed every 6 months for the first 3 years and then, abdominal CT/MRI after the fifth year. All the patients gave the oral and written consent on management options. Moreover, they have been fully informed about the risk of recurrence during the active surveillance approach. For patients with higher cancer stage at diagnosis, active treatment was preferred. Meanwhile, disease relapse was defined as imaging or physical examination evidence of metastases and/or elevated tumor markers. Follow-up data of the AS protocol or the post-surgical AT approach were collected. Moreover, the overall survival (OS) rate and recurrence free survival (RFS) rate was measured. Data analysis The authors confirm the availability of, and access to, all original data reported in this study. Categorical data were described by absolute and relative frequency. In order to compare the histologic categories (seminomas, non-seminomas) in the Group A and the Group B in different stages (IS, I, II, III), the z-test for two proportions was applied. An RFS analysis was performed using the Kaplan-Meier method and the log-rank test was used to detect differences between “Group A” and “Group B” curves. The significance was fixed at < 0.05. All analyses, descriptive and inferential, were carried out by SPSS v.26.

RESULTS

The Group A (children-adolescents) included 22 patients (42.3%) and the Group B (young adults) comprised 30 patients (57.7%). The median age in Group A was 16.0 years (range: 18.0 months-21.0 years), while the median age in Group B was 28.0 years (range: 22.0-39.0 years). In the Groups B, 2/30 patients (6.6%) reported a paternal family history of seminoma, and 1/30 patient (3.3%) underwent surgery for cryptorchidism. The most common clinical presentation was a palpable and painless testicular mass in 42/52 cases (80.7%), or testis swelling in 10/52 patients (19.2%). Three patients (10.0%) in the Group B showed distant metastasis at diagnosis: 1 patient (3.3%) had cervical

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supraclavicular lymph node metastasis as primary clinical presentation and 2 patients (6.7%) had mediastinal lymph node metastasis associated with respiratory symptoms (wheezing, coughing and chest tightness). All patients reported total testosterone, estradiol, FSH and LH levels, in the normal range. Tumor markers were expressed in 14/52 cases (26.9%). In all patients with increased tumor markers, normal levels were reached within 12 months after surgery. The median US tumor size was 20.0 mm in the Group A (range: 10.0-70.0 mm size) and 22.4 mm in the Group B (range: 10.0-50.0 mm). Inguinal orchiectomy was performed in all cases. One patient in the Group A underwent a scrotal incision due to high volume tumor mass. RPLND was performed simultaneously with orchiectomy in 4 patients (7.7%), resulting in lymph-node involvement at the final pathological analysis. Frozen section examination was performed in 33 patients (63.5%): 14 cases in the Group A (63.5%) and 19 cases in the Group B (36.5%). A testicular prosthesis was placed in 44 patients (84.6%): 17 in the Group A (77.3%) and 27 in the Group B (90%). The prosthesis insertion occurred during orchiectomy in 42 cases (95.5%) and after surgery in 2 cases (4.5%). Histopathological examination was carried out. In 26 cases (50.0%) typical Seminomatous Germ Cell Tumor (SGCT) was reported: 7 (31.8%) in the Group A and 19 (63.3%) in the Group B. Twenty-six (50.0%) examinations detected typical Non Seminomatous Germ Cell Tumor (NSGCT): 15 (68.2%) in the Group A and 11 (33.7%) in the Group B. The histologic distribution of TGCT is reported in Table 1. Our study showed that NSGCT are significantly more frequent (p-value = 0.050) in children-adolescents, rather than in adults. A histopathology comparison between the two Table 1. Histologic distribution of TGCT. Statistics: frequency (%). Histology SGCT NSGCT Embryonal carcinoma Yolk sac tumor Mixed

Total 26 (50) 26 (50) 19 (36.5) 4 (7.7) 3 (5.7)

Group A (n = 22) 7 (31.8) 15 (68.2) 11 (50) 4 (18.2) 0 (0)

Group B (n = 30) 19 (63.3) 11 (33.7) 8 (26.6) 0 (0) 3 (10)

p-value 0.050 0.150 0.057 0.354

Table 2. Histologic category compared between Group A and Group B in different stages. Statistics: frequency (%). Stage Stage IS Stage I (a/b) Stage II (a/b/c) Stage III (a) Total

Group A

Group B

p-value

SGCT NSGT

1 (4.6) 0 (0)

1 (3.3) 0 (0)

0.625 -

SGCT NSGT

5 (22.8) 13 (59)

11 (36.7) 5 (16.7)

0.442 0.04

SGCT NSGT

1 (4.6) 2 (9)

6 (20) 5 (16.7)

0.232 0.630

SGCT NGCT

0 (0) 0 (0) 22

1 (3.3) 1 (3.3) 30

0.868 0.868

TCGT in adolescents and young adults

Histology SGCT

NSGT

Stage IS I II III IS I II III

AS 1 (4.5) 5 (22.7) 13 (59.1) -

RT -

Group A (22 cases) CT CT+RT 1 (4.5) 2 (9.1) -

RPLND -

AS 1 (3.3) 7 (23.3) 5 (16.7) -

groups in different stages is reported in Table 2. Comparison of tumor stages at presentation did not show significant differences among groups. AS was performed in 32 patients (61.5%), while AT was performed in 20 patients (38.5%). Post-surgical management is reported in Table 3. After an average follow-up period of 7.0 years (range: 3.59.0 years), 11 relapses (21.1%) were recorded within the first 2 years after orchiectomy. Recurrence was higher in Group B although we must highlight that initial stage distribution was not homogeneous in the two groups. Recurrences occurred respectively in retroperitoneal lymphnodes, in retroperitoneal and retromediastinal lymph nodes, or in retroperitoneal lymph nodes with lung metastasis. Each of these cases presented with increased tumor markers. Out of them, 1

Group B (30 cases) RT CT CT+RT 1 (3.3) 2 (6.7) 5 (16.7) 1 (3.3) 1 (3.3) 2 (6.7) 1 (3.3) -

RPLND 1 (3.3) 3 (10) -

Table 3. Post-surgical management of SGCT-NSCT, comparison between Group A and Group B (AS: Active Surveillance; RT: Radiotherapy; CT: Chemotherapy; RPLND: Retroperitoneal Lymphadenectomy). Statistics: frequency (%).

patient underwent RPLND, while the other ones underwent systemic chemotherapy. Overall, 8 recurrences (25.0%) were recorded in the AT sample, of which 1 case (5.0%) belonging to the Group A was diagnosed as NSGCT, involved the retroperitoneal lymph nodes and was treated with RPLND. The Group B had 7 cases (35.0%) of recurrence, all of them treated with chemotherapy and radiotherapy: 5 of them were SGCT and 2 cases were NSGCT. All those 7 patients showed a tumor mass greater than 3 cm, local lymphovascular invasion (LVI) signs and infiltration of the rete testis. The overall survival rate is 100%. Furthermore, as shown in Figure 1, the relapse risk is significantly higher for the patients in the Group B, displaying a recurrence free-survival rate of 72% versus 95% (Group A).

Figure 1. Recurrence Free-survival analysis between Group A (rate 95%) and Group B (rate 72%).

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DISCUSSION

Testicular cancer is largely found in young and middle-age men, but around 7% of cases occur in children (11-19). TGCTs represent 71% of all testicular neoplasms and they include yolk sac tumors, teratoma, seminoma, choriocarcinoma and embryonal carcinoma (20). Gonadal stromal tumors (NTGCTs) include Leydig cell tumor, Sertoli cell tumor, juvenile granulosa cell tumor and gonadoblastoma (21, 22). As reported in literature, testicular tumors may be different, based on age-related range in histopathology, molecular biology, malignant potential, clinical behavior and treatment (12, 22-24). Moreover, malignant potential is significantly lower in the pediatric age group compared to the other age groups (25). In our study, the incidence of NSGCT is higher in the children’s group than in the young-adults group (p = 0.04). An important role in the diagnosis and follow-up is played by serum tumor markers (23, 26). In our case series, tumor markers were expressed in 26,9% of cases. This was true for both age groups for NSGCT, where markers reflect tumor widespread, aggressiveness and constitute a prognostic factor for the cancer itself (18); in the young adults group, markers were expressed only in SGCT. After surgical treatment, we reached normal levels of serum tumor markers in absence of metastatic disease. On the other hand, we found tumor markers increasing in patients with relapse, in accordance with data reported the literature (24-26). Treatment of the primary TGCT is performed by radical orchiectomy. Post-surgical treatment was based on histopathologic features and disease stage at surgery (2, 27, 28). Management options after surgery included surveillance, adjuvant chemotherapy, radiotherapy and RPLND (2, 30). Considering the relatively low risk of relapse in testicular cancer, many guidelines recommend surveillance as the preferred initial treatment for all stage I SGCT and low-risk stage I NSGCT (31). Therefore, active surveillance has also been recently adopted by some cancer centers for high-risk stage NSGCT, considering that many patients do not require further therapy and those with relapses can be treated with highly effective salvage therapy (16, 27). Regarding SGCT, the recent strategic algorithm considers surveillance alone for stage I patients with almost 100% of overall survival. Eventual relapses may be cured by radiation or chemotherapy (2). Adjuvant treatments have declined in recent decades, as surveillance has been increasingly used to avoid unnecessary treatment and related long-term toxicities (2, 30). Indeed, historically active surveillance became an option in the 1980’s when it was demonstrated that cisplatin-based chemotherapy could cure almost all recurrences. Today, it is the management option suggested by the guidelines because it has nearly the same overall survival rate of other adjuvant treatments as well as being a safe and non-invasive option in selected cases (3, 30-32). The trend nowadays is a de-escalation of therapy toward AS for early stage testicular cancers. The main debate against adjuvant chemotherapy is due to the lack of improved overall survival and the association with long-term side effects, including infertility, secondary malignancies, increased risk for cardiovascular disease,

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impaired kidney function, hearing impairment and peripheral neuropathy (2, 30, 33, 34). Nappi et al. (34) found that active surveillance is highly relevant in avoiding overtreatment in 50-85% of patients, with no long-term side effects in non-relapsing patients and an overall survival of almost 100% even in patients with recurrent disease. A study by Nayan et al. (35) conducted on 1239 patients with TGCT, treated with active surveillance after orchiectomy for clinical stadium I, showed that the risk percentage of relapse in the first 5 years after orchiectomy was 42.4% for high risk NSGCT, 17.3% for low risk NSGCT, 20.3% for SGCT more than 3 cm wide, and 12.2% for SGCT less than 3 cm wide. In a study by Albers et al. (16) in patients with stage I NSGCT, the tumors had a 30% risk of progression which required treatment. Furthermore, it is known that the risk of relapse in Stage I NSGCT is substantially related to the presence of Lympho-Vascular Invasion (LVI), which implies a 30-50% recurrence risk (25, 36). Moreover, as discussed by Yilmaz et al. (37) in their study, LVI could be considered a prognosticating indicator for NSGCT, thus the status of rete testis and testicular hilum should be taken into consideration when choosing therapies. Cohn-Cedermark et al. (38) advice chemotherapy for patients with at least two risk factors like tumor size and invasion of the rete testis. High-risk patients can also be managed with initial surveillance to spare the 50% in whom disease will not progress, but other studies recommend precautionary chemotherapy (33-35). Recurrences occur most commonly in the retroperitoneum, with the majority diagnosed within 2 years after orchiectomy (39, 40). Although recurrence rates are not comparable in the two groups due to different initial staging, in our study we observed relapses in the first 2 years after orchiectomy preeminently in the retroperitoneum, in 32.2% of the patients who underwent AT compared to 11.1% of patients submitted to AS. In the patients with AT, LVI and rete testis signs of infiltration were reported (45.5% NSGCT and 27.3% SGCT). All the relapses in patients with AS were histological samples of NSGCT in the Group B. All the recurrences in both groups presented a tumor mass greater than 3 cm in size.

CONCLUSIONS

AS proves to be a feasible option for stage I TGCT, whereas post-surgical therapy requires to be performed for higher stage of TGCT. The Kaplan-Meier curve shows a significant difference of RFS for younger patients although they presented with different stage at presentation. Considering the overall excellent outcomes of AS both in terms of OS and RFS, our experience suggests that post-orchiectomy active treatments might be limited to selected patients with well-known relapse risk factors, such as tumor size, lymphovascular and rete testis invasion, while the other patients could benefit from an accurate active surveillance approach.

TCGT in adolescents and young adults

ACKNOWLEDGMENTS

A special thanks to Helen Romito from Sant’Anna School of Advanced Studies in Pisa for her editing work.

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22. Chung JM, Lee SD. Overview of pediatric testicular tumors in Korea. Korean Journal of Urology. 2014; 55:789-96.

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23. Sun H, Kim P, Jia P, et al. Distinct telomere length and molecular signatures in seminoma and non-seminoma of testicular germ cell tumor. Brief Bioinform. 2019; 20:1502-1512.

5. McGlynn KA, Trabert B. Adolescent and adult risk factors for testicular cancer. Nature Reviews Urology. 2012; 9:339-49.

24. Nistal M, Paniagua R, González-Peramato P, et al. Perspective in pediatric pathology, Chapter 25. Testicular and paratesticular tumors in the pediatric age group. Pediatr Dev Pathol. 2016; 19:471-492.

6. Chien FL, Schwartz SM, Johnson RH. Increase in testicular germ cell tumor incidence among hispanic adolescents and young adults in the United States. Cancer 2014; 120:2728-34. 7. Schmiedel S, Schuz J, Skakkebaek NE, et al. Testicular germ cell cancer incidence in an immigration perspective, Denmark, 1978 to 2003. The J Urol. 2010; 183:1378. 8. Erin L. Marcotte, Pankratz N, Amatruda J Fetal. Variants in BAK1, SPRY4 and GAB2 are Associated with pediatric germ cell tumors: are port from the children’s oncology group. Genes Chromosomes Cancer. 2017; 56:548-558. 9. Le Cornet C, Fervers B, Pukkala E, et al. Parental occupational exposure to organic solvents and testicular germ cell tumors in their offspring: NORD-TEST study. Environ Health Perspect. 2017; 125:067023.

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29. Ehrlich Y, Beck SD, Foster RS, et al. Serum tumor markers in testicular cancer. Urol Oncol. 2013; 31:17-23.

11. DeRouen MC, Mujahid M, Srinivas S, et al. Disparities in adolescent and young adult survival after testicular cancer vary by histologic subtype: a population-based study in California 1988-2010. J Adolesc Young Adult Oncol. 2016; 5:31-40.

30. Gumus M, Bilici A, Odabas H, et al. Outcomes of surveillance versus adjuvant chemotherapy for patients with stage IA and IB non seminomatous testicular germ cell tumors. World J Urol. 2017; 35:1103-1110.

12. Leslie SW, Villanueva CA. Cryptorchidism. In Stat Pearls, Treasure Island (FL)-Stat Pearls Publishing 2018.

31. Alanee S, Nicholson A, Slaton J. Contemporary treatment of low risk stage I non-seminomatous germ cell testicular tumors: a survey of the society of Urologic Oncology. Urol. Oncol. 2012; 30:749-51.

13. Shaw PH, Reed DR, Yeager N, et al. Adolescent and young adult (AYA) oncology in the United States: a specialty in its late adolescence. J Pediatr Hematol Oncol. 2015; 37:161-9. 14. Hisamatsu E, Takagi S, Nakagawa Y, et al. Prepubertal testicular tumors: A 20-year experience with 40 cases. Int J Urol. 2010; 17:956-9. 15. Sobin LH, Gospodarowicz MK, Wittekind Ch. TNM Classification of Malignant Tumors, International Union Against Cancer. 2009. 16. Albers P, Albrecht W, Algaba F, et al. European Association of Urology. Guidelines on Testicular Cancer: 2015 Update. Eur Urol. 2015; 68:1054-68. 17. Oldenburg J, Fosså SD, Nuver J, et al. ESMO Guidelines Working Group. Testicular seminoma and non-seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013; 24 Suppl 6:vi125-32. 18. Tryakin A, Fedyanin M, Bulanov A, et al. Dose-reduced first cycle of chemotherapy for prevention of life-threatening acute com-

32. Patel HD, Srivastava A, Alam R, et al. Radiotherapy for stage I and II testicular seminomas: secondary malignancies and servival. Urol Oncol. 2017; 35:606.e1- e7. 33. Leveridge MJ, Siemens DR, Brennan K, et al. Temporal trends in management and outcomes of testicular cancer: A population-based study. Cancer. 2018; 124:2724-2732. 34. Nappi L, Nichols CR, Kollmannsberger CK. New treatments for stage I testicular cancer. Clinical Adv Hematol Oncol. 2017; 15:626631. 35. Nayan M, Jewett MAS, Hosni A, et al. Conditional risk of relapse in surveillance for clinical stage I testicular cancer. Eur Urol. 2017; 71:120-127. 36. Richie JP. Cardiovascular Disease Mortality after chemotherapy or surgery for testicular non seminoma:a population-based study. J Urol. 2016; 196:1448-1449. 37. Yilmaz A, Cheng T, Zhang J, Trpkov K. Testicular hilum and Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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vascular invasion predict advanced clinical stage in nonseminomatous germ cell tumors. Mod Pathol. 2013; 26:579-86. 38. Cohn-Cedermark G, Stahl O, Tandstad T. SWENOTECA. Surveillance vs.adjuvant therapyof clinical stage I testicular tumors-a review and the SWENOTECA experience. Andrology. 2015; 3:102-10.

39. Smart, Lopes, Rice S, et al. Chemotherapy drugs cyclophosphamide, cisplatin and Doxorubicin induce germ cell loss in an in vitro model of the prepubertal testis. Sci Rep. 2018; 8:1773. 40. Chung P, Warde P. Contemporary management of stage I and II seminoma. Curr Urol Rep. 2013; 14:525-33.

Correspondence Claudio Spinelli, MD claudio.spinelli@unipi.it Marco Ghionzoli, MD marcoghionzoli@hotmail.com Alessia Bertocchini, MD villinofibbiani@hotmail.com Beatrice Sanna, MD beatricesanna.md@gmail.com Silvia Strambi, MD sil.strambi@gmail.com Division of Pediatric, Adolescents and Young Adults Surgery, Department of Surgical Pathology, Medical, Molecular and Critical Area, University of Pisa, Pisa (Italy) Gianmartin Cito, MD (Corresponding Author) gianmartin.cito@gmail.com Girolamo Morelli, MD girolamomorelli@gmail.com Department of Urology and Andrology Surgery, Careggi Hospital, University of Florence Largo Brambilla, 3 50134 Florence (Italy) Luca Galli, MD lgalli@unipi.it Medical Oncology II, University of Pisa, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa (Italy) Andrea Antonuzzo, MD aantonuzzo@unipi.it Medical Oncology I, National Health Service Department of Translational Medicine Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa (Italy) Riccardo Morganti, MD r.morganti@ao-pisa.toscana.it Section of Statistics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa (Italy)

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DOI: 10.4081/aiua.2021.3.307

ORIGINAL PAPER

Stone composition of renal stone formers from different global regions Adam Haliński 1, Kamran Hassan Bhatti 2, Luca Boeri 3, Jonathan Cloutier 4, Kaloyan Davidoff 5, Ayman Elqady 6, Goran Fryad 7, Mohamed Gadelmoula 6, Hongyi Hui 8, Kremena Petkova 9, Elenko Popov 5, Bapir Rawa 10, Iliya Saltirov 9, Francisco R. Spivacow 11, Belthangady Monu Zeeshan Hameed 12, Alberto Trinchieri 13, Noor Buchholz 13 1 Private

Medical Center "Klinika Wisniowa" Zielona Gora; Poland; Unit, City Hospital Pakpattan, Pakistan; 3 Department of Urology, IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy; 4 CHU de Québec, Laval University, Québec City, Canada; 5 Acibadem City Clinic Tokuda Hospital, Sofia, Bulgaria; 6 Urology Department, Assiut University, Assiut, Egypt; 7 Shar Teaching Hospital, Sulaymanyah City, Iraq; 8 Department of Urology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; 9 Department of Urology and Nephrology, Military Medical Academy, Sofia, Bulgaria; 10 Smart Health Tower, Sulaymaniyah, Kurdistan region, Iraq; 11 Instituto de Investigaciones Metabólicas (IDIM Department of Urology), Buenos Aires, Argentina; 12 Department of Urology, Kasturba Medical College, Manipal, Karnataka, India; 13 U-merge Ltd (Urology for emerging countries), London, UK. 2 Urology

Summary

Objective: To study urinary stone composition patterns in different populations around

the world. Materials and methods: Data were collected by reviewing charts of 1204 adult patients of 10 countries with renal or ureteral stones (> 18 years) in whom a stone analysis was done and available. Any method of stone analysis was accepted, but the methodology had to be registered. Results: In total, we observed 710 (59%) patients with calcium oxalate, 31 (1%) with calcium phosphate, 161 (13%) with mixed calcium oxalate/calcium phosphate, 15 (1%) with carbapatite, 110 (9%) with uric acid, 7 (< 1%) with urate (ammonium or sodium), 100 (9%) with mixed with uric acid/ calcium oxalate, 56 (5%) with struvite and 14 (1%) with cystine stones. Calciumcontaining stones were the most common in all countries ranging from 43 to 91%. Oxalate stones were more common than phosphate or mixed phosphate/oxalate stones in most countries except Egypt and India. The rate of uric acid containing stones ranged from 4 to 34%, being higher in Egypt, India, Pakistan, Iraq, Poland and Bulgaria. Struvite stones occurred in less than 5% in all countries except India (23%) and Pakistan (16%). Cystine stones occurred in 1% of cases. Conclusions: The frequency of different types of urinary stones varies from country to country. Calcium-containing stones are prevalent in all countries. The frequency of uric acid containing stones seems to depend mainly on climatic factors, being higher in countries with desert or tropical climates. Dietary patterns can also lead to an increase in the frequency of uric acid containing stones in association with high obesity rates. Struvite stones are decreasing in most countries due to improved health conditions.

KEY WORDS: Urinary calculi; Epidemiology; Gender; Age; Calcium oxalate; Calcium phosphate; Uric acid; Struvite; Cystine. Submitted 18 August 2021; Accepted 25 August 2021

BACKGROUND

Most data on chemical stone composition have been collected in the Western world (1-8). It is well known that stone composition is dependent on lifestyle and diet, which in turn is dependent on country, climate and culture. Therefore, it is of interest to establish a more globalised map of chemical stone composition around the globe. U-merge, an association gathering urologists from all over the world, is the ideal platform for this task. For this reason, the scientific office of U-Merge launched a study to collect the results of urinary stone analyses among different populations in the countries of its members.

MATERIALS

AND METHODS

All members of U-merge were invited to join in the study. Data were collected by reviewing charts of adult patients (> 18 years) with renal or ureteral stones observed in each participating center who had chemical analysis of the stone available. Gender, age, country and stone composition of each patient were recorded in an Excel data base. Any method of stone analysis was accepted, but the methodology had to be known and registered. A minimum number of 30 patients per center was required. Stones analyzed by wet chemical were classified as calcium oxalate (CaOx) (unspecified), calcium phosphate (CaP) (unspecified), mixed calcium oxalate/calcium phosphate (CaOx/CaP), struvite, uric acid (UA), mixed uric acid/calcium oxalate (UA/CaOx) and cystine. Stones analysed by infrared spectroscopy or X-ray diffractometry were classified as CaOx dihydrate (> 50%), CaOx monohydrate (> 50%), CaP (> 50%), mixed CaOx/CaP (if CaP > 10%), struvite (> 50%), carbonate apatite (50%), UA anhydrous (> 50%), UA dihydrate (> 50%), ammonium

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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N° M F Age

Argentina 300 179 (59%) 121 (41%) 45+12

Bulgaria 183 122 (67%) 61 (33%) 48+13

Canada 50 28 (56%) 22 (44%) 56+14

China 90 58 (64%) 32 (36%) 50+12

Egypt 73 57 (78%) 16 (22%) 40+12

India 35 26 (74%) 9 (26%) 50+12

Iraq 36 26 (72%) 10 (28%) 38+13

Italy 360 226 (63%) 134 (37%) 56+14

Pakistan 44 38 (86%) 6 (14%) 40+8

Poland 33 16 (48%) 17 (52%) 50+17

Table 1. Average age and M/F ratio of RSFs from different countries.

Age p = 0.000; M/F p = 0.002.

urate (> 50%), sodium urate (> 50%), mixed UA/CaOx, cystine. The Statistical Package for the Social Sciences (SPSS) version 11.5 for Windows was used for statistical analysis. Comparisons were considered to differ significantly if p < 0.05.

RESULTS

In total, 1204 renal stone formers (RSFs) were considered (776 males, 428 females) from 10 countries (Argentina, Bulgaria, Canada, China, Egypt, India, Iraq, Italy, Pakistan and Poland). Twelve institutions from 10 countries have joined the survey as listed below: - Department of Urology, Instituto de Investigaciones Metabólicas, Buenos Aires (Argentina) - Acibadem City Clinic Tokuda Hospital, Sofia (Bulgaria) - Department of Urology and Nephrology, Military Medical Academy, Sofia (Bulgaria) - CHU de Québec, Laval University, Québec City (Canada) - Dep of Urolotgy, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (China) - Urology Department, Assiut University, Assiut (Egypt) - Department of Urology, Kasturba Medical College, Manipal, Karnataka (India) - Urology Department, Sulaymaniyah Surgical Teaching Hospital, Sulaymaniyah (Iraq) - Shar Teaching Hospital, Sulaymanyah City (Iraq) - Department of Urology, IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan (Italy) - City Hospital Pakpattan, Pakpattan (Pakistan) - Private Medical Center Klinika Wisniowa, Zielona Gora (Poland) The average age of patients was 49.3+14.4 and the M/F ratio was 1.81. The number, average age and M/F ratio of RSFs from different countries are shown in Table 1. The average age of RSFs in Italy and Canada was greater than that of the RSFs of Argentina (p = 0.000), Bulgaria (p = 0.000 and p = 0.001), Egypt (p-0.000), Iraq (p = 0.000, and Pakistan (p = 0.000). The average age of RSFs in Italy was higher than that of the RSFs in China (p = 0.011). The lowest average age was observed in Egypt, Iraq, and Pakistan, where the average age of RSFs was lower than those of RSFs in Canada (p = 0.000), Italy (p = 0.000) and China (p = 0.000, p = 0.000 and p = 0.001). In Egypt and Iraq, the average age of the RSFs was also lower than in Bulgaria (p = 0.001, p = 0.002), Poland (p = 0.020, p = 0.007) and India (p = 0.009 and p = 0.004). The frequency of the disease was slightly higher in women in Poland (52%), whereas it tended to be higher in men in Canada (56%), Argentina (59%), Italy (63%), China (64%) and Bulgaria (67%). Highest rates in men

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Table 2. Spectrum of stone composition by gender and age.

CaOx COM COD CaOx/CaP CaP Carbapatite

Gender Males Females 461 (59%) 249 (58%) 223 105 52 23 89 (11%) 72 (16%) 18 (2.3%) 13 (3.0%) 4 (0.5%) 11 (2.5%)

18-39 200 (59%) 73 20 46 (13%) 12 (3.5%) 5 (1.5%)

Age class 40-59 318 (57%) 136 34 80 (14%) 14 (2.5%) 8 (1.5%)

> 60 Total 192 (62%) 710 (59%) 119 328 21 75 35 (11%) 161 (13%) 5 (1.5%) 31 (3%) 2 (0.5%) 15 (1%)

Ca-containing UA Urate UA/CaOx UA-containing Struvite Cystine Total

572 (74%) 84 (11%) 4 (0.5%) 75 (10%) 163 (21%) 33 (4.2%) 8 (1.1%) 776

263 (77%) 22 (6.4%) 0 (0%) 25 (7%) 47 (14%) 23 (7%) 8 (2.5%) 341

420 (76%) 49 (8.8%) 4 (0.5%) 55 (10%) 108 (19%) 22 (4%) 4 (0.5%) 554

234 (76%) 39 (12.6%) 3 (1%) 20 (6%) 62 (20%) 11 (3.5%) 2 (0.5%) 309

345 (80%) 26 (6%) 3 (0.7%) 25 (6%) 54 (13%) 23 (5.4%) 6 (1.4%) 428

917 (76%) 110 (9%) 7 (0.5%) 110 (9%) 217 (18%) 56 (5%) 14 (1%) 1204

were observed in Pakistan (86%), Egypt (78%), India (74%) and Iraq (72%). The spectrum of stone composition by gender and age is shown in Table 2. In total, we observed 710 (59%) patients with calcium oxalate, 31 (1%) with calcium phosphate, 161 (13%) with mixed calcium oxalate/calcium phosphate, 15 (1%) with carbapatite, 110 (9%) with uric acid, 7 (< 1 %) with urate (ammonium or sodium), 100 (9%) with mixed with uric acid/ calcium oxalate, 56 (5%) with struvite and 14 (1%) with cystine stones. In the calcium-containing group, calcium oxalate stones accounted for 77% and phosphate or mixed calcium phosphate/calcium oxalate stones for the remaining 23%. The frequency of calcium phosphate or mixed calcium phosphate/calcium oxalate ranged from 9 to 74%. The great variability depends on the different methods of analyzing stones and reporting the results. In 403 patients with calcium oxalate stones analyzed by infrared spectroscopy, calcium oxalate monohydrate stones (COM) were more frequent than calcium oxalate dihydrate (COD) stones. Frequency of calcium oxalate stones was equal in women and men (58% vs 59%), whereas frequency of uric acid containing stones was lower in women than in men (13% vs 21%) and frequency of calcium phosphate and mixed calcium phosphate/calcium oxalate stones (21% vs 14%) and frequency of struvite stones were higher in women. Frequency of COM stones tended to be higher in men than in women (78 vs 71%) and to increase with age (1839 =78%, 40-59 = 80%, > 60% = 85%).

Worldwide renal stone composition

Table 3. Spectrum of stone composition in different countries.

CaOx COM COD CaOx/CaP CaP Carbapatite Ca-containing Ox % UA pure UA urate UA/CaOx UA - containing Struvite Cystine Total

Argentina 239 (80%) 12 (4%) 7 (2%) 0 (0%) 258 (86%) 92% 27 (9%) 0 (0%) 6 (2%) 33 (11%) 9 (3%) 0 (0%) 300

Bulgaria 97 (53%) 79 18 17 (9%) 0 (0%) 3 (2%) 117 (64%) 85% 8 (4.5%) 6 (3.5%) 39 (21%) 53 29% 10 (5.4%) 3 (1.6%) 183

Canada 23 (46%) 11 (22%) 2 (4%) 10 (20%) 46 (92%) 50% 1 (2%) 0 (0%) 1 (2%) 2 (4%) 1 (2%) 1 (2%) 50

China 65 (72%) 49 16 11 (12%) 6 (7%) 0 (0%) 82 (91%) 79% 5 (5%) 0 (0%) 1 (1%) 6 6% 2 (3%) 0 (0%) 90

Egypt 12 (16%) 12 0 34 (47%) 0 (0%) 0 (0%) 46 (63%) 26% 0 (0%) 0 (0%) 22 (30%) 22 (30%) 4 (5.5%) 1 (1.5%) 73

Frequency of uric acid stones was higher in males and tended to increase with age. The distribution of the different types of stones in RSFs in different countries is described in Table 3. Calcium-containing stones were the most common in all countries. Among calcium-containing stones, calcium oxalate stones were more frequent in all countries except in Egypt and India where the frequency of calcium phosphate or mixed calcium phosphate/calcium oxalate was 74% in Egypt and 53% in India, respectively. Among calcium oxalate stones, the rate of COM stones was 100% in Egypt, 83% in Italy, 81% in Bulgaria, 75% in China, and 69% in Iraq. The rate of uric acid containing stones ranged 4 to 34% in most countries with the highest rates observed in Egypt, India, Poland, and Bulgaria. Struvite stones were less than 5% in all countries but India (23%) and Pakistan (16%). Cystine stones were less than 2%.

DISCUSSION Stone composition by age and sex In the present study, calcium-containing stones were the

India 7 (20%)

8 (23%) 0 (0%) 0 (0%) 15 (43%) 46% 5 (14%) 0 (0%) 7 (20%) 12 (34%) 8 (23%) 0 (0%) 35

Iraq 16 (44%) 11 5 7 (20%) 0 2 (5%) 25 (69%) 64% 8 (22%) 0 (0%) 1 (3%) 9 (25%) 1 (3%) 1 (3%) 36

Italy 214 (59%) 178 36 57 (16%) 14 (4%) 0 (0%) 285 (79%) 72% 39 (10.5%) 1 (0.5%) 18 (5%) 58 (16%) 12 (3,5%) 5 (1.5%) 360

Pakistan 21 (48%)

0 (0%) 2 (4%) 0 (0%) 23 52% 91% 11 (25%) 0 (0%) 0 (0%) 11 (25%) 8 (18%) 2 (5%) 44

Poland 16 (49%) 4 (12%) 0 0 20 61% 80% 6 (18%) 0 (0%) 5 (15%) 11 (33%) 1 (3%) 1 (3%) 33

Tot 710 (59%)

161 (13%) 31 (3%) 15 (1%) 917 (76%) 77% 110 (9%) 7 (1%) 100 (8%) 217 (18%) 56 (5%) 14 (1%) 1204

most frequent, followed by uric acid-containing stones, while struvite and cystine are less frequent. In accordance with previous reports (9), uric acid containing stones were more frequent in males and in older ages, whereas phosphate stones were more frequent in women. The average age of RSFs in different countries varies but these differences reflect those that are observable in the general population of their countries, which averaged about 20 years lower (Figure 1). M/F ratio is different in countries, being balanced between men and women or slightly in favor of men in the countries of North America, Europe, South America and China but heavily weighted in favor of men in Egypt, Pakistan, India and Iraq. This finding confirmed the tendency to an increase of stone formation in women of Western countries (9), and more recently of China (10), while in Egypt, Pakistan, India and Iraq the ratio of males to females is still similar to what was observed in Western countries forty years ago (11). This trend can be explained by the so-called nutrition transition, that is the change in dietary habits across the world with a convergence towards an increased consumption of unhealthy Figure 1. Average age in RSFs and general population.

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foods that is the cause of the increase in non-communicable diseases in almost all regions of the world in both sexes (12). Consumption of unhealthy foods is still limited in some regions of North Africa and South Asia that maintain dietary patterns with a lower risk of urinary stones forming. Moreover, in some countries the characteristics of family structure and cultural rules still present a nutritional disadvantage for women (13). Stone composition by country The spectrum of composition of urinary stones is quite variable in different countries. Differences could be attributable to the different characteristics by age and gender of the populations studied, reflecting the distribution by age and gender in the general population of each country. On the other hand, the modality of stone analysis and reporting in the different centers may be a confounding factor (14). For this reason, the most robust data are those comTable 4. Mean temperature, precipitation fall and climate classification in the countries involved in the study. Country

Town

Argentina Bulgaria Canada China Egypt India Pakistan Iraq Italy Poland

Buenos Aires Sofia

Temperature mean 16.8 °C. 10.2 °C

Quebec

4.8 °C.

Shanghai Asyut

16.1 °C. 22.6 °C. 26.7 °C 24.8 °C 16.2 °C

Karnataka Pakpattan Sulaymaniyah Milan Zielona Gora

13.1°C 8.8 °C

Precipitation fall 1040 mm 581 mm 1101 mm 1066 mm 2 mm 4866 mm 234 mm 906 mm. 1013 mm 572 mm

Climate Warm temperate Warm temperate Cold temperate Warm temperate Hot desert Tropical Hot desert Warm temperate Warm temperate Warm temperate

Figure 2. Rate of uric-acid containing stones and mean temperature.

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paring the rates of calcium-containing with those of uric acid containing stones, whereas it is less significant to compare the results of different countries in relation to the specific crystallographic composition, which should be compared between patients whose stones have been analyzed and reported in the same laboratory. Calcium-containing stones were the most common in vast majority of countries with a rate ranging from 52 to 91%. The highest rates of calcium-containing stones were observed in North America, South America, China and some European countries. In most countries, calcium oxalate stones (in particular, COM stones) were the more frequent calcium-containing stones, although calcium phosphate and mixed calcium oxalate/calcium phosphate stones were more frequent than pure calcium oxalate stones in some countries such as Egypt and India. This trend agrees with previous observation in North America where a tendency has been reported of an increase in oxalate stones and a decrease in phosphate stones during the last two decades (4, 5). The highest rates of acid uric containing stones were observed in Iraq, Köppen-Geiger climate Pakistan, India, Egypt and Poland and classification system Bulgaria. In general, uric acid-conCfa taining stones should be more freCfb quent in older male patients, but surDfb prisingly in our study the highest Cfa rates of uric acid-containing stones BWh were observed in two countries with Am the lowest mean age, namely Egypt and Iraq. This result can be BWh explained by the finding that the freCsa quency of a type of stone is not a Cfa measure of the prevalence of the disCfb ease in the population, but is the result of the prevalence of different types of urinary stones. In other words, a high frequency of uric acid stones may be due to an increase in the prevalence of uric acid stones but, alternatively, a lower prevalence of other types of stones in the population studied. On the other hand, the impact of environmental factors could be decisive, considering that high temperatures and high humidity cause a decrease of urinary volumes and urinary pH values resulting in an increase of urinary uric acid saturation and of the incidence of uric acid stones (15, 16). In fact, the highest values of uric acid-containing stones were observed in countries with high mean temperatures (17) and tropic or hot desert climates such as Egypt, India, Pakistan and Iraq (Table 4) (Figure 2). Our data confirm previous evidence in the literature showing a high rate of uric acidcontaining stones in Pakistan, Egypt, and Iraq (18-21). In the present

Worldwide renal stone composition

study, the prevalence of uric acid containing stones was also high in Southern India in accordance with previous reports. In fact, the frequency of uric acid-containing stones was reported low (4.28%) or very low (< 1%) in North Western India (22, 23), but higher in Southern India (24). This difference can be explained by different regional eating habits: in the Northern and Western regions, a more traditional vegetarian diet is consumed with exclusive consumption of fruit, vegetables and legumes, whereas in the Southern regions the consumption of sweets, snacks and pork meat is common (25). On the other hand, in our study the lowest rate of uric acid containing stones was observed in Canada, the country with the lowest mean temperature. Intermediate rate values were observed in countries with a temperate climate, such as China and Italy. The high frequency of uric acid-containing stones in Poland is less easily explained, mainly because it contrasts with previous findings showing lower rates of uric acid stones in a series of stones analyzed by infrared spectroscopy (26). Possible explanations are high obesity rate of the population (45%) and unfavorable dietary patterns (27). In fact, the adherence to the traditional Polish dietary pattern, characterized by high intake of refined grains, potatoes, sugar and sweets is associated with a higher risk of abdominal obesity and hypertriglyceridemia (28). Similarly, in Bulgaria the frequency of uric acid-containing stones is associated with obesity rates which are among the highest in Europe (46%) (27), and with an unhealthy nutritional pattern characterized by high consumption of fatty meats and meat products, highfat milk and a high alcohol intake (29). The rate of struvite stones is generally lower than described in the past, due to improved health conditions and early diagnosis and treatment of urinary tract infections by urease-producers, although in some countries such as Pakistan and India it still accounts for a quarter of cases. Cystine stone rates are similar in all countries, with similar rates than those reported in the literature. In conclusion, the frequency of different types of urinary stones varies from country to country. Calcium-containing stones are the most frequent in all countries, with frequencies of up to 90%. The frequency of uric acid containing stones seems to depend mainly on climatic factors, being more frequent in warmer countries with desert or tropical climates although dietary patterns can also lead to an increase in the frequency of uric acid containing stones in association with high obesity rates. Struvite stones are decreasing in most countries except India and Pakistan.

REFERENCES

weight and composition in 15,624 stones: comparison of resutls for 1980 to 1983 and 1995 to 1998. J Urol. 2000; 164:302-7. 5. Moses R, Pais VM Jr, Ursiny M, et al. Changes in stone composition over two decades: evaluation of over 10,000 stone analyses. Urolithiasis. 2015; 43:135-9. 6. Singh P, Enders FT, Vaughan LE, et al. Stone composition among first-time symptomatic kidney stone formers in the community. Mayo Clin Proc. 2015; 90:1356-65. 7. Xu LHR, Adams-Huet B, Poindexter JR, et al. Temporal changes in kidney stone composition and in risk factors predisposing to stone formation. J Urol. 2017; 197:1465-1471. 8. Kittanamongkolchai W, Vaughan LE, Enders FT, et al. The changing incidence and presentation of urinary stones over 3 decades. Mayo Clin Proc. 2018; 93:291-299. 9. Lieske JC, Rule AD, Krambeck AE, et al. Stone composition as a function of age and sex. Clin J Am Soc Nephrol. 2014; 9:2141-6. doi: 10.2215/CJN.05660614. 10. Zeng G, Mai Z, Xia S, et al. Prevalence of kidney stones in China: an ultrasonography based cross-sectional study. BJU Int. 2017; 120:109-116. doi: 10.1111/bju.13828. Epub 2017 Mar 21. 11. Johnson CM, Wilson DM, O'Fallon WM, et al. Renal stone epidemiology: a 25-year study in Rochester, Minnesota. Kidney Int. 1979; 16:624-31. 12. Imamura F, Micha R, Khatibzadeh S, et al. Global Burden of Diseases Nutrition and Chronic Diseases Expert Group (NutriCoDE) Dietary quality among men and women in 187 countries in 1990 and 2010: a systematic assessment. Lancet Glob Health. 2015; 3:e132-42. 13. Rao T, & Pingali P. The role of agriculture in women's nutrition: Empirical evidence from India. PloS one 2018; 13:e0201115. 14. Siener R, Buchholz N, Daudon M, et al. Quality Assessment of Urinary Stone Analysis: Results of a Multicenter Study of Laboratories in Europe. PloS one 2016; 11:e0156606. 15. Stuart RO 2nd, Hill K, Poindexter J, Pak CY. Seasonal variations in urinary risk factors among patients with nephrolithiasis. J Lithotr Stone Dis. 1991; 3:18-27. 16. Baker PW, Coyle P, Bais R, Rofe AM. Influence of season, age, and sex on renal stone formation in South Australia. Med J Aust. 1993; 159:390-2. 17. https://it.climate-data.org/ 18. Rafique M, Bhutta RA, Rauf A, Chaudhry IA. Chemical composition of upper renal tract calculi in Multan. J Pak Med Assoc. 2000; 50:145-8. 19. Sheir KZ, Mansour O, Madbouly K, et al. Determination of the chemical composition of urinary calculi by noncontrast spiral computerized tomography. Urol Res. 2005; 33:99-104 20. Afaj AH, Sultan MA. Mineralogical composition of the urinary stones from different provinces in Iraq. Scientific World Journal. 2005; 5:24-38.

1. Daudon M, Donsimoni R, Hennequin C, et al. Sex- and age-related composition of 10 617 calculi analyzed by infrared spectroscopy. Urol Res. 1995; 23:319-26.

21. Popov E, Almusafer M, Belba A, et al. Obesity rates in renal stone formers from various countries. Arch Ital Urol Androl. 2021; 93:189-194.

2. Trinchieri A, Rovera F, Nespoli R, Currò A. Clinical observations on 2086 patients with upper urinary tract stone. Arch Ital Urol Androl. 1996; 68:251-62.

22. Bhat A, Singh V, Bhat M, et al. Spectrum of urinary stone composition in Northwestern Rajasthan using Fourier transform infrared spectroscopy. Indian J Urol. 2018; 34:144-148. doi: 10.4103/ iju.IJU_363_16.

3. Knoll T, Schubert AB, Fahlenkamp D, et al. Urolithiasis through the ages: data on more than 200,000 urinary stone analyses. J Urol. 2011 Apr;185(4):1304-11. doi: 10.1016/j.juro.2010.11.073. 4. Gault MH, Chafe L. Relationship of frequency, age, sex, stone

23. Ansari MS, Gupta NP, Hemal AK, et al. Spectrum of stone composition: structural analysis of 1050 upper urinary tract calculi from northern India. Int J Urol. 2005; 12:12-6. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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24. Marickar YMF. Epidemiology of stone disease in Kerala, South India. In Talati J, Tiselius H-G, Albala DM, Ye Z (eds.) Urolithiasis: basic science and clinical practice, Springer Verlag, London, pp 47-51. 25. Green R, Milner J, Joy EJ, et al. Dietary patterns in India: a systematic review. Br J Nutr. 2016; 116:142-8. doi: 10.1017/ S0007114516001598. 26. Wrobel A, Rokita E, Taton G, Thor P. Chemical composition and morphology of renal stones. Folia Med Cracov. 2013; 53:5-15.

27. Kotseva K, Wood D, De Bacquer D, et al. A European Society of Cardiology survey on the lifestyle, risk factor and therapeutic management of coronary patients from 24 European countries. Eur J Prev Cardiol. 2016; 23:636-48. doi: 10.1177/2047487315569401. 28. Suliga E, Kozieł D, Ciesla E, et al. Dietary patterns in relation to metabolic syndrome among adults in Poland: a cross-sectional study. Nutrients. 2017; 9. pii: E1366. doi: 10.3390/nu9121366. 29. ncpha.government.bg/files/hranene-en.pdf

Correspondence Adam Haliński, MD adamhalinski@gmail.com Private Medical Center "Klinika Wisniowa" Anieli Krzywon street 2; 65-001 Zielona Gora (Poland) Kamran Hassan Bhatti, MD kamibhatti92@gmail.com City Hospital Pakpattan (Pakistan) Luca Boeri, MD dr.lucaboeri@gmail.com Department of Urology, IRCCS Ca’ Granda Ospedale Maggiore Policlinico University of Milan, Milan, Italy Kaloyan Davidoff, MD shennyp@yahoo.com Elenko Popov, MD shennyp@yahoo.com Acibadem City Clinic Tokuda Hospital - Sofia, Bulgaria Sofia, bul N. Vaptzarov 51 B Ayman Elqady, MD Mohamed Gadelmoula, MD mgad73@aun.edu.eg Urology Department - Assiut University - Assiut (Egypt) Goran Fryad, MD goranfryad@yahoo.com Shar Teaching Hospital - Malik Mahmood Circle street, Sulaimani City (Kurdistan Region-Iraq) PO Box: Baxtyary 36B Hongyi Hui, MD 1095340463@qq.com Department of Urology, Renji Hospital, Shanghai Jiaotong University School of Medicine No.160, Pujian Road, Shanghai, 200127, China Kremena Petkova, MD dr_petkova@yahoo.com Iliya Saltirov, MD saltirov@vma.bg Department of Urology and Nephrology, Military Medical Academy 3, Georgi Sofiiski blvd, 1606 Sofia, Bulgaria Bapir Rawa, MD dr.rawa@yahoo.com Smart Health Tower, Sulaymaniyah, Kurdistan region, Iraq Francisco R Spivacow, MD frspivacow@gmail.com Instituto de Investigaciones Metabólicas (IDIM) Libertad 836, 1° piso, Ciudad Autónoma de Buenos Aires (Argentina) Belthangady Monu Zeeshan Hameed, MD zeeshanhameedbm@gmail.com Kasturba Medical College, Manipal Department of Urology, KMC Hospital, Manipal-576104, Karnataka, India Alberto Trinchieri, MD alberto.trinchieri@gmail.com Noor Buchholz, MD (Corresponding Author) noor.buchholz@gmail.com U-merge Ltd. (Urology for emerging countries), London, UK

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DOI: 10.4081/aiua.2021.3.313

ORIGINAL PAPER

Stone free rate and clinical complications in patients submitted to retrograde intrarenal surgery (RIRS): Our experience in 571 consecutive cases Orazio Maugeri 1, Ettore Dalmasso 2, Dario Peretti 2, Fabio Venzano 2, Germano Chiapello 2, Carlo Ambruosi 2, Claudio Dadone 2, Astrid Bonaccorsi 1, Pietro Pepe 1, Letterio D’Arrigo 1, Michele Pennisi 1 1 Urology 2 Urology

Unit - Cannizzaro Hospital, Catania, Italy; Unit - S. Croce and Carle Hospital, Cuneo, Italy.

Summary

Introduction: The purpose of this study is to report the stone free rate (SFR) and clinical complications in patients submitted to retrograde intrarenal surgery (RIRS). Materials and methods: A total of 571 procedures of upper urinary stones treated using flexible ureteroscopy and holmium laser lithotripsy from January 2014 to February 2020 have been analyzed. Overall SFR was evaluated after 3 months following the procedure by means of a non-contrast computed tomography. Success was considered as stone-free status or ≤ 0.4 cm fragments. Results: The overall SFR was 92.3% in group 1 (stone size: < 1 cm), 88.3% in group 2 (stone size: > 1 ≤ 2 cm), 56.7% in group 3 (stone size: 2-3 cm) and 69.6% in group 4 (multiple stones). Post-operative complications, according to the ClavienDindo (CD) classification system, were recorded in 32 (5.6%) procedures. The major complications recorded were: one case of subcapsular hematoma (SRH) associated with pulmonary embolism two days after the procedure (CD Grade IIIa) treated conservatively and one case of hemorrhagic shock 2 hour with multiple renal bleedings requiring urgent nephrectomy (CD Grade IVA). Conclusions: The RIRS is an effective and safe procedure with a high SFR significantly correlated with the stone size; at the same time, RIRS could be characterized by severe clinical complications that require rapid diagnosis and prompt treatment.

KEY WORDS: RIRS; Complications; Stone free rate. Submitted 18 March 2021; Accepted 7 May 2021

INTRODUCTION

The retrograde intrarenal surgery (RIRS) was introduced in 2008 as an alternative to extracorporeal shock wave lithotripsy (ESWL) and percutaneous nephrolithotomy (PNL) in patients with ESWL-refractory and lower pole stones; today, according to the more recent European Guidelines (EAU guidelines), RIRS represents one of the first line treatments for < 2 cm renal stones (1, 2). In fact, in 2013 EAU guidelines RIRS has been reported as an effective and definitive therapeutic option for renal stones with higher stone free rate (SFR) and low rate of complications (3). Many studies have compared RIRS to percutaneous surgery (PNL) with results that seem to be similar even

for larger volume stones, but with few severe complications (4, 5); on the other hand, other studies described also life threatening complications of RIRS. In every day practice is RIRS a really uncomplicated technique? What are the real risks? The purpose of this study is to report the stone free rate (SFR) and clinical complications in patients submitted to RIRS.

MATERIALS

AND METHODS

Outcomes of 514 (mean age was 55 yrs; range: 24-84) consecutive patients (313 males and 201 females) who underwent RIRS for renal stones from January 2014 to February 2020 have been retrospectively analyzed. 213 (41.4%) vs 301 (68.6%) stones were located in the right and left kidney; in detail, 213 (41.3%) vs 101 (19.5%) vs 75 (10.6%) vs 239 stones (46.6%) were located in the lower pole vs the middle pole vs the upper pole vs the renal pelvis, respectively. The median stone size was 1.3 cm (range 0.6-3 cm), in 128/514 (24.9%) cases the stones were multiple; CT stone density (HU) 859 (range 436 1674). Preintervention double-J stenting was performed in 208/571 (36.5%) cases. Overall SFR was evaluated after 3 months following the procedure by means of a non-contrast computed tomography (N-CCT). Patients who were not considered stone free at the end of the procedure were rescheduled for second look. Success was considered as stone-free status or ≤ 0.4 cm fragments Clinically Insignificant Residual Fragments (CIRF). The 30 days complication rate was classified according to the Clavien-Dindo (CD) classification system (6). Surgical technique All patients were operated in the standard lithotomy position, under general or spinal anesthesia according to anesthetist-patients counseling. Preliminary semirigid ureteroscopy (using a 6.5-7 F. ureterorenoscope) was performed to observe the ureter and obtain a preconditioning ureteral dilation. A ureteral access sheath (UAS) was positioned (10/12 or 12/14 F - Retrace® Coloplast; 9.5/11.5 or 10.7/12.7 F Flexor® Cook Urological) depending on the ureteral diam-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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eter and compliance. The length of the UAS Table 1. inserted was 35 cm for women, 45 cm for Stone free rate in the 514 patients submitted to RIRS. men. Fluoroscopy was always performed in Number of stone Single < 1 cm Single 1-2 cm Single 2-3 cm Multiple all cases for instrumentation and control. Number of patients 202 247 37 128 A 7.5 F flexible fiberoptic ureteroscope and a Overall Success rate, pt (%) 186 (92.3%) 130 (88.3%) 21 (56.7%) 89 (69.6%) 200 or 272 micron fiber were used depending Overall Stone free rate, pt (%) 175/186 (94%) 89/130 (68.4%) 14/21 (66.6%) 67/89 (75.2%) on the type of laser. Overall CIRF rate, pt (%) 11/186 (5.9%) 41/130 (31.5%) 7/21 (33.3%) 22/89 (24.7%) Stone treatment consisted in fragmentation Stone free rate after I look pt (%) 158/175 (90.2%) 71/89 (79.7%) 6/14 (42.8%) 44/67 (65.6%) and/or dusting, performed by Sphinx® Jr 30W Stone free rate after II look pt (%) 17/175 (9.7%) 18/89 (20.2%) 8/14 (57.1%) 23/67 (34.3%) Ho:YAG laser system (LISA laser) (412 cases; 72.1%), or 120-W high-power Ho:YAG laser Stone free rate after III look pt (%) system (Lumenis® Ltd.,) (104 cases; 18.2%) or CIRF rate after I look pt (%) 11/11 (100%) 35/41 (85.3%) 5/7 (71.4%) 21/22 (95.4%) Dornier Medilas H Solvo 30 Watt CIRF rate after II look pt (%) 6/41 (14.6%) Holmium:YAG laser (Olympus®) (55 cases; CIRF rate rate after III look pt (%) 2/7 (14,2%) 1/22 (4.5%) 9.6%), depending on the availability of the different lasers case by case. The most appropriate setting and technique depended on stone size and hardness and on the laser - IQR 1-66). Median post-operative stay was 1.8 days used (Table 4). (IQR 1-19). At 3 months N-CCT, the overall success rate For stone size < 1 cm the treatment of choice was fragwas 82.8% (426/514 cases); after the first RIRS 345/514 mentation and complete extraction of the fragments using patients were completely free from urolithiasis (SFR: a zero tip 1.9 Fr nitinol basket. 67.1%), while 72/514 patients had ≤ 4 mm stone fragFor stone size > 1 or ≤ 3 cm RIRS procedure was comments in the same renal localization of previously treated posed by 3 phases: lithiasis (CIRF rate: 14%). 54 patients had residual stones 1) First phase: stone dusting using low energy, high frerequiring second-look and three needed a third-look for quency and long pulse width with a persistent contact significant residual fragments. between laser fiber and stone. Table 1 shows success rate, stone free rate and CIRF after 2) Extraction of fragments: the major fragments derived first treatments according to stone volume and number; from stone dusting were extracted using a zero tip 1.9 the stone composition by spectrophotometric analysis is Fr nitinol basket. All fragments were conserved for reported in Table 2. stone analysis. Intraoperative complications were reported in 4 patients: 3) Second stage: “popcorn effect”: high energy, high fre– Intraoperative bleeding: one during laser lithotripsy quency and short pulse duration. and one after placement of the UAS. In both cases Continuous irrigation with gravity drainage (40 to 50 cm bleeding led to poor visibility and abortion of the proH2O) and syringe-based systems were gently applied to cedure that was rescheduled. obtain and sustain a clear the operative field. – Two ureteral wall injuries secondary to UAS placeAt the end of the procedure a 4.8-6 Fr double J stent was ment: a grade 2 lesion according to Traxer classificaplaced in radioscopy, with or without strings depending tion (6) were treated with a double J stent for a long removal time (cut-off was 7 days). period; a grade 3 lesion required percutaneous drainIn 48 procedures (9.3%), UAS could not be applied and ing of the kidney. No subsequent strictures were noted consequently the procedure was performed without during follow up (13 and 18 months). access sheath. Post-operative complications were recorded in 31 (5.4%) We used: UAS 9.5 Fr (n = 33), 10-12 Fr (n = 158), 10.7procedures (Table 3): 12.7 Fr (n = 43), 12-14 (n = 195).

RESULTS

RIRS was performed in 514 patients for a total of 571 procedures (54 second look and 3 third look); preoperative assessment included physical examination, routine urine culture, and N-CCT. RIRS was performed on standard antibiotic prophylaxis (according to local guidelines) or on targeted antibiotic therapy in case of preoperative positive urine culture (in this case therapy was started 5 days before surgery and continued for 3 more days). Preoperative urine cultures were positive in 103 patients (20%). All the infections were treated by specific antibiotic therapy. Mean operative time was 67 minutes (range: 17-172); 351 (61.4%) patients underwent RIRS under spinal anesthesia, while 220 (38.5%) patients were operated under general anesthesia. The median period between intervention and JJ stent removal was 7 days (Interquartile range

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Table 2. Stone composition to spectrophotometric analysis. Stone composition. no. (%) Calcium oxalate monohydrate Calcium oxalate dihydrate Uric acid Mixed Calcium oxalate and phosphate Calcium oxalate and uric acid Carbapatite Brushite Urate ammonium Cystine Struvite Various types

Value 194 (37.7%) 102 (19.8%) 88 (17.1%) 87 (16.9%) (68) (19) 17 (3.3%) 4 (0.7%) 6 (1.1%) 4 (0.7%) 2 (0.3%) 10 (1.9%)

Stone free rate and complications of RIRS

Table 3. Clinical complications following RIRS classified according to Clavien-Dindo Grading System. Clavien-Dindo Grade System Grade I

N° of patients 12

Grade II

Grade III a

Grade III b Grade IV a

– Eight patients complained severe pain and/or urinary urgency probably as a double J related side effect.

Description

Treatment

11 nausea and vomiting 1 cefalea 12 urosepsis 2 haematuria 3 urosepsis with double J displacement 1 subcapsular renal haematoma (SRH) associated with pulmonary embolism Multiple subcapsular haematoma

Anti-emetics and supportive care Antibiotic therapy Bladder irrigation and prolonged catheterization Antibiotic therapy + double J substitution Selective artery embolisation + inferior vena cava filter and anticoagulation therapy Urgent left nephrectomy

Table 4. Setting laser. Energy (Joule) Frequency (Hertz) 30W Ho:YAG laser system Sphinx® Jr (LISA laser) Fragmentation 0,8/1J 10/15 Hz Dusting 0,5/0,8 J 18/20 Hz Pop corn 0,8/1J 15/18 Hz 120-W high-power Ho:YAG laser system (Lumenis®) Fragmentation 1J/1,5 J 25/30 Hz Dusting 0,2/0,5 J 50/70 Hz Pop-dusting 0,5 J 80 Hz 30 W Ho:YAG laser Medilas H Solvo (Dornier, Olympus®) Fragmentation 0,8/1J 10/15 Hz Dusting 0,5/0,8 J 18/20 Hz Pop corn 0,8/1J 15/18 Hz

Pulse width

DISCUSSION

In the last years, RIRS has become increasingly popular and probably the more common procedure for kidney stones up to 2 cm (7); the high SFR with minimal invasiveness and the outpatient setting have been pointed out as specific benefits by several authors (8, 9). Standard success rates range between 65% and 92%. In our study SFR was 86% with a mean operative time of 72 minutes.

Figure 1. Subcapsular hematoma (SRH) of left kidney (a: CT axial evaluation) (b: CT coronal evaluation). a. b.

Short pulse (300 μs) Long pulse (650 μs) Short pulse (450 μs) Long Pulse (650 μs) Long Pulse (1000 μs) Short Pulse (300 μs) -

– one patient (0.1%) had a cerebrospinal fluid leak after spinal anesthesia causing headache (CD Grade I) treated with bed rest and paracetamol/caffeine; – eleven patients (1.9%) had post-operative nausea and vomiting requiring specific therapy; – fifteen patients (2.6%), developed urosepsis, defined as clinical signs of bacterial infections with positive blood culture (CD Grade II-IIIA). Among them, twelve (2.8%) required antibiotic therapy (CD Grade II), while in three (0,5%) double J was replaced due to concomitant hydronephrosis with double J displacement (CD Grade IIIA); – two patients (0.3%) on antiplatelet therapy had postoperative hematuria which required bladder irrigation and prolonged catheterization (CD Grade II). – two patients had hemorrhagic events (0.3%) at the second look of complex multiple kidney stones: 1) Subcapsular hematoma (SRH) associated with pulmonary embolism two days after the procedure (CD Grade IIIa). Treatments consisted in two blood unit transfusion and angiography, which did not show any blood spill. Inferior vena cava filter was placed and anticoagulant therapy was continued for 6 months. 6 months follow up CT scan shows a complete reabsorption of the hematoma (Figure 1). 2) Hemorrhagic shock 2 hour after RIRS due to massive renal bleeding (CD Grade IVa) (Figure 2). CT scan and angiography showed multiple renal bleedings requiring urgent nephrectomy;

Figure 2. Kidney hematoma with multiple renal bleedings following RIRS. a: multiple stones of left kidney (preoperative CT evaluation); b: hematoma of left kidney (CT ev-aluation); c: rupture of left kidney (CT evaluation); d: kidney specimen. a.

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These results are comparable to the main previous literature (10-12). Even if RIRS is generally considered a safe procedure, a wide spectrum of intra and mostly post-operative severe events must be considered. Literature is weak about detailed analysis of complications even if some reports deal with serious and life threatening complications. Cindolo et al. in 2016 (13) in a multi-institutional study reporting fatal cases after RIRS, highlighted how this “safe” procedure hides potentially dramatic and fatal complications and the need of a careful post-operative patient monitoring: four patients died for septic complications, one for a cardiac event and one due to hemorrhagic complication. Cindolo et al. (14) evaluated life-threatening complications after ureteroscopy for lithiasis, reporting 12 cases of serious complications requiring urgent treatment and even one fatal case. Ureteral injury is the most common intraoperative complication; beneficial effects and convenience of using access sheaths have been debated. UAS main purpose is to facilitate reentries into renal collecting system, theoretically reducing possible injuries to ureter and urethra. In recent studies, the routine intraoperative use of UAS during RIRS was recommended because it decreases duration of the interventions, with a minimal morbidity associated (14, 15). In our series, we used ureteral access sheaths for nearly all patients, recording two significant ureteral damage correlated to UAS (16). Proper management of such complications is crucial to avoid further short- and long- term complications. The urinary tract infection is the most common event (228% of the cases) (17); in our study, 15 (2.6%) patients experienced these clinical complications; all the cases required specific antibiotic therapy with no need of intensive care support (CD II and IIIa). Double J displacement, noted in three patients, could have been the reason of post-operative infection. We suggest to check its position by X ray in case of infection, especially when antibiotic therapies are not effective. Bleeding and renal rupture are less frequent but could lead to serious consequences. In our series two patients had serious hemorrhagic complications; subcapsular hematoma after RIRS is rarely described in the literature and its etiology is not perfectly known (18). Various authors have tried to understand what is the cause of subcapsular renal hematoma: increase intrarenal pressure leading to rupture of the fornix and separation of the capsule from the parenchyma, urinary infection and infiltration of leukocytes into the parenchyma which can be damaged by irrigation, laser and guide wires (1922). The sudden expansion and rupture of renal parenchyma is probably the most likely explanation of our cases. Chronic hydronephrosis was present in our two haemorrhagic cases; sudden increase in intrarenal pressure was showed to cause twisting, stretching and /or obstruction of the main intrarenal vessels (23). It is remarkable that retrograde pyelogram performed at the end of the procedure didn’t show any leak or renal absorption of contrast dye; clinical complications were suspected for an uncontrolled renal pain, hypotension and hemoglobin drop. In conclusion, RIRS should be considered an effective

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and safe procedure in the treatment of renal stones, but a wide spectrum of complications must be considered. Even if rare, complications could lead to life-threatening conditions requiring quick diagnosis and prompt treatment. Intraoperative signs of possible post-operative complications may be missing and a careful monitoring is crucial to recognize these events as early as possible.

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17. De S, Autorino R, Kim FJ, et al. Percutaneous nephrolithotomy versus retrograde intrarenal surgery: a systematic review and metaanalysis. Eur Urol. 2015; 67:125-37. 18. Bai J, Li C, Wang S, et al. Subcapsular renal haematoma after holmium:yttrium-aluminum-garnet laser ureterolithotripsy. BJU Int. 2012; 109:1230-41. 19. Tao W, Cai CJ, Sun CY, et al. Subcapsularrenal hematoma after ureteroscopy with holmium:yttrium-aluminum-garnet laser lithotripsy. Lasers Med Sci. 2015; 30:1527-32. 20. Hyams ES, Munver R, Bird VG, et al. Flexible ureterorenoscopy and holmium laser lithotripsy for the management of renal stone bur-

den\s that measure 2 to 3 cm: a multi-institutional experience. J Endourol. 2010; 24:1583-88. 21. Riley JM, Stearman L, Troxel S. Retrograde ureteroscopy for renal stones larger than 2.5 cm. J Endourol. 2009; 23:1395-98. 22. Di Mauro D, La Rosa VL, Cimino S, Di Grazia E. Clinical and psychological outcomes of patients undergoing Retrograde Intrarenal Surgery and Miniaturised Percutaneous Nephrolithotomy for kidney stones. A preliminary study. Arch Ital Urol Androl. 2020; 91:256260. 23. Nuttall MC, Abbaraju J, Dickinson IK, et al. A review of studies reporting on complications of upper urinary tract stone ablation using the holmium:YAG laser. Br J Med Surg Urol. 2010; 3:151-59.

Correspondence Orazio Maugeri, MD (Corresponding Author) omaugeri@gmail.com Bonaccorsi Astrid, MD Pietro Pepe, MD piepepe@hotmail.com D’Arrigo Letterio, MD Michele Pennisi, MD Urology Unit - Cannizzaro Hospital, Via Messina 829, Catania (Italy) Dalmasso Etttore, MD Peretti Dario, MD Venzano Fabio, MD Chiapello Germano, MD Ambruosi Carlo, MD Dadone Claudio, MD Urology Unit - S. Croce and Carle Hospital, Cuneo, (Italy)

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DOI: 10.4081/aiua.2021.3.318

ORIGINAL PAPER

Do we have a limit for retrograde intrarenal surgery for solitary kidney stone? Bulent Kati, Eyyup Sabri Pelit, Mehmet Demir, Ismail Yagmur, Adem Tuncekin, Halil Ciftci Harran University, Faculty of Medicine, Urology Department, Sanliurfa, Turkey.

Summary

Objective: The management of urolithiasis in patients with a solitary kidney is challenging for urologists. This study aimed to evaluate the safety of retrograde intrarenal surgery (RIRS) in the treatment of stones in patients with solitary kidney and to reply to the question if there is any limit for this surgery. Methods: Between January 2016 and December 2019, we enrolled 52 patients who had a solitary kidney and underwent RIRS. We collected data on preoperative patient characteristics, stone dimensions, and postoperative outcomes. Stone size, duration of operation, duration of fluoroscopy, type of anesthesia, and degree of surgical complication were evaluated retrospectively. Surgeries performed in less and more than 60 minutes and with and without complications were compared. Results: A total of 52 patients with a kidney stone and a solitary kidney were evaluated. The mean stone size was 14 ± 0.4 cm and surgical success rate was 87.3%. In our study, 13 patients (24.5%) had grade 1 minor complications, and none required a blood transfusion. The mean operation time was 51.9 ± 17.3 minutes. The postoperative creatinine value increased in 6 patients. The duration of operation in the group with complications was significantly higher than that in the group without complications. In patients who underwent an operation lasting ≥ 60 minutes, stone size, fluoroscopy time, and complication rate were significantly higher than in patients who underwent an operation lasting ≤ 60 minutes. Conclusion: Our opinion is to be careful in patients with a solitary kidney with a big stone and we recommend assigning these procedure to experienced hands for not exceeding 60 minutes in one session.

KEY WORDS: Renal stone; Ureteroscopy; Retrograde intrarenal surgery; Complication; Solitary kidney. Submitted 3 June 2021; Accepted 27 June 2021

INTRODUCTION

Due to recent advances in endourology, increases have been made in the success of surgical treatment of kidney stones as well as of the variety of complications that may develop. Minimally invasive surgery for kidney stones is particularly important for patients with renal failure or with solitary kidney. Extracorporeal shock wave lithotripsy (ESWL) treatment is a minimally invasive option that is frequently applicable due to its safety and success rate (1). However, since complications that may develop after ESWL in patients with solitary kidney may be more severe and require urgent intervention, ESWL is far from being

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No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

the first option in such patients without pre-stenting (2). In recent years, the advent of medical engineering has increased the suitability of surgical instruments used for the urinary system. In general, retrograde intrarenal surgery (RIRS) has been performed successfully and safely in patients with kidney stones (3). In patients undergoing RIRS, minor and major complications may occur due to the operator’s surgical experience, the patients’ unique situations and technical equipment. Complications can be treated palliatively but in patients with solitary kidneys, they should be considered more serious (4-5), although many studies have suggested that this surgery can be performed safely in solitary kidneys (6-7). We collected data to evaluate surgical outcomes and to identify limits of RIRS for safe treatment of these patients.

MATERIALS

AND METHODS

This study was approved by the local ethics committee at our university. We retrospectively reviewed 52 patients with solitary kidneys who were treated with RIRS for renal stones between January 2016 and December 2019 including patients who were older than 18 years of age and were without any additional chronic diseases. The pre-operative urine cultures of all patients were confirmed to be negative. The stone burden was assessed by obtaining the stone’s length, which was calculated according to the European Association of Urology guidelines. The RIRS procedures were performed by the same surgical team using a 9.5 F access sheath and the same flexible ureteroscope (Karl Storz™ Germany). A double J stent was used in patients who were unable to have an access sheath inserted and the surgery was postponed for 3-4 weeks later. The stones were broken using a Holmium YAG laser device (Sphinx Xjr™, Germany) with a force of 6-18 Kw. The anaesthesia type was evaluated in conjunction with the anaesthesiologist who performed high spinal or general anaesthesia according to the condition of the patient. Serum creatinine levels were evaluated preoperatively, at one day postoperatively and at one-week follow-up. Any surgical complications in the patients were assessed using a modified Satava Classification System (SCS). The stone sizes, duration of operation, duration of fluoroscopy, type of anaesthesia, and degree of surgical complications were evaluated retrospectively. Operations performed in less or more than 60 minutes were compared to set a time limit for risk of complication.

RIRS for solitary kidney stones

Statistical analysis Mean, standard deviation, median, range, frequency and ratio values were used in the descriptive statistics of the data. The distribution of the variables was measured with the Kolmogorov-Smirnov test. An independent sample ttest and the Mann-Whitney U test were used to analyse the quantitative independent data. In the analysis of dependent quantitative data, the Wilcoxon test was used. A chi-square test was used to analyse the qualitative independent data. For the data analysis, the Statistical Package for the Social Sciences (SPSS), version 22.0, was used.

RESULTS

Table 1. General characteristics of patients with solitary kidney stones. Age Gender Side

Min-max Median 3.0 - 84.0 45.5 Female Male Right Left

Kidney stone size (cm) Operation time (min.) Anesthesia Type < 60 ≥ 60 Floroscopy time (sec.) Anesthesia Type General Spinal Complication (-) (+) Minor complication (grade 1) Major complication (> grade 1) Pre-op serume creatinine (mg/dL) Post-op serume creatinine (mg/dL) Creatinine difference (mg/dL)

0.8 - 2.2 15.0 - 90.0

1.3 50.0

5.0 - 95.0

45.0

Fifty-two stone patients with solitary kidney were evaluated before and after surgery (Table 1). The solitary kidneys were congenital in 15 cases (28.3%), caused by a previous contralateral nephrectomy in 21 cases (39.6%) and caused by a non-functioning con0.70 ± 3.00 tralateral unit in 16 cases (32.1%). The postoperative fol0.40 - 8.20 low-up period was approximately 3 months. -1..50 - 6.60 Our surgical success rate was 87.3%. Residual stones less than 4 mm were considered clinically insignificant and were evaluated by non-contrast computerized tomography (CT) after postoperative double J stent extraction. Double J stents were removed after an average of 25 ± 7.3 days in patients without additional intervention. Stone location was the lower pole of the kidney in 22 (42.3%) patients, lower pole and pelvis or middle pole in 16 (30%) patients, renal pelvis in 10 patients and upper pole in 4 patients. Mean age, sex and kidney side distribution and mean stone size in patients with and without complications did not differ significantly (p > 0.05) (Table 2). The duration of surgical time in the group with complications was significantly higher than in the group without complications (p < 0.05). There was no significant difference in the duration of fluoroscopy time in the group with and without complications. There was no significant difference (p > 0.05) of anaesthesia type in the group with and without complications (Table 2). The preoperative creatinine value was not significantly different (p > 0.05) in Figure 2. patients with or without any compliRelationship between operation time and complications. cations. In the group with complications, the postoperative increase of serum creatinine was higher than the value recorded in the group without complications (p < 0.05) (Table 2). Mean age and sex, anaesthesia type and kidney side distribution of the patients were not significantly different between the groups in terms of operation time (p < 0.05). In the group with operation time ≥ 60 min groups, stone size (Figure 1), duration of fluoroscopy time and any complication rate (Figure 2) were significantly higher than in the group with operation time was ≤ 60 min (p < 0.05) (Table 3).

1.20 1.00 -0.10

Mean + s.d./n-% 45.3 ± 17.9 22 42.3% 30 57.7% 25 48.1% 27 51.9% 1.4 ± 0.4 50.1 ± 17.3 33 63.5% 19 36.5% 42.0 21.8 15 28.8% 37 71.2% 40 76.9% 12 23.1% 1.1 21.2% 2 3.8% 1.28 ± 0.55 1.47 ± 1.54 0.19 ± 1.55

Figure 1. Relationship between stone size and operation time.

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B. Kati, E. Sabri Pelit, M. Demir, I. Yagmur, A. Tuncekin, H. Ciftci

Table 2. Comparison of patients with complications (minor or major) and without complications after RIRS.

Age Gender Side

Female Male Right Left

Stone size (cm) Operation time (min.) Süresi Dk Floroscopy time (min.) Anesthesia Type General Spinal Serum creatinine (mg/dL) Pre-op Post-op Preop-postop difference In-group difference (p)

Complication (-) Mean ± s.s./n-% Median 45.8 ± 18.9 45.5 16 42.4% 24 57.6% 19 54.5% 21 45.5% 1.3 ± 0.4 1.1 46.8 ± 15.1 45.0 39.3 ± 20.8 40.0 11 27.5% 29 72.5% 1.23 ± 0.44 1.03 ± 0.43 -0.20 ± 0.61 0.052 w

t: t test; m: Mann-Whitney u test; X2: Chi-square

Complication (+) Mean ± s.s./n-% Median 43.8 ± 14.7 45.5 6 50.0% 6 50.0% 6 50.0% 6 50.0% 1.6 ± 0.4 1.5 61.3 ± 19.4 60.0 51.1 ± 23.4 52.5 4 33.3% 8 66.7%

1.20 0.90 -0.10

1.42 ± 0.83 2.93 ± 2.72 1.52 ± 2.70 0.109 w

1.15 2.05 0.40

test; w: Wilcoxon test

Table 3. Comparison of RIRS cases above and below 60 minutes of operation time.

Age Gender Side

Female Male Right Left

Stone size (cm) Fluoroscopy time (min.) Anesthesia Type General Spinal Complication (-) (+) Minor complication Major complication Serum creatinine (mg/dL) Pre-op Post-op Preop-postop difference In-group difference (p)

Operation time < 60 min. Operation time ≥ 60 min. Mean ± s.s./n-% Median Mean ± s.s./n-% Median 44.8 ± 17.8 41.0 46.2 ± 18.6 52.0 14 42.4% 8 42.1% 19 57.6% 11 57.9% 18 54.5% 7 36.8% 15 45.5% 12 63.2% 1.2 ± 0.4 1.0 1.6 ± 0.4 1.8 31.4 ± 15.1 30.0 60.4 ± 19.4 60.0 7 21.2% 8 42.1% 26 78.8% 11 57.9% 29 87.9% 11 57.9% 4 12.1% 8 42.1% 3 9.1% 8 42.1% 1 3.0% 1 5.3%

t: t test; m: Mann-Whitney u test; X2: Chi-square

1.2 ± 0.5 1.2 ± 1.0 0.0 ± 1.2 0.201 w

1.2 0.9 0.1

1.3 ± 0.6 1.9 ± 2.1 -0.5 ± 2.0 0.950 w

1.3 1.0 0.0

test; w: Wilcoxon test

DISCUSSION

Flexibility and thinning of endoscopic instrumentation have increased day by day for making more comfortable diagnosis and treatment of the urinary system. Innovations in technology allowed improvement of ureteroscope design, surgical technique, and accessory instrumentation (8). Although less invasive procedures have been developed for the treatment of kidney stones, the first procedure to be considered for certain types of stones is extracorporeal shock wave lithotripsy (ESWL), whose use is controversial

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in patients with solitary kidneys. In fact, even if it is not invasive, ESWL is characterized by the risk of complications that may affect renal function and may be risky in patients with solitary kidneys due to a lack of funcP tional compensation by the contralateral kidt 0.735 ney. Ureteral obstruction by residual stone X2 0.539 fragments (steinstrasse), urinary tract infection and sepsis, asymptomatic renal hematoma, 0.879 X2 kidney nephron losses, may vary between 610% in total and may be a more important 0.099 m risk for patients with solitary kidneys (9). t 0.010 While percutaneous nephrolithotomy (PCNL) is 0.100 t the first surgical option that can be consid0.696 X2 ered for kidney stones larger than 2 cm, RIRS is more preferred in patients with solitary kidney stones to prevent organ loss and greater 0.810 m risk of complications. In recent studies, com0.005 m plications like those of RIRS are described for m 0.014 miniaturized PCNL, which can be used instead of standard PCNL (10). RIRS is an increasingly common and widely preferred procedure because of its high success rate for 1-3 cm kidney stones and its low complication rates (11-12). However, some minor complications, such as haematuria, hydronephrosis, ureteral obstruction by stone fragments and ureteral double J stent dislocation, might be not significant in a P patient with two functional kidneys but could t 0.798 be more important for patients with solitary X2 0.982 kidneys requiring urgent intervention. Concern about the risk of renal dysfunction X2 0.219 and subcapsular hematoma associated with the use of high-pressure irrigation during m 0.003 RIRS has been raised (13). t 0.000 Animal studies have shown that high-pressure 0.109 X2 irrigation (> 150 mmHg) during ureterorenoscopy without a renal access X2 0.013 sheath can lead to parenchymal damage and focal injury of the kidney (14). Therefore, this 0.005 X2 risk should be taken into consideration espe0.687 X2 cially in patients with solitary kidney and renal access sheath should be used (15). Even if the m 0.723 success rate in the operations does not change, 0.264 m the use of urethral sheath is recommended, if m 0.381 possible, because it keeps the intrarenal pressure low during the procedure and reduces the risk of post-operative infection (16). We used a 9.5 F renal access sheath in all patients without pre-stenting. It has been shown that inserting a DJ stent before surgery does not affect complication or success (17, 18). Performing RIRS should be more careful in patients with a solitary kidney stone. The application of access sheaths and use of laser should not harm the kidney or ureter and at the end of the procedure, it should be checked DJ stent correct placement (3, 7). In our study surgery in solitary kidney was performed by experienced surgeons. The mean stone size was 14 ± 0.4 cm, surgical success was 87.3% and 4 patients (7.5%) had residual stones of

RIRS for solitary kidney stones

more than 4 mm. After all the procedures, DJ stents were applied and checked and left for the second session. Classification systems have been proposed over time for grading complications that can develop during and after RIRS. We assessed complications using a modification of Satava Classification System (SCS) (19). Ural et al. reported nearly 32% grade 1 intraoperative complications after RIRS according to modified SCS. Grade 1 complications included minimal haematuria, ureteral mucosal surface damage, and difficulties in reaching the stone (20). Kuroda et al. reported a rate of minor complication about 5% in a study comparing RIRS performed in solitary kidneys and normal patients (14). Atis et al. reported a rate of minor complications of 16.6% with no major complications and no need of blood transfusions (6). In our study, 11 patients (20.5%) had grade 1 minor complications (most of them mild haematuria that was observed in 8 patients) and no one needed for blood transfusion. DJ stent migration is especially troublesome in postoperative follow-up of patients with solitary kidney. Although DJ stents are known to cause post-operative irritating symptoms, they should be applied after RIRS especially in patients with solitary kidneys (21). Accordingly, we applied DJ stents to all patients at the end of the procedure. Grade 3-4 complications after RIRS can threaten the health of patients. Although they are rare in the literature, deficit of post-operative follow-up and patient unconsciousness can increase the importance of these complications (22, 23). Two of our patients developed postoperative high serum creatinine and oliguriaanuria after discharge. The first patient did not receive enough post-operative hydration causing a reduced urine output until oliguria developed. On postoperative day 4th, urine output and serum creatinine levels returned to normal with appropriate hydration. The other patient presented with anuria on the 5th postoperative day. He reported that his urine output had decreased and ceased for the last two days. Despite appropriate hydration, urine output did not increase, and serum creatinine values increased to around 8.9 mg/dl. The patient was urgently operated: after DJ stent removal, ureteroscopy demonstrated a dust of fragments adherent along the ureter, ureter was cleaned, and a new 6 F DJ stent was placed. Although postoperative urine output increased, serum creatine values did not fall below 4.3 mg/dl. After the consultation of the nephrology department, it was decided to enter in a dialysis program with the diagnosis of chronic renal failure. Although major complications after RIRS are not common in the literature, poor socioeconomic conditions can affect the post-operative recovery of the patients (3-7). It has been reported that patients with solitary kidney have very low complication rates compared to percutaneous nephrolithotomy (PCNL) (11, 22). RIRS has been considered a better alternative to PCNL surgery because of similar surgical success, but less blood loss and hospital stay (24). When we evaluated our patients, we observed that minor and major surgical complications increased significantly after surgery of stone greater than 20 mm and when surgery time was more than 60 minutes. (Table 3) Although

RIRS appears to be safe and successful in patients with solitary kidneys, the prolongation of surgery may lead to an increase of postoperative complications. We set the 60-minute limit although this limit can be influenced by the characteristics of the patient, of the stone and of the surgical procedure. Patients with solitary kidneys should be well informed and followed up before and after surgery. When evaluating a patient, attention should be paid to the size of the stone and therefore to the risk of increased surgical time. For cases that are thought to exceed one hour, we recommend leaving a DJ stent for a second session.

REFERENCES

1. El-Assmy A, El-Nahas AR, Hekal IA, et al. Long-term effects of extracorporeal shock wave lithotripsy on renal function: our experience with 156 patients with solitary kidney. J Urol. 2008; 179:2229-32. 2. Ruiz Marcellan FJ , Ibarz Servio L, et al. Treatment of lithiasis in the patient with a solitary kidney Eur Urol. 1988; 15:13-7. 3. Bas O, Tuygun C, Dede O, et al. Factors affecting complication rates of retrograde flexible ureterorenoscopy: analysis of 1571 procedures-a single-center experience. World J Urol. 2017; 35:819-826. 4. Gao X, Peng Y, Shi X, et al. Safety and efficacy of retrograde intrarenal surgery for renal stones in patients with a solitary kidney: a single-center experience. J Endourol. 2014; 28:1290-4. 5. Breda A, Oreoluwa O, John T, et al. Flexible ureteroscopy and laser lithotripsy for multiple unilateral intrarenal stones Eur Urol. 2009; 55:1190-6. 6. Atis G, Gurbuz C, Arikan O, Kilic M, et al. Retrograde intrarenal surgery for the treatment of renal stones in patients with a solitary kidney. Urology. 2013; 82:290-4. 7. Giusti G, Proietti S, Cindolo L, et al. Is retrograde intrarenal surgery a viable treatment option for renal stones in patients with solitary kidney? World J Urol. 2015; 33:309-14. 8. Holden T, Pedro RN, Hendlin K, et al. Evidence-based instrumentation for flexible ureteroscopy: a review J Endourol. 2008; 22:1423-6. 9. Wagenius M, Jakobsson J, Stranne J, Linder A. Complications in extracorporeal shockwave lithotripsy: a cohort study. Scand J Urol. 2017; 51:407-413. 10. Di Mauro D, La Rosa VL, Cimino S, et al. Clinical and psychological outcomes of patients undergoing Retrograde Intrarenal Surgery and Miniaturised Percutaneous Nephrolithotomy for kidney stones. A preliminary study. Arch Ital Urol Androl. 2020; 91:256-260. 11. Zhang Y, Wu Y, Li J, et al. Comparison of percutaneous nephrolithotomy and retrograde intrarenal surgery for the treatment of lower calyceal calculi of 2-3 cm in patients with solitary kidney. Urology. 2018; 115:65-70. 12. Aboumarzouk OM, Monga M, Kata SG, et al. Flexible ureteroscopy and laser lithotripsy for stones > 2 cm: a systematic review and meta-analysis J Endourol. 2012; 26:1257-63. 13. De Rose AF, Di Grazia E, Magnano San Lio V, et al. Complications of endourological procedures and their treatment. Arch Ital Urol Androl. 2020; 92:321-325. 14. Schwalb DM, Eshghi M, Davidian M, et al. Morphological and physiological changes in the urinary tract associated with ureteral dilation and ureteropyeloscopy: an experimental study. J Urol. 1993; 149:1576-85. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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15. Breda A, Territo A, López-Martínez JM. Benefits and risks of ureteral access sheaths for retrograde renal access Curr Opin Urol. 2016; 26:70-5. 16. Kuroda S, Fujikawa A, Tabei T, et al. Retrograde intrarenal surgery for urinary stone disease in patients with solitary kidney: A retrospective analysis of the efficacy and safety. Int J Urol. 2016; 23:69-73.

21. Somani BK, Giusti G, Sun Y, et al. Complications associated with ureterorenoscopy (URS) related to treatment of urolithiasis: the Clinical Research Office of Endourological Society URS Global Study World J Urol. 2017; 35:675-681.

17. Shvero A, Herzberg H, Zilberman D, et al. Is it safe to use a ureteral access sheath in an unstented ureter? BMC Urol. 2019;19:80.

22. Cindolo L, Castellan P, Primiceri G, et al. Life-threatening complications after ureteroscopy for urinary stones: survey and systematic literature review Minerva Urol Nefrol. 2017; 69:421-431.

18. Karaaslan M, Tonyali S, Yilmaz M, et al. Ureteral access sheath use in retrograde intrarenal surgery. Arch Ital Urol Androl. 2019; 91:112-114.

23. Adanur S, Aydin HR, Mohamed O, et al. Retrograde intrarenal surgey versus percutaneous nephrolithotomy in patients with significant comorbidities and solitary kidney Urolithiasis. 2015; 43:385-386.

19. Tepeler A, Resorlu B, Sahin T, et al. Categorization of intraoperative ureteroscopy complications using modified Satava classification system World J Urol. 2014; 32:131-6.

24. Lianchao J, Bing Y, Zhe Z, Ningchen Li. Comparative efficacy on flexible ureteroscopy lithotripsy and miniaturized percutaneous nephrolithotomy for the treatment of medium-sized lower-pole renal calculi J Endourol. 2019; 33:914-919.

20. Oguz U, Resorlu B, Ozyuvali E, et al. Categorizing intraopera-

Correspondence Bulent Kati, MD, Associate Prof. (Corresponding Author) bulentkati@harran.edu.tr Eyyup Sabri Pelit, MD dreyyupsabri@hotmail.com Mehmet Demir, MD drdemir02@gmail.com Ismail Yagmur, MD dr_iyagmur@hotmail.com Adem Tuncekin, MD dr_adem65@hotmail.com Halil Ciftci, MD halilciftci63@hotmail.com Harran University, Faculty of Medicine Hospital, Urology, 63340 Sanliurfa (Turkey) Osmanbey Kampusu Urology Bolumu 63320 Sanliurfa (Turkey)

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tive complications of retrograde intrarenal surgery. Urol Int. 2014; 92:164-8.

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ORIGINAL PAPER

Predicting negative ureteroscopy for stone disease – Minimizing risk and cost Miguel Eliseu, Roberto Jarimba, Pedro Moreira, Pedro Simões, Paulo Temido, Arnaldo Figueiredo Urology and Renal Transplantation Department, Coimbra Hospital and University Center, Coimbra, Portugal.

Summary

Introduction: Urolithiasis is common worldwide, with ureteric stones being a particular burden. Ureteroscopy (URS) is one of the most useful procedures in treating ureteric stones not passed spontaneously; this procedure has a complication risk of 4%. Negative URS, with described rates up to 15%, represents an avoidable patient risk and use of medical resources. Objectives: To describe rates and identify predictive factors for negative URS and to define strategies which would minimize patient and financial burden from these unnecessary procedures. Materials and methods: A retrospective cohort study analyzed patients who underwent URS in our Center to treat ureteric stones over a period of 2 years. Patient age, gender, and comorbidities, as well as laboratory and imaging findings, were analyzed. Results: 262 patients underwent URS for ureteric stones. The female population was 50.8% with a mean age of 56.89 years. A total of 78 (29.8%) URS procedures were negative. Univariate analysis showed a higher prevalence of negative URS in female patients, as well as in primary, smaller, and radiolucent stones. At multivariate analysis, a logistic regression model correctly classified 76% of patients, with smaller stone size and radiolucency being significant predictors of negative URS. Discussion and conclusions: Our Center showed a high rate of negative URS, higher than commonly described in the literature. Female patients tend to have an even higher rate, possibly due to unnoticed passage of stones. Patients with small, radiolucent stones showed the highest rates of negative URS.

KEY WORDS: Urolithiasis; Ureteric; Stone; Ureteroscopy; Negative. Submitted 2 January 2021; Accepted 2 July 2021

INTRODUCTION

Urolithiasis is very common worldwide, with prevalence rates described in general population of 1-20% (1-4); countries with high standard of life show increasing rates over the past decades, with over 10% reported prevalence (5-7). Ureteric stones pose a particular burden with frequent need of emergency visits and possible need for admittance and invasive procedures (7, 8). Ureteroscopy (URS) is one of the most useful methods for treating ureteric stones not passed spontaneously (4, 10, 11). This procedure is generally considered safe, involving a complication risk of 4%, with many being performed in an outpatient basis (12-14). A mean overall cost of $2801 per procedure has been described in a systematic review (13).

When a patient is offered a URS for a ureteric stone, the possibility of spontaneous expulsion still exists before the procedure, eventually unnoticed by the patient. If no other measures are taken to detect persistence of stones before surgery, a “stoneless” or “negative” procedure (hence, unnecessary) would be performed (14). Negative URS, with described rates up to 15%, represents a avoidable patient risk and use of medical resources (15-18). Predicting negative URS preoperatively and cancelling the procedure would prevent this unnecessary burden (14). Several factors predicting negative URS have been studied. Smaller stone size is associated with increased probability of unnoticed expulsion and negative URS (15, 17); other reported factors include distal stone positioning (17) and female gender (15, 16). Time since last imaging study does not appear to influence stoneless procedure rates (17). Other potential influencing factors showed varying results (15-18). The objective of this paper is to describe rates and identify predictive factors of negative URS and to define strategies which would minimize patient and financial burden of these unnecessary procedures.

MATERIALS

AND METHODS

A retrospective cohort study analyzed all patients who underwent URS in our Center over a period of 2 years. Only procedures to treat ureteric stones were included; all were performed in the same Center, with similar surgical equipment. Several factors were reviewed, including patient age, gender and comorbidities, previous procedures, as well as clinical, laboratory and imaging findings. To comply with the purpose of the study, patients with negative URS were identified, and a potential correlation with the above-mentioned factors was investigated. Patients who had negative URS were followed with ultrasound or computerised tomography (CT), and those with presence of stone suspected of retrograde migration were not included; patients in which complete URS was not feasible were also not included. Statistical analysis was performed using SPSS 23®, including univariate Mann-Whitney and KruskalWallis tests, and a multivariate logistic regression model.

RESULTS

During the defined period, 262 patients underwent URS as planned treatment for ureteric stones while meeting the selection criteria. The population was 50.8% female,

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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Table 1. Patient/stone characteristics and acute episode clinical variables; frequencies represented in percentage of valid results and absolute number of cases excluding missing values in brackets. Patient and stone characteristics Sex

Female Male Age in years 20-34 35-49 50-64 65-80 80 or more Number of episodes *1 Primary Recurrent disease Stone anatomical location Upper ureter Mid-ureter Lower ureter Radiopacity *2 Radiopaque Radiolucent Medical expulsive therapy Alfa-blockers Corticosteroids Perc. nephrostomy in acute episode (performed) JJ stenting in acute episode (performed)

Frequency in valid % (n) excluding missing 50.8% (133) 49.2% (129) 7.3% (19) 22.9% (60) 37% (97) 24.4% (64) 8.4% (22) 81.5% (203) 18.5% (46) 22.0% (52) 23.7%(56) 54.3% (128) 86.3% (202) 13.7% (32) 53.8% (141) 11.5% (30) 11.8% (30) 57.5% (146)

*1 missing value in 12 cases with dubious history of stones (patient unsure and no previous imaging available);

*2 based on KUB; missing value in 26 cases that did not undergo KUB and 2 cases for which KUB was not available to

the authors (from other institutions).

with a mean age of 56.89 years (SD +/- 15.705 years). Patients had a mean stone size of 7.7 mm (SD +/- mm); 47.8% of patients had stones between 5 and 9 mm. According to pre-procedure imaging, the lower ureter was the most common stone location (54.3%), followed by mid (23.7%) and upper ureter (22%). Approximately 86.3% of stones studied were radiopaque on plain X ray of Kidney-Ureter-Bladder (KUB). Regarding imaging techniques applied at initial diagnosis, renal ultrasound was most used (99.2% of patients); KUB X-ray was performed in 90.2% of cases and CT in 78.6%. Stenting in the acute setting was performed at physician discretion, with Center policy including best practice guidelines; stenting was performed in cases with associated infection, compromised renal function or long-standing pain (over 14 days) irrespective of planned URS or not. A significant proportion of patients underwent ureteric stenting in the acute setting (57.5%; n = 146); of those proposed to URS after stenting, 67.8% (n = 99) underwent KUB, 15.1% (n = 22) underwent CT, with 2.7% (n = 4) having both exams; 29 patients (19.9%) had no imaging between stenting and surgery. Cases where no evidence of stones was found were not considered for URS. The mean time between the acute episode and subsequent URS was 61.8 days (+/- 27.076). In patients who underwent stenting prior to URS, mean time from stenting to surgery was 65.3 days (+/- 28.278). Patient and stone characteristics are displayed in Table 1. A total of 78 URS procedures were negative for stones, representing 29.8%. Several factors were investigated in univariate analysis, which showed a higher prevalence of negative URS in female patients (p = 0.023), as well as in primary (p = 0.001), smaller (p = 0.010), and radiolucent stones (p = 0.035). These results are displayed in Table 2.

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Several other factors were analyzed, but not found to be predictors of negative URS (Table 3). Namely, anatomical stone position (p = 0.646), mean time between the acute episode and subsequent URS (p = 0.207) and mean time from stenting to surgery (p = 0.614) did not appear to influence the risk of negative ureteroscopy. There was also no significant difference between patients who did or did not undergo CT scan (negative URS rates of 28.6% vs 33.9%, p = 0.139). At multivariate analysis, a logistic regression model correctly classified 76% of patients, with smaller stone size (p = 0.026) and radiolucency (p = 0.011) being significant predictors of negative URS, and accounting for 47.7% of the variance. Each mm increase in stone size, showed an impact on OR for negative URS of 0.815 (expB=-0.204), while radiopaque stones showed an OR Table 2. Significant variables in univariate analysis with respective rates of negative URS in each subgroup and corresponding p values. Negative URS was more common in females, primary cases, small and radiolucent stones. Clinical Variables Primary Recurrence Female Male 0-4.9 mm 5-9.9 mm 10 mm or more Radiopaque Radiolucent

% negative URS 32.5% 8.7% 36.1% 23.3% 56.3% 33.7% 15.5 % 19.8% 43.8%

p value < 0.001 0.023 0.010

0.035

Table 3. Non-significant variables which did not show influence on the rate of negative URS. Univariate non-significant patient and stone characteristics Age in years

20-34 35-49 50-64 65-80 80 or more Stone anatomical location Upper ureter Mid-ureter Lower ureter Diagnosis Imaging Including CT No CT Medical expulsive therapy Alfa-blockers Corticosteroids None Time from acute episode to URS 0-29 days 30-59 days 60-89 days ≥ 90 days Time from stenting to URS 0-29 days 30-59 days 60-89 days ≥ 90 days Percutaneous nephrostomyin acute episode Yes No JJ stenting in acute episode Yes No

Frequency of negative URB (%) 47.4% 26.7% 30.9% 28.1% 22.7% 25% 28.6% 27.3% 28.6% 33.9% 33.1% 40% 27% 28.6% 33.1% 27.9% 21.4% 35.7% 36.8% 37.9% 29.4% 30% 28.6% 36.3% 21.3%

p value 0.442

0.646

0.139 0.282

0.207

0.614

0.777 0.464

Predicting negative ureteroscopy

Table 4. Logistic regression model accounting for 47.7% of the variance in the dependent variable (probability of negative URS), correctly classifying 76% of patients; each mm increase in stone size with OR of 0.815 and radiopaque stones with OR of 0.240 for negative URS. Applied variables Sex Stone size (absolute value in mm) Primary vs Recurrence Radiopacity

Significance (p) 0.234 0.026 0.198 0.011

exp (B) -

-0.204

0.815 -

-3.716

0.240

tract stone disease in England: evidence from the Hospital Episodes Statistics (HES) database. Urol Int. 2017; 98:391-6. 6. Hesse A, Brändle E, Wilbert D, et al. Study on the prevalence and incidence of urolithiasis in Germany comparing the years 1979 vs. 2000. Eur Urol. 2003; 44:709-13. 7. Stamatelou KK, Francis ME, Jones CA, et al. Time trends in reported prevalence of kidney stones in the United States: 19761994. Kidney Int. 2003; 63:1817-23. 8. Kim JW, Kim JY, Ahn ST, et al. Analysis of patients with urolithiasis visiting the emergency department between 2014 and 2016 in Korea: data from the National Emergency Department Information System. Sci Rep. 2019; 9:16630.

for negative ureteroscopy of 0.240 (expB=-3.716). Table 4 summarises these results.

9. Gomes J, Vendeira P, Ribau U, Reis M. Urolitíase e cólica renal. Perspectiva terapêutica em Urologia [Urolithiasis and renal colic. Therapeutic approach in urology]. Acta Med Port. 2002; 15:369-80.

DISCUSSION

10. Geraghty RM, Jones P, Somani BK.Worldwide trends of urinary stone disease treatment over the last two decades: a systematic review. J Endourol. 2017; 31:547-56.

AND CONCLUSIONS

Our Center showed a high rate of negative URS, more than previously described in the literature. A recent systematic review suggests that a publication bias may exist, resulting in series with higher rates of URS not being submitted for peer review, leading to underestimation of its prevalence (19). Stone position has been described in one previous study as an influencing factor, with distal stones resulting in higher negative URS rates (17); this did not seem to be the case with our population. In accordance with previously reported data (17) time to surgery from last imaging study or stenting also did not influence negative URS rates. Of note, our series presents a significant number of pre-stented patients, more than in previously reported retrospective studies (15) and 19.9% of those did not undergo further imaging before URS. Female patients tend to have a higher rate of negative URS, as described in two recent studies (15, 16). This is possibly explained by frequent unnoticed passage of stones (due to shorter urethral length and lower voiding pressure) or by a higher frequency of pelvic phleboliths mistaken as ureteric stones (19). Patients with small, radiolucent stones showed the highest rates of negative URS; this is also in accordance with previously described series (15, 17). These patients would benefit the most from pre-operative repeat imaging studies, eventually with non-contrast CT, to identify and preclude unnecessary treatments and costs (14). Prospective studies could help identify more precisely which imaging studies, in which patients and in what timeframe would impact the most in terms of change in planned treatment, to suggest clear guidelines regarding this matter.

REFERENCES

1. Trinchieri A. Epidemiology of urolithiasis.Arch Ital Urol Androl. 1996; 68:203-49. 2. Trinchieri A. Epidemiology of urolithiasis: an update. Clin Cases Miner Bone Metab. 2008; 5:101-106. 3. Sorokin I, Mamoulakis C, Miyazawa K, et al. Epidemiology of stone disease across the world. World J Urol. 2017; 35:1301-20. 4. Turney BW, Reynard JM, Noble JG, Keoghane SR. Trends in urological stone disease. BJU Int. 2012; 109:1082-7. 5. Rukin NJ, Siddiqui ZA, Chedgy ECP, Somani BK. Trends in upper

11. Pietropaolo A, Proietti S, Geraghty R, et al. Trends of 'urolithiasis: interventions, simulation, and laser technology' over the last 16 years (2000-2015) as published in the literature (PubMed): a systematic review from European section of Urotechnology (ESUT). World J Urol. 2017; 35:1651-1658. 12. Somani BK, Giusti G, Sun Y, et al. Complications associated with ureterorenoscopy (URS) related to treatment of urolithiasis: the Clinical Research Office of Endourological Society URS Global study. World J Urol. 2017; 35:675-681. 13. Geraghty RM, Jones P, Herrmann TRW, et al. Ureteroscopy is more cost effective than shock wave lithotripsy for stone treatment: systematic review and meta-analysis.World J Urol. 2018; 36:1783-1793. 14. Lloyd P, Johnston T, Coode-Bate J, Keoghane SR. A negative ureteroscopy for stone disease: is it acceptable and is it avoidable? Urol New. 2018; 22(6). 15. Katafigiotis I, Sabler IM, Heifetz EM, et al. “Stoneless” or negative ureteroscopy: a reality in the endourologic routine or avoidable source of frustration? Estimating the risk factors for a negative ureteroscopy. J Endourol. 2018; 32:825-30. 16. Lamberts RW, Conti SL, Leppert JT, Elliott CS. Defining the rate of negative ureteroscopy in the general population treated for upper tract urinary stone disease. J Endourol. 2017; 31:266-71. 17. Kreshover JE, Dickstein RJ, Rowe C, et al. Predictors for negative ureteroscopy in the management of upper urinary tract stone disease. Urology. 2011; 78:748-52. 18. Prattley S, Rice P, Pietropaolo A, et al. Predictors and results of negative ureteroscopy for treatment of consecutive ureteric stones done as a primary procedure: prospective outcomes from a University Hospital. Urol Int. 2019; 103:143-148. 19. Rice P, Prattley S, Somani BK.’Negative ureteroscopy’ for stone disease: evidence from a systematic review. Curr Urol Rep. 2019; 20:13. Correspondence Miguel Eliseu, MD (Corresponding Author) mgl.nobre@gmail.com Roberto Jarimba - rjarim-ba@gmail.com Pedro Moreira - pedronetomoreira@gmail.com Pedro Simões - pedrocorreiasimoes@gmail.com Paulo Temido - ptemido@gmail.com Arnaldo Figueiredo - ajcfigueiredo@gmail.com Urology and Renal Transplantation Department, Coimbra Hospital and University Center Praceta Professor Mota Pinto, 3004-561 Coimbra (Portugal) Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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DOI: 10.4081/aiua.2021.3.326

ORIGINAL PAPER

Comparison of a single-use, digital flexible ureteroscope with a reusable, fiberoptic ureteroscope for management of patients with urolithiasis Panagiotis Mourmouris 1, Lazaros Tzelves 1, Grigorios Raptidis 2, Marinos Berdempes 1, Titos Markopoulos 1, Grigorios Dellis 2, Ioannis Siafakas 2, Andreas Skolarikos 1 1 National 2 251

and Kapodistrian University of Athens, 2nd University Department of Urology, Sismanoglio Hospital, Athens, Greece; Airforce General Hospital, Urology Department, Athens, Greece.

Summary

Objectives: Ureteroscopy is one of the commonest procedures performed to manage urolithiasis. Flexible ureteroscopy has been traditionally based on reusable, fiber-optic ureteroscopes. Technology advancements permitted the development of single-use scopes with digital image. The aim of this study is to compare efficacy and safety between a reusable, fiberoptic ureteroscope with a single-use, digital scope. Patients and methods: We collected data based on chart review from a prospectively collected database on a tertiary, high-volume hospital in Greece. Baseline, perioperative and postoperative data were gathered and analyzed. Chi-square and Fisher's exact test was used to compare qualitative data and unpaired t-test for continuous data, with a statistical significance set at a = 0.05. Results: 40 patients underwent flexible ureteroscopy with a single-use digital scope, while 37 with the reusable scope. The two groups were matched regarding baseline characteristics and stone-related parameters. After data analysis, a shorter operative time in favor of single-use flexible ureteroscope was detected (45 vs 65 min, p = 0.001), while safety was also in favor of this type of scope with a significantly higher immediate stonefree rate (70% vs 43%, p = 0.005). Overall complications did not differ between the two groups, although a lower sepsis rate was detected in patients treated with single-use scope. Conclusions: Our findings indicate that single-use, digital ureteroscopes are a viable alternative for flexible ureteroscopy and management of urolithiasis, especially in centers with deficient facilities for sterilization and ensured funds for more expensive reusable scopes.

KEY WORDS: Urolithiasis; Flexible ureteroscope; Kidney stone disease; Digital ureteroscope; Single-use ureteroscope; Fiber-optic ureteroscope; Reusable ureteroscope. Submitted 11 July 2021; Accepted 25 July 2021

INTRODUCTION

Geography and climatic changes along several regions affect kidney stone disease prevalence. In Greece, urolithiasis is found to affect around 15% of population (1), while in contrast US citizens suffer from kidney stones to a lesser extent of around 9% (2). The total annual cost directed to this condition reaches around 5.3 billion $ in

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No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

US (3, 4). Technological advances have contributed to the development of new technologies and techniques, that play a major role in the management of this disease. Semirigid and flexible ureteroscopes constitute a basic component of endourologist armamentarium. After the first appearance of digital technology in ureteroscopes in 2004 (5) many more followed. Reusable instruments offer repeatability but with uncertain endurance. Legemate et al. (6) report that shaft bending, kinking and dent of coating is an issue that appears not seldom in everyday use. Moreover sterilization procedures that apply for reusable instruments are accompanied by increased costs, necessary time intervals between operations and trained staff members (7). The first single-use digital flexible ureteroscope, was launched back in 2015 (8). Equipped with a tip diameter of 7.7 Fr, outer diameter of 9.5 Fr, a wide enough working channel for baskets and laser fibers (3.6 Fr), digital imaging and deflection angle up to 270 degrees, it is a great aid for the endourologist 8. A wide variety of movements, such as pronation/ supination, downward and upward deflection, along with back and forth movements, offers a great degree of freedom for the operator (8). Literature search revealed data of in vitro/in vivo studies (8) and cadavers (9), while initial results on comparison with reusable fiberoptic ureteroscope showed better results in the single-use group regarding procedural time, failure of procedure and complications. Despite the convincing results more studies should be conducted to reach safe conclusions. The aim of this study is to compare intra- and postoperative complications and parameters while using a single-use, digital flexible ureteroscope, in comparison with a reusable fiberoptic ureteroscope in a prospective cohort of matched population for their baseline characteristics and their disease.

PATIENTS

AND METHODS

Study design Data collection was performed from an ongoing prospective database regarding patients treated for urolithiasis with a single-use, digital or reusable fiberoptic ureteroscope.

Single-use, digital versus reusable, fiberoptic ureteroscope

Chart review for patient demographic characteristics, stone disease parameters and perioperative details was performed. Cross-match of patients for confounders was also performed (stone disease parameters, age, ASA score). Settings Data were derived from Second Urology Department in Sismanoglio, a tertiary Hospital in Greece, which is considered a reference center for stone disease, between a 12month period (06/2017-06/2018). A high volume of fURS cases is performed yearly at out center (> 100). Participants Inclusion criteria were: patients older than 18 y/o with diagnosed stone disease based on imaging studies (ultrasound, CT scan or x-Ray). Patients with non-radiopaque stone disease, history of urinary tract neoplasm or those undergoing a diagnostic workup for hematuria were excluded. The Ethics Committee of Hospital approved study protocol and patients were informed about inclusion and signed informed consent in case of participation. The study was conducted according to the principles of Helsinki Declaration. Assignment to the specific treatment arm was done according to patient choice after being informed for the potential choices and availability of equipment. Variables The demographic profile of patients was based on collection of data like age, gender, American Society of Anesthesiologists (ASA) score according to anesthesiologic evaluation, side of disease, presence of bacteriuria and potential anatomic malformation of kidneys. Perioperative variables like operation room time, technique and equipment used during ureteroscopy, complications and duration of hospital stay, stone free rates, as well as stone disease characteristics were also gathered (stone location, maximum diameter, and total burden). Data sources and measurements In the study six experienced urologists performed the total number of cases either with LithoVueTM (Boston Scientific) single-use, digital ureteroscope or the Flex X2 (Karl Storz) fiberoptic, reusable fiberoptic ureteroscope. The exact same equipment was used between the two groups concerning laser fiber, baskets and other retrieval devices, as well as access sheaths in order to minimize confounding effect. Antibiotic prophylaxis was administered to all patients according to existing EAU Guidelines and preoperative urine culture results. Data regarding perioperative details were recorded by the urologist, the residents who were present in the operating room or by scrub nurses. The total operative time was defined as the length of time from ureteroscope entry until completion of stone pulverization. The patient stone burden was determined based on the most accurate imaging modality, while in order to categorize a patient stone free, no fragments of residual stone disease or clinically insignificant fragments < 2 mm (CIFRs) should have been identified during patient follow-up with imaging tests. Bias In order to limit confounding bias, we performed a cross-

matching of cases regarding baseline characteristics and stone disease parameters. Statistical methods Categorical variables are described as proportions, while Fisher’s exact test or chi-square test were used for comparing them. Continuous data are presented as mean ± standard deviation or medians and analyzed using unpaired Student’s t-test or Mann-Whitney U test. The choice of Mann-Whitney or t-test according to normal distribution was determined based on assessment of Q-Q plots and Shapiro-Wilk test. Statistical significance was set at a = 0.05. All analyses were done with IBM SPSS Statistics 25.0 software (SPSS Inc., Chicago, IL.).

RESULTS

During the study recruitment period, 77 patients were treated, including 40 in the single-use scope group and the rest 37 in reusable scope group. The two groups were balanced with respect to mean age (55.73 ± 13.47 vs 55 ± 11.2, p = 0.797), use of access sheath (88% vs 92%, p = 0.713) and semirigid ureteroscope (60% vs 59%, p > 0.99) but more men (55% vs 38%) and more patients with positive urine culture preoperatively (23% vs 11%) were included in the single-use scope group, although this did not reach statistical significance (Table 1). Maximum stone size didn’t differ between the groups (12.63 vs 12.52 mm, p = 0.914), while the most common stone location was renal pelvis and lower pole calyces. CT scan was used more frequently for diagnosis in the singleuse scope group (78% vs 57%, p = 0.087) and hydronephrosis was more frequent, but this didn’t reach statistical significance (Table 2). Regarding the laser fiber used from stone fragmentation, in single-use scope group the 270 μm was more frequently used (57.5% vs 30%, p = 0.092) but results didn’t differ significantly. All patients received post-operative insertion of a double-J stent and a similar proportion in both groups was pre-stented. Ancillary use of basket for stone removal and laser setting use for stone fragmentation were also similar between the two groups (Table 3). Median operative time (45 vs 65 min, p < 0.001), sepsis rate (0% vs 11%, p = 0.049) and stone free rate at day one after surgery (78% vs 43%, p < 0.001) favored use of single-use scope. No intraoperative complications were observed in both groups. Finally, length of hospital stay and rates of Table 1. Baseline demographic characteristics of patients. Characteristic Mean age ± SD Male sex - no. (%) ASA Score ≤ 2 - no. (%) Positive urine culture - no. (%) Kidney laterality left - no. (%) Present renal anomaly - no. (%) Use of semirigid ureteroscope - no. (%) Use of access sheath - no. (%)

Single-use, digital (n = 40) 55.73 ± 13.47 22 (55) 39 (98) 9 (23) 19 (47) 4 (10) 24 (60) 35 (88)

Reusable, fiber-optic ureteroscope (n = 37) 55 ± 11.2 14 (38) 34 (22) 4 (11) 17 (46) 1 (3) 22 (59) 34 (92)

P-value 0.797 0.172 0.441 0.228 > 0.999 0.359 > 0.999 0.713

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P. Mourmouris, L. Tzelves, G. Raptidis, M. Berdempes, T. Markopoulos, G. Dellis, I. Siafakas, A. Skolarikos

Table 2. Stone characteristics. Parameter Median number of stones (mm) Median maximum stone diameter (mm) Median total stone burden (mm) Present pre-operative hydronephrosis - no. (%) Use of CT scan for diagnosis - no. (%) Pelvicalyceal location of stones - no. (%) Upper ureter Renal pelvis Middle renal pole Lower renal pole Renal pelvis/Upper pole Renal pelvis/Middle pole Renal pelvis/Lower pole Multiple calyces

Single-use, digital (n = 40) 1.07 12.63 17.36 20 (50) 31 (78)

Reusable, fiber-optic ureteroscope (n = 37) 1.65 12.52 15.22 15 (41) 21 (57)

P-value

2 (5) 16 (40) 2 (5) 5 (12.5) 1 (2.5) 2 (5) 10 (25) 1 (2.5)

7 (19) 10 (27) 2 (5) 4 (11) 1 (3) 11 (30) 0 (0) 1 (3)

Single-use, digital (n = 40)

Reusable, fiber-optic ureteroscope (n = 37)

P-value

12 (30) 14 (35) 40 (100)

13 (35) 13 (35) 37 (100)

0.902 > 0.999

23 (57.5) 9 (22.5) 6 (15)

11 (30) 15 (41) 8 (20)

25 (62.5) 2 (5) 6 (15) 5 (12.5)

14 (38) 2 (5) 9 (24) 10 (27)

0.625 0.914 0.284 0.494 0.087 0.698

Table 3. Procedural characteristics. Characteristic Use of basket for remaining stone fragments - no. (%) Pre-operative JJ stent - no. (%) Post-operative JJ stent - no. (%) Size of laser fiber used for stone fragmentation - no. (%) 270 μm 365 μm 270 & 365 μm Laser settings used - no. (%) Dusting Chipping Dusting & Popcorn Chipping & Popcorn

0.092

Table 4. Intraoperative and postoperative outcomes. Outcome Median operative time (min) Mean length of stay in hospital ± SD (days) Immediate stone free status - no. (%) Stone free status 24 hours postoperatively - no. (%) Intraoperative complications - no. (%) Postoperative complications - no. (%) Postoperative fever - no. (%) Postoperative hematuria - no. (%) Postoperative sepsis - no. (%)

Single-use, digital (n = 40) 45.00 1.75 (1.96) 28 (70)

Reusable, fiber-optic ureteroscope (n = 37) 65.00 1.38 (0.64) 16 (43)

31 (78) 0 (0) 2 (5) 2 (5) 2 (5) 0 (0)

16 (43) 0 (0) 6 (16) 6 (16) 3 (8) 4 (11)

P-value < 0.001 0.261 < 0.005 < 0.001 0.144 0.144 0.667 0.049

post-operative fever and macroscopic hematuria didn’t differ significantly between the two groups (Table 4).

DISCUSSION

Innovations in equipment technology resulted in improvement of clinical outcomes and rendered endo-

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scopic management of stone disease the gold-standard (10). In this study we performed a comparison of clinical outcomes with the use of a disposable, single-use and digital flexible ureteroscope or a re-usable, fiber-optic flexible ureteroscope. The single-use ureteroscope performance in animal studies showed promising results regarding its efficacy and safety. The risk of transmitting potentially fatal infections with repeated use of duodenoscopes (11) or ureteroscopes (12), along with the associated costs for sterilization and maintenance, favor the adoption of single-use scopes, when efficacy is similar. A mean maximum deflection of 270 degrees when used with an empty working channel was found by Winship (13), while after insertion of a laser fiber, an 8.3 degrees reduction in deflection angle was noted. Duration of this type of scope proved satisfying since after 200 full deflections, a mean 21.8 degrees loss was detected, thus maintaining the desired deflection of > 250 degrees (13). This bench-top study also indicates no distortion of digital imaging after laser insertion through the working channel (13). In our study, we found a significant reduction in operative time equal to 20 minutes, although the two groups were similar in term of demographic characteristics, stone size and location. The reduction of operative time by 30% can save time for completion of further cases, reduce the physical burden of staff and the total associated costs. The lower weight of the single-use scope, which adds dexterity to the operator and reduces physical strain during ureteroscopy can be a possible explanation for these findings (6). Endourologists frequently suffer from orthopedic problems in wrists/upper arms, as reported by Healy et al. (14) in their survey, where 32% of urologists performing fURS responded dealing with such issues. Proietty et al. (15) reported that such a single-use scope is 10-300% lighter with camera head and light cable attached when compared to its counterpart reusable digital/fiberoptic scopes. Less physical strain of endourologist might contribute to reduced operating time detected to our study. Improved visual field during use of digital imaging also contributes to reduction of operative time and increases safety intraoperatively, according to Somani et al. (16). Another important advantage offered by the single use nature is that inexperienced users like residents, can handle it without the excess fear of scope breakage. According to Mager et al. (17) and Kam et al. (18), low-volume centers (< 51-60 fURS yearly) might benefit from establishing a single-use scope based program, while high-volume centers (> 10/month) are more likely to save costs with reusable scopes, especially when they are handled properly. Of course, current local market prices in each country may dictate different adaptations in a case-specific scenario. To ensure the superiority of a single-use scope regarding cost-effectiveness, further dedicated studies are needed. Results of the CROES Global study (19) imply an 80% stone-free rate (SFR) for stones < 15 mm after a single fURS, which is comparable with the 78% SFR found in this study sample when using a single-use scope, for a median stone size of 12.63 mm. Of course, the several definitions used for stone-free rate across studies, may weaken these results, but the increased SFR seems promising, since this is the main primary outcome and the main determining factor to guide future management of

Single-use, digital versus reusable, fiberoptic ureteroscope

patients with urolithiasis. The fact that this a relatively new equipment and learning curve did not negatively impact perioperative results, further strengthens its use. Post-operative fever shows a reported incidence equal to 0-10.8% (20-23) after operating in the urinary tract for stones less than 20 mm, using fURS. The main contributing factors are female gender, increased body mass index, positive pre-operative urine culture, increased operative time and increased renal pelvic pressure. In our study we detected a rate of 5% in single-use scope group, which lies in agreement with existing literature. The reduction in operative time can be a protective factor for post-operative fever and sepsis when using single-use scopes, mainly due to less extend increase of renal pelvic pressure. Patients in single-use scope group also suffered less hematuria and sepsis, which is quite important considering morbidity and mortality of urosepsis. This study has certain limitations. Since this is not a randomized controlled trial, there is the possibility for selection bias, which we tried to minimize by cross-matching the groups for baseline demographic characteristics and stone disease parameters. The learning curve and the limited follow-up could also obscure the results regarding stone-free rates.

CONCLUSIONS

This study compares a single-use, digital flexible ureteroscope with a re-usable, fiber-optic flexible ureteroscope for treatment of stone disease. The fact that single-use scope significantly decreases procedural duration and sepsis rates, while increased immediate-stone free rates, makes it a viable option for management of stone disease. Further randomized trials and cost-effectiveness studies are needed to confirm these results.

gle-use digital flexible ureteroscope versus nondisposable fiber optic and digital ureteroscope in a cadaveric model. J Endourol. 2016; 30:655-659. 10. Kartal I, Baylan B, Cakici MC, et al. Comparison of semirigid ureteroscopy, flexible ureteroscopy, and shock wave lithotripsy for initial treatment of 11-20 mm proximal ureteral stones. Arch Ital Urol Androl. 2020; 92:39-44. 11. Epstein L, Hunter JC, Arwady MA, et al. New Delhi metallo- lactamase-producing carbapenem-resistant Escherichia coli associated with exposure to duodenoscopes. JAMA. 2014; 312:1447-1455. 12. Chang CL SL, Lu CM, et al. Outbreak of ertapenem-resistant Enterobacter cloacae urinary tract infections due to a contaminated ureteroscope. J Hosp Infect. 2013; 85:118-24. 13. Winship B WD, Carlos E, Li J, et al. Avoiding a lemon: performance consistency of single-use ureteroscopes. J Endourol. 2019; 33:127-131. 14. Healy KA PR, Cleary RC, Colon-Herdman A, Bagley DH. Hand problems among endourologists. J Endourol. 2011; 25:1915-1920. 15. Proietti S, Somani B, Sofer, et al. The "Body Mass Index" of flexible ureteroscopes. J Endourol. 2017; 31:1090-1095. 16. Somani BK, Al-Qahtani SM, de Medina SD, Traxer O. Outcomes of flexible ureterorenoscopy and laser fragmentation for renal stones: comparison between digital and conventional ureteroscope. Urology. 2013; 82:1017-1019. 17. Mager R KM, Höfner T, Frees S, et al. Clinical outcomes and costs of reusable and single-use flexible ureterorenoscopes: a prospective cohort study. Urolithiasis. 2018; 46:587-593. 18. Kam J, Yuminaga Y, Beattie K, et al. Single use versus reusable digital flexible ureteroscopes: A prospective comparative study. Int J Urol. 2019; 26: 999-1005. 19. Skolarikos A, Gross AJ, Krebs A, et al. Outcomes of flexible ureterorenoscopy for solitary renal stones in the CROES URS Global Study. J Urol. 2015; 194:137-143.

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21. Hollenbeck BK ST, Faerber GJ, Wolf JS. Flexible ureteroscopy in conjunction with in situ lithotripsy for lower pole calculi. Urology. 2001; 58:859-863.

1. Stamatiou K, Karanasiou VI, Lacroix R et al. Prevalence of urolithiasis in rural Thebes, Greece. Rural Remote Health. 2006; 6:610.

3. Ghani KR, Sammon JD, Karakiewicz PI, et al. Trends in surgery for upper urinary tract calculi in the USA using the Nationwide Inpatient Sample: 1999-2009. BJU International. 2013; 112:224-230. 4. Saigal CS JG, Timilsina AR. Direct and indirect costs of nephrolithiasis in an employed population: opportunity for disease management? Kidney Int. 2005; 68:1808-1814. 5. Shah K MM, Knudsen B. Prospective randomized trial comparing 2 flexible digital ureteroscopes: ACMI/Olympus Invisio DUR-D and Olympus URF-V. Urology. 2015; 85:1267-1271. 6. Legemate JD, Kamphuis, G. M., Freund, J. E., et al. Durability of flexible ureteroscopes: a prospective evaluation of longevity, the factors that affect it, and damage mechanisms. Eur Urol Focus. 2019; 5:1105-1111. 7. Semins MJ GS, Allaf ME, Matlaga BR. Ureteroscope cleaning and sterilization by the urology operating room team: the effect on repair costs. J Endourol. 2009; 23:903-905. 8. Dale J, Kaplan AG, Radvak D, Shin R, et al. Evaluation of a novel single-use flexible ureteroscope. J Endourol. 2021; 35:903-907. 9. Proietti S DL, Molina W, Doizi S, et al. Comparison of new sin-

22. Jung H NB, Osther PJ. Retrograde intrarenal stone surgery for extracorporeal shock-wave lithotripsy-resistant kidney stones. Scand J Urol Nephrol. 2006; 40:380-384. 23. El-Nahas AR IH, Youssef RF, Sheir KZ. Flexible ureterorenoscopy versus extracorporeal shock wave lithotripsy for treatment of lower pole stones of 10-20 mm. BJU International. 2012; 110:898-902. Correspondence Panagiotis Mourmouris, MD - thodoros13@yahoo.com Lazaros Tzelves, MD, Msc (Corresponding Author) - lazarostzelves@gmail.com Andreas Skolarikos, MD - andskol@yahoo.com 2nd University Department of Urology, Sismanoglio Hospital, Sismanogliou 37, Athens (Greece) Grigorios Raptidis, MD - gregrapt@otenet.gr Marinos Berdempes, MD - marinosberdebes@hotmail.com Titos Markopoulos, MD - titosmark@gmail.com Grigorios Dellis, MD - grdellis@yahoo.gr Ioannis Siafakas, MD - sfksgnns@yahoo.com 251 Airforce General Hospital, Urology Department, Athens (Greece) Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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DOI: 10.4081/aiua.2021.3.330

ORIGINAL PAPER

Outcome of Transperitoneal Laparoscopic Ureterolithotomy (TPLU) for proximal ureteral stone > 15 mm: Our experience with 60 cases Ali Eslahi 1, 2, Faisal Ahmed 3, Mohammad Rahimi 1, Seyed Hamed Jafari 4, Seyyed Hossein Hosseini 1, Saleh Al-wageeh 5, Pegah Mohammad Zadeh Shirazi 1, Khalil Al-naggar 3, Ebrahim Al-shami 3, Mohammad Hossein Taghrir 6 1 Department

of Urology, School of medicine, Shiraz University of Medical Sciences, Shiraz, Iran; Geriatric Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; 3 Urology research center, Al-Thora hospital, Department of Urology, Ibb University of Medical Since, Ibb, Yemen; 4 Medical Imagining Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; 5 Department of General Surgery, Ibb University of Medical Science, Ibb, Yemen; 6 Trauma Research Center, Shahid Rajaee (Emtiaz) Trauma Hospital, Shiraz University of Medical Sciences, Shiraz, Iran. 2 Shiraz

Summary

Purpose: We aim to review our experience of transperitoneal laparoscopic ureterolithotomy (TPLU) for proximal ureteric stone more than 15 mm. Patients and methods: Between June 2017 to December 2020, sixty patients with a history of unsuccessful Extracorporeal shock wave lithotripsy (ESWL) and/or failed ureteroscopy for impacted ureteral calculi more than 15 mm who accepted TPLU were enrolled in our study. The patients' demographic information and post-treatment results were gathered and analyzed, retrospectively. Results: The patients' mean age was 46.25 ± 12.56 years. The mean size of the stone was 20.11 ± 4.76 mm. 37 (61.7%) patients had severe hydronephrosis (HDN) and 46 (76.7%) stones were radio-opaque. Almost all of the patients underwent TPLU by a single urologist. The mean operation time was 72.86 ± 6.07 minutes without intraoperative complication (only 3 stones had upward migration to the pyelocaliceal system). The main operative blood loss was 88.86 ml. The average length of stay in the hospital was 45.8 ± 8.11 hours. The stone free rate (SFR) at discharge was 57 (95%). The overall complication rate was 27 (45%). Regarding early complications, fever was found in 8 (13.3%) patients, and 3 patients (5%) had paralytic ileus. The rate of urine leak was 8.3%, and 8 (13.3%) patients required blood transfusions. In multivariate analysis, the multiple stones, bigger stone in size, incomplete SFR, longer duration of hospital admission, and severe HDN were associated with a high early complication rate (p = 0.05, 0.04, < 001, 0.03, and 0.01, respectively). Conclusions: TPLU is a harmless option for managing proximal ureteric stone as a primary procedure or salvage procedure with good outcomes and acceptable complication rates.

(ESWL), which is really the first option, percutaneous nephrolithotomy (PCNL), flexible ureteroscopy, laparoscopic ureterolithotomy, and open ureterolithotomy (1). On the other hand, novel equipment for endoscopic stone fragmentation and improved expertise of many urology surgeons in laparoscopic surgeries have limited the indications for open surgery (2). Where the endoscopic access is impossible or inefficient due to the anatomy of the ureter or size of the stone, the ureterolithotomy laparoscopic technique can be another viable option to open surgery, which may be performed via retroperitoneal laparoscopic ureterolithotomy (RLP) or transperitoneal laparoscopic ureterolithotomy (TPLU) (3). Skolarikos et al. attempted to determine the evidence level and recommendation score for the laparoscopic technique for removal of the stone. Laparoscopic ureteral surgery has the greatest degree of evidence. When compared to open ureterolithotomy, it is entirely feasible and has a reduced post-surgical morbidity. It is often used to treat large impacted calculi or when endoscopic ureteral surgery and ESWL have failed (1). TPLU is recommended for the less experienced surgeons; moreover, it provides more workspaces and allows for more accurate recognition of anatomical structures. On the other hand, prior surgery of the abdomen with the high risk of adhesions may be a restrictive factor (4). In this study, we represent our experience of TPLU for proximal ureteric stone in 60 cases.

KEY WORDS: Proximal Ureteral Stones; Laparoscopy; Ureterolithotomy; Transperitoneal approach; Complication.

Study design The ethics committees of Shiraz University of Medical Sciences approved this project (approval code# IR.SUMS.MED.REC.1399.585), and it was carried out in compliance with the Helsinki Declaration. In a cross-sectional study, which was also conducted retrospectively, the patients who had undergone TPLU for proximal ureteral stone more than 15 mm between June 2017 and

Submitted 16 June 2021; Accepted 9 July 2021

INTRODUCTION

Proximal ureteric calculi could be handled in a variety of different ways such as extracorporeal shock wave lithotripsy

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No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

MATERIALS

AND METHODS

Transperitoneal laparoscopic ureterolithotomy for proximal ureteral stone

December 2020 in our referral centers (Nemazi Teaching Hospital and Ali-Asghar Teaching Hospital, Shiraz, southern Iran) were considered for this study. During this period, 60 patients were enrolled in our study. Inclusion criteria Patients who accepted TPLU in our center, including those with failed and/or refused ESWL or ureteroscopy, impacted stones, stones larger than 15 mm, and stones located in the proximal ureter (between the ureteropelvic junction and the upper edge of the pelvis). Exclusion criteria Patients with stone less than 15 mm, uncorrected coagulopathy, active urinary tract infection (UTI), contraindication to general anesthesia, previous surgery in the ureter or abdomen, and urinary tract abnormality. Data collection The information about gender, age, size of ureteral stones, laterality, stone opacity, main symptoms, amount of hydronephrosis (HDN), operating time, blood loss, stonefree rate (SFR), postoperative hospital stay, complications, stone analysis, and data on follow-up, time of follow-up, stone recurrence, and other complications were collected retrospectively. Also, a full blood count (CBC) and a renal function test (BUN and creatinine), urine analysis and urine culture were done. Those with positive cultures were treated with proper antibiotic and admitted with sterile urine for operation. All patients were admitted 12 hours before the operation and received parenteral hydration and a single dose of prophylactic antibiotic. They were definitely diagnosed before operation, using the results of plain abdominal X-ray, ultrasonography (US), intravenous urography (IVU), and abdominal pelvic computed tomography (CT) scan (5). All of them were informed that they would be monitored for three months after the surgery. In a CT scan, the stone-free rate (SFR) was identified as the absence of any residual stone. Prolonged drainage was defined as urine leakage requiring drainage for more than 3 days. Also, paralytic ileus was defined as absence of bowel sound lasting for over 36 hours. In order to figure out what factors could influence the rate of early complications, we evaluated the preoperative factors such as age, gender, body mass index (BMI), laterality, stone size, main symptoms, previous surgery (ESWL, URS), serum creatinine, amount of HDN and stone opacity, and operation factors such as the mean operative time, bleeding, SFR and hospital stay; then, we compared them with early complications such as need to a second procedure, blood transfusion, fever, ileus, urinary leakage, and stent migration. Operative technique All the procedures were carried out by one skilled urologist (A.E.), who specialized in urologic laparoscopic surgery. After anesthesia induction, the patients were put in flank position while the table of operation was flexed. A pneumoperitoneum of 12-15 mm Hg was obtained by a Veress needle placed into the abdominal cavity through the umbilicus. The operation was carried out through three ports; the first was a 10 mm camera trocar implant-

ed two finger breadths lateral and upper to the umbilicus or lateral umbilical depending on the patient's stature and the other 2 ports were developed at the iliac fossa (10 mm) and subcostal (5 mm) in the mid-clavicular line in cases of the left side, while in the case of the right side, a 5 mm port was placed in the right iliac fossa, and a 10 mm port in the subcostal area in the mid-clavicular line. In certain circumstances, an extra port at the flank was placed for the assistant. In right-side cases, a fourth 5 mm trocar is sometimes implanted for retraction of the liver. The ureter was detected after reflection of the colon, and the stone was found and removed via electrocautery vertical ureterotomy. After that, a 6 F ureteral feeding catheter was implanted as a double J stent, and the ureteral incision was sutured with 5/0 Vicryl sutures. The calculi were removed in a sac via the 10 mm port using a 5 mm scope. A small drain was implanted and removed until the fluid level dropped below 20 ml, and the ureteral catheter was removed 7-10 days later via cystoscopy. Statistical analysis The mean ± SD, median, and Inter-Quartile Range (IQR) described the quantitative variables, and for qualitative variables, frequency (percent) was used. Non-parametric test was used if data distribution was not standard. Chisquare test was used to assess the potential statistically significant difference. ANOVA was applied to compare the difference of the means between more than two different levels. A P value of 0. 05 or less was considered statistically significant. SPSS version 20 was used to analyze the data.

RESULTS

Table 1 shows the patients’ characteristics and perioperative details. The mean age of the patients was 46.25 ± 12.56 years. The mean size of the stone was 20.11 ± 4.76 mm. There were 40 (66.6%) males and 20 (33.4%) females; 36 (60%) ureteral calculi were on the left side and 24 (40%) on the right side. The mean BMI of the patients was 23.66 ± 35.1 kg/m2 (range 18-35); 31 (51.7%) patients were selected for TPLU as the primary procedure, 21 (35%) patients had failed ESWL, and 8 (13.3%) had failed ureteroscopy (URS). About 37 (61.7%) patients had severe HDN and 46 (76.7%) stones were radiopaque. The main symptoms at presentation were flank pain which was present in 24 (40%) patients. All procedures were carried out via laparoscopy, with no switch to open ureterotomy. Mean operation time was 72.86 ± 6.07 min (range 60-85 minutes). The overall operative blood loss was 88.86 ml (range 21-200 mL). The hospital stay was 45.8 ± 8.11 hours (range 36-72 hours). The SFR at discharge was 95%. During the surgery, 3 (5%) patients were reported to have ureteral calculus that had moved to the pyelocaliceal system. Stones were captured in the pyelocaliceal system by passing a semirigid ureteroscope via one of the ports and then via ureteral incision. Then, the stones were removed using non-crushing grasping forceps. The mean time resuming the oral intake was 24.2 ± 2.8 hours. The mean drain removal time in our study was 3.3 days (range 2-7). Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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Table 3. Preoperative and intraoperative data in patients without/with early complications.

Table 1. Characteristics of the patients. Variables Gender (male/female) Age (year) a BMI (kg/m2) a Stone size (mm) a History of failed (ESWL/ URS) b Pre-op hemoglobin (mg/dL) a Main symptoms of presentation b Flank pain Vomiting Hematuria Fever Creatinine rise Abdominal pain Indication for laparoscopy b Primary procedure History of failed ESWL History of failed URS Laterality (left/right) Degree of HDN b No Mild Moderate Severe Stone opacity b Radiopaque Radiolucent

40/20 46.25 ± 12.56, (22-77) 23.66 ± 35.1, (18-35) 20.11 ± 4.76 21 (35%)/8 (13.3%) 13.85 ± 0.91, (12-16) 24 (40%) 9 (15%) 8 (13.3%) 8 (13.3%) 7 (11.7%) 4 (6.7%) 31 (51.7%) 21 (35%) 8 (13.3%) 36/24 2 (3.3%) 5 (8.3%) 16 (26.7%) 37 (61.7%) 46 (76.7%) 14 (23.3%)

a Data was presented as Mean ± SD, range, and b Data was presented as n (%).

BMI; body mass index, ESWL; Extracorporeal shock wave lithotripsy, HDN; hydronephrosis, URS; Ureteroscopy.

Regarding early complication, fever was found in 8 (13.3%) patients who were treated with antipyretic therapy. Three patients (5%) had paralytic ileus which resolved with observational management, and 2 (3.3%) of those patients had UTI which was treated with antibiotic therapy. Stent migration was seen in 6 (10%) patients. Additionally, the rate of urine leak was 8.3%. Eight (13.3%) patients required blood transfusions to restore the hemodynamic state. Regarding late complications, Table 2. Intraoperative and postoperative data. Variables Operation time (minutes) a Stone free rate b Hospital admission (hours) a Post-op hemoglobin (mg/dL) a Drain removal (days) Blood loss (mm) a Early complications b Stone migration Blood transfusion Fever/UTI confirmed Ileus Urinary leakage Late complications b Recurrence of stone

72.86 ± 6.07, (60-85) 57 (95%) 45.8 ± 8.11, (36-72) 13.10 ± 1.04, (10.5-15) 3 (2-7) 88.86 ± 45.23, (21-200) 27 (45%) 3 (5%) 8 (13.3%) 8 (13.3%), 2 (3.3%) 3 (5%) 5 (8.3%) 2 (3.3%)

a Data was presented as Mean ± SD, range, and b Data was presented as n (%).

UTI; Urinary tract infection.

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Variable Age (years) a Sex b

No (N = 33) Yes (N = 27) 45.97 ± 12.87 (22-70) 46.84 ± 12.18 (32-77) Male 29 11 Female 12 8 BMI (kg/m2) a 23.53 ± 3.69 (19-35) 23.94 ± 3.17 (18-30) Laterality b Left 25 11 Right 16 8 Stone opacity b Radiolucent 12 2 Radiopaque 29 17 Amount of HDN b No 2 0 Mild 1 4 Moderate 12 4 Severe 28 9 History of failed URS b No 36 16 Yes 5 3 History of ESWL b No 25 14 Yes 16 5 Stone size (mm) a 18.85 ± 3.38 (14-30) 22.31 ± 6.23 (15-35) Number of stones b Single 37 16 Multiple 1 6 Pre-op hemoglobin (mg/dL) a 13.87 ± 0.92 (12-16) 13.81 ± 0.90 (12-15) Operation time (minutes) a 72.04 ± 5.69 (60-85) 74.63 ± 6.65 (65-85) Blood loss (ml) a 90 ± 43 (23-200) 86 ± 51 (21-200) Hospital admission (hours) b 36 13 4 48 28 12 72 0 13 Stone free rate b Complete 41 16 Non complete 0 3

P value 0.80 0.32 0.36 0.82 0.11 0.01*

0.70 0.33 0.04* 0.05* 0.94 0.20 0.57 0.03*

0.00*

P-values < 0.05 were considered significant. a mean ± SD (Range), b number. BMI; body mass index, ESWL; Extracorporeal shock wave lithotripsy, HDN; hydronephrosis, URS; Ureteroscopy.

over a mean follow-up period of 10.8 ± 6.6 (range 3-24) months, 2 patients (3.3%) experienced stone recurrence (Table 2). Regarding stone analysis, calcium oxalate stone was seen in 28 (46.7%) patients, uric acid in 11 (18.3%), struvite in 9 (15%), mixed stone in 8 (13.3%), and cystine in 4 (6.7%). We additionally compared preoperative, operative factors and SFR with early complications and found that multiple stone, large stone, incomplete SFR, longer duration of hospital stay, and severe HDN were associated with a higher early complication rate with a p value of 0.05, 0.04, < 001, 0.03, and 0.01, respectively (Table 3).

DISCUSSION

ESWL, PCNL, RLU and URS are standard treatment options for proximal ureteral calculi (6). However, the ESWL lower stone-free rate, possibility of increasing the risk of hypertension and diabetes mellitus in the long-term, and possible need for multiple treatment sessions are the main limitations of this procedure since complete stone removal is the target (7, 8). After ESWL, re-treatment is needed in up to 36% of cases. Approximately 7% of ureteral stones treated with ureteroscopic therapy required additional operations, and approximately 1-10% required open surgical approach. Many of these additional interventions increased the patient's morbidity. As a result, TPLU is a

Transperitoneal laparoscopic ureterolithotomy for proximal ureteral stone

viable option for handling these difficult stones (9). Laparoscopic ureteral surgery is progressively replacing the open surgery as the surgeon’s experience improves. It is accompanied with reduction in the overall morbidity as well as decrease in hospital stay, and improved cosmetic outcomes with comparable functional outcomes (10). It is a valuable alternative to open ureterolitholithotomy as the first option for proximal ureteric calculi greater than 15 mm in today’s world of minimally invasive surgery (3). Furthermore, proximal location of ureteral stone and stone impaction are the primary predictors of unfavorable URS effects (11). Laparoscopy can be performed with two methods, TPLU or RLU, with the primary determinant of the choice being the surgeon's preference and experience. The disadvantages of the RLU include a small working space, which might cause difficulties with orientation, visualization, organ trapping, trocar spacing, and freeing periureteral inflammatory adhesions due to long impaction time of the stone (12). Furthermore, damage to intraperitoneal organs and hernia can arise following balloon inflation of the extraperitoneal cavity. Complication rate, number of medications for pain relief required, duration of the hospital stay, and time required to resume daily activities after the procedure were similar in transperitoneal and retroperitoneal approaches (9, 10). The mean age of the patients in our study was 46.25 years with a range of 22 to77 years and male to female ratio of 2:1. The mean age of the patients in the study of El-Feel et al. was 39.8 years with a range of 13 to 60 years (13). The most common indication of TPLU in our study was primary procedure for impacted upper stones in 51.7% of patients, followed by failed ESWL in 35%, and failed URS in 13.3% of cases. Our results are similar to previous papers such as those of Huan et al. (14), El-Moula et al. (2), and Nasseh et al. (15). In our report, 61.7% of patients had severe HDN. Hsiao et al. investigated the effect of HDN on the outcome of ESWL of a single upper ureteral calculus and found that in patients with stone more than 10 mm, the outcome of ESWL was poor if the HDN was moderate or severe. Other procedures like ureteroscopic therapy and laparoscopic surgery can be used as the primary therapy or when a first session of ESWL fails (16). Therefore, there are not major differences of our study compared with other studies. In the study by Wani et al., the main symptom was flank pain which presented in 80% of patients and it was followed by burning micturition in 36.6% of patients (17). Similarly, in our study, 40% of patients had flank pain, 15% vomiting, and 13.3% fever. The mean BMI in our study was 23.66 ± 35.1 kg/m2 (range 18-35 kg/m2). Similarly, the mean BMI reported in a previous study was 22.5 ± 2.20 kg/m2 (range 19.3-27.9 kg/m2) (14). Mean size of the stone in our study was 20.11 ± 4.76 mm and, similarly, El-Feel et al. reported a mean stone size of 1.9 ± 0.7 mm (13). The operation time of our study was shorter than those of Al-Sayyad who reported a mean time of 107 ± 49.5 minutes (4) and of El-Feel et al. who reported a mean operation time of 145 ± 42 minutes (13). The shorter operative time may be due to the high number of cases who under-

go laparoscopy via TPUL method in our center. Furthermore, the operation was accompanied with reduced operative blood loss, with a mean of 88 ml in our study, which was consistent with previous studies such as that by El-Feel et al. (13). The time of operation gradually reduces with developing of skills and experience. The global issues that affect the time of operation are the time to identify the ureter, identification of the stone location, skillful passage of the catheter stent with antegrade approach, and quick intracorporeal suturing of the ureter. Identification of the ureter might be difficult and frustrating (18, 19). In our study, we had problematic ureteric identification in some patients. We think that identification of the ureter and stone is not easy in the patients with previous double J stent placement because the amount of HDN is insignificant and the total course of the ureter is dilated. Sweeping in distal to proximal direction should be avoided during dissection since the stone could migrate to the pyelocaliceal system. The easiest method to find the ureter is to identify the psoas muscle and look anteriorly for the ureter. If that's not sufficient, it can be identified in front of the iliac vessels (18). In our report, 3 (5%) patients had ureteral stones that moved to the pyelocaliceal system during the procedure. The stone was chased in the pyelocaliceal system using a semi-rigid ureteroscope which entered via one of the ports and then via the site of ureterotomy. The stones were then extracted using non-crushing grasping forceps (18, 20). There was no intra-operative complication in this study and all the laparoscopic procedures were completed successfully; none of them had to be converted to open surgery. This can be attributed to careful patient selection and the operative surgeon's expertise. The SFR of 83100% and a low conversion rate confirmed the safety and efficiency of TPLU performed by experienced surgeons (1). Simforoosh et al published a large-scale study of ureteral laparoscopic surgery on 123 participants; the RLU vs. TPLU approach was compared for proximal ureteral stone. The total SFR was 96.7% and the operative time of the TPLU was shorter (137 vs. 171 min; p = 0. 02). Minor complications were observed in 11.4% of patients. The migration of the stone necessitated switching to open surgery in one patient (21). Compared with previous series, we had an acceptable SFR of 95%. In our study the mean removal time of drain was 3.3 days (range 2-7), which was like reported by other articles such as that of You et al. which removed the drain after 3.1 ± 1.3 days in the laparoscopy stented group (22). Mean hospital stay in this study was 45.8 ± 8.11 (36-72) hours, which was consistent with Matias et al., who reported a 3.3 days of hospital stay after operation (23). The overall number of post-op complications in this study was 25 (41%). However, most of our complications were minor and easily managed. The most common complication of TPLU is prolonged urinary leakage which is observed when the site of ureterotomy is not sutured or when stenting of the ureter is not used (1). We did laparoscopic suturing and inserted a ureteral catheter as a stent in all the cases of TPLU. Urine leakage in the present study was seen in 5 (8.3%) patients; in persistent leakage, the position of feeding tube catheter was evaluArchivio Italiano di Urologia e Andrologia 2021; 93, 3

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ated, and if it was migrated, it was taken out and the leak was prevented by the insertion of double J stent. In another study of RLU approach on 50 patients with large ureteric stone (1.5 cm), 20% of the patients experienced urinary leakage, necessitating secondary drainage with a double J stent (24). In the study carried out by Gaur et al., the prolonged leakage of urine (more than 7 days) was seen in 20 out of 101 patients although in 14 of these patients the site of ureterotomy was not sutured and the stenting of the ureter was not used (25). El-Feel et al. reported about TPUL in 27 patients. They experienced postoperative paralytic ileus in one patient (13). In our study, paralytic ileus was observed in 3 (5%) patients and resolved with observational management in 2-5 days. Colon mobilization, blood and urine spill in the peritoneal cavity, as well as visceral dissection and retraction during the procedure might be the main factors for paralytic ileus. Keeley et al. reviewed their experience with TPLU in 14 patients; in their study, low grade fever was detected in one patient (26). In the study by Khalil and coworkers, postoperative fever was observed in 15.4% of the TPLU group (27). In our study, low grade fever was present in 8 (13.3%) patients which relieved by administration of a suitable antipyretic drug. More non-opaque stones and ileus could explain this higher rate of fever (28). Furthermore, UTI was documented in 2 (3.3%) of those patients, which was treated with suitable antibiotic therapy. Blood transfusion was needed to restore the hemodynamic state in 8 (13.3%) patients. In the study by Khalil and coworkers, the need for blood transfusion in the TPLU group was 15.4% (27). Chen et al., comparing safety and efficacy between TPLU and RLU for proximal ureteral stones > 10 mm, mentioned that the overall rate of blood transfusion was 2.8% (12). Our explanation for the high rate of blood transfusion might be due to mild anemia in our patients and previous ESWL, which caused extensive adhesions making difficult dissection and obscured anatomy leading to excessive bleeding. In adjunct to preoperative factors, operative factors and SFR may be associated with early complication rate in our study. We found that multiple stones, larger stone size, non-SFR status, longer duration of hospital stay, and severe HDN were associated with high early complication rate. It is important to mention that the significance of the stone size was due to the total stone size calculated by non-contrast CT scan, and the single large stone did not significantly have an effect on the complication rate. Sing et al. compared the TPLU and RLU in a prospective randomized study and stated that treating proximal and mid-ureteral stone, larger stone, and impacted stones with TPLU were correlated with additional pain, more tramadol necessity, ileus, and prolonged hospital stays than RLU (29). El-Feel et al. reported TPUL in 27 patients and analyzed the factors that may affect the operation time concluding that BMI, laterality, and stone level had no statistically significant effect on the mean operative time (13). According to Huri et al., prolonged hospital stay and operative time can be attributed to larger stones and excessive urinary leakage. However, in their view, the general achievement is that ureteral laparoscopic surgery

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is a viable and appropriate method, particularly for calculi that cannot be effortlessly treated with endoscopic surgery (30). The small sample size and retrospective nature of this study were our major limitations together with lack of comparison with other procedures. In fact, SWL and URS are more likely considered for primary treatment of proximal ureteral stone. While TPLU could also produce an acceptable result, its use would be limited due to greater difficulty and trauma. Indeed, given the procedures and practice, as well as the patients' circumstances, the best approach is the safest for patients. Furthermore, we have limited our study to the short-term assessment of TPLU. After all, TPLU damages the natural structure of the ureter. The long-term effects of TPLU are still unknown, and further research is needed to draw definitive conclusions.

CONCLUSIONS

Our study supports the results of previous studies, suggesting TPLU as a harmless choice for treating proximal ureteral calculi as a primary procedure or salvage procedure with excellent outcomes and acceptable complications. Additionally, larger stone size, multiple stones, incomplete stone-free rate, longer duration of hospital stay, and severe hydronephrosis were associated with a high rate of early complication.

ACKNOWLEDGEMENTS

The authors would like to thank Shiraz University of Medical Sciences, Shiraz, Iran and also Center for Development of Clinical Research of Nemazee Hospital and Dr. Nasrin Shokrpour for editorial assistance.

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Transperitoneal laparoscopic ureterolithotomy for proximal ureteral stone

raphy in detecting urinary tract calculi compared to CT scan. Res Rep Urol. 2018; 10:199. 9. Wani MM, Durrani AM. Laparoscopic ureterolithotomy: Experience of 60 cases from a developing world hospital. J Minim Access Surg. 2018; 15:103-8. 10. Yasui T, Okada A, Hamamoto S, et al. Efficacy of retroperitoneal laparoscopic ureterolithotomy for the treatment of large proximal ureteric stones and its impact on renal function. Springerplus 2013; 2:600. 11. El-Nahas AR, El-Tabey NA, Eraky I, et al. Semirigid ureteroscopy for ureteral stones: a multivariate analysis of unfavorable results. J Urol. 2009; 181:1158-62. 12. Chen H, Chen G, Chen H, et al. Comparison of the safety and efficacy between transperitoneal and retroperitoneal approach of laparoscopic ureterolithotomy for the treatment of large (>10mm) and proximal ureteral stones: A systematic review and meta-analysis. Urol J. 2020; 18:11-18.

27. Khalil M, Omar R, Abdel-Baky S, et al. Laparoscopic ureterolithotomy; which is better: Transperitoneal or retroperitoneal approach?Turk J Urol. 2015; 41:185-90. 28. Zhu W, Li J, Yuan J, Liu Y, et al. A prospective and randomised trial comparing fluoroscopic, total ultrasonographic, and combined guidance for renal access in mini-percutaneous nephrolithotomy. BJU Int. 2017; 119:612-8. 29. Singh V, Sinha RJ, Gupta DK, et al. Transperitoneal versus retroperitoneal laparoscopic ureterolithotomy: a prospective randomized comparison study. J Urol. 2013; 189:940-5. 30. Huri E, Basok EK, Ugurlu O, et al. Experiences in laparoscopic removal of upper ureteral stones: multicenter analysis of cases, based on the TurkUroLap Group. J Endourol. 2010; 24:1279-82.

13. El-Feel A, Abouel-Fettouh H, Abdel-Hakim AM. Laparoscopic transperitoneal ureterolithotomy. J Endourol. 2007; 21:50-4. 14. Yang H, Yu X, Peng E, et al. Urgent laparoscopic ureterolithotomy for proximal ureter stones accompanied with obstructive pyelonephritis: Is it safe and effective without preoperative drainage? Medicine (Baltimore). 2017; 96:e8657. 15. Nasseh H, Pourreza F, Kazemnejad Leyli E, et al. Laparoscopic transperitoneal ureterolithotomy: a single-center experience. J Laparoendosc Adv Surg Tech A. 2013; 23:495-9. 16. Hsiao HL, Huang SP, Wu WJ, et al. Impact of hydronephrosis on treatment outcome of solitary proximal ureteral stone after extracorporeal shock wave lithotripsy. Kaohsiung J Med Sci. 2008; 24:507-13. 17. Wani R, Para M. Transperitoneal laparoscopic management of ureteric stones: a prospective study. World journal of Minimal Access Surgery 2020, 8:1 (Monday, November 16, 2020). 18. Farooq Qadri SJ, Khan N, Khan M. Retroperitoneal laparoscopic ureterolithotomy--a single centre 10 year experience. Int J Surg. 2011; 9:160-4. 19. Radfar MH, Valipour R, Narouie B, et al. Role of the gonadal vessels on the stone lodgment in the proximal ureter: Direct observation during laparoscopic ureterolithotomy. Arch Ital Urol Androl. 2018; 90:163-5. 20. Kadyan B, Sabale V, Mane D, et al. Large proximal ureteral stones: Ideal treatment modality? Urol Ann. 2016; 8:189-92. 21. Simforoosh N, Basiri A, Danesh AK, et al. Laparoscopic management of ureteral calculi: a report of 123 cases. Urol J. 2007; 4:138-41. 22. You JH, Kim YG, Kim MK. Should we place ureteral stents in retroperitoneal laparoscopic ureterolithotomy?: Consideration of surgical techniques and complications. Korean J Urol. 2014; 55:511-4. 23. Matias DB, Alvim RG, Ribas M, et al. Laparoscopic treatment of ureterolithiasis: our experience. Actas Urol Esp. 2009; 33:667-9. 24. Derouiche A, Belhaj K, Garbouj N, et al. Retroperitoneal laparoscopy for the management of lumbar ureter stones. Prog Urol. 2008; 18:281-7. 25. Gaur DD, Trivedi S, Prabhudesai MR, Madhusudhana HR, Gopichand M. AA. BJU Int. 2002; 89:339-43. 26. Keeley FX, Gialas I, Pillai M, et al. Laparoscopic ureterolithotomy: the Edinburgh experience. BJU Int. 1999; 84:765-9.

Correspondence Ali Eslahi, MD alieslahi@yahoo.com Mohammad Rahimi, MD mohammadrahimi888@gmail.com Seyyed Hossein Hosseini, MD shhosseini_6687@yahoo.com Pegah Mohammad Zadeh Shirazi, MD mohammadzadeh.sh6@gmail.com Department of Urology, School of Medicine, Shiraz University of Medical Sciences, Shiraz (Iran) Faisal Ahmed, MD (Corresponding Author) fmaaa2006@yahoo.com Urology Office, Al-Thora Hospital, Alodine street, Ibb (Yemen) Seyed Hamed Jafari, MD hamed338@yahoo.com Medical Imagining Research Center, Shiraz University of Medical Sciences, Shiraz, (Iran) Saleh Al-wageeh, MD alwajihsa78@gmail.com Department of General Surgery, Ibb University of Medical Science, Ibb (Yemen) Khalil Al-naggar, MD Ebrahim Al-shami, MD Urology Office, Al-Thora General Hospital, Alodine street, Ibb (Yemen) alshami_ebrahim@yahoo.com Mohammad Hossein Taghrir, PhD mhtaghrir@gmail.com Urology Office, Faghihi Hospital, Zand Blvd., Shiraz (Iran)

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ORIGINAL PAPER

Effect of bladder dysfunction on development of depression and anxiety in Parkinson’s disease Erdal Benli 1, Fahriye Feriha Ozer 2, Nesrin Helvaci Yilmaz 3, Ozge Arici Duz 3, Ahmet Yuce 4, Abdullah Cirakoglu 1, Tuba Saziye Ozcan 5 1 Department

of Urology, Ordu University, Faculty of Medicine, Ordu, Turkey; of Neurology, Koç University Faculty of Medicine, Istanbul, Turkey; 3 Department of Neurology, Istanbul Medipol University, Faculty of Medicine, Istanbul, Turkey, 4 Department of Urology, Darende Hulusi Efendi State Hospital, Malatya, Turkey; 5 Department of Neurology, Sancaktepe Sehit Prof. Dr. Ilhan Varank Training and Research Hospital, Istanbul, Turkey. 2 Department

Summary

Objectives: Parkinson's disease (PD) often presents with movement disorder. However, besides motor complaints, there are many complaints such as anxiety, depression, urinary complaints and constipation. The aim of this study was to investigate whether neurogenic lower urinary dysfunction (NLUD), which is frequently seen in PD, has an effect on the development of anxiety and depression in these patients. Materials and methods: The study included 32 males (66.6%) and 16 females (33.3%); in total 48 subjects were registered. For the diagnosis and severity of PD, the UK Parkinson's Disease Society Brain Bank Criteria, Unified Parkinson's Disease Rating Scale (UPDRS) and the Hoehn-Yahr scale were used. Urological evaluation was performed using history, physical examination, laboratory tests and standard forms such as IPSS and OAB-V8. Results: There was no difference between the genders in terms of duration, severity and NLUD (p > 0.05). The incidence of anxiety and depression in PD patients was 62.8% and 72.1%, respectively. The prevalence of NLUD was 67.4% and depression and anxiety was found to increase (1.06 and 1.28 times, respectively) in relation to NLUD. In particular, there was a relationship between storage lower urinary tract symptoms and anxiety and depression development (p < 0.05). Conclusions: As expected, it was found that the incidence of NLUD, anxiety and depression was increased in PD. In addition, NLUD was found to be a risk factor for the development of anxiety and depression. Therefore, it is concluded that NLUD, which can potentially cause important complications, as well as motor complaints, should be closely monitored and treated in PD patients.

KEY WORDS: Bladder Dysfunction; Anxiety; Depression; Parkinson’s disease. Submitted 13 May 2021; Accepted 25 June 2021

INTRODUCTION

Idiopathic Parkinson's disease (PD) is a common movement disorder characterized by damage to dopaminergic neurons in the substantia nigra. It is the second most common neurodegenerative disease after Alzheimer's disease (1). Although the most prominent symptoms of PD are

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motor disorders such as muscle rigidity, bradykinesia, tremor, many nonmotor symptoms (NMS) may occur in these patients such as sleep disturbances, anxiety, depression, sexual and urinary complaints (2, 3). NMSs are known to be associated with deterioration of quality of life or the development of major complications such as head trauma and hip fractures. Neurogenic lower urinary dysfunction (NLUD) is a common disorder in PD patients that seriously affects the patient's daily work (4). In particular, frequent urination, urgency, and incontinence seriously affect the quality of life. It could lead the patient to stay home to get close to the toilet and away from people. It is known that psychiatric problems such as anxiety and depression are more common in Parkinson's patients than their healthy peers. The exact cause of psychiatric problems is not known. However, refusal of treatment, deterioration of quality of life, and suicidal thinking can lead to important problems. In our opinion, NLUD, which causes significant problems even in healthy people, may be a cause for the development of anxiety and depression in Parkinson's patients. The aim of this study was to investigate whether there is a relationship between NLUD and psychological problems such as anxiety and depression in PD.

MATERIALS

AND METHODS

This study was planned jointly by the neurology and urology clinics of Ordu University Medical Faculty. The files of the patients who were admitted to the movement disorder clinic between 2017 and 2019 with the diagnosis of PD and underwent urological evaluation were evaluated retrospectively. 48 patients who met the study criteria were enrolled in the study. For the diagnosis and severity of Parkinson's disease, the UK Parkinson's Disease Society Brain Bank Criteria, the Unified Parkinson's Disease Rating Scale (UPDRS) and Hoehn-Yahr scale (H&Y) were used (5, 6). Secondary parkinsonism, psychiatric disease or drug use, history of pelvic radiotherapy or prostate, bladder and gynecological surgery, urinary tract infection, drug use related to prostate or bladder in the last 3 months,

Parkinson’s disease and bladder dysfunction

patients who could not fill in the questionnaire forms by themselves or with the help of their relatives were excluded. Depression and anxiety levels of the patients were determined by Hamilton Depression (HAMD) and Hamilton Anxiety (HAMA) scales. The HAMD scale consists of 17 questions and the total score is obtained by adding the scores given to each question. The severity of depression is classified according to the total score (0-7 normal, 8-16 moderate depression, > 17 major). The HAMA scale consists of 14 questions and the total score is obtained by adding scores (0-5 points normal, 6-14 medium, > 14 major) (7). Urological evaluation of the patients was performed by a specialist in this field with history, physical examination and necessary laboratory studies. Urinary complaints of the patients were evaluated using standard questionnaires such as IPSS (International Prostate Symptom Score) and OAB-V8 (overactive bladder-V8). IPSS is an internationally approved form used to describe the patient's lower urinary tract complaints over the past month. The IPSS form evaluates the patient's quality of life (QoL) as well as complaints related to storage and voiding. This form consists of 8 questions, 7 related to urinary system complaints and one related to QoL. Each question is given a score between 0-5. The total IPSS score in the range of 0-35 is obtained by summing the answers to 7 questions. According to the total IPSS score, LUTS complaints are classified as mild (07), moderate (8-19), and severe (20-35) (8). The internationally accepted OAB-V8 form was used for storage lower urinary tract symptoms. The presence of at least one of the symptoms such as frequent urination, difficulty in urination, urgency and urinary incontinence associated with urgency was considered as OAB. This form consists of 8 questions and each question is given a score between 0-5, the total score is obtained by adding these points (9). The study received permission from the local ethics committee (Number: 2020/118). Statistical analysis Statistical analyses were performed using commercial software (Excel Statistics Ver. 20.0). Student-T test was used to compare mean values. The effect of urinary symptoms on anxiety and depression scores was evaluated using binary logistic regression test. The relationship between anxiety and depression scores and QoL and IPSS total scores was evaluated by simple regression and correlation analysis. The p value of < 0.05 was used for statistical significance.

RESULTS

A total of 48 subjects 32 men (66.6%) and 16 women (33.3%) were enrolled in the study. Mean age (± std) was 69.84 ± 7.47, mean age by gender was 69.22 ± 7.53 and 71.64 ± 7.13 years for men and women, respectively (not significant difference, p = 0.36). The distribution of disease duration by gender was 5.29 ± 3.76 years for males and 5.64 ± 3.13 years for females (p = 0.78). The distribution of UPDRS total score by gender was 25.77 ± 15.26 for men and 26.10 ± 9.32 for women (p = 0.95) (Table 1). There was no difference between the groups in

Table 1. Demographic distribution of patients. Parameters Average age Disease duration Age of onset of disease UPDR total

Men Women Men Women Men Women Men Women

Mean 69.22 71.64 5.29 5.64 63.84 66 25.77 26.10

Std. dev. 7.53 7.13 3.76 3.13 8.85 7.62 15.26 9.32

P-value 0.36 0.78 0.47 0.95

terms of disease stage (p < 0.05). HAMD and HAMA mean scores were; 22.95 ± 9.79 (1-42) and 8.51 ± 5.12 (1-22) respectively. The prevalence of anxiety and depression in patients with Parkinson's disease was 62.8% and 72.1%, respectively. The overall mean score of OAB-V8 and IPSS was 12.60 ± 7.18 (3-26) and 9.58 ± 6.08 (1-25), respectively. The distribution of HAMA, HAMD, OAB-V8, IPSS and QoL scores by gender is shown in Table 2. Urinary complaints were present in 67.4% of patients in general and in 68.4% of males and 63.6% of females (p = 0.75). Storage lower urinary tract symptoms were found in 61% in general, 62.8% in males and 54.5% in females, respectively (p = 0.72). The prevalence of nocturia was 62.8% in general, 63.5% in women and 62.5% in men (p = 0.94). 83% of the patients had never been evaluated or questioned in terms of urinary complaints before. In general, urinary complaints were correlated with anxiety and depression scores (p < 0.05 for both). The risk of depression and anxiety increased with the presence of urinary complaints (1.06 and 1.28 times, respectively). In subgroup analyses, especially storage lower urinary tract symptoms were associated with anxiety and depression scores (p = 0.04). This complaint increased the anxiety and depression scores by 1.05 and 1.07 times, respectively. The prevalence of nocturia was 62.8%. Nocturia was found to be associated with both anxiety and depression (p < 0.05). Nocturia increased the risk of anxiety by 1.19 times (Table 3). IPSS total score was correlated with depression and anxiety (p = 0.03 and p = 0.005, respectively). Table 2. Scores of validated questionnairies of asses depression, anxiety and lower urinary tract symptoms. Parameters Hamilton anxiety score

Men Women Hamilton depression score Men Women IPSS total score Men Women Q-life skor Men Women OAB Men Women

Mean 7.5 10.72 22.15 25.10 9.78 9 2.41 2 11.94 13.45

Std. dev. 4.42 5.44 1036 8.14 6.24 5.76 1.60 1.54 7.02 8.75

P-value 0,06 0,42 0,717 0,46 0.61

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Table 3. Changes in anxiety and depression scores with bladder complaints. Parameters General urinary complaints Storage Nocturia Incontinence

No Yes No Yes No Yes No Yes

Mean 4.55 9.50 6.73 10.41 4.69 10.42 7.33 11.16

Std. dev. P-value 2.50 0.01 5.25 5.67 0.04 4.96 3.06 < 0.001 4.90 4.85 0.02 4.91

Mean 16.11 25.18 18.64 25.43 18.25 25.20 22.73 23.45

Std. dev. 9.41 8.93 10.41 8.95 10.83 8.58 9.45 11.03

Total IPSS score increased the risk of depression and anxiety 1.1 fold. There was a relationship between quality of life score (QoL) and depression and anxiety (p = 0.03 and p = 0.03), which increased the risk of anxiety and depression (0.9 and 1.5 times), respectively.

DISCUSSION

Parkinson 's disease is a multi-systemic disease which is associated with autonomic dysfunction (especially gastrointestinal problems such as constipation and sexual problems such as urinary and erectile dysfunction), anxiety, depression, sleep disturbance as well as motor complaints. The risk of developing at least one NMS in these patients is close to 100% (10). In our patients, urologic problems, such as urinary complaints, and psychiatric disorders, such as anxiety and depression, were commonly observed. During daily practice, most PD patients are monitored only for motor complaints and they receive treatment in this regard. In other words, urinary problems are neglected. Our study results support this view. Most of our patients (83%) had never been evaluated for NLUD before. Patients considered NLUD as the natural consequence of this disease. The results of the study conducted by Gallagher and colleagues also support our conclusions. In this study, NMS incidence and their treatment rates in PD patients were examined. As a result of the study, it was found that one patient had an average of 11 NMS and only 5 of them received treatment (11). Consequently, it was shown that problems other than motor symptoms are frequently neglected in PD patients. Studies have shown that NLUD is a more common nonmotor disorder in PD patients than in the control group (12). The reason for this is not known exactly. Rate of NLUD has been reported in the range of 38-71% in the literatüre (13). In our study, the incidence of NLUD was 67.4%. OAB which is composed of storage lower urinary tract symptoms such as frequent urination, urgency and incontinence is the most common disorder in this patient group. Uchiyama et al. reported the incidence of OAB as 64% (14). In our study, this rate was 61%. Dopaminergic system and autonomic nerve dysfunction in the substantia nigra which is disrupted in PD may be the cause of this pathology (15). When PD deteriorates, the quality of life is affected due to PD because the patient becomes dependent on other people but also because suffers from urinary dysfunction.

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Problems are amplified by a domino effect. For example, nocturia, urgency and fear of urinary incontinence can cause significant problems in P-value the patient's daily life. The daily activities of the patients must be planned in a way that the 0.01 patient is always close to an accessible toilet and nocturia can cause insomnia and dizziness 0.04 and in the elderly the risk of falling at night. Thus, the patients start to have problems such 0.01 as staying at home, loneliness, anger, anxiety, frustration and deterioration of social relations. 0.84 Consequently the quality of life is severely impaired (16, 17). This negative environment may facilitate the development or aggravation of psychiatric problems such as anxiety and depression. In a study on this topic, Starkstein et al. examined the relationship between autonomic symptoms and the development of depression. The authors reported that the presence of 3 or more autonomic symptoms is a strong predictor of depression (18). For this reason, the American Academy of Neurology recommends regular monitoring of NMS in adjunct to motor complaints (19). It is known that psychiatric problems such as anxiety and depression in PD are more common (7-80%) than the general population and other chronic neurological diseases such as multiple sclerosis. The exact cause of anxiety and depression in these patients is unknown. It may occur as a part of the neurodegenerative process of PD. NLUD, which seriously deteriorates the quality of life, even in normal people, can trigger or worsen psychiatric problems in these patients. According to the result of our study, anxiety and depression rates were 76% and 83%, respectively. In addition, there was a relationship between NLUD and anxiety and depression development. These results were consistent with the literature. In a study on this topic, Engström et al. examined the relationship between NLUD and sadness and joy. The Authors reported that patients with urinary complaints felt unhappy and sad about twice as much as the control group (20). In another study, Irwin et al. examined the relationship between bladder dysfunction and work life, social environment, and emotional well-being. At the end of the study, they reported that NLUD has an effect on social intercourse, productivity in business life and feeling good (21). In another study, Brittian et al. examined the relationship between post-stroke depression and bladder complaints. At the end of the study, they reported that urinary complaints increased the risk of depression twice (15% vs. 30%). The Authors suggested that NLUD should be taken seriously in these patients because of the close relationship between depression and suicide (22). In another study, Melvilla et al. reported that the risk of developing depression in women with storage lower urinary tract symptoms increased by 3-4 times (23). In our study, QoL was assessed with a question in the IPSS questionnaire. There was a correlation between QoL and anxiety and depression scores. This result is also important for creating a vicious circle. Deteriorating quality of life triggers psychological problems and psychological problems can lead to more deterioration of quality of life. In one study, the relationship between depression and QoL was investigated.

Parkinson’s disease and bladder dysfunction

The researchers reported that 83% of depression predicted impaired QoL (24). In another study by Schwarz et al., the relationship between anxiety and depression and HRQoL (healthrelated quality of life) was examined. In this study, anxiety and depression were reported as the most important risk factors adversely affecting HRQoL (25). When the results of the above study are examined in general, there is an inverse interaction between quality of life and depression and anxiety. Therefore, especially in this age group, because of the close relationship between depression and suicide, the causes of depression in PD patients should be investigated and treated. As seen in the results of our study, NLUD appears to be an important risk factor for the development of anxiety and depression. In our study, rate of nocturia was found to be 62.8%, and it was also identified as a risk factor for the development of anxiety and depression. Sleep disorders may be the basis of the relationship between nocturia and anxiety and depression. In other studies, it was found that sleep disorder frequently develops in PD (19). Going to the toilet frequently at night results in a sleep break that may manifest itself with fatigue, dizziness, exhaustion, irritability, and depressive mood. Insomnia, which causes significant problems even in normal individuals, can have more serious consequences in PD patients. For this reason, nocturia in these patients should be noticed in a timely manner and necessary precautions should be taken. Our study has some limitations. The most important of these is the low number of patients and the retrospective design of the study. In addition, other causes of anxiety and depression were not searched in this study. However, we think that this study is one of the few studies examining the relationship between bladder dysfunction and the development of anxiety and depression in PD.

CONCLUSIONS

In conclusion, NMS such as neurogenic lower urinary dysfunction, anxiety and depression are common in PD patients. However, in daily practice, clinicians who treat these patients often neglect these symptoms because they are more concerned with motor complaints. According to the results of our study, NLUD is a risk factor for the development of anxiety and depression. These patients, whose quality of life is already deteriorated due to PD, should not be exposed to problems related to NLUD (such as falling, head trauma due to falls, hip fractures, insomnia, anxiety and depression) and the necessary precautions should be followed closely. Patients should not be expected to discuss these complaints, because, as we have seen in our study, these complaints can sometimes be forgotten or considered by patients as a natural part of the disease.

REFERENCES

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Correspondence Erdal Benli, MD Abdullah Cirakoglu, MD Department of Urology, Ordu University, Faculty of Medicine, Ordu (Turkey) Fahriye Feriha Ozer, MD Department of Neurology, Koç University Faculty of Medicine, Istanbul (Turkey) Nesrin Helvaci Yilmaz, MD Ozge Arici Duz, MD Department of Neurology, Istanbul Medipol University, Faculty of Medicine, Istanbul (Turkey) Ahmet Yuce, MD (Corresponding author) ahmetyuce7@gmail.com Department of Urology, Darende Hulusi Efendi State Hospital, Malatya, Turkey Tuba Saziye Ozcan, MD Department of Neurology, Sancaktepe Sehit Prof.Dr. Ilhan Varank Training and Research Hospital, Istanbul (Turkey)

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25. Schwarz J, Odin P, Buhmann C, et al. Depression in Parkinson's disease. J Neurol. 2011; 258:336-338.

DOI: 10.4081/aiua.2021.3.341

ORIGINAL PAPER

Summary

Objective: To evaluate the long-term effects of the coronavirus disease 2019 (COVID-19) pandemic on sexual functions and behavior in men with heterosexual partners. Materials and methods: A total of 602 participants completed an online questionnaire, shared via social networks, between November 20 and December 20, 2020. Pre-pandemic sexual intercourse frequency, International Erectile Dysfunction Index (IIEF-15) score, intravaginal ejaculatory latency time (IELT), premature ejaculation diagnostic tool (PEDT) score, and activities during sexual intercourse were compared to the ones during the pandemic. In addition, the effects of various variables on participants’ sexual functions were evaluated and analyzed according to age groups. Results: The mean number of weekly sexual intercourse during the pandemic was 1.7+1.7, which was significantly lower than in the pre-pandemic period (p < 0.001). The ED score was significantly lower during the pandemic (p < 0.001) compared to the pre-pandemic period, however orgasmic function (p = 0.016), sexual intercourse satisfaction (p < 0.001), general satisfaction (p < 0.001), and PEDT scores (p = 0.004) were significantly higher. There was no significant difference in IELT before and during the pandemic (p = 0.391). Full-time employment and low education level were risk factors for developing ED and PE. The negative affect of the pandemic on sexual life was most prominent in the > 65 age group. Although kissing, oral and anal sex, and face-to-face sex positions decreased during the pandemic in all age groups, kissing and face-to-face sex positions remained the most preferred sexual behavior pattern (p = 0.002). There was no reduction in risky sexual behavior in the majority of the participants. Conclusions: At the end of one year with COVID-19, a decrease in erectile function and an increase in PE incidence were observed in men. Despite this, there was an increase in sexual desire and satisfaction. Although there were some changes in sexual behavior, the majority of pre-pandemic habits continued.

the World Health Organization (WHO) declared it a pandemic on March 11, 2020 (2). The WHO generated a global epidemiological situation report based on the national data received from each country and Turkey was reported as having the highest number of cases in the European region (33% of all cases in Europe, 194.476 new cases total, and 2.306 new cases per 1 million population) (3). The first COVID-19 case in Turkey was identified on the same day the WHO declared the global pandemic. Several measures limiting individual and social life were quickly implemented by the Turkish government. People have been living with these limitations, and the accompanying physical, psychological, economic, and social effects, for a long time. It was inevitable that sexual health, defined by the WHO as the physical, emotional, mental, and social well-being of an individual, would also be affected during this period (4). Quarantine measures and some of the limitations in daily life imposed during the recent Severe Acute Respiratory Syndrome (SARS), H1N1 influenza, Middle East Respiratory Syndrome (MERS), and Ebola epidemics have been reported to negatively affect sexual life (5). The COVID-19 pandemic has significantly affected the quality of life, with negative effects on interpersonal relationships, community life, and sexual health (6). A few studies have evaluated the effects of the COVID-19 pandemic on sexual life during the first months of the pandemic; however they mostly focused on investigating sexual behaviors rather than sexual function, and presented various opinions (7, 8). The effects of this prolonged pandemic, which has reshaped all our lives, on sexual behavior patterns and sexual function are not yet known. In this study, we evaluated the medium-term effects of the COVID-19 pandemic on sexual function and behaviors in men with heterosexual partners.

KEY WORDS: Coronavirus disease 2019 (COVID-19); Erectile dysfunction; Premature ejaculation; Sexual behavior; Mid-term effect.

MATERIALS

Submitted 1 March 2021; Accepted 21 April 2021

INTRODUCTION

Coronavirus disease 2019 (COVID-19) caused by the SARS CoV-2 virus first appeared in Wuhan, China, in December 2019 (1). It quickly spread across the globe, and finally

AND METHODS

Study design In this cross-sectional study, men were asked to complete a 34-item online questionnaire, which took approximately 20 minutes, consisting of multiple-choice and open-ended questions evaluating their sexual function and behaviors between November 06 and December 06, 2020. The questionnaire, which was created using a Turkish online survey

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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platform (http://www.surveey.com), was delivered to the participants online via social networks. The inclusion criteria of the study were being a heterosexual male older than 18 years, having an active sexual life that had continued for at least 6 months in the pre-pandemic period, no history of radical pelvic surgery, sexual dysfunction, or psychiatric disorder, and not having COVID-19. We evaluated men with heterosexual partners, because it has been reported that performing sexual activity with a partner provides higher sexual satisfaction than activity alone (9), and since the intravaginal ejaculation latency time (IELT) was used for evaluation of ejaculation function. Inclusion criteria were presented on the survey entry page on the website, and those who met these conditions and agreed to participate were asked to fill out the survey.

Sociodemographic data, medical history, and personal habits were investigated in the first part of the study. Age, education, marital status, work situation, income level during the pandemic, the number of individuals living at home during the pandemic, comorbidities, smoking, and alcohol use were evaluated. The second part of the study focused on evaluating changes in sexual behaviors such as the number of episodes of intercourse per week, IELT, sexual activities during intercourse, risky sexual activities, and changes in sexual attitudes such as the timing of intercourse during the day, during the pandemic, compared to the pre-pandemic period. In addition, the psychological effects of information about the pandemic obtained from news sources (television, radio, newspapers, magazines, and social media applications such as

Table 1. Comparison of demographic data between group 1 and group 2. Characteristic Marital status Single Married Education level High school and below University Master or above Working frequency (during pandemic) Not working Part time Full time Home office Change in incomelevel (during pandemic) Decreased Increased or Not changed Change in the number of sexual partners(during pandemic) Decreased Increased or Not changed Change in the number of people lived together Decreased Increased or Not changed Alcohol and smoking use Smoking Alcohol Both of them None of them Comorbidities No Yes Diabetes mellitus Hypertension Coronary artery disease Congestive heart failure Others Communication tools (during pandemic) Television Radio Social media (Facebook, Twitter, Instagrametc.) Newspaper, magazine The effect of pandemic news on psychological status Good Bad Have you had sexual intercourse at different times of the day during the pandemic compared to before the pandemic? Yes No Risky sexual behavior during the pandemic Decreased Increased or not changed I never engage in risky sexual behavior

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Total (n = 602) n (%)

Group 1 (n = 211) n (%)

Group 2 (n = 391) n (%)

240 (39.9) 362 (60.1)

104 (49.3) 107 (50.7)

136 (34.8) 255 (65.2)

165 (27.4) 291 (48.3) 146 (24.3)

65 (30.8) 111 (52.6) 35 (16.6)

100 (25.5) 180 (46.0) 111 (28.4)

122 (20.3) 131 (21.8) 171 (28.4) 178 (29.6)

38 (18.0) 48 (22.7) 67 (31.8) 58 (27.5)

84 (21.5) 83 (21.2) 104 (26.6) 120 (30.7)

235 (39.0) 367 (61.0)

106 (50.2) 105 (49.8)

129 (33.0) 262 (67.0)

133 (22.1) 469 (77.9)

85 (40.3) 126 (59.7)

48 (12.3) 343 (87.7)

45 (7.5) 557 (92.5)

22 (10.4) 189 (89.6)

23 (5.9) 368 (94.1)

106 (17.6) 119 (19.8) 172 (28.6) 205 (34.1)

42 (19.9) 31 (14.7) 65 (30.8) 73 (34.6)

64 (16.4) 88 (22.5) 107 (27.4) 132 (33.8)

482 (80.1) 120 (19.9) 32 (5.1) 33 (5.2) 18 (2.9) 2 (0.3) 62 (9.9)

180 (85.3) 31 (14.7) 12 (5.6) 6 (2.8) 3 (1.4) 0 (0) 14 (6.5)

448 (41.2) 55 (5.1) 480 (44.1) 105 (9.7)

147 (43.2) 14 (4.1) 153 (45.0) 26 (7.6)

301 (40.2) 41 (5.5) 327 (43.7) 79 (10.6)

218 (36.2) 384 (63.8)

66 (31.3) 145 (68.7)

152 (38.9) 239 (61.1)

271 (45.0) 331 (55.0)

85 (40.3) 126 (59.7)

0.086 186 (47.6) 205 (52.4)

98 (16.3) 186 (30.4) 318 (52.8)

66 (31.3) 58 (27.5) 87 (41.2)

32 (8.1) 128 (32.8) 231 (59.1)

P value 0.001 0.002

0.437

< 0.001 < 0.001 0.043 0.122

0.018 0.021

0.319

0.064

< 0.001

Male sexual function in COVID-19 pandemic

Facebook, Twitter, Instagram, and WhatsApp), and whether such news had a negative effect on their sexual activity during the pandemic were investigated. In the third part of the study, sexual functioning including erection and ejaculation were evaluated using internationally validated questionnaires. This study complied with the relevant ethical regulations (institutional ethics committee protocol number: 2020/117). All participants reviewed and signed the informed consent page prior to filling out the online survey on the website. Evaluation of sexual function The International Index of Erectile Function (IIEF-15), which was translated and validated by the Turkish Andrology Association in 2002, was used to investigate five areas of male sexual function, including erectile function, orgasmic function, sexual desire, sexual satisfaction, and general satisfaction before and during the pandemic (10). In our study, participants with an IIEF score < 26 were considered to have erectile dysfunction (ED), and those ≥ 26 were considered to have normal erectile function. Participants were asked to choose their IELT from one of the following options: < 1 min, 1-3 min, 3-25 min, and ≥ 25 min. The premature ejaculation diagnostic tool (PEDT), a 5-item questionnaire that evaluates the control, frequency, minimum stimulation, distress, and interpersonal difficulties of ejaculation, the Turkish version of which has been validated, was used in the evaluation of premature ejaculation (PE) before and during the pandemic (11). In our study, participants with a PEDT score of ≥ 9 were considered to have PE. Participants who reported a decrease in the number of episodes of sexual intercourse per week during the pandemic were classified as Group 1, and those who reported an increase or no change as Group 2. In addition, participants were divided into three groups according to their ages: < 40 years, 40-65 years, and ≥ 65 years. The changes in these groups from before and during the pandemic were compared. Also, the characteristics of men who had normal erectile function before the pandemic, but had newly developed ED and PE during the pandemic, were evaluated by logistic regression analysis. Statistical analyses The survey data were evaluated using SPSS software (ver.21.0 for Windows; SPSS Inc, Chicago, IL, USA). The compliance of continuous variables with normal distribution was investigated using visual (histogram and probability graphs) and analytical (Kolmogorov-Smirnov/ Shapiro-Wilk tests) methods. For the descriptive statistics, mean and standard deviation were used for data that fitted the normal distribution, and the median and minimummaximum for data that did not fit the normal distribution. Chi-square test was used to determine whether there was a difference between categorical variables. Student’s t-test or one-way ANOVA were used to compare continuous variables with parametric properties in independent groups, and Mann-Whitney U Test or Kruskal-Wallis analysis of variance were used to compare continuous variables without parametric properties in independent groups. The T-test was used to compare continuous vari-

ables with parametric properties in dependent groups, the Wilcoxon test was used to compare continuous variables with non-parametric properties in dependent groups, and McNemar’s Chi-Square test was used to compare categorical variables in dependent groups. P value of < 0.05 was considered statistically significant.

RESULTS

A total of 1.309 men participated in the study. The data of 602 participants who completed the questionnaire and met the inclusion criteria were evaluated. The response rate was 45.9%. The mean age of all participants was 36.1 ± 11.6 years. While the mean weekly frequency of sexual intercourse was 2.1 ± 1.5 in the pre-pandemic period, it was 1.7 ± 1.7 during the pandemic (p < 0.001). Of the participants, 35% (n = 211) were in Group 1 and 65% (n = 391) in Group 2. The demographic characteristics of all participants and the distribution of these characteristics according to both groups are summarized in Table 1. Erectile function score during the pandemic was significantly lower (p < 0.001) than before the pandemic, while orgasmic function (p = 0.016), sexual intercourse satisfaction (p < 0.001), general satisfaction (p < 0.001), and PEDT (p = 0.004) scores were significantly higher (Table 2). All subdomains of IIEF-15 were significantly lower in Group 1 than in Group 2. However, the PEDT score was higher in Group 1, but not statistically significant (p = 0.055). No significant difference was found in self-reported IELT scores before and during the pandemic (p = 0.391) (Figure 1). While a significant decrease was observed in sexual behaviors such as kissing, oral sex and face-to-face sex positions during the pandemic, a significant increase was observed in non-face-to-face positions (Table 3). During the pandemic, 45% (n = 271) of participants had intercourse at times of the day that differed from their pre-pandemic routine habits. Among 284 who reported risky sexual behaviors such as sexual intercourse without condoms, multiple partners, intercourse with new acquaintances and/or sex workers in the pre-pandemic period, only 98 (34.5%) reported a decrease in these behaviors during the pandemic. Evaluation according to age groups indicated that all IIEF15 subdomains were significantly lower in the ≥ 65 years age group compared to other groups during the pandemic. In addition, their PEDT scores were significantly higher than other age groups. In terms of sexual behaviors, kissing, and face-to-face sex positions decreased during the pandemic in all age groups but remained the most common sexual behavior pattern (p = 0.002). The data of 39 participants (8.8%) who had normal erectile function (IIEF score ≥ 26) before the pandemic, but developed ED of varying degrees (IIEF < 26) during the pandemic, and 25 (5.3%) participants who did not have PE complaints (PEDT score < 9) before the pandemic, but were assessed as having PE during the pandemic (PEDT score ≥ 9), were evaluated separately. When the factors affecting the development of ED and PE during the pandemic were examined with univariate analysis, ED was significantly more common in full-time workers (odds ratio: 5.011, 95% confidence interval: 1.191-21.090, p = 0.028), while PE was significantly more common in Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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Figure 1. Self-reported IELT scores before and during the pandemic.

men with a lower education level (odds ratio: 1.892, 95% confidence interval: 0.708-5.056, p = 0.040) (Table 4). Most of respondents obtained information about the

COVID-19 pandemic through social media applications (Facebook, Twitter, Instagram, WhatsApp) (44.1%) and television (41.2%). Among the participants, 63.8% stated

Table 2. Comparison of male sexual functions according to pre-pandemic, post-pandemic, group 1 and group 2, and age groups. Erectile function (max. score 30) Before pandemic (n = 602) mean (SD) median (min-max) * During pandemic (n = 602) mean (SD) median (min-max) * P value Group 1 (n = 211) mean+SD median (min-max) * Group 2 (n = 391) mean+SD median (min-max) * P value Before pandemic < 40 years (n = 436) mean+SD median (min-max) * 40-65 years (n = 145) mean+SD median (min-max) * > 65 years (n = 21) mean+SD median (min-max) * P value During pandemic < 40 years (n = 436) mean+SD median (min-max) * 40-65 years (n = 145) mean+SD median (min-max) * > 65 years (n = 21) mean+SD median (min-max) * P value

International Index of Erectile Function-15 (IIEF-15) Orgasmic function Sexual desire Intercourse satisfaction Overall satisfaction (max. score 10) (max. score 10) (max. score 15) (max. score 10)

26.9 (5.2) 30 (6-30)

3.9 (1.7) 4 (2-10)

3.7 (1.7) 4 (2-10)

5.3 (2.1) 5 (0-12)

4.0 (2.0) 4 (0-10)

4.1 (6.5) 0 (0-20)

26.5 (6.0) 30 (6-30) < 0.001

4.1 (2.2) 4 (2-10) 0.016

3.9 (2.0) 4 (2-10) 0.082

6.0 (2.0) 6 (0-11) < 0.001

4.9 (2.2) 4 (0-10) < 0.001

4.3 (6.3) 0 (0-20) 0.004

25.6 (6.6) 30 (6-30)

4.0 (2.2) 4 (2-10)

3.7 (2.0) 3 (2-10)

5.9 (1.7) 6 (0-11)

4.6 (1.9) 4 (0-10)

4.9 (6.5) 0 (0-20)

26.9 (5.6) 30 (6-30) 0.008

4.4 (2.1) 4 82-10) 0.005

4.3 (2.1) 4 (2-10) < 0.001

6.2 (2.4) 6 (0-11) 0.043

5.5 82.5) 6 (0-10) < 0.001

4.0 (6.2) 0 (0-20) 0.055*

28.3 (3.6) 30 (8-30)

3.9 (1.7) 4 (2-8)

5.0 (2.9) 5 (2-10)

7.2 (1.8) 7 (0-9)

6.3 (1.7) 6 (0-9)

3.5 (6.3) 0 (0-20)

24.7 (5.7) 26 (8-30)

4.0 (1.8) 4 (2-8)

4.0 (1.7) 4 (2-8)

5.6 (1.9) 5 (0-11)

4.3 (1.8) 4 (0-10)

5.0 (6.5) 2 (0-20)

13.9 (6.6) 15 (6-30) < 0.001

3.9 (1.7) 4 (2-10) 0.993

3.6 (1.6) 4 (2-8) 0.006

5.2 (2.2) 5 (0-12) < 0.001

3.8 (1.9) 4 (0-10) < 0.001

8.3 (7.6) 12 (0-19) < 0.001

28.0 (4.4) 30 (6-30)

4.9 (2.2) 4 (2-8)

6.0 (2.5) 7 (2-10)

7.4 (1.2) 7 (4-10)

6.7 (1.2) 6 (4-10)

3.7 (6.1) 0 (0-20)

23.7 (6.9) 25 (6-30)

4.5 (2.2) 4 (2-10)

4.7 (2.1) 4 (2-10)

6.1 (2.1) 6 (0-11)

5.0 (2.3) 4 (0-10)

5.6 (6.2) 4 (0-20)

14.4 (6.5) 15 (6-30) < 0.001

4.0 (2.1) 4 (2-10) 0.007

3.5 (1.8) 3 (2-10) < 0.001

5.9 (1.9) 6 (0-11) < 0.001

4.8 (2.1) 4 (0-11) < 0.001

9.6 (6.8) 12 (0-19) < 0.001

SD: Standard Deviation. * Statistical significance was evaluated in the data expressed as median (min-max).

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Male sexual function in COVID-19 pandemic

Table 3. Comparison of sexual intercourse and sexual activities by pre-pandemic and post-pandemic, group 1 and group 2, and age groups. Number of sexual intercoursein a week, mean (SD) Before pandemic (n = 602) During pandemic (n = 602) P value Group 1 (n = 211) Group 2 (n = 391) P value Age (Before pandemic), year < 40 years (n = 436) 40-65 years (n = 145) > 65 years (n = 21) P value

Kissing

Oral sex

2.1 (1.5) 1.7 (1.7) < 0.001 1.0 (1.0) 2.1 (1.9) < 0.001

488 (29.9) 402 (28.3) < 0.001 130 (28.0) 272 (28.4)

246 (15.1) 200 (14.1) < 0.001 73 (15.7) 127 (13.3)

1.8 (1.9) 1.6 (1.1) 0.8 (0.5) 0.017

279 (27.5) 104 (29.1) 19 (38.8)

168 (16.6) 31.0 (8.7) 1 (2.0)

Sexual activities, n (%) Anal sex Face-to-face Sex positions (e.g. missionary) 42 (2.6) 522 (32.0) 33 (2.3) 429 (30.2) 0.064 < 0.001 12 (2.6) 129 (27.8) 21 (2.2) 300 (31.3) 0.554 23 (2.3) 10 (2.8) 0 (0.0)

Nonface-to-face Sex positions (e.g. doggystyle) 332 (20.4) 357 (25.1) 0.023 120 (25.9) 237 (24.8)

289 (28.5) 121 (33.8) 19 (38.8)

255 (25.1) 92 (25.7) 10 (20.4)

0.002

Table 4. Univariate analysis of erectile dysfunction and premature ejaculation.

Age Education level Working frequency (during pandemic) Change in income level (during pandemic) Marital status Change in the number of sexual partners (during pandemic) Change in the number of people lived together Comorbidities The effect of pandemic news on psychological status

OR 1.002 1.191 5.011 0.732 0.835 0.542 0.967 3.148 0.589

Erectile dysfunction p 0.903 0.627 0.028 0.348 0.601 0.084 0.957 0.060 0.160

Univariate analysis %95 CI 0.974-1.030 0.589-2.410 1.191-21.090 0.381-1.404 0.425-1.641 0.270-1.086 0.286-3.273 0.953-10.402 0.281-1.232

OR 0.995 1.892 1.192 0.438 1.352 2.164 1.301 0.587 1.241

Premature ejaculation p 0.833 0.040 0.786 0.098 0.540 0.309 0.801 0.326 0.666

%95 CI 0.953-1.039 0.708-5.056 0.337-4.214 0.164-1.166 0.514-3.556 0.489-9.585 0.169-10.043 0.203-1.700 0.465-3.308

Figure 2. The reasons reported by the participants for the decrease in sexual activities during the pandemic.

that they were psychologically negatively affected by this information, and 30.9% attributed their decrease in frequency of sexual intercourse during the pandemic to the news obtained from the press and social media (Figure 2).

DISCUSSION

This is the first study to evaluate medium-term effects of the COVID-19 pandemic on sexual function and behavior in men. In this study, as in many reports in the litera-

ture, the number of episodes of sexual intercourse was taken as the basis for sexual health evaluation. Although there are studies defending the contrary (12), one of the main factors determining sexual satisfaction remains the frequency of sexual intercourse (13). Sexual satisfaction is both the result and indicator of a healthy sex life (14). An online survey study conducted in some Southeast Asian countries involving participants with a high level of education, reported that there was no significant difference in the frequency of sexual intercourse during the Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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COVID-19 pandemic compared to the pre-pandemic time (15). Li et al. (8) found that during the pandemic, 37% of respondents experienced a decrease in the frequency of sexual intercourse and 25% in sexual desire. These reductions were greater in men than in women, and a decrease in sexual satisfaction was found in 32% of the men. Jacob et al. (7) found that young age, male gender, being married, and consuming alcohol were associated with increased sexual activity. An increased number of days spent in self-isolation also positively affected the frequency of sexual intercourse. Studies reporting a decrease in the frequency of sexual desire and intercourse concluded that limited living space, prolonged decrease in domestic privacy, increase in differences of opinion between the spouses, and exacerbation of previous conflicts were reasons for the changes in sexual behavior. In addition, the effects of various pandemic-related stress factors, together with anxiety and depression caused by economic deterioration have also been reported (16). Although there are conflicting reports, most studies reported that the severity of anxiety and depression was correlated with the loss of sexual desire (17). In our study, although there was a decrease in the frequency of sexual intercourse, there was an increase in sexual desire and satisfaction. Various physical factors such as the requirement to live apart from their partner, and staying away from their partner due to fear of getting sick may have affected the frequency of sexual intercourse during this period (18). However, the increase in sexual desire may be a result of the individual’s internal struggle in dealing with the long-term negative psychological factors. Mollaioli et al. (19) reported that all types of sexual activity have protective effects against anxiety and mood disorders related to quarantine in both sexes. However, it is not necessary to have a lot of sexual intercourse for sexual health and satisfaction (12). Although there is no evidence that COVID-19 is transmitted through sexual intercourse, the close contact of partners due to the nature of sex creates a potential risk for SARS-CoV-2 transmission through respiration and saliva. This, in addition to other factors, can lead to avoidance of sexual activity during the pandemic despite a healthy partner (20). Even if intercourse is not avoided, activity preferences during intercourse may be affected. Culha et al. (21) reported that foreplay, kissing, oral, and anal sex were less common and that couples preferred non-face-to-face sexual positions during the COVID-19 pandemic. However, Baran and Aykac (22) reported that the vast majority of couples did not fear COVID-19 transmission during sex, and married couples had the least amount of fear. In our study, only 14.6% of men stated that their sex life was negatively affected due to the fear of infecting themselves or their partner. Face-to-face positions such as the missionary position in vaginal intercourse as well as kissing, oral, and anal sex decreased compared to the pre-pandemic period, but face-to-face positions remained the preferred type of sexual behavior during the pandemic. In addition, we found that only 34.5% of men who reported risky sexual activities in terms of transmission such as sexual activity without a condom, multiple partners, and intercourse with new acquaintances or sex workers during the pre-pandemic

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period reduced such activities during the pandemic. However, a decrease in risky sexual behaviors has been reported in the early stages of the pandemic (8). Erectile function was evaluated with international erectile function indices (IIEF-5, IIEF-15), and a decrease was found in the early stages of COVID-19 compared to the pre-pandemic period (22). Fang et al. (23) stated that men reported worsening of erectile function and ejaculation control ability during the pandemic. In that study, it was observed that 31.9% of participants had a decrease in their IIEF-5 scores, and 17.9% had an increase in their PEDT scores. In our study, the erection score was significantly lower but all other subdomains of IIEF-15 were significantly higher during the pandemic. The number of men who reported their IELT as < 1 minute during the pandemic was higher than before the pandemic. In addition, there was a significant increase in the PEDT score compared to the pre-pandemic period. In the European Urology Guideline, it has been reported that PE is affected by low education level, absence of physical activity, and religious beliefs (a majority of Muslim countries have higher levels of PE) (24). Stress and limitation of movement in a country with a majority Muslim population such as Turkey might therefore be expected to cause an increase in PE. However, we did not find any risk factor other than a low education level in the univariate analysis of respondents with newly developed PE during the pandemic. With advanced age, low testosterone levels in men increase the loss of libido and negatively affect sexual behavior, thus reducing the quality of sexual life (25). It is not surprising that erectile function also decreases due to androgen deficiency and increased stress factors. We found that erectile function and sexual desire were lower in the older age group. When we evaluated PE according to age groups, we found that during the pandemic PEDT scores were higher in men ≥ 65 years of age. Our study had some limitations. The data were selfreported. Requesting information from the pre-pandemic period may have created memory difficulties for participants and introduced bias. Other than those of the international questionnaires, our questions were non-validated. In addition, because we wanted to keep the number of questions low to make participation easier, we did not evaluate their current anxiety and/or depression status with approved questionnaires. We only included participants who did not have a known psychiatric problem. However, participants reported that they were psychologically negatively affected by news about COVID-19 and that this affected their sexual life the most. This can be considered a separate limitation. Society's perception of sexuality is effective in shaping individual sexual behavior. This may limit generalization of our results. We believe that the results of our study, conducted in Turkey, where the culture is a blend of the values of both western and eastern civilizations, can contribute to knowledge about changes in sexual function and behavior during the COVID-19 pandemic.

CONCLUSIONS

It has been one year since the start of the COVID-19 pandemic. In our study of men in Turkey, frequency of sex-

Male sexual function in COVID-19 pandemic

ual intercourse and erectile function have decreased, although sexual desire and sexual satisfaction have both increased. In addition, complaints of PE have increased. In terms of sexual behavior, pre-pandemic habits have continued, including engaging in risky sexual behavior.

17. Beutel ME, Burghardt J, Tibubos AN, et al. Declining sexual activity and desire in men-findings from representative German surveys, 2005 and 2016. J Sex Med. 2018; 15:750-6.

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1. Zhu N, Zhang D, Wang W, et al. A novel Coronavirus from patients with pneumonia in China. N Engl J Med. 2019; 382:727-33. 2. World Health Organization, (2020). (March 11, 2020). DirectorGeneral’s opening remarks at the media briefing on COVID-19 - 11 March 2020. Retrieved from https://www.who.int/dg/speeches/detail/ who-director-general-s-opening-remarks-at-the-media-briefing-oncovid-19---11-march-2020. 3. World Health Organization, (2020). (December 22, 2020). Coronavirus disease (COVID-19) Weekly Epidemiological Update and Weekly Operational Update-22 December 2020. Retrieved from https://www.who.int/publications/m/item/weekly-epidemiologicalupdate---22-december-2020. 4. Glasier A, Gülmezoglu AM, Schmid GP, et al. Sexual and reproductive health: a matter of life and death. Lancet. 2006; 368:1595-607. 5. Brook 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. 6. Maretti C, Privitera S, Arcaniolo D, et al. COVID-19 pandemic and its implications on sexual life: Recommendations from the Italian Society of Andrology. Arch Ital Urol Androl. 2020; 92:73-7. 7. Jacob L, Smith L, Butler L, et al. Challenges in the practice of sexual medicine in the time of COVID-19 in the United Kingdom. J Sex Med. 2020; 17:1229-36.

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19. Mollaioli D, Sansone A, Ciocca G, et al. Benefits of sexual activity on psychological, relational, and sexual health during the COVID-19 breakout. J Sex Med. 2021; 18:35-49. 20. Scorzolini L, Corpolongo A, Castilletti C, et al. Comment on the potential risks of sexual and vertical transmission of COVID-19. Clin Infect Dis. 2020; 71:2298. 21. Culha MG, Demir O, Sahin O, Altunrende F. Sexual attitudes of healthcare professionals during the COVID-19 outbreak. Int J Impot Res. 2021; 33:102-9. 22. Baran O, Aykac A. The effect of fear of covid-19 transmission on male sexual behaviour: A cross-sectional survey study. Int J Clin Pract. 2021; 75:e13889. 23. Fang D, Peng J, Liao S, et al. An online questionnaire survey on the sexual life and sexual function of Chinese adult men during the Coronavirus disease 2019 Epidemic. Sex Med. 2021; 9:100293. 24. Salonia A, Bettocchi C, Carvalho J, et al. Sexual and reproductive health. EAU Guidelines 2020. Edn. Presented at the EAU Annual Congress Amsterdam 2020. ISBN 978-94-92671-07-3. 25. Forbes MK, Eaton NR, Krueger RF. Sexual quality of life and aging: a prospective study of a nationally representative sample. J Sex Res. 2017; 54:137-48.

8. Li W, Li G, Xin C, et al. Challenges in the practice of sexual medicine in the time of COVID-19 in China. J Sex Med. 2020; 17:1225-8. 9. Brod S, Costa RM. Satisfaction (sexual, life, relationship, and mental health) is associated directly with penile-vaginal intercourse, but inversely with other sexual behavior frequencies. J Sex Med. 2009; 6:1947-1954. 10. Akkus E, Kadioglu A, Esen A, et al. Prevalence and correlates of erectile dysfunction in Turkey: a population-based study. Eur Urol. 2002; 41:298-304. 11. Serefoglu EC, Cimen HI, Ozdemir AT, et al. Turkish validation of the premature ejaculation diagnostic tool and its association with intravaginal ejaculatory latency time. Int J Impot Res. 2009; 21:13944. 12. Muise A, Schimmack U, Impett EA. Sexual frequency predicts greater well-being, but more is not always better. Soc Psychol Personal Sci. 2015; 7:295-302. 13. Gillespie BJ. Correlates of sex frequency and sexual satisfaction among partnered older adults. J Sex Marital Ther. 2017; 43:403-23. 14. Palha-Fernandes E, Alves P, Lourenço M. Sexual satisfaction determinants and its relation with perfectionism: A cross-sectional study in an academic community. Sexual and Relationship Therapy, DOI: 10.1080/14681994.2019.1677884. 15. Arafat SMY, Alradie-Mohamed A, Kar SK, et al. Does COVID19 pandemic affect sexual behaviour? A cross-sectional, crossnational online survey. Psychiatry Res. 2020; 289:113050. 16. Ko NY, Lu WH, Chen YL, et al. Changes in sex life among people in Taiwan during the COVID-19 pandemic: the roles of risk per-

Correspondence Erhan Ates, Associate Professor of Urology (Corresponding Author) drerhanates@yahoo.com Hakan Gorkem Kazici, MD hgkazici@yahoo.com Ahmet Emre Yildiz, MD aemreyildiz@gmail.com Saparali Sulaimanov, MD sulaimanovsaparali@gmail.com Arif Kol, Assistant Professor of Urology drarifkol@hotmail.com Haluk Erol, Professor of Urology halukerol@yahoo.com Department of Urology, Aydin Adnan Menderes University School of Medicine, 09010, Aydin (Turkey)

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DOI: 10.4081/aiua.2021.3.348

ORIGINAL PAPER

Urologists’ knowledge base and practice patterns in Peyronie’s disease. A national survey of members of the italian andrology society Gianni Paulis 1, Francesca Pisano 2, Alessandro Palmieri 3, Tommaso Cai 4, Fabrizio Palumbo 5, Bruno Giammusso 6 1 Peyronie’s

Care Center, Department of Uro-Andrology, Castelfidardo Medical Team, Rome, Italy; of Urology, Fundacio Puigvert, Autonomous University of Barcelona, Spain; 3 Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples Federico II, Naples, Italy; 4 Department of Urology, Santa Chiara Regional Hospital, Trento, Italy; 5 Department of Urology, Di Venere Hospital, Bari, Italy; 6 Urology Clinic, Policlinic “Morgagni”, Catania, Italy. 2 Department

Summary

Peyronie’s disease is a chronic inflammatory disease involving the formation of plaque in the tunica albuginea of the corpora cavernosa, resulting in penis deformity. It is often associated with penile pain, especially in younger patients, but it is not rare for pain to be absent; the disease is also associated with erectile dysfunction and a depressive state in a large percentage of cases. Objective: Aim of our study was to explore the basic knowledge base and diagnostic and therapeutic practice patterns in Peyronie's disease (PD) of a large number of physicians belonging to the Italian Andrology Society (SIA). Methods: Our survey is based on two questionnaires which were e-mailed to the members of the SIA. The first questionnaire explored diagnostic and therapeutic practice patterns of SIA physicians, while the second questionnaire focused on their knowledge of the disease, as well as their training and level of experience in the specific field. We then planned to compare our outcomes with similar PD surveys from other countries. Results: The first questionnaire was answered by 142 SIA physicians. The second questionnaire was answered by 83 SIA physicians. Most respondents (74.6%) chose penile ultrasonography as first-line diagnostic approach and 47.1% prefer to perform a color Doppler ultrasound after pharmaco-induced erection. Concerning the therapeutic practice patterns in active stage of the disease, most respondents (99.29%) prefer conservative medical therapy. Additionally, most respondents (64.78%), when failure of conservative treatment had been established, considered surgical treatment necessary, specifically corporoplasty, which may be associated with other techniques. Conclusions: The results of our survey show that, in comparison to their foreign counterparts, Italian SIA uro-andrologists have a more proactive diagnostic approach right from when patients first present. When PD is still in its active stage, SIA uro-andrologists mostly opt for medical therapy. In advanced disease or if conservative treatment fails, our survey indicates a greater preference for surgical treatment. Answers to the theoretical knowledge questions showed that SIA physicians have a good understanding of the disease’s etiology, epidemiology, and clinical picture, and of the appropriate indications for treatment.

KEY WORDS: Peyronie’s disease; Penile curvature; Erectile dysfunction; Peyronie’s disease treatment; Practice patterns; Survey. Submitted 28 June 2021; Accepted 9 August 2021

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No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

INTRODUCTION

Peyronie’s disease (PD) is a chronic inflammatory disease of the tunica albuginea of the corpora cavernosa, involving the formation of a fibrous or even calcified plaque which almost always causes penile curvature and/or deformity (divot, hourglass deformity, shortening). It is often associated with penile pain, especially in younger patients, but it is not rare for pain to be absent; the disease is also associated with erectile dysfunction (ED) (in over 30% of cases) and a depressive state in a large percentage of cases (48%) (1-3). Although the exact etiology of the disease is unknown, according to the most credited theory, injury, or micro-traumas to the tunica albuginea of the corpora cavernosa of the penis play a decisive role in its pathogenesis (4-7). Penile trauma, by causing delamination of the layers of the tunica albuginea with consequent rupture of the small perforating blood vessels, is thought to result in the formation of a small hematoma which triggers the inflammatory process (5, 6). Supposedly, fibrin accumulation then causes recruitment of inflammatory cells (neutrophils and macrophages), with consequent overproduction of pro-inflammatory fibrogenic cytokines and reactive oxygen species (ROS) (7-12). Once the inflammatory process has been triggered, the subsequent chain of biochemical events is then thought to result in hyperproliferation of fibroblasts and myofibroblasts, leading to excessive production and deposition of collagen at the site (8). Genetic predisposition is certain to play a fundamental role in the possibility of developing the disease, with an autosomal dominant inheritance pattern (13-16). Several epidemiological studies have found that disease prevalence in adult males varies between 3.2% and 13%; a study by La Pera et al. (2001) detected a 7.1% prevalence of PD in Italian males (17-19). The disease generally affects adult males of 50-60 years of age, but in the past few years a considerable increase in PD incidence has been reported in patients under 40 years of age (10.8%-16.9% of cases) (20, 21). In its first stages, PD is characterized by the presence of an inflammatory area (corresponding to the plaque) in which fibroblasts and myofibroblasts produce excess collagen (8, 22, 23). Several studies have shown that local hyperproduction of collagen

Peyronie’s disease SIA survey

in PD is directly connected with elevated production of pro-inflammatory fibrogenic cytokines, among which the most important are transforming growth factor beta-1 (TGFß1) and platelet-derived growth factor (PDGF) (6, 24-26). The natural history of the disease has two stages: an initial remodeling phase, which is the inflammatory stage and lasts about 12-18 months; the second phase consists in stabilization of the disease: in this phase, pain is typically absent, while the penile deformity stops progressing (27-29). Conservative medical treatment is indicated in the first (active) stage and includes oral therapy, local intralesional therapy, and physical treatment: vitamin E, colchicine, tamoxifen, potaba, antioxidants, etc.; injections with verapamil, pentoxifylline, hyaluronic acid, corticosteroids, collagenase clostridium histolyticum (CCH/Xiaflex-Xiapex), interferon-α2b (IFNa2b); extracorporeal shock wave therapy (ESWT), iontophoresis, penile extender devices, vacuum devices, etc. (30-37). In particular, use of CCH was approved in the USA in 2013 by the US Food and Drug Administration (FDA) only in patients with stable PD; the same guidelines were issued by the American Urological Association, which recommends its use in stable disease (38). However, use of CCH has recently been proposed even in the acute (initial) phase of the disease (32, 39). Surgical therapy is indicated when the disease has been stable for at least 6 months and sexual intercourse has become impossible due to the presence of severe penile deformity or treatment-resistant ED; surgical treatment is also indicated when there is extensive calcification of the plaque, or when patients want a rapid, assured result (40-44). Despite the ample range of treatments proposed in the literature, there is no complete consensus among urologists about modality of therapeutic approach; this is partly due to an incomplete knowledge of the pathophysiological mechanisms of the disease. It is a fact that none of the therapeutic options mentioned in international guidelines on PD has a grade A recommendation (45-48). Over the past few years, several articles have been published that focused on PD surveys and questionnaires (49-54). The surveys described in the articles explored and assessed the basic knowledge and different diagnostic and therapeutic approaches of urologists, and these articles also found that practice patterns vary, especially with regards to treatment. Aim of our study was to explore the basic knowledge and diagnostic and therapeutic practice patterns in PD in a large number of physicians belonging to the Italian Andrology Society (SIA).

MATERIALS

AND METHODS

The survey was carried out last year (2020). Two questionnaires were e-mailed by the SIA office to all its uroandrologist members. A reminder e-mail was then sent to non-responders about one month after the initial mailing. No compensation was offered for completion of the questionnaires. The questionnaires used templates from the Google Doc web platform (docs.google.com). They were shared with and approved by the SIA Board and Scientific Committee. The first questionnaire comprised 5 multiple-choice questions and explored the diagnostic and therapeutic

approach of SIA physicians (see Table 1) (some questions required more than one answer as first question). The second questionnaire (see Table 2) contained 15 multiple-choice questions. The first 11 questions explored the uro-andrologists' basic knowledge on PD. The remaining 4 questions focused on the physicians' specialty, as well as their level of experience and clinical practice in the specific field. The analysis of the results did not require any particular statistical software, since we merely collected the percentages of answers to each question. Finally, adequacy of answers to the treatment-specific questions of the second questionnaire was assessed based on current approaches in the scientific literature on PD.

RESULTS

The first questionnaire was answered by 142 specialists (urologists and andrologists). The second questionnaire was answered by 83 specialists (urologists and andrologists). Results are reported in Table 1 and 2.

DISCUSSION

Most SIA respondents chose penile ultrasonography as first-line diagnostic approach (74.6%); most respondents prefer to perform a color Doppler ultrasound after pharmaco-induced erection (47.1%), while the remaining 27.4% opt for a flaccid penile ultrasound, using color Doppler ultrasound with pharmaco-induced erection only in cases where ED is also present. However, it must be pointed out that 9.1% of SIA respondents believes simple palpation of the penile nodule to be a sufficient diagnostic method. In most other similar surveys on PD in the literature (4954), diagnosis is not discussed; when it was included as an item, penile ultrasonography was deemed to be necessary in 22% to 28.2% of cases (52, 54). Although international guidelines do not consider penile ultrasound mandatory, our survey shows instead that most Italian uro-andrologists who responded to the SIA questionnaire (75.3%) believes a diagnostic imaging test should be performed (40, 45-48). With regards to therapeutic practice patterns in active stage PD, we found that in almost all cases SIA respondents (99.29%/141 out of 142) favor conservative medical therapy. In our survey, the conservative approach almost always (85.9%/122 out of 142) consisted in oral therapy associated most of the time with a physical treatment (vacuum device, ESWT, ultrasound therapy, iontophoresis, laser therapy) or penile injections (collagenase, verapamil, and/or corticosteroid, etc.). The oral therapy varies: besides several antioxidants (see results), it includes colchicine, potaba, pentoxifylline, and PDE-5 inhibitors. Comparing our survey with other existing surveys in the literature, we found the closest approach to ours to be that of the US survey in which LaRochelle & Levine (2007) found that 72% of urologists preferred medical treatment for PD, while 29% did not believe any treatment was necessary, and 28% preferred surgery only in case of associated severe curvature (50). In our survey, however, the "non-therapeutic" approach was only supported by one respondent out of Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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Table 1. Replies to first questionnaire. Questions 1) After first seeing patients presenting with Peyronie's disease, before proceeding to treatment…

2) Your first therapeutic approach in patients with Peyronie's disease (in its active stage, when it has not stabilized) is the following 3) If you opt for a conservative medical approach, what treatment do you prescribe?

4) How long after the start of conservative medical treatment do you consider it to have failed?

5) If conservative medical treatment fails, what do you do?

Answers I simply perform palpation and locate the penile plaque I refer the patient for a flaccid penile ultrasound I refer the patient for a penile dynamic Doppler ultrasound (*) I refer the patient for a penile dynamic Doppler ultrasound only with concomitant ED I refer the patient for an MRI of the corpora cavernosa (*) I refer the patient for the above-mentioned exam even though I did not find any palpable nodule Other - palpation and photograph of erect penis - unspecified penile ultrasonography - photograph of erect penis - stretched penile length measurement - invalid answers Conservative medical therapy Surgical therapy No therapy Oral therapy + physical treatment (Generic oral antioxidants, vitamin E, colchicine, avocado + soybean, potaba, pentoxifylline, PDE-5 inhibitors), various types of physical treatment (vacuum device, ESWT, ultrasound, laser therapy, iontophoresis with verapamil and/or cortisone, iontophoresis with pentoxifylline and/or verapamil) Oral therapy only - oral antioxidants (single or in combination: vitamin E, propolis, blueberry, astaxanthin, paba, arginine, Centella asiatica) - vitamin E + tamoxifen - antioxidants + colchicine - potaba - oral cortisone - antioxidants + oral cortisone - unspecified Penile injections only - collagenase (CCH) with modeling - verapamil - verapamil + corticosteroid - PRP (platelet rich plasma) - unspecified agent Physical treatment only - vacuum device - ESWT - iontophoresis - iontophoresis + ESWT - iontophoresis + ESWT + ultrasound therapy Oral therapy + penile injections Oral therapy + physical treatment + penile injections Oral therapy + vacuum device Conservative medical therapy on a case-by-case basis No therapy After 3 months After 6 months After 9 months After 12 months After - no exact time limit - inadequate answers I refer the patient for surgery - corporoplasty - corporoplasty + grafting - corporoplasty + implant - corporoplasty + implant only if ED is present - plaque excision + grafting - plaque excision + grafting + implant - it depends on the specific case - unspecified surgical treatment I try out another medical treatment - intraplaque collagenase (CCH) injection with modeling - intraplaque corticosteroid injection - intraplaque corticosteroid injection + antioxidants - generic intraplaque injection - injections with verapamil or orgotein + antioxidants - oral antioxidants - generic iontophoresis (no drug specified) - ESWT - ESWT + iontophoresis - vacuum device - unspecified physical treatment - oral antioxidants + unspecified physical treatment - oral antioxidants + iontophoresis with pentoxifylline - new therapy attempt with a different unspecified drug - it depends on the case No answer

% (Number) 17.6% (25 out of 142) 27.4% (39 out of 142) 47.1% (67 out of 142) 26.05% (37 out of 142 0.7% (1 out of 142) 9.1% (13 out of 142) 0.7% (1 out of 142) 0.7% (1 out of 142) 4.2% (6 out of 142) 0.7% (1 out of 142) 0.7% (1 out of 142) 99.2% (141 out of 142) 0% (0) 0.7% (1 out of 142) 35.9% (51 out of 142) 17.6% (25 out of 142) - 76.0% (19 out of 25) - 4.16% (1 out of 25) - 4.0% (1 out of 25) - 4.0% (1 out of 25) - 4.0% (1 out of 25) - 4.0% (1 out of 25) - 4.0% (1 out of 25) 7.7% (11 out of 142 ) - 63.6% (7 out of 11) - 9.09% (1 out of 11) -9.09% (1 out of 11) - 9.09% (1 out of 11) - 9.09% (1 out of 11) 3.5% (5 out of 142) - 20.0% (1 out of 5) - 20.0% (1 out of 5) - 20.0% (1 out of 5) - 20.0% (1 out of 5) - 20.0% (1 out of 5) 32.3% (46 out of 142) 0.7% (1 out of 142) 0.7% (1 out of 142) 0.7% (1 out of 142) 0.7% (1 out of 142) 21.1% (30 out of 142) 44.3% (63 out of 142 9.8% (14 out of 142) 19.01% (27 out of 142) 0.7% (1 out of 142) 4.9% (7 out of 142) 64.7% (92 out of 142) - 21.8% (31 out of 142) - 4.9% (7 out of 142) - 5.6% (8 out of 142) - 2.8% (4 out of 142) - 7.7% (11 out of 142) - 2.1% (3 out of 142) - 14.7% (21 out of 142) - 4.9% (7 out of 142) 31.6% (45 out of 142) - 4.9% (7 out of 142) - 0.7% (1 out of 142) - 0.7% (1 out of 142) - 2.1% (3 out of 142) - 0.7% (1 out of 142) - 1.4% (2 out of 142) - 0.7% (1 out of 142) - 4.2% (6 out of 142) - 0.7% (1 out of 142) - 0.7% (1 out of 142) - 0.7% (1 out of 142) - 0.7 % (1 out of 142) - 0.7% (1 out of 142) - 0.7% (1 out of 142) 11.9% (17 out of 142) 3.5% (5 out of 142)

(*) = possible further answer ED = erectile dysfunction; MRI = Magnetic resonance imaging; ESWT = extracorporeal shock wave therapy: PDE-5 = phosphodiesterase-5 inhibitors; CCH = collagenase clostridium histolyticum; PRP = platelet rich plasma.

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Table 2. Replies to second questionnaire. Questions 1) The prevalence of Peyronie's disease: 2) Peyronie's disease is very rare in patients under 40 years of age 3) Erectile dysfunction is associated with Peyronie's disease… 4) Pain is always present in Peyronie's disease 5) Symptoms of depression are present in over 40% of patients with Peyronie's disease 6) In Peyronie's disease, partial calcification of the plaque indicates with certainty that the disease has stabilized 7) Can Peyronie's disease be treated? 8) When is surgical treatment preferable?

9) When is corporoplasty indicated? 10) What surgical option is the most indicated in stable Peyronie's disease associated with severe curvature without erectile dysfunction? 11) In your opinion, which of the following is the most valid etiology hypothesis

12) Your medical training:

13) Main field of clinical practice

14) Number of patients with Peyronie's disease seen each month 15) Level of experience and years in practice

Answers Is < 1% Varies in the literature between 3.2% and 13% Varies in the literature between 1% and 3% The statement is correct The statement is wrong In about 30% of cases In about 10%-20% of cases In over 50% of cases The statement is wrong The statement is correct The statement is correct The statement is wrong The statement is wrong The statement is correct Yes, but treatment must be adapted to disease stage There is no treatment The disease resolves spontaneously in most cases After at least 6-12 months since the plaque has stopped growing and/or when curvature is so severe as to prevent intercourse Never In all cases When curvature is so severe as to prevent intercourse and penile pain is absent When curvature is severe When the patient desires it Corporoplasty with or without grafting Plaque excision + corporoplasty with grafting Penile implant The disease arises in genetically predisposed individuals after penile injury (low-grade or major trauma) Idiopathic Autoimmune hypothesis Urology specialty Andrology specialty Urology specialty + Andrology specialty Endocrinology specialty + Andrology specialty Urology resident Urology and andrology in equal measure Prevalent andrology practice Prevalent urology practice General urology <5 Between 5 and 10 10 or more < 5 years Between 5 and 10 years Between 10 and 20 years > 20 years

142 (0.7%). With respect to the practice of "not treating" PD patients, in their 2015 survey of urologists belonging to the American Urology Association (AUA), Sullivan et al. found that 26% of specialists believed PD to be a condition that does not warrant any treatment, while 59% of urologists decided to initiate medical treatment, and 38% of urologists thought an initial period of observation was necessary before deciding on any treatment (52). A PD survey by Hauck et al. (2005) found that 62% of German urologists preferred medical treatment, while 26.9% preferred surgical treatment, and only 6.8% did not consider any treatment warranted (49). When comparing the treatment approaches found by our survey with the treatment practice patterns of foreign colleagues, we obtained the following results. A recent US PD survey (Oberlin et al., 2016) found that 82% of urologists opted for intralesional injections, while in 18% of cases a surgical approach was preferred (53). A Korean PD survey published in 2014 found that in the

% (Number) 4.8% (4 out of 83) 67.4% (56 out of 83) 27.7% (23 out of 83) 57.8% (48 out of 83) 42.1% (35 out of 83) 50.6% (42 out of 83) 26.5% (22 out of 83) 22.8% (19 out of 83) 89.1% (74 out of 83) 10.8% (9 out of 83) 68.6% (57 out of 83) 31.3% (26 out of 83) 81.9% (68 out of 83) 18.07% (15 out of 83) 87.9% (73 out of 83) 8.4% (7 out of 83) 3.6% (3 out of 83) 98.7% (82 out of 83) 1.2% (1 out of 83) 0% (0 out of 83) 87.9% (73 out of 83) 9.6% (8 out of 83) 2.4% (2 out of 83) 50.6% (42 out of 83) 44.5% (37 out of 83) 4.8% (4 out of 83) 80.7% (67 out of 83) 13.2% (11 out of 83) 6.02% (5 out of 83) 72.2% (60 out of 83) 13.2% (11 out of 83) 8.4% (7 out of 83) 2.4% (2 out of 83) 3.6% (3 out of 83) 38.5% (32 out of 83) 27.7% (23 out of 83) 25.3% (21 out of 83) 8.4% (7 out of 83) 39.7% (33 out of 83) 44.5% (37 out of 83) 15.6% (13 out of 83) 18.3% (15 out of 83) 18.3% (15 out of 83) 16.9% (14 out of 83) 46.9% (39 out of 83)

initial phase of the disease most urologists preferred oral therapy with the following agents: vitamin E (80.2%), phosphodiesterase-5 (PDE-5) inhibitors (27.4%), potaba (20.1%), carnitine (16.7%), colchicine (11.7%), tamoxifen (10.4%), pentoxifylline (7.0%). However, 71.9% of Korean urologists also used intralesional injections, while 41.8% preferred to start intralesional therapy only when oral therapy had failed (54). In their Illinois- and Wisconsin-based PD survey, LaRochelle & Levine (2007) found that 81% of urologists recommended vitamin E for PD patients, the next most frequent therapeutic choice (35%) was treatment with potaba, and only 15%-20% of urologists preferred instead medical treatment with non-steroidal anti-inflammatory drugs (NSAIDs), colchicine, penile injections with steroids, interferon, verapamil, and topical verapamil (50). In their German survey, Hauck et al. (2005) analyzed the practice patterns of urologists who preferred a conservative medical treatment and found that 57.8% of them used the Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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following oral agents (in decreasing order of preference): potaba, vitamin E, tamoxifen, colchicine. Among urologists who opted for medical treatment, 13.83% used injection therapy with the following agents (in decreasing order of preference): corticosteroids, verapamil, superoxide-dismutase (SOD). Among urologists opting for conservative medical treatment, 28.37% preferred physical treatment with the following methods (in decreasing order of preference): ESWT, radiation therapy, iontophoresis (49). Sullivan et al. (2015), in their PD survey of members of the American Urology Association, found that physicians who had decided to treat their patients conservatively favored the following therapies (in decreasing order of preference): oral therapy (81%) with vitamin E, colchicine, potaba; intralesional injection therapy (9%) with verapamil, corticosteroids, interferon (52). In our survey of SIA members, a broad majority of physicians judged therapeutic failure to occur when the initial conservative therapy gave no results after 6-12 months (73.23/104 out of 142); additionally, most uro-andrologists (64.78%/92 out of 142), when failure of conservative treatment had been established, considered surgical treatment necessary, specifically corporoplasty, which may be associated with other techniques (grafting, plaque excision/incision, penile implant). Comparing our survey to other surveys in the literature, we found no comparable questions on the time after which medical therapy is seen as having failed. Whereas with respect to the therapeutic approach taken when conservative treatment has failed, in other surveys we found that 67.6% of Korean urologists decided surgical treatment was indicated, specifically corporoplasty (84.1%/190 out of 226), plaque excision/incision + grafting (42.9%/97 out of 226), or prosthesis implant (14.2%/32 out of 226) (54). In our second questionnaire, in response to the question about the prevalence of PD, most SIA respondents (67.4%) answered that prevalence of the disease varies between 3.2% and 13%, and this matches the data in the literature (12, 55, 56). We found the same question regarding disease prevalence in the US survey by LaRochelle & Levine (2007) which established that 41% of interviewed urologists believed PD occurs in less than 1% of men (50). The PD survey by Sullivan et al. (2015) found that 21% of urologists believed the prevalence of PD to be less than 1%, while 5% believe the prevalence to be over 10% (52). Our second questionnaire also asked whether PD is very rare in patients under 40 years of age; 57.8% of SIA respondents believes PD is very rare in this age group, while the remaining respondents believe this is false. We only found a similar question in the U.S. survey by LaRochelle & Levine (2007) which reported that only 9% of responding urologists believe PD cannot present in men under 40 years of age (50). The literature on this topic informs us that PD is all but rare in patients under 40; as a matter of fact, a number of articles report a 10.8%-16.9% incidence in this age group (20, 21). A more recent article by Stuntz et al. (2016) should be mentioned, in which a study of a large sample of US population found that the mean age of PD patients has decreased and is now 48.9 years, and prevalence of the disease in the 18-to-34-year age range is as high as 29.76% (57). The answers to our survey in response to the question

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about whether ED is present in PD showed that most SIA members (50.6%) believe ED is associated with PD in about 30% of cases, and this matches the data in the literature (58-60). A similar question in the LaRochelle & Levine PD survey revealed that 37% of responding urologists did not believe there is a close association between PD and ED (50). In answer to the same question, in the PD survey by Sullivan et al. (2015), 40% of urologists stated that ED is present in PD in less than 30% of cases (52). In the Korean PD survey, on the other hand, only 2.1% of Korean urologists found ED in patients with PD (54). The international literature on ED in patients with PD reports that ED is present in a proportion that varies between 31.5% and 60.1% (3, 17, 29, 40, 58, 59). Analyzing the question in our survey on the presence of pain in PD, 89.15% of SIA members believes pain is not always present in PD. In the Korean survey, 13.5% of Korean urologists found erection to be painful in patients with PD (54). In the international literature, incidence of pain in PD varies between 20% and 70% (1, 17, 60). In response to our survey question on the presence of symptoms of depression in PD, most SIA members (68.6%) answered that symptoms of depression are present in PD patients in over 40% of cases. In response to a similar question in the PD survey by Sullivan et al. (2015) most respondents (75%) stated that a diagnosis of depression can be made in less than 25% of PD patients (52). In the literature, the prevalence of psychological problems in PD patients is very high, ranging from 62.4% to 81% of cases (30, 59, 61, 62). An interesting study published by Nelson (2008) on the same topic detected a 48% prevalence of clinically significant depression in patients suffering from PD (63). With respect to our survey question on partial calcification of plaque and its clinical significance in terms of disease state, most SIA uro-andrologists (81.96%) believes this situation does not necessarily correspond to disease stabilization. The above-mentioned PD surveys had no similar questions. However, an interesting article by Levine et al. (2013) dealt with this topic in depth, postulating that plaque calcification does not appear to be an indicator of mature, stabilized disease, as in their study the authors detected that in 54.2% of patients with plaque calcification, symptoms had arisen less than 6-12 months earlier (64). When asked whether it is possible to treat PD, 87.9% of SIA uro-andrologists answered affirmatively, specifying that treatment must be adapted to disease stage. A more detailed account of the type of practice patterns has already been given with regard to treatment-specific questions. When asked in what cases surgical therapy is preferable, 98.7% of SIA members answered that a surgical approach is indicated in the stable stage of the disease, when the plaque has stopped growing at least 6-12 months before and/or penile deformity already makes sexual intercourse impossible. This choice of surgery in case of stable disease or severe curvature is widely supported in the literature and by international urology guidelines (28, 30, 38, 40, 41, 47, 48, 65-69). With respect to the question on the correct indication for the performance of corporoplasty, 87.9% of SIA uroandrologists answered they believed this type of surgery to

Peyronie’s disease SIA survey

be indicated in patients with severe penile curvature and in the absence of penile pain, a sign of disease stabilization. There is broad consensus in the field of urology on this approach, as well (28, 30, 38, 40, 41, 47, 48, 65-69). With respect to the correct surgical indication in stable PD associated with severe curvature and in the absence of ED, 50.6% of SIA members answered that they opt for corporoplasty, reflecting – even in this case – the most frequent approach in the international literature. In answer to the question on their opinion on which of the most frequent etiology hypotheses for PD is more likely valid, 80.7% of SIA uro-andrologists believes PD onset occurs in genetically predisposed subjects and following penile injury (low-grade or major trauma). The remaining specialists believe the more likely etiology is autoimmune (6%) or idiopathic (13.2%). Even in this case, the majority opinion (80.7%) in our survey is supported by several studies (4-7, 13-16, 70-73). Our questionnaire also included a question on the specialist training of the physicians who participated in the survey. The answers yielded the following data: Urology specialty in 72.2% of cases; Andrology specialty in 13.2% of cases; Urology specialty + Andrology specialty in 8.4% of cases; Endocrinology specialty + Andrology specialty in 2.4% of cases; Urology residents were 3.6%. It must be borne in mind, however, that this result reflects the training of SIA members who participated in the survey and is very likely not identical with the training of all SIA practitioners. The specific question on what clinical field respondent mainly practiced was answered as follows: urology and andrology in equal measure in 38.5% of cases; prevalent andrology practice in 27.7% of cases; prevalent urology practice in 25.3% of cases: general urology practice in 8.4% of cases. With respect to the number of patients suffering from PD who are seen each month by SIA physicians, the result was the following: between 5 and 10 patients per month in 44.5% of cases; fewer than 5 patients per month in 39.7% of cases; 10 or more patients per month in 15.6% of cases. With respect to their experience and years in practice, SIA members answered as follows: over 20 years in 46.9% of cases; between 5 and 10 years in 18.3% of cases; between 10 and 20 years in 16.9% of cases; less than 5 years in 18.3% of cases. We were able to find a few data to compare the training, prevalent clinical practice, and level of experience of the physicians who participated in our survey with those of respondents of other PD surveys. In the PD survey carried out by Sullivan et al. (2015) among members of the American Urology Association, 75% of respondents described their practice as general urology; over half of respondents reported an interest in sexual medicine, 40% of respondents considered themselves as specialists in sexual medicine (52). In the PDsurvey by Oberlin et al. (2016), only 5.3% of responding urologists also had a subspecialty in andrology (53). In the PD survey by Shindel et al. (2008), out of the total number of urology specialists, 8.8% had received specific training in andrology (51). In the Korean survey, the median duration of practice since completing specialty training was 12 years (range,

0-41 years); 59% of urologists had a clinical experience of over 10 years; 66% of respondents had seen fewer than five PD patients per year, while 16.6% of urologists managed more than 10 PD patients per year (54).

CONCLUSIONS

The results of our survey indicate that Italian SIA uroandrologists, compared to their foreign counterparts, have a more proactive diagnostic approach right from when PD patients first present. Furthermore, a preference for conservative medical treatment appears evident in our survey when PD is still in its active stage, at initial presentation, and in most cases; conservative treatment consists in oral therapy, which may be associated with physical treatment and injections. In advanced disease or in case of failure of the initial conservative treatment, our survey instead shows a greater preference for a surgical approach (corporoplasty with or without grafting, associated with prosthesis implant in case of associated ED). With regards to theoretical knowledge, the answers to our survey showed that Italian SIA physicians have in-depth knowledge of the etiology of the disease, its epidemiology, as well as its clinical presentation and correct therapeutic indications. From the point of view of medical training, our survey found that 96.3% of SIA respondents is a specialist in Urology or a specialist in Andrology, while 10.8% specialized in two fields (Urology, Andrology, or Endocrinology). Furthermore, 63.8% of Italian SIA physicians who participated in our survey reported having between 10 and over 20 years of experience in clinical practice.

COLLABORATORS

(Uro-andrologists who participated in the survey): Andriani Egidio, Angelozzi Giovanni, Artegiani Antonio, Azzarito Giuseppina, Barletta Davide, Barrese Francesco, Belgrano Emanuele, Benvenuto Sara, Bianchi Bruno, Bierti Sergio, Bitelli Marco, Bizzotto Leonardo, Boeri Luca, Bottone Francesco, Branchina Antonino, Buono Girolamo, Caraceni Enrico, Casarico Antonio, Cassutti Valter, Castiglioni Mirco, Certo Marco, Chiancone Francesco, Cocci Andrea, Colombo Fulvio, Cornacchia Michele, Corretti Giorgio, Corvasce Antonio, D'Elia Carolina, De Grande Gaetano, De Luca Francesco, De Pasquale Filippo, De Santis Claudio, De Stefano Lorenzo, Dehó Federico, Della Camera Pier Andrea, Delle Rose Augusto, Di Domenico Dante, Di Filippo Aldo, Di Franco Carmelo Agostino, Di Gregorio Leonardo, Di Palma Paolo, Di Trapani Danilo, Fabiani Andrea, Fiordelise Stefano, Fiorillo Alessandro, Forte Saverio, Giammusso Bruno, Giovannone Riccardo, Godano Adriana, Granata Antonio Maria, Guerani Attilio, Guttilla Andrea, Iannotta Luca, Irianni Gabriele, Izzo Alessandro, La Pera Giuseppe, Lacava Gregorio, Larocca Lorenzo, Laruccia Nicola, Lauretti Stefano, Letizia Piero, Liguori Giovanni, Littara Alessandro, Mahlknecht Alois, Malvestiti Gianmario, Manica Michele, Manno Giuseppe, Maruccia Serena, Mastrocinque Giuseppe, Mavilla Luca, Mazziotti Raffaele, Mercenaro Maurizio, Michetti Paolo Maria, Milioto Vincenzo, Militello Andrea, Mondaini Nicola, Montalcini Gino, Morrone Giancarlo, Motta Maurizio, Natali Alessandro, Negro Carlo, Olivieri Valerio, Palumbo Fabrizio, Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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G. Paulis, F. Pisano, A. Palmieri, T. Cai, F. Palumbo, B. Giammusso

Paolini Riccardo, Papini Alessandro, Passavanti Giandomenico, Paulis Gianni, Pavan Nicola, Pavone Carlo, Pescatori Edoardo, Pezzoni Fabio, Piubello Giorgio, Polito Chiara, Polito Massimo, Principi Emanuele, Ragni Francesca, Raimoldi Annibale, Ressa Gaetano, Risi Oreste, Rizzo Giorgio, Rolle Luigi, Ruoppolo Michele, Russino Giovanni, Russo Giorgio, Saccomanni Mauro, Salacone Pietro, Salhi Jamal, Salvia Giuseppe, Sarto Giuseppe, Savino Antonio, Scalvini Tiziano, Scroppo Fabrizio, Soli Marcello, Sorrentino Michelangelo, Speroni Alberto, Tiscione Daniele, Titta Matteo, Tripodi Vincenzo, Turchi Paolo, Ughi Gianni, Vagnoni Valerio, Vecchio Daniele, Vedovo Francesca, Vella Riccardo.

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DOI: 10.4081/aiua.2021.3.356

ORIGINAL PAPER

Immediate insertion of a soft penile prosthesis as a new option for a safe and cost-effective treatment of refractory ischemic priapism Franco Palmisano 1, Valerio Vagnoni 2, Alessandro Franceschelli 2, Giorgio Gentile 2, Fulvio Colombo 2 1 ASST

Fatebenefretalli-Sacco, Luigi Sacco University Hospital, Department of Urology, Milan, Italy; Unit, Department of Urology and Gynecology, Sant’Orsola University Hospital, Bologna, Italy.

2 Andrology

Summary

Objective: The aim of this study is to assess the management of refractory ischemic priapism (IP) by the immediate insertion of a soft penile prosthesis (sPP). Patients and methods: We identified men affected by IP who underwent early sPP placement from May 2017 to October 2019. All patients underwent a detailed medical history review; intraoperative, postoperative features and adverse events were recorded. We evaluated the penile lengthening and bending, presence of complementary erection, ability to have sexual intercourse, postoperative sexual life satisfaction (International Index of Erectile Function [IIEF] questionnaire - question number 5). A cost-analysis was included. Results: A total of six patients were identified. Median time (range) since onset was 78 (48-108) hours with a mean age (SD) of 33 (6.9) years. Median operative time (range) was 82 minutes (62-180). No complications were recorded. Median follow-up was 9 months (range 3-17). No significant loss of penile length, neither penile angulation was recorded. Despite a transient reduction of penile sensitivity, all patients reported satisfactory sexual intercourse (mean score question number 5 from IIEF-5 of 4). The cost of sPP was € 1769,00 with a surgeryrelated reimbursement fee from the National Health System of € 3856,75. Conclusions: The insertion of a sPP for patients with refractory IP results in immediate pain relief, preservation of sexual function and penile size, with a higher surgery reproducibility in an emergency. In addition to this, financial and resource burdens of IP on the health-care system can be potentially reduced.

KEY WORDS: Priapism; Soft tutors; Penile prosthesis; Virilis; Ischemic priapism; Early implantation. Submitted 2 March 2021; Accepted 20 April 2021

INTRODUCTION

Ischemic priapism (IP) is a pathological condition presenting itself as a persistent erection marked by the rigidity of the corpora cavernosa with little or no cavernous arterial inflow accounting for more than 95% of all priapism episodes (1). Beyond 4 hours, IP is considered a compartment syndrome which severely compromises cavernous circulation, leading to progressive destruction of cavernous sinusoids and consequently smooth muscle

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No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

cells necrosis. Emergency medical intervention is required, treated on a flaccid, non-painful state, to minimize potential irreversible consequences, such as corporal fibrosis and permanent erectile dysfunction (ED) (2-3). Episodes lasting < 36 hrs may still respond to corporal blood aspiration and a-adrenergic agents, e.g. phenylephrine, unlike in delayed cases (> 72 h) that then often require surgical intervention, creating a permanent shunt between the cavernous bodies and the glans or the spongious urethra (4-5). It is intuitable that all patients affected by ischemic priapism lasting over 36 hours, have no chance to regain any erectile function (not even supported by drugs) (6). In the light of this, early penile prosthesis (PP) implantation in refractory IP has been proposed by some Authors (1-7). Actually, with the immediate PP insertion of either malleable and inflatable, can offer many advantages for these patients: resolving painful erection, providing sufficient rigidity for satisfactory intercourses, and counteracting inevitable penile shortening, which are cavernous fibrosis consequences (8, 9). Moreover, the immediate implant of PP is easier to perform while, rather than if delayed which may be technically challenging, with higher complication rates and the need to implant downsized cylinders (9). In case of the acute PP insertion, the technical complexity of surgery, the cost-related issue and the possible unavailability of the devices in many centers or in emergency settings must be considered as critical points. In this study, we report our experience with the use of particular non-inflatable prosthesis, made of soft silicon (sPP), in the surgical management of a refractory IP.

PATIENTS

AND METHODS

In this retrospective study, we identified men affected by IP attending our emergency department in a tertiary referral center from May 2017 to October 2019 who underwent early sPP placement. The patient’s work-up consisted of: a) detailed medical history review for sickle cells disease, malignancy, hematological conditions such as thrombophilia or other hemoglobinopathies, assumption of pharmaceutical compounds or illicit drugs; b) general physical and androlog-

Soft penile prosthesis treating ischemic priapism

ical examination; c) comprehensive laboratory tests, including a complete blood count, white blood count with blood cell differential, platelet count, coagulation profile and fetal hemoglobin assessment; d) cavernosal blood sample for gas analysis. Intraoperative, postoperative features and adverse events were recorded. Follow-up was based on a standard internal protocol that consisted of scheduled re-evaluations, considering the following items: postoperative question number 5 from IIEF-5, the onset of penile bending (if any), presence of complementary erection, ability to have sexual intercourse, possible penile shortening and any troubles in genital sensitiveness. The healthcare-related costs of treatment were included in this analysis. This study was conducted according to the guidelines and principles of the Declaration of Helsinki and the standard ethical conduct of research involving humans; after the approval from the Ethical Committee for this Clinical Research, all patients signed an informed consent agreeing to supply their anonymous data for this and for future studies. Surgical technique and technical considerations The SPP insertion was performed by the same experienced surgical team. A longitudinal incision, along the scrotal raphe, is made 1 cm below the penoscrotal junction. A Scott or Lone-star retractor is helpful in maintaining the exposure. A traction stitch through the glans penis is mandatory to obtain adequate stretching of the cavernous bodies. After dissection of the dartos layer, the urethra is identified and laterally mobilized; a bilateral longitudinal corporotomy (at least 3 cm) is then performed on the ventral aspect of two corpora cavernosa. The use of blunt scissors within the corpora, under direct vision, helps to minimise the risk of urethral injury or crossover, not infrequent in the case of extensive fibrosis of the apex. Bleeding is generally minimal and any coarse clots are evacuated. After an extensive corporal irrigation with antibiotic solution, the insertion of the soft medicalgrade silicone Virilis I™ (Giant medical, Cremona, Italy) axial implant (Ø 10 mm) is performed, shaping and adapting its length to that of the corpora cavernosa, in the maximal stretch condition. The limited diameter of the prosthetic cylinders allows the peripheral displacement of the residual erectile tissue, making it possible for the subsequent realization of a complementary erection. Bilateral corporotomy are closed with running sutures. In our practice, a closed suction drain is always inserted.

RESULTS

A total of six patients underwent the sPP insertion for refractory IP treatment. Median time (range) since onset was 78 (48-108) hours with a mean age (SD) of 33 (6.9) years. Three cases were referred from other centers after having had unsuccessful conservative management with aspiration and intracorporal injection of alpha-adrenergic agonists. Two of the patients reported a medical history of sickle cells disease; all of them denied the assumption of either any pharmaceutical compound or illicit drugs. In one case, a new diagnosis of sickle cell disease was

Table 1. Cost-analysis comparing different types of penile prosthesis (please note that the reported costs may vary in different centers and between different Countries). Surgery-related national health service reimbursement € 3856,75

Soft penile prosthesis Malleable penile prosthesis

€ 3856,75

3-piece inflatable penile prosthesis

€ 3856,75

Penile prosthesis cost € 1768,00 (4% VAT included) € 2600,00 (4% VAT included) € 7964,51 (4% VAT included)

Potential economic benefit + € 2088,75 + € 1256,75 - € 4107,76

made. Low-flow priapism was confirmed with the gas evaluation of cavernosal blood, revealing blood hypoxia and acidosis in all cases. Median operative time (range) was 82 minutes (62-180). No intraoperative complications and no subsequent infection were recorded. Median follow-up was 9 months (range 3-17). No significant loss of penile length, neither penile angulation or apical extrusion was recorded. Despite a transient reduction of penile sensitivity, all patients have been satisfied with the results of the surgery (mean score question number 5 from International Index of Erectile Function of 4), and all were successfully engaging in satisfactory sexual intercourse. The cost of sPP was € 1769,00 with a surgery-related reimbursement fee from the National Health System of € 3856.75. Cost analysis comparing different types of PP are reported in Table 1.

DISCUSSION

The aim of the present study was to evaluate the outcomes of sPP placement surgery for men with refractory or delayed IP in an emergency situation, as a possible alternative to the traditional inflatable or malleable implants. Albeit the number of treated patients is limited, the sPP implantation seem to be an effective option for the surgical treatment of IP, with a low risk of complications and high patient satisfaction. Of clinical importance, our results revealed no significant loss of penile length or de-novo angulation at the follow-up. To the best of our knowledge, this is the first report on the use of this device in a priapism setting, with a reduction of surgery-related technical expertise required and National Public Health-care costs.This strategy could be an attractive chance for patients to maintain, at least in part, their natural erectile response. If case of unsatisfactory rigidity for penetration at follow-up, the sPP can be replaced by an upsized hydraulic PP with no risk of penile retraction. As this is an emergency condition requiring immediate intervention, the treatment for recent onset IP episode is sequential, going from conservative measures such as aspiration of cavernous blood and irrigation with saline solution to surgical shunts, while in cases with > 36 hours onset, even if surgical interventions can obtain detumescence, the benefits of preserving erectile function are scarce (10). To date, relative indications for immediately implanting a PP in acute IP include (1): Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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Table 2. Soft penile prosthesis in a refractory ischemic priapism setting: key points. •

Cheaper devices

•

Costs fully covered by the surgery-related National Health Service reimbursement

•

Higher availability of the device in an emergency setting

•

Simpler and faster surgery

•

Prompt pain resolution

•

Maintain penile size

•

Good coital function (association of residual erection)

•

In case of later inflatable penile prosthesis exchange, later upsizing of the cylinders is allowed

• ischaemia that has been presented for more than 36 hours; • failure of aspiration and sympathomimetic intracavernous injections; • failure of distal and proximal shunting (although in delayed cases, implantation might be considered ahead of shunt surgery) • MRI or corporal biopsy evidence of corporal smooth muscle necrosis. The early versus delayed placement of a PP has been a topic of debate. The immediate insertion of a penile pros-

thesis has been recommended to avoid the difficulties and complications presented with delayed surgery in the presence of corporal fibrosis. Early surgery also offers the opportunity to maintain penile size, which is inevitably compromised by delayed surgery (7). During early PP implantation, the corporal dilatation is generally easy; however, distal perforation can occur in 6% of patients who have previously undergone previous needles and shunt procedures, especially when a malleable device is placed (11, 12). Moreover, a six-fold infection rate higher than virgin implant has been reported, with a 12% of revision rate at 16 months (913). On the other hand, delayed insertion of PP must face inevitable penile fibrosis which is particularly challenging even for experienced surgeons. This often results in penile shortening, in a down-sized PP, in complication rates as high as 65%, a 30% of infection rate, and a PP survival – for inflatable devices – of 50% at 1 year (13, 14). No clear indication on the ideal type of implant to be used in priapism setting has been given. In the largest series reported by Ralph in 2009, 86% underwent the immediate insertion of a malleable device (7). In addition to this, Zacharakis et al. noted, in patients that previously underwent malleable PP placement for IP, a median upsize of 1 cm at the time of implant exchange and a patient satisfaction rate of 90% after 3 months (15). On the other hand, Sedigh et al.

Figure 1. Proposed algorithm for the management of Ischemic Priapism (adapted from Zacharakis et al. (9). MRI: Magnetic resonance imaging.

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Soft penile prosthesis treating ischemic priapism

remarked the cosmetic and functional superiority of inflatable PP, leading to a higher satisfaction rate (11). In the light of this, placing a malleable device followed by an inflatable prosthesis exchange means to subject the patient to 2 separate operations (11). The authors also proposed a copious antibiotic use and a conscious and aggressive sizing of the prosthesis placement against the risk of prosthetical infection and loss of length (11). The advantages of using sPPs in a prolonged IP are shown in Table 2. These flexible devices were first proposed by Louis Subrini in 1982 and then successively popularized by Austoni et al. in 2005 for the treatment of Peyronie's disease, with the goal of avoiding penile retraction typically caused by traditional surgery for this condition (16, 17). The idea of sPP as ideal prosthetic model for treating IP comes from our thirty-year experience with the use of these prostheses in the treatment of Peyronie’s disease where they represent a good option, incorporating technical simplicity and surgical time-sparing, offering good aesthetic and functional results. A pre-operative MRI, when available, can provide useful features regarding the state of the residual erectile tissue. In this context, these findings must be integrated with the macroscopic aspect of the tissue observed intraoperatively: in young patients, with apparent partial sparing of the cavernous tissue, a sPP could represent a less invasive solution than a malleable or inflatable prosthesis allowing greater acceptance by the patient who, thanks to the complementary erection, could benefit from a lower psychological impact deriving from this condition (Figure 1). As also recently underlined by Zaazaa et al., cavernous tissue preservation and subsequent tumescence would transform the implant’s artificial erection to a more normal physiological and satisfactory one, with higher satisfaction rate (18). Potential economic benefits in positioning a malleable penile prosthesis in an IP context have been suggested by Tausch et al. (19). Although they ruled that prosthesis itself represents only 5% of the total cost treating these patients, specifically $3.850, the surgery results in a durable cure that provides relief in all cases without need for prolonged treatment of subsequent erectile dysfunction. In addition to this, a considerable consumption of health-care resources was stressed with an average US $ 83.818, whereas in 4 emergency room visits, 2 hospital admissions, 1.5 shunt procedure, 5 irrigation and drainage have been included in the analysis (19). The present case series has shown how convenient the use of sPPs is and can potentially reduce the financial and resource burdens of IP on the health-care system. The potential economic benefits must be interpreted considering different limitations: shunt procedure is not included in this analysis. Moreover, the costs of PP can vary between different hospitals and different Countries. In addition to this, the reimbursement fee from the National Health System may also vary in different regions of our Country, sometimes falling to € 1800.00. Despite this, sPP placement is completely covered by the surgery-related reimbursement of the National Health-care System and for this reason the devices can always be available in the operating rooms even in an emergency situation.

CONCLUSIONS

The insertion of a sPP for patients with refractory (delayed) IP results in immediate pain relief, preservation of sexual function and penile size, with a higher surgery reproducibility in an emergency situation. The case series reported shows a low risk of complications and high patient satisfaction. In addition to this, financial and resource burdens of IP on the health-care system can be potentially reduced.

REFERENCES

1. Salonia A, Eardley I, Giuliano F, et al. EAU Guidelines on Priapism. Edn. presented at the EAU Annual Congress Madrid 2015. 978-94-92671-07-3. Publisher: EAU Guidelines Office. Place published: Arnhem, The Netherlands. http://www.uroweb.org/guidelines/online-guidelines/. 2. El-Bahnasawy MS, Dawood A, Farouk A. Low-flow priapism: risk factors for erectile dysfunction. BJU Int. 2002; 89:285-90. 3. Spycher MA, Hauri D. The ultrastructure of the erectile tissue in priapism. J Urol. 1986; 135:142-7. 4. Lue TF, Broderick G. Evaluation and nonsurgical management of erectile dysfunction and priapism. In Campbell MF, Retik AB eds, Campbell’s Urology, 7th edn. Philadelphia, PA: WB Saunders Co., 2002, pp. 1619-71. 5. Burnett AL, Sharlip ID. Standard operating procedures for priapism. J Sex Med. 2013; 10:180-94. 6. Reddy AG, Alzweri LM, Gabrielson AT, et al. Role of penile prosthesis in priapism: a review. World J Mens Health. 2018; 36:4-14. 7. Ralph DJ, Garaffa G, Muneer A, et al. The immediate insertion of a penile prosthesis for acute ischaemic priapism. Eur Urol. 2009; 56:1033-8. 8. Zacharakis E, Raheem AA, Freeman A, et al. The efficacy of the T-shunt procedure and intracavernous tunneling (snake maneuver) for refractory ischemic priapism. J Urol. 2014; 191:164-8. 9. Zacharakis E, Garaffa G, Raheem AA, et al. Penile prosthesis insertion in patients with refractory ischaemic priapism: early vs delayed implantation. BJU Int. 2014; 114:576-81. 10. Broderick GA, Gordon D, Hypolite J, Levin RM. Anoxia and corporal smooth muscle dysfunction: a model for ischemic priapism. J Urol. 1994;151:259-62. 11. Sedigh O, Rolle L, Negro CL, et al. Early insertion of inflatable prosthesis for intractable ischemic priapism: our experience and review of the literature. Int J Impot Res. 2011; 23:158-64. 12. Salem EA, El Aasser O. Management of ischemic priapism by penile prosthesis insertion: prevention of distal erosion. J Urol. 2010; 183:2300-3. 13. Martínez-Salamanca JI, Mueller A, Moncada I, et al. Penile prosthesis surgery in patients with corporal fibrosis: a state of the art review. J Sex Med. 2011; 8:1880-9. 14. Mishra K, Loeb A, Bukavina L, et al. Management of priapism: a contemporary review. Sex Med Rev. 2020; 8:131-139. 15. Zacharakis E, De Luca F, Raheem AA, et al. Early insertion of a malleable penile prosthesis in ischaemic priapism allows later upsizing of the cylinders. Scand J Urol. 2015; 49:468-471. 16. Subrini L. Flexible penile implants in the restoration of erectile function. Ann Urol. 1993; 27:183-91. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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17. Austoni E, Colombo F, Romanò AL, et al. Soft prosthesis implant and relaxing albugineal incision with saphenous grafting for surgical therapy of Peyronie's disease: a 5-year experience and long-term follow-up on 145 operated patients. Eur Urol. 2005; 47:223-9. 18. Zaazaa A, Mostafa T. Spontaneous penile tumescence by sparing

Correspondence Franco Palmisano, MD (Corresponding Author) franco.palmisano@hotmail.it ASST Fatebenefretalli-Sacco, Luigi Sacco University Hospital, Department of Urology via Giovanni Battista Grassi 74, 20157, Milan (Italy) Valerio Vagnoni, MD Alessandro Franceschelli, MD Giorgio Gentile, MD Fulvio Colombo. MD Andrology Unit, Department of Urology and Gynecology, Sant’Orsola University Hospital, Bologna (Italy)

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cavernous tissue in the course of malleable penile prosthesis implantation. J Sex Med. 2019; 16:474-478. 19. Tausch TJ, Zhao LC, Morey AF, et al. Malleable penile prosthesis is a cost-effective treatment for refractory ischemic priapism. J Sex Med. 2015; 12:824-6.

DOI: 10.4081/aiua.2021.3.361

ORIGINAL PAPER

Erectile dysfunction treatment with Phosphodiesterase-5 Inhibitors: Google trends analysis of last 10 years and COVID-19 pandemic Müslim Doğan Değer 1, Serdar Madendere 2 1 Department 2 Department

of Urology, Edirne Sultan 1st Murat State Hospital, Edirne, Turkey; of Urology, Gümüşhane State Hospital, Gümüşhane, Turkey.

Summary

Objectives: We aimed to analyze the trend change of the most popular Phosphodiesterase-5 Inhibitors (PDE5i) over time and geography by using Google Trends (GT) data in 10 years period and COVID-19 pandemic. Materials and methods: GT is able to generate a “line-graph”, showing how interest has increased or decreased over a period within specific territories. The search values for specific terms are indexed as relative search volume (RSV), which is presented on a scale from 0-100. Avarage annual percentage change (AAPC) and RSV were analyzed to evaluate gain or loss of interest in trends. Search terms were generated for Food and Drug Administration (FDA)-approved PDE5i; tadalafil, sildenafil, vardenafil, avanafil, and their most-used brand names. The data was within “worldwide” from 1 January 2010, to 31 December 2020, using the ‘‘global’’ query category. Results: The overall interest in PDE5i has doubled. Sildenafil has become the most trend PDE5i of today with a regular increase (AAPC: 0.016, p < 0.01). Although the search trend of tadalafil remained almost constant until 2014, the rate of increase in the last 6 years raised and tadalafil has become the 2nd most popular PDE5i recently (AAPC: 0.007, p < 0.01). For vardenafil there has been a decreased interest (AAPC: -0.009, p < 0.01). There is no significant change in avanafil trend (AAPC: 0.000, p: 0.5). All PDE5i interest on GT decreased notably from February to June 2020. But after June, search trends reached the level before the COVID-19 period in a month. Conclusions: These findings show us, with its increasing prevalence, erectile dysfunction (ED) has become a major public health problem. People from different geographies search the internet for ED treatment options. Patients should be informed that ED may be the first sign of many comorbid diseases, and patients with ED should be referred to a health institution for diagnosis and treatment.

KEY WORDS: Google trends; Erectile dysfunction; Phosphodiesterase type-5 inhibitors; Health behaviors; Real-world evidence. Submitted 28 April 2021; Accepted 14 June 2021

INTRODUCTION

Erectile dysfunction (ED) is the recurrent or persistent inability of men to achieve and/or maintain adequate penile erections for satisfactory sexual performance (1). It is pre-

dicted that 322 million men around the world will have ED by 2025 (2). The increasing prevalence of ED leads to a more significant economic burden. At this point, oral phosphodiesterase-5 inhibitors (PDE5i) are the first choice of treatment for ED because they are safe, efficient, costeffective and non-invasive (3). PDE5i which were approved by the Food and Drug Administration (FDA) for ED and other diseases are shown on the timeline (4, 5) (Figure 1). Considering sexual disorders, patients may not feel comfortable to share their problems with the doctors. Then they can try to find out how to treat their sexual problems by themselves on the web (6). A survey from The National Men’s Health Week showed that 44% of men who developed symptoms of ED, would hesitate to look for a treatment, and 11% of them would not visit a doctor if they decide they might need a medical treatment like PDE5i (7). Google trends (GT) is one of these search tools which provides worldwide data about the popularity of searched items during a period. Thus, GT has been continuously used more by marketing specialists for gathering information about potential client interest, as well as differences in that interest by geographic location and time. In the medical area, GT has been used to specify patient interest in surgical procedures and medical treatments (8). Therefore, we aimed to analyze the trend change of the most popular PDE5i over time including COVID-19 pandemic and geography by using GT data. We also aimed to reveal the possible reasons for the trend changes of PDE5i in terms of time and geography.

MATERIALS

AND METHODS

GT produces worldwide search volume info since 2004, offering time-period and category patterns according to a specific term. GT is able to generate a “line-graph”, showing how interest has increased or decreased over a period within specific territories. The search values for specific terms are indexed as relative search volume (RSV), which is presented on a scale from 0-100. A value of RSV 100 indicates the highest search trends, while 50 represents half of the searches. However, 0 demonstrates that no sufficient data were found for the term. By using the estimated annual RSV (ARSV) annual percentage

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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Figure 1. Milestones in the development of phosphodiesterase type 5 inhibitors.

change (APC), linear trends in RSV were shown. To measure variations in ARSV between 2 join points, APC was evaluated. Estimated average APC (AAPC) and respective confidence of intervals (CIs) were used to determine linear trends of ARSV during the whole period. AAPC analysis in rate during a period is provided by a natural log-linear model ([ln(y)=xb]). A negative value of AAPC shows a decreasing RSV and a positive rate refers to increased interest. A log (x+1) transformation was used to the whole dataset if a dependent variable was zero. To assess any inflection points with a significant difference in the trend’s slope, a permutation test was used. When slopes were identified or not the trends were called non-constant or constant, respectively.

The Kendall Trend Tau Test was applied to compare data which is collected over time for trends decreasing or increasing consistently. Search terms were generated for FDAapproved PDE5i; tadalafil, sildenafil, vardenafil, avanafil, and their most-used brand names. The data was within “worldwide” from 1 January 2010, to 31 December 2020, using the ‘‘global’’ query category. Data obtained from search terms were plotted in polynomial trend lines. Moreover, international trends for each PDE5i individually were searched and shown in a separate figure. All trend and statistical analyses were performed using Microsoft Excel v.16.0 (Redmond, Wash) and SPSS v.24.0 (SPSS Inc., Chicago, IL, USA).

RESULTS Trends in geographic locations Interest in sildenafil was mostly high in South America and Europe, interest in vardenafil was highest in the Eastern European and Asian countries. Interest in tadalafil was not superior especially in a specific region. The highest interest in avanafil was in Mediterranean countries (Figure 2) (Table 1). Trends in interest over time The overall interest in PDE5i has doubled in the last 10 years. The leading trend was vardenafil from 2010 to

Figure 2. International trends in phosphodiesterase- 5 inhibitors.The world map shows the countries with the highest Google Trends search volumes for each search term. The darker regions indicate the places where the search terms are more likely to be searched. If a region on the map isn't highlighted, it doesn't mean the term is not used in that region, however, it is less popular than other regions.

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Web searches for erectile dysfunction treatments

Figure 3. Google Trends relative search volume for phosphodiesterase-5 inhibitors by month, January 2010 to December 2020.

Table 1. Most trend five countries for each PDE5i. Sildenafil Finland Chile Colombia Argentina Peru

Vardenafil Japan Russia Ukraine Bulgaria Israel

Tadalafil Brazil Vietnam France India United Arab Emirates

Avanafil Italy Portugal Egypt France China

Table 2. AAPC results of PDE5i queries from 2010 until 2020. PDE5i Sildenafil Vardenafil Tadalafil Avanafil

Lower Upper endpoint endpoint 2010 2020 2010 2020 2010 2020 2010 2020

AAPC 0.016 -0.009 0.007 0.000

Lower CI 0.015 -0.0010 0.006 0.000

Upper CI 0.017 -0.0010 0.008 0.000

Test *p-value statistic 0.874 < 0.01 -0.806 < 0.01 0.791 < 0.01 0.192 0.5

CI: Confidence interval; AAPC: Avarage annual percentage change; PDE5i: Phosphodiestarese-5 inhibitors. * The Kendall Trend Tau Test was applied to define p value.

2013, but it has been decreasing over time (AAPC: -0.009, p < 0.01). Sildenafil has become the most trend PDE5i of today with a regular increase (AAPC:0.016, p < 0.01). Although the search trend of tadalafil remained almost constant until 2014, the rate of increase in the last 6 years raised geometrically like sildenafil, and tadalafil has become the 2nd most popular PDE5i recently (AAPC: 0.007, p < 0.01). Avanafil has not become widespread and its trend has shown slight movement in the last 1 year, but it has not been a competitor in general (AAPC: 0.000, p: 0.5) (Figure 3) (Table 2). The global interest in the term "erectile dysfunction" on GT

has been substantially lower than the interest in all PDE5i. There was no relationship between the PDE5i interest and the interest in global erectile dysfunction issue. Trends in interest in COVID-19 period All PDE5i interest on Google Trend decreased notably from February to June 2020. But after June, search trends reached the level before the COVID-19 period in a month. Then the increase-decrease routine continued as before (Figure 3).

DISCUSSION

With the aging population and the increase of comorbid diseases, ED has become more prevalent. Accordingly, the demand for ED treatments is increasing (9, 10). Because PDE5i are both non-invasive and more costeffective treatments of ED compared to other methods (3, 11), we can see a rising interest in them over the world in the last 10 years in our results. Jena et al. found a strong correlation between web searches for Human Immunodeficiency Virus (HIV) terms and HIV regional incidence rates in the United States (US) (12). Tijerina et al. found also a correlation between breast surgery procedures search terms and annual case volumes of breast procedures performed in the US (13). Similarly, in our study, there was a correlation between the trend rate and the amount of PDE5i sales in Europe (14). We demonstrated that people initially search for treatment options for ED on the web, then they buy the most suitable one for themselves. On this point, there is a risk that can endanger patients’ health. Countrefeit PDE5i have been an important problem in both well-developed and developing countries. They are cheaper and easy to obtain Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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through the web (15). Considering the side effects of the drugs and their interactions with other drugs, the patient may be harmed. Moreover, clinical examination is necessary because ED can be the first symptom of cardiovascular diseases, also multiple risk factors and comorbidities are generally associated with ED (16). Both to prevent the use of counterfeit medicines and ensure the correct use of FDA-approved PDE5i, patients’ awareness should be raised to see a doctor when they have ED. When the trends of PDE5i are interpreted separately, it is seen that sildenafil has a clear superiority in recent years. According to the “CONSER” survey conducted by the Italian Society of Andrology, the speed of action is the most important factor for both physicians and patients when choosing a PDE5i. On this point, a new oro-soluble form of sildenafil offers advantages (17). Comparing the total numbers of PDE5i prescriptions in Europe, sildenafil is superior to tadalafil and vardenafil in the literature similar to our results of search trends (14). Being the first product in the market, brand name recognition, high efficacy and patient satisfaction are the main factors that maintain the popularity of sildenafil. Another important point is the lower cost of sildenafil compared to other PDE5i. Hansen et al. showed that ED treatment with sildenafil was a costeffective alternative compared to vardenafil and tadalafil (18). Moreover, sildenafil searches seem to be prominent, especially in Latin American countries. Successful results in ED treatment with sildenafil in Latin America may have made sildenafil popular in this region (19). On the other hand, higher prescription rates of tadalafil in a prospective study in Latin America show that trends in the region may change in times advancing (20). Our study shows that the trend of tadalafil has increased significantly and tadalafil has become popular in many countries from different continents recently. This popularity in different geographies can be interpreted with the high satisfaction of patients. The long duration of action of tadalafil gives the freedom to have unplanned sexual intercourse. This takes away timing concerns and provides sexual self-confidence, especially for the young men with mild sexual dysfunction (21). No interaction with fatty food is another advantage of tadalafil (22). Other important developments that increased the use of tadalafil were the approval for BPH and suggestions for the early use after radical prostatectomy (23, 24). Additionally, the increase in vardenafil trend in 2011 can be explained with the international study conducted with a large patient group in this period (25). This study may have increased the interest in vardenafil on web searches. However, the interest in vardenafil in the later period appears to be less than sildenafil and tadalafil. In addition to this, there is no significant peak of avanafil trend in the last 10 years. Less generic drugs of avanafil and vardenafil compared to sildenafil and tadalafil may also have made this difference in trends (15). On the other hand, high trends of avanafil in Mediterranean countries and vardenafil in the Eastern European and Asian countries can be investigated with further studies in these regions. Mulhall et al. indicated that patients who were previously prescribed sildenafil were more likely tended to continue with the same medication compared with patients who have previously prescribed tadalafil or vardenafil

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(26). On the other hand, there are contradictory results that show that patients are more likely to prefer tadalafil after experiencing sildenafil (27). A study from Canada showed that most patients and physicians preferred tadalafil instead of sildenafil (28). Thus, additional prospective studies are necessary to provide advanced insights into this issue. In February 2020, when the COVID-19 pandemic started, a trend decreases up to 20% was observed in all PDE5i. Higher interest in COVID-19 related searches can be a reason of this decrease. Moreover, sexual behaviors seem to be negatively affected by the pandemic because of quarantine rules, multiple contact restrictions and fear of contamination (29). Karagöz et al. found that the frequency of sexual intercourse decreased in both sexes during the pandemic period compared to the pre-pandemic period (30). However interestingly 3 months later the trend of PDE5i came back to old levels and then started to rise again. Considering that stress and anxiety increase the frequency of ED, as well as the need of PDE5i. So, the pandemic affected the PDE5i trend both badly and well. To the best of our knowledge, this is the first study that focuses on the differences of PDE5i on Google searches from the aspect of time and geography. Our study has some limitations. Firstly, GT data are anonymous and do not give the possibility for analyzing sub-population groups. Besides, we only had access to RSV and access to raw data was not possible. Furthermore, because the internet is more popular among the young population there may be inadequate data for older men. Lastly, search terms except English languages are not considered. However, we believe that our results reveal the current PDE5i search trends on the web.

CONCLUSIONS

In conclusion, people from different geographies search the internet for ED treatment options. Patients should be informed that ED may be the first sign of many comorbid diseases, and patients with ED should be referred to a health institution for diagnosis and treatment. In recent years apart from the first months of the COVID-19 pandemic, interest and search volume for PDE5i has increased continuously. These findings show us that ED has become a major public health problem with its increasing prevalence. Studies with broad participation are needed to examine different geographical trends in detail.

REFERENCES

1. Hatzimouratidis K, Amar E, Eardley I, et al. Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. Eur Urol. 2010; 57:804-814. 2. Aytaç IA, McKinlay JB, Krane RJ. The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int. 1999; 84:50-56. 3. Rezaee ME, Ward CE, Brandes ER, et al. A Review of economic evaluations of erectile dysfunction therapies. Sex Med Rev. 2020; 8:497-503. 4. Chen L, Staubli SEL, Schneider MP, et al. Phosphodiesterase 5 inhibitors for the treatment of erectile dysfunction: a trade-off network meta-analysis. Eur Urol. 2015; 68:674-80.

Web searches for erectile dysfunction treatments

5. Tzoumas N, Farrah TE, Dhaun N, et al. Established and emerging therapeutic uses of phosphodiesterase type 5 inhibitors in cardiovascular disease . Br J Pharmacol. 2020; 177:5467-5488 6. Cacciamani GE, Bassi S, Sebben M, et al. Consulting “Dr. Google” for prostate cancer treatment options: a contemporary worldwide trend analysis. Eur Urol Oncol. 2019; 1:1-8. 7. National study shows U.S. men avoid the doctor. Available at: http://edition.cnn.com/HEALTH/men/9906/14/mens.health/ Accessed January 6, 2021. 8. Nuti SV, Wayda B, Ranasinghe I, et al. The use of google trends in health care research: A systematic review. PLoS One. 2014; 9:e109583. 9. Wessells H, Joyce GF, Wise M, Wilt TJ. Erectile dysfunction. J Urol. 2007; 177:1675-1681. 10. Shabsigh R. Socioeconomic considerations in erectile dysfunction treatment. Urol Clin North Am. 2001; 28:417-422. 11. Tan HL. Economic cost of male erectile dysfunction using a decision analytic model: For a hypothetical managed-care plan of 100 000 members. Pharmacoeconomics. 2000; 17:77-107. 12. Jena AB, Karaca-Mandic P, Weaver L, Seabury SA. Predicting new diagnoses of HIV infection using internet search engine data. Clin Infect Dis. 2013; 56:1352-1353. 13. Tijerina JD, Morrison SD, Vail DG, et al. The utility of Google trends data for analyzing public interest in breast procedures. Ann Plast Surg. 2019; 82(5S Suppl 4):S325-S331. 14. Causanilles A, Rojas Cantillano D, Emke E, et al. Comparison of phosphodiesterase type V inhibitors use in eight European cities through analysis of urban wastewater. Environ Int. 2018; 115:279-284. 15. Chiang J, Yafi FA, Dorsey PJ, Hellstrom WJG. The dangers of sexual enhancement supplements and counterfeit drugs to “treat” erectile dysfunction. Transl Androl Urol. 2017; 6:12-19. 16. Corona G, Rastrelli G, Isidori AM, et al. Erectile dysfunction and cardiovascular risk: a review of current findings. Expert Rev Cardiovasc Ther. 2020; 18:155-164. 17. Palmieri A, Silvani M, Giammusso B, et al. A “real life” investigation on the prescriptive habits among Italian andrologists: The “CONSER” survey from Italian Society of Andrology (SIA) on Sildenafil oral film. Arch Ital Urol Androl. 2019; 91:115-118. 18. Hansen SA, Aas E, Solli O. A cost-utility analysis of phosphodiesterase type 5 inhibitors in the treatment of erectile dysfunction. Eur J Heal Econ. 2020; 21:73-84. 19. Muneer A, Ralph DJ, Minhas S. Sildenafil citrate (ViagraTM). J Drug Eval. 2003; 1:225-246.

20. Rubio-Aurioles E, Reyes LA, Borregales L, et al. A 6 month, prospective, observational study of PDE5 inhibitor treatment persistence and adherence in Latin American men with erectile dysfunction. Curr Med Res Opin. 2013; 29:695-706. 21. Raheem AA, Kell P. Patient preference and satisfaction in erectile dysfunction therapy: A comparison of the three phosphodiesterase-5 inhibitors sildenafil, vardenafil and tadalafil. Patient Prefer Adherence. 2009; 3:99-104. 22. Wright PJ. Comparison of phosphodiesterase type 5 (PDE5) inhibitors. Int J Clin Pract. 2006; 60:967-975. 23. Cantrell MA, Baye J, Vouri SM. Tadalafil: A Phosphodiesterase5 inhibitor for benign prostatic hyperplasia. Pharmacotherapy. 2013; 33:639-649. 24. Montorsi F, Brock G, Stolzenburg JU, et al. Effects of tadalafil treatment on erectile function recovery following bilateral nervesparing radical prostatectomy: A randomised placebo-controlled study (REACTT). Eur Urol. 2014; 65:587-596. 25. van Ahlen H, Zumbé J, Stauch K, Hanisch JU. The real-life safety and efficacy of Vardenafil (REALISE) study: results in men from Europe and Overseas with erectile dysfunction and cardiovascular or metabolic conditions. J Sex Med. 2010; 7:3161-3169. 26. Mulhall JP, McLaughlin TP, Harnett JP, et al. Medication utilization behavior in patients receiving phosphodiesterase type 5 inhibitors for erectile dysfunction. J Sex Med. 2005; 2:848-855. 27. Eardley I, Mirone V, Montorsi F, et al. An open-label, multicentre, randomized, crossover study comparing sildenafil citrate and tadalafil for treating erectile dysfunction in men naïve to phosphodiesterase 5 inhibitor therapy. BJU Int. 2005; 96:1323-1332. 28. Lee J, Pommerville P, Brock G, et al. Physician-rated patient preference and patient- and partner-rated preference for tadalafil or sildenafil citrate: Results from the Canadian “Treatment of Erectile Dysfunction” observational study. BJU Int. 2006; 98:623-629. 29. Maretti C, Privitera S, Arcaniolo D, et al. COVID-19 pandemic and its implications on sexual life: Recommendations from the Italian society of andrology. Arch Ital Urol Androl. 2020; 92:73-77. 30. Karagöz MA, Gül A, Borg C, et al. Influence of COVID-19 pandemic on sexuality: a cross-sectional study among couples in Turkey. Int J Impot Res. 2020 Dec 16:1-9. doi: 10.1038/s41443-020-003784. Epub ahead of print.

Correspondence Müslim Doğan Değer, MD Department of Urology, Edirne Sultan 1st Murat State Hospital, Edirne (Turkey) Serdar Madendere, MD (Corresponding Author) serdarmadendere@gmail.com Department of Urology, Gümüşhane State Hospital Hasanbey Mahallesi, 29000, Gümüşhane (Turkey)

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LETTER TO EDITOR

DOI: 10.4081/aiua.2021.3.366

Digital informed consent on radical prostatectomy surgery A turning point on patient communication means Pedro Sousa Passos 1, 2, Nuno Carvalho 1, Sara Teixeira Anacleto 1, Mário Cerqueira Alves 1, Paulo Oliveira Mota 1, 3 1 Department

of Urology, Hospital de Braga, Portugal; of Urology, Hospital de Guimarães, Portugal; 3 Institute of Life and Health Sciences, University of Minho, Portugal. 2 Department

Submitted 8 June 2021; Accepted 9 July 2021

To the Editor, Radical Prostatectomy (RP) is one of the preferred treatments for localized prostatic cancer and although surgical complications have been reduced over the years, urinary incontinence and erectile dysfunction are still common and significantly impact the patient’s life (1). Therefore, adequate patient education and counselling before RP is essential. Informed Consent (IC) is a crucial element of doctor-patient interaction, and it must ensure that patients receive and understand all the information regarding their diseases and treatments. Implicit in providing IC is assessing the patient’s understanding, since accessible communication enables them to make informed decisions consciously and autonomously about their health status (2, 3). IC assumes higher relevance in surgery since it comprises invasive procedures, related consequences, and greater anxiety levels from patients (4). Several studies demonstrate that patients’ education about their clinical process leads to lower anxiety levels and low existing postoperative complications (4, 5). Recent studies showed that animated illustrations, with audio explanations, led to better learning and processing of information, reducing the gap between patients with lower and higher health literacy levels (6). With this preliminary study, we aimed to determine the benefit of a video-based educational tool on the patient’s health information compared to a healthcare provider’s verbal explanation. We also intend to evaluate the impact of the patient’s educational level in this process.

MATERIALS

AND METHODS

Patient population Men over 18 years old, with different educational levels and followed at the Urology Department of Hospital de Braga, submitted to a RP, open or laparoscopic, between November and December 2020. There were no exclusion criteria. Study design Presentation of an educational animated video by the health care provider to the study group on the preoperative consultation before getting the IC for the RP. This video contained general information about the procedure: postoperative period, potential complications, and reasons to seek medical help. Representative frames of the video are shown in Figure 1. For this preliminary study, the sample population was randomly divided into two groups: Control Group (verbal explanation before providing the IC) and Study Group (educational animated video before the IC). After the preoperative consultation, each group would answer two questionnaires. Questionnaires We created both questionnaires having as an example, a previous and similar study of the European Association of Urology (Cronbach’s alpha coefficient of 0.861) (7). Each questionnaire included: Nine patient satisfaction questions, regarding the contentment about the information they received during the preoperative consultation, and before signing the IC; two multiple-choice knowledge questions, regarding patient-s knowledge about RP. Statistical analysis For analytical purposes, the patient satisfaction answers (Qscore) involved five options: strongly agree (5 points), agree (4 points), I do not know (3 points), disagree (2 points) and strongly disagree (1 point). The maximum score was 45 points. In the two knowledge questions (Pscore), each patient received one point per corrected item. The variable Pscore was dichotomised, so those who answered none or one correct answer were coded 0, and those who responded correctly to both questions were coded 1. A similar process was conducted for the variable Educational Level, as patients who studied until the primary educational level were coded 0 and those who studied secondary educational level, or more were coded 1. A p-value < 0.05 was considered as statistically significant, and the Confidence Interval (CI) used was 95%.

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No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

Digital informed consent for radical prostatectomy

Figure 1. Representative frames of the video presented to the study group before IC.

RESULTS

Sample description 32 patients were included in this preliminary study, and all subjects completed and returned the questionnaires. The groups were divided in: Control Group: 21 patients, that did not visualise the educational animated video and only received verbal information from their healthcare giver before signing IC; Study Group: 11 patients that visualized the educational animated video before signing IC. As shown in Table 1, most of the participants in both groups had studied until primary education level (81.0% vs 63.6%). Video’s impact on patient satisfaction questions In this section of the questionnaire and, by comparing the medians of satisfaction scores, we found that patients from the study group presented statistically significantly higher satisfaction levels - QScore = 44.0 (2.00), than those from the control group - QScore = 32.0 (6.00); p < 0.001. Video’s impact on patient knowledge questions In this section of the questionnaire and according to the results, we concluded that the study group subjects gave more correct answers than those from the control group. Educational level’s impact on patient satisfaction questions We did not find any significant differences on patients’ satisfaction questions between patients with “until primary level of education” variable - QScore = 36.0 (11.5) and those with “secondary level of education” - QSCore = 42.0 (15.5); p = 0.326. Educational level’s impact on patient knowledge questions Patients with lower educational level failed more questions than those with higher educational level. We performed Fisher’s Exact Test, and results showed that Pscore is dependent on educational level (p = 0.038; Phi = .404). Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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Table 1. Descriptive statistics of the education level variable in each group. Control group Study group

Until primary educational Level secondary education or more Total frequency (n) 17 (81.0%) 4 (19%) 21 7 (63.6%) 4 (36.4%) 11

Table 2. Results of the multiple linear regression for Qscore, to predict patients’ satisfaction. Unstandardised coefficients B Std. error Constant Video Educational level

32.9 10.8 -0.918

1.26 2.06 2.26

Standardised coefficients β t p-value 0.708 -0.055

26.0 5.24 -0.406

< 0.001 < 0.001 0.688

95% Confidence interval for B Lower Upper bound bound 30.3 35.5 6.59 15 -5.55 3.71

Table 3. Results of the logistic regression for Pscore.

Patient satisfaction questions predictors We performed a multiple linear regression to predict patients’ satisfaction using “video visualization” and “educational level” as variables. These were coded as No video visualization = 0 and Video visualization = 1; Primary educational level = 0 and secondary level of education or more = 1. Video visualization was the only statistically significant predictor. Patients who watched the video, from the study group, had 10.8 (95% CI 6.59 to 15.0) more points than those from the control group, as shown in Table 2. Patient knowledge questions predictors For patients’ knowledge predictors, we performed a binary Logistic Regression and, as presented in Table 3, video visualization was statistically significantly (p = 0.004). Pscore was coded as one correct answer = 0 and two correct answers = 1. Patients who visualized the video were 3.12 (95% CI 2.78 to 186) times more likely to correctly answer both questions.

DISCUSSION

Using an educational animated video to communicate health information to patients is associated with higher levels of patients’ satisfaction and knowledge about the surgical Educational level 2.25 1.16 3.78 1 0.052 9.47 procedure. This study also suggests that educational level Video 3.12 1.07 8.48 1 0.004 22.7 can influence the patient’s understanding of health informa(Constant) -2.10 0.75 7.79 1 0.005 0.12 tion. Video-based education has shown promising early results. In 2002, Mayer showed that illustrations help create a mental image; therefore, facilitate learning and overlapping text-based learning (8). On their study, Abed et al., using image illustration and due to the video’s portability and repeatability, showed that an educational animation can increase patients’ understanding and information acquisition and their satisfaction with the health care provided (9, 10). In this study, we confirmed that subjects who only received verbal information had wrong ideas about the procedure they were undertaking, reinforcing the need for new alternatives to explain and better inform patients. We verified that we could increase patients’ knowledge by showing the educational video since the study group had statistically significantly higher P scores. Although patient´s satisfaction scores did not statistically differ amid different education levels, those with higher education levels performed better on knowledge questions. These results meet what the literature suggests. We found that patients who visualized the video scored higher on patient satisfaction and knowledge questions, concluding that accessible information can influence the way patients understand clinical information and eventually, positively impact clinical outcomes (4, 11, 12). B

Std. Wald DF p-value error

EXP (B)

95% Confidence interval for B Lower bound Upper bound 0.98 91.2 2.78 186

CONCLUSIONS

Empowering patients with knowledge improves clinical outcomes, patient’s compliance and it should be a fundamental philosophy of clinical excellence. Addressing to current times, the COVID-19 pandemic has proven the importance of accurate information and showed the significance of providing people with accessible and correct health information. It is important to enable everyone to make informed decisions and ensure that they can act as a public health agent, which will undeniably positively affect the worldwide population.

REFERENCES

1. Daniyal M, Siddiqui ZA, Akram M, et al. Epidemiology, etiology, diagnosis and treatment of prostate cancer. Asian Pac J Cancer Prev. 2014; 15:9575-8. 2. Sousa J, Araújo M, Matos J. Consentimento Informado:Panorama atual em Portugal. Revista Portuguesa de Ortopedia e Traumatologia. 2015; 23:6-17. 3. Osime OC, Okojie O, Osadolor F, Mohammed S. Current practices and medico-legal aspects of preoperative consent. East Afr Med J. 2004; 81:331-335. 4. Winter M, Kam J, Nalavenkata S, et al. The use of portable video media vs standard verbal communication in the urological consent process:A multicentre, randomised controlled, crossover trial. BJU International. 2016; 118:823-828. 5. Armstrong AW, Alikhan A, Cheng LS, et al. Portable video media for presenting informed consent and wound care instructions for skin biopsies: A randomised controlled trial. Br J Dermatol. 2010; 163:1014-1019.

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6. Meppelink CS, Van Weert JC, Haven CJ, Smit EG. The effectiveness of health animations in audiences with different health literacy levels: An experimental study. J Med Internet Res. 2015; 17:e11. 7. Bach T, Behrendt M, Tanidir Y, et al. Harnessing new media tools in patient information. Eur Urol. 2018; 74:685-687. 8. Mayer RE. Multimedia learning. Psychology of learning and motivation. Academic Press. 2002; 41:85-139. 9. Wilson EA, Park DC, Curtis LM, et al. Media and memory: The efficacy of video and print materials for promoting patient education about asthma. Patient Educ Counsel. 2010; 80:393-398. 10. Green MJ, Peterson SK, Baker MW, et al. Effect of a computer-based decision aid on knowledge, perceptions, and intentions about genetic testing for breast cancer susceptibility: A randomised controlled trial. JAMA. 2004; 292:442-452. 11. Idriss NZ, Alikhan A, Baba K, Armstrong AW. Online, video-based patient education improves melanoma awareness: A randomised controlled trial. Telemed J E Health. 2009; 15:992-997. 12. Luck A, Pearson S, Maddem G, Hewett P. Effects of video information on pre colonoscopy anxiety and knowledge: A randomised trial. Lancet. 1999; 354:2032-2035.

Correspondence Pedro de Sousa Passos, MD pedrosousapassos@gmail.com Nuno Carvalho, MD nunofsc9@gmail.com Sara Teixeira Anacleto, MD sara.anacleto241@gmail.com Mário Cerqueira Alves, MD mcerqueiraalves@gmail.com Paulo Oliveira Mota, MD damota.paulo@gmail.com Largo Bairro do Jardim 3, 4900-467 Viana do Castelo (Portugal)

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369

LETTER TO EDITOR

DOI: 10.4081/aiua.2021.3.370

Stereotactic Body Radiation Therapy (SBRT) for prostate cancer: Preliminary results of toxicity Asmâa Naim * 1, 3, Safae Mansouri * 2, Kamal Saidi 3, Abdeljalil Heddat 1, 4, Younes Elhoury 1, 4, Redouane Rabii 1, 4 1 Mohammed

VI University of Health Sciences (UM6SS), Morocco; Center of Meknes, Morocco; 3 Department of Radiotherapy, Casablanca Cancer Center, International hospital Cheikh Khalifa, Casablanca, Morocco; 4 Department of Urology, International Hospital Cheikh Khalifa, Casablanca, Morocco. * Both Authors had participated equally to this manuscript. 2 Oncology

Submitted 18 April 2021; Accepted 27 April 2021

To the Editor, Prostate cancer is the second most common cancer in men in Morocco after lung cancer. External radiotherapy (RTE) is a curative therapeutic option for localized prostate cancer, However the conventional RTE remains a long treatment (78 weeks, 5 days a week) which is demanding for patients and make difficult to manage the waiting lists. The development of imaging and irradiation techniques over the last decades has allowed a high precision in the delivery of the dose to the target organ and a better protection of the organs at risk (OAR), which has encouraged the hypo fractionated irradiation of localized prostate cancer, especially after the results of radiobiology studies that suggested a low report a/b for the prostate. Therefore, several trials have attempted to prove the efficacy and tolerance of hypo fractionated regimens ranging from moderate hypofractionation (20 sessions) to extreme hypofractionation (4-7sessions) called also Stereotactic Body Radiotherapy (SBRT). In fact, it has been demonstrated the same toxicity profile as normo-fractionated (1-3) as well as non-inferiority for tumor control (6, 8-10). Advanced technology in radiotherapy like SBRT is still difficult to access in incoming countries, although we have the opportunity to practice this technique in our institution. The aim of our paper is to share our experience and to present our preliminary results in term of toxicity after SBRT of low and intermediate risk prostate cancer. From January 2017 to December 2018, we treated patients with stereotactic radiotherapy at a total dose of 36.25 Gy in 5 sessions of 7.25Gy. Prostatic re-irradiation was excluded.

METHODS

All our cases were discussed in Multidisciplinary Consultation Meeting including urologist, oncologist, radiotherapist, radiologist and pathologist and decision of stereotactic radiotherapy was validated. After patient consenting, the team of urology procced to transrectal placement of electromagnetic markers Calypso® transponders to follow the prostate during radiotherapy treatment. In fact, the transponders allow a real time tracking of the target as well as a perfect repositioning of the prostate in intrafraction. The placement of the transponders proceeds as fellow: administration of premedication as prescribed by the anesthetist, lithotomy positioning of the patient, transrectal ultrasound in the transverse and sagittal planes, determination of the position by means of three-dimensional probe tracking, intra-prostatic implantation of three transponders (2 at the base and 1 at the apex). After 7-10 days after transponders have been inserted, a simulation scan is performed as follow: rectal and bladder preparation, dorsal decubitus with means of restraint (knee block/foot block), sub-millimetric scan sections. The radiotherapist proceeds to the delineation of the target volumes and organs at risk specially the urethra. Target volume received a dose of 3625 cGy in 5 fractions, considering a/b =1.5 and a Biological Dose Equivalent (BED) of 286 Gy. The clinical target volume was covered by 100% of the prescribed doses, all organs at risk were delineated and doses constraints were met for all according to SFRO recommendations and the TG101 report of the medical physics (4, 5). Then the medical physician starts to plan a treatment and finally the best proposition of treatment is validated by the radiotherapist before to initiate the treatment. All patients were treated with the latest generation linear accelerator (True Beam STX). Calypso was used as tracking system: the electromagnetic antenna of its optical system allowed real time tracking of the target.

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Stereotactic radiotherapy for prostate cancer

Biological control Increasing doses per fraction may improve the carcinology outcome. In fact, the meta-analysis of Zaorsky has shown that when the Biological Equivalent Dose is between 140 Gy to 200 Gy we have a better tumor control for prostate cancer. It has been also reported that SBRT improved by 12% biological progression free survival (bPFS) (6, 7). Phase I-III trials proved the non-inferiority of SBRT compared to the standard regimen in terms of tumor control and acute and delayed toxicity 8-10]. SBRT is still an option as an alternative for the treatment of low-risk prostate cancer and may be considered for intermediate risks in multi-center trials. In our study, we achieved BED > 200 Gy but it is still too early to assess biological control. At 2 years, nine patients were in biological control, two patients died by other diseases: lung cancer and pulmonary embolism. Acute toxicity Acute toxicity considered any complication occurring within 3 months of the end of irradiation. Genitourinary (GU) acute complications were cystitis grade 1 and 2 (with a frequency of 25%); no acute grade 3 GU toxicity was seen. Gastrointestinal (GI) acute complications were proctitis grade 1 and 2 (with a frequency of 8.4%); no grade 3 GI toxicity was seen. Our results are similar to the literature (11, 12). Late toxicity In our preliminary results, no late GI toxicity was detected but we had two cases of urethral stenosis. In Jackson's meta-analysis, concerning 6000 patients treated in 38 prospective studies, with two phase III randomized trials and a median follow-up of at least 5 years, late toxicity Grade ≥ 3 GU was 2.2% and GI was 0.8% (12). Pan et al. reported similar late GU and GI toxicity but they also observed a significantly higher risk of urinary fistula at 2 years after SBRT (1% vs. 0.1%; p = 0.009) (13). Due to the heterogeneity of risk groups, doses and techniques used in different trials, long-term results of further phase III trials are underway to confirm the current data. Trials are open to evaluate SBRT in high-risk prostate cancer (SPARC trial /PACE C) and others to evaluate fractionation and optimal dose: (PATRIOT) (14, 15). Meanwhile, our preliminary results are extremely encouraging in terms of toxicity and local control but we need longer follow up and a larger sample to draw relevant conclusions for this innovative treatment of localized prostate cancer.

REFERENCES

1. Katz AJ, Kang J. Quality of life and toxicity after SBRT for organ-confined prostate cancer, a 7-year study. Front Oncol. 2014; 4:301. 2. Widmark A, Gunnlaugsson A, Beckman L, et al. Ultrahypofractionation for prostate cancer: Outcome from the Scandinavian phase 3 HYPORT-PC trial. Lancet 2019; 394(10196):385-395. 3. Van As NJ, Brand D, Tree A, et al. PACE: Analysis of acute toxicity in PACE-B, an international phase III randomized controlled trial comparing stereotactic body radiotherapy (SBRT) to conventionally fractionated or moderately hypofractionated external beam radiotherapy (CFMHRT) for localized prostate cancer (LPCa). J Clin Oncol. 2019; 37(Suppl 7):1-1. 4. Noël G, Antoni D, Barillot I, et al. Délinéation des organes à risque et contraintes dosimétriques. Cancer/Radiothérapie. 2016; 20 Suppl:S3660. 5. Benedict SH, Yenice KM, Followill D, et al. Stereotactic body radiation therapy: The report of TG101. Med Phys. 2010; 37:4078-101. 6. Hoffman KE, Voong KR, Levy LB, et al. Randomized trial of hypofractionated, dose-escalated, intensity- modulated radiation therapy (IMRT) versus conventionally fractionated IMRT for localized prostate cancer. J Clin Oncol. 2018; 36:2943-2949. 7. Zaorsky NG, Palmer JD, Hurwitz MD, et al. What is the ideal radiotherapy dose to treat prostate cancer? A meta-analysis of biologically equivalent dose escalation Radiother Oncol. 2015; 115:295-300 8. Aluwini S, Pos F, Schimmel E, et al. Hypo fractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): Late toxicity results from a randomized, non- inferiority, phase 3 trial. Lancet Oncol. 2016; 17:464-474 9. Dearnaley D, Syndikus I, Mossop H, et al. Conventional versus hypo fractionated high-dose intensity- modulated radiotherapy for prostate cancer: 5- year outcomes of the randomized, non- inferiority, phase 3 CHHiP trial. Lancet Oncol. 2016; 17:1047-1060. 10. Hoffman KE, Skinner H, Pugh TJ, et al. Patient reported urinary, bowel, and sexual function after hypofractionated intensity-modulated radiation therapy for prostate cancer: Results from a randomized trial. J Clin Oncol. 2018; 41:558-567. 11. Madsen BL, Hsi RA, Pham HT, et al. Stereotactic hypofractionated accurate radiotherapy of the prostate (SHARP), 33.5 gy in five fractions for localized disease: first clinical trial results. Int J Radiat Oncol Biol Phys. 2007; 67:1099-105. 12. Jackson WC, Silva J, Hartman HE, et al. Stereotactic body radiation therapy for localized prostate cancer: a systematic review and metaanalysis of over 6,000 patients treated on prospective studies. Int J Radiat Oncol Biol Phys. 2019; 104:778-789. 13. Pan HY, Jiang J, Hoffman KE, et al. Comparative toxicities and cost of intensity-modulated radiotherapy, proton radiation, and stereotactic body radiotherapy among younger men with prostate cancer. ,J Clin Oncol. 2018; 36:1823-1830. 14. Morrison K, Tree A, Khoo V, et al. The PACE trial: International randomised study of laparoscopic prostatectomy vs. stereotactic body radio-

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therapy (SBRT) and standard radiotherapy vs. SBRT for early stage organ- confined prostate cancer. J Clin Oncol. 2018; 36(Suppl 6):TPS153TPS153. 15. Quon HC, Ong A, Cheung P, et al. Once-weekly versus every-other-day stereotactic body radiotherapy in patients with prostate cancer (PATRIOT): a phase 2 randomized trial. Radiother Oncol. 2018; 127:206-212.

Correspondence Asmâa Naim, MD (Correspondent Author) doc.a.naim@gmail.com Hôpital International Cheikh Khalifa, Casablanca (Morocco) Safae Mansouri, MD m-safae@hotmail.fr Oncology Center of Meknes, Meknes, Morocco Kamal Saidi, Medical physicist Department of Radiotherapy, Casablanca Cancer Center Hôpital International Cheikh Khalifa, Casablanca (Morocco) Abdeljalil Heddat, MD Younes Elhour, MD Redouane Rabii, MD Department of Urology, Hôpital International Cheikh Khalifa, Casablanca (Morocco)

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DOI: 10.4081/aiua.2021.3.373

LETTER TO EDITOR

Potential prognostic value of miR-132 and miR-212 expression in mCRPC patients Mariano Pontico 1, Viviana Frantellizzi 2, Luca Cindolo 3, Giuseppe De Vincentis 2 1 Program

in Morphogenesis & Tissue Engineering, Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy; 2 Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, Rome, Italy; 3 Department of Urology, "Villa Stuart" Private Hospital, Rome, Italy. Submitted 13 November 2020; Accepted 11 January 2021

To the Editor, we have been very pleased to read the interesting work proposed by Salemi et al. (1) regarding the expression of specific fragments of microRNA (miRNA), particularly miR-132 and miR-212, as potential key regulators in prostate cancer (PCa). As outlined by the Authors, the altered expression of miRNAs in cancer pathogenesis represents a well-consolidated knowledge in the current literature (2, 3). More specifically, both miR-212 and miR-132 regulate subsets of genes involved in tumor progression in several tumor cell types as PCa, proving a central role in tumorigenesis, cell adhesion, and angiogenesis. In addition, a strong association between miR-132 expression and high Gleason score PCa has been lately depicted. Several studies have identified specific miRNA expression profiles in the serum of cancer patients, as well as an increased expression of certain miRNAs in the blood of patients with metastatic PCa compared with non-metastatic PCa (4). Thus, miRNA expression profiles could act as potential biomarkers for PCa diagnosis and prognosis. In this context, data achieved by Salemi et al. remarked an increased expression of miR-132 and miR-212 in PCa tissue compared to control and, by contrast, a reduced expression of miR132 and miR-212 in metastatic lymph node. The intriguing findings obtained by this case are likely to suggest a different biologic behavior between the primary PC and metastatic lymph nodes. Recently, we described the outcomes obtained in a real-world setting by the biggest cohort of mCRPC patients undergoing 223-Ra radiometabolic treatment in our country and one of the most extensive in the whole of Europe (5). The risk of developing metastatic localizations during follow-up ranges from 26% to 38% after primary radical approaches and about 4% of the patients are ex-Novo diagnosed with metastatic disease. Bone-metastatic PCa occurs in up to 90% of mCRPC patients and represents a leading cause of morbidity in these subjects, being associated with significant clinical complications and quality of life impairment. Although there is no consensus regarding the very optimal treatment of high-risk or locally advanced PCa, in the last years, multi-modal therapy has demonstrated a clinical advantage and many clinical trials are ongoing to evaluate the best clinical therapeutic approach for each patient. Thus, there is an urgent need to better understand high-risk PCa prognosis using new biomarkers (i.e., histological and molecular genetics patterns), aiming to reach the most appropriate optimization of current treatment strategies to improve outcomes, avoid or postpone complications, and accordingly to enhance the patient's overall quality of life. Currently, it is still unequivocal how to best apply them in a real clinical practice setting, particularly in case of decisions concerning treatment sequencing and combination options (6). In general, for mCRPC patients, androgen deprivation therapy with or without chemotherapy was recommended by EAU guidelines (7, 8). With the successful application of cytoreductive surgery for metastatic cancers and the signs of progress achieved in surgical and radiotherapy techniques, the role of the cytoreductive prostatectomy approach for mCRPC has gained great interest. As pointed out by the results of our study (9), cytoreductive prostatectomy may have the potential to enhance mCRPC disease control, however, the lack of randomized controlled trials and the low level of evidence in the current literature preclude any firm conclusions on the benefit of cytoreductive strategy in mCRPC and to clearly identify the patients who would benefit most from their primary PCa ablation. Based on this growing experience and believing in the great potential of the integration of the perspective emerged from molecular findings by Salemi et al. with our PCa patients cohort, we focus on the opportunity to cross-reference the miR expression analysis in mCRPC enrolled for 223-Ra treatment, to evaluate the clinical and prognostic relevance of miR aberrations in this peculiar group of PCa patients. More in detail, different groups of patients clustered for multiple PCa biological (Gleason Score, histopathologic and molecular patterns), biochemical (PSA, LDH, tALP) (10), and clinical features (TNM score, performance status, secondary skeletal burden) could be designed, aiming to assess the precise relation, if any, between miR expression with every single variable. The final goal would consist of the achievement of the most effective treatment sequence possible, relying on the individual No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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clinical and biomolecular characteristics specific of each patient, in a real patient-centered treatment approach (11). In this direction, it would be very interesting other than useful to assess molecular miRNAs patterns of PCa bone secondary localizations, investigating whether these peculiar pathological entities act like the lymph nodal ones rather than the primary PCa discussed in the case reported by Salemi et al., thus respectively showing under- or over-expression of miR132 and miR-212. A detailed analytical assessment of these new molecular variables in mCRPC patients could eventually lead to a clinically useful prognostic stratification of which kind of PCa patient would rather benefit from a specific treatment strategy, such as 223-Ra treatment. The outcomes of molecular miRNAs expression assessment in skeletal PCa metastases could potentially help to shed light on the role of primary tumor cytoreduction in mCRPC and its still enigmatic biological causes. Several studies are suggesting the existence of a critical interaction between primary tumors, their circulating and disseminated cells, and the development and maintenance of secondary lesions, via a complex connecting network. This tangled connection could justify how primary tumor ablation is demonstrated in many cases to prevent the development of new metastases and even promote their regression in a phenomenon known as the abscopal effect (12, 13). Even if the biological mechanisms underlying this hypothesis are not yet known in detail, most of the actual evidence confirm that ablative treatment of the primitive tumor, purposing to reduce the local load of disease, is able to positively influence the biological behavior of secondary locations too, along with their response to systemic therapies. Whether these theories apply to all or only specific solid tumors remains still to be determined. In this regard, we hope in the development of further detailed studies with a larger number of PCa patients that could definitely lead to many solid achievements, with the purpose to help the determination of peculiar miRNA expression profiles for PCa, supporting its early diagnosis, stratification, and prognosis clinical workup.

REFERENCES

1. Salemi M, Pettinato A, Fraggetta F, et al. Expression of miR-132 and miR-212 in prostate cancer and metastatic lymph node: Case report and revision of the literature. Arch Ital Urol Androl. 2020; 92:209-210. 2. Hassan O, Ahmad A, Sethi S, and Sarkar FH. Recent updates on the role of microRNAs in prostate cancer. J Hematol Oncol. 2012; 5:9. 3. Zhang W, Edwards A, Fan W, et al. miRNA-mRNA correlation-network modules in human prostate cancer and the differences between primary and metastatic tumor subtypes. PLoS One. 2012; 7:e40130. 4. Chen ZH, Zhang GL, Li HR, et al. A panel of five circulating microRNAs as potential biomarkers for prostate cancer. Prostate. 2012; 72:144352. 5. Frantellizzi V, Monari F, Mascia M, et al. Radium-223 in mCPRC patients: a large real-life Italian multicenter study. Minerva Urol Nefrol 2020. doi: 10.23736/S0393-2249.20.03808-4. Epub ahead of print. 6. Frantellizzi V, Lazri J, Pontico M, et al. Bone pain palliation outcomes and possibility of Radium-223 re-treatment in mCRPC. Arch Ital Urol Androl. 2020; 92:196-199 7. De Vincentis G, Follacchio GA, Frantellizzi V, et al. 223Ra-dichloride therapy in an elderly bone metastatic castration-resistant prostate cancer patient: a case report presentation and comparison with existing literature. Aging Clinical and Experimental Research. 2017; 30:677-80. 8. Ricci M, Frantellizzi V, Bulzonetti N, De Vincentis G. Reversibility of castration resistance status after Radium-223 dichloride treatment: clinical evidence and review of the literature. Int J Radiat Biol. 2019; 95:554-561. 9. Frantellizzi V, Costa R, Mascia M, et al. Primary radical prostatectomy or ablative radiotherapy as protective factors for patients with mCRPC treated with radium-223 dichloride: an Italian multicenter study. Clin Genitourin Cancer. 2020; 18:185-91. 10. De Vincentis G, Follacchio GA, Frantellizzi V, et al. Prostate-specific antigen flare phenomenon during 223Ra-dichloride treatment for bone metastatic castration-resistant prostate cancer: a case report. Clinical Genitourinary Cancer. 2016; 14:e529-e33. 11. Prelaj A, Rebuzzi SE, Buzzacchino F, et al. Radium-223 in patients with metastatic castration-resistant prostate cancer: Efficacy and safety in clinical practice. Oncol Lett. 2019; 17:1467-76. 12. Abuodeh Y, Venkat P, Kim S. Systematic review of case reports on the abscopal effect. Curr Probl Cancer. 2016; 40:25-37. 13. Yilmaz MT, Elmali A, Yazici G. Abscopal Effect, From Myth to Reality: From Radiation Oncologists' Perspective. Cureus. 2019;11:e3860. Correspondence

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Pathology, Sapienza, “Sapienza” University of Rome Viale Regina Elena 324, 00161 Rome (Italy)

Mariano Pontico, MD mariano.pontico@uniroma1.it Program in Morphogenesis & Tissue Engineering, Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome (Italy)

Luca Cindolo, MD, PhD lucacindolo@virgilio.it Department of Urology, "Villa Stuart" Private Hospital, Rome (Italy)

Viviana Frantellizzi, MD, PhD (Corresponding Author) viviana.frantellizzi@uniroma1.it Department of Radiological Sciences, Oncology and Anatomical

Giuseppe De Vincentis, MD, PhD giuseppe.devincentis@uniroma1.it Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, Rome (Italy)

Archivio Italiano di Urologia e Andrologia 2021; 93, 3

DOI: 10.4081/aiua.2021.3.375

LETTER TO EDITOR

Studying the electrolyte changes in ileal urine at the time of radical cystectomy and ileal conduit diversion Mohamed Adel Atta 1, Tamer Abou Youssif 1, Ahmed Kotb 1, 2 1 Urology 2 Urology

Department, Alexandria University, Alexandria, Egypt; Department, Northern Ontario School of Medicine, Thunder Bay, ON, Canada.

Submitted 15 May 2021; Accepted 6 July 2021

To the Editor, Radical cystectomy (RC) for bladder cancer is a life-changing surgery, associated with high morbidity and mortality rate. Ileal neobladder seems as an attractive way for urine management post cystectomy but would carry the risk of retaining urine in the ileal pouch for a long time, resulting in serum electrolyte changes, that may add to the patients’ morbidity. EAU guidelines recommend against ileal neobladder for patients with liver and renal disorders, as well as for patients > 80 years old (1). Metabolic complications after RC are well known; including hyperchloremic metabolic acidosis and hyperkalemia. All known information about these changes are available through blood work-up done during follow-up of these patients (2). An interesting recent study compared metabolic complications post-neobladder versus ileal conduit. They could identify that there is no significant difference of the metabolic and electrolyte changes between both procedures (3). The goal of our research was to look for the electrolyte’s changes in ileal urine, as early as 1 hour of exposure, in an in vivo model. Twenty consecutive patients with muscle invasive bladder tumor (MIBT) undergoing RC and ileal neobladder were included in the study. Exclusion criteria were patients with renal and hepatic disorders, presence of hydroureteronephrosis, and patients older than 80-year-old. No bowel preparation was done before surgery. Ethical approval was obtained from the ethical committee of Alexandria University, Egypt. Consents were obtained from all patients prior to RC. At the time of RC, we started the surgery through intraperitoneal exposure, dissecting both ureters and cutting them, obtaining 120 ml of urine. We then do the ileal resection anastomosis. We separate 40 cm of ileum 20 cm from the ileocecal junction. We generally use GIA 80 stapler Covidien. Ileal contents are squeezed out, then 100 ml of urine is injected into the isolated ileal segment, and 20 ml are left as a control. RC and extended lymphadenectomy were then completed. Urine is withdrawn from the isolated ileal segment after 1 hour and sent for analysis. The study was completed over 8 months. The mean age of the patients was 58 (45-65). The study included 17 men and 3 women. The mean reduction in urine volume was 17.5 + 3.45. the mean increase in urine pH was 1.41 + 0.46. Urine sodium, calcium, phosphorus and magnesium were increased while potassium, urea and creatinine were reduced, within the ileal segment. Figures 1 and 2 illustrate these changes. The changes were consistent in all patients. The bowel is frequently incorporated into the urinary tract following RC or for augmentation. Because the permeability and functional properties of the bowel mucosa are different from those of the bladder epithelium, several metabolic disturbances are expected in these patients, including metabolic acidosis, water and electrolyte changes (2-5). The current knowledge of these metabolic changes comes mainly from studying the final outcome of serum changes in these patients. The exact pathogenesis of the metabolic changes that happen after interposition of the intestine in the urinary system has not been studied properly. This is attributed to the lack of a model that records the transepithelial movements of electrolytes after urinary diversion. In the present study, we constructed a model to investigate the early electrolyte changes following inspissation of urine in the ileal segment. Our model provides a direct way to know the exact movement of different electrolyte forms and of the inspissated urine in the ileum, with avoidance of any confounding factors. Following urine diversion, sodium (Na) is secreted in exchange of hydrogen (H) and bicarbonate (HCO3) in the exchange of chloride (Cl), resulting in the hyperchloremic metabolic acidosis (6). This was well represented in our model, as there was an increased urine sodium and pH level after retention for an hour in the ileal segment. This may explain Cho et al. (3) findings of no significant electrolyte changes identified between the ileal conduit and neobladder, as initiation of electrolyte changes and acid base imbalance need < 1 hour to be initiated. The observed decreased potassium (K) level in urine after one hour can be explained by the greater ability of the ileum to reabsorb potassium passively compared to the colon segments, thereby attenuating the risk of hypokalemia that occurs as a result of chronic metabolic acidosis (7). The absorption of K from urine contrast with the clinical observation of No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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Figure 1. Biochemical changes of ileal urine.

hypokalemia in these patients. This, however, can be explained by the loss of potassium in the mucus which is excessively secreted in the neobladder. In our model, there was a decline in urinary urea and creatinine levels. This can be attributed to the passive absorption of urea and creatinine. This would explain why these patients would normally have a decreased estimated glomerular filtration rate (eGFR) in the absence of obstructive uropathy or a pathological cause. Urine osmolality is an index of the concentration of osmotically active particles, particularly chloride, sodium, urea, and potassium. In our model, there was a decrease in urine osmolality. This can be attributed to decreased potassium and urea levels. Polydipsia is one of known complications of ileal diversion (8). We think that the increased osmolality in the interstitium secondary to urea absorption stimulates peripheral osmoreceptors that cause polydipsia, even without the plasma effects that would trigger brain osmoreceptors. In animal models, evidence for the presence of peripheral osmoreceptors in the portal vein and liver was identified (9). Humans could be having similar receptors that cause the persistent sense of thirst in these patients, explained by persistent urea and K diffusion through the ileum. The observed decrease in the urine volume after one hour can be explained by water absorption against the osmolarity gradient. This contrasts with the clinical observation of increased urine output in these patients, which can be explained by thirst and subsequent diuresis. In our study, the calcium level is raised after one hour; this can be explained by the paracellular transport of calcium. In vitro studies show that calcium is absorbed only in the duodenum and secreted in the jejunum and ileum (10) and this selective absorption and secretion of calcium was referred to as “anomalous solvent drag effect” (11). Ileal diversion is so associated with the inherent loss of calcium that can be even before calcium loss from bone as a compensatory mechanism to metabolic acidosis.

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Ileal urine

Figure 2. Electrolytes changes of ileal urine.

The length of the ileal segment and the duration of contact of urine to the ileal segment would affect the metabolic outcomes. This study, however; explains why patients with ileal conduit urine diversion would still have some degree of electrolyte imbalance. Our study is unique in being a prospective study looking at the pathophysiology of electrolyte changes in a unique model avoiding confounding factors. Our study is limited by the relatively small number of patients. In Conclusions the present in vivo human model shows that there is an inherent property of the human ileum to absorb water, creatinine, urea and potassium and to secrete sodium, calcium, magnesium and phosphorus. These changes would happen regardless of the type of urine diversion using ileum. Early preventive measures to the patients’ post-ileal urine diversion would be then recommended.

REFERENCES

1. Alfred Witjes J, Lebret T, Compérat EM, et al. Updated 2016 EAU guidelines on muscle-invasive and metastatic bladder cancer. Eur Urol. 2017; 71:462-475. 2. Tanrikut C, McDougal WS. Acid-base and electrolyte disorders after urinary diversion. World J Urol. 2004; 22:168-71. 3. Cho A, Lee SM, Noh JW, et al. Acid-base disorders after orthotopic bladder replacement: comparison of an ileal neobladder and an ileal conduit. Ren Fail. 2017; 39:379-384. 4. Mills RD, Studer UE. Metabolic consequences of continent urinary diversion. J Urol. 1999; 161:1057-66. 5. Lockhart JL, Davies R, Persky L, et al. Acid base changes following urinary tract reconstruction for continent diversion and orthotopic bladder replacement. J Urol. 1994; 152:338-42. 6. Gough DC. Enterocystoplasty. BJU Int. 2001; 88:739-43. Archivio Italiano di Urologia e Andrologia 2021; 93, 3

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7. Gilbert SM, Hensle TW. Metabolic consequences and long-term complications of enterocystoplasty in children: a review. J Urol. 2005; 173:1080-6. 8. Lee RK, Abol-Enein H, Artibani W, et al. Urinary diversion after radical cystectomy for bladder cancer: options, patient selection, and outcomes. BJU Int. 2014; 113:11-23. 9. Lechner SG, Markworth S, Poole K, et al. The molecular and cellular identity of peripheral osmoreceptors. Neuron. 2011; 69:332-44. 10. Karbach U, Rummel W. Cellular and paracellular calcium transport in the rat ileum and the influence of 1,25- dihydroxyvitamin D3 and dexamethasone. Naunyn Schmiedebergs Arch Pharmacol. 1987; 336:117-24. 11. Nellans HN, Kimberg DV. Anomalous Calcium Secretion in Rat Ileum: Role of Paracellular Pathway. Am J Physiol. 1979; 236:E473-81.

Correspondence Mohamed Adel Atta, MD, Professor Tamer Abou Youssif, MD Alexandria University, Alexandria (Egypt) Ahmed Kotb, MD, Assistant Professor (Corresponding Author) drahmedfali@gmail.com Northern Ontario School of Medicine 980 Oliver Rd, Thunder Bay, P7B 6V4, Ontario (Canada)

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