Archivio Italiano di Urologia e Andrologia - Vol. 92 - n. 1 - 2020 by Edizioni Scripta Manent

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Archivio Italiano di Urologia e Andrologia / Archives of Italian Urology and Andrology - Vol. 92; n. 1 March 2020

Vol. 92; n. 1, March 2020

ORIGINAL PAPERS 1

Adjustable bulbourethral male sling: Experience after 30 cases of moderate to severe male stress urinary incontinence Michele Cotugno, Daniel Martens, Giacomo Pirola, Martina Maggi, Carmelo Destro Pastizzaro, Michele Potenzoni, Bernardo Maria Cesare Rocco, Salvatore Micali, Andrea Prati

Prognostic value of p16INK4a overexpression in penile cancer Mário Pereira-Lourenço, Duarte Vieira e Brito, Miguel Eliseu, Noémia Castelo-Branco, João Pedro Peralta, Ricardo Godinho, Paulo Conceição, Mário Reis, Carlos Rabaça, Amìlcar Sismeiro

Hexaminolevulinate blue light cystoscopy (Hal) assisted transurethral resection of the bladder tumour vs white light transurethral resection of the bladder tumour in non-muscle invasive bladder cancer (NMIBC): A retrospective analysis Marco Capece, Lorenzo Spirito, Roberto La Rocca, Luigi Napolitano, Roberto Buonopane, Sergio Di Meo, Maurizio Sodo, Umberto Bracale, Nicola Longo, Alessandro Palmieri, Ferdinando Fusco, Paolo Verze, Gianluigi Califano, Felice Crocetto, Ciro Imbimbo, Vincenzo Mirone, Vittorio Imperatore, Massimiliano Creta

Time changes of renal dimensions and variations of glomerular filtration rate in chronic kidney disease patients Simone Brardi, Gabriele Cevenini

Comparison of the patient’s satisfaction underwent penile prosthesis; Malleable versus Ambicor: Single center experience Omer Bayrak, Sakip Erturhan, Ilker Seckiner, Mehmet Ozturk, Haluk Sen, Ahmet Erbagci

Influence of dietary energy intake on nephrolithiasis - A meta-analysis of observational studies Gianpaolo Perletti, Vittorio Magri, Pietro Manuel Ferraro, Emanuele Montanari, Alberto Trinchieri

Effectiveness of a novel oral combination of D-Mannose, pomegranate extract, prebiotics and probiotics in the treatment of acute cystitis in women Dario Pugliese, Anna Acampora, Angelo Porreca, Luigi Schips, Cindolo Luca

Comparison of semirigid ureteroscopy, flexible ureteroscopy, and shock wave lithotripsy for initial treatment of 11-20 mm proximal ureteral stones Ibrahim Kartal, Burhan Baylan, Mehmet Caglar Cakıcı, Sercan Sarı, Volkan Selmi, Harun Ozdemir, Fatih Yalçınkaya

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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ORIGINAL PAPERS 45

Influence of sociodemographic factors on treatment’s choice for localized prostate cancer in Portugal Mário Pereira-Lourenço, Duarte Vieira e Brito, João Pedro Peralta, Ricardo Godinho, Paulo Conceição, Mário Reis, Carlos Rabaça, Amílcar Sismeiro

Papillary vs non-papillary access during percutaneous nephrolithotomy: Retrospective, match-paired case-control study Ahmet Tahra, Resul Sobay, Ahmet Bindayi, Ferhat Yakup Suceken, Eyup Veli Kucuk

CASE REPORTS 53

Surgical treatment of large hemangioma of the scrotum in a young adult male

Not fatal venous air embolism after holmium laser enucleation of the prostate: Case report and review of literature

Massimo Iafrate, Nicolo ̀ Leone, Cesare Tiengo, Filiberto Zattoni

Daniele Romagnoli, Mobin Ghaemian, Daniele D’Agostino, Paolo Corsi, Marco Giampaoli, Alessandro Del Rosso, Matteo Cevenini, Riccardo Schiavina, Eugenio Brunocilla, Giorgio Davià, Walter Artibani, Angelo Porreca

A surgical approach to squamous cell carcinoma of penis that also resolved the psychological dysfunction of the patient Napoleon Moulavasilis, Konstantina Yiannopoulou, Marios Frangoulis, Ioannis Katafigiotis, Georgios Liapis, Aikaterini Anastasiou, Ioannis Anastasiou

Be cautious of “complex hydrocele” on ultrasound in young men Evangelos N. Symeonidis, Petros Sountoulides, Irene Asouhidou, Chrysovalantis Gkekas, Ioannis Tsifountoudis, Ioanna Tsantila, Asterios Symeonidis, Christos Georgiadis, Apostolos Malioris, Michail Papathanasiou

Case reports of benign intrascrotal tumors: Two epidermoid cysts and one scrotal calcinosis Tuncay Toprak, Cagri Akin Sekerci

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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.

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DOI: 10.4081/aiua.2020.1.1

ORIGINAL PAPER

Free prostate-specific antigen outperforms total prostate-specific antigen as a predictor of prostate volume in patients without prostate cancer Sinan Avci, Efe Onen, Volkan Caglayan, Metin Kilic, Murat Sambel, Sedat Oner University of Health Sciences, Bursa Yuksek Ihtisas Training and Research Hospital, Department of Urology, Bursa, Turkey.

Summary

Objective: In the management of benign prostatic hyperplasia (BPH), urology guidelines recommend medical or surgical treatments according to different prostate volumes (PV). The aim of this study was to analyze the relationships between PV and age, total and free prostate specific antigen (tPSA, fPSA) and fPSA/tPSA ratio in patients without histologically proven prostate cancer. Materials and methods: A retrospective analysis was made of the data of 1334 patients who underwent transrectal ultrasound (TRUS)-guided prostate biopsy between January 2016 and October 2018. A total of 438 patients with available data for age, tPSA and fPSA levels and PV calculated by TRUS were enrolled in the study. Patients with chronic prostatitis pathology in addition to BPH were also noted and evaluated as a separate group. Results: There were significant correlations between PV and age, tPSA, fPSA, fPSA/tPSA ratio (r = 0.210, r = 0.338, r = 0.548, r = 0.363 respectively). In multivariate linear regression analysis, fPSA was found to be the only predictor for PV (p < 0.001) when compared to age (p = 0.097), tPSA (p = 0.979) and fPSA/tPSA ratio (p = 0.425). In patients with chronic prostatitis pathology there were significant correlations between PV and age, tPSA, fPSA, fPSA/tPSA ratio (r = 0.279, r = 0.379, r = 0.592, r = 0.359, respectively). The multivariate linear regression analysis showed a significant correlation only between PV and tPSA and fPSA/tPSA ratio but not with fPSA and age (p = 0.008, p = 0.015, p = 0.430, p = 0.484, respectively). In men with only BPH pathology there were significant correlations between PV and age, tPSA, fPSA, fPSA/tPSA ratio (r = 0.223, r = 0.385, r = 0.520, r = 0.287, respectively) In multivariate linear regression model the significant correlation was shown only between PV and fPSA (p < 0.001). Conclusions: Although tPSA was significantly correlated with PV in patients without prostate cancer, the correlation between fPSA and PV was much stronger. However, it should be kept in mind that the efficacy of fPSA may be limited in patients with clinically unknown prostatic inflammation.

KEY WORDS: Benign prostatic hyperplasia; Chronic prostatitis; Free prostate-specific antigen; Free prostate-specific antigen/total prostate-spesific antigen ratio; Prediction; Prostate-specific antigen; Prostate volume. Submitted 18 July 2019; Accepted 1 September 2019

INTRODUCTION

Lower urinary tract symptoms (LUTS) have traditionally been related to bladder outlet obstruction, which is often caused by benign prostatic enlargement resulting from

the histological condition of benign prostatic hyperplasia (BPH) (1, 2). Prostate volume (PV) predicts symptom progression and the risk of complications such as urinary retention (3). PV may also be determinative in the decision for BPH treatment. For example, in urology guidelines the use of 5 alpha reductase inhibitors in prostate volumes > 40 cc is recommended for medical treatment. Surgical treatment options also vary according to the prostate volume in guidelines (4). Therefore, it is important to know the PV correctly for the prognosis and treatment of the disease. Digital-rectal examination (DRE) is the simplest way to assess PV, but the correlation to PV is poor. Underestimation of PV by DRE increases with increasing transrectal ultrasound (TRUS) volume, particularly where the volume is > 30 mL (5). TRUS is more accurate in determining PV than DRE and transabdominal ultrasound so it is the standard method recommended for measurement of PV (6, 7) However, it is an expensive, time-consuming, and uncomfortable modality for the initial evaluation of men with LUTS. Therefore, another cheaper and simply applicable method, other than DRE is needed to predict the PV correctly in our daily practice. The prediction of PV can be based on total and free prostate specific antigen (PSA). Both PSA forms predict the TRUS prostate volume (Âą 20%) in > 90% of cases (8, 9). The aim of this study was to analyze the relationships between total PSA, free PSA, age and prostate volume in patients with histologically proven BPH. Furthermore, the implication of the use of free PSA as a proxy marker to estimate PV was analyzed.

MATERIALS

AND METHODS

The data of 1334 men who underwent transrectal ultrasound (TRUS) guided prostate biopsy between January 2016 and October 2018 were analyzed retrospectively. Approval for the study was granted by the Local Ethics Committee (reg. no: 2011-KAEK-25 2018/11-03). Patients with pathological results of cancer, prostatic intraepithelial neoplasia (PIN) or atypical small acinar proliferation (ASAP), aged < 40 years, with PSA levels > 30 ng/dl, with a history of 5alpha-reductase inhibitor therapy, phytotherapy or any invasive therapy for BPH were excluded. Patients who had a cystoscopy, colonoscopy, TRUS, prostate biopsy, acute prostatitis,

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2020; 92, 1

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Sinan Avci, Efe Onen, Volkan Caglayan, Metin Kilic, Murat Sambel, Sedat Oner

urinary tract infection and urinary retention during the previous month were also omitted. Those with a subsequent positive prostate biopsy were also excluded, and those with negative prostate biopsies were included. The pathology reports with chronic prostatitis in addition to BPH were also noted. The PV of the patients were calculated by measuring three dimensions of the prostate with TRUS, and using the ellipsoid formula (PV=height*width*length*0.52). For prostate enlargement, a volume of 40 ml was considered as the cut-off value. Serum PSA levels were measured using the chemiluminescent microparticle immunoassay (CMIA) method prior to any prostate manipulation, including DRE, TRUS and biopsy. A total of 438 patients who met the inclusion criteria, with the available data of age, total-free PSA levels and PV calculated by TRUS were enrolled in the study. Patients were stratified by age into three groups: < 60 years, 60-70 years and > 70 years. Patients with PSA levels < 10ng/dl and PSA levels between 10 ng/dl and 30ng/dl were also evaluated as two separate groups. Data obtained in the study were analysed using SPSS version 15.0 software (SPSS, Inc., Chicago, IL, USA). Correlation and linear regression analyses were performed to evaluate the relationships between age, total PSA, free PSA and PV. Receiver operating characteristics (ROC) curves were constructed to evaluate the ability of free PSA to predict PV for the entire cohort and each subgroup. A value of p < 0.05 was accepted as statistically significant.

RESULTS

A total of 896 patients with any exclusion criteria or with incomplete data were excluded from the study. The remaining 438 patients had a mean age of 64.82 ± 7.18 years, median total PSA value of 6.82 ng/dl (min-

max = 2.75-29.85), median free PSA value of 1.68 (minmax = 0.24-11.25), median free PSA/total PSA ratio of 0.235 (min-max = 0.02-0.82) and median PV of 74 cc (min-max = 40-422). The baseline characteristics of the entire cohort and each subgroup are shown in Table 1. Statistically significant correlations were determined between PV and age, total PSA, free PSA, free PSA/total PSA ratio when the entire cohort was analyzed (p < 0.001 and r = 0.210, p < 0.001 and r = 0.338, p < 0.001 and r = 0.548, p < 0.001 and r = 0.363 respectively) (Table 2). Free-PSA was found to be the only predictor for PV (p < 0.001) in the multivariate linear regression model when compared to age (p = 0.097), total PSA (p=0.979) and free PSA/total PSA ratio (p = 0.425) (Table 3). Patients with chronic prostatitis pathology and patients with pathology reported as BPH only were evaluated separately. In the chronic prostatitis group there were significant correlations between PV and age (p = 0.011 and r = 0.279), total PSA (p < 0.001 and r = 0.379), and free PSA (p < 0.001 and r = 0.592), fPSA/tPSA ratio (p < 0.001 and r = 0.359) (Table 2). In the multivariate linear regression model, a significant correlation was shown only between PV and tPSA, fPSA/tPSA (p = 0.008, p = 0.015 respectively) (Table 3). In the BPH only group, there were significant correlations between PV and age (p < 0.001 and r = 0.223), total PSA (p < 0.001 and r = 0.385), free PSA (p < 0.001 and r = 0.520) and fPSA/tPSA ratio (p < 0.001 and r = 0.287) (Table 2). In the multivariate linear regression model, a significant correlation was shown only between PV and fPSA (p < 0.001) (Table 3). There were correlations between free PSA and PV in all three age groups (< 60 years p < 0.001 and r = 0.546, 6070 years p < 0.001 and r = 0.506, > 70 years p < 0.001 and r = 0.483) (Table 4). There were correlations between free PSA and PV when the cohort was separated according to total PSA value as below or above 10 ng/dl

Table 1. Characteristics of the patient population.

Age groups

< 60 60-70 > 70

Number of patients 121 (28%) 224 (51%) 93 (21%)

Age (years) (mean ± SD) 56.05 ± 3.66 65.43 ± 2.72 74.72 ± 2.94

Total PSA (ng/dl) (median, min-max) 5.59 (2.75-29.85) 7.19 (2.9-28.62) 9.05 (2.75-28.63)

Free PSA (ng/dl) (median, min-max) 1.20 (0.24-7.74) 1.70 (0.36-9.56) 2.21 (0.50-1.25)

fPSA/tPSA ratio (median, min-max) 0.208 (0.03-0.69) 0.24 (0.02-0.82) 0.26 (0.07-0.55)

Prostate volume (cc) (median, min-max) 61 (40-290) 80 (40-422) 83 (40-297)

6.37 (2.9-24.09) 6.86 (2.75-29.85)

1.71 (0.48-9.56) 1.805 (0.24-0.26)

0.252 (0.09-0.69) 0.248 (0.03-0.82)

81 (40-297) 79.5 (40-422)

5.995 (2.75-9.91) 13.84 (10.04-29.85) 6.82 (2.75-29.85)

1.43 (0.24-5.28) 3.05 (0.36-1.25) 1.69 (0.24-1.25)

0.239 (0.03-0.82) 0.230 (0.02-0.56) 0.235 (0.02-0.82)

68.50 (40-234) 95.0 (40-422) 74 (40-422)

Pathology results Chronic prostatitis group Only BPH group

114 (26%) 324 (74%)

< 10 ng/dl

325 (74%) 113 (26%) 438 (100%)

65.69 ± 6.19 64.39 ± 7.09

tPSA levels

> 10 ng/dl Total cohort

63.93 ± 7.09 67.34 ± 6.91 64.82 ± 7.19

tPSA: Total prostate-specific antigen; fPSA: Free prostate-specific antigen; BPH: Benign prostatic hyperplasia; SD: Standard deviation; min: Minimum; max: Maximum.

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Free PSA as useful tool to predict prostate volume

(PSA < 10 ng/dl p < 0.001 and r = 0.494, PSA > 10 ng/dl p < 0.001 and r = 0.512) (Table 4). The cut-off level for free PSA was determined as 1.285 ng/dl for the prediction of prostate volume > 40 cc (Table 5). The cut-off levels are shown in Table 5 for the other

subgroups in which free PSA was significant in predicting PV. The receiver operating characteristic (ROC) curves of each group for fPSA in the prediction of prostate volume < 40cc or > 40cc are shown in Figure 1.

Table 2. Correlations between prostate volume and age, total PSA, free PSA, free PSA/total PSA ratio.

DISCUSSION

In the management of benign prostatic hyperplasia (BPH), urology guidelines recommend medical or surgical treatments according to different prostate volumes (PV). Total cohort Chronic prostatitis group Only BPH group Therefore, accurate determination of PV is crucial for the Correlation p Correlation p Correlation p choice of treatment and for the prediction of treatment coefficient coefficient coefficient PV - Age 0.210 < 0.001 0.279 0.011 0.223 < 0.001 outcomes such as the probability of urinary retention PV - tPSA 0.338 <0.001 0.379 < 0.001 0.385 < 0.001 and the need for surgery (10-13). Nevertheless, BPH is a PV - fPSA 0.548 < 0.001 0.592 < 0.001 0.520 < 0.001 progressive disease and that progression is related to proPV-fPSA/tPSA 0.363 < 0.001 0.359 < 0.001 0.287 < 0.001 static enlargement (14-16). PV, prostate volume; tPSA, total prostate-specific antigen; fPSA, free prostate-specific antigen. Transrectal ultrasound (TRUS) is more accurate in determining PV than transabdominal ultrasound so it is the reference method used to measure PV Table 3. (6, 7). However, it is an expensive, Multivariate analysis of factors effecting the PV. time-consuming and uncomfortable method, and the equipment is Unstandardized Standardized 95% CI not available in most primary setcoefficients coefficients t p ß SE ß Lower bound Upper bound tings. Moreover, in the initial evalTotal cohort uation of BPH patients, neither Age 0.450 0.265 0.075 1.696 -0.71 0.972 0.091 TRUS nor transabdominal ultratPSA 0.023 0.890 0.003 0.026 -1.726 1.772 0.979 sound is recommended according fPSA 11.640 3.178 0.427 3.663 5.394 17.886 < 0.001 fPSA/tPSA ratio 25.800 31.322 0.067 0.824 -35.763 87.363 0.411 to the urology guidelines. DigitalChronic prostatitis group rectal examination (DRE) is simple Age 0.476 0.677 0.068 0.703 -0.873 1.825 0.484 to perform and useful for estimattPSA 7.312 2.706 0.671 2.702 1.924 12,699 0.008 ing the PV but it may assess small fPSA -6.615 8.341 -0.224 -0.793 -23.220 9.991 0.430 prostates as larger, and large ones fPSA/tPSA ratio 169.948 68.279 0.456 2.489 34.015 305.880 0.015 Only BPH group as smaller. Therefore, there is a Age 0.494 0.385 0.076 1.283 -0.265 1.252 0.201 need for a reliable, practical and tPSA -1.437 1.387 -0.158 -1.036 -4.169 1.295 0.301 cheap method as an alternative to fPSA 17.079 4.879 0.615 3.500 7.465 26.692 < 0.001 fPSA/tPSA ratio -27.425 46.072 -0.067 -0.595 -118.201 63.351 0.552 ultrasonography and DRE in daily PV: Prostate volume; tPSA: Total prostate-specific antigen; fPSA: Free prostate-specific antigen; SE: Standart error; CI: Confidence interval. practice (17). Several independent investigators have verified the log-linear relaTable 4. tionship between serum total PSA Correlations between free PSA and PV in different age groups and total PSA levels. and PV in different populations and races with similar results Age tPSA levels (18). Hochberg et al. (19) and < 60 years 60-70 years > 70 years < 10 ng/dl > 10 ng/dl Coban et al. (20) found the corren = 121 (28%) n = 224 (51%) n = 93 (21%) n = 325 (74%) n = 113 (26%) Correlation Correlation Correlation Correlation Correlation lation coefficient between total coefficient p coefficient p coefficient p coefficient p coefficient p PSA and PV to be 0.39 and 0.41, PV-fPSA 0.546 < 0.001 0.506 < 0.001 0.487 < 0.001 0.494 < 0.001 0.473 < 0.001 respectively. Similarly, in the presPV: Prostate volume; tPSA: Total prostate-specific antigen; fPSA: Free prostate-specific antigen. ent study, a significant correlation was determined between total PSA and PV (r = 0.33) but this Table 5. result was not confirmed in the Receiver operating characteristic (ROC) curves for free PSA to predict whether prostate multivariate analysis (Table 3, volume is > 40cc or < 40cc. p: 0.979). In agreement with the AUC SE p 95% CI Sensitivity (%) Specificity (%) Cutoff levelT current study multivariate analyTotal cohort 0.780 0.036 < 0.001 0.709-0.851 72.8 73.5 1.285 sis findings, some investigators Only BPH group 0.749 0.054 < 0.001 0.643-0.855 66.5 76.0 1.495 have proposed that the variability Age < 60 years 0.782 0.059 < 0.001 0.667-0.897 77.0 71.4 0.875 in the relationship between total Age 60-70 years 0.738 0.067 0.001 0.606-0.869 71.8 72.2 1.365 PSA and PV can preclude the Age > 70 years 0.854 0.074 < 0.001 0.708-0.999 90.4 80.0 1.325 accurate prediction of the PSA < 10 ng/dl 0.753 0.044 < 0.001 0.666-0.840 75.5 71.8 1.105 prostate volume using the total PSA > 10 ng/dl 0.892 0.054 < 0.001 0.787-0.998 89.3 80.0 1.660 PSA alone for an individual AVAUC: Area under curve; SE: Standart error; CI: Confidence interval. patient (9, 21). Archivio Italiano di Urologia e Andrologia 2020; 92, 1

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Sinan Avci, Efe Onen, Volkan Caglayan, Metin Kilic, Murat Sambel, Sedat Oner

Figure 1. ROC curves of each group for free PSA to predict whether prostate volume is > 40 or < 40 cc. The areas under curve and p values of each group are shown in Table 5.

Although there have been numerous studies investigating the correlation of total PSA and PV in patients with BPH, the relationship between free PSA and PV has received little attention. To the best of our knowledge, there have only been seven studies that have examining the relationship between free PSA and PV (8, 9, 20, 2225). All of these studies showed that free PSA was superior to total PSA for predicting PV, and this result was also demonstrated in the multivariate analyses in five of the aforementioned studies (8, 9, 20, 24, 25). In the current study, both total PSA and free PSA were correlated with PV (r = 0.33, r = 0.54, respectively) but multivariate analysis showed a significant relationship only between free PSA and PV (p < 0.001). The superiority of the free PSA to total PSA found in the current study is consistent with findings in literature (8, 9, 20, 22-25). There were significant correlations between total PSA and PV in the multivariate analysis of 3 of the 5 previously mentioned studies (8, 20, 24), whereas in the other two studies, a significant relationship was found only between free PSA and PV, as was the case in this current study (9, 25). Prostatic inflammation appears to play a role in BPH pathogenesis and progression (26, 27) but in the aforementioned studies (8, 9, 20, 22, 24, 25), other than Mao et al. (23), who reported that patients with pathological results of only BPH were included in the study, there is no information about the presence of inflammatory conditions such as chronic prostatitis in the pathology results of patients. According to the pathology results of the current study, patients were divided into two groups as only BPH and BPH with chronic prostatitis. Significant correlations were found between free PSA and PV in both

Archivio Italiano di Urologia e Andrologia 2020; 92, 1

groups. However, in multivariate analysis, the BPH only group showed a significant correlation between free PSA and PV, similar to the entire cohort, but that correlation was not found in BPH with chronic prostatitis group, whereas there was a significant correlation between total PSA and PV. It can be hypothesized that free PSA may be less influenced by prostatic inflammation in which serum total PSA elevation may occur as a result of disruption of the normal prostatic architecture, in other words, the greater increase in free PSA may result from a larger benign prostate tissue and prostatic inflammation contributes a greater increase to total PSA than free PSA. In the above-mentioned studies (8, 20, 24) where a significant correlation was determined between total PSA and PV in multivariate analysis, this result could be attributed to possible prostatic inflammation. However, as prostatic inflammation is a pathological diagnosis, it may not be known before biopsy, especially in patients without symptoms associated with such a pathological condition. According to the current study results, the correlation between free PSA and prostate volume was comparatively decreased in the case of inflammation in the prostate. Therefore, the recommendations of previous studies and the current one for the use of free PSA to predict PV may be relatively limited in men with clinically unknown prostatic inflammation. In this respect, the importance of defining this point, which has not been explored in previous studies, should be emphasized. The relationship between free PSA and PV according to different age ranges and total PSA values was also examined in this study. The patients were stratified into three age groups of < 60 years, 60-70 years and > 70 years.

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Free PSA as useful tool to predict prostate volume

In all three age groups a significant correlation was determined between free PSA and PV and the highest degree of correlation was found in the group aged < 60 years (r = 0.54, r =0.50, r = 0.48 respectively). In three previous studies where patients were similarly classified according to age, a correlation between free PSA and PV was shown in all age groups (22-24). However, the age groups with the highest correlations were different from the current study. In two of the studies (23, 24) the highest correlations were seen in the group aged 60-70 years, while in the other study (22) it was the group of patients > 70 years. In some studies (20, 22, 23) patients with total PSA values > 10 ng/dl have been excluded to reduce the possibility of including patients with prostate cancer. Nevertheless, in some studies (8, 24) there is no information about the upper limit of total PSA while in another study (9), patients with total PSA > 10 ng/dl were included. In addition, no study has evaluated the correlation between free PSA and PV in patients with total PSA values > 10 ng/dl. In the current study, the correlation was analysed between free PSA and PV in total PSA-stratified cohorts as total PSA above or below 10ng/dl. The data obtained showed that the value of the correlation coefficient was slightly greater for the total PSA < 10 ng/dl cohort than for the total PSA > 10 ng/dl cohort, suggesting that free PSA may correlate better to PV when the possibility of patients with prostate cancer decreases (r = 0.494, r = 0.473, respectively). However, from another perspective, because of the small difference in the correlation values between the groups, it can be said that in patients with total PSA > 10 ng/dl, free PSA can be used safely for the prediction of PV. In the current study, the diagnostic performance of free PSA as a proxy for PV was evaluated using ROC curves for each group, and free PSA was determined to be significant for PV with AUC values ranging from 0.73 to 0.89 for all subgroups (Table 5). In these analyses, the PV threshold was 40cc, which is of great importance as guidelines have suggested not prescribing 5Îą-reductase inhibitors to patients with a prostate volume < 40cc (4). In the ROC curves of the current study, when the cutoff value of free PSA was taken as 1.28 ng/dl to predict prostate volume > 40cc, sensitivity and specificity were determined as 72.8% and 73.5%, respectively and the AUC was 0.78 for the entire cohort. This result of AUC as 0.78 for free PSA to predict whether PV was > 40cc or < 40cc was slightly better than the values reported in previous studies (AUCs for references 8, 20, 22-24 were 0.72, 0.75, 0.71, 0.75, 0.75, respectively). There continues to be value in the use of free/total PSA for the stratification of the risk of prostate cancer and to decide on a biopsy for patients with 4-10 ng/mL total PSA and negative DRE. A previous study reported that prostate cancer was detected by biopsy in 56% of men with free/total PSA < 0.10, but in only 8% with free/total PSA > 0.25 ng /mL (28). Those studies indicate that the probability of BPH increases as free PSA levels increase. Therefore, free PSA is more closely related to BPH and this link is parallel to the current study results. In the multivariate analysis results, the patients with chronic prostatitis pathology showed a significant relationship between free/total PSA and PV. This finding can be con-

sidered to be related to inflammation-induced total PSA increase, as discussed above. When the results were evaluated of the relationship between age and PV, a significant correlation (r = 0.21) was determined, similar to other studies in the literature (8, 9, 20, 22, 23) but that correlation was not seen in the multivariate analysis (p: 0.091). This was consistent with the study of Morote et al. (9) whereas the opposite was reported in studies by Kayikci et al. (7) and Coban et al. (20) (p: < 0.01 and < 0.01, respectively). The present study is one of a limited number of trials suggesting that free PSA is a strong predictor for PV and that it is better than total PSA. Initially, the efficacy of free PSA at predicting PV in patients with inflammatory pathology reports in addition to BPH and total PSA levels >10ng/dl were reported. These conditions were then evaluated as separate groups to eliminate any bias. In addition, separate cut-off levels for free PSA in the prediction of PV were established for different subgroups of patients. This study had some limitations, primarily the retrospective nature of the study, the probability of occult cancers that could not be detected by biopsy and the criteria used for subject recruitment on the basis of the indications for prostate biopsy rather than a clinical diagnosis of BPH. Nevertheless, the data suggest that because of the ability to obtain more accurate estimates of the PV without the help of more expensive, invasive diagnostic evaluations, free PSA could provide a more reasonable contribution in the proper management of patients with BPH.

CONCLUSIONS

Although total PSA was significantly correlated with PV, this correlation was not shown in multivariate analyses unlike free PSA. The superiority of free PSA may be used to estimate PV with easily obtained serum tests and could be a useful tool for therapeutic decison-making and longitudinal follow-up in patients with BPH. However, in patients with prostatic inflammation, considering that there is a significant relationship between free PSA and PV only in univariate analysis, it should be kept in mind that the efficacy of free PSA may be limited in this group of patients.

REFERENCES

1. Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002; 21:167-178. 2. Kupelian V, Wei JT, Oâ&#x20AC;&#x2122;Leary MP, et al. Prevalence of lower urinary tract symptoms and effect on quality of life in a racially and ethnically diverse random sample: the Boston Area Community Health (BACH) Survey. Arch Intern Med. 2006; 166:2381-2387. 3. Wilkinson AG, Wild SR. Is pre-operative imaging of the urinary tract worthwhile in the assessment of prostatism?. Br J Urol. 1992; 70:53-57. 4. Gravas S, Cornu JN, Drake MJ, et al. Guidelines on the Management of Non-neurogenic Male LUTS. Uroweb 2018. Available from:http://uroweb.org/guideline/treatment-of-non-neurogenic-male-luts/. Archivio Italiano di Urologia e Andrologia 2020; 92, 1

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5. Roehrborn CG. Accurate determination of prostate size via digital rectal examination and transrectal ultrasound. Urology. 1998; 51:19-22.

17. Roehrborn CG, Girman CJ, Rhodes T, et al. Correlation between prostate size estimated by digital rectal examination and measured by transrectal ultrasound. Urology. 1997; 49:548-557.

6. Terris MK, Stamey TA. Determinetion of prostate volume by transrectal ultrasound. J Urol. 1991; 145:984-987.

18. Trivedi MR, Choudhary BA. Digital rectal examination, transrectal ultrasound and prostate specific antigen as a triple assessment diagnostic tool for benign enlargement of prostate. Natl J Med Res. 2015; 5:244-248.

7. Trop-Pedersen S, Juul N, Jakobsen H. Transrectal prostatic ultrasonography: equipment, normal findings, benign hyperplasia and cancer. Scand J Urol Nephrol. Suppl 1988; 107:19-25. 8. Kayikci A, Cam K, Kacagan C, Tekin A, Ankarali H. Free prostate-specific antigen is a better tool than total prostate-specific antigen at predicting prostate volume in patients with lower urinary tract symptoms. Urology. 2012; 80:1088-1092. 9. Morote J, Encabo G, Lopez M, de Torres IM. Prediction of Prostate Volume Based on Total and Free Serum Prostate-Specific Antigen: Is It Reliable?. Eur Urol. 2000; 38:91-95. 10. Jacobsen SJ, Jacobsen DJ, Girman CJ, et al. Natural history of prostatism: risk factors for acute urinary retention. J Urol. 1997; 158:481-487. 11- Jacobsen SJ, Jacobsen DJ, Girman CJ, et al. Treatment for benign prostatic hyperplasia among community dwelling men: the Olmsted County study of urinary symptoms and health status. J Urol. 1999; 162:1301-1306. 12. Bosch JL, Bohnen AM, Groneveld FP. Validity of digital rectal examination and serum prostate specific antigen in the estimation of prostate volume in community-based men aged50 to 78 years: the Krimpen study. Eur Urol. 2004; 46:753-759. 13. Marberger MJ, Andersen JT, Nickel JC. Prostate volume and serum prostate-specific antigen as predictors of acute urinary retention: combined experience from three large multinational placebocontrolled trials. Eur Urol. 2000; 38:563-568. 14. Kaplan SA, Roehrborn CG, McConnell JD, et al. Long-term treatment with finasteride improves results in a clinically significant reduction in total prostate volume compared to placebo over the full range of baseline prostate sizes in man enrolled in the MTOPS trial. J Urol. 2008; 180:1030-2. Discussion 1032-1033. 15. Kaplan SA, Lee JY, Meehan AG, et al. Long-term treatment with finasteride improves clinical progression of benign prostatic hyperplasia in men with an enlarged versus a smaller prostate: data from the MTOPS trial. J Urol. 2011; 185:1369-1373. 16. Emberton M, Andriole GL, de la Rosette J et al. Benign prostatic hyperplasia: a progressive disease of aging men1. Urology 2003;61:267-273.

Correspondence Sinan Avci, MD (Corresponding Author) sinavci@yahoo.com Efe Onen, MD efe17@yahoo.com Volkan Caglayan, MD volkantuysuz@hotmail.com Metin Kilic, MD kilicmetin@hotmail.com Murat Sambel, MD muratsambel@hotmail.com Sedat Oner, Associate Professor sedatoner@yahoo.com University of Health Sciences, Bursa Yuksek Ihtisas Training and Research Hospital, Department of Urology, Bursa, Turkey

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19. Hochberg DA, Armenakas NA, Fracchia JA. Relationship of prostate-specific antigen and prostate volume in patients withbiopsy proven benign prostatic hyperplasia. Prostate. 2000; 45:315-319. 20. Coban S, Doluoglu OG, Keles I, et al. Age and total and free prostate-specific antigen levels for predicting prostate volume in patients with benign prostatic hyperplasia. The Aging Male. 2016; 19:124-127. 21. Roehrborn CG, Boyle P, Gould AL, Waldstreicter J. Serum prostate-specific antigen as a predictor of prostate volume in men with benign prostatic hyperplasia. Urology. 1999; 53:581-589. 22. Choi H, Park JY, Shim JS, et al. Free prostate-specific antigen provides more precise data on benign prostate volume than total prostate-specific antigen in Korean population. Int Neurourol J. 2013; 17:73-77. 23. Mao Q, Zheng X, Jia X, et al. Relationships between total/free prostate-specific antigen and prostate volume in Chinese men with biopsy-proven benign prostatic hyperplasia. Int Urol Nephrol. 2009; 41:761-766. 24. Masuda H, Kawakami S, Sakura M, et al. Performance of free PSA better than total PSA for estimation of prostate volume in elderly men without prostate cancer (abstract). Eur Urol Suppl. 2011; 10:32. 25. Canto EI, Singh H, Shariat SF, et al. Serum BPSA outperforms both total PSA and free PSA as a predictor of prostatic enlargement in men without prostate cancer. Urology. 2004; 63:905-910. 26. Ficarra V, Rossanese M, Zazzara M, et al. The role of inflammation in lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) and its potential impact on medical therapy. Curr Urol Rep. 2014; 15:463. 27. He Q, Wang Z, Liu G, et al. Metabolic syndrome, inflammation and lower urinary tract symptoms: possible translational links. Prostate Cancer and Prostatic Dis. 2016; 19:7. 28. Catalona WJ, Partin AW, Slawin KM, et al. Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA 1998; 279:1542-1547.

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DOI: 10.4081/aiua.2020.1.7

ORIGINAL PAPER

Adjustable bulbourethral male sling: Experience after 30 cases of moderate to severe male stress urinary incontinence Michele Cotugno 1, Daniel Martens 1, Giacomo Pirola 2, Martina Maggi 2, Carmelo Destro Pastizzaro 1, Michele Potenzoni 1, Bernardo Maria Cesare Rocco 3, Salvatore Micali 3, Andrea Prati 1 1 Dipartimento

Chirurgico, U.O. di Urologia, Ospedale di Vaio-Fidenza, Fidenza, Italy; di Chirurgia Generale e specialistica, U.O.C Urologia, Ospedale di Arezzo, Arezzo (Italy); 3 Dipartimento di Chirurgia Generale e Specialità Chirurgiche, U.O di Urologia, Azienda Ospedaliero-Universitaria di Modena, Italy. 2 Dipartimento

Summary

Objective: To report our experience using the Argus perineal sling from July 2015 to April 2018 for male stress urinary incontinence (SUI) after prostatic surgery. To evaluate the safety, efficacy and healthrelated quality of life in patients undergoing this procedure. Patients and methods: The positioning of an adjustable bulbourethral male sling provides a perineal incision, exposure of the bulbospongiosus muscle and the application of the sling bearing on it with transobturator passage of the two extremities with out-in technique. To modulate the bearing tension on the urethra, with a rigid cystoscope the Retrogade Leak Point Pressure is measured, increasing it by 10-15 cm of H20 from baseline. We retrospectively evaluated the results of this implant performed by the same operator on 30 patients who presented post-operative SUI from medium to severe (> = 2 pads/day, pad test at one hour > = 11 g). Mean operative time and possible intra and postoperative complications were evaluated. Postoperatively each patient was reassessed according to the following parameters: number of pads consumed/die, pad tesy at one hour, ICQS-F, any related side effects. Results: After the intervention, 21 of 30 patients (70% of the total) were totally continent (< 1 pad / day, pad test at 1 h < 1-2 g, ICQS-F < 11), out of them 4 required a single adjustment at 3 months in order to achieve this result. 9 of 30 patients (30 %) achieved a clinically significant improvement without obtaining total continence (mean reduction of the n° pads/day: -2.5 ± 1 DS; average reduction of the pad test at 1 h: -20 g ± 4 DS; ICQS-F average reduction: -6 points ± 2 DS), out of them 5 required a 3 month adjustment to obtain these improvements resulting, 4 needed 2 adjustments resulting because the first adjustment was not satisfactory and one who ameliorated from severe to moderate incontinence decided to live in this clinical condition. Conclusions: The results of our study show that the positioning of this sling represents a valid treatment for the moderate and severe post-surgical male SUI. The possibility of adjusting the tension of the sleeve in a "second look" makes the intervention adaptable according to the results obtained. Only multicentric clinical trials on larger series would clarify and eventually confirm the clinical benefits of this sling in post-surgical male SUI.

KEY WORDS: Male stress urinary incontinence; Sling; Prostatectomy. Submitted 30 July 2019; Accepted 21 September 2019

INTRODUCTION

Stress urinary incontinence (SUI), defined according to International Continence society (ICS) as leakage from the urethra synchronously with exertion/effort or sneezing/coughing (1), can be listed within iatrogenic complications following different prostatic surgeries. This condition represents a major issue since it has been proven that its occurrence negatively impacts patients’ quality of life (QoL), leading to withdrawal from social activities (2-6) and affecting primary disease treatments outcomes (7, 8). In these cases, according to different surgical technique implemented, the incidence of male SUI widely ranges, showing 0-2% rate following benign prostatic surgery and 5-35% after radical prostatectomy (RP) (9, 10). These high differences in SUI incidences can be due to a wide variation within different continence definitions, variable diagnostic evaluation, inclusion/exclusion criteria and type of surgical procedures performed among available literature evidence (11). It is important to remember that the incidence of this disorder will also depend on the general condition of the patient before surgery (26). This can change the risk that each individual patient will have to develop post-operative IUS. According to the European Association of Urology (EAU) guidelines, surgical treatment is recommended when initial conservative treatments (i.e. floor muscle training, biofeedback and behavioral modifications) failed. Artificial urinary sphincter (AUS, AMS 800®, American Medical Systems, USA) represents the gold standard to treat SUI, achieving continence rate of 59-90% with high patient satisfaction and best long-term outcomes (10, 12-14). Nevertheless, mechanical failure, infection or erosion have been documented within 25% at 10 years (15). Implantation of male sling either fixed (Advance®, American Medical Systems, Minnetonka, MN, USA) or adjustable (ARGUS®, Promedon SA, Cordoba, Argentina; REEMEX®, Neomedic International, Barcelona, Spain; ATOMS®, Agency for Medical Innovations A.M.I., Feldkirch, Austria) has been considered an option for surgical treatment of SUI following prostatic surgery (13). Even if the AUS demonstrated superior long-term outcomes, slings are attractive to patients since these devices showed sev-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2020; 92, 1

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M. Cotugno, D. Martens, G. Pirola, M. Maggi, C.D. Pastizzaro, M. Potenzoni, B.M.C. Rocco, S. Micali, A. Prati

eral advantages: absence of mechanical parts, no need for device training, immediate efficacy and no need to cycle device before micturition (16). Argus® (Promedon SA; Cordoba, Argentina) adjustable male sling system is a minimally invasive device developed to treat male SUI and to achieve urinary continence. The possibility of intraoperative adjustments and postsurgical readjustments represent its main advantage allowing the necessary coaptation of the bulbar urethra, with low tension, reaching the needs of each patient and at the same time minimizing risks of erosion, ischemia and urine retention. The aim of the present study was to report our preliminary results with the implementation of Argus male perineal sling for male SUI after prostatic surgery. To this purpose, we evaluated efficacy, safety and patients’ health-related QoL outcomes in our retrospective cohort of patients suffering from SUI.

MATERIALS

AND METHODS

The following analysis represents a single-center study in which 30 men who underwent male Argus sling implant as treatment for SUI following prostatic surgery were retrospectively reviewed from July 2015 to April 2018. The study received formal Institutional Review Board. Written informed consent was obtained from all enrolled patients. Patients were informed about the opportunity for AUS implantation as well as risks and benefits of the Argus sling positioning, including the possible need of additional surgeries over the time. All patients were suffering from moderate to severe SUI as result of prostatic surgery as follows: 23 (76.7%) post Radical Prostatectomy (RP), 5 (16.7%) post RP followed by adjuvant Radiotherapy (RT), 1 (3.3%) post transurethral resection of the prostate (TURP) and 1 (3.3%) post Holmium laser enucleation of the prostate (HoLEP) (Table 1). Three out of 30 patients (10%) had previously undergone an adjustable non-circumferential constrictor that was simultaneously explanted during the sling placement. All patients presenting with persistent moderate to severe SUI (≥ 2 pads/day, pad Test at one hour ≥ 11 g) for > 1 year after surgery, despite conservative treatments, were enrolled in our study. Patients previously diagnosed with urethral stricture, bladder neck sclerosis and/or bladder overactivity were excluded. All procedures were performed by the same single surgeon. According to Romano et al, the technique was previously described (17). Table 1. Causes of SUI and previous surgery characteristics of the 30 men who underwent male Argus sling implant. Parameter RP RP+RT TURP HoLEP

Number (%) 23 (76.7) 5 (16.7) 1 (3.3) 1 (3.3)

RP = Radical Prostatectomy; RT = Radiotherapy; TURP = transurethral resection of the prostate; HoLEP = Holmium laser enucleation of the prostate.

Archivio Italiano di Urologia e Andrologia 2020; 92, 1

The positioning of the ARGUS sling (Promedon SA, Cordoba, Argentina) consisted in a perineal incision followed by exposure of the bulbospongiosus muscle and the application of the sling bearing on it with transobturator passage of the two extremities with out-in technique. Two vials of Gentamicin 80 mg were distributed at the level of the exposed tissues following the 3 incisions and always after positioning the sling. To modulate the bearing tension on the urethra, with a rigid cystoscope (Optic 0°) the Retrogade Leak Point Pressure was measured, increasing it by 10-15 cm of H20 from baseline without exceeding 40 cm of H20. All patients were evaluated at baseline before surgery, and then every 3 months for 2 years. Pre-operative assessment included: number of pads used/day; pad-test at one hour (mild SUI < 10 g, moderate between 11 and 50 g, severe > 50 g); administration of the International Consultation on Incontinence Questionnaire - Short Form (ICQS-F) (pathological value > 11, score 021); cystoscopy (to assess the presence and extent of the sphincter deficiency and to exclude post-surgical neck sclerosis or urethral stricture); urodynamic examination. Mean operative time and possible intra and post-operative complications were collected. Post-operatively each patient was evaluated according to the following parameters: number of pads used/day, padtest at one hour, ICQS-F, any related side effects. We defined patients as either totally continent if they were using no pads to 1 security pad/day or a urinary leakage of < 1-2 g at 1 h, or with a significant improvement if there was a reduction of > 50% in number of pads used/day or urinary leakage at 1 h.

RESULTS

Overall, 30 men with median age of 73.5 years (range 5179) undergone our male sling implant and were evaluated with a median follow-up of 13.5 months (range 3-24). Results reported are those obtained from the last follow-up visit of each patient. Surgical procedures were carried out within median operative time of 58 minutes (range 38-95) and no intraoperative complications were reported. Postoperatively 21 out of 30 patients (70%) were totally continent (< 1 pad/day, pad-test at 1 h < 1-2 g, ICQS-F < 11); of these 4 (13.3%) required a single adjustment of the sling 3 months after the intervention in order to achieve continence. Nine out of 30 patients (30%) found a clinically significant improvement in their continence, with a mean reduction of the number of pads used/day of -2.5 ± 1, a mean reduction of the pad-test at 1 h of -20 ± 4 g and a mean reduction of ICQS-F of -6 ± 2 points. Out of these, 5 (16.7%) required single adjustment of the sling at 3 months to obtain this result, while 4 (13.3%) needed 2 revisions (at 3 and 6 months, respectively) since they were not satisfied after the first adjustment. All of these 9 patients presented with a severe pre-operative SUI (> 5 pads/die, pad-test at 1 h > 50 g, ICIQ-SF score 21), and 5 out of 9 were previously submitted to RT. The mean operative time for surgical revisions (increase of sleeve tension on the urethra) was 35 ± 8 min. Early post-operative complications to report included: difficulties in emptying the bladder, which occurred in 3

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Adjustable bulbourethral male sling

patients (10%) and resolved spontaneously within 18 days (range 14-21); perineal and/or inguinal pain, which occurred in 17 patients (56.6%) and was conservatively managed with the use of NSAIDs (none required sling removal) within a maximum of 45 days (range 18-45).

DISCUSSION

Male SUI almost exclusively recognizes prostatic surgery as a leading cause responsible for the majority of the cases. Injuries of the distal urethral sphincter are the basis of the pathophysiology of this form of incontinence. TURP, Holep and open adenomectomy give relatively low 1-year incontinence rates achieving 1% at 12 months after surgery (18). On the contrary RP has a higher percentage of risk, especially in elderly patients and associated with pelvic radiation or a previous TURP (14). Ficarra et al in their recent systematic review found that the mean continence rates at 12 months were 89-100% for patients treated with Robotic-assisted laparoscopic prostatectomy (RALP) and 80-97% for patients treated with radical retropubic prostatectomy (RRP) (19). A prospective controlled non-randomized trial of patients undergone RP in 14 centers using RALP or RRP showed an incontinence rate of 21.3% and 20.2% at 12 months for RALP and RRP respectively (OR 1.08, 95%CI: 0.87-1.34) (20). Regardless of the considered studies it seems that increased surgical experience has lowered the complication rates of RP and improved cancer cure (21). The placement of an AUS represents today the first line treatment for male SUI. Despite it is the most established surgical procedure, with a high degree of patients’ satisfaction and success (59-90%), it has shown a risk of revision due to mechanical failure, infection or erosion of 25% at 10 years (15). According to these considerations, over the last decade, a raising interest in male sling to treat SUI has been developed. In 2007, Rehder and Gozzi published their pilot study on the use of AdVance®, transobturator fixed sling which aimed to re-establish the anatomical position of the external sphincter (22, 23). In order to avoid overcorrection and to enable the sling to adapt to functional or anatomical changes in the patients, adjustable systems have been developed. The ARGUS system has become a valid option since it has countless advantages: minimally invasive approach, no exposure of the urethra, average learning curve and, above all, the possibility of adjusting the tension of the sleeve on the urethra, which allows us to "customize the sling" for each type of urinary incontinence. In our series the percentage of patients with total postoperative continence was 70% with a median follow-up of 13.5 months. This percentage is similar to those reported by the current literature. Hubner WA et al. demonstrated a total continence rate of 79.2% in their 101 patient series after a 2.1 year mean follow-up (24). Romano SV et al. obtained 73% of continence rate in 48 patients after a mean follow-up of 7.5 months (17). Regarding readjustments of the sling tension, the extreme ease and the reduced operating time reported in our series (mean operative time 35 ± 8 min), make this treatment extremely personalized and adaptable to each single case. In the present study, post-operative sling adjustments

(one or more) were necessary in 43.3% of patients, due to either persistence of incontinence or patient’s dissatisfaction. This percentage is higher than those experienced by Romano SV et al. (4 cases, 8%) and Hubner WA et al. (39 cases, 38.6%) (17, 24). The most frequent complication experienced in our patient series was inguinal and/or perineal pain (56.6% of patients), which has always been transient and never required explant of the device. Interestingly, in our study, none of the cases experienced erosion and/or infection of the sling that required removal of the device. This data significantly differs from other available evidences in which infection and device removal rates of the sling are 5.4-8% and 10-15%, respectively (24, 25). This result could be explained by several factors: 1. the sling was opened only after the needle has passed through the obturator foramen; 2. the routinary use of 2 vials of Gentamicin 80 mg for each operation; 3. the positioning of the sling was always performed by the same operator who already had therefore a considerable experience. In men who underwent adjuvant pelvic RT, the efficacy of the sling is unclear and results in the literature are still conflicting. Hubner et al in their series with 22 radiated men reported a good success rate of 90.9% (20 of 22 patients were dry) and a sling explantation rate of 9.1% (2 of 22 patients) (24); differently, Bochove-Overgaauw and Schrier in a series of 13 radiated men found a significantly worse success rate (15%, 2 of 13 patients) and sling explantation rate (27%, 4 of 15 patients) (25). In our study all 5 cases with a prior RT found a clinically significant improvement in their continence, thus demonstrating the feasibility of this surgery also in radiated patients. Several limitations of our study should be acknowledged. Our sample size was limited to 30 cases, thus affecting clinical deducible implications from our analysis. The design of the present study is retrospective without a control arm for comparison. All surgical procedures were performed by a single experienced urologist and results may be a related to the surgical skills of the surgeon and may not be similar for naïve operators. Our follow-up does not allow an evaluation of efficacy and complications occurred 24 months after surgery, thus a longer follow-up should be necessary to report efficacy and safety data over the time.

CONCLUSIONS

Results from our study show that implantation of this type of sling represents a valid option to treat moderate and severe post-surgical male SUI. The technique by not providing exposure to the urethra minimizes the risk of iatrogenic damage, erosion and infection of the device and is feasible in radiated patients, especially if performed by experienced surgeons. On the other hand, the possibility to adjust postoperatively the tension of the sleeve makes the intervention adaptable according to the obtained results, thus achieving better patients’ compliance and continence rate. Only multi-centric clinical trials with a larger cohort of patients could clarify and eventually confirm the clinical benefits of this sling in postsurgical male SUI. Archivio Italiano di Urologia e Andrologia 2020; 92, 1

Cotugno_Stesura Seveso 14/04/20 13:53 Pagina 10

M. Cotugno, D. Martens, G. Pirola, M. Maggi, C.D. Pastizzaro, M. Potenzoni, B.M.C. Rocco, S. Micali, A. Prati

REFERENCES

1. Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology in lower urinary tract function: report from the standardization sub-committee of the International Continence Society. Urology. 2003; 61:37-49. 2. Fosså SD, Bengtsson T, Borre M, et al. Reduction of quality of life in prostate cancer patients: experience among 6200 men in the Nordic countries. Scand J Urol. 2016; 50:330-337. 3. Wagner TH, Patrick DL, Bavendam TG, et al. Quality of life of persons with urinary incontinence: development of a new measure. Urology 1996; 47:67-71. 4. Powel LL. Quality of life in men with urinary incontinence after prostate cancer surgery. J Wound Ostomy Continence Nurs. May 2000; 27:174-178. 5. Sciarra A, Gentilucci A, Salciccia S, et al. Psychological and functional effect of different primary treatments for prostate cancer: A comparative prospective analysis. Urol Oncol. 2018; 36:340.e7340.e21.

A randomized controlled trial comparing transurethral resection of the prostate, contact laser prostatectomy and electrovaporization in men with IPB: analysis of subjective changes, morbidity and mortality. J Urol. 2003; 169:1411-6. 19. Ficarra V, Novara G, Rosen RC, et al. Systematic review and meta-analysis of studies reporting urinary continence recovery after robot-assisted radical prostatectomy. Eur Urol. 2012; 62:405. 20. Haglind E, Carlsson S, Stranne J, et al. Urinary incontinence and erectile dysfunction after robotic versus open radical prostatectomy: a prospective, controlled, nonrandomised trial. Eur Urol. 2015. 68:216. 21. Augustin H, Hammerer P, Graefen M, et al. Intraoperative and perioperative morbidity of contemporary radical retropubic prostatectomy in a consecutive series of 1243 patients: results of a single center between 1999 and 2002. Eur Urol. 2003; 43:113. 22. Rehder P, Gozzi C. Transobturator sling suspension for male urinary incontinence including post radical prostatectomy. Eur Urol. 2007; 52:860-6.

6. Maggi M, Gentilucci A, Salciccia S, et al. Psychological impact of different primary treatments for prostate cancer: A critical analysis. Andrologia. 2019; 51:e13157.

23. Rehder P, Gozzi C. Re: surgical technique using AdVance sling placement in the treatment of post-prostatectomy urinary incontinence. Int Braz J Urol. 2007; 33:560-1.

7. Cornu JN, Sèbe P, Ciofu C, et al. Mid-term evaluation of the transobturator male sling for post-prostatectomy incontinence: focus on prognostic factors. BJU Int. 2011; 108:236-40.

24. Hubner, W.A, Gallistl H, Rutkowski M, et al. Adjustable bulbourethral male sling: Experience after 101 cases of moderate-tosevere male stress urinary incontinence. BJU Int. 2011; 107:777-82.

8. Stothers L, Thom DH, Calhoun EA. Urinary incontinence in men. Urologic diseases in America. US department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease. Available at: <http://kidney. niddk.nih.gov/statistics/uda/Urinary_ Incontinence_in_Men-Chapter06.pdf>.

25. Bochove-Overgaauw DM, Schrier BP. An adjustable sling for the treatment of all degrees of male stress urinary incontinence: Retrospective evaluation of efficacy and complications after a minimal followup of 14 months. J Urol. 2011; 185:1363-8.

9. Aagaard MF, Khayyami Y, Hansen FB, et al. Implantation of the argus sling in a hard-to-treat patient group with urinary stress incontinence. Scand J Urol. 2018; 52:448-452.

26. Padilla-Fernández B, Virseda-Rodríguez ÁJ, Valverde-Martínez LS, et al. Influence of secondary diagnoses in the development of urinary incontinence after radical prostatectomy. Arch Ital Urol Androl. 2017; 89:34-38.

10. Kirkeby HJ, Nordling J. Urinary incontinence after prostatic surgery. Danish Medical Journal. 2007; 169:1910-1912. 11. Bauer RM, Bastian PJ, Gozzi C, Stief CG. Postprostatectomy incontinence: all about diagnosis and management. Eur Urol. 2009; 55:322-33. 12. Trost L, Elliott DS. Male stress urinary incontinence: a review of surgical treatment options and outcomes. Adv Urol. 2012; 2012:287489 13. Thuroff JW, Abrams P, Andersson K-E, et al. EAU guidelines on urinary incontinence. Eur Urol.Urol. 2011; 59:387-400. 14. Herschorn S, Bruschini H, Comiter C, et al. Surgical treatment of stress incontinence in men. Neurourol Urodyn. 2010; 29:179190. 15. Abrams P, Andersson KE, Birder L, et al. 4th International Consultation on Incontinence. Recommendations of International Scientific Committee: Evaluation and treatment of urinary incontinence, pelvic organ prolapse and fecal incontinence. Neurourology and Urodynamics. 2019; 29:213-240. 16. Welk BK, Herschorn S. The male sling for post-prostatectomy urinary incontinence: a review of contemporary sling designs and outcomes. BJU Int. 2012; 109:328-44. 17. Romano V, Metrebian SE, Vaz F, et al. An adjustable male sling for treating urinary incontinence after prostatectomy: a phase III multicentre trial BJU Int. 2006; 97:533-9. 18. Van Melick HH, Van Venrooij GE, Eckhardt MD, Boon TA.

Archivio Italiano di Urologia e Andrologia 2020; 92, 1

Correspondence Michele Cotugno, MD (Corresponding Author) mikcot88@libero.it Daniel Martens, MD dmastens@ausl.pr.it Pastizzaro Carmelo Destro, MD pdestro@ausl.pr.it Michele Potenzoni, MD mpotenzoni@ausl.pr.it Andrea Prati, MD aprati@ausl.pr.it Dipartimento Chirurgico, U.O.C di Urologia, Ospedale di Vaio-Fidenza, Fidenza (Italy) Giacomo Pirola, MD gmo.pirola@gmail.com Martina Maggi, MD martina.maggi@uniroma.it Dipartimento di Chirurgia Generale e specialistica, U.O.C Urologia, Ospedale di Arezzo, Arezzo (Italy) Bernardo Maria Cesare Rocco, MD bernardo.rocco@gmail.com Salvatore Micali, MD smicali@unimore.it Dipartimento di Chirurgia Generale e Specialità Chirurgiche, U.O di Urologia, Azienda Ospedaliero-Universitaria di Modena, Modena (Italy)

Lourenco_Stesura Seveso 14/04/20 13:54 Pagina 11

DOI: 10.4081/aiua.2020.1.11

ORIGINAL PAPER

Prognostic value of p16INK4a overexpression in penile cancer Mário Pereira-Lourenço 1, Duarte Vieira e Brito 1, Miguel Eliseu 2, Noémia Castelo-Branco 3, João Pedro Peralta 1, Ricardo Godinho 1, Paulo Conceição 1, Mário Reis 1, Carlos Rabaça 1, Amílcar Sismeiro 1 1 Urology

department Portuguese Institute of Oncology Coimbra, Coimbra, Portugal; and Kidney transplant department Coimbra Hospital University Centre, Coimbra, Portugal; 3 Pathology department Portuguese Institute of Oncology Coimbra, Coimbra, Portugal. 2 Urology

Summary

Introduction: Penile cancer is rare, accounting for less than 1% of all male cancers in industrialized countries. It is most common in areas of high prevalence of HPV, being a third of cases attributed to the carcinogenic effect of HPV. Tumour cells infected with HPV overexpress p16INK4a, as such p16INK4a has been used as a surrogate of HPV infections. Objective: To evaluate the prognostic factor of p16INK4a overexpression in penile cancer. Methods: Retrospective analysis of patients diagnosed with penile cancer, submitted to surgery in a Portuguese Oncological Institution in the last 20 years (n = 35). Histological review of surgical pieces and immunohistochemical identification of p16INK4a. Relation between p16INK4a and the following factors were studied: age, histological subtype, tumour dimensions, grade, TNM stage, perineural invasion, perivascular invasion, disease free survival (DFS) and cancer specific survival (CSS). Results: p16INK4a was positive in 8 patients (22.9%). Identification of p16INK4a did not correlate with none of the histopathological factors. In this work we identified a better DFS and CSS in patients positive for p16INK4a (DFS at 36 months was 100.0% vs. 66.7%; CSS at 36 months was 100.0% vs. 70.4%), although without statistical significance (p > 0.05). In multivariate analysis of histopathological factors studied, only N staging correlated with DFS and CSS (p = 0.017 and p = 0.014, respectively). Discussion: the percentage of cases positive for p16INK4a is smaller than the one found in literature, which can suggest a less relevant part of HPV infection in the oncogenesis of penile cancer in the studied population. Identification of p16INK4a did not relate with other clinicopathological factors. Tendency for a more favourable prognosis in patients with p16INK4a agrees with results found in literature. The most relevant factor for prognosis is nodal staging. Conclusions: penile cancer positive for p16INK4a shows a trend for better survival, although the most relevant factor is nodal staging.

KEY WORDS: Penile cancer; HPV; p16; Prognosis. Submitted 29 August 2019; Accepted 1 September 2019

INTRODUCTION

In industrialized countries, penile cancer is rare, having an incidence of approximately 1/100000 in Europe and the United States of America, accounting for less than 1%

of all male cancers (1-3). However, in other regions of the world, particularly South America, Southeast Asia and parts of Africa, the incidence of penile cancer is much greater, accounting for about 2% of all male cancers, although in some countries it can reach 10% (4, 5). The incidence of penile cancer increases with age, reaching a peak in the six decade, although it can occur in much younger patients (1, 6). Penile cancer is most common in areas with high prevalence of HPV, with a third of cases attributed to the carcinogenic effects of HPV (1, 7). Other risk factors identified where: phimosis (8, 9), chronic penile inflammation/ lichen sclerosus (10), psoralene and phototherapy with ultraviolet radiation A (11), smoking (8), residing in rural areas/low socioeconomical level (12, 13) and multiple sexual partners (8). In relation to penile cancer, HPV DNA was identified in 30-40% of cases, varying in accordance to histological subtype. The histological subtypes most associated with HPV are Basaloid Penile Squamous Cells Carcinoma (PSCC) (76%), mixed Warty-basaloid PSCC (82%) and Warty PSCC (39%). The Usual PSCC and Papillary PSCC are not associated with HPV (14, 15). Although the classic PSCC is normally characterized as non-related to HPV, a recent metanalysis identified an association in over 30% of cases (16). The subtypes of HPV most commonly associated with penile cancer are 16 and 18 (17). The World Health Organization (WHO), utilizing the hypothesis of independent pathways of carcinogenesis, categorizes PSCC regarding HPV (18, 19). The prognostic value of the association with HPV is still controversial, with recent studies showing a better outcome in HPV associated penile cancer (20-22), while others do not show significant differences (18, 23). Various methods can be used to detect HPV in tumour cells, such as PCR amplification to detect HPV DNA. Due to the overexpression of p16INK4a in HPV infected cells, p16INK4a expression can be used as a surrogate of active HPV infections (16). In cervical cancer and in other squamous cell carcinomas, expression of p16INK4a is used as a marker for the presence of high-risk HPV (17-19). Progression and regression of low grade intraepithelial cervical cancer can be estimated utilizing p16INK4a and mark a better cancer specific survival (CSS). However, the

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2020; 92, 1

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M. Pereira-Lourenço, D. Vieira e Brito, M, Eliseu, N. Castelo-Branco, J.P. Peralta, R. Godinho, P. Conceição, M. Reis, C. Rabaça, A. Sismeiro

correlation between expression of p16INK4a and HPV infection in penile cancer is still controversial (24). The main aim of this paper is to evaluate the prognostic value of p16INK4 expression in penile cancer. Other goals are to evaluate the epidemiologic association between HPV and penile cancer in Portugal (indirect assessment by assessing expression of p16INK4a) and to evaluate the association between HPV and histological subtypes of PSCC and the initial staging of the disease.

METHODS Patient selection and data collection Retrospective analysis of all patients with the primary diagnosis of penile cancer treated in a Portuguese oncological institution, in the last 20 years. Retrospective evaluation of patient data. Pathological and immunohistochemistry evaluation All surgical specimens of the identified patients were revaluated for this study. The material was fixed in 10% formol, embedded in paraffin and stained with haematoxilin-eosine, and was reviewed by a genitourinary pathologist that determined the histologic subtyping and the pathological grade using the morphologic criteria presented in the WHO classification of tumours of the penis of 2016 and tumour staging was made according the AJCC cancer staging manual of 2017 (19, 25). Immunohistochemical analysis was performed on the BenchMark-Ultra platform (Ventana R). Antigenic retrieval was performed using the Ultraview Universe Dab Detection Kit (Ventana R). Slides were then incubated with monoclonal antibody to P16ink4a (mouse clone E6H4, CINtec R p16 Histology, Ventana R). The Bond Polymer Refine detection system (Ventana) was used for secondary antibody and visualization. Cervical squamous cell carcinoma was used as positive control, and benign skin as negative control. Cases were scored by a genitourinary pathologist. To define the expression patterns of p16INK4a, the classification of Cubila et al. (26) was adapted, and overexpression of p16INK4a was defined as diffuse, continuous, and strong nuclear and cytoplasmic staining of the neoplastic cells. Discontinuous, focal and weak staining as well the absence of staining was interpreted as negative for p16INK4a overexpression. Statistical analysis The program SPSS 21 was used for statistical analysis. We used the Mann-Whitney test to assess the relation between clinical and pathological characteristics and p16INK4a. Survival related to each individual factor were calculated by the Kaplen-Meyer curves. Multivariate analysis utilizing Cox regression was utilized for the impact of clinical and pathological factors on survival.

RESULTS Clinicopathological data The total number of patients was 35, the median age was 69 (range 33-90 years) and the median tumour size was

Archivio Italiano di Urologia e Andrologia 2020; 92, 1

of 2.5 cm (range, 0.4-12.0). Eight patients (22.9%) presented with positive p16INK4a test. Relating to T staging, 1 (2.9%) presented with Tis, 13 (37.1%) T1, 11 (31.4%) T2 and 10 (28.6%) T3. The clinicopathological results are summarized in Table 1. P16INK4a immunoexpression The relation between p16INK4a expression and the remaining clinicopathological results are summarized in Table 2. P16INK4a immunoexpression did not correlate in a significant way (p > 0.05) with none of studied factors. P16INK4a immunoexpression and prognosis The median follow-up was 63 months (range 6-204). The Kaplan-Meyer curves of disease-free survival (DFS) and cancer specific survival (CSS) in relation to P16INK4a immunoexpression are presented in Figures 1, 2, respectively. Although a tendency to a longer survival with positive P16INK4a immunoexpression, this was not statically significant (DFS: p = 0.219; CSS: p = 0.067). The DFS and CSS at 3 years for patients with positive P16INK4a immunoexpression were 100.0% and 100.0%, respectively. The DFS and CSS at 3 years for patients with negative P16INK4a immunoexpression were 66.7% and 70.4%, respectively. Other clinicopathological factors and prognosis The disease-free survival and cancer specific survival in relation to T stage, N stage, tumour grade, perineural invasion and perivascular invasion were evaluated. In relation to DFS, the following factors were associated with higher survival: T stage T ≤ 1 (p = 0.002) and N = 0 (p < 0.001). Table 1. Clinicopathological results. N (%) Age (years) • < 65 • ≥ 65 PSCC histologic subtype • Usual • Warty • Verrucous • Mixed Warty-Basaloid Dimension (cm) •<4 •≥4 p16INK4a • Positive • Negative Differentiation grade • G1 • G2 • G3 T stage •≤1 •>1 Lymph node metastasis • No • Yes Died of the disease • No • Yes

13 (37.1%) 22 (62.9%) 28 (80%) 3 (8.6%) 2 (5.7%) 2 (5.7%) 26 (74.8%) 9 (25.7%) 8 (22.9%) 25 (78.1%) 14 (40%) 15 (42.9%) 6 (17.1%) 14 (40.0%) 21 (60.0%) 26 (74.3%) 9 (25.7%) 26 (74.3%) 9 (25.7%)

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p16INK4a overexpression in penile cancer

Table 2. Relation between p16INK4a expression and the remaining clinicopathological results.

Figure 2. Cancer specific survival for p16INK4a positive and negative patients.

N (%) Age (years) • < 65 • ≥ 65 PSCC histologic subtype • Usual • Warty • Verrucous • Mixed Warty-Basaloid Dimension (cm) •<4 •≥4 Differentiation grade • G1 • G2 • G3 Perineural invasion • No • Yes Lymphovascular invasion • No • Yes T stage •≤1 •>1 Lymph node metastasis • No • Yes Died of the disease • No • Yes

2 (25.0%) 6 (75.0%)

11 (40.7%) 16 (59.3%)

0.425

6 (75%) 1 (12.5%) 0 (0.0%) 1 (12.5%)

22 (81.5%) 2 (7.4%) 2 (7.4%) 1 (3.7%)

0.800

6 (75.0%) 2 (25.0%)

20 (74.1%) 6 (22.2%)

0.318

4 (50.0%) 3 (37.5%) 1 (12.5%)

10 (37.0%) 12 (44.4%) 5 (18.5%)

0.510

7 (87.5%) 1 (12.5%)

4 (14.8%) 23 (85.2%)

0.871

7 (87.5%) 1 (12.5%)

24 (88.9%) 3 (11.1%)

0.915

3 (37.5%) 5 (62.5%)

11 (40.7%) 16 (59.3%)

0.871

8 (100.0%) 0 (0.0%)

18 (66.7%) 9 (33.3%)

0.062

8 (100.0%) 0 (0.0%)

18 (66.7%) 9 (33.3%)

0.062

Analysing CSS the following factors presented statistically significant improved survival: age < 65 years (p = 0.042), stage T ≤ 1 (p = 0.005), stage N = 0 (p < 0.001). In a multivariate Cox regression analysis with the previously described factors and HPV, the model was statistically significant in relation with DFS and CSS, although Figure 1. Disease free survival for p16INK4a positive and negative patients.

only N stage presented with statically relevance (p = 0.017 and p = 0.014, respectively).

DISCUSSION

In this study, we identified 22.9% of P16INK4a positive PSCC, a value smaller than the one calculated by a recent metanalysis, which identified P16INK4a in 42.6% (95% CI; 36.2-47.0) worldwide (2995 cases) and 44.9% (95% CI; 38.4-51.1) in Europe (16). A Spanish study (Barcelona), interesting to compare due to the geographic proximity with Portugal, identified a P16INK4a positivity in 34.0% of 72 cases (22). In order to understand this result, it is essential to comprehend the meaning of positive P16INK4a and its correlation with the physio-pathological role of HPV infection in penile cancer. The most sensitive method for the detection of HPV in tumoral tissue is PCR amplification (27). Due to the strong correlation between active HPV and P16INK4a overexpression in neoplastic cells, it has been used as a surrogate marker for HPV (28). The incorporation of high-risk HPV (HRHPV) in the host genome, leads to the overexpression of oncoproteins (E7 and E6). The protein E7 binds to retinoblastoma protein, leading to the increased expression of p16 (tumour suppressing protein). This overexpression can be used as a reliable marker for high-risk HPV infection (26). Sensitivity and specificity of P16INK4a expression in HR-HPV was 100% and 57%, respectively (29). This lack of specificity leads some authors to defend that identification of HPV DNA is fundamental (30). According to Cubilla et al., positivity for P16INK4a in penile cancer has a strong correlation with the presence of HR-HPV (26). In the presence of a negative P16INK4a, infection with a low risk HPV genotype or absence of HPV infection can be suspected (24). In the previously addressed metanalysis by Olesen et al. (16), 79.6% of HPV positive cases presented with a positive P16INK4a, while 18.5% of HPV negative cases also presented with positive P16INK4a. One of the explanaArchivio Italiano di Urologia e Andrologia 2020; 92, 1

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M. Pereira-Lourenço, D. Vieira e Brito, M, Eliseu, N. Castelo-Branco, J.P. Peralta, R. Godinho, P. Conceição, M. Reis, C. Rabaça, A. Sismeiro

tions for this variation and apparent incoherence may be the cut-off value used to consider a positive P16INK4a, although Olesen et al. did not find a significant difference between different cut-offs (16). Two recent reviews identified a prevalence of HPV positive PSCC (identified by PCR amplification) of 33.1% (31) and 39.4% (32). Nevertheless, various authors consider that a tumour can only be considered HPV positive if it presents with double positivity for HPV and P16INK4a (16, 18, 33). In an interesting way, positivity for P16INK4a correlates with the presence of high-risk HPV subtypes (HPV 16, HPV18 e HPV59) (18). In this work there was no correlation between P16INK4a and histologic subtype. In the case of Usual PSCC, 6 (21.4%) were P16INK4a positive. Concerning Warty PSCC, Mixed PSCC (Basaloid + Warty) and Verrucous PSCC, the number of P16INK4a positive patients was 1 (33.3%), 1 (50%) and 0 (0%) respectively. The last World Health Organization (WHO), divides PSCC in tumours related to HPV and non-related to HPV, as there may be prognostic importance in this division (19). Curiously, usual PSCC is identified as non-related with HPV (as are Papillary, Verrucous, Sarcomatous and others), although data collected from literature indicates a prevalence of HPV DNA in Usual PSCC of 32.2% and positive P16INK4a of 36.9% (16). Our results and data from analysed literature, indicates that the classification Usual PSCC as independent of HPV is limited. In relation to Warty PSCC and mixed Basaloid-Warty PSCC (both classified as tumours related to HPV), literature indicates positivity for P16INK4a in > 90% of cases (16). The low number of Warty and Mixed Basaloid-Warty PSCC in our series does not allow for sustained comparations, although they corroborate the limitations present on the suggest classification presented by the WHO. In our work we did not directly study the presence of HPV, as such we cannot logically study the different HPV subtypes associated with PSCC. In developed and undeveloped countries, the predominant HRHPV associated with PSCC is HPV-16 as shown by several studies. Although uncommon in European countries, HPV-18 is the second most prevalent in PSCC in the World (22, 34). In the metanalysis conducted by Olesen et al., HPV16 (68.3%), followed by HPV6 (8.1%%) and HPV18 (6.9%). were the predominant oncogenic subtypes (16). In our study, we did not find any relation between P16INK4a and other histologic characteristics. Pone et al. did not find a relation between P16INK4a and other histologic characteristics (size, clinical stage, histological grade, or lymphatic or perineural invasion), although identified a relation with histologic subtype (24). Our series did not present with any Basaloid tumour, although literature indicates a relation between positive P16INK4a and this histological subtype (26). Ferrándiz-Pulido et al. identified a connection between positive P16INK4a and histological differentiation (P16INK4a was associated with G3/4) and histological subtype (22). Some works distinguish between penile epithelial neoplasia (PEN) and PSCC in evaluating the importance of HPV and P16INK4a, as most of PEN (> 70%) are HPV+. We decided not to exclude the single patient with PEN from our work, as positivity for P16INK4a between PEN and PSCC are very

Archivio Italiano di Urologia e Andrologia 2020; 92, 1

similar (49.5% vs. 41.6%, respectively) (16). Analysing prognosis, we did not find, in this work, a significant statistical relation between P16INK4, DSF and CSS. Nevertheless, there is a clear trend for a better outcome in patients positive for P16INK4a with only one patient presenting with recurrence and no case of disease related mortality. The absence of statistical significance is probably related with the low number of P16INK4a positive tumours in our sample. Various works have studied the effect of HPV and P16INK4a in the prognosis of PSCC. Regarding the effect HPV in DFS, Afonso et al. (112 patients, median follow-up of 20 months) and Lorenzo et al. (30 patients, median follow-up of 24 months) did not detect significant differences (35, 36). Scheiner et al. (72 patients) reported a better DFS at 5 years, although without statistical significance (37). Concerning the effects of HPV in CSS, in the review by Sand et al. (649 patients, 174 HPV+) a better CSS for patients HPV positive was noted (HR 0.61; 95% CI: 0.38-0.98) (32). Analysing the effects of HPV in Overall Survival (OS), studies did not show a significant relation (32, 38). Tang et al. described a better DFS in patients positive for P16INK4a (119 patients, 59 P16INK4a positive, median follow-up of 30 months) (44). However, other works did not show a relation between P16INK4a and DFS. The effect of P16INK4a in CSS was studied by Sand et al. (review of 414 patients, 191 positive for P16INK4a) with a HR of 0.45 (95% CI: 0.30- 0.69) for patients positive for P16INK4a (32). The percentage of patients alive 4 or 5 years after diagnosis range from 69% to 100% for P16INK4a positive and from 51% to 77% if P16INK4a negative (22, 23, 29, 39-43). All the study-specific HRs are below 1 and ranging from 0.21 to 0.81, however only one (40) was statistically significant. Regarding OS, Pone et al. reported a better OS in patients positive for P16INK4a, with a HR of 0.88 (95%CI: 0.49-1.59) (24). Zargar-Shoshtari et al. found that men with penile cancer positive for P16INK4a had a significant better OS compared with negative P16INK4a (HR = 0.33; 95% CI: 0.130.85) in a multivariable model adjusting for pathological nodal status, adjuvant chemotherapy and age (42). Tang et al. did not find a connection between P16INK4a and OS (44). In this work, due to the discharge from follow-up of some patients and limitation in the quality of data collection outside our institution, we did not calculate OS. In general, bibliography demonstrates a better survival for patients positive for HPV, as reported in other tumours related with HPV (vulvar, oropharyngeal) (32). Sand et al., in the previously referred metanalysis, that analysed the HR of CSS of P16INK4a and CSS of HPV positive patients, discovered that the HR of CSS P16INK4a positive patients was lower than that of HPV positive patients. This could suggest that P16INK4a expression may be a stronger predictor of CSS than HPV, similar to studies of neck and head cancer (32). The prognostic value of HPV is still uncertain. Some have suggested that the presence of a viral infection (HPV), might increase immune surveillance, making HPV positive cancer less aggressive than non-viral cancers (21). In univariate analysis with other clinicopathological factors, a significant relation was found between T staging and N staging with DFS and CSS, while age > 65 years

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p16INK4a overexpression in penile cancer

presented with lower CSS. In multivariate analysis, only N staging correlated with survival. A work by Wen et al. (135 patients), reported a relation between N staging (clinical and pathologic) and CSS. In multivariate analysis, only pathologic N staging related with CSS (absence of relation between CSS and age, presence of phimoses, smoking, type of surgery, T stage or grade) (46). Our study presented with some limitations. Our series presents a limited number of patients, with only eight P16INK4a positive patients, which limits statistical results. In our work we did not evaluate the presence of HPV DNA, which can be relevant to corroborate the know connection between P16INK4a status. Lastly, due to the number present in our series, we did evaluate the influence of other factors that might influence prognosis, particularly the use of adjuvant or neoadjuvant therapies.

CONCLUSIONS

Penile cancer positive for P16INK4a present with a trend for better outcome, although the most relevant factor is node stage. The probable prognosis importance of P16INK4a corroborates the indication for its determination on penile cancer.

REFERENCES

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11. Stern RS, Study PF-U. The risk of squamous cell and basal cell cancer associated with psoralen and ultraviolet A therapy: a 30year prospective study. J Am Acad Dermatol. 2012; 66:553-62. 12. Koifman L, Vides AJ, Koifman N, et al. Epidemiological aspects of penile cancer in Rio de Janeiro: evaluation of 230 cases. Int Braz J Urol. 2011; 37:231-40; discussion 40-3. 13. McIntyre M, Weiss A, Wahlquist A, et al. Penile cancer: an analysis of socioeconomic factors at a southeastern tertiary referral center. Can J Urol. 2011; 18:5524-8. 14. Stankiewicz E, Kudahetti SC, Prowse DM, et al. HPV infection and immunochemical detection of cell-cycle markers in verrucous carcinoma of the penis. Mod Pathol. 2009; 22:1160-8. 15. Hakenberg OW, Compérat EM, Minhas S, et al. EAU guidelines on penile cancer: 2014 update. Eur Urol. 2015; 67:142-50. 16. Olesen TB, Sand FL, Rasmussen CL, et al. Prevalence of human papillomavirus DNA and p16. Lancet Oncol. 2019; 20:145-58. 17. Muñoz N, Castellsagué X, de González AB, Gissmann L. Chapter 1: HPV in the etiology of human cancer. Vaccine. 2006; 24 Suppl 3:S3/1-10. 18. Hölters S, Khalmurzaev O, Pryalukhin A, et al. Challenging the prognostic impact of the new WHO and TNM classifications with special emphasis on HPV status in penile carcinoma. Virchows Arch. 2019; 475:211-21. 19. Moch H, Cubilla AL, Humphrey PA, et al. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours. Eur Urol. 2016; 70:93-105. 20. Djajadiningrat RS, Jordanova ES, Kroon BK, et al. Human papillomavirus prevalence in invasive penile cancer and association with clinical outcome. J Urol. 2015; 193:526-31. 21. Lont AP, Kroon BK, Horenblas S, et al. Presence of high-risk human papillomavirus DNA in penile carcinoma predicts favorable outcome in survival. Int J Cancer. 2006; 119:1078-81. 22. Ferrándiz-Pulido C, Masferrer E, de Torres I, et al. Identification and genotyping of human papillomavirus in a Spanish cohort of penile squamous cell carcinomas: correlation with pathologic subtypes, p16(INK4a) expression, and prognosis. J Am Acad Dermatol. 2013; 68:73-82. 23. Bezerra AL, Lopes A, Santiago GH, et al. Human papillomavirus as a prognostic factor in carcinoma of the penis: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. Cancer. 2001; 91:2315-21. 24. Martins VA, Pinho JD, Teixeira Júnior AAL, et al. P16INK4a expression in patients with penile cancer. PLoS One. 2018; 13:e0205350. 25. Amin MB, Greene FL, Edge SB, et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging. CA Cancer J Clin. 2017; 67:93-9. 26. Cubilla AL, Lloveras B, Alejo M, et al. Value of p16(INK)4(a) in the pathology of invasive penile squamous cell carcinomas: A report of 202 cases. Am J Surg Pathol. 2011; 35:253-61. 27. Halec G, Alemany L, Lloveras B, et al. Pathogenic role of the eight probably/possibly carcinogenic HPV types 26, 53, 66, 67, 68, 70, 73 and 82 in cervical cancer. J Pathol. 2014; 234:441-51. 28. Rietbergen MM, Snijders PJ, Beekzada D, et al. Molecular characterization of p16-immunopositive but HPV DNA-negative oropharyngeal carcinomas. Int J Cancer. 2014; 134:2366-72. Archivio Italiano di Urologia e Andrologia 2020; 92, 1

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M. Pereira-Lourenço, D. Vieira e Brito, M, Eliseu, N. Castelo-Branco, J.P. Peralta, R. Godinho, P. Conceição, M. Reis, C. Rabaça, A. Sismeiro

29. Steinestel J, Al Ghazal A, Arndt A, et al. The role of histologic subtype, p16(INK4a) expression, and presence of human papillomavirus DNA in penile squamous cell carcinoma. BMC Cancer. 2015; 15:220. 30. Sakamoto J, Shigehara K, Nakashima K, et al. Etiological role of human papillomavirus infection in the development of penile cancer. Int J Infect Dis. 2019; 78:148-54. 31. Alemany L, Cubilla A, Halec G, et al. Role of Human Papillomavirus in Penile Carcinomas Worldwide. Eur Urol. 2016; 69:953-61. 32. Sand FL, Rasmussen CL, Frederiksen MH, et al. Prognostic Significance of HPV and p16 Status in Men Diagnosed with Penile Cancer: A Systematic Review and Meta-analysis. Cancer Epidemiol Biomarkers Prev. 2018; 27:1123-32. 33. Braakhuis BJ, Snijders PJ, Keune WJ, et al. Genetic patterns in head and neck cancers that contain or lack transcriptionally active human papillomavirus. J Natl Cancer Inst. 2004; 96:998-1006. 34. Rubin MA, Kleter B, Zhou M, et al. Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis. Am J Pathol. 2001; 159:1211-8. 35. Afonso LA, Carestiato FN, Ornellas AA, et al. Human papillomavirus, Epstein-Barr virus, and methylation status of p16. J Med Virol. 2017; 89:1837-43. 36. Di Lorenzo G, Perdonà S, Buonerba C, et al. Cytosolic phosphorylated EGFR is predictive of recurrence in early stage penile cancer patients: a retropective study. J Transl Med. 2013;11:161. 37. Scheiner MA, Campos MM, Ornellas AA, Chin EW, Ornellas MH, Andrada-Serpa MJ. Human papillomavirus and penile cancers in Rio de Janeiro, Brazil: HPV typing and clinical features. Int Braz J Urol. 2008; 34:467-74; discussion 75-6.

Correspondence Mário Pereira-Lourenço, MD (Corresponding Author) mariolourenco88@gmail.com Duarte Vieira e Brito, MD João Pedro Peralta, MD Ricardo Godinho, MD Paulo Conceição, MD Mário Reis, MD Carlos Rabaça, MD Amílcar Sismeiro, MD Urology Department Portuguese Institute of Oncology Coimbra, Coimbra (Portugal) Rua Maria Bourbon Bobone, n57, RE/Esq, Coimbra, 3030-481, Portugal Miguel Eliseu, MD Urology and Kidney transplant Department Coimbra Hospital University Centre, Coimbra (Portugal) Noémia Castelo-Branco, MD Department Portuguese Institute of Oncology Coimbra, Coimbra (Portugal)

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38. Mannweiler S, Sygulla S, Tsybrovskyy O, et al. Clear-cell differentiation and lymphatic invasion, but not the revised TNM classification, predict lymph node metastases in pT1 penile cancer: a clinicopathologic study of 76 patients from a low incidence area. Urol Oncol. 2013; 31:1378-85. 39. McDaniel AS, Hovelson DH, Cani AK, et al. Genomic profiling of penile squamous cell carcinoma reveals new opportunities for targeted therapy. Cancer Res. 2015; 75:5219-27. 40. Gunia S, Erbersdobler A, Hakenberg OW, et al. p16(INK4a) is a marker of good prognosis for primary invasive penile squamous cell carcinoma: a multi-institutional study. J Urol. 2012; 187:899-907. 41. Bezerra SM, Chaux A, Ball MW, et al. Human papillomavirus infection and immunohistochemical p16(INK4a) expression as predictors of outcome in penile squamous cell carcinomas. Hum Pathol. 2015; 46:532-40. 42. Zargar-Shoshtari K, Spiess PE, Berglund AE, et al. Clinical Significance of p53 and p16(ink4a) Status in a Contemporary North American Penile Carcinoma Cohort. Clin Genitourin Cancer. 2016; 14:346-51. 43. Bethune G, Campbell J, Rocker A, et al. Clinical and pathologic factors of prognostic significance in penile squamous cell carcinoma in a North American population. Urology. 2012; 79:1092-7. 44. Tang DH, Clark PE, Giannico G, et al. Lack of P16ink4a over expression in penile squamous cell carcinoma is associated with recurrence after lymph node dissection. J Urol. 2015; 193:519-25. 45. Guerrero D, Guarch R, Ojer A, et al. Hypermethylation of the thrombospondin-1 gene is associated with poor prognosis in penile squamous cell carcinoma. BJU Int. 2008; 102:747-55. 46. Wen S, Ren W, Xue B, et al. Prognostic factors in patients with penile cancer after surgical management. World J Urol. 2018; 36:435-40.

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DOI: 10.4081/aiua.2020.1.17

ORIGINAL PAPER

Hexaminolevulinate blue light cystoscopy (Hal) assisted transurethral resection of the bladder tumour vs white light transurethral resection of the bladder tumour in non-muscle invasive bladder cancer (NMIBC): A retrospective analysis Marco Capece 1, Lorenzo Spirito 2, Roberto La Rocca 2, Luigi Napolitano 2, Roberto Buonopane 1, Sergio Di Meo 1, Maurizio Sodo 2, Umberto Bracale 2, Nicola Longo 2, Alessandro Palmieri 2, Ferdinando Fusco 2, Paolo Verze 2, Gianluigi Califano 2, Felice Crocetto 2, Ciro Imbimbo 2, Vincenzo Mirone 2, Vittorio Imperatore 2, Massimiliano Creta 2 1 Madonna

del Buon Consiglio, “Fatebenefratelli” Hospital, Naples; degli Studi di Napoli “Federico II”, Naples.

2 Università

Summary

Background: Bladder cancer is the eleventh most commonly diagnosed cancer worldwide. The recurrence rate of this cancer can be very high, up to 45%. Photodynamic diagnosis (PDD) is more sensitive than standard procedures for the detection of malignant tumours. The aim of the study was to evaluate oncological outcomes in white light TURB (WL-TURB) and hexaminolevuninate blue light TURB (Hal-TURB). Patients and methods: This was a retrospective longitudinal single-center study. In the period between January 2016 and October 2016 WL-TURB was the only therapeutic option available. From November 2016 until April 2017 all TURBs were fluorescence-guided (Hal-TURB). Kaplan-Meier curves have been used to estimate recurrence free survival rates. Results: One hundred and eleven patients underwent HalTURB and 137 underwent WL-TURB. Recurrence rate after 12 months was 19.8% (22 out of 111 patients) and 37.2% (51 out of 137 patients) in HAL-group and WL-group respectively (p < 0.01). The recurrence-free period was longer in HAL-group rather than WL-group (8.9 months vs 7.3 months, p < 0.05). Moreover, the recurrence rate during the first 6 months was 3.7% in patients who underwent HAL-TURB and 16% in those who received WL-TURB (p < 0.01). Conclusion: The results of the study show that recurrence-free survival was longer in patients undergoing HAL-TURB compared to the patients who received standard WL-TURB.

KEY WORDS: Bladder cancer; Hexaminolevulinate; TURB; PDD; Fluorescence cystoscopy. Submitted 3 June 2019; Accepted 19 July 2019

INTRODUCTION

Bladder cancer is the eleventh most commonly diagnosed cancer worldwide, with the highest incidence among men (1). The recurrence rate of this cancer at the first follow-up evaluation can be very high, up to 45% in patients with multiple tumours at the first diagnosis (2). Many studies suggest that early second transurethral resection of bladder tumor (re-TURB) improves staging

and reduces the recurrence as well as progression rates in high-risk bladder cancer patients (3). In fact, considering the stochastic nature of the technique, a re-TURB performed 2-6 weeks after the first TURB may find residual tumour in up to 76% of patients (4). One of the reasons for the high recurrence risk of non-muscle invasive bladder cancer (NMIBC) is likely to be the persistence of residual lesions following initial TURB (5). A key goal in the treatment of NMIBC is the successful identification and removal of cancerous tumors to prevent either recurrence and progression of the disease in order to improve cancer-free and overall survival. Photodynamic diagnosis (PDD) is performed using violet light after intravesical instillation of 5-aminolaevulinic acid (ALA) or hexaminolaevulinic acid (HAL). It has been confirmed that fluorescence-guided biopsy and resection are more sensitive than conventional procedures for the detection of malignant tumours, particularly for CIS (6). Moreover hexaminolevulinate-induced fluorescence cystoscopy, by improving the detection of bladder cancer, leads to a more complete resection and significantly better disease-free survival (7). The aim of our study was to analyze the use of hexaminolaevulinate (HAL: Hexvix®, Photocure, Norway) during TURB in naïve patients and compare it to white light TURB (WL-TURB) in terms of recurrence rate within 12 months after TURB.

PATIENTS

AND METHODS

This is a retrospective longitudinal single-center study. Naïve patients with a suspicion of Ta/T1 bladder tumour had been recruited from the urology outpatient clinic. The suspicion of bladder tumour had been based on positive urine cytology and flexible cystoscopy performed in the outpatient department by two qualified urologists. Exclusion criteria were previous diagnosis of bladder or upper urinary tract cancer, history of chronic specific or

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2020; 92, 1

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M. Capece, L. Spirito, R. La Rocca, et al.

aspecific bladder cystitis, known allergy to HAL, presence of porphyria. In the period between January 2016 and October 2016 WL-TURB was the only therapeutic option available. From November 2016 until March 2017 all TURBs were fluorescence-guided (HAL-TURB). The HAL solution was instilled into the bladder by a Nelaton catheter and was to be retained for at least 1 h. Blue light induction was obtained with D-light C system by Karl Storz. At a first instance bladder inspection had been carried out under white light source, and the TURB had been performed under white light. Subsequently the bladder had been inspected under blue light to identify residual neoplastic tissue at the resection sites or additional tumours that had been missed during white light inspection. WL TURB was performed using 1588 Aim Camera system (Stryker, San Jose, CA) instead. None of the patients received one-shot chemotherapy after TURB. The histopathological evaluation and staging were performed in accordance with the TNM 2009 classification. Patients were treated and followed-up according to the European Association of Urology guidelines (6). All patients received the first cystoscopy at three months. If negative, the cystoscopy was repeated every 3 months in high-risk and intermediate-risk patients, while in low-risk patients it was repeated 9 months after. A recurrence was defined as macroscopic tumour with the histopathological confirmation. Adverse events were recorded at each follow-up visit. All data have been recorded and analyzed with SPSS v. 25 (IBM Corp., Armonk, NY, USA). Recurrence free survival rates were estimated according to the Kaplan-Meier method, and differences were compared by a log-rank test.

Table 2. Hystology of the patients.

Hystology Urothelial carcinoma

Total

Count % in Hystology % in Type of TURB Other tumours Count % in Hystology % in Type of TURB CIS Count % in Hystology % in Type of TURB Urothelial carcinoma Count + CIS % in Hystology % in Type of TURB No cancer Count % in Hystology % in Type of TURB Count % in Hystology % in Type of TURB

Type of TURB Hal-TURB WL-TURB Chemotherapy/ Immunotherapy after TURB

MMC

BCG

The number of patients who underwent HAL-TURB for a suspicion of bladder cancer was 111, whilst 137 patients underwent WL-TURB. Only 17 patients were lost at folTotal

Age

Hal-TURB (mean) WL-TURB (mean) Lesion size (cm) Hal-TURB (mean) WL-TURB (mean) Sex Men Hal-TURB (n) WL-TURB (n) Women Hal-TURB (n) WL-TURB (n) Smokers Hal-TURB (n) WL-TURB (n) Positive cytology Hal-TURB (n) WL-TURB (n) Positive ultrasound Hal-TURB (n) WL-TURB (n) Positive cystoscopy Hal-TURB (n) WL-TURB (n)

111 137 111 137 76 92 35 45 72 106 19 25 95 126 99 128

61.68 60.7 2.194 1.996 45.20% 54.80% 43.80% 56.30% 29.80% 43.80% 7.70% 10.10% 38.30% 50.80% 39.90% 51.60%

Archivio Italiano di Urologia e Andrologia 2020; 92, 1

Total 197 100.0% 79.4% 18 100.0% 7.3% 9 100.0% 3.6% 14 100.0% 5.6% 10 100.0% 4.0% 248 100.0% 100.0%

Table 3. Chemotherapy/Immunotherapy after TURB.

RESULTS

Table 1. Demographical and clinical characteristics.

Type of TURB Hal-TURB WL-TURB 80 117 40.6% 59.4% 72.1% 85.4% 11 7 61.1% 38.9% 9.9% 5.1% 5 4 55.6% 44.4% 4.5% 2.9% 9 5 64.3% 35.7% 8.1% 3.6% 6 4 60.0% 40.0% 5.4% 2.9% 111 137 44.8% 55.2% 100.0% 100.0%

Count % in Chemotherapy/ Immunotherapy after TURB % in Type of TURB Count % in Chemotherapy/ Immunotherapy after TURB % in Type of TURB Count % in Chemotherapy/ Immunotherapy after TURB % in Type of TURB

Total

102

37.3% 55.9% 30

62.7% 66.7% 32

100.0% 62.2% 62

48.4% 44.1% 68

51.6% 33.3% 96

100.0% 37.8% 164

41.5% 58.5% 100.0% 100.0% 100.0% 100.0%

p 0.463 0.122 0.826

0.124 0.817 0.108 0.233

low-up and were not included in statistical analysis (11 in HAL-TURB group and 6 in WL-TURB group). All TURBs were performed by 2 experienced surgeons. Demographical and clinical characteristics of the two populations were summarized in Table 1. The populations were homogeneous. Mean age was 61.7 years (range 39-91) and 60.7 (range 39-81) in HAL-TURB group and WL-TURB group respectively (p = 0.463). Of 248 patients with suspicion of bladder cancer 197 had a urothelial carcinoma, 14 concomitant CIS and urothelial carcinoma, 9 only CIS, 18 other tumors and 10 had no tumor (Table 2). Only ten patients were diagnosed with T2 or more invasive disease, however 38 patients underwent a cystectomy. No significant differences were found among the populations of the two groups in terms of

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Hexaminolevulinate blue light cystoscopy (Hal) assisted transurethral resection of the bladder tumour vs white light transurethral resection...

Figure 1. Kaplan-Meier curves on RFS.

patients’ characteristics, smoking habits, lesion size. Furthermore, no difference was detected between the percentages of patients undergoing chemotherapy or immunotherapy after TURB (Table 3). None of the patients received one-shot chemotherapy after TURB. Recurrence rate after 12 months was 19.8% (22 out of 111 patients) and 37.2% (51 out of 137 patients) in HAL-group and WL-group respectively (p < 0.01) (Figure 1). The recurrence-free period was longer in HAL-group rather than WL-group (8.9 months vs 7.3 months, p < 0.05). In addition to that, recurrence rate during the first 6 months was 3.7% in patients who underwent HAL-TURB and 16% in those who received WL-TURB (p < 0.01). No adverse events after the administration of HAL were recorded in the group who received the instillation.

DISCUSSION

Nowadays the use of Hexvix on naïve patients with bladder cancer suspicion is not advisable according to EAU guidelines (6). A German multicenter study has confirmed that in patients undergoing TURB the use of HAL has improved by 6.8% the detection of cancerous lesions in comparison to the standard WL-TURB (8). In addition to that, a recent meta-analysis has confirmed the effectiuveness of HAL-TURB in reducing recurrence rate, however further studies have been claimed to reach a change in the clinical management of the disease (9). As shown in the literature it is also possible to evaluate a risk model for prediction of bladder cancer recurrence (10). In another systematic review and meta-analysis the rate of cancerous progression was significantly lower in

patients treated with HAL- vs. WLbased TURB (11). At the present time there are no long-term results on disease progression and overall survival, however it is desirable that these variables will decrease. Meanwhile the use of HAL-TURB leads to a reduction of further hospitalizations which in turn reduces hospital costs (12). In our study we compared data of two different approaches to naïve patients with suspicion of bladder cancer. Our results show that recurrence-free period was longer in patients undergoing HAL-TURB rather than patients who received the standard WL-TURB. Interestingly the recurrence rate during the first 6 months was hugely reduced in HAL-group than in WL-group (3.6% vs 16% respectively). A reasonable explanation might be better bladder cancer visualization which results in a more precise and complete initial resection. Therefore in our study we lay the foundation for a future stratification of the risk based on the use of violet light after intravesical instillation of 5-aminolaevulinic acid during the initial TURB. The future goal will be the preoperative identification of a sub-group of patients who can benefit from the HalTURB at the first resection.

CLINICAL

PRACTICE POINTS

Many studies have pointed the benefit of performing fluorescence-guided TURB in terms of recurrence rate and progression rate. In our study we have demonstrated that in patients undergoing Hal-TURB the recurrence free survival was dramatically reduced in the first 6 months. This might be helpful in the search of pre-operative selection of the patients who will definitely benefit from this treatment.

REFERENCES

1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN2012. Int J Cancer. 2015; 136:E359-86. 2. Witjes JA, Kiemeney LA, Oosterhof GO, Debruyne FM. Prognostic factors in superficial bladder cancer. A review. Eur Urol. 1992; 21:89-97. 3. DobruchJ, Borówka A, Herr HW. Clinical value of transurethral second resection of bladder tumor: systematic review. Urology. 2014; 84:881-5. 4. Creta M, Mirone V, Di Meo S, et al. Endoscopic Spatulation of the intramural ureter: a technique to prevent stenosis of the ureterovesical junction in patients undergoing resection of the ureteral orifice. J Endourol. 2016; 30:913-7.

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M. Capece, L. Spirito, R. La Rocca, et al.

5. Witjes JA, Babjuk M, Gontero P, et al. Clinical and cost effectiveness of hexaminolevulinate-guided blue-light cystoscopy: evidence review and updated expert recommendations. Eur Urol. 2014; 66:863-71. 6. Babjuk M, Burger M, Compérat E, et al. Non-muscle invasive bladder cancer. European Association of Urology guidelines 2019. 7. Stenzl A, Burger M, Fradet Y, et al. Hexaminolevulinate guided fluorescence cystoscopy reduces recurrence in patients with nonmuscle invasive bladder cancer. J Urol. 2010; 184:1907-13. 8. Bach T, Bastian PJ, Blana A, et al. Optimised photodynamic diagnosis for transurethral resection of the bladder (TURB) in German clinical practice: results of the noninterventional study OPTIC III. World J Urol. 2017; 35:737-744. 9. Lee JY, Cho KS, Kang DH, et al. A network meta-analysis of therapeutic outcomes after new image technology-assisted transurethral

Correspondence Marco Capece, MD drmarcocapece@gmail.com Roberto Buonopane, MD robertobuonopane@libero.it Sergio Di Meo, MD sedime72@yahoo.com Madonna del Buon Consiglio, “Fatebenefratelli” Hospital, Naples Lorenzo Spirito lorenzospirito@msn.com Roberto La Rocca, MD robertolarocca87@gmail.com Luigi Napolitano, MD nluigi89@libero.it Maurizio Sodo, MD maurizio.sodo@unina.it Umberto Bracale, MD umberto.bracale@unina.it Nicola Longo, MD nicolalongo20@yahoo.it Alessandro Palmieri, MD info@alessandropalmieri.it Ferdinando Fusco, MD ferdinando.fusco2@libero.it Paolo Verze, MD pverze@gmail.com Gianluigi Califano, MD gianl.califano2@gmail.com Felice Crocetto , MD felice.crocetto@gmail.com Ciro Imbimbo, MD cimbimbo@unina.it Vincenzo Mirone, MD mirone@unina.it Vittorio Imperatore, MD v.imperatore1@gmail.com Massimiliano Creta, MD max.creta@gmail.com Università degli Studi di Napoli “Federico II”, Naples

Archivio Italiano di Urologia e Andrologia 2020; 92, 1

resection for non-muscle invasive bladder cancer: 5-aminolaevulinic acid fluorescence vs hexylaminolevulinate fluorescence vs narrow band imaging. BMC Cancer. 2015; 15:566. 10. Vartolomei MD, Ferro M, Cantiello F, et al. Validation of Neutrophil-to-lymphocyte Ratio in a Multi-institutional Cohort of Patients With T1G3 Non–muscle-invasive Bladder Cancer. Clin Genitourin Cancer. 2018; 16:445-452. 11. Gakis G, Fahmy O. Systematic review and meta-analysis on the impact of hexaminolevulinate - versus white-light guided transurethral bladder tumor resection on progression in non-muscle invasive bladder cancer. Bladder Cancer. 2016; 2:293-300. 12. Klaassen Z, Li K, Kassouf W, et al. Contemporary cost-consequence analysis of blue light cystoscopy with hexaminolevulinate in non-muscle-invasive bladder cancer. Can Urol Assoc J. 2017; 11:173-181.

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DOI: 10.4081/aiua.2020.1.21

ORIGINAL PAPER

Time changes of renal dimensions and variations of glomerular filtration rate in chronic kidney disease patients Simone Brardi 1, Gabriele Cevenini 2 1 Hemodialysis 2 Department

Unit, S. Donato Hospital, Arezzo, Italy; of Medical Biotechnologies, University of Siena, Italy.

Summary

Background: The aim of this longitudinal prospective study was to search if even in the absence of total or partial nephrectomy the kidney size can increase as the kidney function improves. Methods: We randomly enrolled 80 adult patients with various degrees of chronic renal failure but non-dialysis dependent neither totally or partially nephrectomized nor affected by any of the pathological conditions that can increase kidney size. The patients underwent a first examination comprehensive of a blood sample and renal ultrasonography and then were submitted to a therapeutic intervention aimed at removing all nephrotoxic agents to finally be subjected to a last similar medical examination. Results: The statistical analysis displayed a strong positive correlation between the percentage variation of the renal diameters’ average and the time changes of the GFR (r 0.731; p < 0.01) as well as the percentage variation of the GFR and the time changes variations of the right (r 0.487; p < 0.01) and left cortical kidney thickness (r 0.519; p < 0.01) and finally a strong negative correlation between the removal of nephrotoxic agents and the percentage variation of the renal diameters’ average (r - 0.293; p < 0.01) and the time changes of the GFR (r - 0.429; p < 0.01). Conclusions: In patients with chronic kidney disease, even in the absence of total or partial nephrectomy, under the stimulus of the removal of any nephrotoxic agents, there may be a limited increase in renal size according to a model that sees them vary according to the changes in GFR.

KEY WORDS: Longitudinal prospective study; Renal length variations; GFR time changes; Renal ultrasound; CKD patients. Submitted 4 October 2019; Accepted 13 November 2019

INTRODUCTION

The best measure of renal size is the volume which correlates well with the glomerular filtration rate (1). However, calculation of volume is prone to significant error because three independent measurements are used (2). Therefore, measurement of maximum renal length has become the clinical standard because it is simple, mode accurate and correlates well with renal volume (3, 2). Renal length averages about 11 cm in adults (3) so that 10-12 cm is a useful range for normal renal length, the discrepancy in size between the two kidneys is not abnormal provided that the smaller kidney is not less than 37% of the total renal volume. All measured kidney dimensions of patients with chronic kidney disease (CKD) correlate significantly with kidney function while the correlation with anthropometric parameters which is otherwise present in healthy subjects is lost in patients

with CKD (4, 5). More in detail the renal length, as renal failure progresses, significantly decreases (6). Therefore, the sonographic appearance of chronic renal failure consists of a decrease in renal size, thinning of the parenchyma (particularly the cortex) and increased echogenicity of the cortex. When cortical thickness cannot be determined because the medullary pyramids are not visible thinning of the cortex can still be appreciated as thinning of the entire parenchyma defined by a cutoff of 12 mm (3). The decrease of renal size and cortical thinning are often most noticeable in renovascular disease and hypertensive nephrosclerosis whereas in glomerular disorders particularly diabetic nephropathy the cortical thickness is often preserved even late in the disease (7). Instead, a physiological enlargement is known to occur only in solitary kidneys and during pregnancy while compensatory hypertrophy is seen in adults after nephrectomy (7). Nowadays therefore it is well known that average value of kidney’s volume shows a linear decrease with the progression of chronic kidney disease (8) and that kidney volume and its surrogate parameter that is the renal length correlate with GFR (4, 5) but we don’t know if this process, in the absence of total or partial nephrectomy, may be reversible, because until now it was never evaluated if the kidney length correlated also with the time changes of GFR, as can be recorded in a longitudinal type study. So, in order to investigate a similar renal regrowth in the absence of total or partial nephrectomy, we conducted this longitudinal prospective study.

MATERIALS

AND METHODS

This study was undertaken between June 2015 to September 2019 in the outpatient nephrology clinic of San Donato Hospital in Arezzo. The study population was randomly selected among adult patients with various degrees of chronic renal failure but non-dialysis dependent and affected or not by hypertension but not by diabetes mellitus neither totally or partially nephrectomized and with the exclusion of those with obstructive uropathy, ischemia, pregnancy, polycystic kidney disease, and malignant diseases. After obtaining the respective informed consent from all participating subjects, we enrolled 80 patients (35 females and 45 males, with an average age, at the time of enrollment, of 71.5 ± 11.7 years) almost all hypertensive (except only four). The average glomerular filtration rate (GFR) (calculated by the CKD EPI equation) (9) at the time of enrollment, was

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2020; 92, 1

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49.4 ± 16.8 ml/min/1.73 m2. After the evaluation of medical history including the complete list of medications and every dietetic therapy, we submitted the enrolled patients to an accurate physical examination, comprehensive of the recording of anthropometric parameters (weight and height) and of a measurement of blood pressure that was taken with a mercury sphygmomanometer applied around each patient’s non-dominant arm after the patient had rested for 15 minutes in a sitting position and with his/her arm placed at the level of the heart. Two consecutive blood pressure recordings, taken at a 5-minute interval, were averaged to provide clinic systolic and diastolic blood pressure values. Blood samples were taken for serum creatinine and sodium and, where possible, 24-hour urine collection for albuminuria was executed. Finally, a B-mode and Doppler renal ultrasound was performed. All renal ultrasound examinations were carried out by the same nephrol-

ogist experienced in ultrasound examination using the same ultrasound device that was a Logiq S7 (GE Medical Systems Italy S.P.A. Milan, Italy) sonographic system equipped with 3 to 5 Mhz transducers. Any dimensional parameter of each kidney (i.e. length or else diameter in the longitudinal axis and parenchymal thickness) was registered as the average of two single measurements. The diameter in the longitudinal axis was assessed in a section visually estimated to represent the largest diameter. The cortical thickness was registered in the portion closer to the upper pole and the lower pole of the same kidney (4). Doppler signals were obtained from the interlobar arteries from the upper, middle and lower third of both kidneys and resistive index was calculated as the average of 6 measurements (3 from each of the 2 kidneys) taken for each patient. The Doppler angle was chosen as close to 0° as possible and special care was taken not to compress the kidney and not to have the patient performing Valsalva maneuver because both of them can increase the renal Table 1. Basic and final characteristics of the enrolled population resistive index value. Then the patients were submitted to and percentage changes (mean ± standard deviation). a full therapeutic and dietetic intervention to ameliorate the renal impairment by a wide range of actions such as Parameters Basal values Follow-up values Delta removal of nephrotoxic drugs (i.e. the hydrochlorothiazide Age (years) 71.5 ± 11.7 73.99 ± 11.39 3.72 ± 3.47 diuretics, non-steroidal anti-inflammatory drugs, etc.) as Weight (kg) 74.3 ± 11.7 72.4 ± 13 -2.37 ± 7.37 well as any variation of drug therapy in order to reduce Body mass index (BMI) (kg/m^2) 28.3 ± 4.7 27.6 ± 4.9 -2.36 ± 7.4 proteinuria and improve blood pressure control avoiding Glomerular filtration rate (GFR) (ml/min/1.73 m^2) 49.4 ± 17 50.6 ± 15.2 6.93 ± 32.4 both too low blood pressure values and those that are too 24-hour urinary albumin excretion (gr/24h) 0.2 ± 0.75 0.13 ± 0.6 -7.31 ± 98.5 high (10). Eventually, when it was indicated, it was introRight kidney diameter in the longitudinal axis (mm) 101.7 ± 9.7 101.91 ± 8.37 0.70 ± 8.5 duced an hypoproteic, hyposodic as well as hypocaloric diet (11). After on average of 2.5 (± 2.2) year interval the Left kidney diameter in the longitudinal axis (mm) 103.4 ± 10.4 103.43 ± 9.23 0.33 ± 7 same patients were submitted to a second and last medical renal diameters’ average in the longitudinal axis (mm) 102.6 ± 9.4 102.67 ± 7.84 0.47 ± 6.9 examination (to evaluate the outcome of the therapeutic Right kidney Renal resistive index 0.73 ± 0.1 0.72 ± 0.07 -0.54 ± 10 and/or dietetic actions undertaken) which was conducted Left kidney renal resistive index 0.73 ± 0.1 0.72 ± 0.08 -0.68 ± 9.7 in the same way as the first one. Sample descriptive statisBlood serum natrium (mmol/L) 142 ± 2.2 141.82 ± 2.30 -0.16 ± 2.2 tics were calculated, including mean and standard deviaSystolic blood pressure (mmHg) 122.6 ± 17.3 117.79 ± 16.9 -2.6 ± 16.7 tion for quantitative variables, and frequency counts and Diastolic blood pressure (mmHg) 75.9 ± 11.7 72.38 ± 12.68 -3.4 ± 19.3 percentages for qualitative variables (Tables 1-3). A Pearson Mean arterial pressure (mmHg) 91.4 ± 11 87.51 ± 11.81 -3.3 ± 16.4 correlation analysis was performed between quantitative variables, particularly between the time changes Table 2. of GFR and the average of left/right renal diameRates of patients having a preserved kidney cortical thickness (≥ 1.2 cm) ters. The linear correlation coefficient, r, was or a slightly reduced kidney cortical thickness (> 1 <1.2 cm) computed and its statistical significance was or a reduced kidney cortical thickness (< 1 cm). evaluated at a minimum level of 95% (p < 0.05). All the statistical computations were executed Number of patients Basal values Follow-up values Delta using the SPSS package, version 10. Number of patients having a preserved right kidney cortical thickness 28 (35%) 30 (37.5%) 7.14 Number of patients having a preserved left kidney cortical thickness Number of patients having a slightly reduced right kidney cortical thickness Number of patients having a slightly reduced left kidney cortical thickness Number of patients having a reduced right kidney cortical thickness Number of patients having a reduced left kidney cortical thickness

25 (31.25%) 19 (23.75%) 23 (28.75%) 33 (41.25%) 32 (40%)

28 (35%) 22 (27.5%) 24 (30%) 28 (35%) 28 (35%)

12.00 15.79 4.35 -15.15 -12.50

Table 3. Rates of patients taking different drugs or being on a specific diet. Number of patients (percentage of the total) Number of patients having hypo protein diet Number of patients having hyposodic diet Number of patients taking ACE inhibitors or angiotensin receptor blockers Number of patients taking diuretics Number of patients taking nephrotoxic drugs

Basal values Follow-up values 24 (30%) 57 (71.25%) 24 (30%) 62 (77.5%) 58 (72.5%) 52 (65%) 36 (45%) 22 (27.5%) 26 (32.5%) 1 (1.25%)

Archivio Italiano di Urologia e Andrologia 2020; 92, 1

Delta 137.5 158.33 -10.34 -38.89 -96.15

RESULTS

In order to investigate if the dimensional parameters of the kidney correlate or not with the variations of the GFR, we compared the percentage variation between basal and final examination (Table 4), or Delta, of each variable with the percentage variation of the renal diameters’ average in the longitudinal axis and the time changes of GFR (Figure 1). The statistical analysis so displayed first a strong positive correlation between the Delta of the average renal diameter in the longitudinal axis and time changes of GFR (r 0.731; p < 0.01) and then an equally strong positive correlation between the same Delta of GFR and

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Time changes of renal dimensions and glomerular filtration rate variations in chronic kidney disease patients

Table 4. Statistically significant correlations. Variables Delta of the renal diameters’ average Delta of the GFR Delta of the age at the moment of the examination Delta of the systolic blood pressure Delta of the mean arterial pressure Delta of the right kidney diameters Delta of the left kidney diameters Delta of the right kidney cortical thickness Delta of the left kidney cortical thickness Delta of the number of patients having a hyposodic diet Delta of the number of patients taking diuretics Delta of the number of patients taking nephrotoxic drugs

r p N r p N r p N r p N r p N r p N r p N r p N r p N r p N r p N r p N

Delta of the renal Delta diameters’ average of the GFR / 0.731 / < 0.001 / 80 0.731 / < 0.001 / 80 / -0.360 -0.304 0.001 0.006 80 80 0.238 0.370 0.035 0.001 79 79 0.190 0.289 0.093 0.01 79 79 0.907 0.661 < 0.001 < 0.001 80 80 0.866 0.637 < 0.001 < 0.001 80 80 0.506 0.487 < 0.001 < 0.001 80 80 0.535 0.519 < 0.001 < 0.001 80 80 0.068 0.250 0.546 0.025 80 80 -0.262 -0.226 0.019 0.044 80 80 -0.293 -0.429 0.008 < 0.001 80 80

Figure 1. A graphical representation of the correlation that was found between the percentage variation of the average of the renal diameters and the time changes of the GFR with respect to the values at the time of the enrollment.

the percentage variations of the right (r 0.487; p < 0.01) and left (r 0.519; p < 0.01) kidney cortical thickness. As obvious a similarly strong correlation was found between time changes of right (r 0.661; p < 0.01) and left (r 0.637; p < 0.01) kidney diameters in the longitudinal axis and the time changes of the GFR. Instead, no statistical correlation was found between time changes of GFR

and percentage variations of right or left renal resistive indices as well as body mass index and proteinuria. About the percentage variations of the blood pressure parameters we found a strong positive correlation only between the time changes of systolic blood pressure and the percentage variation of GFR (r 0.370; p < 0.01) and a weaker positive correlation between the same Delta of systolic blood pressure and the time changes of renal diameters’ average in the longitudinal axis (r 0.238; p < 0.05), moreover a strong positive correlation was found between the Delta of the mean arterial pressure and the Delta of GFR (r 0.289; p < 0.01). A weak negative correlation was found between the strong reduction of the diuretics usage and the Delta of the renal diameters’ average in the longitudinal axis (r -0.262; p < 0.05) or the Delta of GFR (r -0.226; p < 0.05) while a stronger negative correlation was found between the almost complete removal of any nephrotoxic drugs and the Delta of the renal diameters’ average in the longitudinal axis (r -0.293; p < 0.01) or the Delta of GFR (r -0.429; p < 0.01). A weak positive correlation was found between the introduction of a low-salt diet and the time changes of GFR (r 0.250; p < 0.05) but no statistical correlation was found between the Delta of the renal diameters’ average in the longitudinal axis or the Delta of GFR and the variations of serum sodium, the introduction of an low protein diet or the usage of ACE inhibitors or angiotensin receptor blockers. Finally a strong negative correlation was found between the time changes of the age at the moment of the examination and the Delta of the renal diameters’ average in the longitudinal axis (r -0.360; p < 0.01) and the time changes of GFR (r- 0.304; p < 0.01).

DISCUSSION

In this longitudinal prospective observational type study comparing the average of left and right renal diameters and the time changes of GFR we found a strong positive correlation between the two ones as well as a similar strong positive correlation between the time changes of the GFR and percentage variations of the right and left kidney cortical thickness. All the above means that the renal sizes may increase or decrease synchronously with the time changes of GFR even in absence of the classic conditions that promote the compensatory renal hypertrophy (i.e. mainly radical or partial nephrectomy) as well as of any other condition that may increase the renal dimensions such as mainly the diabetes mellitus. Now it is well known that after unilateral radical or partial nephrectomy a compensatory renal growth, promoting significant restoration of lost renal function, is observed in the remnant kidney. This compensatory renal growth following nephrectomy is predominantly due to a renal hypertrophy (i.e. an increase in cell size) dominated by tubular cells (since mainly proximal tubules show increase of length, diameter and volume) and produces a GFR increase so can be termed physiologic compensatory renal hypertrophy in contrast to the so-called pathologic renal hypertrophy that, typical of diabetic nephropathy, it is dominated by a glomerular and podocyte hypertrophy and can lead to further nephron damage, interstitial fibrosis and ultimately end-stage kidney disease (12). Lastly, it is known that compensatory kidney growth was not only found to occur Archivio Italiano di Urologia e Andrologia 2020; 92, 1

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after renal mass reduction by partial nephrectomy but also after partial renal parenchymal damage induced by nephrotoxins (13, 14). Now in this study we exercised a decise action aimed at removing all nephrotoxic pharmacological agents and the most common ones that we eliminated at the time of the enrollment were thiazide diuretics with the use of which apoptosis has been observed in the distal tubular cells, just those that dominate the physiological renal hypertrophy (15). Therefore, it seems probable that the removal of nephrotoxic agents done in this study may be the action that mostly induced compensatory kidney growth. About the strong positive correlation that we found between time changes of systolic blood pressure and percentage variations of the GFR and the weaker positive correlation found between Delta of the systolic blood pressure and time changes of renal diameters’ average in longitudinal axis, we suppose that when in CKD, aorta is stiffed, a decrease of systolic blood pressure can limit the renal perfusion that, in this condition, is mostly dependent by stroke volume, causing a decrease of GFR, reversible with the restoration of systolic blood pressure (10). In fact at the time of enrollment, as part of our action to improve kidney function, we accurately corrected not only the high systolic blood pressure values but also those excessively reduced (i.e. next or less than 100 mmHg) which in the population enrolled were relatively frequent. To the characteristics of the population enrolled in terms of systolic blood pressure, can be probably due the correlation that was found between the reduction of diuretics usage (which can significantly contribute to reducing the systolic blood pressure) and the time changes of renal diameters’average in the longitudinal axis or the Delta of the GFR. Lastly, as known, another parameter that correlates with kidney length is age: in adults there is a gradual reduction in renal length that becomes more precipitous after age 50 years and that is due entirely to loss of parenchyma. (4, 3, 16). This likely can explain the strong negative correlation that was found between percentage variation of age at the moment of the examination and Delta of the average of renal diameters in the longitudinal axis and time changes of GFR. It is our opinion therefore that, in the chronic kidney disease patients, also in the absence of total or partial nephrectomy as well as of any other condition that may increase the renal dimensions such as mainly diabetes mellitus, under the stimulus of the removal of any agent that may hamper renal function (such as, mainly, nephrotoxic drugs or excessively reduced values of systolic blood pressure), can be found a limited increase of the renal sizes according to a model that sees the same renal dimensions reduce or increase depending on changes in the GFR. Moreover, in the chronic kidney disease patients, repeated accurate ultrasound measurements of the kidney sizes correlate significantly with the variations of kidney function and therefore can be used as a tool to confirm the trend of renal function.

AUTHORS’

CONTRIBUTIONS

Each author declares to have fully participated in the drafting of the work and assumes all public responsibility for the content.

Archivio Italiano di Urologia e Andrologia 2020; 92, 1

REFERENCES

1. Troell S, Berg U, Johansson B, et al. Comparison between renal parenchymal sono graphic volume, renal parenchymal urographic area, glomerular filtration rate and renal plasma flow in children. Scan J Urol Nephrol. 1988; 22:207. 2. Emamian SA, Nielsen MB, Pedersen JT. Intraobserver and interobser variations in sonographic measurements of kidney size in adult volunteers. Acta Radiol. 1995; 36:399. 3. Emamian Sa, Nielsen MB, Pedersen JF, et al. Kidney dimensions at sonography: correlation with age, sex, and habitus in 665 adult volunteers. AJR 1993; 160:83. 4. Jovanovic D, Gasic B, Pavlovic S, Naumovic R. Correlation of kidney size with kidney function and anthropometric parameters in healthy subjects and patients with chronic kidney diseases. Ren Fail. 2013; 35:896-900. 5. Sanusi AA, Argundade FA, Famirewa OC, et al. Relationship of ultrasonographically determined kidney volume with measured GFR, calculated creatinine clearance and other parameters in chronic kidney disease (CKD). Nephrol Dial transplant. 2009; 24:1690-1694. 6. Mazzotta L, Sateschi LM, Carlini A, Antonelli A. Comparison of renal ultrasonographic and functional biometry in healthy patients and in patients with chronic renal failure. Arch Ital Urol Androl. 2002; 74:206-9. 7, O’Neill W. C. Sonography of the normal kidney. In: O’Neill W. C. Atlas of renal ultrasonography. WB Saunders Company , Philadelphia, USA: 2001; pp. 10-19. 8. Zubovic SV, Kristic S, Pasic IS. Relationship between ultrasonographically determined kidney volume and progression of chronic kidney disease. Med Glas (Zenica) 2016; 13:90-94. 9. Levey AS, Stevens LA, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009; 150:604-612. 10. Brardi S, Cevenini G. Low systolic blood pressure values, renal resistive index measurement and glomerular filtration rate in a nondialysis dependent chronic kidney disease population. Arch Ital Urol Androl. 2019; 90:288-292. 11. Di Iorio B, De Santo NG, Anastasio P, et al. The GiordanoGiovannetti diet. J Nephrol. 2013; 26(Suppl. 22):143-152. 12. Rojas-Canales DM, Li JY, Makuei L, Gleadle JM. Compensatory renal hypertrophy following nephrectomy: When and how? Nephrology (Carlton). 2019; 24:1225-1232. 13. Cleper R. Mechanisms of compensatory renal growth. Pediatric Endocrinology reviews (PER) 2012; 10:152-63. 14. Wesson LG. compensatory growth and other growth responses of the kidney. Nephron. 1989; 51:149-184. 15. Reungjui S, Pratipanawatr T, Johnson RJ, Nakagawa T. Do thiazides worsen metabolic syndrome and renal disease? The pivotal roles for hyperuricemia and hypokalemia. Curr Opin Nephrol Hypertens. 2008; 17:470-476. 16. Miletic D, Fuckar Z, Sustic A, et al. Sonographic measurement of absolute and relative renal length in adults. J Clin Ultrasound. 1998; 26:185. Correspondence Simone Brardi, MD (Corresponding Author) sibrardi@gmail.com Hemodialysis Unit, S. Donato Hospital, Arezzo (Italy) Gabriele Cevenini, MD Department of Medical Biotechnologies, University of Siena (Italy)

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DOI: 10.4081/aiua.2020.1.25

ORIGINAL PAPER

Summary

Objective: To compare the surgical results, complications, and satisfaction levels of patients who underwent malleable penile prosthesis implantation (M-PPI) and Ambicor penile prosthesis implantation (A-PPI). Material and methods: One hundred forty two patients who underwent penile prosthesis implantation [M-PPI (PromedonTube®, Cordoba, Argentina): 81, and A-PPI (American Medical Systems, Minnesota, USA): 61] between 2013-2018 were evaluated retrospectively. Patients’ age, body mass index, smoking history, etiological factors, modified “Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) Questionnaire” scores, shortening of the penis, and complications were recorded. Results: The patients who performed A-PPI implantation were younger (56.27 ± 10.81 vs. 51.47 ± 11.79, p = 0.009). The EDITS scores of 31(38.2%) patients who underwent M-PPI and 44 (72.4%) patients who underwent A-PPI were available. It was observed that the scores on the following questions were statistical significantly higher in the A-PPI group: “Overall, are you satisfied with your penile prosthesis?, How much of your expectations did penile prosthesis meet?, How often do you use your penile prosthesis?” (p = 0.05, p = 0.048, p = 0.038). No difference was observed between the groups in terms of the scores on the other three questions (p = 0.447, p = 0.326, p = 0.365). A 61.3% of patients in MPPI (19/31) group, and 56.8% of patients in A-PPI (25/44) group stated penile shortening (p = 0.417). Mean shortening was reported as 2.1 ± 0.45 cm, and 2.12 ± 0.52 cm, in M-PPI and A-PPI groups, respectively (p = 0.90). Conclusion:It is remarkable that the patients who underwent A-PPI experienced higher satisfaction with their prosthesis. Even though it has not been evidenced in the current literature data, patients who have had either M-PPI or A-PPI should be informed about the risk of penile shortening.

KEY WORDS: Erectile dysfunction; Penile prosthesis; Satisfaction; Complication. Submitted 17 October 2019; Accepted 12 December 2019

INTRODUCTION

Erectile dysfunction (ED) is the second most common male sexual disorder after premature ejaculation and is defined as “a man’s inability to achieve and/or maintain erection sufficient to have sexual intercourse, for at least six months” (1, 2). First and second-line conservative treatments, including medical therapies using either oral

treatment or intracavernous injection as well as lifestyle changes, are the initial current methods suggested to patients with ED. Phosphodiesterase Type 5 inhibitors, intracavernous injections, intraurethral alprostadil and vacuum devices may cause treatment failure or lead the necessity to discontinue treatment in around 80% of the patients (3, 4). Penile prosthesis implantation is recommended as a thirdline therapy in ED patients who do not respond to oral or non-surgical therapies or who are unable to accept such treatments for any reason (5). The surgical treatment has been modified many times in recent years to decrease the risk of complications, to reduce the mechanical dysfunction, and to increase patient/partner satisfaction. Currently, penile prostheses are still commonly used as third line therapy in the treatment of ED (5, 6). In our study, we aimed to compare the surgical results, complications and satisfaction levels of patients who did not respond to first- and second-line therapies and who therefore underwent malleable penile prosthesis implantation (M-PPI) and Ambicor penile prosthesis implantation (A-PPI).

MATERIAL

AND METHODS

Study participants Following the approval of the local ethics committee, 142 patients with ED who underwent penile prosthesis implantation in our clinic between 2013-2018 were evaluated retrospectively. It was found that 81 patients had M-PPI (Promedon-Tube®, Cordoba, Argentina) and 61 patients had A-PPI (American Medical Systems, Minnesota, USA). Pre-operative informed consents were obtained from all patients. Before the operations, the patients were given general information about the procedure and potential complications. Detailed information on M-PPI or A-PPI prosthesis types was provided to the patients. A-PPI implantation was primarily recommended to patients who were able to pay the price gap for PPI (cost of M-PPI: approximately USD 1000, cost of A-PPI: approximately USD 2000), were in a good mental state, and had good manual dexterity. Patients who had a history of unstable urethral or bladder neck stricture, abnormal psychiatric

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2020; 92, 1

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O. Bayrak, S. Erturhan, I. Seckiner, M. Ozturk, H. Sen, A. Erbagci

condition, a genital or systemic infection, perineal wounds, severe liver failure, uncontrolled hypertension or diabetes were excluded from the study. Efficacy and complication evaluations Patients’ age, body mass index (BMI), smoking history, and etiological factors [diabetes mellitus (DM), coronary artery disease, hypertension, chronic kidney failure, neurological pathologies, radical prostatectomy and other pelvic surgeries] were recorded. The patients’ scores for the modified “Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) Questionnaire” at the post-operative 6th month, shortening of the penis, and complications (wound site infections, removal of prosthesis, hematoma, skin erosion and soft glans syndrome) were noted. The data on penile size was based only on the patient’s perception. The “Erectile Dysfunction Inventory of Treatment Satisfaction Questionnaire”, and modified EDITS forms are reli- Table 1. Demographic data. able and validated questionnaires, which were created by Althof et al. to define satisfaction levels with ED Age (year) therapies (7). The modified EDITS BMI (kg/m2) patient questionnaire is composed Cigarette consumption (n, %) of six questions inquiring as level of Etiology (n, %) satisfaction with ED treatment methods, level of expectations meet, suitability for continuous use, level of pleasure and confidence during sexual intercourse, and satisfaction of partners. Overall satisfaction is measured on a 5-point scale: 1- not satisfied at all, 3- partially satisfied and 5- very satisfied (7-9). Surgical procedure After spinal or general anesthesia, the pubic area of the patient was shaved and the genital area was washed with a povidone iodine solution for 10 minutes. Intravenous cefazolin and gentamicin were administered for prophylaxis simultaneously. After placement of a 18 F Foley catheter, in a supine position, the corpora cavernosa were reached through a skin incision of approximately 3 cm from the penoscrotal region and a 2 cm bilateral corporotomy was performed. Afterwards, the sites where the penile prosthesis would be placed were created in the corpora cavernosa with Hegar dilators. Measurements were undertaken to choose a suitable size for the cylinder. During these procedures, the corpora cavernosa were irrigated with solutions containing gentamicin. The prosthetic cylinders were inserted after the surgical site was

prepared. A pump was placed by creating a subdartos pouch in the scrotum in patients who underwent A-PPI. Following a hydraulic test, the corporotomies were closed with previously placed 2/0 vicryl sutures. The procedure was completed by suturing the subcutaneous tissue and skin. We recommended to patients, to start sexual intercourse after six weeks from the surgical procedure. Statistical analyses The “SPSS 11 for Windows” software package was used for the statistical calculations and the data was expressed as arithmetic mean and standard deviation. The Chi-square distribution test and the Mann-Whitney U test were used to calculate categorical variables and compare mean values, respectively. The 95% confidence interval (p < 0.05) was accepted as statistical significance.

M-PPI (n = 81) 56.27 ± 10.81 27.19 ± 2.43 65 (80.2%) DM: 57 (70.3%) CAD: 22 (27.1%) HT: 18 (22.2%) CRF: 2 (2.5%) Neurological pathologies : 3 (3.7%) RP: 7 (8.6%) Other pelvic surgeries : 6 (7.4%) (TUR-prostate, orchiectomy, radical cystectomy, urethroplasty) Prosthesis replacement: 4 (4.93%)

A-PPI (n = 61) 51.47 ± 11.79 26.78 ± 2.25 46 (75.4%) DM: 43 (70.4%) CAD: 5 (8.2%) HT: 9 (14.75%) CRF: Neurological pathologies : 1 (1.6%) RP: 5 (8.2%) Other pelvic surgeries : 8 (13.1%) (TUR-prostate, orchiectomy, radical cystectomy, urethroplasty) Prosthesis replacement: 5 (8.1%)

p 0.009 0.211 0.490 0.569

Table 2. Comparison of patients’ satisfaction according to Modified ‘’Erectile Dysfunction Inventory of Treatment Satisfaction Questionnaire’’. Modified EDITS questionnaire Overall, are you satisfied with your penile prosthesis?

How much of your expectations did penile prosthesis meet?

How often do you use use your penile prosthesis

Is it easy for you to use penile prosthesis?

Do you trust your ability of pleasure during intercourse?

How is the satisfaction of your partner?

Grade of satisfaction I am not satisfied I’m partially satisfied I’m very satisfied Did not meet Partially met Fully met Almost never Sometimes Very often Not easy Partially easy Very easy No Partly Fully Not satisfied Partially satisfied Very satisfied

n: Number of patients. EDITS: Erectile Dysfunction Inventory of Treatment Satisfaction Questionnaire. M-PPI: Malleable penile prosthesis implantation. A-PPI: Ambicor penile prosthesis implantation.

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M-PPI (n, %) 3 (9.6%) 5 (16.1%) 23 (74.2%) 3 (9.6%) 4 (12.9%) 24 (77.4%) 3 (9.6%) 10 (32.2%) 18 (56.2%) 3 (9.6%) 3 (9.6%) 25 (80.6%) 3 (9.6%) 2 (6.4%) 26 (83.8%) 2 (6.45%) 2 (6.45%) 27 (87.1%)

A-PPI (n, %) 1 (2.3%) 3 (6.8%) 40 (90.1%) 1 (2.3%) 2 (4.5%) 41 (93.1%) 1 (2.3%) 8 (18.2%) 35 (79.5%) 1 (2.3%) 8 (18.2%) 35 (79.5%) 1 (2.3%) 3 (6.8%) 40 (90.1%) 1 (2.3%) 2 (4.5%) 41 (93.1%)

p 0.05*

0.048*

0.038*

0.447

0.326

0.365

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Malleable versus Ambicor penile prosthesis

Figure 1. Comparison of patients’ satisfaction who underwent malleable penile prosthesis implantation (M-PPI) and Ambicor penile prosthesis implantation (A-PPI).

RESULTS

The mean age of patients who underwent implantation of Ambicor-PPI was lower than the mean age of patients who underwent implantation of M-PPI (51.47 ± 11.79 vs. 56.27 ± 10.81, p = 0.009). Diabetes mellitus was as the most common etiological factor in both groups (70.3% vs. 70.4%). No differences were found between the two groups for body mass index and smoking history (p = 0.211, p = 0.490, respectively) (Table 1). Six-month scores of the EDITS forms were available in 31 (38.2%) patients who had M-PPI implantation, and 44 (72.1%) patients who had A-PPI. It was found that the scores for the following questions were statistical signifiTable 3. Complications after penile prothesis implantation.

Wound infection (n, %) Removal of prosthesis (n, %) Hematoma (n, %) Skin erosion due to tube kinging (n, %) Skin erosion due to pump (n, %) Soft glans syndrome (n, %) Overall complications (n, %) n: Number of patients. M-PPI: Malleable penile prosthesis implantation. A-PPI: Ambicor penile prosthesis implantation.

M-PPI (n = 81) 5 (6.17%) 3 (3.7%) 1 (1.2%) 2 (2.4%) 11 (13.5%)

A-PPI (n = 61) 4 (6.55%) 2 (3.2%) 1 (1.6%) 1 (1.6%) 8 (13.1%)

p 0.594 0.183 0.394 0.430 0.430 0.324 0.570

cantly higher in favor of the A-PPI group: “Overall, are you satisfied with your penile prosthesis?, How much of your expectations did penile prosthesis meet?, How often do you use your penile prosthesis?” (p = 0.05, p = 0.048, p = 0.038, respectively). However, no significant difference was observed between the two groups in terms of the scores for the following questions: “Is it easy for you to use penile prosthesis?, Do you trust your ability of pleasure during intercourse?, How is the satisfaction of your partner?” (p = 0.447, p = 0.326, p = 0.365, respectively). Additionally, it was evaluated if the length of the patients’ penis had shortened postoperatively or not. A 61.3% (19/31) of patients in M-PPI group, and 56.8% (25/44) of patients in A-PPI group stated that the length of their penis had shortened (p = 0.417). Mean shortening was 2.1 ± 0.45 cm, and 2.12 ± 0.52 cm in M-PPI group and A-PPI group, respectively (p = 0.90) (Table 2, Figure 1). There was no difference between the groups in terms of complications (p = 0.569); however, seven (77.7%) of nine patients who had wound site infection, and all (100%) three patients whose prostheses were removed, had a history of DM (Table 3). Tube kinking and skin erosion occurred in a patient at postoperative 6th week, and pump erosion occurred in another patient at postoperative 8th week. Both patients were re-operated in collaboration with a plastic surgeon, the tube and pump were fixed to deeper tissue and a skin flap was rotated. The wound sites of both patients recovered without complication. Archivio Italiano di Urologia e Andrologia 2020; 92, 1

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DISCUSSION

In the literature, among the treatment options for ED, PPI has been reported to be the most successful surgical method with the highest level of satisfaction (10). Different prostheses have different advantages and disadvantages that may affect the satisfaction of the patient (11). M-PPI has a structure that enables bending downwards during dressing, and urination and upwards during intercourse. The superior characteristics of M-PPI are: low mechanical failure rates, more easier operative procedure, shorter operation time, and relative costeffectiveness. However, as a disadvantage, it may cause difficulties during endoscopic procedures which may become necessary at later time. Inflatable prostheses have cosmetic advantages and benefits such as increase in penile length, and girth that mimics a natural erection. The most important disadvantage of this prosthesis type is likelihood of mechanical damage (9). Today, a three-piece PPI is recommended, and inserted as the first choice at many centers as its deflated appearance has a close to normal appearance, and it provides axial rigidity in various lengths. A-PPI constitutes almost 5% of all prostheses inserted (12). Two-piece prostheses are generally preferred by surgeons who do not wish to place a reservoir in the abdomen or the Retzius space (13). In our clinical practice, the patient’s choice is taken into consideration after informing the patients of all penile prosthetic choices. However, one of the most important factors that play a role in the selection of an inflatable prosthesis is the cost. In present circumstances in our country, the approximate cost of a one-piece PPI is USD 1000, a two-piece PPI is USD 2000, and a three-piece PPI is USD 3000. Therefore, all patients referred to our clinic preferred MPPI or A-PPI. Another factor playing a role in the selection in our study is age. In particular, it has been seen that younger patients more often prefer A-PPI (51.47 ± 11.79 vs. 56.27 ± 10.81, p = 0.009). Patient satisfaction depends on multiple factors including pre-operative expectations, post-operative pain and edema, undesired side effects, functionality of prosthesis, ease of use and acceptability by partners (9). In our series, penile prosthesis implantation has high rates of satisfaction due to being able to ensure rapid, and full rigidity. Although our patients who underwent M-PPI implantation felt dissatisfied with constant rigidity in the first few days, this problem was accepted by patients over time. The most common side effects in patients who had an inflatable penile prosthesis implantation were pain, and discomfort associated with the pump in the scrotum, however, these patients learnt how to use the pump as a result of training provided by the clinic. None of the patients required the removal of the prosthesis as a result of dissatisfaction or inability to use. Scores for high satisfaction with penile prostheses (90.1% vs. 74.2%, p = 0.05), meeting the expectations (93.1% vs. 77.4%, p = 0.048) and more frequent sexual intercourse (79.5% vs. 56.2%, p = 0.038) were significantly higher in the A-PPI group. In their series in 2007, Lux et al. implemented A-PPI in 146 patients at two centers. The Authors reported the rate of mechanical failure as 0.7% in a mean follow-up period of 38 months. 95% of patients reported to have had little

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or no problem in learning how to use the prosthesis, and 84% of them expressed that they were able to achieve good or excellent rigidity during coitus with A-PPI. Patient and partner satisfaction were reported to be 85% and 76%, respectively. It is noteworthy that Ambicor had a low rate of infection of 7%, despite the fact that it did not contain any topical antimicrobial agents or InhibiZone (8). In previous studies reported by Levine et al., it was seen that the prosthesis functioned without any problem in follow-ups over 70 months in 97% of 131 patients who had A-PPI. More importantly, 93% of patients and 90% of partners stated that they would suggest A-PPI to other couples. In this study, particularly in examining partner experience, 76% of partners reported to experience more satisfaction with A-PPI during sexual intercourse (14). In the current study, higher satisfaction rates were reported in the M-PPI group and A-PPI group, of 87.1% and 93.1%, respectively, although there was no statistically significant difference between the rates of satisfaction with intercourse (p = 0.365). The complication rates of Ambicor-PPI were reported as 7.6%, 2.1% and 9.5% in studies by Levine et al., Lux et al. and Gentile et al. (8, 14, 15). Infection-related complications have been reported to be 2-3% in the existing literature (16). In our study, the overall complication rates were 13.5% in the M-PPI group, and 13.1% in the A-PPI group. The most feared complication, in particular with PPI, is infection (M-PPI: 6.17 vs. A-PPI: 6.55, p = 0.594). In the current study, in seven (77.7%) out of nine patients occurred wound site infection, and all three patients (100%) whose prostheses were removed had a history of DM. Moreover, in one patient with A-PPI, tube kinking occurred at 6th week postoperatively, and pump erosion occurred in another patient at 8th week postoperatively. Both patients were operated in combination with a plastic surgeon, and a reconstruction was performed. The tube and pump were fixed to deeper tissue, and a flap was rotated. The wound sites of both patients recovered without any complication. Additionally, this study assessed whether the size of the patients’ penis had shortened compared to the period before implantation. A 61.3% of patients who had M-PPI (19/31), and 56.8% of patients who had A-PPI (25/44) stated that the length of their penis had shortened (p = 0.417). Mean shortening was 2.1 ± 0.45 cm, and 2.12 ± 0.52 cm in M-PPI group and A-PPI group, respectively (p = 0.90). Lux et al. also reported a mean shortening of 1.5 inches in the size of the penis for 70% of patients, in their study (8). On the other hand, in a study by Deveci et al., the stretched penile length was measured in patients who had undergone penile prosthesis surgery for the first time. Deveci reported that the A-PPI did not affect the stretched penile length at 1 and 6 month postoperative follow up (17). The current study is one of the rare single-center investigations in the current literature comparing M-PPI and A-PPI over a large number of patients. However, its retrospective nature, the absence of randomization, and more EDITS scores available on the A-PPI group were significant limitations of our study. In addition, the data on penile shortening was based only on the patient’s perception.

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Malleable versus Ambicor penile prosthesis

CONCLUSIONS

It is remarkable that patients who underwent A-PPI experienced higher satisfaction with their prosthesis. Although no difference was observed between either PPIs in terms of complications, patients who have diabetes should be particularly warned against post-operative complications. Even though it has not been evidenced in the current literature, all patients who had either M-PPI or A-PPI should be informed about the risk of shortening of the penis.

REFERENCES

1. Lindau ST, Schumm LP, Laumann EO, et al. A study of sexuality and health among older adults in the United States. N Engl J Med. 2007; 357:762-74. 2. NIH Consensus Conference. Impotence. NIH Consensus Development Panel on Impotence. JAMA. 1993; 270:83-90. 3. Mulhall JP, Bella AJ, Briganti A, et al. Erectile function rehabilitation in the radical prostatectomy patient. J Sex Med. 2010; 7:1687-98. 4. Gontero P, Fontana F, Zitella A, et al. A prospective evaluation of efficacy and compliance with a multistep treatment approach for erectile dysfunction in patients after non-nerve sparing radical prostatectomy. BJU Int. 2005; 95:359-65. 5. Evans C. The use of penile prostheses in the treatment of impotence. Br J Urol. 1998; 81:591-8. 6. Minervini A, Ralph DJ, Pryor JP. Outcome of penile prosthesis implantation for treating erectile dysfunction: experience with 504 procedures. BJU Int. 2006; 97:129-33. 7. Althof SE, Corty EW, Levine SB, et al. EDITS: development of questionnaires for evaluating satisfaction with treatments for erectile dysfunction. Urology. 1999; 53:793-9.

8. Lux M, Reyes-Vallejo L, Morgentaler A, et al. Outcomes and satisfaction rates for the redesigned 2-piece penile prosthesis. J Urol. 2007; 177:262-6. 9. Kilicarslan H, Kaynak Y, Gokcen K, et al. Comparison of patient satisfaction rates for the malleable and two piece-inflatable penile prostheses. Turk J Urol. 2014; 40:207-10. 10. Rajpurkar A, Dhabuwala CB. Comparison of satisfaction rates and erectile function in patients treated with sildenafil, intracavernous prostaglandin E1 and penile implant surgery for erectile dysfunction in urology practice. J Urol. 2003; 170:159-63. 11. Anafarta K, Safak M, BedĂźk Y, et al. Clinical experience with inflatable and malleable penile implants in 104 patients. Urol Int. 1996; 56:100-4. 12. Henry GD, Karpman E, Brant W, et al. The who, how and what of real-world penile implantation in 2015: the PROPPER registry baseline data. J Urol. 2016; 427:195. 13. Abdelsayed GA, Levine LA. Ambicor 2-Piece Inflatable Penile Prosthesis: Who and How? J Sex Med. 2018; 15:410-5. 14. Levine LA, Estrada CR, Morgentaler A. Mechanical reliability and safety of and patient satisfaction with the Ambicor inflatable penile prosthesis: results of a 2 center study. J Urol. 2001; 166:9327. 15. Gentile G, Franceschelli A, Massenio P, et al. Patientâ&#x20AC;&#x2122;s satisfaction after 2-piece inflatable penile prosthesis implantation: an Italian multicentric study. Arch Ital Urol Androl. 2016; 88:1-3. 16. Goldstein I, Newman L, Baum N, et al. Safety and efficacy outcome of mentor alpha-1 inflatable penile prosthesis implantation for impotence treatment. J Urol. 1997; 157:833-9. 17. Deveci S, Martin D, Parker M, et al. Penile length alterations following penile prosthesis surgery. Eur Urol. 2007; 51:1128-31.

Correspondence Omer Bayrak dromerbayrak@yahoo.com Sakip Erturhan mserturhan@yahoo.com Ilker Seckiner iseckiner@yahoo.com Mehmet Ozturk mehmetozturk000@hotmail.com Haluk Sen drhaluksen@gmail.com Ahmet Erbagci gantepuro@gmail.com Department of Urology, Gaziantep University School of Medicine, Gaziantep, Turkey.

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DOI: 10.4081/aiua.2020.1.30

ORIGINAL PAPER

Influence of dietary energy intake on nephrolithiasis A meta-analysis of observational studies Gianpaolo Perletti 1,2, Vittorio Magri 3, Pietro Manuel Ferraro 4,5, Emanuele Montanari 6, Alberto Trinchieri 7 1 Department

of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, University of Insubria, Varese, Italy; of Medicine and Medical Sciences, Ghent University, Belgium; 3 Urology Secondary Care Clinic, ASST-Nord, Milan, Italy; 4 U.O.C. Nefrologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy; 5 Università Cattolica del Sacro Cuore, Roma, Italy; 6 Department of Urology, IRCCS Ca’ Granda Ospedale Maggiore Policlinico - University of Milan, Milan, Italy; 7 School of Urology, University of Milan, Milan, Italy. 2 Faculty

Summary

Objective: Obesity has been associated with an increased risk of kidney stone formation. The presence of obesity is due to an imbalance between energy intake and energy consumption resulting from physical activity and resting metabolic rate. The purpose of this meta-analysis was to assess the differences in dietary energy intake levels between patients developing urinary stones versus healthy individuals. Materials and methods: Medline/PubMed and EMBASE databases search was performed using the terms “urolithiasis”, “kidney stones*”, “calcul*”, “energy”, “calor*”, “intake”, “food”, “kilojoule/kjoule”, “Kilocal*/kcal” from January 1st, 2000, and were assessed as up to date on September 30th, 2019. Results: After having screened 1.782 records, four studies were included in the meta-analysis. The total population was 467.063, including 453.078 healthy men and/or women and 13.985 men and/or women affected by nephrolithiasis. When energy intake data were pooled irrespective of the sex of participants, mean calory intake values were significantly higher in nephrolithiasis patients, compared to healthy individuals. The mean difference (MD) was 39.16 kcal (95% CI 18.53 to 59.78, p = 0.0002, random-effects model, inverse-variance weighing). The odds ratio for this comparison – calculated from the standardized mean difference – is significant (OR = 1.946; 95% CI: 1.869 to 5.561). Conclusions: Patients affected by urolithiasis show a significantly higher energy intake in various patient populations (USA, China and Korea) including subjects of both sexes. The relevance of this finding should be confirmed by studies in populations showing different and diverse dietary patterns, and by evaluating energy consumption linked to physical activity and metabolic rate in renal stone formers.

KEY WORDS: Urinary calculi; Energy intake; Obesity; Nutrition; Diet. Submitted 14 October 2019; Accepted 29 February 2020

INTRODUCTION

A recent meta-analysis (1) confirmed that obesity is associated with an increased risk of renal stone formation. However, it has not been clarified which of the factors determining obesity are directly implicated in increasing the risk of formation of kidney stones. In fact, obesity is due to the altered balance between

dietary energy intake and energy consumption resulting from physical activity and resting metabolic rate. The meta-analysis by Aune et al. (1) showed that renal stone formers do not have a lower level of physical activity when compared to non-stone forming subjects, but the impact of dietary energy intake on the risk of stone formation was not assessed in that study. The purpose of this meta-analysis was to investigate whether there were any differences between dietary energy intake levels in patients affected by urolithiasis versus healthy individuals, thus pointing to a possible association between dietary energy intake and the risk of renal stone formation.

MATERIALS

AND METHODS

Types of studies We included only full-text articles written in English, reporting prospective cohort studies evaluating the relationship between daily dietary energy intake and the incidence of kidney stones in subjects of any age, men and/or women. We excluded case-control studies. Primary outcomes The single outcome considered for this review is the assessment of differences in dietary energy intake (mean daily kilocalories intake) between subjects developing kidney stones versus healthy individuals. Search strategy and study selection Records were identified by searching the Medline/PubMed, Cochrane and EMBASE databases, using the terms urolithiasis, kidney stone*, calcul*, energy, calor*, intake, food, kilojoule/kjoule Kilocal*/kcal. Hand searching was performed by browsing the references of published papers on the matter. Database searches were performed starting from January 1st, 2000, and were assessed as up to date on December 31st, 2019. This time frame has been chosen according to the meta-analysis of Aune et al. who selected studies published after 2000. Data extraction and analysis Data extraction was performed by two independent No conflict of interest declared.

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Influence of dietary energy intake on nephrolithiasis - A meta-analysis of observational studies

researchers (GP, AT). When energy intake data in women (W) and men (M) were presented separately (e.g. the Shu 2017 study) (2) the combined mean energy intake and combined variance of the entire population (women and men) were calculated with the formulas: X = (nWXW+nMXM)/(nW+nM) and S = nWSW = nMSM+NW(XW-X)^2+nM(XM-X)^2/(nW+nM) (n = number of observations, X = mean, and S = variance). When energy intake data were expressed as median Kcal intake and interquartile ranges (IQRs) (e.g., the Kim 2018 study) (3), data were converted into means and standard deviations according to Wan et al. (4). Differences in energy intake between nephrolithiasis patients and healthy subjects To analyze differences in continuous data from the included studies (average daily energy intake, expressed as kilocalories/day) we calculated crude mean differences (MD) and standardized mean differences (SMD). Odds ratios for the comparisons were calculated with the formula: OR = antilnSMD*π/√3. Analysis included the calculation of 95% confidence intervals (CI) and Z statistics. For meta-analysis we adopted a random-effects model and the inverse variance weighing method. Heterogeneity was assessed by calculating the I^2 value. Pooled analysis was performed using the RevMan 5.3 software. Funnel plots, the Egger’s and Begg’s tests, and “trim and fill” effect size adjustments were performed with the Meta-Essentials Excel workbook 1.0 (Erasmus Research Institute of Management, Erasmus University, Rotterdam, The Netherlands). Optimal information size for metaanalysis was calculated with the C*Power 3.1 software (assuming as an α level equal to 0.05 and 1-β error equal to 0.95). Assessment of risk of bias in included studies Quality assessment The risk of bias (ROB) of included studies was assessed independently by two researchers (GP, AT). This meta-analysis included non-randomized studies, and the Cochrane ROB tool had limited application. We identified two main possible biases for the included studies: recall bias and reporting bias. Since recall and reporting biases may overlap to some extent, we adopted the following definitions: In the included studies, recall bias may have occurred when study participants forgot to recall past episodes of kidney stones (or the number of such episodes) during follow-up visits, whereas reporting bias may have occurred when patients gave inaccurate account of their food and energy intake by selectively revealing or omitting essential information.

The risk of bias was classified as low, high or unknown according to Cochrane criteria (5). Publication bias and small-study effect were investigated by visually assessing funnel plots and by performing both the Egger’s regression test and the Begg’s rank correlation analysis. The “trim and fill” missing study imputation approach was applied to funnel plots and adjusted overall effect sizes were calculated according to Duval and Tweedie (6). The quality of evidence resulting from analysis of pooled data was evaluated according to GRADE criteria (7).

RESULTS Description of studies After having screened 1.782 records, four studies (2, 3, 8, 9) including data from 6 cohorts were included in the meta-analysis (Table 1). The total population was 467.063, including 453.078 healthy men and/or women and 13.985 men and/or women affected by nephrolithiasis. From the studies by Shu et al. (2) and Sorensen et al. (8) the data regarding women only could be extracted (total: 153.391; healthy 149.548; nephrolithiasis: 3.843). Men strata could be extracted only from the Shu study (2) (total: 58.054; healthy 56.852; nephrolithiasis: 1.202). Meta-analysis When energy intake data were pooled irrespective of the sex of participants (men and women, or women only), mean energy intake values were significantly higher in urolithiasis patients, compared to healthy individuals. The mean difference (MD) was 39.16 calories (95% CI: 18.53 to 59.78, p = 0.0002; Figure 1). This comparison showed “considerable” heterogeneity (I^2 = 79%; p = 0.002). The study of Ferraro et al. (9) was identified as a source of heterogeneity. When this study was excluded from analysis, the overall effect remained significant (MD: 49.57; 95% CI: 37.73 to 61.40, p < 0.00001) and the heterogeneity was eliminated (I^2 = 0, p = 0.37). Sensitivity analysis was completed by excluding one by one the remaining studies, and the result remained significant (not shown). Since the methods used to measure energy intake may have differed among studies, we confirmed the results of this analysis by calculating the standardized mean difference for the same comparison. The standardized mean difference was found to be equally significant (SMD: 0.07 units of standard deviation; 95% CI: 0.03 to 0.12, p = 0.001). The approximate odds ratio for the comparison is also significant (OR = 1.946; 95% CI: 1.869 to 5.561). Pooled comparison in women (2, 8) was devoid of statistical significance (MD: 21.41; 95% CI: -23.95 to 66.78, P = 0.35, Figure 1). Being based on only two: studies, this analysis does not allow further investigation.

Table 1. Characteristics of included studies. Study reference, location Ferraro 2015, USA Kim 2018, Korea Shu 2017, China Sorensen 2014, USA TOTAL

Study design Prospective cohort study (20 years follow up) Prospective study (2011-2014) Prospective cohort study (1996-2006) Longitudinal prospective cohort study (1993-2006)

Patients Men and women; 25-75 years; Healthy: 209778; Nephrolithiasis: 5355: Total: 215133 Men and women; Healthy: 59728; Nephrolithiasis: 2363: Total: 62091 Men and women; 40-70 years; Healthy: 124567; Nephrolithiasis: 2653: Total: 127220 Postmenopausal women; < 50 years; Healthy: 81833; Nephrolithiasis: 2392: Total: 84255 Healthy: 475906; Nephrolithiasis: 12763: Total: 488669

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G. Perletti, V. Magri, P.M. Ferraro, E. Montanari, A. Trinchieri

Figure 1. Pooled analysis of energy intake values in urolithiasis patients compared to healthy individuals.

Recall bias The recall in bias was rated as high in the Sorensen et al. (8) and Shu et al. (2) studies, as in both cases nephrolithiasis episodes were self-reported and not confirmed using a validated method. In the Kim et al. study (3) the risk of recall bias was low, since measures were taken (periodical ultrasonography) to confirm the self-reported occurrence of nephrolithiasis, as well to detect asymptomatic cases. The recall bias was rated as low in the Ferraro et al. study (9), as self-reported episodes of kidney stones were confirmed by official medical records in over 97% of patients. Reporting bias The risk of reporting bias was reputed to be low in the Ferraro et al. study (9), as validated questionnaires were periodically administered to participants, and their analysis took into consideration corrections for energy-adjusted nutrients. In the Sorensen et al. study (8), attempts were made to correct some of the biases associated with reporting, as for energy intake was concerned. However, the authors admit that self-reported dietary intake in their study might have been prone to bias. Thus, the bias was rated as unknown. A validated food intake questionnaire was also administered by Shu et al. (2), but the Authors do not disclose whether any bias correction was attempted (unknown ROB). In the Kim et al. study report (3), the Authors did not disclose whether validated systems were implemented to assess the energy intake of patients (high risk of reporting bias). In the methods section, Kim et al. (3) refer to “standardized, self-administered questionnaires”. However, such questionnaires assessed medical history, medication use, family history, physical activity, alcohol intake, smoking habits, and education level, but not dietary/energy intake. Publication bias Funnel plots were generated to analyze the publication bias for the comparison of data in the overall population (men

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and or women).The funnel plot indicated symmetry of the data distribution and such visual impression was confirmed by the Egger’s test or by Begg’s rank correlation analysis, as neither test reached statistical significance (Egger’s, p = 0.36; Begg’s, p = 0.49). The “trim and fill” method applied to the funnel plot imputed no missing studies (Figure 2), and no adjusted estimate of the overall effect size could be calculated for this comparison.

DISCUSSION

The results of the present meta-analysis demonstrate a higher dietary energy intake in renal stone formers compared to non-stone forming subjects. This might be an important finding because it would better explain the association between obesity and the risk of renal stone formation. However, we still have limited data on the energy consumption in renal stone formers, which is linked to physical activity but especially to the resting metabolic rate, which is the largest component of daily energy consumption and is characterized by significant inter-individual differences (10). Furthermore, the energy intake of food nutrients that is calculated experimentally through direct calorimetry as thermal energy could differ from the net energy that is extracted through human metabolism. Efficiency of digestion for different foods depends on their coefficient of digestibility. Notably, energy loss occurs during the process of metabolism. The present findings should be considered provisional and should be interpreted conservatively, since our meta-analysis was based on a limited number of observational studies from three countries (USA, China and Korea) that are characterized by very diverse dietary patterns. The typical US diet is based on abundant consumption of meat and animal fats, sugar, carbonated beverages, and insufficient consumption of fruits and vegetables. On the other hand, China and Korea are char-

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Influence of dietary energy intake on nephrolithiasis - A meta-analysis of observational studies

Figure 2. The “trim and fill” method applied to the funnel plot imputed no missing studies.

acterized by dietary patterns that have a balanced intake of animal and plant-derived foods, at the same time based on a high sodium intake (11, 12). The association between dietary energy intake and the risk of renal stone formation could be different in other countries with healthier dietary patterns, with limited consumption of animal fats and meat and reduced salt consumption. In particular, in countries consuming a Mediterranean diet, an increase in dietary energy intake could have a different effect on the risk of stone formation, as it is related to a higher intake of healthy foods such as cereals, nuts, fruit, vegetables, fish, olive oil, and dairy products. Hence, such food could cause an increase in body weight without concurrently increasing the risk of renal stone formation. In fact, it was shown that adherence to the Mediterranean diet (13) or the DASH diet (14), a diet suggested for the prevention of hypertension that provides for a reduction in the consumption of animal proteins and fats in favor of increased consumption of fruits and vegetables, is associated with a reduction in the risk of renal stone formation. In conclusion, the present meta-analysis, based on a large pool of subjects from the United States of America, China and Korea, showed that the mean energy intake of patients affected by urolithiasis is significantly higher than the corresponding intake in healthy individuals. Assessment of the standardized mean difference allowed the calculation of the odds ratio for such comparison. Such odds ratio (OR = 1.946 (95% CI: 1.869 to 5.561) is significant and points to an association between higher dietary energy intake and urolithiasis. The extensive significance of this finding could be better evaluated when data from other populations with different dietary patterns and more data on energy consumption linked to physical activity and metabolic rate in renal stone formers will be collected.

REFERENCES

1. Aune D, Mahamat-Saleh Y, Norat T, Riboli E. Body fatness, diabetes, physical activity and risk of kidney stones: a systematic review

and meta-analysis of cohort studies. Eur J Epidemiol. 2018; 33:1033-1047. 2. Shu X, Cai H, Xiang YB, et al. Nephrolithiasis among middle aged and elderly urban Chinese: a report from prospective cohort studies in Shanghai. J Endourol. 2017; 31:1327-34. 3. Kim S, Chang Y, Sung E, et al. Association between sonographically diagnosed nephrolithiasis and subclinical coronary artery calcification in adults. Am J Kidney Dis. 2018; 71:35-41. 4. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014; 14:135. 5. Higgins JP, Altman DG, Gøtzsche PC, et al. Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011; 343: d5928. 6. Duval S, Tweedie R. Trim and fill: a simple funnel-plot based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000; 56:455-63. 7. https://training.cochrane.org/handbook 8. Sorensen MD, Chi T, Shara NM, et al. Activity, energy intake, obesity, and the risk of incident kidney stones in postmenopausal women: a report from the Women’s Health Initiative. J Am Soc Nephrol. 2014; 25:362-9. 9. Ferraro PM, Curhan GC, Sorensen MD, et al. Physical activity, energy intake and the risk of incident kidney stones. J Urol. 2015;193:864-8. 10. Goran MI. Energy metabolism and obesity. Med Clin North Am. 2000; 84:347-62. 11. Zhang R, Wang Z, Fei Y, et al. The difference in nutrient intakes between Chinese and Mediterranean, Japanese and American diets. Nutrients. 2015; 7:4661-88. 12. Shu X, Calvert JK, Cai H, et al. Plant and animal protein intake and risk of incident kidney stones: results from the Shanghai men's and women's health studies. J Urol. 2019; 202:1217-1223. 13. Leone A, Fernández-Montero A, de la Fuente-Arrillaga C, et al. Adherence to the Mediterranean dietary pattern and incidence of nephrolithiasis in the Seguimiento Universidad de Navarra followup (SUN) cohort. Am J Kidney Dis. 2017; 70:778-786. 14. Taylor EN, Fung TT, Curhan GC. DASH-style diet associates with reduced risk for kidney stones. J Am Soc Nephrol. 2009; 20:2253-9.

Correspondence Gianpaolo Perletti, Dr. Sci, M.Clin. Pharmacol. (Corresponding Author) gianpaolo.perletti@uninsubria.it Department of Biotechnology and Life Sciences, Section of Medical and Surgical Sciences, University of Insubria, Varese, Italy Vittorio Magri, MD - vittorio.magri@virgilio.it Urology Secondary Care Clinic, ASST-Nord, Milan, Italy Pietro Manuel Ferraro, MD - pietromanuel.ferraro@unicatt.it U.O.C. Nefrologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy Emanuele Montanari, MD - emanuele.montanari@unimi.it Department of Urology, IRCCS Ca’ Granda Ospedale Maggiore Policlinico University of Milan, Italy Alberto Trinchieri, MD - alberto.trinchieri@gmail.com School of Urology, University of Milan, Italy Archivio Italiano di Urologia e Andrologia 2020; 92, 1

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DOI: 10.4081/aiua.2020.1.34

ORIGINAL PAPER

Effectiveness of a novel oral combination of D-Mannose, pomegranate extract, prebiotics and probiotics in the treatment of acute cystitis in women Dario Pugliese 1, Anna Acampora 2, Angelo Porreca 3, Luigi Schips 4, Cindolo Luca 1 1 Department

of Urology “Villa Stuart” Private Hospital, Rome, Italy; of Public Health, Catholic University of Sacred Heart, Rome, Italy; 3 Department of Robotic Urological Surgery, Abano Terme Hospital, Abano Terme, Italy; 4 Department of Urology, “G. D'Annunzio” University, Chieti, Italy. 2 Institute

Summary

Objective: Urinary tract infections (UTIs) are defined as the symptomatic presence of pathogens in the urinary tract that are typically diagnosed by microscopy and culture of urine samples. Over the long-term antibiotic courses, alternative prophylactic methods as probiotics, cranberry juices and D-mannose have been introduced for recurrence prevention. The present study aimed to determine whether a new combination of D-Mannose, Pomegranate extract, Prebiotics and Probiotics is effective in modifying symptoms reported by women with acute uncomplicated acute cystitis. Material and methods: This is a pilot study, performed between September 2018 and November 2018 at the Department of Urology of Villa Stuart Private Hospital. A dose of a new combination of agents was administered twice daily for 5 days and then once a day for 10 days. Together with the compound, forced hydration (> 2 liters/day) has been strongly suggested. Antibiotics were permitted only in case of clinical worsening. Changes in patients’ symptoms, the therapeutic effects and changes in quality of life (QoL) were evaluated clinically and through a validated questionnaire, the Acute Cystitis Symptom Score (ACSS) at the first visit (T0), 15 (T1) and 30 (T2) days later. Results: Thirty-three patients were enrolled in the study (mean age 38,1 ± 11.2 years) and all completed the treatment protocol. At T1 visit, all symptoms or the majority of symptoms went off in 10 women (30.3%) and at T2 in 30 women (90.9%); some symptoms still remained in 16 women (48.5%) at T1 and in 3 women (9.1%) at T2; the persistence of all symptoms or the worsening of the condition was observed in 7 patients (21.2%) at T1 and in none at T2. The mean score reported at all the ACSS sub-scales significantly decreased between baseline and T1 and T2. Typical symptoms decreased from 11.5 (10.5-12.6) to 4.9 (4.0-5.9) and to 2.7 (2.1-3.3) (p-values < 0.0001); differential symptoms decreased from 3.1 (2.6-3.6) to 0.6 (0.3-0.9) and to 0.3 (0.1-0.5) (p-values 0.009 to < 0.0001); QoL mean score also decrease from 7.2 (6.77.7) to 4.0 (3.3-4.6) and to 1.7 (1.2-2.1) (p-values < 0.0001). Six patients required antibiotics and no adverse events were recorded. Conclusions: Our study suggests that the action of the compounds, administered in this new combination, could help in an effective management of symptoms of acute cystitis in women, without antibiotics, in a wide majority of the cases. Lack of microbiological assessment is a clear limitation of the study. Moreover, lack of a control group is another important limitation. Finally, hyperhydration could have been a confounding factor in interpretation of results.

KEY WORDS: Urinary tract infection; Cystitis; Female; Fructooligosaccharide; Mannose; Prebiotics; Probiotics; Pomegranate; Symptom score. Submitted 9 August 2019; Accepted 22 November 2019

INTRODUCTION

Urinary tract infections (UTIs) are common in general practice, and their diagnosis relies on a combination of characteristic signs and symptoms, urinalysis and a positive urine culture (1). An acute uncomplicated cystitis corresponds to a subset of UTIs including new-onset or recurrent cystitis in non-pregnant women, female patients without relevant anatomical or functional abnormalities of the urinary tract, not related to indwelling urinary catheters, and in the absence of relevant comorbidities such as renal diseases, immunocompromising diseases or diabetes (2, 3). Nowadays, antibiotic therapy represents the treatment of choice, recommended by EAU guidelines, as it is effective towards the rapid symptoms resolution (2). However, antibiotic usage is related to side effects and increases resistance rates and, consequently, leads to high medical costs, prolonged hospital stays, and increased mortality (2, 4-5). Thus, alternative therapies are needed to reduce the risk of antimicrobial resistance development. Probiotics (6), cranberry products (7) and D-mannose (8) have been introduced and studied as a single component or in several combinations (9). The aim of this pilot study was to investigate whether a new combination of D-mannose, pomegranate extract, prebiotics and probiotics is effective in modifying symptoms reported by women with acute uncomplicated cystitis.

MATERIAL

AND METHODS

This is an uncontrolled experimental pilot study, performed between September 2018 and November 2018 at the Department of Urology of Villa Stuart Private Hospital. All patients provided written informed consent. The trial was conducted according to the Good Clinical Practice guidelines and the declaration of Helsinki (10) and was approved by the local ethics committee. Female patients admitted at our institution during the recruitment period, complaining of urinary symptom suggestive of UTI were included in the study. Patients were excluded if they presented relevant comorbidities. The exclusion criteria were: pregnancy, antibiotic therapy for UTI within the last month, genital infection, not No conflict of interest declared.

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well compensated diabetes mellitus, abnormality of the urinary tract, signs of pyelonephritis (i.e. fever over 38°C, chills, kidney tenderness by palpation), urine incontinence requiring pads. At the time of inclusion (T0), eligible patients completed the Acute Cystitis Symptom Score (ACSS), a validated questionnaire, specifically developed for self-assessment of acute uncomplicated cystitis (AUC) assessing typical and differential symptoms, quality of life, and changes after therapy in female patients with AUC (11-13). Typical symptoms including frequency, urgency, pain or burning with urination, pain in the suprapubic area, feeling of incomplete bladder emptying and gross hematuria were scored from 0 (not at all) to 3 (severe). Secondly, differential symptoms, such as low back pain, vaginal discharge, urethral discharge or fever and chills were also scored from 0 (not at all) to 3 (severe). In addition, patients recorded how much they felt bothered by their symptoms and how much symptoms impacted on their work/everyday practice and social activities (impairment score, range 0 to 3). Changes from baseline at first and second follow-up collected as dynamics are categorized from 0 to 4 (0: All symptoms have gone away; 1: Majority of symptoms has gone away; 2: Majority of symptoms is still present; 3: No changes in my symptoms; 4: Now I feel worse). A dose of a new combination of agents, (Prolactis IVU©, Omega Pharma, Cantù, Italy) was administered twice daily for 5 days and then once a day for 10 days. According to the company data, Prolactis IVU contains D-mannose 2 g, Prebiotics (fructo-oligosaccharide 1g), pomegranate extract 250 mg (with 70% titration of ellagic acid 175 mg) and Probiotics (Lactobacillus plantarum Lp115 ≥ 2 billion colony-forming unit). Each component has a peculiar mechanism of action that contributes to contrast bacteria. D-mannose provides anti-adesive properties against bacteria, in particular E. coli (14). Pomegranate extract and, in particular ellagic acid, has proven anti flagellar-propelled motility of certain strains of E. coli (15). Lactobacillus plantarum improves vaginal colonization of Lactobacilli, a natural mechanism of defense against urinary tract infections (16). In particular, Lactobacilli can prevent the adherence, growth and colonization of uropathogenic bacteria (17). Fructo-oligosaccharides are prebiotics, that stimulate the growth and activity of intestinal bacteria in the large bowel by acting as a substrate for them (18). Together with the combination of agents, forced hydration (> 2 liters/day) has been strongly suggested. Patients were instructed to contact the Department in case of worsening, persistence or recurrence of symptoms. In case a patient returned with ongoing complaints during the study period, further treatments, including antibiotics, were considered depending on the specific case and on physician choice. Dynamics changes, changes in total ACSS and its subscales were assessed at day 15 (T1) via a telephone interview by a certified Urologist, and at day 30 (T2), during the end of study in-office visit. Response to treatment in terms of complete response, improvement of symptoms, persistence of symptoms or worsening of symptoms were registered as efficacy out-

come. Incidence of adverse events and numbers of secondary antibiotic treatment were also registered. Statistical analysis Descriptive statistics were performed calculating mean value and related standard deviation for continues variables as age, and by frequencies and percentages for categorical variables as menopausal status, presence of cystocele, diabetes mellitus, number of episodes per year ≥ 3. Data regarding changes in dynamics were also reported as frequencies and percentages at first and second follow-up. Mean scores, mean differences between baseline and first and second follow-up along with their 95% confidence interval were also reported. Paired t-test comparing mean scores between baseline and first or second follow-up visit was used in order to test the hypothesis that no differences exist after a period of administration of the studied compound in total or subscale scores. A p-value < 0,05 was considered for statistical significance. All the analyses were performed using statistical package STATA 13.1

RESULTS

Forty-two female patients were admitted at our institution, complaining of urinary symptom suggestive of UTI. Nine patients were excluded due to relevant comorbidities, neurologic bladder or grade IV cystocele according to Baden-Walker classification (19) with high post-void residual urine (> 100 ml). Thirty-three patients were, eventually, enrolled (mean age 38 ± 11.2) and completed the treatment protocol. Twenty-one percent were postmenopausal, 24% had a clinically significant cystocele, 27% suffered from wellcompensated diabetes. About 79% reported < 3 episodes of UTI/year (Table 1). At first follow-up (f-up) T1 visit, all symptoms or the Table 1. Characteristics of the study sample. Characteristic Age (mean, SD) BMI (n, %) < 25 ≥ 25 Menopause (n, %) Cystocele (n, %) Diabetes (n, %) Episodes per year (n, %) <3 ≥3

Study sample (n = 33) 38.1 (11.2) 21 (63.6) 12 (36.4) 7 (21.2) 8 (24.2) 9 (27.3) 26 (78.8) 7 (21.2)

BMI: Body Mass Index.

Table 2. Dynamics at first and second follow-up visit (n° and %).

Dynamic

0 1 2 3 4

Follow-up 1 2 (6.1) 8 (24.2) 16 (48.5) 6 (18.2) 1 (3.0)

Follow-up 2 19 (57.6) 11 (33.3) 3 (9.1) -

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D. Pugliese, A. Acampora, A. Porreca, L. Schips, L. Cindolo

Total

BMI

Menopause

Cystocele

Diabetes

Dynamic at first follow-up - n (%) < 25 ≥ 25 0 2 (6.1) 2 (9.5) 0 (0) 1 8 (24.2) 8 (38.1) 0 (0) 2 16 (48.5) 9 (42.9) 7 (58.3) 3 6 (18.2) 2 (9.5) 4 (33.3) 4 1 (3.0) 0 (0) 1 (8.3) p value 0.015

Yes 2 (28.6) 0 (0) 2 (28.6) 3 (42.9) 0 (0)

No 0 (0) 8 (30.8) 14 (53.9) 3 (11.5) 1 (3.9) 0.010

Yes 0 (0) 0 (0) 5 (62.5) 3 (37.5) 0 (0)

Dynamic at second follow-up - n (%) < 25 ≥ 25 0 19 (57.6) 15 (71.4) 4 (33.3) 1 11 (33.3) 4 (19.1) 7 (58.3) 2 3 (9.1) 2 (9.5) 1 (8.3) 3 4 p value 0.077

Yes 3 (42.9) 3 (42.9) 1 (14.3) -

No 16 (61.5) 8 (30.8) 2 (7.7) 0.551

Yes No 18 (72.0) 1 (12.5) 5 (20.0) 6 (75.0) 2 (8.0) 1 (12.5) 0.006

No 2 (8.0) 8 (32.0) 11 (44.0) 3 (12.0) 1 (4.0) 0.172

Yes 1 (11.1) 2 (22.2) 2 (22.2) 3 (33.3) 1 (11.1)

No 1 (4.17) 6 (25.0) 14 (58.3) 3 (12.5) 0 (0) 0.123

<3 ≥3 2 (7.7) 0 (0) 7 (26.9) 1 (14.3) 12 (46.1) 4 (57.1) 4 (15.4) 2 (28.6) 1 (3.9) 0 (0) 0.873

Yes No 15 (62.5) 4 (44.4) 6 (25.0) 5 (55.6) 3 (12.5) 0 (0) 0.248

<3 ≥3 17 (65.4) 2 (28.6) 8 (30.8) 3 (42.9) 1 (3.9) 2 (28.6) 0.097

Table 4. Mean (95% Confidence Interval) ACSS scores changes between baseline and first follow-up ACSS Sub-scales Baseline First Follow-up Difference between baseline and first follow-up Typical 11.5 (10.5 to 12.6) 4.9 (4.0 to 5.9) - 6.6 (- 5.9 to - 7.3) Differential 3.1 (2.6 to 3.6) 0.6 (0.3 to 0.9) - 2.5 (- 2.0 to - 2.9) Quality of Life 7.2 (6.7 to 7.7) 4.0 (3.3 to 4.6) - 3.2 (- 2.5 to - 3.9) ACSS scores changes first and second follow-up First Follow-up Second Follow-up Difference between first and second follow-up Typical 4.9 (4.0 to 5.9) 2.7 (2.1 to 3.3) - 2.2 (- 1.4 to - 3.0) Differential 0.6 (0.3 to 0.9) 0.3 (0.1 to 0.5) - 0.3 (- 0.1 to - 0.6) Quality of Life 4.0 (3.3 to 4.6) 1.7 (1.2 to 2.1) - 2.3 (- 1.7 to - 2.8) ACSS scores changes between baseline and second follow-up Baseline Second Follow-up Difference between baseline and second follow-up Typical 11.5 (10.5 to 12.6) 2.7 (2.1 to 3.3) - 8.8 (- 7.8 to - 9.8) Differential 3.1 (2.6 to 3.6) 0.3 (0.1 to 0.5) - 2.8 (- 2.2 to - 3.3) Quality of Life 7.2 (6.7 to 7.7) 1.7 (1.2 to 2.1) - 5.5 (- 4.9 to - 6.1)

majority of symptoms went off in 10 women (30.3%) (Table 2 - Dynamics at T1) and at second follow-up visit in 30 women (90.9%) (Table 3 - Dynamics at T2); some symptoms still remained in 16 women (48.5%) at T1 and in 3 women (9.1%) at T2. Persistence of symptoms or the worsening of the condition were observed in 7 patients (21.2%) at T1 and in none at T2. BMI and premenopausal state were statistically associated with worse symptom score at T1 (p = 0.015 for BMI ≥ 25 and p = 0.01 for pre-menopausal state). This difference was not confirmed at T2 whereas a trend of association was present for patients with cystocele (p = 0.06) (Table 2). Regarding the mean score at the ACSS subscales, the analysis showed a significant reduction in all the subscales between baseline visit and both T1 and T2. The reported mean score in typical symptoms at baseline was 11.5 (10-5--12-6), falling to 4.9 (4.0-5.9) at T1 and to 2.7 (2.1-3.3) at T2 (p-values < 0.0001). The mean score in differential symptoms was 3.1 (2.6-3.6) at baseline, falling to 0.6 (0.3-0.9) at T1 and to 0.3 (0.1-0.5) at T2 (p-values 0.009 to < 0.0001). Lastly, the QoL mean score was 7.2 (6.7-7.7) at baseline, falling to 4.0 (3.3-4.6) at

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Episodes/year

p-value < 0.0001 < 0.0001 < 0.0001 p-value < 0.0001 0.009 < 0.0001

Table 3.

T1 and to 1.7 (1.2-2.1) at T2 (p-values < 0.0001). Also difference in mean scores between baseline and T1 and T2 are reported in Table 4. Six patients required antibiotics, during T1 (2 patients after 5 days and 4 patients after 7 days) due to symptoms persistence or worsening. These patients were included in symptoms analysis too both in T1 and T2. No adverse events were recorded.

DISCUSSION

The aim of this pilot study was to investigate a new combination of D-Mannose, pomegranate extract, prebiotics and probiotics as p-value an effective treatment in modifying a specific < 0.0001 questionnaire in women with acute uncom< 0.0001 plicated cystitis. ACSS is an 18-item self< 0.0001 reporting questionnaire including six questions about “typical” symptoms of AUC, four questions regarding “differential” symptoms suggestive of alternative diagnoses and three questions on quality of life items (11-13, 20). Even if antibiotic therapy is currently the treatment of choice due to high efficacy, this must be balanced against the emergence of microorganism resistant to a great variety of antibiotics. Thus, the pain and discomfort of the UTI must be balanced with the cost and risk of developing resistance when using antimicrobials (4-5, 21-23). Thus, even if continuous prophylaxis and self-starting antibiotic treatment are commonly accepted options for prophylaxis, a non-antibiotic management could be effective also in limiting these recurrences (24-28). The results of this pilot study showed that the majority of patients enrolled were safely treated with progressive resolution of symptoms. In particular, after fifteen days all symptoms or the majority of symptoms went off in 10 women (30.3%) and after thirty days this result was obtained in 90.9% of women. Thus, our results sustain the hypothesis that UTI is a self-limiting disorder in many patients. Even without antibiotic treatment, symptomatic infection seems to heal in a substantial number of women (24). There is no

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general consensus in clinical trial results. A trial by Christiaens et al. compared clinically suspected UTI treated with nitrofurantoin or placebo. In the placebo group, more than half had some symptomatic improvement and the effect of the treatment was not statistically significant (p = 0.08) (29). Conversely, Ferry et al. compared different pivmecillinam regimens and a placebo in a large UTI trial with slightly a clear advantage in favor of any antibiotic regimen in terms of symptoms resolution (30). Moreover, another study of Ferry et al., which included 288 patients placebo-treated showed slow decline of symptom. After one week, 30% of women were completely symptoms-free, while 75% were free from suprapubic and loin pain, 45% from urgency and dysuria. At end of study (at six weeks) percentage rose up to 90, 70 and 55%, respectively for specific symptoms and to 54% for all symptoms (31). Our result at one-month follow-up is quite similar (57.6%) of complete symptom resolution. To our knowledge, this is the first study which analyses in a real life setting whether hyperhydration and a formula of D-mannose, prebiotics, probiotics and pomegranate extract might be effective in modifying a cystitisspecific questionnaire in women with symptoms of acute cystitis. However, none of these studies involved a symptomatic treatment arm. There are some limitations in our study. Lack of control arm and microbiological confirmation of UTI are the main limitations. However, in common clinical practice it is difficult to perform a urine culture in many situations like in the week-end or in the evening and night. Moreover, we included some women who do not fit the definition of uncomplicated UTI according to EAU guidelines, including also post-menopausal women, diabetic and with pelvic organ prolapse. A strength point could be that we included also a subset of recurrent UTIs (rUTIs). In fact rUTIs that are defined as having greater than two infections in a 6-month period, or three infections over twelve months, are included in uncomplicated UTI but are typically excluded in randomized clinical trial dealing with AUC. Another limitation of the study is the absence of long term follow up to investigate recurrence in the months after the treatment. Given the uncontrolled design of the study, it is not possible to verify the amount of contribution of each component of the formula.

CONCLUSIONS

2. Bonkat G, Bartoletti RR, Bruyère F, et al. EAU Guidelines on Urological Infections. Retrieved from:https://uroweb.org/guideline/ urological-infections/Access date 05/08/2019. 3. Bent S, Nallamothu BK, Simel DL, et al. Does this woman have an acute uncomplicated urinary tract infection? JAMA. 2002; 287:2701-2710. 4. Chen YH, Ko W C, Hsueh PR. Emerging resistance problems and future perspectives in pharmacotherapy for complicated urinary tract infections. Expert Opin. Pharmacother. 2013; 14:587-596. 5. Bader MS, Loeb M, Brooks AA. An update on the management of urinary tract infections in the era of antimicrobial resistance. Postgrad Med. 2017; 129:242-258. 6. Schwenger EM, Tejani AM, Loewen PS. Probiotics for preventing urinary tract infections in adults and children. Cochrane Database Syst Rev, 2015; (12):CD008772. 7. Stothers L. A randomized trial to evaluate effectiveness and cost effectiveness of naturopathic cranberry products as prophylaxis against urinary tract infection in women. Can J Urol. 2002; 9:1558-62. 8. Kranjcec B, Papeš D, Altarac S. D-mannose powder for prophylaxis of recurrent urinary tract infections in women: a randomized clinical trial. World J Urol. 2014; 32:79-84. 9. Beerepoot MA, Geerlings SE, van Haarst EP, et al. Nonantibiotic prophylaxis for recurrent urinary tract infections: a systematic review and meta-analysis of randomized controlled trials. J Urol 2013; 190:1981-89. 10. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2013; 310:2191-4. 11. Alidjanov JF, Abdufattaev UA, Makhsudov SA, et al. New selfreporting questionnaire to assess urinary tract infections and differential diagnosis: acute cystitis symptom score. Urol Int. 2014; 92:230-36. 12. Alidjanov JF, Naber KG, Abdufattaev UA, et al. Reliability of Symptom-Based Diagnosis of Uncomplicated Cystitis. Urol Int. 2019; 102:83-95. 13. Alidjanov JF, Naber KG, Abdufattaev UA, et al. Reevaluation of the Acute Cystitis Symptom Score, a self-reporting suestionnaire. Part I. Development, diagnosis and differential diagnosis. Antibiotics (Baseel) 2018; 7(1). pii: E6. 14. Wellens A, Garofalo C, Nguyen H, et al. Intervening with urinary tract infections using anti-adhesives based on the crystal structure of the FimH-oligomannose-3 complex. PLoS One. 2008; 3:e2040. 15. Asadishad B, Hidalgo G, Tufenkji N. Pomegranate materials inhibit flagellin gene expression and flagellar-propelled motility of uropathogenic Escherichia coli strain CFT073. FEMS Microbiol Lett. 2012; 334:87-94.

Our study suggests that the synergistic action of the components of this new combination could help the bacterial washout resulting in an effective management of acute cystitis in women without antibiotics in a wide majority of the cases. This approach was also safe because no women had consequences of non-antibiotic management. However, a larger sample size and longer follow-up are needed to confirm these promising results.

16. Vladareanu R, Mihu D, Mitran M, et al. New evidence on oral L. plantarum P17630 product in women with history of recurrent vulvovaginal candidiasis (RVVC): a randomized double-blind placebo-controlled study. Eur Rev Med Pharmacol Sci. 2018; 22:262267.

REFERENCES

18. Liao N, Luo B, Gao J, et al. Oligosaccharides as co-encapsulating agents: effect on oral Lactobacillus fermentum survival in a simulated gastrointestinal tract. Biotechnol Lett. 2019; 41:263-272.

1. Flores-Mireles AL, Walker JN, Caparon M, Hultgren SJ. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat Rev Microbiol. 2015; 13:269-84.

17. Akgül T, Karakan T. The role of probiotics in women with recurrent urinary tract infections. Turk J Urol. 2018; 44:377-383.

19. BadenWF, WalkerTA. Genesis of the vaginal profile: a correlat-

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ed classification of vaginal relaxation.Clin Obstet Gynecol. 1972; 15:1048-54.

of recurrent urinary tract infections. Minerva Urol Nefrol. 2013; 65:9.

20. Alidjanov JF, Naber KG, Pilatz A, et al. Evaluation of the draft guidelines proposed by EMA and FDA for the clinical diagnosis of acute uncomplicated cystitis in women. World J Urol. 2020; 38:63-72.

27. Del Popolo G, Nelli F. Recurrent bacterial symptomaticcystitis: A pilot study on a new natural option for treatment. Arch Ital Urol Androl. 2018; 90:101-103.

21. Pendleton JN, Gorman SP, Gilmore BF. Clinical relevance of the ESKAPE pathogens. Expert Rev. Anti Infect Ther. 2013; 11:297308. 22. Bauer KA, Kullar R, Gilchrist M, File TM Jr. Antibiotics and adverse events: the role of antimicrobial stewardship programs in 'doing no harm'. Curr Opin Infect Dis. 2019; 32:553-558. 23. Fenwick EA, Briggs AH, Hawke CI. Management of urinary tract infection in general practice: a cost-effectiveness analysis. Br J Gen Pract. 2000; 50:635-9. 24. Sihra N, Goodman A, Zakri R, et al. Nonantibiotic prevention and management of recurrent urinary tract infection. Nat Rev Urol. 2018; 15:750-776. 25. Bleidorn J, Gagyor I, Kochen MM, et al. Symptomatic treatment (ibuprofen) or antibiotics (ciprofloxacin) for uncomplicated urinary tract infection? Results of a randomized controlled pilot trial. BMC Med. 2010; 8:30. 26. Wagenlehner FM, Vahlensieck W, Bauer HW, et al. Prevention

Correspondence Dario Pugliese, MD (Corresponding Author) dariopugliese87@gmail.com Luca Cindolo, MD lucacindolo@gmail.com Department of Urology “Villa Stuart” Private Hospital Via Trionfale, 5952 Rome (Italy) Anna Acampora, MD anna.acampora@unicatt.it Institute of Public Health, Catholic University of Sacred Heart Largo A. Gemelli, 8 Rome (Italy) Angelo Porreca, MD angelo.porreca@casacura.it Department of Robotic Urological Surgery, Abano Terme Hospital Piazza Cristoforo Colombo, 1, 35031 Abano Terme PD (Italy) Luigi Schips, MD luigischips@hotmail.com Department of Urology, “G. D'Annunzio” University Via S. Camillo de Lellis, 66054 Vasto (CH) (Italy)

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28. Vicariotto F. Effectiveness of an association of a cranberry dry extract, D-mannose, and the two microorganismsLactobacillus plantarum LP01 and Lactobacillusparacasei LPC09 in women affected by cystitis: a pilot study. J Clin Gastroenterol. 2014; 48 Suppl 1:S96-101. 29. Christiaens TC, De Meyere M, Verschraegen G, et al. Randomised controlled trial of nitrofurantoin versus placebo in the treatment of uncomplicated urinary tract infection in adult women. Br J Gen Pract. 2002; 52:729-34. 30. Ferry SA, Holm SE, Stenlund H, et al. Clinical and bacteriological outcome of different doses and duration of pivmecillinam compared with placebo therapy of uncomplicated lower urinary tract infection in women: the LUTIW project. Scand J Prim Health Care. 2007; 25:49-57. 31. Ferry SA, Holm SE, Stenlund H, et al. The natural course of uncomplicated lower urinary tract infection in women illustrated by a randomized placebo controlled study. Scand J Infect Dis. 2004; 36:296-301.

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DOI: 10.4081/aiua.2020.1.39

ORIGINAL PAPER

Comparison of semirigid ureteroscopy, flexible ureteroscopy, and shock wave lithotripsy for initial treatment of 11-20 mm proximal ureteral stones Ibrahim Kartal 1, Burhan Baylan 1, Mehmet Caglar Cakıcı 1, 2, Sercan Sarı 1, 3, Volkan Selmi 1, 3, Harun Ozdemir 1, 4, Fatih Yalçınkaya 1 1 Department

of Urology, Dıskapı Yıldırım Beyazıt Training and Research Hospital, Health Sciences University, Ankara, 06110, Turkey; 2 Department of Urology Goztepe Training and Research Hospital, Faculty of Medicine, Medeniyet University, Istanbul, Turkey; 3 Department of Urology, Faculty of Medicine, Bozok University, Yozgat, Turkey; 4 Department of Urology, Ministry Of Health Haseki Education Research Hospital, Health Sciences University, Istanbul, Turkey.

Summary

Objective: We aimed to retrospectively evaluate the effectiveness and safety of flexible ureteroscopy (f-URS), semirigid ureteroscopy (sr-URS), and shock wave lithotripsy (SWL) to treat single 11-20 mm stones in the proximal ureter. Materials and methods: Patients treated at our clinic for 11-20 mm single stones in the proximal ureter who underwent f-URS, sr-URS or SWL as initial lithotripsy methods were compared in terms of their clinical characteristics and treatment outcomes. Results: A comparison among 201 patients who had undergone f-URS, 119 patients who had undergone sr-URS, and 162 patients who had undergone SWL showed no significant baseline differences in patients’ demographic and stone characteristics. Stone-free rates on the 15th day and 3rd month were higher with f-URS (89.6% and 97%, respectively) than with sr-URS (67.2% and 94.1%, respectively) and SWL (41.4% and 79.0%, respectively; all p < 0.001). Retreatment rates were significantly higher with SWL than with the other two modalities (p < 0.001); auxiliary procedure rates were significantly lower with f-URS than with the other two modalities (p < 0.001). Treatment-related complication rate at the end of the 3rd month was lower with f-URS than with SWL (p = 0.022). Furthermore, f-URS was more effective than sr-URS for treating impacted stones. Conclusions: We found that f-URS was highly successful as an initial lithotripsy procedure for medium-sized proximal ureteral stones, and it helped achieve early stone-free outcomes with a lower need for retreatment and auxiliary procedures, lower complication rates, and higher effectiveness on the impacted stones compared with sr-URS and SWL.

KEY WORDS: Lithotripsy; Ureter; Ureteroscopy. Submitted 28 July 2019; Accepted 22 November 2019

INTRODUCTION

Urinary tract stones are frequently encountered in urology practice. Shock wave lithotripsy (SWL), ureteroscopy (URS), percutaneous nephrolithotomy, laparoscopy, and open surgery are available as the treatment modalities for proximal ureteral stones sized > 1 cm (1, 2). European Association of Urology guidelines recommend URS and SWL as primary treatments for stones sized

1.1-2 cm. The American Urological Association guidelines recommend URS as the optimal treatment but state that patients must be informed about the increased risk of complications and morbidity associated with URS compared with that with other methods (3, 4). The effectiveness and safety of the available methods for treating large proximal ureteral stones have been compared in various recent studies and meta-analyses (1, 5-8). The use of flexible ureteroscopy (f-URS) for stones in the proximal ureter has increased due to advances in technology. Flexible URS has been compared with semirigidureterorenoscopy (sr-URS) and sr-URS has been compared with SWL; (9, 11) however, comparisons including all three procedures for the treatment of stones in the proximal ureter are not available. This study evaluated the outcomes, safety, effectiveness, and associated complications of f-URS, sr-URS, and SWL as the initial lithotripsy treatment for patients with proximal ureteral stones sized 11-20 mm.

MATERIALS

AND METHODS

Following approval by the local ethics committee, patients treated at our clinic between January 2013 and June 2018 for single stones sized 11-20 mm and located in the proximal ureter were retrospectively evaluated. The proximal ureter was defined as the region between the ureteropelvic junction and the sacroiliac joint (12). Patients with multiple stones, history of surgery or anatomical anomalies on the same side, solitary kidneys, concurrent pregnancy, and concomitant intrarenal stones and those aged < 18 years were excluded. Detection of stone and evaluation of the treatments were performed using kidney-ureter-bladder X-ray, ultrasound imaging, and/or contrast/non-contrast computed tomography. The procedure was selected after patients were informed in detail about possible re-treatment rates, the possibility of shifting to other treatment, and complications. Written informed consents were taken from all patients. In patients for whom URS was chosen, f-URS was pre-

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ferred mostly for patients with grade 3 and 4 hydroureteronephrosis or with stones closer than 5 cm to the ureteropelvic junction. On the other hand, sr-URS was preferred mostly for patients with stones located more than 5 cm away from the ureteropelvic junction by considering the cost. Furthermore, several factors such as the repair process of the device or the intensive use of the f-URS device were effective factors in the device selection in our clinic. To conclude, the device to be used was decided following the joint evaluation of factors such as patient and stone characteristics, socioeconomic reasons, and choice of surgeon. Patients with active infections were treated after administering antibiotic therapy and obtaining clean urine cultures. For the analysis, patients were stratified by lithotripsy procedure into f-URS, sr-URS, or SWL groups. The patient characteristics included in the analysis were age, sex, side, stone size (recorded as the longest of axial, coronal, or sagittal diameters), body mass index (BMI, kg/m²), operation time (in minutes), stone-free rate (SFR %) on the 15th day and 3rd month, length of hospital stay (in days), complication rate, and need for retreatment and auxiliary procedures. In this study, local inflammation and swelling associated with impacted stones in the sr-URS and f-URS groups was confirmed through endoscopy as previously described (13). The preoperative and postoperative outcomes of the selected ureteroscopy type were assessed. Treatment success required achievement of a complete stone-free state or the presence of clinically insignificant residual fragments < 3 mm, which was also considered to be a stone-free state. The 15-day follow-up evaluation included the outcomes of the first session of any procedure. The 3-month follow-up included evaluation of any auxiliary procedures. Effectiveness was determined on the basis of the percentage of procedures that resulted in a stone-free state at 3 months. The efficiency quotient was calculated using the formula: = (stone free % × 100)/[100 + retreatment (%) + auxiliary procedures (%)]. Perioperative complications were graded based on the modified Clavien classification system. SWL SWL was performed as an outpatient procedure using an electrohydraulic extracorporeal lithotripter (Multimed Classic, Elmed, Ankara, Turkey). The procedure and its effectiveness have been previously described (7, 14). Intramuscular nonsteroidal anti-inflammatory medication was administered prior to the procedure, and fluoroscopy and/or ultrasonography was used as the focusing method, with patients in the prone position. The procedure was concluded after seeing fragmentation on fluoroscopy or after a maximum of 3,000 shock waves. Patients without clearance after three sessions were referred for other modalities or follow-up. Additional sessions were not scheduled earlier than 15 days. sr-URS The procedures were performed under general anesthesia using a 6/7.5 F sr-URS device (Richard Wolf, Knittlingen, Germany or Karl Storz, Tuttlingen, Germany).

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Lithotripsy was performed using a Medilas H20 holmium laser (Dornier Med-Tech GmbH, Wessling, Germany). An energy of 0.8-1.5 joules and a frequency of 8-12 Hz were preferred. Insertion of a 4.8-F, 26-cm ureteral stent was not standard but was performed based on the surgeon’s judgment. Ureteral stents were removed after 2-4 weeks. In cases where stones in the proximal ureter were pushed back to the kidney, the procedure was switched to f-URS in the same session. Such patients were considered sr-URS failures and were not included in the f-URS group as the intervention was intrarenal. Switching from sr-URS to f-URS was accepted as an auxiliary procedure. f-URS The procedures were performed under general anesthesia using a 7.5-F f-URS device (Flex X2; Karl Storz GmbH, Tuttlingen, Germany). A 0.038-inch floppy guidewire was advanced past the stone through the ureteral orifice following cystourethroscopy. In some cases, a 9.5–11-F access sheath (Elit Flex, Ankara, Turkey) was passed over the guidewire. Either a 20 watt Dornier Medilas H-20 or a 30 watt Medilas H Solvo holmium laser at a wavelength of 2.1 µm (Dornier Med-Tech, Wessling, Germany) was used. Insertion of a 4.8-F, 26-cm ureteral stent was not standard but was performed depending on the surgeon’s choice. The ureteral stent was removed in 2-4 weeks. Push-up of the stone was not considered as a complication or failure in the f-URS procedure and lithotripsy was continued in the intrarenal area. Statistical analysis Statistical analysis was performed using IBM SPSS Statistics 17.0 (IBM Corporation, Armonk, NY, USA). Kolmogorov-Smirnov test was used to evaluate whether the distribution of continuous quantitative variables was normal. Levene test was used to determine whether the precondition of homogeneity of variances was fulfilled. Descriptive statistics were reported as means ± standard deviation for quantitative variables and as numbers and percentages (%) for categorical variables. The significance of differences in quantitative variables that met the assumptions of the parametric test statistics was evaluated using one-way analysis of variance (ANOVA). The significance of differences in the quantitative variables that did not meet the assumptions of the parametric test statistics was evaluated using Mann-Whitney U test for two independent groups and Kruskal-Wallis test for more than two independent groups. If the results of the Kruskal-Wallis test were significant, Conover’s test of multiple comparisons was used to determine the reason for the difference. Categorical variables were evaluated using Pearson’s chi-square, Fisher’s exact probability, chi-square with continuity correction, or likelihood ratio tests. A P value of < 0.05 was considered statistically significant.

RESULTS

A total of 482 patients, 119 who underwent sr-URS, 201 who underwent f-URS patients, and 162 who underwent SWL for initial lithotripsy, were included in the analysis. The groups did not differ in age, sex, side, American

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Society of Anesthesiologists (ASA) score, BMI, the presence of hydronephrosis, or stone size (p ≥ 0.05). Patients in the SWL group exhibited shorter operation time and length of hospital stay than those in either URS group (p < 0.001). The success rate was higher with f-URS than

with either sr-URS or SWL (p < 0.001) and was higher with sr-URS than with SWL (p < 0.001, Figure 1). Stones were either intraoperatively pushed back into the kidney, or optimal fragmentation was not achieved, in 24 sr-URS procedures; a stone-free state was achieved in 21 of the 24 patients following a switch to f-URS. Any extra related complication was not Figure 1. seen in this switch. In 152 (75.6%) of the 201 Stone-free response achieved on the 15th day and 3rd month after patients who underwent initial f-URS, the the initial lithotripsy procedure. lithotripsy procedure was initiated after insertion of an access sheath. A ureteral stent was inserted for 20 patients to passively dilate the ureter since access could not be achieved. These patients were re-treated at least two weeks later; 6 patients were treated with sr-URS and 14 patients with f-URS. Insertion of the ureteral stent may cause bias in evaluations since there were patients who underwent stent insertion before SWL for reasons such as renal colic, and there were some groups who prefer stent insertion before ureteroscopy to passively dilate the ureter. Therefore, this process should be considered as a part of the procedure and not considered as failure. The patients were included in the groups according to the subsequent procedures. Retreatment rates were significantly higher with SWL than with the other modalities (p < 0.001). The auxiliary procedure rate was significantly lower with f-URS than with sr-URS or SWL (both p < 0.001). Auxiliary procedures were Table 1. performed in 28 sr-URS patients. The high rate Patient characteristics, interventions, and treatment outcomes on 15th day and 3rd month after the initial lithotripsy treatment. resulted from conversion to f-URS in 20.2% of the sr-URS procedures. SFRs were higher with sr-URS f-URS SWL URS than with SWL procedures (p < 0.001). (n = 119) (n = 201) (n = 162) p-value The highest efficiency quotient was 0.89, which At the end of the 15th day a was achieved in the f-URS group (Table 1). Age 43.9 ± 13.1 44.5 ± 13.1 43.6 ± 12.6 0.774 A maximum of three sessions were performed Gender (female/male) 32/87 49/152 35/127 0.586b for each SWL procedure. The mean number of Side (right /left) 59/60 96/105 79/83 0.950b ASA score 1.65 ± 0.73 1.73 ± 0.68 1.70 ± 0.70 0.415c shockwaves and the power decreased at each Anticoagulant use, n (%) 1 (0.8%) 7 (3.5%)e 0 (0.0%)e 0.010d subsequent session, but the complication rate BMI (kg/mm2) 25.1 ± 2.5 25.3 ± 2.7 24.8 ± 2.1 0.186a increased (Table 2). Hydronephrosis had a negPresence of hydronephrosis, n (%) 102 (85.7%) 178 (88.6%) 129 (79.6%) 0.059b ative effect on treatment success in the SWL c Stone size (mm) 13.9 ± 2.6 13.6 ± 2.4 13.4 ± 2.6 0.062 group patients (odds ratio = 40.042, 95% conOperation time (minutes) 41.6 ± 13.7f,g 50.2 ± 10.9e,f 30.9 ± 3.9e,g < 0.001c fidence interval: 9.108-176.035; p < 0.001). b Complication, n, (%) 22 (18.5%) 24 (11.9%) 15 (9.3%) 0.066 Regarding complication rates, there was no sigg e,g c Length of hospital stay 1.5 ± 1.6 1.3 ± 1.1e 0.3 ± 1.1 < 0.001 nificant difference among the three groups on SFR (day 15) 39/80 (67.2%)f 21/180 (89.6%)e,f 95/67 (41.4%)e < 0.001b the 15th day after the initial procedure (p = Efficiency quotient 0.51 0.89 0.24 0.066); however, a significant difference was At the end of the 3rd month observed at the end of the 3rd month (p = Additional intervention 0.022). The mentioned difference was caused Retreatment 8 (6.7%)g 8 (4.0%)e 75 (46.3%)e,g < 0.001b by the higher complication rates associated with Auxiliary procedure 28 (23.5%)f 9 (4.5%)e,f 42 (25.9%)e < 0.001b SWL than with f-URS (p = 0.006). However, all e e b Total complications * 22 + 2 (20.2%) 24 + 3 (13.4%) 15 + 25 (24.7%) 0.022 three groups showed no differences with regard Emergency department visit 5 (4.2%)g 4 (2.0%)e 23 (14.2%)e,g < 0.001b to the distribution of complications based on Total operation time (min) * 44.9 ± 17.8f,g 53.3 ± 17.5f 61.4 ± 33.0g < 0.001c the modified Clavien classification system (MCCS) Total length of hospital stay(day) * 1.6 ± 1.6g 1.4 ± 1.4e 0.9 ± 1.8e,g 0.001b 3rd month SFR * 7/112 (94.1%)g 6/195 (97.0%)e 34/128 (79.0%)e,g < 0.001b (p > 0.05). Although SWL was associated with a Mean number of interventions 1.3± 0.5f,g 1.2 ± 0.4e,f 1.9 ± 1.0e,g < 0.001c higher overall complication rate, the complica*first + additional procedures; a one-way ANOVA; b Pearson’s chi-square test; c Kruskal–Wallis test; tions were minor as per MCCS. Sepsis develd likelihood ratio; e p < 0.05; f-URS vs. SWL; f p < 0,01; sr-URS vs. f-URS; g p < 0,01; sr-URS vs. SWL. oped in one patient each in the f-URS and srsr-URS = semirigid ureteroscopy; f-URS = flexible ureteroscopy; SWL = shock wave lithotripsy; ASA = American Society of Anesthesiologists; BMI = body mass index; SFR = stone-free rate. URS groups and required monitoring in the intensive care unit. None of the patients died Archivio Italiano di Urologia e Andrologia 2020; 92, 1

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DISCUSSION

Table 2. Properties of the shock wave lithotripsy sessions. Session 1 Session 2 Session 3 Number of patients 162 76 35 Presence of hydronephrosis n (%) 129 (79.6%) 75 (98.7%) 34 (97.1%) Success n (%) 95 (58.6%) 56 (73.7%) 29 (82.9%) Complication n (%) 15 (9.3%) 10 (13.2%) 8 (22.9%) Number of shocks 2574.4 ± 332.4 2439.5 ± 315.8 2201.4 ± 373.1 Power (kV) 16.6 ± 1.2 16.3 ± 1.2 15.4 ± 0.4

Table 3. Complications following the initial procedure based on the modified Clavien classification system. I II III IV V

sr-URS (n = 119) 12 (10.1%) 6 (5.0%) 3 (2.5%) 1 (0.8%) 0 (0.0%)

f-URS (n = 201) 11 (5.5%) 8 (4.0%) 4 (2.0%) 1 (0.5%) 0 (0.0%)

SWL (n = 162) 9 (5.6%) 4 (2.5%) 2 (1.2%) 0 (0.0%) 0 (0.0%)

p-value 0.220a 0.517a 0.716b 0.411b -

a Pearson’s chi-square test; b likelihood ratio test.

sr-URS: semirigid ureteroscopy; f-URS: flexible ureteroscopy; SWL: shock wave lithotripsy.

Table 4. Intraoperative and postoperative outcomes of ureteroscopic lithotripsy in the treatment of impacted stones. Stone size (mm) Operation time (min) 15th day SFR Total SFR Total complication n (%) Length of hospital stay (days) Retreatment n (%) Auxiliary procedure n (%)

sr-URS (n = 41) f-URS (n = 91) 15.4 ± 2.6 14.8 ± 2.5 50.1 ± 20.9 59.2 ± 21.3 20/21 (51.2%) 17/74 (81.3%) 5/36 (87.8%) 5/86 (94.5%) 12 (29.3%) 14 (15.4%) 2.3 ± 2.3 1.6 ± 1.7 5 (12.2%) 6 (6.6%) 13 (31.7%) 8 (8.8%)

p-value 0.246a 0.023a < 0.001b 0.284c 0.105b 0.011a 0.316c 0.002b

a Mann-Whitney U test; b chi-square test with continuity correction; c Fisher’s exact probability test.

SFR: stone-free rate.

(Table 3). The rate of visit to the emergency department for renal colic or other reasons was significantly higher after SWL than after the URS procedures (p ≤ 0.001). In addition to the treatments needed to manage the complications occurring after the primary treatment, for temporary relief, four ureteral stents and one percutaneous nephrostomy were needed in sr-URS patients, two ureteral stents and one percutaneous nephrostomy in fURS patients, and three ureteral stents and one percutaneous nephrostomy in SWL patients. These events were included in the analysis as auxiliary procedures. A sub-analysis was performed to evaluate the difference in outcomes achieved with f-URS and sr-URS in impacted stones. A SFR of 81.3% was achieved with f-URS compared with 51.2% achieved with sr-URS following the first session (p ≤ 0.001). Stone size, total SFR, and complication and retreatment rates did not differ significantly with the type of URS (p > 0.05). However, f-URS was associated with longer operation times (p = 0.023), shorter length of hospital stay (p = 0.011), and less need for auxiliary treatments (p = 0.002) compared with sr-URS (Table 4).

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As only about 22% of upper ureteral stones are spontaneously passed, surgical intervention is usually required (15). Given the ineffectiveness of medical expulsion therapy, nearly all patients with stones of the size treated in this study require intervention (16). The method chosen to treat upper ureteral stones depends on factors including stone size, pain severity and duration, presence of obstruction, cost, quality of life, surgeon experience, and available resources (17). SWL and URS are most commonly used methods; both the procedures have specific advantages and disadvantages and variable outcomes have been reported (8, 18). SWL was previously preferred even for stones sized < 10 mm, but the outcomes with SWL and URS have been currently reported to be comparable and either can be recommended as the primary treatment (18). URS may provide higher SFRs for stones sized > 10 mm, but it is associated with higher complication rates than SWL. This short-term study is consistent with previous reports of higher success and lower complication rates with f-URS compared with srURS and SWL. A recent meta-analysis has reported that URS-associated complications have been decreasing without any corresponding decrease in SFR because of improved technology, flexible devices, better tools, and the use of holmium YAG lasers (8). A prospective study of over 9600 patients reported increased success rates and decreased complications in the treatment of proximal ureteral stones using flexible devices (19). The risk of pushing a stone into the kidney is increased if it is located near the ureteropelvic junction; this occurred in 22% of the sr-URS procedures in this study. The switch to f-URS involves increased time, effort, and cost. Possible hemorrhage and loss of clear vision (10, 20) can make it difficult to switch to f-URS in the same session. However, even if the stone is pushed back with f-URS, intrarenal stones can be accessed, providing the opportunity to complete the treatment without additional interventions as opposed to sr-URS and SWL. Moreover, the superiority of f-URS is obvious in cases of concomitant upper ureteral and renal stones (21), which were not included in this study.The high rate of intraoperative conversion to f-URS in this study explains the large percentage of auxiliary procedures that were performed in patients initially treated with sr-URS f-URS offers advantages such as being easily maneuvered in the ureter and, in particular, is less affected by a long urethra in males and by the restricted motion in the proximal urethra, unlike sr-URS. Besides, a conversion can be made from srURS to f-URS in appropriate cases when the stone is pushed back. In this study, a conversion from sr-URS to f-URS was made in 24 (20.1%) patients, and despite prolonged operation times, stone-free states were achieved in a single session in 21 (87.5%) of the 24 patients. These results suggest that, even if the procedure is initiated with sr-URS, f-URS must be available during the procedure to save patients from undergoing additional sessions. Even though SWL is less invasive than f-URS, it cannot be used in patients with bleeding diathesis and morbid obesity or in pregnant patients. It is accompanied by high radiation exposure from fluoroscopy, is affected by stone composition, and requires repeated application to

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Treatment of proximal ureteral stones

achieve a stone-free state (22). The use of radiation in f-URS is decreasing, and some reports have described a successful use f-URS with no radiation exposure (23). Success rates with a single SWL session are low, but stone-free outcomes comparable to those with URS can be achieved with repeated sessions. Repetition improved the SWL success rate in this study, but it remained lower than that achieved with URS. The stone-free outcome with SWL was not lower than that reported in previous studies, but SWL was not as effective as f-URS in this patient series because of the quality of the ureteroscopy devices and experience of the surgeons. Other investigators have reported fewer complications after SWL than URS. In this study, treatment-associated complications were more frequent with SWL than with f-URS or srURS because of the occurrence of renal colic in our SWL group patients. It was generally of mild severity but often resulted in a visit to the emergency department for outpatient treatment. Our results are in line with previous studies reporting renal colic as a frequent complication of SWL (24, 25) The low complication rates associated with URS might result from the use of advanced, flexible ureteroscopy devices and the experience of the surgeons at our clinic, who have performed nearly 3,000 f-URS procedures. The occurrence of renal colic was not been monitored in all studies, which would also contribute to a low incidence of complications. The safety of f-URS in elderly patients with comorbidities compared with that of SWL and sr-URS may also make it the preferred choice for initial lithotripsy in that population (26). Although the cost of f-URS is high, it offers cost benefits because of its high success rate, low complication rate, low need for retreatment, and short recovery time. The treatment of impacted stones is challenging and is associated with decreased success and increased complication rates with both URS and SWL (27, 28). Endoscopy is the most objective method to identify impacted stones, and we evaluated the effectiveness of URS for treating impacted stones in the proximal ureter. Better results were observed with f-URS than with sr-URS, similar to the report of Legateme et al. (13). Length of hospital stay was greater with sr-URS than with f-URS, which probably reflects the more frequent occurrence of sr-URS complications. When used as the initial treatment, f-URS also provided greater success with fewer auxiliary procedures than sr-URS, and beginning the treatment of impacted stones with f-URS appears to be advantageous overall. The study had some limitations such as not including stone composition in the comparison and not being able to perform a cost analysis. The single-center retrospective design and lack of randomization limit the ability to generalize the findings. Other limitations include not considering development of lower urinary tract symptoms and the need for analgesics, which might have influenced treatment selection. Finally, late complications such as ureteral obstruction might have been missed because of the short follow-up.

CONCLUSIONS

In this patient series, f-URS was found to be more effective than sr-URS and SWL for initial lithotripsy of 11-20-

mm proximal ureteral stones. f-URS helped achieve a better success rate at 15 days with less need for retreatment and auxiliary procedures and better effectiveness for impacted stones compared with sr-URS and SWL. These results support the need for a prospective randomized controlled trial to provide sufficient evidence to recommend f-URS as the initial procedure for lithotripsy of proximal ureteral stones.

REFERENCES

1. Lopes Neto AC, Korkes F, Silva JL, 2nd, et al. Prospective randomized study of treatment of large proximal ureteral stones: extracorporeal shock wave lithotripsy versus ureterolithotripsy versus laparoscopy. J Urol. 2012; 187:164-168. 2. Rukin NJ, Siddiqui ZA, Chedgy ECP, Somani BK. Trends in upper tract stone disease in England: evidence from the hospital episodes statistics database. Urol Int. 2017; 98:391-396. 3. Turk C, Petrik A, Sarica K, et al. EAU Guidelines on interventional treatment for urolithiasis. Eur Urol. 2016; 69:475-482. 4. Assimos D, Krambeck A, Miller NL, et al. Surgical Management of Stones: American Urological Association/Endourological Society Guideline, PART II. J Urol. 2016; 196:1161-1169. 5. Aboutaleb H, Omar M, Salem S, Elshazly M. Management of upper ureteral stones exceeding 15 mm in diameter: Shock wave lithotripsy versus semirigid ureteroscopy with holmium:yttrium-aluminum-garnet laser lithotripsy. SAGE Open Med. 2016; 4:2050312116685180. 6. Cavildak IK, Nalbant I, Tuygun C, et al. Comparison of flexible ureterorenoscopy and laparoscopic ureterolithotomy methods for proximal ureteric stones greater than 10 mm. Urol J. 2016; 13:2484-2489. 7. Ozturk MD, Sener NC, Goktug HN, et al. The comparison of laparoscopy, shock wave lithotripsy and retrograde intrarenal surgery for large proximal ureteral stones. Can Urol Assoc J. 2013; 7:E673-676. 8. Cui X, Ji F, Yan H, et al. Comparison between extracorporeal shock wave lithotripsy and ureteroscopic lithotripsy for treating large proximal ureteral stones: a meta-analysis. Urology. 2015; 85:748-756. 9. Karadag MA, Demir A, Cecen K, et al. Flexible ureterorenoscopy versus semirigid ureteroscopy for the treatment of proximal ureteral stones: a retrospective comparative analysis of 124 patients. Urol J. 2014; 11:1867-1872. 10. Alkan E, Saribacak A, Ozkanli AO, et al. Flexible ureteroscopy can be more efficacious in the treatment of proximal ureteral stones in select patients. Adv Urol. 2015; 2015:416031. 11. Galal EM, Anwar AZ, El-Bab TK, Abdelhamid AM. Retrospective comparative study of rigid and flexible ureteroscopy for treatment of proximal ureteral stones. Int Braz J Urol. 2016; 42:967-972. 12. Frober R. Surgical anatomy of the ureter. BJU Int. 2007; 100:949965. 13. Legemate JD, Wijnstok NJ, Matsuda T, et al. Characteristics and outcomes of ureteroscopic treatment in 2650 patients with impacted ureteral stones. World J Urol. 2017; 35:1497-1506. 14. Bas O, Bakirtas H, Sener NC, et al. Comparison of shock wave lithotripsy, flexible ureterorenoscopy and percutaneous nephrolithotripsy on moderate size renal pelvis stones. Urolithiasis. 2014; 42:115-120. 15. Turk C, Knoll T, Seitz C, et al. Medical Expulsive Therapy for Archivio Italiano di Urologia e Andrologia 2020; 92, 1

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Ureterolithiasis: The EAU Recommendations in 2016. Eur Urol. 2017; 71:504-507. 16. Morse RM, Resnick MI. Ureteral calculi: natural history and treatment in an era of advanced technology. J Urol. 1991; 145:263-265. 17. Nikoobakht MR, Emamzadeh A, Abedi AR, et al. Transureteral lithotripsy versus extracorporeal shock wave lithotripsy in management of upper ureteral calculi: a comparative study. Urol J. 2007; 4:207-211. 18. Drake T, Grivas N, Dabestani S, et al. What are the benefits and harms of ureteroscopy compared with shock-wave lithotripsy in the treatment of upper ureteral stones? A systematic review. Eur Urol. 2017; 72:772-786. 19. Perez Castro E, Osther PJ, Jinga V, et al. Differences in ureteroscopic stone treatment and outcomes for distal, mid-, proximal, or multiple ureteral locations: the Clinical Research Office of the Endourological Society ureteroscopy global study. Eur Urol. 2014; 66:102-109.

22. Turna B, Tekin A, Yagmur I, Nazli O. Extracorporeal shock wave lithotripsy in infants less than 12-month old. Urolithiasis. 2016; 44:435-440. 23. Sarikaya S, Senocak C, Selvi I, et al. Does the use of fluoroscopy really affect the success rate of retrograde intrarenal surgery? Arch Esp Urol. 2018; 71:772-781. 24. Salem HK. A prospective randomized study comparing shock wave lithotripsy and semirigid ureteroscopy for the management of proximal ureteral calculi. Urology. 2009; 74:1216-1221. 25. Lee JH, Woo SH, Kim ET, et al. Comparison of patient satisfaction with treatment outcomes between ureteroscopy and shock wave lithotripsy for proximal ureteral stones. Korean J Urol. 2010; 51:788-793. 26. Berardinelli F, De Francesco P, Marchioni M, et al. RIRS in the elderly: Is it feasible and safe? Int J Surg. 2017; 42:147-151.

20. Liu DY, He HC, Wang J, et al. Ureteroscopic lithotripsy using holmium laser for 187 patients with proximal ureteral stones. Chin Med J (Engl). May 2012; 125:1542-1546.

27. Seitz C, Tanovic E, Kikic Z, Fajkovic H. Impact of stone size, location, composition, impaction, and hydronephrosis on the efficacy of holmium:YAG-laser ureterolithotripsy. Eur Urol. 2007; 52:1751-1757.

21. Manikandan R, Mittal JK, Dorairajan LN, et al. Endoscopic combined intrarenal surgery for simultaneous renal and ureteral stones: a retrospective study. J Endourol. 2016; 30:1056-1061.

28. Sarica K, Kafkasli A, Yazici O, et al. Ureteral wall thickness at the impacted ureteral stone site: a critical predictor for success rates after SWL. Urolithiasis. 2015; 43:83-88.

Correspondence Ibrahim Kartal, MD ibrahimguvenkartal@gmail.com ORCID ID (Ibrahim Kartal): 0000-0002-2313-3522 Fatih Yalçınkaya, MD nykaya2@hotmail.com Burhan Baylan, MD baylanburhan@gmail.com Ziraat Mahallesi, Şehit Ömer Halis Caddesi, 06110, Dışekapı-Altındağ, Ankara, Turkey Mehmet Caglar Cakıcı, MD mcaglarcakici@hotmail.com Eğitim Mah. Dr. Erkin Cad. Kadıköy/!stanbul 34722, Turkey Sercan Sarı, MD sercansari92@hotmail.com Çapanoğlu Mah. Cemil Çiçek Cad Bozok Üniversitesi Erdoğan Akdağ Yerleşkesi Atatürk Yolu 7. KM, 66100 Azizli/Yozgat Merkez/Yozgat, Turkey Volkan Selmi, MD volkanselmi@hotmail.com Cemil Çiçek Cad Bozok Üniversitesi Erdoğan Akdağ Yerleşkesi Atatürk Yolu 7. KM, 66100 Azizli/Yozgat Merkez/Yozgat, Turkey Harun Ozdemir, MD dr.harun-17@hotmail.com Üniversite Neighboord Yeni Yuva St. Num:4 Avcılar/!stanbul (By the side of Borusan firstschool), Turkey

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DOI: 10.4081/aiua.2020.1.45

ORIGINAL PAPER

Influence of sociodemographic factors on treatment’s choice for localized prostate cancer in Portugal Mário Pereira-Lourenço, Duarte Vieira e Brito, João Pedro Peralta, Ricardo Godinho, Paulo Conceição, Mário Reis, Carlos Rabaça, Amílcar Sismeiro Urology Department Instituto Português de Oncologia Francisco Gentil, Coimbra, Portugal.

Summary

Introduction: Patients with localized prostate cancer (PCa) are active participants in the choice of treatment. Objectives: To access the effects of social and demographic factors in the choice of treatment in cases of localized PCa, in a Portuguese population. Methods: Identification of all patients with the diagnosis of localized PCa in the last four years in an oncological centre. Evaluation of the effects of sociodemographic factors (age, profession, literacy, marital status, district and number of inhabitants of the place of residence) in the choice of treatment. Results: 300 patients with localized PCa were evaluated: 17.3% (n = 52) opted for radical prostatectomy (RP); 39,3% had (n = 118) external radiotherapy; brachytherapy in 29.3% (n = 88) and other options (active surveillance, cryotherapy and hormonal therapy) in 14.1% (n = 42). In relation to surgical treatment (RP) the following results were obtained: a) > 70 years: 3.9% (n = 5); ≤ 70 years: 27.5% (n = 47), p < 0.001; b) primary sector: 10.3% (n = 3); secondary sector: 16.2% (n = 27); tertiary sector: 24.1% (n = 21); quaternary sector: 8.3% (n = 1), p = 0.296; c) marital status married: 17.9% (n = 47); single: 0% (n = 0); divorced: 25.0% (n = 5); widow: 0% (n = 0), p = 0.734; d) residency in a city: 14.1% (n = 13); city > 4000 habitants: 22.7% (n = 15); city ≤ 4000 habitants: 16.9% (n = 24), p = 0.701. Using multinomial regression with age (p = 0.001), district (p = 0.035), marital status (p = 0.027) and profession (0.179), this model explained 17.2%-28.4% of therapeutic choices (p < 0.001). Conclusions: The main socioeconomical factor that influence treatment choice was age. Unmarried patients over 70 years choose less radical prostatectomy. Other sociodemographic factors have minor influence in the choice of the treatment.

KEY WORDS: Localized prostate cancer; Treatment; Sociodemographic factors; Portugal. Submitted 19 September 2019; Accepted 13 November 2019

INTRODUCTION

Prostate cancer (PCa) is the second most common male cancer, accounting for 13.5% of all cancers diagnosed in the male population. The incidence is greater in developed countries, mostly due to the generalized use of Prostate Specific Antigen (PSA) (1). The use of PSA allowed for an increased number of diagnosed PCa, mostly increasing diagnosis of early stage PCa (localized disease), although the benefit on mortality is small and not altering the global mortality (2). Patients with PCa, for prognostic and therapeutic effects are classified in low-risk, intermediate-risk and high-risk.

This classification utilizes PSA value, stage and histological grade by the Gleason Score or by the International Society of Urological Pathology (ISUP) classification (3). In low-risk patients, knowing that PCa behaves many times as an indolent cancer, therapeutic options are active surveillance (AS), radical prostatectomy (RP) or radiotherapy (RT), with focus on brachytherapy (BT) and external beam radiotherapy (EBRT) (3). There are no differences in oncological results between the different options (4). However, high risk patients present with a significant risk of disease progression and death by PCa, as such current guidelines recommend active treatment with RP with bilateral lymphadenectomy, EBRT plus 2 or 3 years of androgen deprivation therapy (ADT) or BT plus EBRT with or without ADT (3). Again, oncological results are similar between treatment options (4). Treatment of localized PCa is paradigm of doctor and patient shared choice. The urologist must discuss with the patient the advantages and disadvantages of each treatment, its side effects and allow for the informed and conscious choice by the patient (3, 5). Notwithstanding all this recommendations, the agreement between the physician perception and patient preference is inferior to 40% (6). What motivates these patients with the same disease to choose different treatments? Is the patient ready for such a hard choice? This choice may be influenced by the beliefs and knowledge of the own patient (7). Patients that choose RP believe that this represents their best chance of cure and longevity, as all tumour is removed. Patients that opt for RT believe that it is a less invasive treatment, less painful and with less severe side effects (8-10). Literacy in health, defined by the ability to access, understand and use health related information various greatly among patients. Patients with lower levels of health literacy have a tendency for greater stress levels during the choice of treatment and receive different therapies (11). It is necessary to understand that various sociodemographic factors influence the choice of treatment for localized PCa. Various demographic, economic and social factors have been described and influencing factors such as age (7, 12-17), race (15-20), financial status (15, 16, 18, 19, 21), health financing by private insurance (7, 17, 19, 20), educational level (21), marriage status (7, 15, 17), populational density of residence area (15, 16, 22) or hospital where treatment is provided (12, 20).

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2020; 92, 1

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M. Pereira-Lourenço, D. Vieira e Brito, J.P. Peralta, R. Godinho, P. Conceição, M. Reis, C. Rabaça, A. Sismeiro

In Portugal there is a lack of data for the degree of influence that sociodemographic factors have in the choice of treatment for localized PCa. This work takes advantage of the fact that it was conducted in an Oncological Centre that treats patients from all the central region of Portugal, and has as main objective to access the sociodemographic factors that influence patient preference for surgical treatment (in detriment of other treatments) and to understand if there is any asymmetry in the access of different treatments from patients residing in rural areas.

METHODS Study design and population A retrospective study identified all patients that were submitted to a first prostate biopsy in an oncology reference centre (Portuguese Institute Of Oncology of Coimbra) between January 2014 and December 2018. Patients with the diagnosis of localized PCa were selected. The choice of treatment was accessed, particularly the option for surgical treatment. We excluded all the patients that did not receive a treatment with curative purpose. Evaluated variables and data collection methodology • Choice of treatment: RP (classic or laparoscopic), BT, EBRT and other options (patients clinical process). • Clinical variables: initial PSA and ISUP classification in prostate biopsy (patients clinical process) • Social variables: age at diagnosis, marital status, education and profession (patients clinical process). Regarding profession, we classified into four categories: primary sector (extracting and collecting of natural resources, such as farming, fishing, forestry and mining); secondary sector (processing of raw materials, such as manufacturing and construction industries); tertiary sector (services, such as retail, banking, insurance, transports, restaurants, etc.); quaternary sector (knowledge applicable to some business activity that usually involves the provision of services, such as information gathering, distribution and technology, research and development, vocational education, business consulting and strategic financial services). • Demographic variables: number of inhabitants of area of residence (city, ≥ 4000 inhabitants, < 4000 inhabitants, accessed by consulting the demographic data of the census of 2011 by the National Institute of Statistic). Statistical analysis Univariate analysis utilizing the Mann-Whitney test. Multivariate analysis with multinomial regression. The patients that choose RP were compared with patients that opted for other therapies (evaluated together). A value of p ≤ 0.05 was considered significative. The program SPSS v21 was utilized.

RESULTS

Population characteristics are summarized in Table 1. Of the 576 biopsied patients, 300 presented with the diagnosis of localized PCa.

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Table 1. Population characteristics. Number of biopsied patients Diagnosis of PCa • Localized PCa Number of inhabitants • City • > 4000 • ≤ 4000 Education level • Primary school • High school • College • No data Marital status • Married • Single • Divorced • Widow • No data Profession • Primary sector • Secondary sector • Tertiary sector • Quaternary sector • No data PSA (median) • ≤ 10 ng/ml • > 10 ng/ml

576 60.0% (n = 347) 86.5% (n = 300) 31.3% (n = 181) 22.1% (n = 121) 46.5% (n = 269 74.7% (n = 432) 19.2% (n = 111) 5.4% (n = 31) 0.7% (n = 4) 87.5% (n = 506) 2.8% (n = 16) 6.4% (n = 37) 2.8% (n = 16) 0.5% (n = 3) 8.1% (n = 47) 54.9% (n = 317) 30.1% (n = 174) 5.7% (n = 33) 1.2% (n = 7) 8.3 ng/ml 60.3% (n = 328) 39.7% (n = 216)

Analysing patient’s treatment choice for localized PCa, 39.3% (n = 118) opted for EBRT, 29.3% (n = 88) for BT, 17.3% for RP (n = 52) and 14.0% (n = 42) opted for other treatments (20 patients opted for active surveillance, 9 patients opted for cryosurgery and 13 patients received hormonotherapy). Of note 9 of the RP were laparoscopic. The effect of the variables studied (univariate analysis) in the choice of surgical treatment is summarized in Table 2. In univariate analysis, only age related with the choice of surgical treatment, as 27.5% of patients aged ≤ 7 0 years opted for RP, in contrast with only 3.9% of patients over 70 years (p < 0.001). To evaluate if sociodemographic influenced the choice of surgical treatment, an analysis was conducted utilizing multinomial regression with all the previously described variables, resulting the following statistical significance for variables: age (p < 0.001), profession (p = 0.044), marital status (p = 0.027). Another multimodal regression with only the variables that presented statistical significance [age (p < 0.001), marital status (p = 0.027) and profession (0.179)], produced a model that explains 17.2% to 28.4% of choices of surgical treatment (p < 0.001).

DISCUSSION

Treatment of localized PCa has been regarded as a model of “treatment sensible to patient choice”, where the patients beliefs and knowledge, together with clinical data provided by the physician lead to a shared decision about therapeutic option, even in the absence of strong scientific evidence (23). Data from the most recent study

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Influence of sociodemographic factors on treatment’s choice for localized prostate cancer in Portugal

cryotherapy or hormonotherapy. Poor acceptance of AS reflects the low tradition of our institution in applying AS protocols. Furthermore, the majority of p* Other patients want to “get rid of” or “cure” the cancer by undergoing 0.071 15.2% (n = 14) aggressive therapy, even with 9.1% (n = 6) awareness of the potential for sig15.5% (n = 22) nificant side effects. Most men seem unaware of the 0.850 15.7% (n = 37) uncertainty/controversies that 4.3% (n = 2) aggressive treatment may not cure 16.7% (n = 2) 25.0% (n = 1) their cancer or improve their survival. Limited knowledge about AS 0.734 12.5% (n = 33) is common, and few patients think 50.0% (n = 4) of it as a viable option, rather, 5.0% (n = 1) many men perceive it as “doing 44.4% (n = 4) nothing” (24). We observed that 13 patients only received hormonotherapy, corresponding to 0.296 5.6% (n = 5) treatment-indicated patients who 15.6% (n = 26) refused invasive therapies. 9.2% (n = 8) 16.7% (n = 2) Such an important choice promot25.0% (n = 1) ed doubt in most patients. A prospective study with psycho0.956 9.6% (n = 16) logical evaluation of patients dur14.5% (n = 24) ing choice of treatment for PCa, 11.8% (n = 2) determined that most men presented stress related to the choice and 0.956 14.6% (n = 38) patients that present higher levels 10.5% (n = 4) of doubt felt more negative about therapeutic choice. < 0.001 6.4% (n = 11) 24.0% (n = 31) However, stress related to treatment choice decreased progressively, independently of treatment chosen (25). In something so subjective and dependent on the individual perception of each patient and communication skills, it is highly likely that sociodemographic factors could influence patient choice and their urologist. Gordon et al. (26) showed that > 50% Afro-Americans and 24% of white American studied, understood their disease as “non aggressive”, even after a diagnosis of high risk disease. In our work, age was the only factor that individually influenced the choice of treatment, as patients over 70 years were virtually not subjected to RP (only 3.9%). The influence of age is in agreement with literature (7, 12-17), although such a small number leaves a doubt if some patients were excluded from a valid treatment because of their age. It must be understood that an individual with a life expectancy superior to 10 years should receive the same treatment as a young patient (3). Camargo Cancela et al. showed in their work that men over 70 years opted 5 times less for curative treatment (PR or RT), being age the main factor in choice, even after adjusting for other clinical and socioeconomical factors (14). In relation to RP, it is likely that older patients do not have this option discussed as much with their urologist, most likely due to the fear of complication, morbidity and presence of other pathologies (27). In a study about RT modalities, patients residing far

Table 2. The effect of socioeconomical variables in choice of treatment (univariate analysis). *P value obtained in comparison between radical prostatectomy vs other treatments all together.

Number of inhabitants • City • > 4000 • ≤ 4000 Education level • Primary school • High school • College • No data Marital status • Married • Single • Divorced • Widow • No data Profession • Primary sector • Secondary sector • Tertiary sector • Quaternary sector • No data PSA • ≤ 10 ng/ml • > 10 ng/ml • Unknown ISUP •≤3 •>3 Age (median) • ≤ 70 years • > 70 years

14.1% (n = 13) 22.7% (n = 15) 16.9% (n = 24)

45.7% (n = 42) 39.4% (n = 26) 35.2% (n = 50)

25.0% (n = 23) 28.8% (n = 19) 32.4% (n = 46)

17.3% (n = 41) 21.7% (n = 10) 8.3% (n = 1) 0.0% (n = 0)

39.8% (n = 94) 41.3% (n = 19) 25.0% (n = 3) 50.0% (n = 2)

27.1% (n = 64) 32.6% (n = 15) 50.0% (n = 6) 25.0% (n = 1)

17.9% (n = 47) 0.0% (n = 0) 25.0% (n = 5) 0.0% (n = 0)

39.5% (n = 104) 0.0% (n = 0) 45.0% (n = 9) 55.6% (n = 5)

30.0% (n = 79) 50.0% (n = 4) 25.0% (n = 5) 0.0% (n = 0)

10.3% (n = 3) 16.2% (n = 27) 24.1% (n = 21) 8.3% (n = 1) 0.0% (n = 0)

48.3% (n = 14) 41.3% (n = 69) 34.5% (n = 30) 25.0% (n = 3) 50.0% (n = 2)

24.1% (n = 7) 26.9% (n = 45) 32.2% (n = 28) 50.0% (n = 6) 25.0% (n = 1)

18.6% (n = 31) 9.6% (n = 16) 29.4% (n = 5)

32.3% (n = 54) 35.5% (n = 59) 29.4% (n = 5)

39.5% (n = 66) 40.4% (n = 67) 29.4% (n = 5)

17.2% (n = 45) 18.4% (n = 7)

34.9% (n = 91) 68.4% (n = 26)

33.3% (n = 87) 2.6% (n = 1)

27.5% (n = 47) 3.9% (n = 5)

27.5% (n = 47) 55.0% (n = 71)

38.6% (n = 66) 17.1% (n = 22)

ProtecT (Prostate Testing for Cancer and Treatment), showed that during a median follow-up of 10 years, patients with localized PCa treated with active surveillance, RT or RP presented with similar mortality rates. However, surgery and RT presented with a smaller incidence of disease progression and metastasis (4). Consequently, most patients are confronted with a choice of similarly effective treatments. The oncological centre where this work was conducted, not only receives patients from a vast geographic area but offers a wide range of treatments for patients with PCa, without logistical interference (such as different waiting times between options), allowing for a more accurate evaluation of sociodemographic factors. Comparing with other studies, our series presented with a small percentage of patients choosing surgical treatment (17.3%), in contrast with a larger number of patients that choose RT techniques (68.6%) (7, 12, 15-17, 19, 21). This fact can be due to the feeling of some patients that RT is less invasive, less painful nand causing fewer side effects on the short term particularly incontinence (8-10). Other factor can be related to the low availability of laparoscopic surgery, in theory less invasive and better accepted by the patient. We also observed a small number of patients choosing active surveillance (AS), which is why we decided to group these patients with those who chose

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away from the hospital opted for faster and more definitive treatments (28), although our study points in another direction. Another demographic factor is the assessment of the number of inhabitants in the area of residence. In our work we did not find a significative relation, although Schymura et al. described that patients from more urban areas and urban-rural opted more for RP in relation to rural areas (15). In our multinomial model, marital status also influenced treatment choice as surgery was chosen in greater number by married and divorced patients. Most studies report that married patients opt more for surgical treatment (7, 15, 17, 29). The effect that the partner has in the decision is uncertain. Some studies showed the role of support and gathering of information by wives for their husbands, although the final decision was left for the husband (30-32). The effect of personal relations and opinion of friends was studied in other works. Patients with friends that have chosen curative and invasive treatment have a easier time opting for similar options (32). Patients from cultures with strong family ties, tend to rely more on the option of family (33). In our final statistical model, we also considered profession, although it did not present with relevance. Educational level also did not influence choice of treatment. Some previous studies showed that patients residing in areas with higher educational levels chose surgical treatment with greater ease (15, 21). More information concerning the effect of economic capacity in the choice of treatment exists in literature (something that we cannot directly relate from profession and education in Portugal). Patients with greater economic capacity opt more for surgical treatment (15, 16, 21, 34). Assessment of these results should be careful, as access to healthcare in the United States of America is very different from the European and Portuguese reality. With this in mind, patients with access to private health insurance tend to choose more surgical treatment or more aggressive treatments (7, 17, 19, 20). However, a British study also noted that patients with higher socioeconomical level (defined by education, profession, income) have a tendency for more aggressive treatments (35). Although not the main focus of this work, we also evaluated (univariate analysis) the effect of PSA and ISUP on treatment choice and found no relationship. In theory, by including all risk groups for localized disease in the analysis, we could underestimate surgical treatment, as these patients have several less aggressive treatment options to choose. This data indicates that the patient may not understand the risk stratification and its influence in treatment options (36). In our study we did not evaluate the variable urologist in the choice of treatment. Different physicians have different clinical opinion and also communicate differently. In a general way, men that chose surgery tend to refer that their urologists opinion was the most important factor in their decision (16, 17, 37). All this process is complex and multifactorial. Younger individuals tend to consult various information sources and different doctors. Patients with more aggressive disease usually tend to follow in a more strict manure the clinical opinion of their

Archivio Italiano di Urologia e Andrologia 2020; 92, 1

doctor (5). Another important fact, is time allowed to the patient to get a decision. Patients with more time to decide felt more involved in their choice, allowing them for advice from other doctors and family and social network (5). This work has some limitations, starting with the retrospective design. Some factors that can influence choice of treatment were not studied, such as race (not very relevant in the population studied) (15-20) and presence of comorbidities (12, 15). We also decided to compare surgical treatment in relation to other treatments all together, something that can limit the effect of variables between different types of RT or other options. We did not exclude patients with comorbidities, which can interfere in the surgical indication or represent a contraindication for surgery. Other limitation is the lack of information about patient preference, degree of understanding of multiple options, time allowed for decision and degree of satisfaction with the form.

CONCLUSIONS

The main socioeconomical factor that influence treatment choice was age. The choice for RP from patients over 70 years is residual. A model including the variables age, profession and marital status helped to explain in a significant way patients’ therapeutic choice. Factors such as education and residence in rural areas did not seem to influence choice of treatment.

REFERENCES

1. Ferlay J, Colombet M, Soerjomataram I, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019; 144:1941-53. 2. Ilic D, Djulbegovic M, Jung JH, et al. Prostate cancer screening with prostate-specific antigen (PSA) test: a systematic review and meta-analysis. BMJ. 2018; 362:k3519. 3. 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. 4. Hamdy FC, Donovan JL, Lane JA, et al. 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med. 2016; 375:1415-24. 5. Song L, Chen RC, Bensen JT, et al. Who makes the decision regarding the treatment of clinically localized prostate cancer--the patient or physician?: results from a population-based study. Cancer. 2013; 119:421-8. 6. Elkin EB, Kim SH, Casper ES, et al. Desire for information and involvement in treatment decisions: elderly cancer patients' preferences and their physicians' perceptions. J Clin Oncol. 2007; 25:5275-80. 7. Kan CK, Qureshi MM, Gupta A, et al. Risk factors involved in treatment delays and differences in treatment type for patients with prostate cancer by risk category in an academic safety net hospital. Adv Radiat Oncol. 2018; 3:181-9. 8. Gwede CK, Pow-Sang J, Seigne J, et al. Treatment decision-making strategies and influences in patients with localized prostate carcinoma. Cancer. 2005; 104:1381-90. 9. Hall JD, Boyd JC, Lippert MC, Theodorescu D. Why patients

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Influence of sociodemographic factors on treatment’s choice for localized prostate cancer in Portugal

choose prostatectomy or brachytherapy for localized prostate cancer: results of a descriptive survey. Urology. 2003; 61:402-7.

prostate cancer treatment decisions for African American and white men. Cancer. 2019; 125:1693-1700.

10. Holmboe ES, Concato J. Treatment decisions for localized prostate cancer: asking men what's important. J Gen Intern Med. 2000; 15:694-701.

27. Hosain GM, Sanderson M, Du XL, et al. Racial/ethnic differences in treatment discussed, preferred, and received for prostate cancer in a tri-ethnic population. Am J Mens Health. 2012; 6:24957.

11. Seaton CL, Oliffe JL, Rice SM, et al. Health literacy among Canadian men experiencing prostate cancer. Health Promot Pract. 2019:1524839919827576.

28. Mahal BA, Chen YW, Sethi RV, et al. Travel distance and stereotactic body radiotherapy for localized prostate cancer. Cancer. 2018; 124:1141-9.

12. Cooperberg MR, Broering JM, Carroll PR. Time trends and local variation in primary treatment of localized prostate cancer. J Clin Oncol. 2010; 28:1117-23.

29. Tyson MD, Andrews PE, Etzioni DA, et al. Marital status and prostate cancer outcomes. Can J Urol. 2013; 20:6702-6.

13. Weller D, Pinnock C, Silagy C, et al. Prostate cancer testing in SA men: influence of sociodemographic factors, health beliefs and LUTS. Aust N Z J Public Health. 1998; 22(3 Suppl):400-2.

30. Srirangam SJ, Pearson E, Grose C, Bet al. Partner's influence on patient preference for treatment in early prostate cancer. BJU Int. 2003; 92:365-9.

14. de Camargo Cancela M, Comber H, Sharp L. Age remains the major predictor of curative treatment non-receipt for localised prostate cancer: a population-based study. Br J Cancer. 2013; 109:272-9.

31. Berry DL, Ellis WJ, Woods NF, et al. Treatment decision-making by men with localized prostate cancer: the influence of personal factors. Urol Oncol. 2003; 21:93-100.

15. Schymura MJ, Kahn AR, German RR, et al. Factors associated with initial treatment and survival for clinically localized prostate cancer: results from the CDC-NPCR Patterns of Care Study (PoC1). BMC Cancer. 2010; 10:152. 16. des Bordes JKA, Lopez DS, Swartz MD, Volk RJ. Sociodemographic Disparities in Cure-Intended Treatment in Localized Prostate Cancer. J Racial Ethn Health Disparities. 2018; 5:104-10. 17. Wagner SE, Drake BF, Elder K, Hébert JR. Social and clinical predictors of prostate cancer treatment decisions among men in South Carolina. Cancer Causes Control. 2011; 22:1597-606.

32. Davison BJ, Oliffe JL, Pickles T, Mroz L. Factors influencing men undertaking active surveillance for the management of low-risk prostate cancer. Oncol Nurs Forum. 2009; 36:89-96. 33. Drake BF, Keane TE, Mosley CM, et al. Prostate cancer disparities in South Carolina: early detection, special programs, and descriptive epidemiology. J S C Med Assoc. 2006; 102:241-9. 34. Mettlin C, Murphy GP, Menck H. Trends in treatment of localized prostate cancer by radical prostatectomy: observations from the Commission on Cancer National Cancer Database, 1985-1990. Urology. 1994; 43:488-92. 35. Fairley L, Baker M, Whiteway J, et al. Trends in non-metastatic prostate cancer management in the Northern and Yorkshire region of England, 2000-2006. Br J Cancer. 2009; 101:1839-45.

18. Friedlander DF, Trinh QD, Krasnova A, et al. Racial disparity in delivering definitive therapy for intermediate/high-risk localized prostate cancer: the impact of facility features and socioeconomic characteristics. Eur Urol. 2017; pii: S0302-2838(17)30652-8.

36. Liu Q, Xu Z, Mao S, et al. Perineal lipoblastoma: a case report and review of literature. Int J Clin Exp Pathol. 2014; 7:3370-4.

19. Lichtensztajn DY, Leppert JT, Brooks JD, et al. Undertreatment of High-Risk Localized Prostate Cancer in the California Latino Population. J Natl Compr Canc Netw. 2018; 16:1353-60.

37. Scherr KA, Fagerlin A, Hofer T, et al. Physician Recommendations Trump Patient Preferences in Prostate Cancer Treatment Decisions. Med Decis Making. 2017; 37:56-69.

20. Mahal BA, Chen YW, Muralidhar V, et al. National sociodemographic disparities in the treatment of high-risk prostate cancer: Do academic cancer centers perform better than community cancer centers? Cancer. 2016; 122:3371-7. 21. Morris CR, Snipes KP, Schlag R, Wright WE. Sociodemographic factors associated with prostatectomy utilization and concordance with the physician data query for prostate cancer (United States). Cancer Causes Control. 1999; 10:503-11. 22. Cary C, Odisho AY, Cooperberg MR. Variation in prostate cancer treatment associated with population density of the county of residence. Prostate Cancer Prostatic Dis. 2016; 19:174-9. 23. O'Connor AM, Llewellyn-Thomas HA, Flood AB. Modifying unwarranted variations in health care: shared decision making using patient decision aids. Health Aff (Millwood). 2004; Suppl Variation:VAR63-72. 24. Xu J, Neale AV, Dailey RK, et al. Patient perspective on watchful waiting/active surveillance for localized prostate cancer. J Am Board Fam Med. 2012; 25:763-70. 25. Steginga SK, Occhipinti S, Gardiner RA, et al. Prospective study of men's psychological and decision-related adjustment after treatment for localized prostate cancer. Urology. 2004; 63:751-6. 26. Gordon BE, Basak R, Carpenter WR, et al. Factors influencing

Correspondence Mário Pereira-Lourenço, MD (Corresponding Author) mariolourenco88@gmail.com Duarte Vieira e Brito, MD duartevbrito@hotmail.com Juan Pedro Peralta, MD joaopedroperalta@gmail.com Ricardo Godinho, MD ricardogodinhoandrade@gmail.com Paulo Conceição, MD pjcconceicao@hotmail.com Mario Reis, MD reismario58@gmail.com Carlos Rabaça, MD carlosrabaca@gmail.com Amilcar Sismeiro, MD urosc2@ipocoimbra.min-saude.pt Urology Department Instituto Português de Oncologia Francisco Gentil, Coimbra Rua Maria Bourbon Bobone, n57, RE/Esq, Coimbra, 3030-481, Portugal

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DOI: 10.4081/aiua.2020.1.50

ORIGINAL PAPER

Papillary vs non-papillary access during percutaneous nephrolithotomy: Retrospective, match-paired case-control study Ahmet Tahra 1, Resul Sobay 1, Ahmet Bindayi 2, Ferhat Yakup Suceken 1, Eyup Veli Kucuk 1 1 Department 2 Department

of Urology, Health Sciences University, Umraniye Teaching Hospital, Istanbul, Turkey; of Urology, Burhan Nalbantoglu Hospital, Cyprus.

Summary

Objective: The most crucial steps of percutaneous nephrolithotomy (PCNL) are the percutaneous access and dilation of the access route. Recent literature suggests that papillary access to renal calyx is the accepted method. Despite this rule, we do not always make papillary puncture and we puncture wherever we can to achieve stone-free status and reduce unnecessary access. In this study, we present our results with papillary vs non-papillary access in patients with a kidney stone. Material and methods: Two hundred and seven patients with non-papillary access and 69 patients with papillary access who had similar demographics (age, body mass index (BMI), stone size) were selected with pair match analysis (3:1). Preoperative and postoperative data were collected from the patient's chart. Operative time (from starting surgery to nephrostomy tube), drop-in hematocrit level, transfusion rate, duration of hospital stay, perioperative and postoperative complications (Clavien-Dindo Classification) and stone-free status (no or < 3 mm residual stone) were also evaluated in both groups. Results: The mean operative time was similar in between two groups. The mean hematocrit decreases not differ between the two groups (p = 0.56). In papillary group, only 2 patients (3.2%) required transfusion and only one patient (1.4%) in the non-papillary group had a transfusion with no statistically significant difference (p = 0.43). The overall complication rates were 7.1% in the papillary group and 7.2% in the non-papillary group (p = 0.89). Postoperative mean creatinine level was similar between the two groups. Conclusions: In this study, we found that non-papillary access is a feasible option for PCNL in the terms of stone-free status and complication rates.

KEY WORDS: Percutaneous nephrolithotomy; Access; Papillary; Non-papillary. Submitted 14 September 2019; Accepted 13 November 2019

INTRODUCTION

Percutaneous nephrolithotomy (PCNL) is still the standard therapy for the larger calculi in the kidney (1). The most crucial steps of PCNL are the percutaneous access and dilation of the access route. As accepted by literature, punctures must be done through the papilla of the posterior renal calyx to avoid the major vascular structures of the kidney (2). Despite this rule, access through the papilla is not always achievable. In our huge volume percutaneous surgery

centre (over 400 cases per year) we do not always make papillary puncture and we puncture wherever we can to achieve stone-free status and reduce unnecessary access. Non-calyceal puncture method was recently published and the authors concluded that it is feasible and probably not as dangerous as it was stated (3). In this study, we present our results with papillary vs non-papillary access in patients with kidney stone.

MATERIAL

AND METHODS

After an Ethics Committee approval was obtained, a total of 638 patients patient undergoing PCNL between January 2017 and June 2018 were analyzed. Two hundred and seven patients with non-papillary access and 69 patients with papillary access who had similar demographics (age, BMI, maximum diameter of the stone) were selected with pair match analysis (3:1). Preoperative and postoperative data were collected from the patient's chart. Operative time (from starting surgery to nephrostomy tube), drop-in hematocrit level, transfusion rate, duration of hospital stay, perioperative and postoperative complications (Clavien-Dindo Classification) and stone-free status (no or < 3 mm residual stone) were also evaluated in both groups. Preoperative and postoperative third-month creatinine level were also recorded and analyzed. Followup was made with low dose non-enhanced computerized tomography (NECT) three months after surgery. Patients with a solitary kidney, history of previous surgery (open or endoscopic) or Extracorporeal Shock Wave Lithotripsy (ESWL) for the same kidney, congenital anatomical variants (horseshoe kidney, ectopic kidney) were excluded. In surgical technique; after insertion of open-end 4 F ureteral catheter in lithotomy position, patients were set to the prone position. All patients were treated with combined fluoroscopic and ultrasound guided PCNL. In papillary access group, papilla of the calyx was punctured. In the other group, the puncture was made through infundibulum of the calyx. The puncture site was corrected under ultrasound control. After insertion of hydrophilic guidewire all cases were dilated up to 16 F with Amplatz dilators and then balloon dilatation was made up to 30 F. Rigid nephroscope and pneumatic lithotripter were used to remove calculi. Fragments were No conflict of interest declared.

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Papillary vs non-papillary access in PNL

removed using basket catheter and forceps. At the end of the procedure, 14 F nephrostomy catheter was inserted in all cases. Statistical analysis was performed with the IBM SPSS version 20 (IBM Corp., Armonk, NY, USA). Fischer’s exact test, Pair-Match analysis, Mann-Whitney U, t-test and were used for the analysis of the data and statistical significance was accepted as p-value < 0.05.

RESULTS

Patient age, BMI and stone size were similar (nearly the same) in both groups according to case match analysis (Table 1). The mean operative time was also similar. The average of hematocrit decrease was 3.45 ± 2.2 in the papillary group and 3.89 ± 3.3 in the non-papillary group with no difference between the two groups (p = 0.56). In the papillary group, only 7 patients (3.8%) required transfusion and only one patient (1.4%) in the non-papillary group had a transfusion with no statistically significant difference (p = 0.43). The overall complication rates were similar being 7.1% in the papillary group and 7.2% in the non-papillary group (p = 0.89). According to Clavien-Dindo Classification, only one patient in the non-papillary group and three patients in non-papillary group had Class IIIa (required selective angioembolization because of uncontrolled bleeding) complication (p = 0.87). The mean duration of hospital stay was also similar. Postoperative mean creatinine level was similar between the two groups. All statistical analysis are showed in Table 2. Table 1. Patient characteristics.

Age BMI (kg/m2) Stone size (max diameter, cm) Gender F/M, n Location Upper Middle Pelvis Lower

Papillary group (n: 207) 51.6 ± 13.54 28.3 ± 5.2 2.46 ± 4.6 66/141

Non-papillary group (n: 69) 52.2 ± 12.43 27.9 ± 3.6 2.38 ± 5.1 24/45

23 25 82 77

9 11 26 23

p value 0.94 0.93 0.85

Values are presented as mean values ± standard deviation. BMI = body mass index; M = male; F = female.

Table 2. Perioperative and postoperative outcomes and complications. Papillary group (n: 207) Operation time, min 58.3 ± 14.3 Drop in hematocrit level 3.45 ± 2.2 Length of hospital stay, days 4.45 ± 1.9 Stone Free Status (%) 86.4% Mean change in Creatinine, mg/dL 0.06 ± 0.29 Overall complications, (%) 7.1 ≥ Clavien-Dindo Class III 1.4 Transfusion rate (%) 3.8 Values are presented as mean values ± standard deviation.

Non-papillary group (n: 69) 56.8 ± 15.3 3.43 ± 2.7 4.51 ± 1.8 85.5% 0.05 ± 0.41 7.2 1.4 1.4

p value 0.56 0.93 0.42 0.66 0.68 0.89 0.87 0.16

DISCUSSION

After Fernstrom and Johansson reported the first percutaneous nephrolithotomy in 1976 and Alken et al. published the first series of percutaneous interventions for removing renal stones, PCNL started to become widely used for renal stones (4, 5). Operative technique and endoscopic equipment are still evolving to increase success and decrease morbidity. Recent literature suggests that preferred puncture site is papillary access on the avascular line to avoid the risk of bleeding. Sampaio et al. were studied to determine the best route to puncture in 1992 and they found that; in infundibular access, upper site was injured in 67.6% (41.1% venous and 26.5% arterial), mid site of kidney in 61.5% (38.4% venous and 23.1% arterial) and lower site in 68.2% (54.6% venous and 13.6% arterial). In the direct puncture of pelvis 33.2% injuries were recorded but in calyceal fornix overall injuries were recorded only 7.7% and they were all venous injuries (6). This study had three major concerns; firstly, it was cadaveric study and renal-related anatomical tissue was not evaluated, secondly renal and cortical system was naïve and anatomical changes due to stone was not considered, thirdly no renal functional evaluation was made, and recovery was not assessed. Kallidonis et al. published a prospective randomized trial that compared papillary vs non-papillary access in PCNL, and they found that access to infundibulum is the feasible and safe procedure and it is not associated with higher blood loss and transfusion rate (7). Kallidonis et al. evaluated infundibulum of the middle calyx approach technique by 99mTc-dimercaptosuccinic acid SPECT/CT renal scintigraphies and/or computerized tomographies perfusion (CTP); they found that the punctures to the mid calyceal papilla fornix and infundibulum as well as pelvis have similar angles of approach and that effects on parenchyma involved in the tract dilation are similar (8). They concluded that infundibular puncture can be an option to puncture in the performance of PCNL. In another study Kyriazis et al. investigated the feasibility and safety of PCNL with non-calyceal access track; they operated 137 patients consecutively, including 10 cases with anatomical variations, under fluoroscopic guidance (3). Stone free status was 89.2% for a single stone, 80.4% with multiple and 66.7% for staghorn stones. The overall complication rate was 10.2% and the major complication rate was 3.6%. The authors concluded that calyceal access is possible and safe with stone-free status and low complications. The length of hospitalization is a new investigation era for PCNL. The technology continues to improve, and postoperative complications are decreasing, ‘’outpatient’’ procedure is an option now for highly selected patients (9). However, we still routinely admitted patients to follow-up. In terms of hospital stay our results are comparable with a recent literature (10). In this study, the overall complication rates were 7.1% for the papillary group and 7.2% for the non-papillary group. Transfusion rates were 3.8% and 1.4%. In a study by Wiesenthal et al. which compared shockwave lithotripsy, ureteroscopy, and PCNL for renal calArchivio Italiano di Urologia e Andrologia 2020; 92, 1

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A. Tahra, R. Sobay, A. Bindayi, F. Yakup Suceken, E. Veli Kucuk

culi between 100-300 mm2, they found that overall complication in PCNL was 14% (11). In a recent study comparing retrograde intrarenal surgery versus PCNL, in PCNL group bleeding rate was 6.87% and it was higher than our results (10). This study has several limitations; firstly, the study has a retrospective nature. Secondly, control patients were not randomized and selected for analysis. The surgeons (three surgeons) are very experienced â&#x20AC;&#x201C; over 300 cases â&#x20AC;&#x201C; and that may cause low complication rates. Patients are not consecutively enrolled in this study and anatomical variations are not evaluated. Multiple access and longterm complications are not also evaluated. Low number of patients because of the wide exclusion criteria is another limitation of this study.

management of the upper urinary tract. Campbell-Walsh Urology. ninth ed. Saunders Elsevier, Philadelphia, PA. 2007.

CONCLUSIONS

8. Kallidonis P, Kalogeropoulou C, Kyriazis I, et al. Percutaneous nephrolithotomy puncture and tract dilation: evidence on the safety of approaches to the infundibulum of the middle renal calyx. Urology. 2007; 107:43-48.

In this study, we found that non-papillary access is a feasible option for PCNL in terms of stone-free status and complication rates. More anatomical and radiological, prospective randomized studies involving a great number of patients may be needed to determine the safety and efficacy of non-papillary access.

REFERENCES

1. Turk C, Petrik A, Sarica K, et al. EAU Guidelines on Interventional Treatment for Urolithiasis. Eur Urol. 2016; 69:475-482. 2. Gupta M. OM, Shah JB, McDougall EM, Smith, A. Percutaneous

Correspondence Ahmet Tahra, MD (Corresponding Author) ahmettahra@gmail.com Resul Sobay, MD drresulsobay@gmail.com Ferhat Yakup Suceken, MD ykpsckn@gmail.com Eyup Veli Kucuk, MD eyupveli@gmail.com Department of Urology, Health Sciences University Umraniye Teaching Hospital, Istanbul, Turkey Adem Yavuz Cad. No: 1 34766 Istanbul (Turkey) ORCID ID: 0000-0002-5158-5630 Ahmet Bindayi, MD ahmetbindayi@gmail.com Department of Urology, Burhan Nalbantoglu Hospital, Cyprus

Archivio Italiano di Urologia e Andrologia 2020; 92, 1

3. Kyriazis I, Kallidonis P, Vasilas M, et al. Challenging the wisdom of puncture at the calyceal fornix in percutaneous nephrolithotripsy: feasibility and safety study with 137 patients operated via a noncalyceal percutaneous track. World J Urol. 2017; 35:795-801. 4. Fernstrom I, Johansson B. Percutaneous pyelolithotomy. A new extraction technique. Scand J Urol Nephrol. 1976; 10:257-259. 5. Alken P, Hutschenreiter G, Gunther R, Marberger M. Percutaneous stone manipulation. J Urol. 1981; 125:463-466. 6. Sampaio FJ, Zanier JF, Aragao AH, Favorito LA. Intrarenal access: 3-dimensional anatomical study. J Urol. 1992; 148:1769-1773. 7. Kallidonis P, Kyriazis I, Kotsiris D, et al. Papillary vs nonpapillary puncture in percutaneous nephrolithotomy: a prospective randomized trial. J Endourol. 2017; 31:S4- S9.

9. Wei C, Zhang Y, Pokhrel Gm et al. Research progress of percutaneous nephrolithotomy. Int Urol Nephrol. 2018; 50:807-817. 10. Zheng C, Xiong B, Wang Hm et al. Retrograde intrarenal surgery versus percutaneous nephrolithotomy for treatment of renal stones > 2 cm: a meta-analysis. Urol Int. 2014; 93:417-424. 11. Wiesenthal JD, Ghiculete D, D'A Honey RJ, Pace KT. A comparison of treatment modalities for renal calculi between 100 and 300 mm2: are shockwave lithotripsy, ureteroscopy, and percutaneous nephrolithotomy equivalent? J Endourol. 2011; 25:481-485.

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DOI: 10.4081/aiua.2020.1.53

CASE REPORT

Surgical treatment of large hemangioma of the scrotum in a young adult male Massimo Iafrate 1, Nicolò Leone 1, Cesare Tiengo 2, Filiberto Zattoni 1 1 Università

degli studi di Padova, Dipartimento di Scienze Oncologiche Chirurgiche e Gastroenterologiche, Clinica Urologica, Padova, Italy; 2 Università degli studi di Padova, Dipartimento di Neuroscienze, Chirurgia Plastica Ricostruttiva ed Estetica, Padova, Italy.

Summary

A 24-year-old male came to our clinic for a volumetric increase of a suspected scrotal hemangioma with thrombosis episodes. The ultrasound rose the suspicion of hemangioma and the Magnetic Resonance (MR) of the scrotum confirmed the suspicion. The mass was surgically removed and histopathology described a hemangioma cavernous. The postoperative course was regular and no subsequent relapse was shown in 5 months follow-up.

KEY WORDS: Andrology; Hemangioma; Scrotum; Scrotal surgery; Scrotal mass. Submitted 3 February 2020; Accepted 29 February 2020

INTRODUCTION

Hemangiomas are the most common vascular neoplasms in children with an incidence in the first year of age ranging from 3 to 10%. The most frequent localizations are head, neck, trunk, and extremities. Hemangiomas of the scrotum are rare conditions in adult. Many researchers consider them benign neoplasms originating from a congenital vascular anomaly (1).

CASE

REPORT

After a written informed consent was obtained from the participant for the publication of this case report, we present a 24-year-old student male with a history of suspected scrotal hemangioma known from the age of 14 progressively growing over the past 12 months. In the previous 36 months, he went to the emergency room three times for hemangioma thrombosis which was conservatively treated. In medical history, he reported the removal of a lipoma in the sacral region and no previous traumas of genitalia. No significant family history was present. The physical examination showed a soft vascular mass of about 3 x 7 cm positioned in the middle part of the scrotum (Figure 1). The testicles with their funiculum were completely independent from the vascular mass. The remaining physical examination did not show any other significant finding. Hematology, biochemistry, renal, liver function and hormonal panel were in range. MRI of the scrotum documented the presence of a lesion of 6 x 7 x 7 cm made of venous structures dilated developing in the context of the inferior-internal wall of the right scrotum containing some phlebolites, compatible with hemangioma. The lesion was in close contact with

the right cavernous body but did not infiltrate Buck's fascia. Surgical excision was therefore planned. In general anesthesia, a diamond-shaped incision was made in the scrotal skin. With the dissection of the subcutaneous tissue, we identified the hemangioma inside the scrotum. After careful isolation of the neoplasm from the funicular structures and the testicles, we identified the site of origin at the perineal level on the Buck’s fascia. The vessels were then tied to the site of origin with sutures, followed by complete removal of the hemangioma and sent to histological examination (Figure 2). A scrotal drainage in extraction and a bladder catheter were placed. Subcutaneous and skin have been sutured with detached points and a compressive dressing has been applied. The drainage and the catheter were removed the next day. The postoperative course was uneventful. Histopathological examination showed the presence of skin and subcutaneous tissue with vascular proliferation consisting of ectasic vessels with thin walls compatible with scrotal hemangioma. After 5 month, at the follow-up visit, the scar was nearly unrecognizable and there were no signs of recurrence (Figure 3).

DISCUSSION

Cavernous hemangiomas of the scrotum are usually present since birth but come to the attention of the physician only during adolescence due to their unaesthetic aspect. Generally, they are painless masses but sometimes they can be associated with symptoms (pain and bleeding). The imaging helps to characterize the lesion, to assess the extent of the hemangioma, and to detect associated anomalies. Scrotal ultrasonography, however, is frequently not diriment for the diagnostic characterization. A hemangioma may be hypo or hyperechoic. The most typical finding is a mass of soft tissue containing phlebolites (small calcifications). The presence of phlebolites is characteristic of cavernous hemangioma. CT and MRI provide a simple and non-invasive method for the diagnosis and the determination of the extent of these lesions as well as their relationship with adjacent structures. For such reasons, these imaging techniques are considered mandatory before a surgical program (2). The therapeutic choice must take into account different aspects, from the size and the location of the neoplasm to the esthetic outcome. In the litera-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2020; 92, 1

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Figure 1. Physical examination showed a soft vascular mass positioned in the middle part of the scrotum.

choice with safe and satisfactory results, especially for large lesions in adulthood.

REFERENCES

1. Lin CY, Sun GH, Yu DS, et al. Intrascrotal hemangioma. Arch Androl. 2002; 48:259-65. 2. Djouhri H, ArrivĂŠ L, Bouras T, et al. Diffuse cavernous hemangioma of the rectosigmoid colon: imaging findings. J Comput Assist Tomogr. 1998; 22:851-5. 3. Lee JM, Wang JH, Kim HS. Multiple cavernous hemangiomas of the glans penis, penis, and scrotum. Korean J Urol. 2008; 49:92-94. Figure 2. Complete removal of the hemangioma for histological examination.

Figure 3. 5-month follow-up with no signs of recurrence.

ture, good results are reported for small lesions both with Nd: YAG laser or carbon dioxide and with intralesional sclerotherapy. The surgical excision of these tumors of the genital area is burdened with the risk of bleeding due to the high vascularization and the possibility to develop unsightly scars (3). In this case, the surgical option was preferred since there were close relationships with the corpora cavernosa and we needed to avoid treatment options with high odd of necrosis of the erectile tissues.

CONCLUSIONS

The cavernous hemangioma of the scrotum is a rare entity and a diagnostic evaluation with MRI is mandatory in order to have a complete evaluation of the anatomic extension of the lesion. Surgical excision is a therapeutic

Archivio Italiano di Urologia e Andrologia 2020; 92, 1

Correspondence Massimo Iafrate, MD (Corresponding Author) massimo.iafrate@unipd.it NicolĂ˛ Leone, MD nicolo.leone@gmail.com Filiberto Zattoni, MD filiberto.zattoni@unipd.it Clinica Urologica di Padova Via Giustiniani 2 - 35100 Padova (Italy) Cesare Tiengo, MD cesare.tiengo@unipd.it Dipartimento di Neuroscienze, Chirurgia Plastica Ricostruttiva ed Estestetica, Padova (Italy)

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DOI: 10.4081/aiua.2020.1.55

CASE REPORT

Not fatal venous air embolism after holmium laser enucleation of the prostate: Case report and review of literature Daniele Romagnoli 1, Mobin Ghaemian 2, Daniele D’Agostino 1, Paolo Corsi 1, Marco Giampaoli 1, Alessandro Del Rosso 1, Matteo Cevenini 3, Riccardo Schiavina 3, Eugenio Brunocilla 3, Giorgio Davià 2, Walter Artibani 1, Angelo Porreca 1 1 Robotic

Urology and Mini Invasive Urologic Surgery Unit, Abano Terme Hospital, Abano Terme (PD), Italy; and Postoperative Intensive Care Unit, Abano Terme Hospital, Abano Terme (PD), Italy; 3 Department of Specialistic, Experimental and Diagnostic Medicine, Urology, Alma Mater Studiorum-University of Bologna, S. Orsola Hospital, Bologna, Italy. 2 Anesthesiology

Summary

Objective: Holmium laser has demonstrated high efficacy in urethral disobstruction. Venous air embolism (VAE) is a rare complication of prostate surgery. Only two cases of venous air embolism (VAE) in patients submitted to HoLEP, have been described. In this paper we show a third case of not fatal VAE after HoLEP. Materials and methods: A case of VAE occurred in holmium laser enucleation (HoLEP) due to obstructive lower urinary tract symptoms (LUTS) in a 70 years old patient. After the procedure, patient’s end tidal carbon dioxide (ETCO2) levels dramatically decreased at 17 mmHg, with pressure airway (PAW)16 mmHg; oxygen saturation level was at 75%, without any loss in the ventilation circuit and with arterial blood pressure of 94/54 mmHg. Due to the negativity for other suspicions, the suspect of VAE was postulated. Result: The immediate switching from laryngeal mask to Oro Tracheal Intubation increased the oxygen level. A cardiac transthoracic ultrasound was negative for air bubbles inside cardiac cavities, without any alteration in the cardiac kinetics. Arterial blood sample turned negative for any alteration compatible with VAE and catheter continuous vesical irrigation was started to obtain clear washing fluid without blood cloths. The extubated patient showed no neurological defects. Conclusions: An invasive monitoring system is the key to rapidly and correctly identify any embolic episode during this kind of surgery.

KEY WORDS: Holmium Laser enucleation of the prostate; Nitrogen embolus; Transurethral resection of the prostate; Urethral disobstruction; Venous embolism. Submitted 4 August 2019; Accepted 1 September 2019

INTRODUCTION

Air embolism is a rare but documented complication of prostate surgery. Most of the few cases described are reported to have taken place during transurethral resection of the prostate (TURP). Holmium laser has demonstrated high efficacy in disobstruction, both in cases of bladder neck incision (1) and in a pure enucleative setting. Moreover, Holmium Laser enucleation of the prostate in prostatic adenoma is a technique which provides excellent relief from obstructive symptoms with

the advantage of less risk of both bleeding and recurrence. Since HoLEP can be also applied for obstructive symptoms relief in patients with prostate cancer (2, 3), it has gained wide popularity. So far, only two cases of venous air embolism (VAE) in patients submitted to HoLEP, have been described by Kato (4) and Zhang (5). In the present paper another case of VAE is reported.

CASE

REPORT

A 70-year-old patient (172 cm height, 80 Kg weight) was scheduled to HoLEP at our institution due to obstructive lower urinary tract symptoms (LUTS). Serum prostate specific antigen (PSA) was 3.6 ng/mL, digital rectal examination (DRE) was negative for suspicious areas and prostate volume was measured with ultrasound (US) and resulted to be 90 mL. Post void residual volume (PVR) was found to be 200 mL, and preoperatory uroflowmetry showed a Qmax value of 5.1 mL/sec. The patient had been submitted in 2013 to percutaneous coronary angioplasty and coronary stent positioning, and the home therapy consisted of metoprolole, ramipril and cardioaspirin (not preoperatively withdrawn). Preoperative electrocardiogram and chest x-ray were normal, and cardiological evaluation was negative for any modification in the drug scheme. No alterations in preoperative exams were recorded. Standard oxygen monitor was established, and general anesthesia was performed through Superglotty Airway Mask iGel (Intersurgical©) number 4 with gastric tube. Induction was performed with intravenous Propofol (2 mg/Kg and Sufentanyl 0.2 µg/Kg). Anesthesia was realized through Sevoflurane (2.0%) without myorelaxant drugs. Patient was ventilated with mechanical ventilation with tidal volume 7 ml/kg, respiratory rate of 12 rpm, and I:E ratio of 1:1.5. HoLEP was performed using a 120W Ho:YAG VersaPulse® Power Suite™ laser Source (Lumenis®, Santa Clara, California), with a 550 µm SlimLine™ end firing laser fiber. Saline (0.9% w/v) irrigation fluid was used.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2020; 92, 1

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D. Romagnoli, M. Ghaemian, D. D’Agostino, et al.

During the procedure patient remained haemodinamically stable without any loss in the ventilation circuit, with a systemic pressure between 110 and 99 mmHg, a heart rate of 67 bpm, oxygen saturation 99%, end tidal carbon dioxide (ETCO2) 31 mmHg and pressure airway (PAW)16 mmHg. The entire procedure lasted 90 minutes, and before morcellation additional hemostasis with a bipolar loop inserted in a Storz® 24 F resectoscope was performed, in order to achieve the highest level of hemostasis in a patient under antiaggregant therapy. No capsular lesion was documented, and morcellation was performed in clear fluid vision, without any bleeding from the surgical field. At the end of the procedure, in order to check for any remnant chip in the bladder, the surgeon filled the bladder with about 80 mL of air, from the outer sheet of the nephroscope. This procedure usually allows visualization of any remnant prostatic adenoma down piece on the bladder floor, preventing their flooding on the dome, as it usually happens when filling the bladder with saline. The surgeon found no remnant chips in the surgical field, but immediately after the placement of the urethral catheter, patient’s ETCO2 levels dramatically decreased at 17 mmHg, with PAW 16 and oxygen saturation level decreased at 75%, without any loss in the ventilation circuit and arterial blood pressure of 94/54 mmHg. So laryngeal mask was switched to Oro Tracheal Intubation (OTI), in order to increase the oxygen level. Correct positioning of the tube was confirmed by auscultation via stethoscope. Pulmonary US ruled out the presence of pneumothorax and atelectasia. Due to their negativity, the VAE was suspected: the patient was put in Trendelenburg position and cardiac transthoracic US showed no air bubbles inside cardiac cavities, without any alteration in the cardiac kinesis. Arterial blood sample was collected, but was negative for any alteration compatible with VAE. After 5 minutes ETCO2 levels spontaneously returned to 40 mmHg, with fraction of inspired oxygen (FiO2) 40% and Oxygen saturation of 100%, and arterial blood sample was negative for any significant alterations (FiO2 100%, pH 7.29, pO2 217 mmHg, pCO2 53 mmHg, Sat O2 98%, acid-base excess ABE-1.9 mmol/L, Lactate level 0.9 mmol/L). Catheter continuous irrigation was started, and clear washing fluid without blood cloths was so obtained. The patient was extubated and awakened, and no neurological defects were detected. Another arterial blood sample resulted free from any significant alteration (FiO2 40%, pH 7.39, pO2 75.3 mmHg, pCO2 40.5 mmHg, Sat O2 94.9%, acid-base excess ABE-0.1 mmol/L, Lactate level 0.9 mmol/L). Only a conjunctival capillary rupture was detected in the right eye (a sign of augmented endothoracic pressure), but no visus defects were detected. Patient was transferred to the Intensive Care Unit, where a second transthoracic US was performed, together with a serum dosage of myocardial enzymes (Troponine): every analysis was negative for any alteration, so the patient was readmitted to the Urology Ward. Catheter was removed in second postoperative day (POD), while patient was discharged in third POD, without any neurological sequelae.

Archivio Italiano di Urologia e Andrologia 2020; 92, 1

DISCUSSION

The advantage of HoLEP over TURP is the excellent hemostatic effect of Holmium laser compared to standard electrical energy. VAE cases have been described in TURP, while, to the present report, only two cases have been described during HoLEP. The first case (4) was due to an incorrect assembly of the morcellator system, with air entry into the endoscopic circuit. The second (5), has left unanswered the source of the gas leading to a fatal massive VAE. The basis for VAE are the presence of an open venous system and a condition of sub-atmospheric central venous pressure. Moreover (6) air can enter the bloodstream due to active filling: a 5 cm H2O pressure gradient is enough to make air enter the opened vessels (7); this condition may occur in HoLEP enucleative phase, when the Surgeon opens perforating vessels, arising from the capsule to the adenoma. It is important to underline that the entity of VAE is related to the volume of gas entering the venous system. Small size emboli generally have no effect on circulation, thus explaining why there was just a small number of fatal VAE during prostate surgery (7-9). The estimated lethal volume of intravenous air in human circulation is 3-5 mL/Kg (10). There are two possibilities when air enters into the venous bloodstream: if it enters slowly, it can be reabsorbed at the alveolar-capillary interface (11), or, if the air reaches quickly the right heart an acute occlusion of pulmonary artery outflow ensues, leading to fatal VAE. Considering this pathophysiology, we suppose that, in our case, the episode of VAE has been facilitated by air insufflation inside the bladder (“pneumocystoscopy”), to check for any remnant prostatic chip, preventing the flooding of the chips which is caused by suspension in the irrigation fluid. A similar situation had been described when air was inserted through the urinary catheter at the end of the procedure (6) or due to an incorrect assembly of the irrigation system (12) or to an incorrect assembly in the morcellator device (13). In other cases, however, a clear source of air remains either unclear or just postulated: for example, Zhang (5) supposed that fatal VAE had been caused by air entrance into the bladder due to the high-frequency intermittent extraction and insertion of the scope from the sheat during a long lasting procedure (two hours and forty minutes). Chang (14) identified bubbles resulting by water vapor as a possible source of embolism, while Zhang (5) underlined that embolism is linked more likely to air embolus, composed of relatively insoluble nitrogen, than to water embolus resulting from laser absorbance by irrigation fluid. It is also important to underline that, in this case, the patient did not suffer any damage relatd to VAE and spontaneously fully recovered, while most of the cases of VAE related to prostate surgery are characterized by death of the patient due to massive embolism (7). A possible explanation may be both the amount of air entering the bloodstream, not large, and the absence of any cardiac abnormality as a predisposing factor. An effective strategy to treat VAE consists of immediate placement of the patient in left lateral decubitus (Durant’s manouver) maintaining Trendelenburg position, direct aspiration of

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Not fatal venous air embolism after HoLEP

air from the heart via a central catheter and effective cardiopulmonary resuscitation (if required) (5). As a final consideration, the quality of monitoring is crucial to correctly and directly detect. The correct monitoring scheme is the one adopted in case of general anesthesia, with the possibility of rapidly performing, whenever feasible and possible, transesophageal echocardiography, as reported by Hong (15), who described an incidence of 80% of VAE during retropubic radical prostatectomy. This procedure remains the actual most sensitive method for detection of air in the hearth, and the recommended monitoring item. In our case, if we had performed the procedure under spinal anesthesia, without invasive monitoring scheme, we might have missed to identify and recognize the embolic episode. Therefore, care must be taken in order to avoid any air entrance in the bloodstream, either directly or indirectly. An invasive monitoring system is the key to rapidly and correctly identify any embolic episode.

14. Chang CP, Liou CC, Yang YL, Sun MS. Fatal gas embolism during ureteroscopic holmium:yttrium-aluminiium-garnet laser lithotripsy under spinal anesthesia- a casae report. Minim Invasive Ther Allied Technol. 2008; 17:259-61. 15. Hong JY, Kim JY, Choi YD, et al. Incidence of venous gasembolism during robotic-assisted laparoscopic radical prostatectomy is lower than that during radical retropubic prostatectomy. Br J Anaesth. 2010; 105:777-81.

REFERENCES

1. Porreca A, Mineo Bianchi F, D'Agostino D, et al. Ejaculation sparing bladder neck incision with holmium laser in patients with urinary symptoms and small prostates: short-term functional results. Urol Int. 2019; 103:102-107. 2. Noale M, Maggi S, Artibani W, et al. Pros-IT CNR: an Italian prostate cancer monitoring project. Aging Clin Exp Res. 2017; 29:165-172. 3. Grasso A, Cozzi G, De Lorenzis E, et al. Multicenter analysis of pathological outcomes of patients eligible for active surveillance according to PRIAS criteria. Minerva Urol Nefrol. 2016; 68:237-41. 4. Kato T, Sugimoto M, Matsuoka Y, et al. Case of vascular air embolism during holmium laser enucleation of the prostate. Int J Urol. 2015; 22:227-9. 5. Zhang W, Ren M. Fatal massive air embolism during holmium laser enucleation of the prostate (HoLEP). Int J Clin Urol. 2017; 6:60-62. 6. Vacanti CA, Lodhia KL. Fatal massive air embolism during transurethral resection of the prostate. Anesthesiology. 1991; 74:186-7. 7. Tsou MY, Teng YH, Chow LH, et al. Fatal gas embolism during transurethral incision of the bladder neck under spinal anesthesia. Anesth Analg. 2003; 97:1833-4. 8. Albin MS, Ritter RR, Reinhart R, et al. Venous air embolism during radical retropubic prostatectomy. Anesth Analg. 1992; 74:151-3. 9. Memtsoudis SG, Malhotra V. Catastrophic venous air embolus during prostatectomy in the Trendelenburg position. Can J Anaesth. 2003; 50:1084-5. 10. Toung TJ, Rossberg MI, Hutchins GM. Volume of air in a lethal venous air embolis. Anesthesiology. 2001; 94:360-1. 11. Presson RG, Kirk KR, Haselby KA, et al. Fate of air emboli in the pulmonary circulation. J Appl Physiol. 1989; 67:1898-1902. 12. Frasco PE, Caswell RE, Novicki D. Venous air embolism during transurethral resection of the prostate. Anesth Analg, 2004; 99:1864-6. 13. Kato T, Sugimoto M, Matsuoka Y, et al. Case of vascular air embolism during holmium laser enucleation of the prostate. Int J Urol. 2015; 22:227-9.

Correspondence Romagnoli Daniele, MD (Corresponding Author) danieleromagnoli87@gmail.com Dâ&#x20AC;&#x2122;Agostino Daniele, MD daniele.dagostino@casacura.it Corsi Paolo, MD paolo.corsi@casacura.it Giampaoli Marco, MD marco.giampaoli@casacura.it Del Rosso Alessandro, MD adelrosso@casacura.it Artibani Walter, MD prof.artibani@gmail.com Porreca Angelo, MD angeloporreca@gmail.com Robotic Urology and Mini Invasive Urologic Surgery Unit, Abano Terme Hospital Piazza Cristoforo Colombo, 1, 35031 Abano Terme (Padova) (Italy) Ghaemian Mobin, MD mobin.ghaemian@casacura.it Daviaâ&#x20AC;&#x2122; Giorgio, MD giorgio.davia@casacura.it Anesthesiology and Postoperative Intensive Care Unit, Abano Terme Hospital Piazza Cristoforo Colombo, 1, 35031 Abano Terme (Padova) (Italy) Cevenini Matteo, MD matteoceve@gmail.com Schiavina Riccardo, MD rschiavina@yahoo.it Brunocilla Eugenio, MD eugenio.brunocilla@unibo.it Department of Specialistic, Experimental and Diagnostic Medicine, Urology, Alma Mater Studiorum-University of Bologna, S. Orsola Hospital Via Pelagio Palagi, 9, 40138 Bologna, (Italy) Archivio Italiano di Urologia e Andrologia 2020; 92, 1

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DOI: 10.4081/aiua.2020.1.58

CASE REPORT

A surgical approach to squamous cell carcinoma of penis that also resolved the psychological dysfunction of the patient Napoleon Moulavasilis 1, Konstantina Yiannopoulou 2, Marios Frangoulis 3, Ioannis Katafigiotis 1, Georgios Liapis 4, Aikaterini Anastasiou 5, Ioannis Anastasiou 1 1 1st

Department of Urology, National and Kapodistrian University of Athens, Laiko Hospital, Athens, Greece; of Neurology, Henry Dunant Hospital Center, Athens, Greece; 3 Plastic Surgeon, Academic Fellowship, National and Kapodistrian University of Athens, Laiko Hospital, Athens, Greece; 4 Department of Pathology, Medical School of Athens, National and Kapodistrian University of Athens, Greece; 5 Medical School of Athens, National and Kapodistrian University of Athens, Greece. 2 Department

Summary

In this case study, we present an unusual case with squamous cell carcinoma surrounding the penis involving foreskin and glans of penis. In addition, multiple satellite nodules were noted in the pubis. A 57-year-old circumcised heterosexual male patient presented with a penile lesion existing for 10 years. At the same time, he was referred to an outpatient memory clinic because of persistent subjective memory complaints associated with depression and anxiety. The patient was operated under general anaesthesia. The lesion was resected circumferentially with macroscopic clearance, resulting in complete degloving of the penile shaft. Neurovascular bundles were preserved. Histopathological analysis of the lesion revealed an invasive and poorly differentiated squamous cell carcinoma, and the surgical margins were free from tumour. The patient was followed for 18 months. He did not have voiding difficulty. Pelvic tomographic and physical examination findings did not reveal any episode of recurrence or metastasis. Treatment of carcinoma resulted in a simultaneous full recovery of his memory decline and he remained free of depression and anxiety symptoms over time.

KEY WORDS: Squamous cell carcinoma; Penis; Surgical technique. Submitted 10 August 2019; Accepted 21 September 2019

INTRODUCTION

Penile carcinoma is an uncommon tumor which is devastating for the patient and therapeutically challenging for the urologist. Invasive penile carcinoma accounts for 0.4-0.6% of malignant neoplasms among men (1). Carcinoma of the penis usually begins with a small lesion that gradually extends to involve the entire glans, shaft and corpora. Patients with cancer of the penis, more than patients with other types of cancer, seem to delay seeking medical attention. Explanations include embarrassment, fear, guilt and ignorance (2). The oncologic gold standard for definitive treatment of the penile cancer is surgical amputation of the tumor (3). Conservative surgery may be safely performed in well selected patients in order to maintain penile function and length. Additionally, penile cancer sufferers can exhibit significant preoperative and postoperative psy-

chological dysfunction (4). However, it appears that by using established reconstructive surgical techniques we are able to achieve significant improvements of anxiety, depression (5) and subjective memory complaints.

CASE

REPORT

A 57 years old heterosexual male patient presented with a penile lesion existing for 10 years. He has never asked for medical help. As the lesions became aggressive and eventually surrounded the penis, he referred to our department. He suffered from the huge mass, which prevented him from having sex and caused significant voiding diffculty. On physical examination, a tumoural mass resembling a cauliflower measuring nearly 8 x 4 cm encircling the entire penile shaft and satellite nodules in pubis were detected (Figure 1). Clinically and on pelvic computed-tomography, no inguinal lymphadenopathy was noted. At the same time, he was obviously anxious and he also confessed that he suffered from persistent memory decline and depressive symptoms. Consequently, he was referred to an outpatient memory clinic for complete preoperative neuropsychological evaluation. Neurological examination and Magnetic Resonance Imaging (MRI) of the brain were perfectly normal. Nevertheless, the neuropsychological questionnaires revealed a serious depressive and anxiety disorder. He scored 17/21 and 15/21 for anxiety and depression respectively in the Hospital Anxiety and Depression Scale (HADS) (6) and 11/15 the Geriatric Depression Scale (GDS) (7). On the contrary, questionnaires regarding memory difficulties and executive functions (7) were perfectly completed. The patient was operated under general anaesthesia. A complete resection of the glands of penis was performed and the lesion was resected circumferentially with macroscopic clearance, resulting in complete degloving of the penile shaft. Neurovascular bundles were detected during the surgical procedure and preserved. The distal urethra sectioned by the circumcision was reconstructed, and the edges were everted, creating a vertical ureNo conflict of interest declared.

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Surgery of squamous cell carcinoma of penis

Figure 1. Penile lesion.

Figure 2. Penile graft.

Figure 5. Poorly differentiated squamous cell carcinoma with some “basaloid” features and hemorrhage (H&EX100).

Figure 3. Surgical technique.

uneventful, and he was discharged after nine days. His HADS and GDS scores were already improved before discharge and a neuropsychologic reevaluation was scheduled six months later. Reevaluation scores in both questionnaires were found within the normal limits, while his subjective memory complaints were totally resolved. After 18 months of follow-up, our patient had not presented any voiding difficulty. Pelvic computed tomography and physical examination findings did not reveal any episode of recurrence or metastasis (Figure 6). Figure 6. 18 months later.

throstomy. The patient’s penis was reconstructed with partial thickness skin graft. A dermotome was employed to achieve a graft, which was placed for immediate reconstruction after the oncologic resection (Figure 2). A foley catheter was placed for 7 days. The nodules in pubis were resected with macroscopic clearance as well. The large skin defect that was created as a consequence of this resection forced us to translocate the trunk of the penis in a more convenient location that could be covered by the scrotum (Figure 3). According to the pathology report, in gross inspection a tumor of 7.5 x 4 cm in major dimension was noted involving the foreskin and glans of penis. In addition, multiple satellite nodules were noted in pubis. Histologically, the tumor was corresponded to a squamous cell carcinoma, exhibiting a solid pattern and minimal keratin production. In a small relatively area, tumor showed “basaloid features” with a solid pattern and peripheral palisading of nuclei, while tumor cells had small size and dark nuclei. Chromogranin and synaptophysin immunohistochemical stains were negative, so there was no neuroendocrine differentiation (Figures 4, 5). The patient’s post-operative healing was Figure 4. Invasive squamous cell carcinoma (H&EX100).

DISCUSSION

Penile amputation remains the standard therapy for patients with deeply invasive or high grade cancers. Partial penectomy should be considered in well selected patients exhibiting features for organ preservation strategies. Given the fact that the priority is always the cancer treatment, it seems possible that by using established reconstructive surgical techniques, erectile and voiding function, as well as psychological wellbeing of the patients can be preserved (4, 5). Furthermore, it has been already demonstrated that penile cancer sufferers can exhibit significant psychological dysfunction. In our patient, subjective memory complaints were additionally present. Subjective memory complaints are associated either with sub-syndromal depression and anxiety in healthy cognitively normal adults or with mild cognitive decline (7). Therefore, there is a need to identify and assess adequate tools to measure neuropsychological comorbidity in this group of patients (4).

CONCLUSIONS

The treatment of the penile cancer has changed dramatically over the recent years. Organ-sparing treatments should be the first choice in penile squamous cell carcinoma, whenever this technique is adequately safe and efficient in oncological terms. Choosing the right techArchivio Italiano di Urologia e Andrologia 2020; 92, 1

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N. Moulavasilis, K. Yiannopoulou, M. Frangoulis, I. Katafigiotis, G. Liapis, A. Anastasiou, I. Anastasiou

nique for the right patient is of paramount importance. Surgeonâ&#x20AC;&#x2122;s experience accompanied with careful selection of patients suffering from this devastating disease but suitable for the safe organ-sparing surgical procedure, allows patientsâ&#x20AC;&#x2122; access to preserving quality of life treatment options.

COMPLIANCE

WITH ETHICAL STANDARDS

Conflict of interest: Authors declare that they have no conflict of interest. Informed consent: Written informed consent was obtained from the patient for the publication of this Case Repost/any accompanying images.

REFERENCES

1. Vatanasapt V, Martin N, Sriplung H, Chindavijak K, et al. Cancer incidence in Thailand, 1988-1991. Cancer Epidemiol Biomarkers Prev. 1995; 4:475-83. PubMed PMID: 7549802. 2. Lynch HT, Krush AJ. Delay factors in detection of cancer of the penis. Nebr State Med J. 1969; 54:360-7. PubMed PMID: 4238912.

Correspondence Moulavasilis Napoleon, MD napomoul@hotmail.com Katafigiotis Ioannis, MD Anastasiou Ioannis, MD 1st Department of Urology, National and Kapodistrian University of Athens, Laiko Hospital - Agiou Thoma str, Athens, 115 27 (Greece) Yiannopoulou Konstantina, MD Department of Neurology, Henry Dunant Hospital Center, Athens (Greece) Frangoulis Marios, MD Plastic Surgeon, Academic Fellowship, National and Kapodistrian University of Athens, Laiko Hospital, Athens (Greece) Liapis Georgios, MD Department of Pathology, Medical School of Athens, National and Kapodistrian University of Athens (Greece) Anastasiou Aikaterini, MD Medical School of Athens, National and Kapodistrian University of Athens (Greece)

Archivio Italiano di Urologia e Andrologia 2020; 92, 1

3: Horenblas S, Van Tinteren H, Delemarre JF, et al. Squamous cell carcinoma of the penis: accuracy of tumor, nodes and metastasis classification system, and role of lymphangiography, computerized tomography scan and fine needle aspiration cytology. J Urol. 1991; 146:1279-83. PubMed PMID: 1942279. 4. Maddineni SB, Lau MM, Sangar VK. Identifying the needs of penile cancer sufferers: a systematic review of the quality of life, psychosexual and psychosocial literature in penile cancer. BMC Urol. 2009; 9:8. doi: 10.1186/1471-2490-9-8. 5. Rybak J, Larsen S, Yu M, Levine LA. Single center outcomes after reconstructive surgical correction of adult acquired buried penis: measurements of erectile function, depression, and quality of life. J Sex Med. 2014; 11:1086-1091. doi: 10.1111/jsm.12417. 6. Hartung TJ, Friedrich M, Johansen C, et al. The Hospital Anxiety and Depression Scale (HADS) and the 9-Item Patient Health Questionnaire (PHQ-9) as Screening Instruments for Depression in Patients With Cancer. Cancer. 2017; 123:4236-4243. doi: 10.1002/cncr.30846. 7. Balash Y, Mordechovich M, Shabtai H, et al. Subjective memory complaints in elders: Depression, anxiety, or cognitive decline? Acta Neurol Scand. 2013; 127:344-50. doi: 10.1111/ane.12038.

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DOI: 10.4081/aiua.2020.1.61

CASE REPORT

Be cautious of “complex hydrocele” on ultrasound in young men Evangelos N. Symeonidis 1, Petros Sountoulides 1, Irene Asouhidou 2, Chrysovalantis Gkekas 3, Ioannis Tsifountoudis 4, Ioanna Tsantila 5, Asterios Symeonidis 3, Christos Georgiadis 3, Apostolos Malioris 3, Michail Papathanasiou 3 1 Department

of Urology, Aristotle University of Thessaloniki, “G. Gennimatas” General Hospital, Thessaloniki, Greece; of Anatomy and Surgical Anatomy, Aristotle University of Thessaloniki, Thessaloniki, Greece; 3 Department of Urology, 424 General Military Hospital of Thessaloniki, Thessaloniki, Greece; 4 Department of Radiology, 424 General Military Hospital of Thessaloniki, Thessaloniki, Greece; 5 Department of Pathology, 424 General Military Hospital of Thessaloniki, Thessaloniki, Greece. 2 Department

Summary

Hydrocele is the most common benign cause of painless scrotal enlargement and only very rarely can be reactive to an underlying testicular tumor. We present the case of a healthy young man, complaining of mild left scrotal discomfort and swelling. Physical examination revealed a non-tender fluctuant left scrotum and serum tumor markers were normal. Scrotal ultrasonography (US) showed a normal right hemiscrotum and testicle and a fluid collection among thickened irregular septations in the left hemiscrotum, a finding which was considered as a complex hydrocele. Intraoperatively the presumed “complex hydrocele” was in fact a multicystic testicular tumor. We proceeded with orchiectomy through the scrotal incision and pathology revealed a mixed germ cell tumor of the testis consisting of cystic teratoma, in situ germ cell neoplasia unclassified (IGCNU) and Sertoli cell tumor. This is the first reported case of this type of testis tumor presenting as complex hydrocele. The aim of this case presentation is to underline the need for an accurate preoperative diagnosis in cases of suspected scrotal pathology in young males.

KEY WORDS: Hydrocele; Testis tumor; Scrotal ultrasonography; IGCNU; Sertoli cell tumor. Submitted 30 September 2019; Accepted 23 December 2019

INTRODUCTION

Hydrocele is usually caused by either the presence of a patent processus vaginalis or an imbalance in the secretion and absorption of fluid within the tunica vaginalis. Increased fluid secretion may be a result of inflammation, whereas poor absorption commonly results from thickening of the hydrocele sac or impaired lymphatic drainage. So-called reactive hydrocele is present in 10% of testicular tumors. Seminoma is the most common type of testicular tumor (40%) while non-seminomatous germ cell tumors are more rare (1). A mixed germ cell tumor consisting of cystic teratoma, Sertoli cell tumor and in situ germ cell neoplasia unclassified (IGCNU) is very rare. Scrotal ultrasound (US) plays a pivotal role in the diagnosis of hydrocele and other scrotal pathology. However, there are cases where scrotal ultrasonography might fail to reveal a hidden testicular pathology (2-5). We present a case of a hydrocele with complex ultra-

sonographic features which during elective surgery turned out to be an unusual testicular tumor.

CASE

PRESENTATION

A 24-year-old male presented with a complaint of mild left scrotal discomfort of 3 months’ duration. His medical history was unremarkable with no recall of scrotal trauma or other urological symptoms. Physical examination revealed a painless, non-tender, moderately enlarged left hemiscrotum and a non-palpable ipsilateral testis. Complete blood count and urinalysis were normal. Tumor markers were within normal range with alpha-fetoprotein (a-FP) of 0.96 ng/ml and β-human chorionic gonadotropin (β-HCG) < 1.20 mIU/ml. Scrotal US showed a large amount of fluid collection in the left scrotal sac containing multiple thick echogenic septations, a finding described by the radiologist as a “complex hydrocele” (Figure 1). Scrotal US also revealed normal size and echogenicity of both testicles. The sonographic findings were consistent with a “complex” hydrocele of the left testis with inflammatory changes in the surrounding scrotal layers. An elective left hydrocelectomy was performed under the presumptive diagnosis of a complex hydrocele. Scrotal exploration refuted the presence of a hydrocele, instead it revealed the presence of a multicystic testicular tumor distorting the testicular parenchyma. Following intraoperative consensus and informed parental consent we proceeded with orchiectomy via the scrotal incision (Figure 2). Histopathology revealed the presence of a mixed germ cell tumor consisting of cystic teratoma, Sertoli cell tumor and IGCNU (Figure 3). Following multidisciplinary team (MDT) discussion and negative axial tomography staging the patient received prophylactic chemotherapy and is free of recurrence at 6-month follow-up.

DISCUSSION

Although in most cases hydrocele presents as a benign painless swelling, rarely a reactive hydrocele could be

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2020; 92, 1

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E.N. Symeonidis, P. Sountoulides, I. Asouhidou, C. Gkekas, I. Tsifountoudis, I. Tsantila, A. Symeonidis, C. Georgiadis, A. Malioris, M. Papathanasiou

or suspicious sonographic findings (6, 7). MRI can also provide a much more accurate differentiation of testicular lesions (7). MRI can reliably demonstrate detailed information on tissue characteristics and improve differential diagnosis among various scrotal pathology (6, 7). Misdiagnosis of a testicular cancer as a hydrocele is very rare. Harvey et al. described a case of a 63year-old patient initially listed for hydrocele repair. Intraoperatively it was Figure 2. difficult to identify viable Macroscopic appearance of the multicystic mass, depicting testicular parenchyma and the presence of a green the atrophic left testicular parenchyma. caseous material led to the decision for orchiectomy. It is worth mentioning the absence of hydrocele. Histopathology revealed an epidermoid cyst (8). Iqbal et al. reported two cases of testicular cancer which were initially diagnosed as hydroceles and operated via a scrotal approach. Both patients underwent hydrocele repair, and concomitant testicular biopsy revealed embryonal cell carcinoma of the testis which led to radical orchiectomy (9). A metastatic to the testis pancreatic adenocarcinoma was also misdiagnosed as complex hydrocele in a 69-yearpatient who presented with painful swelling of the left scrotum and underwent left hydrocelectomy (10). Testicular teratomas can sometimes have a predominantly cystic appearance closely resembling a hydrocele. Lin et al. presented a case of a 3-year-old boy with a transilluminatthe first and only sign of a testicular tumor (1, 2). Our ing scrotal mass initially diagnosed as a communicating case highlights the diagnostic pitfall of a non-tender hydrocele. Due to impalpable testis they proceeded with scrotal enlargement clinically and radiologically indicaultrasonography which depicted a heterogeneous cystic tive of a complex hydrocele, which proved to be a testicmass with subsequent orchiectomy revealing mature terular tumor in the operating room. atoma (11). There was also a recent report of a case of A â&#x20AC;&#x153;complexâ&#x20AC;? hydrocele on US is characterized by the findadult germ cell testicular tumor with again sonographic ing of multiple thick echogenic septations and calcificafeatures suggestive of hydrocele (12). tions surrounded by fluid with layering echogenic debris Recently, Trenti et al. cited an infrequent case of mesothe(3, 5). Further imaging might be necessary in cases scrotal lioma of the tunica vaginalis testis, secondarily diagUS is ambiguous about the diagnosis of hydrocele. nosed during hydrocele surgery. Contrary to our case, Magnetic resonance imaging (MRI) emerges as a valuable the ultrasonographic findings were that of a simple left problem-solving imaging modality in cases of inconclusive hydrocele (13). In our case histopathology revealed the presence of a mixed germ cell tumor consisting of Figure 3. cystic teratoma, IGCNU Histological images. (A) Hematoxylin - Eosin stain (x100): Sertoli cell tumor composed mostly of solid nests. (B) Hematoxylin - Eosin stain (x100): In situ germ cell neoplasia unclassified and gonadal stromal (ISGNU): proliferation of malignant germ cells resembling primitive gonocytes confined to the tumor (Sertoli cell). This basilar aspect of the seminiferous tubules. (C) Hematoxylin - Eosin stain (x40): Gastrointestinal is the first reported case of type epithelium and endometrial foci in teratoma of the testis. misdiagnosis of this type of testis tumor as complex hydrocele. At MDT discussion of the case one of the proposed reasons for the missed diagnosis was the fact that the extended cystic part of the tumor gave a very hypoechoic image on US mimicking Figure 1. Scrotal ultrasound (US). Arrows depict the anechoic fluid inside the thick septations of the scrotal sac. (A, B, C). Image (D) shows a normal in size and echogenicity left testis. Images (E, G, F, H) demonstrate a right testis with homogeneous echo texture and echogenicity.

Archivio Italiano di Urologia e Andrologia 2020; 92, 1

Simoneidis_Stesura Seveso 14/04/20 13:59 Pagina 63

Be cautious of “complex hydrocele” on ultrasound in young men

the hypoechoic fluid accumulation seen in a typical hydrocele. On the other hand, it was noted that complex hydroceles usually result from previous failed hydrocelectomies or infected hydroceles and very rarely in de novo cases (14). Irrespective of the aetiology, misdiagnosis of a testicular tumor as a complex hydrocele has significant implications in surgical planning as a scrotal incision used for hydroceles is contraindicated in cases of suspected testicular malignancy, and also for patient counselling (2, 9, 15). As a result of this misdiagnosis our patient was listed for a non-urgent elective procedure of hydrocele repair, whereas if a testicular tumor was suspected he should have taken priority and have had the procedure done within days of diagnosis. A high level of suspicion should be maintained in any case of presumed hydrocele with discordance between testicular size, morphology and echotexture on scrotal US especially in younger men. It is important to underline the need for preoperative counseling for the risk of orchiectomy if unanticipated pathology is realized during surgery. In cases of ultrasonographic diagnostic dilemmas, further imaging with scrotal MRI should be the next diagnostic step in cases of complex scrotal conditions.

CONCLUSIONS

What initially appeared to be a complex hydrocele on ultrasound, was finally diagnosed as a testicular tumor. In this setting, we aimed to underline the need for diligent preoperative ultrasound evaluation of the scrotum in young adults.

REFERENCES

1. Mostofi FK, Davis J, Rehm S. Tumors of the testis. IARC Sci Publ. 1994; 111:407-428. 2. Albino G, Nenna R, Inchingolo CD, Marucco EC. Hydrocele with

surprise. Case report and review of literature. Arch Ital Urol Androl. 2010; 82:287-90. 3. Patil V, Shetty SM, Das S. Common and uncommon presentation of fluid within the scrotal spaces. Ultrasound Int Open. 2015; 1:E34-40. 4. Smith ZL, Werntz RP, Eggener SE. Testicular cancer: epidemiology, diagnosis, and management. Med Clin North Am. 2018; 102:251-264. 5. Valentino M, Bertolotto M, Ruggirello M, et al. Cystic lesions and scrotal fluid collections in adults: ultrasound findings. J Ultrasound. 2011; 14:208-15. 6. Tsili AC, Bertolotto M, Rocher L, et al. Sonographically indeterminate scrotal masses: how MRI helps in characterization. Diagn Interv Radiol. 2018; 24:225-236. 7. Parenti GC, Feletti F, Carnevale A, et al. Imaging of the scrotum: beyond sonography. Insights Imaging. 2018; 9:137-148. 8. Harvey J, Noon AP, Beck S, Cutinha P. Epidermoid cyst of the testis misdiagnosed as a hydrocele: a case report. J Med Cases. 2010; 1:6-7. 9. Iqbal SA, Usmani F, Shamim M. Testicular carcinoma misdiagnosed as hydrocele: lesson to learn Pak J Med Sci. 2007; 23:950-952. 10. Kim YW, Kim JW, Kim JH, et al. Metastatic testicular tumor presenting as a scrotal hydrocele: An initial manifestation of pancreatic adenocarcinoma. Oncol Lett. 2014; 7:1793-1795. 11. Lin HC, Clark JY. Testicular teratoma presenting as a transilluminating scrotal mass. Urology. 2006; 67:1290.e3-5. 12. Vallonthaiel AG, Kakkar A, Singh A, et al. Adult granulosa cell tumor of the testis masquerading as hydrocele. Int Braz J Urol. 2015; 41:1226-31. 13. Trenti E, Palermo SM, D'Elia C,et al. Malignant mesothelioma of tunica vaginalis testis: Report of a very rare case with review of the literature. Arch Ital Urol Androl. 2018; 90:212-214. 14. Metcalfe MJ, Spouge RJ, Spouge DJ, Hoag CC. The use of TPA in combination with alcohol in the treatment of the recurrent complex hydrocele. Can Urol Assoc J. 2014; 8:E445-8. 15. Dieckmann KP. Diagnostic delay in testicular cancer: an analytic chimaera or a worthy goal? Eur Urol. 2007; 52:1566-8.

Correspondence Evangelos N. Symeonidis, MD evansimeonidis@gmail.com Petros Sountoulides, MD 1st Department of Urology, Aristotle University of Thessaloniki, “G. Gennimatas” General Hospital, Thessaloniki (Greece) Ethnikis Aminis 41, 54635 Thessaloniki (Greece) Irene Asouhidou, MD Department of Anatomy and Surgical Anatomy, Aristotle University of Thessaloniki, Thessaloniki (Greece) Chrysovalantis Gkekas, MD Asterios Symeonidis, MD Christos Georgiadis, MD Apostolos Malioris, MD Michail Papathanasiou, MD Department of Urology, 424 General Military Hospital of Thessaloniki, Thessaloniki (Greece) Ioannis Tsifountoudis, MD Department of Radiology, 424 General Military Hospital of Thessaloniki, Thessaloniki (Greece) Ioanna Tsantila, MD Department of Pathology, 424 General Military Hospital of Thessaloniki, Thessaloniki (Greece)

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DOI: 10.4081/aiua.2020.1.64

CASE REPORT

Case reports of benign intrascrotal tumors: Two epidermoid cysts and one scrotal calcinosis Tuncay Toprak 1, Cagri Akin Sekerci 2 1 Department 2 Marmara

of Urology, Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Turkey; University Pendik Training and Research Hospital, Pediatric Urology, Istanbul, Turkey.

Summary

Background: The aim this study was to explain the underlying etiology of unknown

scrotal masses. Case presentation: This study included 3 patients with a intrascrotal mass. One patient was over 50 years. The remaining patients were between the ages of 30-50. Patients had no serious complaints (two complained about having 3 testicles and one complained of swelling in the scrotum for the last 6 months). All patients underwent scrotal exploration under general anesthesia and the specimen was sent for pathological examination. All masses were mobile and encapsulated. The masses were not associated with the testicle. Two cases had classical histologic features of epidermoid cyst and one had scrotal calcinosis in the pathological report. Physical examination, operation, magnetic resonance and histological images of scrotal masses were shown in the figures. Conclusions: This study is important in terms of showing the underlying etiology of the rare scrotal masses.

KEY WORDS: Intrascrotal; Epidermoid cyst; Calcinosis cutis. Submitted 29 November 2019; Accepted 30 December 2019

INTRODUCTION

Epidermoid cysts (ECs), also known as sebaceous cysts, are most common encapsulated cysts and usually these cysts have no potential for malignancy (1). The cyst filled with keratin and inflammatory reaction develops due to the outflow of keratin, and many practitioners mistakenly diagnose abscesses and prescribe antibiotics. Although it is known as benign, it has been reported that approximately 1% of these cysts may develop into squamous or basal cell carcinoma. ECs may be found in autosomal dominant Gardner and Gorlin syndrome but most cases are seen as sporadic (2). Scrotal calcinosis (SC), another benign lesion in the scrotum, is a rare disease characterized by multiple papules or calcification nodules in scrotal skin (3). In this study we discussed two cases of epidermoid cysts and one scrotal calcinosis. This study showed the etiology of the rare intrascrotal masses and contributing to the literature about the diagnosis, follow-up and treatment of these masses.

CASE

REPORTS

tal mass between 2018-2019. The laboratory data and tumor markers of all patients were within normal limits in this study. Two was complaining about having 3 testicles and one was complaining of swelling in the scrotum for the last 6 months. The patients were 60, 40, and 35 years old, respectively. All patients had no history of comorbidity, drug use or history of operation. All masses on the physical examination were mobile and well limited. Two on the right side and one on the left side. All patients underwent scrotal exploration under general anesthesia. The masses were not associated with the testicle. During the operation, the adherent skin was dissected and the skin was separated from the mass in two patients. The specimen was sent for pathological examination. Two of the patients had pathological results of EC and one had calcinosis cutis. Pathological images of patients were presented in Figures 3, 4 and 5. Figure 1 shows preoperative, intraoperative and postoperative images of a intrascrotal mass which is later diagnosed histologically with EC. Figure 2 shows preoperative T1, T2 and diffusion-weighted magnetic resonance (MR) images of EC separated from the testis. Following resection of the intrascrotal mass two patients had no recur-

Figure 1. Preoperative (left), intraoperative (right) and postoperative (below) images of the epidermoid cyst.

Written informed consent was obtained from patients for the publication of this case reports. This study included 3 patients who underwent surgery due to the intrascro-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2020; 92, 1

Toprak2_Stesura Seveso 14/04/20 13:59 Pagina 65

Rare intrascrotal masses

Figure 2. T1 (left), T2 (right) and diffusion-weighted MR images of the epidermoid cyst.

Figure 4. Epidermoid cyst; surrounded with stratified squamous epithelium. H & E x40 (left figure). Ruptured area, granulomatous reaction is observed under the multilayer squamous epithelium (right figure).

Figure 5. Calcinosis cutis; the epidermis on the surface is regular. Granular calcified material is surrounded by fibrosis in the dermis H & Ex40 (left figure). Granular calcified material is observed in the dermis and fibroblastic proliferation is observed around it H & Ex100 (right figure).

Figure 3. Epidermoid cyst; surrounded with stratified squamous epithelium. Lamellar keratinous material is observed in the lumen. H & Ex40 (left figure). Granular layer in stratified squamous epithelium. Lamellated keratinous material is observed on the surface of the epithelium. H & Ex400 (right figure).

rence up to 8 months and one patient had no recurrence up to 5 months and no complication was observed.

DISCUSSION

ECs are epithelial cysts and are generally known as nonmalignant (1). In general, these cysts are caused by the occlusion of the follicular orifice. In addition, ECs may occur after traumatic or penetrating injuries leading to epithelial implantation (4).These cysts are composed of a sac surrounded by a stratified squamous epithelium filled with debris, keratin and cholesterol crystals (5). A granular layer is present that is filled with keratohyalin granules (Figure 3). The EC may be associated with the testicle in the scrotum or may be completely separate. In T2-weighted magnetic resonance imaging (MRI), these cysts are observed as high-density, well-limited solid masses surrounded by a low-signal capsule (6). The patients in the study showed the same MRI findings.

Due to the suspicion of testicular cancer, the preoperative diagnosis of an EC is very difficult. Complete surgical excision with the cyst wall is considered the the most effective treatment for an EC. Generally, cysts are asymptomatic but when rupture as in one patient in the study, an inflammatory reaction occurs because of the displacement of the keratin into the dermis and surrounding tissue (Figure 4). The evalution is largely based on history and physical examination. Physical examination usually shows a non-fluctuant, compressible mass between 0.5 cm and several centimeters. Although laboratory examination is not necessary, it can be recommended to take tumor markers when there is a suspicion of testicular cancer. Scrotal MRI was performed in the first few patients. However, it was concluded that it did not benefit much. Calcinosis cutis, another intrascrotal mass in the study, was characterized by multiple papules or calcification nodules on the scrotal skin, but in our patient this was larger than normal SC nodules and was a single lesion in the scrotum. The pathology showed classical histologic features of SC with a granular calcified material in the dermis and fibroblastic proliferation around it (Figure 5). It could be traced to originate from calcification of epidermal cyst or hair follicular and then the epithelial elements disappeared, leaving behind residual areas of calcification.

CONCLUSIONS

This study is valuable in terms of showing the etiology of the rare intrascrotal masses and contributing to the literature about the diagnosis, follow-up and treatment of ECs. Archivio Italiano di Urologia e Andrologia 2020; 92, 1

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T. Toprak, C. Akin Sekerci

Acknowledgements: We would like to thank to Fatih Sultan Mehmet Hospital Pathology Department for providing histological images.

3. Tareen A, Ibrahim RM. Idiopathic scrotal calcinosisâ&#x20AC;&#x201C;A case report. Int J Surg Case Rep. 2018; 44:51-53.

REFERENCES

5. Shah KH, Maxted WC, Chun B. Epidermoid cysts of the testis: a report of three cases and an analysis of 141 cases from the world literature. Cancer. 1981; 47:577-582.

1. Prasad KK, R. Manjunath R Multiple epidermal cysts of scrotum. Indian J Med Res. 2014; 140:318. 2. Zito PM, Scharf R. Cyst, Epidermoid (Sebaceous Cyst), in StatPearls (Internet). 2019, StatPearls Publishing.

Correspondence Tuncay Toprak, MD (Corresonding Author) drtuncay55@hotmail.com Department of Urology, Fatih Sultan Mehmet Training and Research Hospital Anabilim DalÄą Atasehir, Istanbul (Turkey) Cagri Akin Sekerci, MD cagri_sekerci@hotmail.com Marmara University Pendik Training and Research Hospital, Pediatric Urology, Istanbul (Turkey)

Archivio Italiano di Urologia e Andrologia 2020; 92, 1

4. Karaci S, Kulaksiz D, Sekerci CA. A rare cause of clitoromegaly: epidermoid cyst. Arch Ital Urol Androl 2019: 91:137-8.

6. Cho JH, Chang JC, Park BH, et al.. Sonographic and MR imaging findings of testicular epidermoid cysts. AJR Am J Roentgenol. 2002; 178:743-8.

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ORIGINAL PAPERS 1

Time changes of renal dimensions and variations of glomerular filtration rate in chronic kidney disease patients Simone Brardi, Gabriele Cevenini

Influence of dietary energy intake on nephrolithiasis - A meta-analysis of observational studies Gianpaolo Perletti, Vittorio Magri, Pietro Manuel Ferraro, Emanuele Montanari, Alberto Trinchieri

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