Archivio Italiano di Urologia e Andrologia - Vol. 93 - n. 1 - 2021 by Edizioni Scripta Manent

ISSN 1124-3562

Vol. 93; n. 1, March 2021

ORIGINAL PAPERS 1

Bacillus Calmette-Guerin vaccine and bladder cancer incidence: Scoping literature review and preliminary analysis Sabrina Trigo, Kaitlin Gonzalez, Livio Di Matteo, Asmaa Ismail, Hazem Elmansy, Walid Shahrour, Owen Prowse, Ahmed Kotb

Acute kidney injury strongly influences renal function after radical nephroureterectomy for upper tract urothelial carcinoma: A single-centre experience Alessandro Tafuri, Katia Odorizzi, Giacomo Di Filippo, Clara Cerrato, Giulia Fassio, Emanuele Serafin, Alessandro Princiotta, Damiano D’Aietti, Alessandra Gozzo, Antonio B. Porcaro, Matteo Brunelli, Maria Angela Cerruto, Alessandro Antonelli

Age above 70 years and Charlson Comorbidity Index higher than 3 are associated with reduced survival probabilities after radical cystectomy for bladder cancer. Data from a contemporary series of 334 consecutive patients Massimo Maffezzini, Vincenzo Fontana, Andrea Pacchetti, Federico Dotta, Mattia Cerasuolo, Davide Chiappori, Giovanni Guano, Guglielmo Mantica, Carlo Terrone

[68Ga]Ga-PSMA-11 PET-CT: Local preliminary experience in prostate cancer biochemical recurrence patients João Carvalho, Pedro Nunes, Edgar Tavares da Silva, Rodolfo Silva, João Lima, Vasco Quaresma, Arnaldo Figueiredo

Rigid and flexible ureteroscopy (URS/RIRS) management of paediatric urolithiasis in a not endemic country Stefania Ferretti, Monica Cuschera, Davide Campobasso, Claudia Gatti, Riccardo Milandri, Tommaso Bocchialini, Elisa Simonetti, Pietro Granelli, Antonio Frattini, Umberto Vittorio Maestroni

Is there a PSA cut-off value indicating incidental prostate cancer in patients undergoing surgery for benign prostatic hyperplasia? Senol Tonyali, Cavit Ceylan, Erdogan Aglamis, Serkan Dogan, Sedat Tastemur, Mustafa Karaaslan

Maternal hydronephrosis in pregnant women without ureteral stones and characteristics of symptomatic cases who need treatment: A single-center prospective study with 1026 pregnant women

Zeki Bayraktar, ̧Serife Tuğba Kahraman, Elif Seçkin Alaç, I􏰀·rem Yengel, Deniz Sarıkaya Kalkan

Premature ejaculation patients and their partners: Arriving at a clinical profile for a real optimization of the treatment Paolo Verze, Roberto La Rocca, Lorenzo Spirito, Gianluigi Califano, Luca Venturino, Luigi Napolitano, Antonio Cardi, Davide Arcaniolo, Claudia Rosati, Alessandro Palmieri, Vincenzo Mirone

Effects of COVID-19 on male sex function and its potential sexual transmission Héctor Rodriguez Bustos, Gonzalo Bravo Maturana, Felipe Cortés-Chau, Joelle Defaur Torres, Felipe Cortés-Pino, Pablo Aguirre, Camilo Arriaza Onel

The woman and the penile prosthetic implant. Primary or secondary role? Personal experiences on 355 implanted patients Diego Pozza, Alberto Berardi, Mariangela Pozza, Augusto Mosca, Carlotta Pozza

Erectile dysfunction post radical cystectomy. The role of early rehabilitation with pharmacotherapy in nerve sparing and non-nerve sparing group: A randomized, clinical trial Mohamad Moussa, Athanasios G. Papatsoris, Mohamed Abou Chakra, Athanasios Dellis

CASE REPORTS 64

Retroperitoneal extension of massive ulcerated testicular seminoma through the inguinal canal: A case report Alessio Antonaci, Daniela Fasanella, Vikiela Galica, Nicola Tinari, Jamara Giampietro, Pietro Di Marino, Andrea Delli Pizzi, Raffaella Basilico, Luigi Schips, Michele Marchioni

Clear-cell renal cell carcinoma single thyroid metastasis: A single-center retrospective analysis and review of the literature Isabella Ricci, Francesco Barillaro, Enrico Conti, Donatella Intersimone, Paolo Dessanti, Carlo Aschele continued on page III

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Official Journal of SIEUN, UrOP, SSCU and GUN

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

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

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

In memoriam of Prof. Enrico Pisani (1931-2021) It is with great sadness and grief that we announce of the passing of Professor Enrico Pisani. He died in his native Milan on 1st February 2021. He graduated as a medical doctor in Milan and specialized in Urology in Florence under the guidance of Prof. Ulrico Bracci. He joined the Institute of Urology in Milan where he was the Head of the Urologic Clinic for a long period from 1984 to 2003. During the same period he was the Editor of Archivio Italiano di Urologia e Andrologia. After his retirement he was appointed Honorary Editor of the journal which he continued to follow with interest and passion. Professor Pisani’s demise is a great loss to Archivio Italiano di Urologia e Andrologia and the Italian urologic community. He will be sadly missed and fondly remembered from the Editors and Publisher of the journal whose scientific relevance and dissemination he has helped to grow. In grateful appreciation of his merits, we join colleagues worldwide in conveying our deepest condolences to his family, relatives and friends. Alberto Trinchieri Emanuele Montanari Editors Pietro Cazzola Scripta Manent

Archivio Italiano di Urologia e Andrologia 2021, 93, 1

CASE REPORTS 71

Oncology and complications Giuseppe Giordano, Evangelia Kyriazi, Charalampos Mavridis, Francesco Persico, Charalampos Fragkoulis, Piergiorgio Gatto, George Georgiadis, Irene Giagourta, Ioannis Glykas, Rodolfo Hurle, Massimo Lazzeri, Giovanni Lughezzani, Vincenzo Magnano San Lio, Charalampos Mamoulakis, Diego Meo, Helen A. Papadaki, George Piaditis, Charalampos Pontikoglou, Georgios Stathouros

Oncological cases and complications in Urology Massimiliano Bernabei, Antonia Di Domenico, Gil Falcao, Charalampos Fragkoulis, Andrea Benelli, Martina Beverini, Luís Campos Pinheiro, Cabrita Carneiro, Nicolò Fabbri, Ioannis Glykas, Salvatore Greco, Carlo Introini, Konstantinos Ntoumas, Georgios Papadopoulos, Mariangela Rutigliani, Panagiotis Stamatakos, João Vasco Barreira

LETTERS TO EDITOR 82

Movember in a pandemic - it matters, more than ever João Vasco Barreira, Gil Falcão, Mariana Amaral, Pedro Barreira

Clinical impact of combined PTEN and ERG rearrangements in localized prostate cancer Charalampos Fragkoulis, Ioannis Glykas, Athanasios Dellis, Konstantinos Ntoumas, Athanasios Papatsoris

Red man syndrome caused by intracavernous irrigation with vancomycin at the time of placing penile implants Mohamad Moussa, Mohamad Abou Chakra, Athanasios Papatsoris, Athanasios Dellis, Yasmine Moussa

ORIGINAL PAPERS, REVIEW & CASE REPORTS presented at the SIEUN Congress Ancona 30 November - 1 December 2020 88

MRI/US fusion prostate biopsy in men on active surveillance: Our experience Vito Lacetera, Angelo Antezza, Alessio Papaveri, Emanuele Cappa, Bernardino Cervelli, Giuliana Gabrielloni, Michele Montesi, Roberto Morcellini, Gianni Parri, Emilio Recanatini, Valerio Beatrici

Detection limits of significant prostate cancer using multiparametric MR and digital rectal examination in men with low serum PSA: Up-date of the Italian Society of Integrated Diagnostic in Urology Andrea B. Galosi, Erika Palagonia, Simone Scarcella, Alessia Cimadamore, Vito Lacetera, Rocco F. Delle Fave, Angelo Antezza, Lucio Dell’Atti

101 Robot-assisted segmental ureterectomy with psoas hitch ureteral reimplantation: Oncological, functional and perioperative outcomes of case series of a single centre Erika Palagonia, Simone Scarcella, Lucio Dell’Atti, Giulio Milanese, Peter Schatteman, Frederiek D’Hondt, Geert De Naeyer, Andrea Galosi, Alexandre Mottrie

107 Buccal mucosa graft in surgical management of Peyronie’s disease: Ultrasound features and clinical outcomes Andrea Fabiani, Fabrizio Fioretti, Maria Pia Pavia, Luca Lepri, Emanuele Principi, Lucilla Servi

111 Italian experiences in the management of andrological patients at the time of Coronavirus pandemic Carlo Maretti, Andrea Fabiani, Fulvio Colombo, Alessandro Franceschelli, Giorgio Gentile, Franco Palmisano, Valerio Vagnoni, Luigi Quaresima, Massimo Polito

115 COVID-19 and male fertility: Taking stock of one year after the outbreak began Rocco Francesco Delle Fave, Giordano Polisini, Gianluca Giglioni, Arnaldo Parlavecchio, Lucio Dell’Atti, Andrea Benedetto Galosi

120 Unusual clinical scenarios in Urology and Andrology Lucio Dell’Atti, Andrea Fabiani, Erika Palagonia, Agostini Edoardo, Maria Pia Pavia, Simone Scarcella, Valentina Maurelli, Emanuele Principi, Marco Tiroli, Giulio Milanese, Lucilla Servi, Andrea Benedetto Galosi

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GENERAL INFORMATION AIMS AND SCOPE “Archivio Italiano di Urologia e Andrologia” publishes papers dealing with the urological, nephrological and andrological sciences. Original articles on both clinical and research fields, reviews, editorials, case reports, abstracts from papers published elsewhere, book rewiews, congress proceedings can be published. Archivio Italiano di Urologia e Andrologia 2021, 93, 1

III

DOI: 10.4081/aiua.2021.1.1

ORIGINAL PAPER

Bacillus Calmette-Guerin vaccine and bladder cancer incidence: Scoping literature review and preliminary analysis Sabrina Trigo 1, Kaitlin Gonzalez 1, Livio Di Matteo 2, Asmaa Ismail 1, Hazem Elmansy 1, Walid Shahrour 1, Owen Prowse 1, Ahmed Kotb 1 1 Northern

Ontario School of Medicine, Thunder Bay, ON, Canada; of Economics, Lakehead University, Thunder Bay, ON, Canada.

2 Department

Summary

Background: The Bacillus Calmette-Guerin (BCG) vaccine has long been used for the prevention of tuberculosis (TB) around the world. BCG is also used as an immunotherapy agent for the treatment of non-muscle invasive urinary bladder cancer. This scoping literature review and preliminary data analysis aims to summarize the literature correlating infantile BCG vaccination with the incidence of future bladder cancer. Methods: Studies were identified by a formal literature search of MEDLINE and Cochrane Central Registrar of Controlled Trials following PRISMA guidelines. Preliminary data analysis was conducted on publicly accessible data summarizing the impact of gender, BCG vaccination, and socio-economic effects on crude and age-standardized rates of bladder cancer. Results: As part of our analysis, preliminary regression models demonstrated BCG vaccination status, gender, and socio-economic status to have statistically significant effects on crude and age-standardized rates of bladder cancer incidence. BCG vaccination was associated with a 35-37% lower age-standardized rate of bladder cancer incidence. Conclusions: There is very little literature examining the relationship between prior BCG vaccination and rates of bladder cancer incidence. Our limited data analysis indicates that a relationship does exist between infantile BCG vaccination and later bladder cancer development, although extensive future investigation is needed in this area.

KEY WORDS: BCG; Bladder cancer; BCG vaccine; Cancer prevention. Submitted 28 December 2020; Accepted 29 December 2020

INTRODUCTION

The Bacillus Calmette-Guerin (BCG) vaccine is a live attenuated strain of Mycobacterium bovis that has been used for the prevention of tuberculosis (TB) (1). As part of the World Health Organization Global Expanded Immunization Program, since the mid 1900’s, the BCG vaccine has remained as one of the most widely used vaccines around the world (2, 3). Implementation of this vaccine has resulted in significantly decreased rates of TB globally (2, 3). In most western countries, immunization campaigns in the early 20th century have led to near eradication of TB and thus discontinuation of BCG vaccination programs (46). Currently, select countries, primarily in South America

and East Asia continue to vaccinate against TB, while other countries rely on targeted vaccination of only high-risk groups (5-7). For more than thirty years; BCG material has also served as the standard intravesical immunotherapy agent in the treatment of non-muscle invasive urinary bladder cancer (NMIBC) following transurethral resection (TUR) (8, 9). This combined approach to NMIBC offers the most successful treatment for bladder cancer to date (8,10). In the past, the BCG vaccine was examined for its anti-cancer properties, which even until today are not well understood. However, it is speculated that BCG has anti-neoplastic properties through its ability to upregulate immunologic cytokine expression within the urinary bladder and induce a form of trained immunologic memory (11). Presently, urinary bladder neoplasms remain in the top 10 most common cancers around the world (12). Furthermore, incidence rates of bladder cancer have been increasing over the past twenty years, and the rates of bladder cancer are higher in first world countries (13). In these same countries, TB vaccination programs have ceased or target high-risk individuals, including immigrants from TB endemic areas and a select few indigenous populations living in highly crowded conditions (4-6). The role of BCG in the preventing recurrence of NMIBC when combined with TUR is well established and standard of care. However, it is presently unknown if the BCG vaccine given in early childhood actually serves as a protective mechanism for the development of bladder cancer in later life and whether or not increased rates of bladder cancer correlate with decreased BCG vaccination in various nations. This scoping literature review serves to summarize what is presently known of the connection between bladder cancer and BCG vaccination, and whether previous BCG immunization has any protective mechanisms for bladder cancer development in later life. Results from this review will inform future research endeavors in the area of urinary bladder cancer prevention.

METHODS

Rationale The rationale of this scoping literature review is to establish whether there is existing literature examining the link

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

S. Trigo, K. Gonzalez, L. Di Matteo, A. Ismail, H. Elmansy, W. Shahrour, O. Prowse, A. Kotb

between the BCG vaccine and rates of bladder cancer. We also aimed to summarize the impact of gender, BCG vaccination, and socio-economic effects on the crude and age-standardized rates of bladder cancer. The relationship between crude and age standardized rates of bladder cancer incidence versus the aforementioned variables and other confounders was examined to investigate if an inverse relationship between current bladder cancer incidence and current use of BCG vaccines is related. Retrieval of studies A comprehensive virtual literature search was conducted in MEDLINE and the Cochrane Central Registrar of Controlled Trials using PRISMA guidelines for scoping literature reviews. A protocol was created for this literature search but was not submitted for publication. This article is a review and consists solely of a literature search and analysis of publicly accessible information. It did not include patient data, thus was exempt from Research ethics board approval. The literature search was performed on September 6, 2020. The search was conducted for articles pertaining to the BCG vaccine and bladder cancer published in the English language. Search terms used included “bladder cancer” or “urinary bladder neoplasm” and “bcg vaccine” or “bcg” or “mycobacterium bovis”. Two Reviewers independently reviewed titles, abstracts, full articles, and reference lists of articles selected for full-text review. Decision to include an article at any stage of the review was made by consensus, if there was a discrepancy a third reviewer served as a tiebreaker. At each stage of review, all studies were carefully assessed for relevance. Inclusion and exclusion criteria In this analysis, we used the following inclusion criteria: (1) original research from randomized controlled trials, cohort studies, case-control studies, observational studies, or correlational studies; (2) patients vaccinated with BCG prior to bladder cancer diagnosis; (3) reported bladder cancer incidence or associated mortality. We did not consider review articles and guidelines or studies that included unvaccinated patients where the outcome of interest was not a bladder neoplasm. External data analysis Both linear and log-linear regression analysis was conducted using data obtained from the Cancer Incidence in Five Continents, Vol. 10, the BCG World Atlas, and the International Monetary Fund (IMF) World Economic Outlook Database to describe the impact of BCG vaccination on bladder cancer rates. Next, we obtained the age standardized and crude bladder cancer incidence rates for females and males from 70 countries between 2003 and 2007. Additional variables of interest were subsequently assigned to these countries, which included the following: If the country has current Bacillus-CalmetteGuerin (BCG) vaccination programs for TB (1 yes, 0 no); whether the national share of 1-year-olds vaccinated for BCG exceeded 80% (1 yes, 0 no); if the country never had a vaccination program or had or discontinued universal BCG vaccination (1 yes, 0 no); the national share of 1-year-olds immunized for BCG in both 1985 and 2015 (%); the median per capita Gross Domestic Product

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

(GDP) from 2003-07; the median unemployment rate from 2003-07; and, the median government spending to GDP (%) from 2003-07. If we accept that current rates of international BCG vaccination are an acceptable proxy for past levels, then the using country having current BCG vaccination for TB (1 yes, 0 no) and National Share of 1 Y Old’s Immunized (BCG) (WHO) in 2015 > 80% can be used as the TB vaccine variables. As well, we can also use another variable defined as Country Never Had or Discontinued Universal BCG (1 yes, 0 no). This variable may be better at picking up the lagged effects over time of TB vaccine use.

RESULTS

Literature search Our search resulted in 680 articles. Forty-two duplicates were identified and removed. Six hundred and thirtyeight articles underwent title screening. Subsequently, sixteen abstracts were reviewed, followed by 3 full-text articles and corresponding reference lists. Three articles were found to be of relevance to our work, however only one publication examined the relationship between BCG vaccination and bladder cancer. The identified study examined the relationship between childhood BCG vaccination and the subsequent development of lung cancer as the primary outcome of interest and bladder cancer as a secondary outcome. This article found BCG vaccination to not be associated with a decreased rate of bladder cancer (HR, 1.34; 95% CI, 0.22-8.03). The study demonstrated that the rate of lung cancer was significantly lower in those who received the BCG vaccine compared to those who had received the placebo (18.2 vs 45.4 cases per 100 000 person-years; hazard ratio, 0.38; 95% CI, 0.20-0.74; p = .005), controlling for sex, region, alcohol overuse, smoking, and tuberculosis. No other types of malignant neoplasms were significantly different between the 2 groups; notably, leukemia and lymphoma rates were similar in the BCG group vs placebo group (HR, 0.80; 95% CI, 0.35-1.82). Ten individuals had a second malignant neoplasm, including cancers of the skin, breast, uterus, ovary, and pancreas and leukemia. The study was a retrospective review of a clinical trial that had assigned participants to a vaccine group using systematic stratification of participants based on school age, district, and sex. The participants (n = 2963) were subsequently randomized by alternation. The original study occurred at 9 sites in 5 US states in between 1935 and 1998 and involved indigenous and Alaskan school children with no prior evidence of tuberculosis infection. One cohort received a single intradermal BCG injection and the other, a saline placebo. The outcome of interest was diagnosis of cancer following BCG vaccination. Data exploration Age standardized and crude bladder cancer incidence rates for males and females for 70 international geographic units for the period 2003-07 were obtained and additional variables assigned for these national units. These variables include: country has current bcg vaccination for tuberculosis (1 yes, 0 no), country never had or discontinued universal BCG (1 yes, 0 no), national share of 1 y

Bacillus Calmette-Guerin vaccine and bladder cancer incidence

olds immunized (BCG) (WHO) in 2015 > 80%, BCG immunization coverage among 1-year-olds (WHO 2017) (%) in 1985, BCG immunization coverage among 1-yearolds (WHO 2017) (%) in 2015, Median Per Capita GDP 2003-07, Median Unemployment Rate 2003-07 and Median Government Spending to GDP (%) 2003-07. Given that bladder cancer is primarily a disease of age and TB vaccination occurs early in life, one can hypothesis that any relationship between rates of vaccination and bladder cancer incidence is a lagged one with current bladder cancer incidence rates a function of rates of vaccination and coverage 30 to 50 years ago. On the other hand, current rates of vaccination may be a suitable proxy for past rates and useful as a determining variable. As well, for some of these variables, it was not possible to assign a value. Therefore, while the upper bound size of the dataset is 140 observations, some of the analysis would inevitably be restricted to dataset size of just over half the total number of observations. In any event, the analysis is exploratory and very preliminary. If we accept that current rates of international BCG vaccination are an acceptable proxy for past levels, then using country has current BCG vaccination for tuberculosis (1 yes, 0 no) and national share of 1 y olds immunized (BCG) (WHO) in 2015 > 80% can be used as the TB vaccine variables. We can look at the relationship between crude and age standardized rates of bladder cancer incidence versus these variables as well as other confounders to see if an inverse relationship between current bladder cancer incidence and current use of TB vaccine. As well, we can also use another variable defined as Country Never Had or Discontinued Universal BCG (1 yes, 0 no). This variable may be better at picking up the lagged effects over time of TB vaccine use. As well, a variable was generated called National Share of 1 y olds immunized (BCG) (WHO 2017) in 1985 > 50% (1 if > 50%, 0 if < 50% or country never had or discontinued universal BCG = 1). This exploratory analysis will be confined to those variables for which the most observations are available. In terms of results, locally weighted scatterplot smoothing (LOWESS) univariate plots of age standardized bladder cancer incidence versus whether there is current universal BCG vaccination [county has current BCG vaccination for tuberculosis (1 yes, 0 no)] is quite negative for males and slightly negative for females (Figure 1). Plots of the age-standardized incidence rates versus GDP appears to show a hump-shaped relationship for both males and females suggesting rising incidence as GDP rises and then a decline at higher levels of GDP (Figure 2). This can be interpreted as rising incidence during rising socio-economic status as captured by per capita GDP but then a leveling off and decline. However, these plots do not control for confounding factors. Regression analysis is conducted regressing both crude and age-standardized bladder cancer rates controlling for whether male or female incidence, GDP and GDP squared (to model the potential hump-shaped effect of the economic status variable) and BCG vaccination variables. The regressions are for linear and log-linear models. In the linear models for the determinants of both cruse and age standardized incidence, the first set uses current universal

Figure 1. Age standardized bladder cancer incidence rate (2003-07) versus percent of one year old getting BCG vaccination in 1985. A: Males (lowess asrw currentbcgvacc if males=1). Males that did not receive BCG vaccine had a higher incidence rate of bladder cancer.

B: Females (lowess asrw currentbcgvacc if males=0). Females that did not receive BCG vaccine had a slightly higher incidence rate of bladder cancer.

BCG vaccination [county has current BCG vaccination for tuberculosis (1 yes, 0 no)] while the second set uses never or past BCG vaccination [Country Never Had or Discontinued Universal BCG (1 yes, 0 no)] as the BCG variables. The third set uses whether the percent of 1 year olds vaccinated with BCG in 1985 was greater than 50% [national share of 1 y olds immunized (BCG) (WHO 2017) in 1985 > 50% (1 if > 50%, 0 if < 50% or country Figure 2. Age standardized bladder cancer incidence rate (2003-07) versus median per capita GDP (2003-07). A: Males (lowess asrw medpercapgdp2003 07 if males=1, bwidth 0.5). There was a rise in the incidence rate of bladder cancer with increasing income to a certail level, after which, the incidence rate was declining.

B: Females (lowess asrw medpercapgdp2003 07 if females=1, bwidth 0.5). There was a rise in the incidence rate of bladder cancer with increasing income to a certail level, after which, the incidence rate was declining.

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

S. Trigo, K. Gonzalez, L. Di Matteo, A. Ismail, H. Elmansy, W. Shahrour, O. Prowse, A. Kotb

never had or discontinued universal BCG = 1)]. The loglinear models are for the age-standardized rates only. They are of interest, because being log-linear, the coefficients can be interpreted as percentages and therefore allow for interpretation of magnitudes of the effects. In general, the models suggest that gender, BCG vaccinations and socio-economic effects have statistically significant effects on crude and age-standardized rates of bladder cancer incidence at the 5 and 10 percent level. The log-linear models suggest that all other things given, males have just over 4 times the rate of bladder cancer relative to females while the BCG vaccination variables are associated with a 35-37 percent lower age-standardized rate of bladder cancer incidence after controlling for both gender and GDP. When never having BCG or past BCG TB vaccinations is the included vaccination variable, the results show a 20 percent higher rate of bladder cancer incidence, but the effect is not statistically significant. Meanwhile, controlling for gender and BCG vaccination,

incidence rises and peaks at approximately $10,000 in per capita GDP (in PPP$) and then begins to decline. There does seem to be some relationship between rates of TB vaccine inoculation and longer-term bladder cancer incidence in the results from this data. These results are interesting but should be interpreted with extreme caution given the relatively small size of the data set as well as the single point in time nature of the data. These are only the 2003-07 incidence rates and the data set could be expanded to include the 2008-12 data. However, the ultimate limitation is the lack of fine granularity that would be provided by a much larger data set consisting of individuals over time – a time series microdata panel – with corresponding data on BCG vaccination and other individual level socio-economic characteristics. Whether such a data set exists or could be constructed would be interesting. Table 1 illustrate data retrieved from studies countries.

Table 1. Details of countries included in our analysis. A table illustrating all retrieved data is included as a supplementary material. COUNTRY MALES Algeria Argentina Australia Austria Bahrain Belarus Belgium Brazil Bulgaria Canada Chile China Columbia Costa Rica Croatia Cuba Cyprus Czech Rep Denmark Ecuador Egypt Estonia Finland France Germany Iceland India Iran Ireland Israel Italy Jamaica Japan Kuwait Latvia

Total Crude cases rate

ASR (W)

Current BCG vacc

Never or past BCG

Percent BCG 1 yr old 2015 > 80%

Percent BCG 1 yr old 1985

203 1238 12300 7271 77 4406 12617 3906 5237 24778 267 9172 451 486 3338 235 645 8094 6464 190 1231 763 3358 7627 24476 230 3381 133 2009 5033 35154 58 10877 87 1040

8.60 14.93 14.90 20.30 11.60 14.40 32.00 10.68 15.60 18.90 8.07 6.17 4.85 5.40 18.10 8.30 22.50 19.80 26.20 4.55 19.00 15.70 14.20 19.36 23.31 20.40 2.92 8.50 14.20 25.40 32.61 4.10 11.69 7.70 16.30

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

1 1 0 0

0 0 1 1

1 1 0 0

86 90

1 0 1 1 0 1 1 1 1 1 1 0 0 0 0 1 1 0 0 0 0 1 1 1 0 0 1 1 1 1

0 1 0 0 1 0 0 0 0 0 0 0 0 1 1 0 0 1 0 0

1 0 1 1 0 1 1 1 1 1 1 0 0 0 1 1 1 0 0 0 0 1 1 0 0 0 1 1 1 1

5.60 15.75 21.38 36.40 6.60 19.30 61.50 7.38 27.90 31.00 7.17 8.37 4.50 4.50 31.20 14.30 34.30 32.40 48.20 3.65 12.30 24.60 26.10 36.80 47.88 30.50 2.10 5.40 19.40 30.60 68.32 3.70 26.78 3.60 24.70

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

0 0 0 1 1 0 0 0 0

63 99 96 64 76 82 98

80 99 80 90 83 82

8 79 80 68 51 85

Percent BCG Percent BCG MedPer 1 yr old 1 yr old Cap GDP 1985 > 50% 2015 2003-07 1 1 0 1

99 99

0 0 1 1 0 1 1 1 1 0 1 0 0 1 1 1 1 1 1 0 0 0 1 1 1 0 1 1 0 0

97 99 97 93 99 90 83 98 99 98 88 96 95

87 99 77

99 84 99 94

Med unemployment rate 2003-07

MedG/GDP 2003-07

12495.6 15741.187 40460.543 41363.055 43218.759 11173.37 39592.405 12424.455 13086.906 40588.876 16958.13 5669.225 9286.189 11110.728 19252.067

15.265 11.575 5.042 5.225 5.6 1.704 8.267 11.5 10.177 6.758 9.3 4.2 12.042 6.495 17.583

30.765 24.426 34.681 50.378 24.923 46.515 48.933 39.239 34.301 38.662 20.137 18.074 28.103 16.658 46.815

35179.581 25577.306 43342.624 8616.508 9132.877 22409.357 38798.265 37551.869 38597.366 41633.012 3258.168 16089.323 48034.889 26340.356 37066.895 8549.17 35664.003 71142.748 17601.947

4.55 7.77 4.8 7.095 10.917 8.031 8.475 8.825 10.042 2.875

39.127 42.273 51.242 21.213 30.638 33.771 48.331 52.985 46.791 41.303 26.659 19.848 33.343 43.685 47.144 31.349 34.598 31.914 33.478

11.3 4.775 11.2 7.692 11.225 4.425 1.37 10.05

Bacillus Calmette-Guerin vaccine and bladder cancer incidence

Libya Lithuania Malawi Malaysia Malta New Zealand Norway Phillipines Poland Portugal Qatar Korea Russia Saudi Arabia Serbia Singapore Slovakia Slovenia South Africa Spain Sweden Switzerland Thailand Netherlands Tunisia Turkey Uganda UK (England) UK, Northern Ireland UK, Scotland UK, Wales Ukraine Uruguay USA Zimbabwe

174 1930 139 313 390 1617 4467 622 4843 174 19 11962 1745 266 3997 680 2810 1457 12 16120 8256 4108 1388 1243 883 3607 31 46707 1250 5271 3103 21497 1103 60100 75

7.30 24.20 5.90 5.45 38.90 16.00 38.90 2.05 29.40 29.00 3.80 9.80 17.00 2.70 30.30 7.90 21.50 29.60 0.50 61.37 36.80 38.77 5.07 48.00 12.00 23.58 0.70 37.70 29.60 42.90 43.10 19.80 23.00 29.50 2.60

14.90 16.30 13.30 7.18 23.90 9.90 21.40 4.45 20.00 21.70 7.60 9.60 11.70 5.60 16.20 7.10 16.30 18.10 0.70 33.52 17.50 20.38 4.90 28.70 12.90 22.43 2.60 19.60 18.30 22.50 20.50 13.40 15.80 20.80 9.40

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

1 1 1 1 1 0 0 1 1 1 1 1 1 1 1 1 0 0 1 0 0 0 1 0 1 1 1 0 0 0 0 1 1 0 1

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 0 1 0 0 0 1 1 1 1 0 0 1 0

1 1 1 1 0 0 0 0 1 0 1 1 1 1 1 1 0 0 0 0 0 0 1 0 1 1 1 0 0 0 0 0 1 0 1

FEMALES Algeria Argentina Australia Austria Bahrain Belarus Belgium Brazil Bulgaria Canada Chile China Columbia Costa Rica Croatia Cuba Cyprus Czech Rep Denmark Ecuador Egypt Estonia Finland France

6 5 1204 49 0 310 73 159 260 395 1 78 14 1 133 11 4 153 87 5 16 32 161 88

0.20 0.15 1.87 0.20 0.00 1.20 0.30 0.37 1.30 0.50 0.03 0.09 0.10 0.00 1.20 0.70 0.20 0.60 0.60 0.10 0.20 0.90 1.20 0.46

0.20 0.23 1.05 0.10 0.00 0.50 0.10 0.45 0.50 0.20 0.03 0.07 0.08 0.00 0.50 0.50 0.10 0.20 0.30 0.10 0.30 0.30 0.40 0.18

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

1 1 0 0

0 0 1 1

1 1 0 0

1 0 1 1 0 1 1 1 1 1 1 0 0 0 0 1 1 0 0

0 1 0 0 1 0 0 0 0 0 0 0 0 1 1 0 0 1 0

1 0 1 1 0 1 1 1 1 1 1 0 0 0 1 1 1 0 0

87 87 95 65

76 95 82 76 47 89 93 93 70 16 80 90 76 37

92 76

86 90 90

63 99 96 64 76 82 98

80 99 80 90 83 82

1 0 1 1 1 0 0 1 1 1 1 0 0 1 0 1 0 1 1 0 0 0 1 0 1 1 0 0 0 0 0 0 1 0 1

99 97 90 99

80 94 32 97 98 96 98 98 99 90 69 24 99 97 95 93 75 75 75 75 39 98 90

1 1 0 1

99 99

0 0 1 1 0 1 1 1 1 0 1 0 0 1 1 1 1 1 1

97 99 97 93 99 90 83 98 99 98 88 96 95

36946.588 18443.757 802.359 18241.829 27147.829 30803.692 63455.303 4835.821 16982.21 26384.19 124151.906 26340.46 19374.661 45699.25 11017.344 62638.987 19940.36 26804.884 10999.622 33299.088 41206.175 51299.143 11772.887 44098.7 8802.959 15744.75 1559.811 37585.365 37585.365 37585.365 37585.365 7300.773 12872.245 49412.962 2065.22

8.324 3.55 6.942 3.875 4.471 11.35 17.745 7.582 3.55 7.15 5.822 19.53 3.125 16.358 6.342 24.65 9.153 7.042 3.691 1.858 5.014 12.819 9.488 5 5 5 5 7.185 12.142 5.083

33.699 33.424 26.394 25.884 42.322 37.066 41.485 19.532 44.395 45.31 28.727 19.202 29.598 29.453 41.9 12.379 38.762 41.814 27.175 38.315 51.302 32.896 19.331 42.135 24.166 34.31 18.776 37.943 37.943 37.943 37.943 43.658 29.186 33.931 8.542

12495.6 15741.187 40460.543 41363.055 43218.759 11173.37 39592.405 12424.455 13086.906 40588.876 16958.13 5669.225 9286.189 11110.728 19252.067

15.265 11.575 5.042 5.225 5.6 1.704 8.267 11.5 10.177 6.758 9.3 4.2 12.042 6.495 17.583

30.765 24.426 34.681 50.378 24.923 46.515 48.933 39.239 34.301 38.662 20.137 18.074 28.103 16.658 46.815

35179.581 25577.306 43342.624 8616.508 9132.877 22409.357 38798.265 37551.869

4.55 7.77 4.8 7.095 10.917 8.031 8.475 8.825

39.127 42.273 51.242 21.213 30.638 33.771 48.331 52.985

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

S. Trigo, K. Gonzalez, L. Di Matteo, A. Ismail, H. Elmansy, W. Shahrour, O. Prowse, A. Kotb

Germany 181 Iceland 2 India 186 Iran 5 Ireland 19 Israel 32 Italy 216 Jamaica 1 Japan 47 Kuwait 2 Latvia 26 Libya 1 Lithuania 91 Malawi 3 Malaysia 4 Malta 2 New Zealand 47 Norway 139 Phillipines 8 Poland 106 Portugal 8 Qatar 0 Korea 64 Russia 41 Saudi Arabia 4 Serbia 195 Singapore 4 Slovakia 100 Slovenia 51 South Africa 0 Spain 242 Sweden 286 Switzerland 28 Thailand 163 Netherlands 325 Tunisia 5 Turkey 49 Uganda 0 UK (England) 371 UK, Northern Ireland 17 UK, Scotland 60 UK, Wales 26 Ukraine 1871 Uruguay 10 USA 702 Zimbabwe 0

0.40 0.30 0.18 0.20 0.20 0.20 0.43 0.10 0.11 0.10 0.50 0.00 1.00 0.10 0.08 0.20 0.40 1.20 0.00 0.55 1.30 0.00 0.10 0.30 0.00 1.40 0.00 0.70 1.00 0.00 0.88 1.30 0.21 0.72 0.80 0.10 0.33 0.00 0.30 0.40 0.50 0.30 1.50 0.20 0.30 0.00

0.13 0.10 0.21 0.20 0.10 0.10 0.13 0.00 0.01 0.20 0.20 0.10 0.40 0.20 0.05 0.10 0.30 0.50 0.05 0.25 0.50 0.00 0.00 0.10 0.10 0.70 0.00 0.30 0.40 0.00 0.35 0.50 0.11 0.63 0.40 0.10 0.25 0.00 0.10 0.20 0.20 0.20 0.60 0.10 0.20 0.00

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

0 0 1 1 1 0 0 1 1 1 1 1 1 1 1 1 0 0 1 1 1 1 1 1 1 1 1 0 0 1 0 0 0 1 0 1 1 1 0 0 0 0 1 1 0 1

DISCUSSION

0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 0 1 0 0 0 1 1 1 1 0 0 1 0

0 0 1 1 0 0 0 1 1 1 1 1 1 1 1 0 0 0 0 1 0 1 1 1 1 1 1 0 0 0 0 0 0 1 0 1 1 1 0 0 0 0 0 1 0 1

There was one study we identified in our scoping literature review that discussed the relationship between childhood BCG vaccination and subsequent development of lung cancer and secondarily, bladder cancer development. The study occurred at 9 sites in 5 American states between 1935 and 1998 and involved Indigenous schoolchildren with no prior evidence of TB infection. One cohort received a single intradermal BCG injection and the other a saline placebo. BCG vaccination was found not to be associated with a decreased rate of bladder cancer. The authors, however, noted significant limitations to their findings given their

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

Ó 8 79 80 68 51 85

87 87 95 65

76 95 82 76 47 89 93 93 70 16 80 90 76 37

92 76

0 0 0 1 1 1 0 1 1 0 0 1 0 1 1 1 0 0 1 1 1 1 0 0 1 0 1 0 1 1 0 0 0 1 0 1 1 0 0 0 0 0 0 1 0 1

87 99 77

99 84 99 94 99 97 90 99

80 94 32 97 98 96 98 98 99 90 69 24 99 97 95 93 75 75 75 75 39 98 90

38597.366 41633.012 3258.168 16089.323 48034.889 26340.356 37066.895 8549.17 35664.003 71142.748 17601.947 36946.588 18443.757 802.359 18241.829 27147.829 30803.692 63455.303 4835.821 16982.21 26384.19 124151.906 26340.46 19374.661 45699.25 11017.344 62638.987 19940.36 26804.884 10999.622 33299.088 41206.175 51299.143 11772.887 44098.7 8802.959 15744.75 1559.811 37585.365 37585.365 37585.365 37585.365 7300.773 12872.245 49412.962 2065.22

10.042 2.875 11.3 4.775 11.2 7.692 11.225 4.425 1.37 10.05 8.324 3.55 6.942 3.875 4.471 11.35 17.745 7.582 3.55 7.15 5.822 19.53 3.125 16.358 6.342 24.65 9.153 7.042 3.691 1.858 5.014 12.819 9.488 5 5 5 5 7.185 12.142 5.083

46.791 41.303 26.659 19.848 33.343 43.685 47.144 31.349 34.598 31.914 33.478 33.699 33.424 26.394 25.884 42.322 37.066 41.485 19.532 44.395 45.31 28.727 19.202 29.598 29.453 41.9 12.379 38.762 41.814 27.175 38.315 51.302 32.896 19.331 42.135 24.166 34.31 18.776 37.943 37.943 37.943 37.943 43.658 29.186 33.931 8.542

small sample size, and therefore this association may be masked (14). Findings of our literature search yielding 1 article was expected and indicate that additional studies are required in this area. In support of future studies examining the relationship between bladder cancer development and previous BCG vaccination, we performed a preliminary exploration of data, the results of which were discussed above. Racial variation of bladder cancer Bladder cancer is the 9th most common malignancy, with five hundred and fifty thousand new cases annually worldwide. Geographically, there is significant variation

Bacillus Calmette-Guerin vaccine and bladder cancer incidence

in the incidence of NMIBC. Asian countries are found to have the lowest incidence of bladder cancer, while North American and Western European countries have the highest rates. Pursuant to our previous discussion, Asian countries have universal BCG vaccination programs, while many western countries do not. The incidence of bladder cancer also tends to increase as GDP increases, before levelling off and declining at higher levels of GDP. There are also racial and ethnic variations in the incidence of bladder cancer where it is twice as likely to occur in white males compared to African American or Hispanic men (15). BCG vaccination worldwide In 2010, a database was compiled of immunization protocols; among the 180 countries with available data, 157 countries recommend universal BCG vaccination, while the remaining 23 countries have either stopped BCG vaccination due to a reduction in TB incidence, or never recommended mass BCG immunization and instead favored selective vaccination of “at risk” groups. The United States and Canada only recommended BCG immunization for high-risk groups and do not advocate for universal BCG vaccination. In contrast, other countries such as the United Kingdom had universal vaccination programs against TB. The M. tuberculosis genome was initially published in 1921, and since this time comparative genomic studies have demonstrated the evolution of BCG vaccine strains. In other words, there are genetic differences in the antigenic proteins utilized in different vaccines over the years, which may translate into variations in efficacy over time. In spite of these differences, we have observed a 35-37% lower age-standardized rate of bladder cancer incidence in countries that vaccinate with the BCG vaccine, even after controlling for both gender and GDP (17). Early childhood BCG vaccination and its anti-neoplastic effects Although the BCG vaccine is efficacious against childhood TB, its efficacy would be expected to diminish with time and provide variable protection in adulthood. Existing literature surrounding BCG immunization and leukemia gives some indication that long-lasting anti-neoplastic properties of the vaccine may exist, despite the waning immunity of the vaccine against TB. Specifically, these findings were summarized in a meta-analysis combining multiple studies. The aforementioned review indicated that early life-vaccination is associated with lower rates of childhood leukemia (17). Another study demonstrated a reduced incidence of lung adenocarcinoma and squamous cell cancer with infantile BCG vaccination (14). Limitations The findings presented in this scoping literature review and preliminary data exploration should be interpreted with extreme caution given the relatively small data set as well as data giving a sole snapshot of statistics. However, the ultimate limitation is the lack of fine granularity that would be provided by a much larger data set

consisting of individuals over time, such as with a time series microdata panel. A time series microdata panel, which would ideally have corresponding data on BCG vaccination and other individual level socio-economic characteristics and co-founding variables for bladder carcinogenesis such as smoking.

CONCLUSIONS

Bladder cancer remains one of the most common malignancies globally. Prior work suggests there may be a protective relationship between BCG vaccination and rates of certain cancers. This scoping literature review and preliminary data analysis provides a strong call for future work examining whether prior BCG vaccination correlates with a lower incidence of bladder cancer and whether this vaccine actually has a protective effect on the development of bladder malignancy.

REFERENCES 1. Raviglione MC, Snider DE, Kochi A. Global epidemiology of tuberculosis: Morbidity and mortality of a worldwide epidemic. JAMA. 1995; 273:220-226. 2. World Health Organization. Immunization, vaccines and biologicals: National programmes and systems. Retrieved (2020) from https://www.who.int/immunization/programmes_systems/en/#:~:text= The%20EPI%20launched%20at%20that,vaccine)%2C%20measles%2 0and%20poliomyelitis. 3. Keja K, Chan C, Hayden G, Henderson RH. Expanded programme on immunization. World Health Stat Q. 1988; 41:59-63. 4. World Health Organization. BCG vaccine: WHO position paper, February 2018-recommendations. Vaccine. 2018; 24:3408-3410. 5. Faust L, Schreiber Y, Bocking N. A systematic review of BCG vaccination policies among high-risk groups in low TB-burden countries: implications for vaccination strategy in Canadian indigenous communities. BMC Public Health. 2019; 19:1504. 6. World Health Organization. Expanded programme on immunization (EPI) factsheet 2019: South-East Asia region. 7. Gillini L, Cooreman E, Wood T, et al. Global practices in regard to implementation of preventive measures for leprosy. PLoS Negl Trop Dis. 2017; 11:e0005399. 8. Taylor J, Becher E, Steinberg G. Update on the guideline of guidelines: Non muscle-invasive bladder cancer. BJUI. 2020; 125:197-205. 9. Moss JT, Kadmon, D. BCG and the treatment of superficial bladder cancer. DICP. 1991; 25:1355-1367. 10. Chen S, Zhang N, Shao J, Wang X. Maintenance versus non-maintenance intravesical bacillus calmette-guerin installation for non-muscle invasive bladder cancer: A systematic review and meta-analysis of randomized clinical trials. Intl JOS. 2018; 52:248-257. 11. Van Puffelen JH, Keating ST, Oosterwijk E, et al. Trained immunity as a molecular mechanism for BCG immunotherapy in bladder cancer. Nature Rev Uro. 2020; 17:513-525. 12. World Cancer Research Fund. Worldwide cancer data: Global cancer statistics for the most common cancers. Retrieved 82018) from https://www.wcrf.org/dietandcancer/cancer-trends/worldwide-cancerdata. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

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13. Richters A, Aben KH, Kiemeney LA. The global burden of urinary bladder cancer: An update. World J Urol. 2020; 38:1895-1904

der?search=bladder%20cancer%20epidemiology&source=search_resu lt&selectedTitle=1~150&usage_type=default&display_rank=1#H4.

14. Usher NT, Chang S, Howard RS, et al. Association of BCG vaccination in childhood with subsequent cancer diagnoses: a 60-year follow-up of a clinical trial. JAMA Netw Open. 2019; 2:e1912014.

16. Zwerling A, Behr M, Brewer T, et al. The BCG World Atlas: A Database of Global BCG Vaccination Policies and Practises. Retrieved (2011) from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC306 2527/

15. Daneshmand, Siamak. Epidemiology and risk factors of urothelial (transitional cell) carcinoma of the bladder. Retrieved (2020) from: https://www-uptodate-com.proxy.lib.nosm.ca/contents/epidemiologyand-risk-factors-of-urothelial-transitional-cell-carcinoma-of-the-blad-

Correspondence Sabrina Trigo, MD - strigo@nosm.ca Kaitlin Gonzalez, MD - kquinlan@nosm.ca Asmaa Ismail, MD - asmaaismail0782@gmail.com Hazem Elmansy - hazemuro100@yahoo.com Walid Shahrour - walid.shahrour@gmail.com Owen Prowse - owenprowse@rogers.ca Ahmed Kotb, MD (Corresponding Author) drahmedfali@gmail.com Assistant Professor Urology Department, Northern Ontario School of Medicine, Thunder Bay Regional Health Science Centre 980 Oliver Rd, Thunder Bay, ON, Canada, P7B 6V4 Livio Di Matteo, PhD - ldimatte@lakeheadu.ca Department of Economics, Lakehead University, Thunder Bay, ON, Canada

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

17. Morra ME, Kien ND, Elmaraezy A, et al. Early vaccination protects against childhood leukemia: A systematic review and meta-analysis. Sci Rep. 2017; 7:15986.

DOI: 10.4081/aiua.2021.1.9

ORIGINAL PAPER

Acute kidney injury strongly influences renal function after radical nephroureterectomy for upper tract urothelial carcinoma: A single-centre experience Alessandro Tafuri 1, 2, Katia Odorizzi 1, Giacomo Di Filippo 1, 3, Clara Cerrato 1, Giulia Fassio 1, Emanuele Serafin 1, Alessandro Princiotta 1, Damiano D’Aietti 1, Alessandra Gozzo 1, Antonio B. Porcaro 1, Matteo Brunelli 4, Maria Angela Cerruto 1, Alessandro Antonelli 1 1 Department 2 Department

of Urology, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy; of Neuroscience, Imaging and Clinical Science, Physiology and Physiopathology division, “G. D’Annunzio” University,

Chieti, Italy;

3 Department

of General and Hepatobiliary Surgery, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy; 4 Department of Pathology, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy.

Summary

Objective: The aim of our study was to investigate frequency and predictors both of postoperative acute kidney injury (AKI) and renal function decline in a population of consecutive upper tract urothelial carcinoma (UTUC) patients who underwent radical nephroureterectomy (RNU). Materials and methods: Between October 2014 and February 2020, 93 patients underwent RNU at our Institution. After considered exclusion criteria, 89 patients were selected. Perioperative clinical factors were retrospectively collected. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) equation. We defined AKI as an increase in serum creatinine by ≥ 0.3 mg/dl or a 1.5-1.9-fold increase in serum creatinine from baseline to I post-operative day (POD). A significant renal function reduction was defined as an eGFR reduction of 40% from baseline at discharge and at last clinical evaluation. Frequency of AKI and eGFR decline was investigated. Association between perioperative clinical factors and AKI and eGFR reduction at discharged and last follow-up was studied using univariate and multivariate models. Results: AKI was detected at I POD in 45 patients. On multivariate analysis, pre-operative eGFR was an independent predictor of AKI (OR 1.03; p = 0.042). Further, AKI was found to be a significant predictor of eGFR reduction ≥ 40% at discharge at univariate analysis (OR 19.42; p = 0.005) and at multivariate analysis (OR 12.49; p = 0.02). In a multivariate logistic regression model post-operative AKI (OR 5.18; p = 0.033), lack of ipsilateral preoperative hydronephrosis (OR 0.17; p = 0.016), preoperative eGFR (OR 1.04; p = 0.047) and antiplatelet therapy (OR 5.14; p = 0.018) were found to be independent predictors of an eGFR reduction higher than 40% at last clinical evaluation made at a median of 15 (IQR 5-30) months. Conclusions: In our cohort, AKI was present in almost 50% of patients after RNU and it was a strong predictor of renal function decline after RNU.

KEY WORDS: Upper tract urothelial carcinoma; Radical nephroureterectomy; Acute kidney injury; Renal function reduction; Chronic kidney disease. Submitted 26 September 2020; Accepted 15 October 2020

INTRODUCTION

Urothelial carcinoma of the upper urinary tract (UTUC) is among the ten most common cancers, is more frequent in males and diagnosis is generally done in the sixth decade (1, 2). Established risk factors are exposure to tobacco, arsenic, and aristolochic acid, as well as alcohol consumption (3). Some genetic polymorphisms are also associated with an increased risk of UTUC or faster disease progression that introduces variability in the inter-individual susceptibility to the risk factors previously mentioned (4). The disease has high mortality, with more than 150.000 patients dying each year worldwide (1). Extirpative surgery with removal of kidney, entire ureter and bladder cuff – radical nephroureterectomy (RNU) – is the treatment of choice for non-metastatic high-risk UTUC. Conversely, low-risk cases (unifocal, < 2 cm, lowgrade and superficial cancers) are amenable of kidneysparing treatments providing equal survival outcomes but better preservation of renal function (4). Despite this recommendation, a relevant rate of low-risk cases still undergo RNU for several reasons, mainly concerns on clinical understaging or challenging anatomical locations with inherent risk of tumor spillage and complications (4). The issue of renal function impairment after RNU is generally postponed to the need for radicality, but UTUC patients are at high risk of chronic kidney disease (CKD) because of patient’s age and comorbidities, smoking exposure, potential impairment of contralateral kidney due to diagnostic procedures or bilateral UTUC. Indeed, despite adjuvant chemotherapy might prolong survival (5) and reduce the risk of disease recurrence in locallyadvanced UTUC (6), nearly only 50% of patients are still eligible for platinum-based protocols, due to post-operative renal failure (7, 8). Finally, it should be noted that CKD might determine worse mortality due to non-cancer but also cancer-related causes, as found in patients treated for renal cell carcinoma (RCC) (9-11). Thus, the identification of patients at risk of significant renal function decline may allow clinicians to better assess the opportunity of kidney-sparing rather than

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

A. Tafuri, K. Odorizzi, G. Di Filippo, et al.

extirpative surgery when feasible, to adopt appropriate protective strategies during the peri-operative period and to adequately schedule controls during the follow up. The aim of our study is to investigate the prevalence of AKI and CKD, as well as the degree of renal functional impairment, in a population of patients submitted to RNU, in order to identify the most significant predictors of these events.

MATERIALS

AND METHODS

Data were retrospectively collected in our Institutional Review Board (IRB) - approved UTUC dataset prospectively compiled since October 2014. At admission, each patient provided written informed consent for data collection and analysis. Between October 2014 and February 2020, 93 consecutive patients underwent RNU at our Institution as primary treatment for UTUC. Patients who underwent primary neo-adjuvant chemotherapy were not considered. For the purposes of the present study 4 patients with solitary kidney were excluded, leaving 89 patients, 10 of which previously submitted to radical cystectomy. In total 87 patients were submitted to open RNU and 2 to robot-assisted RNU. The following data were considered: gender, age at surgery, body mass index (BMI), performance status [American Society of Anesthesiologists (ASA) classification and Eastern Cooperative Oncology Group (ECOG) score], comorbidities (presence of coronary artery disease (CAD), pulmonary disease, hypertension, hyperlipidemia, diabetes mellitus), smoking exposure, hydronephrosis, operative time, blood loss, intraoperative transfusions, pathological TNM stage (8th edition) (12), grade, presence of tumor necrosis, surgical margins status, length of hospital stay. According to an internal protocol regulating postoperative management, estimated glomerular filtration rate [eGFR, calculated by the CKD-EPI equation (13)] and blood chemistry were collected in all cases on post-operative day (POD) 1, 3 and at discharge. Acute kidney injury was defined as an increase in serum creatinine with respect to baseline by ≥ 0.3 mg/dl or a 1.5-1.9-fold at I POD, according to the Acute Kidney Injury Network (AKIN) classification (14). According to previous reports, a renal function decline was considered significative when eGFR reduction got over 40% with respect to the baseline (15). Based on our internal protocol for low risk patients, follow-up controls were scheduled after 3 months from surgery performing cystoscopy and blood samples. If negative, subsequent cystoscopy and urinary cytology, abdominal ultrasound, and blood samples were scheduled 9 months later and then yearly, for 5 years. For high-risk patients, cystoscopy and urinary cytology at 3 months were performed. If negative, cystoscopy and cytology every 3 months for a period of 2 years, and every 6 months thereafter until five years, and then yearly were considered. Additionally, yearly computed tomography (CT) urography and chest CT was scheduled. However, many patients traveled to our tertiary center from far away only for surgery, and the follow-up controls were often performed elsewhere.

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

Table 1. Study population's characteristics (n = 89). Age at surgery, years Follow up, months Gender Side BMI Smoking status ASA score

Male Female Right Left No Yes Ex

ECOG score Preoperative Hydronephrosis CAD Hypertension Preoperative Hb, mg/dL Preoperative Albumin, mg/dL Preoperative Creatinine, mg/dL Preoperative eGFR, mL/min/1.73 m2 Preoperative CKD stage

Hb I POD, mg/dL Hb III POD, mg/dL eGFR I POD, mL/min/1.73 m2 eGFR III POD, mL/min/1.73 m2 Hyperlipidemia Diabetes Antiplatelet therapy Anticoagulant therapy Antidiabetic therapy Operation time, min Blood loss, mL Transfusions Intraoperative complications pT stage Grade Tumour necrosis Lymph node status Margin Status Length of stay, days eGFR at discharge, mL/min/1.73 m2 eGFR at last follow up, mL/min/1.73 m2 eGFR reduction I POD (%) eGFR reduction at III POD (%) eGFR reduction at discharge (%) eGFR reduction at last follow up (%) AKI I POD eGFR reduction at discharge, from baseline eGFR reduction at last follow up, from baseline

No Yes No Yes No Yes

≤2 >2 0 1 2

1 2 3 4 5

No Yes No Yes No Yes No Yes No Yes No Yes No Yes ≤1 >1 Low High No Yes pN0 pN+ pNx R0 R1

No Yes ≤ 39,9% > 40% ≤ 39,9% > 40%

N, % / Median [IQR] 71 [66-76] 15 [5-30] 61 (68.5%) 28 (31.5%) 43 (48.3%) 46 (51.7%) 25.6 [23.14-28] 24 (27%) 20 (22.5%) 45 (50.6%) 64 (71.9%) 25 (28.1%) 38 (42.7%) 39 (43.8%) 12 (13.5%) 38 (42.7%) 51 (57.3%) 77 (86.5%) 12 (13.5%) 39 (43.8%) 50 (56.2%) 13.4 [11.8-14.36] 38 [35.9-40.4] 1.1 [0.96-1.37] 58.39 [45.32-76.17] 9 (10.1%) 35 (39.3%) 38 (42.7%) 6 (6.7%) 1 (1.1%) 11.8 [10.5-12.9] 11.2 [10.3-12.6] 43.18 [33.49-52.99] 48.5 [36.63-57.23] 74 (83.1%) 15 (16.9%) 68 (76.4%) 21 (23.6%) 58 (65.2%) 31 (34.8%) 82 (92.1%) 7 (7.9%) 68 (76.4%) 21 (23.6%) 200 [178-252] 380 [250-600] 78 (87.6%) 11 (12.4%) 85 (95.5%) 4 (4.5%) 41 (46.1%) 48 (53.9%) 16 (18%) 73 (82%) 72 (83.7%) 14 (16.3%) 32 (36%) 16 (18%) 41 (46.1%) 83 (93.3%) 6 (6.7%) 10 [8-12] 51.16 [41.8-61.09] 48.45 [38.36-55.68] 25.14 [5.5-41.9] 17.7 [ -2.22-34.88] 8.57 [-7.42-32.53] 16.83 [-4.14-34.88] 44 (49.4%) 45 (50.6%) 74 (83.1%) 15 (16.9%) 69 (77.5%) 20 (22.5%)

AKI: Acute Kidney Injury; ASA: American Society of Anesthesiology; BMI: Body Mass Index; CAD: Coronary Artery Disease; CKD: Chronic Kidney Disease; ECOG: Eastern Cooperative Oncology Group; eGFR: estimated Glomerular Filtration Rate; Hb: Haemoglobin; POD: postoperative day.

RNU and renal function decline

Categorical variables were expressed as frequencies and relative percentages. Continuous variables were expressed as median and interquartile range. Patients were divided into two groups according to the presence of I POD AKI. Categorical variables were compared between groups using the 𝞆2 test. Continuous variables were tested between subgroups with the independent samples t-test or MannWhitney test after testing for normality of distributions using Shapiro-Wilk test, as appropriate. Univariate logistic regression was used to identify outcomes’ predictors, and Odds Ratios and 95% confidence intervals were calculated for each significant variable. Significant variables at univariate analysis were entered into a multivariate regression model to identify independent predictors. A p value < 0.05 was considered statistically significant. The analysis was carried out using SPSS software version 25.0 (SPSS Inc, Chicago, IL).

Table 2. Clinicopathological characteristics stratified according I POD AKI.

Age at surgery, years Follow up, months Gender Side BMI Smoking status ASA score

Male Female Right Left No Yes Ex

ECOG score Preoperative Hydronephrosis CAD Hypertension Preoperative Hb, mg/dL Preoperative Albumin, mg/dL Preoperative Creatinine, mg/dL Preoperative eGFR, mL/min/1.73 m2 Preoperative CKD stage

No Yes No Yes No Yes

1 2 3 4 5

RESULTS

Demographics, clinical, operative and pathological data of the entire population are summarized in Table 1. The median age of the cohort was 71 years (IQR 66-76), 61 were males, 28 females; median follow-up time was 15 months (IQR 5-30). Median preoperative Hb was 13.4 g/dL (IQR 11.8-14.36) and median baseline eGFR was 58.39 ml/min/1.73 m2 (IQR 45.32-76.17). 51 patients (57.3%) had preoperative ipsilateral hydronephrosis. Histology found pT1 or less in 41 patients (46.1%) and pT2 or higher in the other 48 (53.9%). Lymph node invasion in the pathological specimen was found in 16 (18%) cases. Post-operative median eGFR at 1, 3 POD and at discharge were 43.18 ml/min/1.73 m2 (IQR 33.49-52.99), 48.5 ml/min/1.73 m2 (IQR 36.63-57.23) and 51.16 ml/min/1.73 m2 (IQR 41.8-61.09) respectively. At the same timepoints, median relative eGFR reduction was equal to 25.14%, 17.7%, and 8.57%. At discharge and last available follow up eGFR reduction was > 40% from the baseline in 15 (16.9%) and 20 (22.5%) patients, respectively. Overall, 45 patients (50.6%) developed AKI after surgery. The clinicopathological characteristics of the two groups (AKI compared to non-AKI) are reported in Table 2. On univariate analysis AKI was found significantly related to preoperative Hb value (OR 1.44; p = 0.003), preoperative eGFR (OR 1.04; p = 0.002), preoperative creatinine serum level (OR 0.23, p = 0.018) and CKD stage < 2 (OR 0.29, p = 0.005).

≤2 >2 0 1 2

No Yes No Yes No Yes No Yes No Yes No Yes No Yes ≤1 >1 Low High No Yes pN0 pN+ pNx R0 R1

≤ 39,9% > 40% eGFR reduction at last follow up, from baseline ≤ 39,9% > 40%

Group 1 (No, n = 44) Group 1 (yes, n = 45) N (%); Median [IQR] N (%); Median [IQR] 71 [66-79] 72 [66-76] 16 [5-35] 15 [5-29] 26 (59.1%) 35 (77.8%) 18 (40.9%) 10 (22.2%) 14 (31.8%) 29 (64.4%) 30 (68.2%) 16 (35.6%) 25.63 [22.99-27.65] 25.6 [23.4-28.8] 12 (27.3%) 12 (26.7%) 8 (18.2%) 12 (26.7%) 24 (54.5%) 21 (46.7%) 29 (65.9%) 35 (77.8%) 15 (34.1%) 10 (22.2%) 18 (40.9%) 20 (44.4%) 22 (50%) 17 (37.8%) 4 (9.1%) 8 (17.8%) 15 (34.1%) 23 (51.1%) 29 (65.9%) 22 (48.9%) 41 (93.2%) 36 (80%) 3 (6.8%) 9 (20%) 22 (50%) 17 (37.8%) 22 (50%) 28 (62.2%) 12.65 [11.05-13.9] 13.9 [13-15.2] 37.7 [35.55-40.35] 38 [36.3-40.9] 1.21 [0.98-1.68] 1.05 [0.91-1.24] 51.34 [40.97-65.89] 69.37 [53.46-80.37] 3 (6.8%) 6 (13.3%) 12 (27.3%) 23 (51.1%) 23 (52.3%) 15 (33.3%) 5 (11.4%) 1 (2.2%) 1 (2.3%) 0 (0%) 11.6 [10.35-12.6] 12 [10.5-13.4] 11.45 [10.5-12.5] 10.9 [10.1-12.7] 51.13 [41.67-62] 38.44 [31.66-45.42] 51.01 [41.31-68.16] 45.42 [36.31-54.13] 36 (81.8%) 38 (84.4%) 8 (18.2%) 7 (15.6%) 32 (72.7%) 36 (80%) 12 (27.3%) 9 (20%) 33 (75%) 25 (55.6%) 11 (25%) 20 (44.4%) 40 (90.9%) 42 (93.3%) 4 (9.1%) 3 (6.7%) 32 (72.7%) 36 (80%) 12 (27.3%) 9 (20%) 200 [161-251] 200 [180-252] 400 [275-600] 365 [250-650] 39 (88.6%) 39 (86.7%) 5 (11.4%) 6 (13.3%) 44 (100%) 41 (91.1%) 0 (0%) 4 (8.9%) 15 (34.1%) 26 (57.8%) 29 (65.9%) 19 (42.2%) 7 (15.9%) 9 (20%) 37 (84.1%) 36 (80%) 35 (83.3%) 37 (84.1%) 7 (16.7%) 7 (15.9%) 17 (38.6%) 15 (33.3%) 9 (20.5%) 7 (15.6%) 18 (40.9%) 23 (51.1%) 38 (86.4%) 45 (100%) 6 (13.6%) 0 (0%) 10 [8-11] 10 [9-13] 53.7 [44.49-64.32] 46.98 [41.35-54.67] 50.43 [39.41-59.84] 46.98 [38.32-54.67] 5.44 [-7.94-12.75] 41.9 [35.50-48.89] -0.35 [-18.41-13.48] 34.83 [22.90-42.15] -3.16 [-16.63-4.68] 30.69 [10.66-43.09] -1.31 [-10.62-17] 33.17 [13.36-44.92] 43 (97.7%) 31 (68.9%) 1 (2.3%) 14 (31.1%) 41 (93.2%) 28 (62.2%) 3 (6.8%) 17 (37.8%)

p value 0.663 0.660 0.058 0.002 0.159 0.908 0.213 0.355 0.105 0.069 0.245 0.001 0.042 0.001 0.001 0.044

0.007 0.003 0.001 0.001 0.741 0.419 0.054 0.671 0.419 0.928 0.388 0.778 0.043 0.025 0.615 0.924 0.615 0.010 0.993 0.004 0.001 0.001 0.001 0.001 0.001 0.001 0.001

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On multivariate analysis, preoperative eGFR was the only independent predictor to the occurrence of AKI (OR 1.03; p = 0.042) (Table 3). On univariate analysis AKI (OR 19.42; p = 0.005), preoperative eGFR (OR 1.05; p = 0.004), preoperative Hb (OR 1.43; p = 0.036), the lack of ipsilateral hydronephrosis (OR 0.30; p = 0.047), III POD creatinine serum level (OR 3.00; p = 0.018), I POD Hb (OR 1.57, p = 0.019) were predictors of eGFR reduction > 40% at discharge. On multivariate analysis only AKI retained its significance (OR 12.49; p = 0.02) (Table 4). Among several factors predicting eGFR reduction > 40% at last follow-up on univariate analysis, AKI (OR 5.18, p = 0.033), preoperative eGFR (OR 1.04, p = 0.047), the lack of ipsilateral hydronephrosis (OR 0.17; p = 0.016), and antiplatelet therapy (OR 5.14; p = 0.018) were found significantly associated to the outcome also on multivariate analysis (Table 5). Table 3. Logistic regression analysis for I POD AKI predictors assessment.

Preoperative CKD stage Preoperative creatinine Preoperative eGFR Preoperative Hb

OR 0.285 0.234 1.038 1.441

Univariate 95% CI 0.12-0.68 0.07-0.78 1.01-1.06 1.13-1.83

p value 0.005 0.018 0.002 0.003

1.027 1.295

Multivariate 95% CI p value

1.00-1.05 0.99-1.68

0.042 0.051

AKI: Acute Kidney Injury; CKD: Chronic Kidney Disease; eGFR: estimated Glomerular Filtration Rate; Hb: Haemoglobin; POD: postoperative day.

Table 4. Logistic regression analysis for the assessment of eGFR reduction > 40% from baseline to discharge. Univariate OR 95% CI p value Preoperative Hb 1.43 1.02-2 0.036 Hb I POD 1.567 1.08-2.28 0.019 Preoperative eGFR 1.053 1.02-1.09 0.004 AKI I POD 19.419 2.42-155.54 0.005 Creatinine III POD 3.004 1.21-7.45 0.018 Preoperative hydronephrosis 0.304 0.09-0.98 0.047

OR 1.091

Multivariate 95% CI p value 0.76-1.57 0.636

1.036 0.99-1.08 12.491 1.48-105.40

0.108 0.02

0.519

0.344

0.13-2.02

AKI: Acute Kidney Injury; CKD: Chronic Kidney Disease; eGFR: estimated Glomerular Filtration Rate; Hb: Haemoglobin; POD: postoperative day.

Table 5. Logistic regression analysis for the assessment of eGFR reduction > 40% from baseline to the last follow-up. Univariate OR 95% CI p value Preoperative Hb 1.359 1.02-1.81 0.037 Hb I POD 1.598 1.13-2.26 0.008 Hb III POD 1.768 1.21-2.58 0.003 Preoperative eGFR 1.055 1.02-1.09 0.001 AKI I POD 8.298 2.22-31 0.002 Creatinine III POD 67.524 8.45-539.64 0.0001 Creatinine at discharge 72.359 9.87-530.65 0.0001 Preoperative hydronephrosis 0.167 0.05-0.52 0.002 Antiplatelet therapy 3.947 1.4-11.16 0.01

OR 1.085

Multivariate 95% CI p value 0.75-1.57 0.663

1.043 5.183

1-1.09 1.14-23.54

0.047 0.033

0.172 5.139

1.14-23.55 1.32-19.93

0.016 0.018

AKI: Acute Kidney Injury; CKD: Chronic Kidney Disease; eGFR: estimated Glomerular Filtration Rate; Hb: Haemoglobin; POD: postoperative day.

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

DISCUSSION

The present study shows that patients with UTUC candidate to RNU have baseline poor renal function, with median eGFR values close to 60 ml/min, and post-operatively suffer from further relevant decline given that an impairment exceeding 40% of baseline function was noted in 22.5% of cases at a median follow-up of 15 months. The factors associated with worse functional outcome were preoperative eGFR, lack of ipsilateral hydronephrosis, antiaggregating therapy and the presence of post-operative AKI, which represent the strongest predictor of CKD after RNU in the present cohort. Definitely these patients have major determinants of baseline impaired function and relevant risks to develop CKD, with inherent effects on non-cancer (11), but also cancer-related survival outcomes, firstly concerning the access to platinum-based chemotherapy regimens that showed significantly improved disease-free survival in locally advanced UTUC (6). Although renal function preservation in UTUC represents a major issue it has been poorly investigated, with sparse reports in the literature. The main reason of this is that UTUC is often featured by aggressiveness and multifocality, so that extirpative treatment is commonly privileged, except for very selected low risk cases for whose kidney-sparing approaches might be preferred (16, 17). In 2006, Meyer et al. retrospectively analyzed 131 RNU patients reporting a 18% deterioration in eGFR after a median follow-up of 5 years. Such deterioration was found to be greater in patients with older age, and comorbidities as diabetes mellitus, hypertension, pre-existing renal impairment and analgesic nephropathy (18). In a multicentric retrospective study evaluating 388 patient who underwent RNU for UTUC, Kaag MG et al. showed a mean 24% of eGFR decrease after surgery. They also reported that eligibility to platinum-based chemotherapy decreased from 49% before surgery to 19% post-surgery using a cut-off of 60 mL/min/1.73 m2, and from 80% to 55% using a cut-off of 45 mL/min/1.73 m2 (19). Kaag M. and his group identified age and preoperative eGFR as a predictors of renal function decline after RNU (20). They retrospectively enrolled 374 RNU patients and assessed early (1-5 months) and late (> 5 months) eGFR after surgery: multivariable analysis identified preoperative eGFR lower than 60 mL/min/1.73 m2 and age > 70 years as preoperative predictors of clinically relevant eGFR loss after RNU, considering clinically relevant a loss of renal function compromising the possibility of chemotherapy recruitment. Shao et al. recently reported that among 242 RNU cases, 42.1% was eligible to cisplatin-based therapy prior to RNU whereas, following surgery, only 15.2% remained eligible, because of the worsening of renal function (8). In the present study, we also investigated the role of postoperative AKI, finding that a half of patients experienced this event. Interestingly, preoperative hemoglobin and preoperative eGFR predicted AKI, but only preoperative eGFR remained an independent predictor of AKI on multivariate analysis. The prevalence of AKI after RNU was previously unreported and resembles the data after radical nephrectomy for RCC (15). The most relevant finding of our analysis

RNU and renal function decline

is that AKI affects long-term renal function impairment, indicating that any effort should be done to prevent AKI, especially in patients at risk. Identification of such patients would allow to optimize the perioperative management in order to reduce the incidence of AKI after surgery and its consequences. A dedicated pre-, intra- and postoperative management with avoidance of potentially nephrotoxic agents, close monitoring of serum creatinine and urine output (remembering that urine output and serum creatinine are changing very late during the development of AKI), optimization of volume status and hemodynamic parameters and use of alternatives to radio contrast agents, represent the best AKI preventative measure to adopt in perioperative time (2123). Also, anesthesiologist may contribute to renal damage prevention avoiding the reduction of renal blood and renal hypoxia, and preventing hypotension during surgery (21). The median percentage eGFR reduction we sought was 8.6% at discharge, 16.8% at last follow-up after a median of 15 months from surgery. The rate of patients experiencing an eGFR decline ≥ 40% at last follow-up was 22.5%. The factors independently associated to this event were post-operative AKI, the lack of preoperative hydronephrosis, preoperative hemoglobin, and antiplatelet therapy. The interpretation of these findings is that already established contralateral hypertrophy due to hydronephrosis of the affected urinary tract, as well as better post-operative course, with less blood loss and without AKI, facilitate the compensatory role of the remnant solitary kidney. Additionally, antiplatelet drugs represent a risk factors for renal function impairing, especially after RNU. As we already mentioned, these patients should be properly managed pre-operatively and accurately followed after surgery. After nephrectomy UTUC patients showed larger eGFR reduction than those with parenchymal tumors, reasonably because the latter are generally younger and with less comorbidities. However, there are some intrinsic differences between these two conditions still to be investigated. Tae et al. indeed investigated by matched-pair comparison 554 patients who underwent nephrectomy for UTUC (n = 277) or parenchymal tumor (n = 277), balanced in terms of age, BMI, baseline eGFR and comorbidities. A significant larger decline in postoperative eGFR was found in UTUC cases (73.3% vs. 66.1%, p = 0.039) and multivariate analysis showed that the indication to nephrectomy due to UTUC (OR 1.84; p = 0.006) was an independent predictor of postoperative impaired renal function (24). Lee et al. showed similar findings in 616 patient who underwent nephrectomy for renal cancer (n = 319), or UTUC (n = 297), with the latter older and more comorbid. The authors reported that UTUC patients had an increased risk of serum creatinine doubling and need for dialysis after radical nephrectomy, and the predictor of these unfavorable outcomes were old age, diabetes, low baseline eGFR and indication to nephrectomy due to UTUC (25). Other tools have been proposed for identifying and monitoring patients at risk of renal failure. Brardi et al. investigated the role of doppler ultrasound derived renal resistive index (RRI) in a CKD population in the monitoring of renal function after a therapeutic and dietetic intervention to ameliorate the renal impairment.

The authors found that RRI was a key parameter in monitoring patients with CKD and a helpful tool to drive clinical efforts to contrast renal function decline (26). The same team recently found that variation in time of eGFR positively correlates to sonographic measurements of average right and left kidney diameters and percentage variations of right and left renal cortical thickness in a population of 80 adult patients with various degrees of chronic kidney disease after received of a therapeutic and dietetic intervention to improve renal function. Patients were not dialysis-dependent, they did not undergo renal surgery, nor they were affected by any of the pathological conditions that can increase kidney size (27). According to these pieces of evidence, renal ultrasound derived parameters together with clinical factors could represent a useful tool for evaluating patients before RNU and subsequent follow up. The present study is a retrospective evaluation of a small population. However, our results are innovative. We showed that AKI at I POD is a strong predictor of renal function decline in patients who underwent RNU for UTUC who might need an adjuvant platinum-based chemotherapy. Identifying patients at high-risk of renal function decline has a pivotal role to provide a correct peri-operative management. A tailored pre-operative management and surgical procedure should be provided to patients at high risk of developing AKI. Additionally, when UTUC patients are counseled before treatment, the risk of renal function decline should be extensively explained. Further higher-level studies are needed to confirm our results.

CONCLUSIONS

In our cohort, almost 50% of patients developed AKI after RNU. Acute kidney injury was a strong predictor of renal function decline after radical nephroureterectomy at discharged and a 15 months follow-up. Identifying patients at high-risk of renal function decline is essential to provide a correct peri-operative management.

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9. Antonelli A, Minervini A, Sandri M, et al. Below safety limits, every unit of glomerular filtration rate counts: assessing the relationship between renal function and cancer-specific mortality in renal cell carcinoma. Eur Urol. 2018; 74:661-667. 10. Antonelli A, Palumbo C, Sandri M, et al. Renal function impairment below safety limits correlates with cancer-specific mortality in localized renal cell carcinoma: results from a single-center study. Clin Genitourin Cancer. 2020; 18:e360-e367.

27. Brardi S, Cevenini G. Time changes of renal dimensions and variations of glomerular filtration rate in chronic kidney disease patients. Arch Ital Urol Androl. 2020; 92:21-24.

11. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. New Engl J Med. 2004; 351:1296-1305. 12. Brierley JD, Gospodarowicz MK, Wittekind C. TNM classification of malignant tumours. 2017: John Wiley & Sons. 13. Levey AS, Stevens LA, Schmid CH, et al., A new equation to estimate glomerular filtration rate. Ann Int Med. 2009; 150:604-612. 14. Bellomo R, Ronco C, Kellum JA, et al. Acute Dialysis Quality Initiative workgroup. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 8:R204-12. 15. Garofalo C, Liberti ME, Russo D, et al. Effect of post-nephrectomy acute kidney injury on renal outcome: a retrospective long-term study. World J Urol. 2018; 36:59-63. 16. Yakoubi R, Colin P, Seisen T, et al. Radical nephroureterectomy versus endoscopic procedures for the treatment of localised upper tract urothelial carcinoma: a meta-analysis and a systematic review of current evidence from comparative studies. Eur J Surg Oncol. 2014; 40:1629-34

23. Bell S, Prowle J. Postoperative AKI-Prevention Is better than cure? J Am Soc Nephrol. 2019; 30:4-6.

Alessandro Tafuri, MD aletaf@hotmail.it Katia Odorizzi, MD katia.odorizzi@virgilio.it Giacomo Di Filippo, MD giacomo.difilippo90@gmail.com Clara Cerrato, MD clara.cerrato01@gmail.com Giulia Fassio, MD fassio.giulia@gmail.com Emanuele Serafin, MD serafin.mnl@gmail.com Alessandro Princiotta, MD alessandroprinciotta0@gmail.com Damiano D’Aietti, MD damiano.daietti@gmail.com Alessandra Gozzo, MD la.ale.gozzo@gmail.com Antonio B. Porcaro, MD antoniobenito.porcaro@aovr.veneto.it Maria Angela Cerruto, MD mariaangela.cerruto@univr.it Alessandro Antonelli, MD (Corresponding Author) alessandro.antonelli@univr.it Department of Urology, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Piazzale Stefani 1, 37126, Verona (Italy)

24. Tae BS, Ku JH, Kwak C, et al. Comparison of renal function after radical surgery for upper tract urothelial carcinoma versus renal cell carcinoma: propensity score matching. Urologia Internationalis. 2018; 101:400-408.

Matteo Brunelli, MD matteo.brunelli@univr.it Department of Pathology, University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Verona (Italy)

17. Fang D, Seisen T, Yang K, et al. A systematic review and metaanalysis of oncological and renal function outcomes obtained after segmental ureterectomy versus radical nephroureterectomy for upper tract urothelial carcinoma. Eur J Surg Oncol. 2016; 42:16251635. 18. Meyer JP, Delves GH, Sullivan ME, et al. The effect of nephroureterectomy on glomerular filtration rate. BJU international. 2006; 98: 845-848. 19. Kaag MG, O'Malley RL, O'Malley P, et al. Changes in renal function following nephroureterectomy may affect the use of perioperative chemotherapy. Eur Urol. 2010; 58:581-587. 20. Kaag M,Trost L, Thompson RH, et al. Preoperative predictors of renal function decline after radical nephroureterectomy for upper tract urothelial carcinoma. BJU international. 2014; 114:674-679. 21. Zarbock A, Koyner JL, Hoste EAJ, et al. Update on perioperative acute kidney injury. Anesth Analg, 2018; 127:1236-1245. 22. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl. 2012; 2:1-138.

Correspondence

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

DOI: 10.4081/aiua.2021.1.15

ORIGINAL PAPER

Age above 70 years and Charlson Comorbidity Index higher than 3 are associated with reduced survival probabilities after radical cystectomy for bladder cancer. Data from a contemporary series of 334 consecutive patients Massimo Maffezzini 1, Vincenzo Fontana 2, Andrea Pacchetti 3, Federico Dotta 3, Mattia Cerasuolo 3, Davide Chiappori 3, Giovanni Guano 3, Guglielmo Mantica 3, Carlo Terrone 3 1 Department

of Urology, Ospedale Nuovo Legnano, Ospedale Fornaroli Magenta, Milano, Italy; Epidemiology Unit, IRCCS Policlinico San Martino, University of Genova, Genova, Italy; 3 Department of Urology, IRCCS Policlinico San Martino, University of Genova, Genova, Italy. 2 Clinical

Summary

Objective: To assess the joint effect of age and comorbidities on clinical outcomes of radical cystectomy (RC). Methods: 334 consecutive patients undergoing open RC for bladder cancer (BC) during the years 2005-2015 were analyzed. Pre-, peri- and post-operative parameters, including age at RC (ARC) and Charlson Comorbidity Index (CCI), were evaluated. Overall and cancer-specific survivals (OS, CSS) were assessed by univariate and multivariate modelling. Furthermore, a three-knot restricted cubic spline (RCS) was fitted to survival data to detect dependency between death-rate ratio (HR) and ARC. Results: Median follow-up time was 3.8 years (IQR = 1.3-7.5) while median OS was 5.9 years (95%CL = 3.8-9.1). Globally, 180 patients died in our cohort (53.8%), 112 of which (62.2%) from BC and 68 patients (37.8%) for unrelated causes. After adjusting for preoperative, pathological and perioperative parameters, patients with CCI > 3 showed significantly higher death rates (HR = 1.61; p = 0.022). The highest death rate was recorded in ARC = 71-76 years (HR = 2.25; p = 0.034). After fitting an RCS to both OS and CSS rates, two overlapping nonlinear trends, with common highest risk values included in ARC = 70-75 years, were observed. Conclusions: Age over 70 years and CCI > 3 were significant factors limiting the survival of RC and should both be considered when comparing current RC outcomes.

KEY WORDS: Radical cystectomy; Comorbidity; Age; Frail patient; Elderly. Submitted 12 November 2020; Accepted 7 December 2020

INTRODUCTION

Bladder cancer is one of the most common urological neoplasms and often requires multiple surgical treatment, as well as radical and invasive therapies (1-3). Surgery in the form of Radical Cystectomy (RC) represents the mainstay treatment for organ-confined and locally advanced muscle-invasive BC (MIBC). Reference studies of RC showed long-term survival rates around 60% and 40% at 5 and 10 years, respectively (4-6). Such

results published in the first years of this century were obtained in patients treated in a time period spanning from 1995 to 2003, with a median age of 65 to 67 years, and no mention with regards to the presence of co-morbidities is available. In recent years, however, global life expectancy has increased in both sexes causing an expansion of the elderly segment of the population. Ageing is one of the reason for increase in cancer incidence worldwide and, with regards specifically to BC, a 1.5-fold rise has been observed in subjects of 70 years of age and beyond (7). In the ageing population systemic diseases are concurrently diagnosed, namely, cardio-vascular, respiratory, metabolic, etc., therefore the need for chronic medications often represents the norm rather than the exception (8-9). The present study was aimed at documenting the association of advanced age together with the presence of co-morbidities on clinical outcomes of RC.

MATERIALS

AND METHODS

Study design and patient population The study population consisted of 334 patients submitted consecutively to RC from 01/01/2005 to 31/12/2015 at our tertiary care center and teaching institution, the University of Genova, Italy. All the charts were examined and data were extracted with regards to pre-, intra-, and post-operative parameters. Follow-up records and life status were retrieved from the internal follow-up database of our Institute, the Liguria Hospitalization Records, the Regional Mortality Registry, and the Genova Cancer Registry. Patients who received neo-adjuvant or adjuvant chemotherapy were excluded from analysis, whereas patients who received salvage (post-RC) chemotherapy and/or radiotherapy were included. Patients’ characteristics The recorded baseline patients’ characteristics were: age at RC (ARC), gender, full medical history, 12 channel Serum Multiple Analysis Compound (SMAC), physical examination, self-reported comorbidities and chronic

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

M. Maffezzini, V. Fontana, A. Pacchetti, F. Dotta, M. Cerasuolo, D. Chiappori, G. Guano, G. Mantica, C. Terrone

need for medications, ECG and cardiologic assessment, anesthesiology assessment and American Society of Anesthesiology (ASA) score, and clinical stage of disease. In addition, the Charlson comorbidity index (CCI) score was assigned based on the recorded data. Clinical staging was based on the pathology report of staging trans-urethral resection and by chest and abdomen CT scan. Additional tests (i.e. bone scans) were requested at the discretion of the treating physician.

TREATMENT

All patients underwent RC with bilateral pelvic lymphadenectomy with the standard technique (4; 5; 6). Briefly, in the male patient the bladder, prostate, and seminal vesicles, and in the female patient the bladder, uterus, ovaries and anterior wall of the vagina, were removed en bloc. Pelvic lymphadenectomy included all the tissue overlaying the major pelvic vessels from the crossing of the ureter over the iliac vessels proximally to the internal inguinal ring distally, and from the genito-femoral nerve laterally to the obturator fossa medially. A form of urinary diversion (i.e. orthotopic reservoirs, ileal conduits, and uretero-cutaneostomy) was selected based on disease stage, ARC, co-morbidities, and the surgeon’s preferences. Additional data searched included pathological stage and grade, post-operative mortality (POM), 90-day post-operative incidence of complications using the ClavienDindo scale (10), and length of hospitalization. Follow-up data comprised evidence of local and/or distant recurrence, need for further treatment, vital status, and cause of death. Outcomes Two survival outcomes were considered: OS when all deceased patients were assumed to die from BC regardless of the certified cause of death, and CSS when patients died from causes other than BC were considered as censored at the date of death. Patients’ characteristics taken into consideration for analysis were: ARC, gender, CCI score, baseline hemoglobin (Hb) and creatinine (Cr) levels, tumor size, lymph-node involvement, histotype, type of urinary diversion and complications. Statistical analysis Patients and disease-related prognostic factors were explored using descriptive statistics. Continuous variables were described using median values and ranges of variation (min-max) and categorized according to statistically or clinically meaningful thresholds, namely quintiles for ARC and a level of 10.0 g/dL, and 1.2 mg/dL for Hb and serum Cr, respectively. A CCI score of 3 was used as a cut-off in order to separate lower from higher comorbid patients. All categorical factors were finally expressed in terms of absolute and relative frequencies. Univariate survival comparisons were carried out using the Kaplan-Meier method and the statistical significance of each comparison was assessed by the log-rank test. The association of ARC and CCI score with survival probability was estimated using the Cox regression modelling and expressed as death rate ratio (HR) and corresponding 95% confidence limits (95% CL). For each prognostic factor the Cox regression allows to obtain an HR value adjusted

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

for the potential confounding effect of other variables entered the same equation. The likelihood ratio test was applied to evaluate the statistical significance of each prognostic variable included in the Cox model (11). In order to point out a non-linear dose-response relationship between ARC and death rates, potentially blurred by the categorization process, a three-knot restricted cubic spline (RCS) was fitted to survival data with the Cox regression equation. RCS is a flexible fitting procedure that allows the observed data to determine a smoothed functional form of dependency between the death rate (i.e., response) and a continuous prognostic variable (i.e., dose) (12). A two-tailed p-value < 0.05 was considered as significant. All analyses were performed using Stata (Stata Corp. Statistical Software, release 14. Statistical Software. College Station, TX: StataCorp LP, 2015). Table 1. Frequency distribution of patients’ baseline characteristics. Patients’ characteristics Age (yrs) at radical cystectomy (median, range) 46-65 66-70 71-76 77-80 81-87 Gender Male Female Raw Charlson comorbidity index ≤3 >3 Missing Tumor stage T0-T1 T2-T3 T4 Histotype Urothelial Non urothelial/rare variant Lymph node involvement N0 N1-N3 NX Preoperative hemoglobin ≤ 10.0 g/dL > 10.0 g/dL Missing Preoperative creatinine ≤ 1.2 mg/dL > 1.2 mg/dL Missing Early complications No Yes Late complications No Yes Urinary diversion Ureterocutaneostomy/ileal conduit Orthotopic neobladder Days of hospitalization (median, range) 2-13 14-17 18-23 24-80 Whole sample

No. 71, 46-87 66 68 66 67 67

% 19.8 20.4 19.8 20.0 20.0

288 46

86.2 13.8

269 59 6

80.5 17.7 1.8

203 93 38

60.8 27.8 11.4

263 71

78.7 21.3

227 73 34

68.0 21.9 10.2

10 302 22

3.0 90.4 6.6

247 65 22

74.0 19.5 6.6

289 45

86.5 13.5

289 45

86.5 13.5

203 131 18, 2-80 88 73 94 79 334

60.8 39.2 26.4 21.9 28.1 23.7 100.0

Age above 70 years and Charlson Comorbidity Index higher than 3 are associated with reduced survival probabilities after radical cystectomy...

Table 2. One-, three- and five-year overall survival probabilities (Pr) estimated through the Kaplan-Meier method according to levels of study prognostic factors.

RESULTS

Baseline patients’ characteristics are listed in Table 1. The median follow-up time was 3.8 years (IQR = 1.3-7.5 years). During the study period, a total of 180 patients died (53.8%), 68 (62.2%) from all causes whereas the remaining 112 patients (37.8%) from BC. The median OS was 5.9 years (95%CL = 3.98.1 years). 288 (86.2%) patients were male whereas 46 (13.8%) patients were female. Table 2 shows the results of univariate OS analysis. ARC, CCI, tumor stage, histotype, preoperative hemoglobin and creatinine levels, and urinary diversion showed a strong association with OS. A significant decreasing tendency in OS probabilities was found to be associated to an increasing ARC (p-value = 0.006). In addition, comorbid patients with CCI score > 3 showed a twofold increased death rate (p-value < 0.001) when compared to patients with lower CCI score (≤ 3). The cumulative effect on OS of ARC and CCI score was assessed in a multivariate context by modelling data using the Cox regression. After adjusting for gender, tumor stage, lymph node involvement, preoperative Hb and Cr levels, complications, and urinary diversion the significant association of ARC and CCI score with OS was confirmed (Table 3, Model 1). Specifically, patients with CCI score > 3 showed a death rate excess of about 60% when compared to patients with CCI score ≤ 3 (HR = 1.61; 95%CL Table 3. Joint effect of age at radical cystectomy (ARC) and Charlson comorbidity index (CCI) on overall and bladder cancerspecific survival estimated through the Cox regression model.

Patients’ characteristics Age at radical cystectomy 46-65 66-70 71-76 77-80 81-87 Gender Male Female Raw Charlson comorbidity index ≤3 >3 Missing Tumor stage T0-T1 T2-T3 T4 Histotype Urothelial Non urothelial/rare variant Lymph node involvement N0 N1+N2 NX Preoperative hemoglobin ≤ 10 > 10 Missing Preoperative creatinine ≤ 1.2 > 1.2 Missing Early complications No Yes Late complications No Yes Urinary diversion Ureterocutanostomy/ileal conduit Orthotopic neobladder Whole sample

D D%

Follow-up Med IQR

66 68 66 67 67

26 34 38 40 42

6.8 4.1 3.5 3.3 2.3

39.4 50.0 57.6 59.7 62.7

2.4-10.0 1.6-8.3 0.9-6.0 1.0-6.5 0.9-6.2

One-year Pr 95%CL

Overall survival Three-year Pr 95%CL

Five-year Pr 95%CL

0.89 0.84 0.70 0.75 0.72

0.71 0.62 0.54 0.58 0.47

0.66 0.55 0.47 0.47 0.43

0.79-0.94 0.72-0.90 0.57-0.79 0.62-0.83 0.59-0.80

0.58-0.80 0.48-0.71 0.41-0.65 0.45-0.68 0.34-0.58

P-value

0.53-0.76 0.41-0.65 0.34-0.58 0.34-0.59 0.30-0.54

0.006

288 155 53.8 46 25 54.3

3.7 1.3-7.5 3.9 1.1-7.2

0.78 0.72-0.82 0.76 0.60-0.85

0.58 0.51-0.63 0.63 0.47-0.75

0.52 0.46-0.57 0.50 0.33-0.63

0.882

269 131 48.7 59 43 72.9 6 6 100.0

4.4 1.7-8.1 1.6 0.9-5.2 0.1 0.0-0.2

0.82 0.76-0.85 0.66 0.52-0.76 0.17 0.00-0.51

0.63 0.56-0.68 0.44 0.31-0.56 0.17 0.00-0.51

0.57 0.50-0.62 0.33 0.21-0.45 0.17 0.00-0.51

< 0.001

203 90 44.3 93 63 67.7 38 27 71.1

5.2 2.3-8.4 1.9 0.9-4.8 1.3 0.4-4.2

0.85 0.79-0.89 0.70 0.59-0.78 0.58 0.40-0.71

0.72 0.65-0.77 0.38 0.28-0.48 0.34 0.19-0.48

0.65 0.57-0.71 0.33 0.23-0.42 0.28 0.14-0.42

< 0.001

263 137 52.1 71 43 60.6

4.0 1.5-8.3 2.2 0.5-6.3

0.81 0.75-0.84 0.68 0.55-0.77

0.62 0.55-0.67 0.46 0.33-0.57

0.53 0.46-0.59 0.46 0.33-0.57

0.032

227 101 44.5 73 53 72.6 34 26 76.5

8.4 2.1-8.4 4.7 0.8-4.6 5.2 0.4-5.2

0.85 0.79-0.89 0.64 0.52-0.74 0.59 0.40-0.73

0.70 0.63-0.75 0.35 0.24-0.46 0.32 0.17-0.48

0.63 0.55-0.68 0.29 0.19-0.40 0.29 0.15-0.44

< 0.001

10 8 80.0 302 156 51.7 22 16 72.7

0.4 0.2-1.0 3.9 1.4-7.4 1.5 0.2-8.2

0.40 0.12-0.67 0.80 0.75-0.84 0.59 0.36-0.76

0.20 0.03-0.47 0.61 0.55-0.66 0.41 0.20-0.60

0.20 0.03-0.47 0.54 0.48-0.59 0.32 0.14-0.51

247 118 47.8 65 46 70.8 22 16 72.7

4.4 1.7-7.9 1.9 0.6-5.6 1.5 0.2-8.2

0.83 0.77-0.87 0.65 0.51-0.74 0.59 0.36-0.76

0.65 0.58-0.70 0.40 0.27-0.51 0.41 0.20-0.60

0.58 0.51-0.63 0.36 0.24-0.48 0.32 0.14-0.51

< 0.001

289 151 52.2 45 29 64.4

4.0 0.7-0.8 1.7 0.4-0.6

0.81 0.75-0.85 0.58 0.42-0.70

0.61 0.55-0.66 0.42 0.27-0.55

0.54 0.47-0.59 0.40 0.25-0.53

0.009

312 167 53.5 22 13 59.1

3.9 1.3-7.5 2.1 0.9-4.5

0.79 0.73-0.82 0.68 0.44-0.83

0.60 0.54-0.64 0.41 0.20-0.60

0.53 0.46-0.58 0.41 0.20-0.60

0.241

203 124 60.9 131 56 42.7 334 180 53.9

2.5 0.9-6.3 5.2 2.2-8.9 3.8 1.3-7.5

0.70 0.64-0.76 0.89 0.83-0.94 0.78 0.73-0.82

0.50 0.43-0.56 0.72 0.64-0.79 0.58 0.53-0.64

0.44 0.37-0.51 0.65 0.56-0.72 0.52 0.46-0.57

< 0.001

0.002

T: sample size; D/D%: number/percent of deceased patients; Med: median of follow-up time (years); IQR: inter-quartile range (min-max); 95%CL: 95% confidence limits for estimated Pr; P-value: probability level associated with the log-rank test.

Regression model 1

Patients’ characteristics Age at radical cystectomy 46-65 66-70 71-76 77-80 81-87 Charlson comorbidity index ≤3 >3 Age at radical cystectomy 46-69 70-80 81-87 Charlson comorbidity index ≤3 >3

Overall survival Deaths = 164 (52.7%) HR 95%CL P-value 0.034 1.00 (Ref.) 1.92 1.06-3.47 2.25 1.28-3.94 2.08 1.19-3.64 2.03 1.16-3.57 0.022 1.00 (Ref.) 1.61 1.07-2.41 0.155 1.00 (Ref.) 1.39 0.97-1.99 1.04 0.59-1.83 0.054 1.00 (Ref.) 1.50 0.98-2.26

Cancer-specific survival Deaths = 101 (32.5%) HR 95%CL P-value 0.750 1.00 (Ref.) 1.57 0.77-3.16 1.41 0.69-2.84 1.44 0.73-2.84 1.41 0.70-2.81 0.253 1.00 (Ref.) 1.38 0.80-2.38 0.431 1.00 (Ref.) 1.09 0.70-1.71 0.68 0.31-1.48 0.437 1.00 (Ref.) 1.26 0.72-2.21

HR: death rate ratio adjusted for gender, tumor size, lymph nodes involvement, pre-operative hemoglobin and creatinine, early and late complications, urinary diversion; 95%CL: 95% confidence limits for HR; Ref.: reference category; P-value: probability level associated with the likelihood ratio test.

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

M. Maffezzini, V. Fontana, A. Pacchetti, F. Dotta, M. Cerasuolo, D. Chiappori, G. Guano, G. Mantica, C. Terrone

Figure 1. Joint effect of age at radical cystectomy (ARC) and raw Charlson comorbidity index (CCI) on life expectancy estimated through the Cox regression model. Overall survival probabilities are adjusted for gender, tumor size, lymph node involvement, pre-operative hemoglobin and creatinine, early and late complications, urinary diversion.

Figure 2. Relationship between overall (OS) and cancer specific (CSS) death rate ratio (HR) and age at radical cystectomy (ARC) estimated using the Cox regression model adjusted for gender, tumor size, lymph node involvement, pre-operative hemoglobin and creatinine, early and late complications, urinary diversion. Smoothed HR point estimates were obtained by fitting three-knot cubic spline functions to OS and CSS data.

= 1.07-2.41; p-value = 0.022). An increase in death rates by ARC was observed although the estimated doseresponse relationship appeared to be non-linear. In other words, assuming the death rate of the lowest ARC category (46-65 years) as a reference (HR = 1.00) the highest rate was estimated in the intermediate category 71-76 years (HR = 2.25, 95%CL = 1.28-3.94).

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

In order to point out better such a non-monotonic tendency, a Cox model was fitted to OS data after rearranging ARC in three categories using 70 and 80 years as threshold values (Table 3, Model 2; Figure 1). In this case, the intermediate category (70-80 years) showed a death rate which was about 40% higher than those in the other two categories (46-69 and 81-87 years), even though a

Age above 70 years and Charlson Comorbidity Index higher than 3 are associated with reduced survival probabilities after radical cystectomy...

loss in statistical power was pointed out (p-value = 0.155). In order to assess the influence of death on the relationship between ARC and CCI on survival, all previous analyses were repeated using CS mortality as an outcome. After fitting a three-knot RCS (Figure 2) to both survival data series, two overlapping non-linear trends with common upmost risk values included in the ARC group 70-75 years were pointed out.

DISCUSSION

Multiple systemic diseases known as co-morbidities are diagnosed in the ageing men and women whom, in addition, are also exposed to the risk of developing cancer (89). Notably, the presence of multiple systemic diseases necessitating chronic treatment can also undermine the results of cancer treatment. The effect of ARC on the prognosis has been investigated previously. The conclusion reported so far are heterogeneous probably because, among other reasons, an objective threshold for dichotomizing this risk factor is not clearly identifiable and, accordingly, the issue remains controversial. Nevertheless, in several studies increased ARC showed an association with poor prognosis and survival (13-16) and although RC is currently performed in advanced age subjects a systematic review of the literature has outlined a decline in both OS and CSS beginning at the age of 70 years (17). The association of comorbidities and survival after RC has also been investigated. The Adult Co-morbidity Evaluation 27 instrument (ACE-27) was used retrospectively in some studies (18-19) showing that co-morbidity score and pathologic stage of disease significantly correlated with reduced OS. Moreover, in the severe comorbidity group the number needed to harm was 6, that is, for every 6 patients dying after RC 1 death occurred due to co-morbidity per se. The CCI score was used also and correlated with the outcomes of RC. Koppie et al. classified RC patients with the age-adjusted CCI (AA-CCI) into three groups, namely i) low AA-CCI score ≤ 2 , ii) moderate AA-CCI score of 3 to 5 , and iii) a high AA-CCI score > 5 (20). They found a median OS time of 6.3 years, 3.9 years, and 1.7 years in the low, moderate, and high score groups, respectively. Mayr et al. compared the ASA score, the ACE 27 instrument, the ECOG scale, and the AA-CCI (21). The Authors found that none of the comorbidity indices were significant predictors for CSS, whereas each index was a significant predictor for cancer-independent mortality. Importantly, based on ARC and comorbidity a weighed prognostic risk model was developed where after 3 years 47% of the patients within the high-risk group died of causes other than BC, compared with 8% of patients within the low-risk group. In a recently published study, D'Andrea et al. analysed a cohort of 46 patients with localized MIBC who were considered unfit for RC or TT, and therefore sent to RT alone (22). Their survival outcomes were compared to an equal number of patients treated with RC. After performing a propensity score analysis CSS and OS of the patients undergoing RT were substantially the same as those who were treated with RC.

The main findings of our study can be summarised as follows. First, after adjusting for known prognostic factors (Table 1), patients in the age group 70-80 years showed the greater mortality risk. Second, after eliminating the competitive risk of death due to causes different from BC, the curves of OS and CSS show a parallel profile, as outlined by the RCS analysis (Figure 2). Finally, in patients with 70-80 years and CCI score > 3 the mortality risk is remarkably higher (HR = 2.09, 95%CL = 1.23-3.53) than all other groups (Figure 1). These findings reproduce closely what reported previously by other authors (21). Certain limitations of our study are to be acknowledged. Firstly, inherent to the retrospective nature of the investigation (study period: 2005-2015), although the comorbidities were listed at the moment of patient enrolment, the CCI score was retrospectively assigned. Secondly, the CCI score has been commonly used to assess survival for various cancers since it offers a general patient evaluation. However, some particular conditions, i.e., hypertension, lung diseases in the absence of chronic obstructive disease, coronary artery disease in the absence of myocardial infarction, etc., are overlooked. Thirdly, based on our dataset we were unable to address several concurrent factors that may have had an influence on survival such as a delay from symptoms-onset and diagnosis/treatment, nutritional status, and post-operative hospitalization in intensive care units, among others. On the other hand, the strengths of our study are to be acknowledged as well. Two factors known to influence prognosis are addressed jointly, namely age and co-morbidities, and we were able to confirm their cumulative effect on survival after RC, as previously observed by other researchers. Moreover, the study cohort consists in series of consecutive subjects treated at a single referral, high volume center, offering a homogeneous treatment to all patients, that is, RC alone (with pelvic lymphadenectomy), and no selection was made to exclude from treatment older and sicker patients.

CONCLUSIONS

In conclusion, in the present cohort analysis of BC patients consecutively submitted to RC we were able to identify age 70-80 years and higher CCI score (> 3) as significant factors limiting a better prognosis. Although in principle we believe that surgery should not be precluded in the presence of advanced age and comorbidities both factors should be attentively considered when comparing outcomes after RC in contemporary series. Implementation of ad hoc trials, focusing on these patients, should be encouraged.

ACKNOWLEDGMENTS

The authors thank Peter De Ville, MA, for linguistic revision.

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1. Jue JS, Koru-Sengul T, Miao F, et al. Neoadjuvant vs adjuvant chemotherapy for muscle-invasive bladder cancer: a propensity matched analysis. Minerva Urol Nefrol. 2020 Jan 30. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

M. Maffezzini, V. Fontana, A. Pacchetti, F. Dotta, M. Cerasuolo, D. Chiappori, G. Guano, G. Mantica, C. Terrone

2. Capece M, Spirito L, La Rocca R, et al. Hexaminolevulinate blue light cystoscopy (Hal) assisted transurethral resection of the bladder tumour vs white light transurethral resection of the bladder tumour in non-muscle invasive bladder cancer (NMIBC): a retrospective analysis. Arch Ital Urol Androl. 2020; 92:17-20. 3. Mantica G, Simonato A, Du Plessis DE, et al. The pathologist's role in the detection of rare variants of bladder cancer and analysis of the impact on incidence and type detection. Minerva Urol Nefrol. 2018; 70:594-597.

13. Clark PE, Stein JP, Groshen SG, et al. Radical cystectomy in the elderly: comparison of clinical outcomes between younger and older patients. Cancer. 2005; 104:36-43. 14. Nielsen ME, Shariat SF, Karakiewicz PI, et al. Advanced age is associated with poorer bladder cancer-specific survival in patients treated with radical cystectomy. Eur Urol. 2007; 51:699-706. 15. Donat SM, Siegrist T, Cronin A, et al. Radical cystectomy in octogenarians--does morbidity outweigh the potential survival benefits? J Urol. 2010; 183:2171-7.

4. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol. 2001; 19:666-75.

16. Chromecki TF, Mauermann J, Cha EK, et al. Multicenter validation of the prognostic value of patient age in patients treated with radical cystectomy. World J Urol. 2012; 30:753-759.

5. Madersbacher S, Hochreiter W, Burkhard F, et al. Radical cystectomy for bladder cancer today - a homogeneous series without neoadjuvant therapy. J Clin Oncol. 2003; 21:690-6.

17. Fonteyne V, Ost P, Bellmunt J, et al. Curative treatment for muscle invasive bladder cancer in elderly patients: a systematic review. Eur Urol. 2018; 73:40-50.

6. Hautmann RE, Gschwend JE, de Petriconi RC, et al. Cystectomy for transitional cell carcinoma of the bladder: results of a surgery only series in the neobladder era. J Urol. 2006; 176:486-92

18. Megwalu II, Vlahiotis A, Radwan M, et al. Prognostic impact of comorbidity in patients with bladder cancer. Eur Urol. 2008; 53:581-9.

7. Dy GW, Gore JL, Forouzanfar MH, et al. Global burden of urologic cancers, 1990-2013. Eur Urol. 2017; 71:437-446.

19. Fairey AS, Jacobsen NE, Chetner MP, et al. Associations between comorbidity, and overall survival and bladder cancer specific survival after radical cystectomy: results from the Alberta Urology Institute Radical Cystectomy database. J Urol. 2009; 182:85-92.

8. Valderas JM, Starfield B, Sibbald B, et al. Defining comorbidity: implications for understanding health and health services. Ann Fam Med. 2009; 7:357-63. 9. Sgrò P, Sansone M, Sansone A, et al. Physical exercise, nutrition and hormones: three pillars to fight sarcopenia. Aging Male. 2019; 22:75-88. 10. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004; 240:205-13. 11. Marubini E, Valsecchi MG. Analyzing survival data from clinical trials and observational studies. John Wiley and Sons, New York, 1995. 12. Harrell FE Jr. Regression Modelling Strategies. 2nd Ed. New York, Springer Verlag, 2015.

20. Koppie TM, Serio AM, Vickers AJ, et al. Age-adjusted Charlson comorbidity score is associated with treatment decisions and clinical outcomes for patients undergoing radical cystectomy for bladder cancer. Cancer. 2008; 112:2384-92. 21. Mayr R, May M, Martini T, et al. Comorbidity and performance indices as predictors of cancer-independent mortality but not of cancer-specific mortality after radical cystectomy for urothelial carcinoma of the bladder. Eur Urol. 2012; 62:662-70. 22. D'Andrea D, Soria F, Zehetmayer S, et al. Comparative effectiveness of radical cystectomy and radiotherapy without chemotherapy in frail patients with bladder cancer (published online ahead of print, Scand J Urol. 2020; 54:52-57.

Correspondence Massimo Maffezzini, MD massimo.maffezzini@gmail.com Department of Urology, Ospedale Nuovo Legnano, Ospedale Fornaroli Magenta Via Papa Giovanni Paolo II, 20025 Legnano (Italy) Vincenzo Fontana, MD vincenzo.fontana@hsanmartino.it Clinical Epidemiology Unit, IRCCS Policlinico San Martino, University of Genova Largo Benzi 10, 16132 Genova (Italy) Andrea Pacchetti, MD a.pacchetti.90@gmail.com Federico Dotta, MD fededotta@hotmail.it Mattia Cerasuolo, MD mattiacerasuolo@hotmail.it Davide Chiappori, MD chiappori.davide@gmail.com Giovanni Guano, MD giovanni.guano@gmail.com Guglielmo Mantica, MD (Corresponding author) guglielmo.mantica@gmail.com Carlo Terrone, MD carlo.terrone@med.uniupo.it Department of Urology, IRCCS Policlinico San Martino, University of Genova Largo Benzi 10, 16132 Genova (Italy)

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

ORIGINAL PAPER

DOI: 10.4081/aiua.2021.1.21

[68Ga]Ga-PSMA-11 PET-CT: Local preliminary experience in prostate cancer biochemical recurrence patients João Carvalho 1, 2, Pedro Nunes 1, 2, Edgar Tavares da Silva 1, 2, Rodolfo Silva 2, 3, João Lima 1, 2, Vasco Quaresma 1, 2, Arnaldo Figueiredo 1, 2 1 Department

of Urology and Renal Transplantation, Coimbra University Hospital Center, Coimbra, Portugal; of Medicine, Coimbra University, Coimbra, Portugal; 3 Department of Nuclear Medicine; Coimbra University Hospital Center, Coimbra, Portugal. 2 Faculty

Summary

Objectives: Clinical approach of prostate cancer (PCa) biochemical recurrence (BCR) is an ever-changing topic. Prostate-specific membrane antigen positron emission tomography ([68Ga]Ga-PSMA-11 PET-CTPSMA PET-CT) has shown good potential in this field. The aim is to evaluate PSMA PET-CT detection rate in PCa BCR and assess its impact on clinical outcome. Material and methods: Out of 319 patients with PCa who underwent PSMA PET-CT between October 2015 and June 2019, 70 had developed BCR after treatment with curative intent. Two groups were created: one with BCR after surgery (RP group) (N: 48; 68.6%) and other with BCR after radiotherapy (RT group) (N: 22; 31.4%). Clinical, analytical, pathological and PSMA PET-CT results were evaluated. Results: Initial age was different between groups (p = 0.008). RP patients were mainly at intermediate risk (85.1% vs 42.9%, p = 0.001) while RT patients were at low risk of recurrence (8.5% vs 47.6%, p = 0.001). In RP and RT groups, PSMA PETCT detected, respectively, pelvic relapse in 31.3% and 63.6%, and extrapelvic relapse in 18.8% and 31.8%. Salvage treatment was performed in 61.9% (n = 26) of RP patients and in 15% (n = 3) of RT patients, p < 0.001. Of RP patients submitted to salvage treatment, 59.1% achieved complete remission. Concerning these patients, local radiotherapy led to complete remission in 68.4% (n = 13). Of RT patients submitted to salvage treatment, two had complete remission and one had partial remission.Concerning detection rate, PSMA PET-CT was positive for pelvic relapse when pre-PET PSA ≥ 0.8 ng/mL (RP) or ≥ 2.3 ng/mL (RT) and for extrapelvic relapse when PSA ≥ 0.4 ng/mL (RP) or ≥ 3.5 ng/mL (RT), p > 0.05. Conclusions: Biochemical persistence rate after salvage therapy was similar (30-40%). The cut-off PSA values for pelvic relapse detected on PSMA PET-CT were ≥ 0.8 ng/mL (RP) and ≥ 2.3 ng/mL (RT).

KEY WORDS: Biochemical recurrence; PSMA PET-CT; Salvage treatment; Prostate cancer. Submitted 18 July 2020; Accepted 28 July 2020

INTRODUCTION

Prostate cancer (PCa) is the second most commonly diagnosed cancer in men, with an estimated 1.1 million new cases worldwide in 2012, accounting for 15% of all cancers diagnosed (1). Radical prostatectomy and radiother-

apy are among the treatments of choice for localized PCa. However, between 27% and 53% of all patients develop a rising PSA and experience biochemical recurrence (BCR) (2). PSA elevation is highly predictive of clinical recurrence but not all patients with BCR after treatment with curative intent have local relapse. Therefore, it is very important to distinguish the ones that may benefit from local salvage treatment from those that don’t. BCR is defined as 2 consecutive PSA values equal or superior to 0.2 ng/mL after radical prostatectomy, or a PSA increase equal or superior to 2 ng/mL above the nadir after radiotherapy (3, 4). However, the indication for further treatments should not be based solely on a pre-determined PSA threshold but should be decided on the individualized risk of progression (5). In BCR, conventional imaging, such as computed tomography (CT), magnetic resonance imaging (MRI) and bone scintigraphy, has limited accuracy for the detection of recurrence sites (local, regional or systemic), especially at low PSA levels, while it is known that the optimal therapeutic window for salvage treatment in BCR is below 0.5-1 ng/mL (6). On the one hand, salvage radiotherapy (SRT) is considered the treatment of choice for PCa patients with BCR after radical prostatectomy. Its efficacy depends on early detection of disease limited to the prostatic fossa. On the other hand, distant metastases require systemic therapies, such as hormonal therapy or chemotherapy (7), whereas local treatment may lead to unnecessary side effects (8). Therefore, to achieve the best possible results while avoiding unjustified therapies and side effects, treatment must be individualized for each patient. In this field, molecular imaging techniques offer a great potential. In 2011, the Heidelberg group introduced [68Ga] Ga-PSMA11 (also known as HBED-CC, Glu-urea- Lys(Ahx)HBED-CC and PSMA-HBED-CC) in Germany for clinical imaging of PCa. Prostate specific membrane antigen (PSMA) is a membrane glycoprotein codified by the PSMA gene (FOLH1) located on the short arm of chromosome 11. Despite the name “specific”, PSMA is also expressed in other tissues such as the brain, salivary glands, liver, kidney, small intestine, ganglia and neovasculature of some solid tumors, but in very lower levels. Concerning prostate, PSMA is expressed in normal, benign and malignant prostatic epithelium but its expres-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

J. Carvalho, P. Nunes, E. Tavares da Silva, R. Silva, J. Lima, V. Quaresma, A. Figueiredo

sion in PCa is 100-1000-fold of what is observed in normal cells (9, 10). The localization of the catalytic site of PSMA in the extracellular domain allows the development of small specific inhibitors that are internalized after ligand binding (11). Over the last years, many articles concerning the use of [68Ga] Ga-PSMA-11 PET/CT (PSMA PET-CT) in this scenario have been published and the results appear to be promising (12-17), leading to treatment plan changes in up to 87.1% of patients (6). A meta-analysis revealed detection rates of 48% at PSA levels of 0.2 ng/mL, increasing to 56% and 70% at levels of 0.5 and 1.0 ng/mL, respectively. These results were quite superior to those observed with conventional imaging techniques and even [18F] Choline PET/CT (18). This study aims to evaluate PSMA PET-CT detection rate in prostate cancer patients with BCR after treatment with curative intent and assess its impact on clinical outcome.

MATERIAL

AND METHODS

This study followed the rules of the local ethics committee and were in accordance with the Helsinki Declaration. It was a preliminary cross-sectional study of prostate cancer patients with BCR after treatment with curative intent at our institution. Within a total of 319 PCa patients who underwent PSMA PET-CT between October 2015 and June 2019, 70 developed BCR after treatment with curative intent. [68Ga]Ga-PSMA-11 was synthesized locally, at ICNAS (Instituto de Ciências Nucleares Aplicadas à Saúde). 68Ga-PSMA-HBEDCC (GluNH-CO-NH-Lys-(Ahx)-[[68Ga]Ga(N,N’-bis-[2-hydroxy5 (carboxyethyl)benzyl]ethylenediamine-N,N’-diaceticacid]) (68Ga-PSMA-11) was prepared in a similar procedure as described by Eder et al. (19). All patients underwent a whole-body PET-CT acquisition (Siemens Biograph, Siemens Healthcare, Gemini GXL Philips, Philips) 60 minutes after intravenous injection of 2 MBq/Kg of [68Ga]Ga-PSMA-11. PSMA PET-CT scans were acquired in three-dimensional mode with 4 minutes per bed position. Patients were well hydrated and voided immediately before the scan. No adverse effects were reported. PSMA PET-CT images were independently interpreted by two nuclear medicine physicians. In case of disagreement, the final diagnosis was reached by requesting a third opinion. The main criteria of positivity for PSMA PET-CT scans were: any area of focal uptake of the radiotracer (single or multiple), higher than the surrounding background, that did not correlate with physiologic tracer uptake. PSMA PET-CT positive lesions were classified as “pelvic relapse” [prostate/prostate bed relapse and/or pelvic lymph nodes, excluding common iliac nodes (LNs)] or “extrapelvic relapse” (inguinal LNs and/or above common iliac bifurcation LNs and/or bone lesions and/or other visceral lesions). PSMA PET-CT negative scans were considered false negative by definition. Two groups were created: patients submitted to surgery (RP group) (N: 48; 68.6%) and patients treated with radiotherapy (RT group) (N: 22; 31.4%). Clinical, analytical, pathological and PSMA PET-CT results were evaluated. All continuous variables were reported as mean and standard deviation. Categorical variables were described according to their frequency and percentage.

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

Descriptive analysis of demographic and clinical variables was performed. Chi-square test was used for categorical variables. Continuous variables were compared using the T student. The detection rate of PSMA PET-CT was assessed. All tests performed were 2-sided. Statistical significance was taken at a p value of less than 0.05. All data were analysed using the Statistical Package for the Social Sciences (SPSS) 23.0 (IBM SPSSS Statistics Corp.; Armonk, New York, USA).

RESULTS

Demographic and clinical data (Table 1) showed that RT patients were older than RP patients (66 ± 6.5 vs 69 ± 6.2 years, p = 0.008), but PSA was similar between groups (8.7 ± 5.7 vs 7.5 ± 5.8 ng/mL, p = 0.4). Patients were divided according to the European Association of Urology (EAU) risk group classification for BCR of localised PCa: Low-risk were defined by PSA < 10 ng/mL and Gleason score < 7 (ISUP grade 1) and cT1-2a; Intermediate-risk was defined by PSA 10-20 ng/mL or Gleason score 7 (ISUP grade 2/3) or cT2b and High-risk was defined by PSA > 20 ng/mL or Gleason score > 7 (ISUP grade 4/5) or cT2c (12). Most patients in RP group were in the intermediate-risk category (85.1%), while in the RT group the low-risk catTable 1. Demographic and clinical data. Data Age at PCa diagnosis (years) Initial PSA (ng/mL) EAU risk groups for BCR of localised PCa - Low-risk - Intermediate-risk - High-risk Time between initial treatment and BCR (months)

RP group (n: 48) 66 ± 6.5 8.7 ± 5.7

RT group (n: 22) 69 ± 6.2 7.5 ± 5.8

8.5% 85.1% 6.4%

47.6% 42.9% 9.5%

23.5 ± 42.7

44.5 ± 42.5

p 0.008 0.4 0.001

0.09

RP group: group previously submitted to surgery; RT group: group previously submitted to radiotherapy; PCa: prostate cancer; EAU: European Association Urology; BCR: biochemical recurrence.

Table 2. Relapse pattern between groups. Data Pelvic relapse Extrapelvic relapse No disease Global SUVmax

RP group (n: 48) 15 (31.3%) 9 (18.8%) 24 (50%) 8.4 ± 5.7 [3.3-16.7]

RT group (n: 22) 14 (63.6%) 7 (31.8%) 1 (4.5%) 5.6 ± 3.9 [2.7-17.4]

p 0.001

0.3

RP group: group previously submitted to surgery; RT group: group previously submitted to radiotherapy; SUVmax: maximum standardized uptake values of [68Ga]Ga-PSMA-11.

Table 3. PSA value in pelvic and extrapelvic relapse between groups if positive PSMA PET-CT. Data RP group + positive PSMA PET-CT RT group + positive PSMA PET-CT

PSA value in pelvic relapse (ng/mL) 0.99 ± 0.9 3.0 ± 2.1

PSA value in extrapelvic relapse (ng/mL) 1.0 ± 13.2 4.5 ± 5.4

RP group: group previously submitted to surgery; RT group: group previously submitted to radiotherapy.

p 0.6 0.2

PET in prostate cancer biochemical recurrence

Table 4. Detection rate of PSMA PET-CT for pelvic relapse in RP patients.

Table 6. Detection rate of PSMA PET-CT for extrapelvic relapse in RP patients.

Sensibility and specificity of PSMA PET-CT for pelvic relapse in RP patients PSA value (ng/mL) Sensibility Specificity p 0.2 93.3% 3% 0.06 0.3 80% 18.2% 0.4 73.3% 33.3% 0.5 73.3% 60.6% 0.6 73.3% 63.6% 0.7 73.3% 66.6% 0.8 73.3% 72.7% 0.9 66.7% 78.8% 1.0 46.7% 78.8%

Sensibility and specificity of PSMA PET-CT for extrapelvic relapse in RP patients PSA value (ng/mL) Sensibility Specificity p 0.2 88.9% 2.6% 0.9 0.3 77.8% 17.9% 0.4 66.7% 30.8% 0.5 55.6% 41% 0.6 44.4% 51.3% 0.7 44.4% 53.8% 0.8 44.4% 59% 0.9 44.4% 66.7% 1.0 44.4% 74.4%

RP group: group previously submitted to surgery.

Table 5. Detection rate of PSMA PET-CT for pelvic relapse in RT patients. Sensibility and specificity of PSMA PET-CT for pelvic relapse in RT patients PSA value (ng/mL) Sensibility Specificity p 0.9 92.9% 12.5% 0.5 1.8 85.7% 25% 2.0 71.4% 25% 2.3 71.4% 37.5% 3.0 50% 37.5% 3.5 42.9% 50% RT: group previously submitted to radiotherapy.

Table 7. Detection rate of PSMA PET-CT for extrapelvic relapse in RT patients. Sensibility and specificity of PSMA PET-CT for extrapelvic relapse in RT patients PSA value (ng/mL) Sensibility Specificity p 0.9 100% 13.3% 0.2 1.8 85.7% 20% 2.0 85.7% 33.3% 2.3 71.4% 33.3% 3.0 71.4% 53.3% 3.5 71.4% 60% 4.0 57.1% 80% 4.5 42.9% 80% RT: group previously submitted to radiotherapy.

egory was the most prevalent (47.6%), with this difference being statistically significant (p = 0.001). The time interval between initial treatment and BCR was similar between groups (Table 1). In RP patients, final pathology revealed pT2a in six (13.4%), pT2c in 16 (33.3%), pT3a in 14 (28.9%) and pT3b in 12 cases (24.4%). N status was N0 in 29 (60.4%), N1 in 13 (27.1%) and Nx in six cases (12.5%). R status revealed R0 in 41 (85.4%) and R1 in seven cases (14.6%). In RP and RT groups, PSMA PET-CT detected pelvic relapse in 31.3% and 63.6% of patients and extrapelvic relapse in 18.8% and 31.8%, respectively. PSMA PET-CT was negative in 24 (50%) of RP group and in one case (4.5%) of RT group. The maximum standardized uptake value (SUVmax) of the lesion with the highest [68Ga]Ga-PSMA-11 uptake per patient was also analysed, and no statistical significant difference was found between groups (Table 2). In positive PSMA PETCT, PSA values were not able to distinguish between pelvic and extrapelvic disease in either groups (Table 3). Salvage treatment was performed in 61.9% (n = 26) of RP group (local radiotherapy in 54.7%, radiotherapy to a single bone metastasis in 2.4% and lymphadenectomy in 4.8%) and in 15% (n = 3) of RT group(radical prostatectomy with bilateral pelvic lymphadenectomy in two and high-dose brachytherapy in one case), p < 0.001. Out of all RP patients submitted to salvage treatment, 59.1% achieved complete remission. Concerning these patients, local radiotherapy led to complete remission in 13 cases (68.4%). Neither extended lymphadenectomy nor radiotherapy to the single bone metastasis led to complete

remission. In fact, none of the removed nodes harboured tumour cells. Out of the three RT patients submitted to salvage treatment, two had complete remission (both submitted to radical prostatectomy with bilateral pelvic lymphadenectomy) and one had partial remission (targeted high-dose brachytherapy). Pathology obtained from salvage radical prostatectomy revealed ISUP grade 2 pT3bN1M0R0 and ISUP grade 2 pT3bN0M0R0. In both cases, the initial biopsy specimens firstly done before radiotherapy revealed an ISUP grade 1. Concerning detection rate, PSMA PET-CT was positive for pelvic relapse when pre-PSMA PET-CT PSA ≥ 0.8 ng/mL (RP) or ≥ 2.3 ng/mL (RT) (Tables 4, 5) and for extrapelvic relapse when PSA ≥ 0.4 ng/mL (RP) or ≥ 3.5 ng/mL (RT), p > 0.05 (Tables 6, 7).

DISCUSSION

This study showed the preliminary experience of PSMA PET-CT in real-world PCa patients that experienced BCR after treatment with curative intention. In BCR patients, 68-Ga PSMA avidity in the pelvic region was higher in the radiotherapy than in prostatectomy cohort (63.6% vs 31.3%), in line with other studies that showed a proportion of 52% vs 22% (14). The negativity of PSMA PETCT was almost exclusive of RP patients (50% versus 4.5%). Gallium 68-PSMA, similarly to most other PSMA based agents, has a significant urinary tracer excretion with high activity often seen in the bladder. This could Archivio Italiano di Urologia e Andrologia 2021; 93, 1

J. Carvalho, P. Nunes, E. Tavares da Silva, R. Silva, J. Lima, V. Quaresma, A. Figueiredo

interfere with the evaluation of the postprostatectomy bed/seminal vesicle bed regions as well as lower pelvic lymph nodes. Salvage treatment in patients previously submitted to radiotherapy was done only after re-biopsy and confirmation of tumour persistence. In our limited experience, radical prostatectomy could portend better results than high-dose brachytherapy. The final pathological upgrading compared to the pre-radiotherapy biopsy has to be seen with caution, given the difficulties in evaluating the Gleason score after radiotherapy. Concerning RP patients, radiotherapy was the only effective salvation treatment. Other attempts to reach complete remission were not succeeded, even extended lymphadenectomy did not reveal ganglia metastases. In fact, according to Budaus et al., the comparison between preoperative PSMA PET-CT lymph nodes findings with histologic work-up after radical prostatectomy performed for high risk prostate cancer only detected 33.3% of the patients as being true positive for lymph node metastasis, and 66.7% of the patients as a false negative. Our population had a reduced incidence of high-risk patients, so we must presume that our results were following the low sensitivity (33.3%) and high specificity (100%) rate of PSMA PET-CT for detection of lymph node metastasis in this work (15). The SUVmax value in our population was low, in line with the findings of Demerci et al. (16). They showed that SUV max values correlated significantly with grade groups of primary tumours. The EAU risk groups for BCR of localised PCa in RP and RT were predominantly intermediate and low-risk respectively. This explained the lower SUVmax detected in RT patients compared with RP patients. The optimal cut-off PSA values for pelvic relapse detected on PSMA PET-CT were ≥ 0.8 ng/mL (RP) and ≥ 2.3 ng/mL (RT). The optimal cut-off values for extrapelvic relapse detected on PSMA PET-CT were ≥ 0.4 ng/mL (RP) and ≥ 3.4 ng/mL (RT). Sanli et al concluded that a PSA value of 0.83 ng/ml was the optimal cut-off value for distinguishing between positive and negative PSMA PETCT in general (17). EAU Guidelines (5) include a weak recommendation for offering PSMA PET-CT scan to men with a persistent PSA > 0.2 ng/mL to exclude metastatic disease. According to our results, this cut-off seems too low. However, it was a preliminary study with few patients and we hope to increase our experience in this setting to see if this cutoff is applied to our population. It has also been reported that patient’s prognosis was improved when salvage therapy was initiated before the PSA level exceeds 0.5 ng/mL (20). In our population, the cut-off of 0.5 ng/mL for RP patients was associated with a sensibility of 73.3% and specificity of 72.7% in pelvic relapse and with a sensibility of 55.6% and specificity of 30.8%. Literature showed that these cut-off values can differ from 17.5% to 61.5% (6). In other studies, the detection sensitivity of PSMA PETCT is dependent on the PSA at the time of imaging, with detection sensitivities in the range of 50-60% when the PSA is as low as 0.2 to 0.5 ng/mL (21, 22). However, the

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

cut-off value for PSA performing PSMA PET-CT has yet to be defined, and thus prospective studies are required to recommend PSMA PET-CT for patients with BCR. With increasing use of PSMA PET-CT scan, its value must be balanced critically with cost and clinical benefit. Given the high costs and limited availability of PSMA PET-CT scan, choline PET-CT is still widely used in patients with prostate cancer relapse, despite its low sensibility for low PSA levels. A meta-analysis by Han et al. (23) showed that PSMA PET-CT altered the management in 54% of patients. They reported that the use of PSMA PET-CT imaging lead to an increase in the proportion of patients receiving radiotherapy (from 56% to 61%), surgery (from 1% to 7%), focal therapy (from 1% to 2%), and multimodal treatment (from 2% to 6%), and to a decrease in patients receiving systemic treatment (from 26% to 12%) and no treatment (from 14% to 11%). The evidence for introducing management changes as a result of PSMA PET-CT findings is low, and prospective studies are required. The risk of early treatments causing more harm than good, as well as the long-term effects on progression-free and overall survival rates are still unclear (24). An interesting potential benefit of PSMA PET-CT could be to select, with higher accuracy, patients to highdose radiotherapy for oligometastatic disease. In our study, there was one patient who underwent radiotherapy to a single bone metastasis, yet no complete remission was achieved. Whether this approach improves patient outcomes remains unclear, the impact of potentially avoiding androgen deprivation therapy and its toxicity would definitely be important. Some limitations must be also elicited as they could influence results and conclusions. The small number of patients, different size groups and the monocentric nature of the study could limit the applicability of these results. Population studied was heterogeneous: patients submitted previously to radiotherapy were fewer, older and belonged to a lower risk group for BCR instead of patients submitted previously to radical prostatectomy were almost the double and belonged to an intermediaterisk group. The lack of PSA kinetics and the lack of comparison with standard conventional imaging could introduce a bias: the majority of patients did not have a simultaneous approach with conventional imaging. However, the available literature supports PSMA PET-CT superiority over conventional imaging in this setting (13).

CONCLUSIONS

PSMA PET-CT has shown good potential for using in patients with BCR, but most studies are limited by their retrospective design. Despite the limited information in major guidelines, it could be standard in patients with recurrent PCa, mainly with low PSA. PSA level is associated with the positivity rate of PSMA PET-CT. The cut-off PSA values for pelvic relapse detected on PSMA PET-CT were ≥ 0.8 ng/mL (RP) and ≥ 2.3 ng/mL (RT). However, PSA levels could not discriminate between PSMA PETCT positivity for pelvic or extrapelvic relapse. Biochemical persistence rate after salvage therapy was similar between groups (30-40%).

PET in prostate cancer biochemical recurrence

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6. Eissa A, Elsherbiny A, Coelho RF, et al. The role of 68Ga-PSMA PET/CT scan in biochemical recurrence after primary treatment for prostate cancer: a systematic review of the literature. Minerva Urol Nefrol. 2018; 70:462-478.

21. Eiber M, Maurer T, Souvatzoglou M, et al. Evaluation of Hybrid Ligand PET/CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy. J Nucl Med. 2015; 56:668-74.

7. Albisinni S, Artigas C, Aoun F, et al. Clinical impact of 68 Gaprostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) in patients with prostate cancer with rising prostate-specific antigen after treatment with curative intent: preliminary analysis of a multidisciplinary approach. BJU Int. 2017; 120:197-203. 8. Emmett L, van Leeuwen PJ, Nandurkar R, et al. Treatment Outcomes from 68Ga-PSMA PET/CT-Informed Salvage Radiation Treatment in Men with Rising PSA After Radical Prostatectomy: Prognostic Value of a Negative PSMA PET. J Nucl Med. 2017; 58:1972-6.

68Ga-PSMA

22. Afshar-Oromieh A, Holland-Letz T, Giesel FL, et al. Diagnostic performance of (68)Ga-PSMA-11 (HBED-CC) PET/CT in patients with recurrent prostate cancer: evaluation in 1007 patients. Eur J Nucl Med Mol Imaging. 2017; 44:1258-68. 23. Han S, Woo S, Kim YJ, Suh CH. Impact of 68Ga-PSMA PET on the management of patients with prostate cancer: a systematic review and meta-analysis. Eur Urol. 2018; 74:179-90. 24. Murphy DG, Sweeney CJ, Tombal B.Gotta catch ‘em al,” or do we? Pokemet approach to metastatic prostate cancer Eur Urol. 2017; 72:1-3.

9. Afshar-Oromieh A, Holland-Letz T, Giesel FL, et al. Diagnostic performance of 68Ga-PSMA-11 (HBED-CC) PET/CT in patients with recurrent prostate cancer: evaluation in 1007 patients. Eur J Nucl Med Mol Imaging. 2017; 44:1258-68 10. Perera M, Papa N, Christidis D, et al. Sensitivity, specificity, and predictors of positive 68Ga-prostate-specific membrane antigen positron emission tomography in advanced prostate cancer: a systematic review and meta-analysis Eur Urol 2016; 70:926-37. 11. Meredith G, Wong D, Yaxley J, et al. The use of 68 G a-PSMA PET CT in men with biochemical recurrence after definitive treatment of acinar prostate cancer. BJU Int. 2016; 118:49-55. 12. Mottet N, van den Bergh R, Briers E, et al. EAU - EANM ESTRO - ESUR - SIOG Guidelines on Prostate Cancer 2020. 13. Aboagye EO, Kraeber-Bodéré F. Highlights lecture EANM 2016: “Embracing molecular imaging and multi-modal imaging: a smart move for nuclear medicine towards personalized medicine”. Eur J Nucl Med Mol Imaging. 2017; 44:1559-1574. 14. Perera M, Papa N, Roberts M, et al. Gallium-68 Prostate-specific Membrane Antigen Positron Emission Tomography in Advanced Prostate Cancer-Updated Diagnostic Utility, Sensitivity, Specificity, and Distribution of Prostate-specific Membrane Antigenavid Lesions: A Systematic Review and Meta-analysis. Eur Urol. 2020; 77:403-417.

Correspondence João André Mendes Carvalho, MD (Corresponding Author) joao.andre.mendes.carvalho@gmail.com Estrada da Beira, nº 248, 2º D, 3000-173 Coimbra, Portugal Pedro Nunes ptnunes@gmail.com Edgar Tavares da Silva edsilva.elv@gmail.com Rodolfo Silva rodolfompsilva@gmail.com João Lima joaopedrosolima@gmail.com Vasco Quaresma vpdquaresma@gmail.com Arnaldo Figueiredo ajcfigueiredo@gmail.com Archivio Italiano di Urologia e Andrologia 2021; 93, 1

DOI: 10.4081/aiua.2021.1.26

ORIGINAL PAPER

Rigid and flexible ureteroscopy (URS/RIRS) management of paediatric urolithiasis in a not endemic country Stefania Ferretti 1, Monica Cuschera 1, Davide Campobasso 2, Claudia Gatti 3, Riccardo Milandri 1, Tommaso Bocchialini 1, Elisa Simonetti 1, Pietro Granelli1, Antonio Frattini 2, Umberto Vittorio Maestroni 1 1 Urology

Unit, University-Hospital of Parma, Italy; Unit, Hospital of Guastalla, Azienda USL-IRCCS of Reggio Emilia, Italy; 3 Paediatric Surgery Unit, University-Hospital of Parma, Italy. 2 Urology

Summary

Introduction: In the last years due to miniaturization of endoscopic instruments and percutaneous surgery, endourology has become very popular in paediatric urinary stone managment. We reported our single-centre experience in retrograde endoscopic procedures in children. Results and complications of URS/RIRS are discussed. Materials and methods: We retrospectively reviewed our experience in patients ≤ 16 years old affected by urinary stones who underwent URS/RIRS procedures performed by two surgeons with expertise in endourology. A total of 30 renal Units (RUs) underwent endoscopic procedures (URS, RIRS or both). Surgical complications according to the ClavienDindo’s classification and stone-free rate were evaluated at 3 months follow-up. Success of URS was defined as stone-free status after single procedure while RIRS success rate was considered as presence of residual stone fragments smaller than 4 mm at first procedure. Results: The mean age of our patients was 8 years, range 216 years. A total of 30 renal units (RUs) underwent 40 endourological procedures (23 URS and 17 RIRS; 10 children underwent both procedures at the same time). 17/30 (56.6%) RUs were pre-stented before surgery. The stone-free status was achieved in 23/30 renal units treated, with a 76.6% success rate. The remaining 7 patients had residual stones greater than 4 mm and underwent further treatments. After a second surgery the stone-free rate turned out to be 93.3% (28/30 renal units). Conclusions: Rigid and flexible ureteroscopy (URS/RIRS) is a reliable technique for treatment of < 2 cm urinary stones in paediatric age group. It shows low rate of major complications and promising results in terms of stone-free rate.

KEY WORDS: Flexible ureterescopy; Paediatric stone disease; RIRS; Laser lithotripsy. Submitted 8 September 2021; Accepted 27 October 2021

INTRODUCTION

The management of paediatric urolithiasis is nowadays more common in the current urologic practice. It is well known as an endemic problem in developing countries, but the incidence of nephrolithiasis in the paediatric population has been steadily growing also in the European

countries and in North America (1). During the last years, we have seen a higher incidence of paediatric stones disease: 5-13% in Western countries and 20% in Saudi Arabia, Egypt, Sudan, India and Thailand (2). All ages of the childhood, and both genders can be affected equally. Reasons are not clear and multiple factors have been suggested like obesity, changes in dietary habits with increased sodium intake, decreased calcium and water assumption and increasing use of fructose and antibiotics (1-3). The treatment is based on similar techniques as for adults, especially extracorporeal shock wave lithotripsy (SWL) and endourological techniques (semirigid ureteroscopy - URS, flexible retrograde intrarenal surgery - RIRS and percutaneous nehrolithotomy - PNL). The aim of stone management in children should be complete stone clearance, prevention of new stone formation and re-growth, preservation of renal function, control of urinary tract infection, minimal invasiveness, less anesthesia, less radiation exposure, as few as possible surgical drainage procedures and correction of both the anatomic abnormalities and the underlying metabolic disorders (4). Decision making for treatment strategies depends on the number, size, location, composition of stones and anatomy of the urinary system. In the last ten years due to miniaturization of endoscopic instruments and increased experience into retrograde and percutaneous treatment on adult patients, endourology has become the best approach to treat urinary stones in children. RIRS is effective and has become a good option in the treatment of renal stones < 2 cm (4-6). The aim of this study is to report our single-centre experience in paediatric stone management with retrograde endoscopic procedures. Results and complications of URS/RIRS are discussed. MATERIALS AND METHODS

We retrospectively reviewed our experience in patients ≤ 16 years old affected by urinary stones who underwent URS/RIRS procedures performed by two surgeons (AF and SF) with expertise in endourology. Twenty-eight patients were studied (19 male and 9 female), 2 of these suffering from bilateral renal stones and treated in separate surgical sessions. A total of 30 renal Units (RUs) underwent endoscopic procedures (URS, RIRS or both). No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

URS-RIRS in paediatric urolithiasis

The data were collected in collaboration with the Paediatric Surgery Unit at the University Hospital of Parma from January 2009 to May 2017. Local ethical committee approval was obtained for data collection (protocol number: 490/2019/OSS*/AOUPR). All patients underwent preoperative blood tests, urine culture and in 78.5% of patients (22/28) a low dose “flash” CT-scan without contrast medium was performed before surgery; all patients underwent abdominal ultrasound. Further evaluation (eg. MRI-scan, voiding cistouretrography, renal scintigraphy) were performed only in selected cases. Stone localization and size measurement were performed by non-contrast helical Computed Tomography (CT) scanning or Kidneyureter-bladder (KUB) radiographs/ultrasound exams. We considered 2 types of stone parameters: a. maximum length of the stones and b. surface area using Tiselius’ formula (SA = length×width×π×0.25). Procedures were performed with ultrathin 6.5/7Fr or 8Fr semirigid ureteroscope (Storz, Germany) or flexible ureteroscope X-Flex2 7.5Fr (Storz, Germany) in RIRS. A 9.5Fr ureteral access sheath (20 cm or 28 cm length – Cook, USA) was inserted when possible. In no case active dilation of distal ureter was performed during surgery due the potential risk of secondary ureteral stricture or vesicoureteral reflux. Stone fragmentation was achieved by 35 W holmium:YAG laser lithotripsy device (Quanta System, Italy). A laser fiber of 200 or 273 micron was used. X-ray was administered by Digital X-Ray EV Endurance Philips with internal protocol reducing doses to ¼ of total adult’s dose. Protective diaphragms were used for thyroid gland and genitalia because of the potential radiation risk. A routine preoperative antibiotic prophylaxis with a third generation cephalosporin or amoxicillin/clavulanic acid was administered to all patients and all procedures were performed under general anesthesia. After surgery, a ureteral catheter, mono-J or double-J was left in place based on the duration of the procedure, degree of ureteral edema and/or residual fragments. Generally, the JJstent’s strings were left if we planned to leave the stent for up 10 days. A bladder catheter was left for 24-48 hours in all patients. The removed stones underwent spectrometric analysis. Surgical complications according to the ClavienDindo’s classification and stone-free rate (assessed by abdominal ultrasound and “flash” helical CT-scan in doubtful cases) were evaluated at 3 months follow-up. All postoperative outcome data of patients referred from other centers (53%) were verified by telephone interview with the local physician and/or the parents. Success of URS was defined as stone-free status after single procedure while RIRS success rate was considered as presence of residual stone fragments smaller than 4 mm (Clinical Insignificant Residual Fragments) at first procedure. We reported the global success rate of both procedures at first step and second step (re-do surgery).

RESULTS

From January 2009 to May 2017, 28 children with urolithiasis were managed at our centre. Ten preschoolage children (1-5 yrs) and 18 school-age children (6-16 yrs). The mean age of our patients was 8 years, range 216 years. Urological comorbidities included: 7 recurrent

urinary infections, 6 ureteropelvic junction dysplasias, 2 megaureters, 1 distal ureteral substenosis, 1 renal double district, 2 vesicoureteral refluxes, 5 observed metabolic disorders (3 idiopathic hypercalciurias, 1 cystinuria, 1 hyperoxaluria). Relevant general comorbidities: 2 infant cerebral palsies, 1 thalassemia, 1 autism, 1 Lowe syndrome, 1 amelogenesis imperfecta. Previous urological surgery: 3 orchidopexies, 2 circumcisions, 2 pyeloplasties, 1 varicocele, 1 bulking agent injection for vesicoureteral reflux, 1 pyelolithotomy, 4 extracorporeal shock wave lithotripsies, 1 percutaneous nephrostomy; other procedures: 1 bowel resection for acute ischemic disease, 1 laparoscopic cholecystectomy, 1 removal of thoracic angiofibroma and 1 stabilization of the hips and femurs. A total of 30 renal units (RUs) underwent 40 endourological procedures (23 URS and 17 RIRS; 10 children underwent both procedures at the same time). In some cases a second look surgery was necessary. At the end of all surgical sessions 25 URS and 24 RIRS were recorded. The average stone area was 1.15 cm2 and the range of maximum stone diameter was 5-24 mm. Preoperative Grade I and II hydropnephrosis was present in 15 RUs (11 grade I, 4 grade II). No Grade III or IV was reported. 17/30 (56.6%) RUs were pre-stented before surgery (16 double JJ and 1 mono J); 15/17 in emergency for pain/fever (first access to paediatric surgery unit), 2/17 for ineffective previous ureteroscopy in other hospital; 13/30 RUs were not pre-stented at first procedure with positive surgical results; the age ranged from 5 to 16 years and the procedures were 8 simple URS and 5 URS/RIRS. In 12/24 RIRS we inserted 9.5 Fr ureteral access sheat- UAS (10/17 at first RIRS and 2/7 at second RIRS). None of the patients experienced access failure at surgery. Demographic and Preoperative data are shown in Table 1. Considering the total amount of procedures (surgery and redo surgery) 37 indwelling ureteral stents (29 double JJ and 8 mono J) were placed. Table 1. Demographic and preoperative data. Data Age (years) Sex (male/female) Lateralization (n) Right Left Bilateral Stone location (%) Ureter Pelvis CI CM CS UPJ Stone size: max lenght (mm) Stone surface area (cm2) Pre-operative hydronephrosis (RUs), n (%) Pre-operative stent insertion for RUs, n (%) MJ DJ

Patients 8 (2-16) 19/9 15 11 2 35 28 16 9 7 5 5-24 1,15 15 (50) 17 1 (5.8) 16 (94.2)

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

S. Ferretti, M. Cuschera, D. Campobasso, C. Gatti, R. Milandri, T. Bocchialini, E. Simonetti, P. Granelli, A. Frattini, U.V. Maestroni

Table 2. Redo surgery data. Data Age (years) Sex (male/female) Pre-operative stenting (n) Surgical procedures (n) RIRS URS&RIRS Mean hospital-stay (days) Post-operative stent insertion (n) MJ DJ Mean stent-indewelling time (days) % Stone-free status (n pts) %

Patients 7 (2-12) 5/2 7/7 5/7 2/7 5.5 (3-14) 3/7 4/7 9 (2-35) 5/7(71.4%)

Table 3. Operative and postoperative outcomes. Data Type of procedures (total n) UAS insertion (n) Operative Time (minutes) X-ray exposure (seconds) Postoperative stent insertion for RUs, n (%) DJ MJ Ureteral stent removal (days) Hospital stay (days) Stone composition (RUs), n (%) Ca oxalate Mixed Ammonium urate Calcium phosphate Unknown Cystine Stone free rate after 1° procedure (RUs), n (%) Stone free rate after 2° procedure (RUs), n (%) Complications (RUs), n (%) Clavien I Clavien II Clavien III Clavien IV Clavien V

Patients 25 URS 24 RIRS 12/24 77.7 (20-140) 14 (2-72) 37 29 (78.3) 8 (21.7) 14 (2-57) 5 (2-13) 30 17 (56.6) 4 (13.4) 3 (10) 3 (10) 2 (6.7) 1 (3.3) 23 (76.6) 28 (93.3) 4 (10.8) 2 2 0 0 0

The average time of indwelling stenting after first procedure was 14 days with a range of 2 to 57 days. During the procedure, the mean X-Ray exposure time was 14 seconds, with a range of 2-72 seconds. The duration of operations was calculated from intubation to awakening from the anesthesia owing to different OR logs in that period of time. Average time recorded was 78 minutes with a range of 30 to 140 minutes. The mean hospital stay was 5 days with a range of 2-13 days. stones were composed of calcium oxalate (56.6%), calcium phosphate (10%), ammonium urate (10%), cystine (3.3%) and mixed (13.4%). The stone-free status was achieved in 23/30 renal units treated, with a 76.6% success rate. The remaining 7 patients had residual stones greater than 4 mm and underwent further treatments. After a second surgery the stone-free rate turned out to be 93.3% (28/30 renal

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

units). In patients needing a surgical reoperation, the second procedure was performed after an average time of 74 days (14 days-330 days). The two failed children underwent renal SWL after 5 months while the last one required a MicroPERC® (PolyDiagnost) for a minor calyx’s residual stone one year later (Table 2). According to the Clavien-Dindo’s classification, complications occurred in 10,8% of all 37 renal units treated. In particular, minor complications (grade I and II) consisted of: fever during postoperative time (1 case), vomiting (1 patient with PEG), hematuria (1 case) and urinary tract infection (1 case). No major complications (grade III and IV) occurred. No patient needed blood transfusion. Two patients died because of their concomitant medical conditions (cerebral palsy and Lowe syndrome) 2 and 5 years after surgery, respectively. One patient affected by hypotrophic kidney before surgery one year later underwent nephrectomy. Operative and post-operative outcomes are summarized in Table 3.

DISCUSSION

Nowadays minimally invasive endoscopic techniques – such as URS/RIRS and mini-PNL – are considered the best approach for the treatment of paediatric urolithiasis in terms of efficacy and safety due to the miniaturization of the surgical instruments, the increasing incidence also in industrialized countries and the experience with adult patients (4-6). The patients we studied showed a high proportion of comorbidities: 42.8% urological malformations, 25% urinary tract infections, 25% non-urologic diseases and, finally, 17.8% metabolic disorders. These data demonstrate that paediatric nephrolithiasis is related to urologic malformations or infections and metabolic disorders (1-3). As many authors have pointed out, thanks to the introduction of flexible ureteroscopy it has become possible to treat both lower and upper urinary tract stones (7-9). This technique is suitable even when stones are located in tricky sites, such as lower calyces, or in case of renal and skeletal malformations where SWL are not recommended. Extracorporeal shock wave lithotripsy (SWL) was introduced twenty years ago, the 2019 European Guidelines on paediatric urolithiasis suggested for pelvic stones less than 2 cm this approach and RIRS or microPNL as secondary treatment options. Moreover, the stone-free rate is significantly affected by various factors. When the stone size increases (> 1.5/2 cm), the need for additional sessions increases in parallel. SWL was found to be less effective for caliceal stones and particularly for lower caliceal stones. Several studies reported stone-free rates varying between 50% and 62% (10). Ather et al. also assessed that stone-free rate decreases with increasing stone size and in case of lower calyxes stones (11). Although SWL is a non-invasive technique, some stones would require multiple sessions with the need of general anaesthesia in younger children. For the treatment of our patients we used semi-rigid ureteroscopy in 34% of cases, flexible instruments in 32% of cases and both in 34% of cases (using semi-rigid to start the procedure and flexible to complete it). Compared to adult URS, paediatric URS is still performed in a much smaller group of patients with an over-

URS-RIRS in paediatric urolithiasis

all risk of complications or failure slightly higher than in adults (6, 12). The importance of expertise in endourological procedures (rigid/flexible) was essential to improve the success rate. For example, Kucukdzman et al. reported an incidence of 3.7%-12% in paediatric ureteroscopy series for proximal ureteral stone migration (13). Today, in many hospital realities, this aspect is not considered as a complication due to the possibility to manage the push-up of the stone in the renal cavities. To share knowledge between paediatric and adult surgeon (twin-surgeon model) as a tutor at the beginning of the learning curve could be the answer for higher and quickly levels of performances (14). The difficulty in performing ureteroscopy in children younger than 3 or 5 years (due to the smaller ureteral diameter) is well known (1516). Our data show that 4 out 13 not pre-stented patients were up to five years old and no one experienced access failure to ureters. Moreover, it is important to use ultrathin semirigid ureteroscopes for negotiation the access to the ureteral meatus with light hydro-dilation and, at the same time, permitting a passive ureteral dilation before retrograde procedures with or without ureteral access sheath (17, 2). The use of UAS is under debate in the paediatric population for the potential risk of ureteral damage. In our experience, 12/24 RIRS were performed with UAS without complications; we believe that in renal stone smaller than 1 cm is not mandatory the use of ureteral access sheath like in adults. Berettini et al. reported a good experience in 13 pts weighing < 20 kg who underwent to RIRS with UAS; all patients presented 2 weeks before surgery. In 93.8% of cases, the UAS was inserted without complications and, at a mean follow up of 22 months, no long-term post-surgical complication was reported (15). Erkurt et al. reported the positioning of UAS in only 61.5% of cases and an incidence of 2 ureteral wall injuries due to sheath but without related complications at long-term follow up; in this population UAS before RIRS was inserted in 94.1% of pre-stented children and only 50% of non-stented patients (9). Chu et al. found a decreased operative time, re-do surgery rates, improved SFR and reduced risk of ureteral injury with the use of UAS in children pre-stented before RIRS (16). At the end of the procedures, all patients had a stent with a general good tolerance except for 2 patients (7%) who complained severe dysuria. Four children held the stent for more than one month while awaiting the second surgery; the prolonged time was due to complex clinical situations (cerebral palsy, two prolonged antibiotic therapies for other diseases). Stent placement after endoscopic procedures is a controversial issue. The device allowed reduction of pain owing to local edema and also limited the risk of infection due ureteral obstruction for residual fragments. At the same time, however, it required a readmission to operating room for removal. In our experience, children older than 14 years were subjected to outpatient stent removal procedure with a mild premedication; in all the other cases a short deep sedation was required. We are convinced of the importance of leaving self-removal strings for less ten days of indwelling time. Considering our patients, the stones showed an average surface area of 1.15 cm2 in accordance with the data from the literature (6-9).

The stones that required a second procedure were located in the pelvis and lower renal calices; the initial stone burden and multiple locations played an important role in re-do surgery. Lower pole stones seem to be more difficult to manage in particular when the stone is in an anterior calyx. Several Authors pointed out the necessity of multiple SWL sessions for obtaining a stone-free status in kidney stones in more than 70% of children. We believe that ureteroscopy reduced the risk of additional general anesthesia sessions, allowed the possibility to treat different stone localizations and to reduce X-ray exposure respect to SWL multiple procedures (18, 19). The data analyzed in our department show 76.6% stonefree rate after the first surgery and 93.3% stone-free rate after second look procedure in accordance with the literature which presents a variable stone-free rate between 77% and 100% (6-9, 17, 2). Complications were evaluated according Clavien-Dindo’s classification with 10.8% of patients showing grade I and II complications. No ureteral perforation was observed differently from a perforation rate of 2 to 7.3% reported in the literature in paediatric URS series (13). Endoscopic management of urinary stones is increasingly used also in paediatric population. The limitations of our study include its retrospective nature and the small series of patients that is due to the location of our hospital (North Italy) in a nonendemic geographic area for stones. On the other hand, our series is a homogeneous cohort of patients treated by only two surgeons with long experience in adult endourology (AF and SF) rather than by surgeons with different levels of expertise influencing stone-free success and complication rate. A larger population-based trial would be essential for confirming these preliminary data.

CONCLUSIONS

Nephrolithiasis in paediatric patients is a relevant disease both in terms of incidence, which is sharply increasing; relapses are quite frequent and can reduce patient’s quality of life. Evaluation of associated conditions such as urologic malformations, urinary tract infections, metabolic disorders, turns out to be fundamental in order to perform an early diagnosis and finally schedule a tailored treatment, with the least possible impact for the child. The choice of treatment has to be made considering patient's anatomical features and stone peculiarities (such as size and location). Our study concludes that rigid and flexible ureteroscopy (URS/RIRS) is a reliable technique for treatment of < 2 cm urinary stones in paediatric age group. It shows low rate of major complications and promising results in terms of stone-free rate. We hope that more and more integration will be possible between adult and paediatric urologists to make endourological procedures more familiar to the latter.

REFERENCES

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3. Atan A, Balcı M. Medical expulsive treatment in pediatric urolithiasis. Turk J Urol. 2015; 41:39-42. 4. Samotyjek J, Jurkiewicz B, Krupa A. Surgical treatment methods of urolithiasis in the pediatric population. Dev Period Med. 2018; 22:88-93. 5. Kılıç Ö, Akand M, Van Cleynenbreugel B. Retrograde intrarenal surgery for renal stones - Part 2. Turk J Urol. 2017; 43:252-260. 6. Whatley A, Jones P, Aboumarzouk O, Somani BK. Safety and efficacy of ureteroscopy and stone fragmentation for pediatric renal stones: a systematic review. Transl Androl Urol. 2019; 8(Suppl 4):S442-S447.

13. Kucukdurmaz F, Efe E, Sahinkanat T, et al. Ureteroscopy with holmium:Yag laser lithotripsy for ureteral stones in preschool children: analysis of the factors affecting the complications and success. Urology. 2018; 111:162-167. 14. Somani BK, Griffin S. Ureteroscopy for paediatric calculi: The twin-surgeon model. J Pediatr Urol. 2018; 14:73-74.

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9 Erkurt B, Caskurlu T, Atis G, et al. Treatment of renal stones with flexible ureteroscopy in preschool age children. Urolithiasis. 2014; 42:241-5.

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19. Muslumanoglu AY, Tefekli AH, Altunrende F, et al. Efficacy of extracorporeal shock wave lithotripsy for ureteric stones in children. Int Urol Nephrol. 2006; 38:225-9.

Correspondence Stefania Ferretti, MD sferretti@ao.pr.it Monica Cuschera, MD monica.cuschera@hotmail.it Claudia Gatti, MD tintswal@libero.it Riccardo Milandri, MD (Corresponding Author) riccardomilandri85@gmail.com Tommaso Bocchialini, MD tommaso.bocchialini@libero.it Elisa Simonetti, MD elisasimonetti88@gmail.com Pietro Granelli, MD granellipietro@gmail.com Umberto Vittorio Maestroni, MD umaestroni@aopr.it Via Gramsci 14, 43126 Parma (Italy) Davide Campobasso, MD d.campobasso@virgilio.it Antonio Frattini, MD antonio.frattini@ausl.re.it Via Donatori di Sangue, 42016 Guastalla (Italy)

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

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

DOI: 10.4081/aiua.2021.1.31

ORIGINAL PAPER

Is there a PSA cut-off value indicating incidental prostate cancer in patients undergoing surgery for benign prostatic hyperplasia? Senol Tonyali 1, Cavit Ceylan 2, Erdogan Aglamis 3, Serkan Dogan 4, Sedat Tastemur 2, Mustafa Karaaslan 2 1 Department

of Urology, Istanbul University Istanbul School of Medicine, Istanbul, Turkey; of Urology, University of Health Sciences, Ankara City Hospital, Ankara, Turkey; 3 Department of Urology, University of Health Sciences, Elazig City Hospital, Elazig, Turkey; 4 Department of Urology, Sancaktepe Sehit Prof. Dr. Ilhan Varank Training and Research Hospital, Istanbul, Turkey. 2 Department

Summary

Aim: To investigate incidental prostate cancer (IPCa) rate and to determine prostate specific antigen (PSA) cut-off value indicating PCa in patients who underwent surgery by being diagnosed with benign prostatic hyperplasia (BPH) clinically or by standard prostate biopsy. Methods: Data of 317 patients, who underwent transurethral resection of the prostate (TURP) or open prostatectomy (OP) with pre-diagnosis of BPH, were evaluated retrospectively. The examined parameters included patients’ demographics, preoperative serum PSA values, digital rectal examination (DRE) findings, surgical method, histopathological findings and Gleason Scores. Results: A total of 317 patients were included the study. The median age of patients was 69 years (min: 51-max: 79) and the median PSA value was 3.24 ng/dl (min: 0.17-max: 34.9). In 21 patients (6.6%); DRE findings were in favor of malignancy, but prostate biopsy resulted as BPH. While 281 (88.6%) of the patients underwent TURP, 36 (11.4%) underwent open prostatectomy. PCa was detected in 21 (6.6%) patients. PSA was statistically higher in patients who underwent OP compared to patient who underwent TUR-P, 5.9 (min: 1.2 max: 27.6, IR: 8.7) vs. 2.8 (min: 0.1-max: 34.9, IR: 4.2) ng/dl, p < .001. The rate of IPCa among four PSA group was similar (p = 0.46). There was no difference between the rate of IPCa in patients younger and older than 70 years, (p = 0.11). Please change whole sentence as 'The median PSA level was slightly higher in patients diagnosed with BPH compared to patients diagnosed with IPCa, 3.2 (min: 0.1-max: 34.9) vs. 2.7 (min: 0.3-max: 26.5) ng/dL, p = 0.9. Conclusions: IPCa still remains an important clinical problem. We were not able to find any correlation of PSA and age with incidental PCa.

KEY WORDS: Incidental; Prostate cancer; Open prostatectomy. Submitted 19 October 2020; Accepted 1 December 2020

INTRODUCTION

Prostate cancer (PCa) is the most commonly diagnosed cancer in men and the most common cause of cancer deaths following lung cancer. According to autopsy studies, the risk of PCa in men > 50-year-old is about 30% (1, 2).

Surgical treatment remains the most effective option in patients with lower urinary tract obstructive symptoms who did not respond to medical therapy and have moderate to severe symptoms. Evaluation of prostate specific antigen (PSA) and digital rectal examination (DRE) constitute the routine urological evaluations before surgery for benign prostatic hyperplasia (BPH) to exclude PCa; PSA density, PSA velocity, free/total PSA and PSA according to age could be utilized if required. A transrectal ultrasound-guided prostate biopsy is the gold standard to rule out PCa in these patients and have been used extensively. Neoplastic tissue may not be detected in sample when biopsy is performed with transrectal ultrasound (TRUS) guidance, even if the PSA levels are high or DRE findings are positive (11). Incidental prostate cancer (IPCa) is the diagnosis of PCa with histopathological examination of resected prostate tissue, which was previously considered benign. IPCa rates after both open prostatectomy (OP) and transurethral resection of prostate (TURP) have been reported to be vary between 5% and 41% in the literature (3-8). Despite normal PSA values, DRE findings, and normal prostate biopsy results before surgery; IPCa is still a challenge for physicians and patients with high expectations. In this study, we aimed to evaluate rate of IPCa after benign prostate surgery and to determine if there is a PSA cut-off value indicating IPCa in Turkish population.

MATERIALS

AND METHODS

The study protocol was approved by the Institutional Review Board of Turkiye Yuksek Ihtisas Training and Research Hospital (Approval Number: 15.03.201829620911-929-E.2475). The data of all consequent patients who underwent TURP or OP with the pre-diagnosis of BPH between 2008-2018 were evaluated retrospectively. Patients with normal DRE and PSA levels in preoperative evaluation as well as patients who underwent TRUS guided prostate needle biopsy prior to surgery due to abnormal DRE and/or high serum PSA values and were reported to have not PCa were included the study. Patients who had a history of PCa or patients who received any treatment

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

S. Tonyali, C. Ceylan, E. Aglamis, S. Dogan, S. Tastemur, M. Karaaslan

due to PCa were excluded from the study. The examined parameters included patients’ demographics, preoperative serum PSA values, DRE findings, surgical method, histopathological findings and Gleason Scores. The relationship between these parameters and IPCa was investigated. Tha patients were divided into 4 groups according to PSA values: Group 1: PSA < 2.5 ng/dL, Group 2: PSA = 2.5-4 ng/dL, Group 3: PSA = 4.10 ng/dL, Group 4: PSA > 10 ng/dL. Statistical analysis Statistical analysis was performed using IBM SPSS statistical package program v 21.0. Continues variables were given in median (minimum-maximum) and categorical variables were given in numbers and percentage. ROC curve analysis was used to determine cut-off value for PSA. Spearman correlation test was performed for the relationship between PSA, age and IPCa. Chi-Square test was used to determine the differences between frequencies in two categorical variables. Mann-Whitney U test was used to compare the age and PSA of the patients with and without prostate cancer when there was not a normal distribution after Kolmogorov-Smirnov test.

who had a Gleason score > 9 were referred to the oncology clinic for adjuvant hormone therapy and radiotherapy. PSA was statistically higher in patients who underwent OP compared to patient who underwent TUR-P, 5.9 (min: 1.2- max: 27.6, IR: 8.7) vs. 2.8 (min: 0.1-max: 34.9, IR: 4.2) ng/dl, p < .001. The rate of IPCa among four PSA group was similar (p = 0.46). There was no difference between the rate of IPCa in patients younger and older than 70 years, (p = 0.11). The median PSA level was slightly higher in patients diagnosed with BPH compared to patients diagnosed with IPCa, 3.2 (min: 0.1-max: 34.9) vs. 2.7 (min: 0.3-max: 26.5) ng/dL, p = 0.9.

DISCUSSION

Today, the rate of IPCa is still found to be high in patients diagnosed with BPH clinically or after prostate biopsy under the guidance of TRUS. The widespread use of new biopsy techniques such as multiparametric magnetic resonance imaging (MRI) - targeted biopsy may decrease the rate of IPCa. In our study, 6.6% IPCa was detected in patients who underwent open prostatectomy or TUR-P with the diagnosis of benign prostatic hyperplasia. Prostate cancer incidence and cancer-related mortality are more common in European countries than in Asian RESULTS countries (12, 13). The rate of diagnosis of IPCa reaches A total of 317 patients were included the study. up to 16% in parallel with the increase in life expectanThe median age of patients was 69 years (min: 51, max: cy and might not to be underestimated (5). The use of 79) and the median PSA value was 3.24 ng/dl (min: PSA and its derivatives in daily urology practice, the 0.17, max: 34.9). In 21 patients (6.6%) DRE findings increase in the number of prostate needle biopsy cores were in favor of malignancy, but prostate biopsy resultand the improvement in technical methods have ed as BPH. While 281 (88.6%) of the patients underwent decreased the rate of IPCa cases over the years but it has TURP, 36 (11.4%) underwent open prostatectomy. PCa not been minimalized (5). Rohr et al. reported a rate of was detected in 21 (6.6%) patients (Table 1). 15% IPCa in 457 TURP operations in 1987 and Merril et The Gleason scores of the patients with IPCa were as folal., reported in their study that the rate of IPCa deterlow: G6 (n = 10), G7 (3 + 4) (n = 2), G7 (4 + 3) (n = 1), mined by TURP gradually decreased between 1980 and G8 (n = 2), G9 (n = 3) and G10 (n = 3). Four patients 1999. They also reported that IPCa rates decreased from with Gleason scores > 6 underwent radical prostatecto39% to 7% from 1980s to 2000 (14, 15). In a study that my. A patient in high-risk group after this radical prostaemphasized the importance of age-specific PSA, IPCa tectomy and a patient with low-surgical performance was observed in 13% of patients who underwent TURP and open prostatectomy, whereas this rate was decreased to 6.3% with age-specific PSA Table 1. assessment (16). In a study by Zigeuner et al., Patient characteristics and comparison of patients with and without it was reported that preoperative DRE and incidental prostate cancer. PSA test combination caused a 50% reducTotal Benign prostate Incidental prostate P value tion in the detection rate of IPCa (16). In our (n = 317) hyperplasia (n = 296) cancer (n = 21) study, we detected IPCa in 6.6% of patients Median age (years) 69 (51-79) that underwent TURP and open prostatectoAge < 70 years 178 170 8 0.11^ my. Our rate is consistent with the literature Age > 70 years 139 126 13 and we think that the decrease in the rate of Median PSA (ng/dL) 3.2 (0.1-34.9) IPCa is related to early diagnosis with the PSA < 2.5 118 (37.2%) 109 9 0.46^ advances in diagnostic tests and biopsy techPSA: 2.5-4.0 73 (23%) 71 2 PSA: 4-10 93 (29.3%) 85 8 niques we utilized in the light of the technoPSA > 10 33 (10.4%) 31 2 logical developments. On the other hand, Gleason score Gleason 3+3 10 (3.15%) with increase in life expectancy, it is obvious Gleason 3+4 2 (0.63%) that IPCa that can be newly diagnosed is that Gleason 4+3 1 (0.31%) was previously named as hidden prostate Gleason 4+4 1 (0.31%) cancer. Perhaps the rate of 19.9% IPCa Gleason 4+5 2 (0.63%) detected by Abedi et al. might be the best Gleason 5+4 1 (0.31%) example of this. This demonstrates that IPCa Gleason 5+5 3 (0.94%) diagnosis rate cannot be minimized and is Gleason 5+3 1 (0.31%) not constantly reduced (4). The lack of

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

Incidental prostate cancer

homogeneous study cohorts and inter-racial differences might explain the wide range of this rate in literature. Zigeuner et al., reported an IPCa of 7.9% in 445 patients who underwent TURP or open prostatectomy after transrectal prostate biopsy due to high PSA level and/or abnormal DRE. The rate of IPCa reported in this study is similar to our results, however the inclusion of patients who underwent transrectal prostate biopsy prior to surgery might affect obtaining a low IPCa rate (17). In a study conducted by Otto et al., 771 patients who underwent TURP were retrospectively analyzed and IPCa was detected in 11 patients (1.4%). Among 11 patients, ten had a (91%) Gleason Score of 3+3 = 6 and one (9%) patient had a Gleason score of 3+4 = 7. Of 11 patients with IPCa, nine had T1a disease and two had T1b disease. (18). When compared with this study, the rate of IPCa was found to be higher in our study. However, in their study, Otto et al., only included patients who underwent TURP and the mean resected tissue weight was 8.1 g. The amount of prostate sample examined may affect the ratio of IPCa. In our study, 47.6% of IPCa cases had a Gleason Score of ≤ 6, which is lower than the rate reported by Otto et al. In another study by Abedi et al., authors reported higher IPCa rates detected via open prostatectomy compared to TURP (4). Although, IPCa ratios detected via open prostatectomy were higher compared to TURP in our study, it was not statistically significant. This might be due to the low number of patients in the open prostatectomy group. In PCa diagnosis, various methods have been developed to prevent unnecessary repeated biopsies and to detect PCa that need to be treated. Multiparametric magnetic resonance imaging (MRI) fusion biopsy is one of these methods gaining importance day by day (19). Several researchers reported that MRI-targeted biopsy is superior to standard transrectal ultrasonography (TRUS)-guided biopsy in detection of PCa (20, 21). European Association of Urology (EAU) guidelines favor MRI guided biopsy to systematic biopsy in detecting ISUP grade ≥ 2 PCa in the repeated-biopsy setting. However, in biopsy-naïve patients this difference was stated to be less significant (22). In their retrospective multicenter study, Porreca et al. investigated the utility of ‘in-bore’ MRI prostate biopsy to exclude significant PCa in patients with BPH scheduled for transurethral laser enucleation of prostate. The authors concluded that including mpMRI and MRI guided biopsy prior to surgery for BPH might lead to low PCa and avoid unnecessary standard TRUS-guided biopsies (23). In our study, prostate biopsy was performed only with conventional TRUS which might be considered a limitation of our study. Incidental PCa detection still remains as a troublesome problem for the patients, urologists and the pathologists. According to the Collage of American Pathologists statement, it was suggested to sample all prostate tissue left behind when T1a PCa was detected (8). In routine practice of pathologists, it is not possible to sample all of the TURP or open prostatectomy materials. This may cause IPCa cases to be overlooked. For this reason, the determination of preoperative clinical parameters that may predict IPCa may change the preoperative approach of the urologists, and may also help the pathologists to

determine the required pathological sample amount for an accurate examination. However, this may also lead to over diagnosis and over treatment risk. Our study is not without limitations. The retrospective nature of our study and the inclusion of patients treated with different surgical methods are the main limitations of our study. In addition, the absence of patients to whom multiparametric MRI-targeted biopsy was applied might be another issue. Prospective multicenter studies with large patient number comparing standard TRUS prostate biopsy and new biopsy techniques such as MRI-targeted prostate biopsy might improve our knowledge in this topic.

CONCLUSIONS

Incidental PCa detection rate is considerably high in patients undergoing surgery for benign prostatic hyperplasia, which was diagnosed clinically or via standard TRUS-guided prostate needle biopsy. Thus, IPCa still remains an important clinical problem. We were not able to find any correlation of PSA and age with incidental PCa. Determination of new parameters that can predict IPCa detection and the widespread use of new biopsy techniques such as MRI-targeted biopsy may decrease the rate of IPCa.

REFERENCES

1. Jemal A, Murray T, Ward E, et al. Cancer statistics. CA Cancer J Clin. 2005; 55:10-30. 2. Stangelberger A, Waldert M, Djavan B. Prostate cancer in elderly men. Rev Urol. 2008; 10:111-119. 3. Yoo C, Oh CY, Kim SJ, et al.. Preoperative clinical factors for diagnosis of incidental prostate cancer in the era of tissue-ablative surgery for benign prostatic hyperplasia: a Korean multi-center review. Korean J Urol. 2012; 53:391-395. 4. Abedi AR, Fallah-Karkan M, Allameh F, et al. Incidental prostate cancer: a 10-year review of a tertiary center, Tehran, Iran. Res Rep Urol. 2018; 10:1-6. 5. Stamey TA, Kabalin JN, McNeal JE. Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of prostate. J Urol. 1989; 141:1076. 6. Voigt S, Hüttig F, Koch R, et al. Risk factors for incidental prostate cancer who should not undergo vaporization of the prostate for benign prostate hyperplasia? Prostate. 2011; 71:1325-1331. 7. Helfand BT, Anderson CB, Fought A, et al. Postoperative PSA and PSA velocity identify presence of prostate cancer after various surgical interventions for benign prostatic hyperplasia. Urology. 2009; 74:177-183. 8. Trpkov K, Thompson J, Kulaga A, Yilmaz A. How much tissue sampling is required when unsuspected minimal prostate carcinoma is identified on transurethral resection? Arch Pathol Lab Med. 2008; 132:1313-6. 9. Jahn JL, Giovannucci EL, Stampfer MJ. The high prevalence of undiagnosed prostate cancer at autopsy: implications for epidemiology and treatment of prostate cancer in the prostate-specific antigen-era. Int J Cancer. 2015; 137:2795-2802. 10. McConnell JD. Epidemiology, etiology, pathophysiology, and diagArchivio Italiano di Urologia e Andrologia 2021; 93, 1

S. Tonyali, C. Ceylan, E. Aglamis, S. Dogan, S. Tastemur, M. Karaaslan

nosis of benign prostatic hyperplasia. In: Walsh PC, Retik AB, Vaughan Jr ED, Wein AJ, eds. Campbell’s Urology. 7thed. Philadelphia: WB Saunders Company. 1998, p.1429-52.

18. Otto B, Barbieri C, Lee R, et al. Incidental prostate cancer in transurethral resection of the prostate specimens in the modern era. Adv Urol. 2014; 2014:627290.

11. Fernández RE, Gómez VF, Alvarez CL, et al. Clinicopathological study of incidental cancer prostate in patients undergoing surgery for symptomatic diagnosis of BPH. Actas Urol Esp. 2006; 30:33-37

19. Borkowetz A, Platzek I, Toma M, et al. Comparison of systematic transrectal biopsy to transperineal MRI/ultrasound-fusion biopsy for the diagnosis of prostate cancer. BJU Int. 2015; 116: 873-9.

12. Parkin DM, Bray F, Ferlay J, Pisani P. 2005. Global cancer statistics. CA Cancer J Clin. 2002; 55:74-108.

20. Kasivisvanathan V, Rannikko AS, Borghi M et al. MRI-targeted or standard biopsy for prostate-cancer diagnosis. N Engl J Med, 2018; 378:1767-77.

13. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics. CA Cancer J Clin. 1999; 49:8-31. 14. Rohr LR. Incidental adenocarcinoma in transurethral resections of prostate. Am J Surg Pathol. 1987; 11:53-8. 15. Merril RM, Wiggins CL. Incidental detection of population based prostate cancer incidence rates trough transurethral resection of the prostate. Urol Oncol. 2002; 7:213-9. 16. Zigeuner RE, Lipsky K, Rieder I, et al. Did the rate of incidental prostate cancer change in the era of PSA testing? A retrospective study of 1127 patients. Urology; 2003; 62:451-5. 17. Zigeuner R, Schips L, Lipsky K, et al. Detection of prostate cancer by TURP or open surgery in patients with previously negative transrectal prostate biopsies. Urology; 2003; 62:883-887.

Correspondence Senol Tonyali, MD (Corresponding Author) senoltonyali@hotmail.com Cavit Ceylan, MD ceylancavit@yahoo.com Sedat Tastemur, MD sedattastemur@yahoo.com Department of Urology, Istanbul University Istanbul School of Medicine Surgery Monobloc Floor:1, 34104 Çapa Fatih, Istanbul (Turkey) Mustafa Karaaslan, MD mustafakaraaslan23@gmail.com Erdogan Aglamis, MD uroloji23@yahoo.com Department of Urology, University of Health Sciences, Elazig City Hospital, Elazig (Turkey) Serkan Dogan, MD sdogan1907@yahoo.co.uk Department of Urology, Sancaktepe Sehit Prof. Dr. Ilhan Varank Training and Research Hospital, Istanbul (Turkey)

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

21. Kasivisvanathan V, Stabile A, Neves JB et al. Magnetic resonance imaging-targeted biopsy versus systematic biopsy in the detection of prostate cancer: a systematic review and meta-analysis. Eur Urol. 2019; 76:284-303. 22. Mottet N, Cornford P, van der Bergh RCN, et al. EAU- EANMESTRO- ESUR- SIOG Guidelines of Prostate Cancer 2020. Available at: https://uroweb.org/guideline/prostate-cancer/ 23. Porreca A, D'Agostino D, Vigo M, et al. "In-bore" MRI prostate biopsy is a safe preoperative clinical tool to exclude significant prostate cancer in symptomatic patients with benign prostatic obstruction before transurethral laser enucleation. Arch Ital Urol Androl. 2020; 91:224-229.

DOI: 10.4081/aiua.2021.1.35

ORIGINAL PAPER

Maternal hydronephrosis in pregnant women without ureteral stones and characteristics of symptomatic cases who need treatment: A single-center prospective study with 1026 pregnant women Zeki Bayraktar 1, Şerife Tuğba Kahraman 2, Elif Seçkin Alaç 2, "rem Yengel 2, Deniz Sarıkaya Kalkan 2 1 Department 2 Department

of Urology, School of Medicine, Istanbul Medipol University, Istanbul, Turkey; of Obstetrics and Gynecology, School of Medicine, Istanbul Medipol University, Istanbul, Turkey.

Summary

Purpose: The aim of this study is to determine the proportion of maternal hydronephrosis and symptomatic cases requiring treatment in pregnant women without ureteral stones and the characteristics of these cases. Materials and methods: Between February 2018 and April 2019, all pregnant women followed for pregnancy in obstetrics and outpatient policlinic were evaluated prospectively. Maternal hydronephrosis rate, degree of hydronephrosis and side, symptomatic hydronephrosis rate, maximum renal anteroposterior diameter of renal pelvis and visual analogue scale were detected. Symptomatic patients were treated conservatively or surgically. Findings in both treatment groups were analyzed by t-test or Chi-squared test. Pearson or Spermean’s tests were used for correlation analyzes. Results: A total of 1026 pregnant women aged 18-45 (27.7 ± 5.2 years) were followed prospectively. The rate of maternal hydronephrosis was 28.7% and the rate of symptomatic hydronephrosis was 4.7%. Of the patients with symptomatic hydronephrosis, 73.4% (3.5% of total) were treated conservatively and 26.5% (1.3% of total) were treated surgically. There was a positive correlation between hydronephrosis and gestational week (p < 0.001), visual analogue scale (p < 0.001) and hematuria (p < 0.05). There was a negative correlation between hydronephrosis and maternal age (p < 0.05) and number of pregnancies (p < 0,001). The anteroposterior diameter of renal pelvis (p < 0.001), visual analogue scale (p < 0.05) and fetal body weight values (p < 0.05) on the right side were higher in the surgical treatment group than the conservative group. Conclusions: The majority of cases with maternal hydronephrosis in pregnant women without ureteral stones are asymptomatic. Most symptomatic cases can also be treated conservatively. In cases requiring surgical treatment (1.3%), fetal body weight, visual analogue scale and anteroposterior renal pelvis diameter are higher.

KEY WORDS: Hydronephrosis; Pregnancy; Maternal; Symptomatic; Treatment. Submitted 27 August 2020; Accepted 21 October 2020

INTRODUCTION

Asymptomatic maternal hydronephrosis during pregnancy may be present in more than 90% of pregnant women (1-3). Therefore, maternal hydronephrosis due to pregnancy is generally considered a normal -physiological- phenomenon. However, there are also cases of maternal hydronephrosis that require treatment. Therefore, maternal pathological obstructive hydronephrosis cases should be differentiated from maternal physiological dilatations. For this purpose, some authors suggest the use of the term "physiological maternal renal pelvic dilatation" to avoid the pathological connotations of the term maternal hydronephrosis (4). According to the literature, the rate of symptomatic maternal hydronephrosis is 0.2-3% (1, 5-10). Untreated cases of symptomatic maternal hydronephrosis can cause fulminant pyelonephritis and urosepsis in the presence of urinary infections (9). Therefore, it should not be late in the treatment of symptomatic hydronephrosis cases. Otherwise, it may cause urosepsis, which may endanger the life of both mother and fetus (5, 11-13). In addition, acute antepartal pyelonephritis significantly increases preterm birth (13, 14). Maternal upper urinary tract dilatations, which are considered physiologically normal, are mostly observed on the right side. It usually develops after the mid-gestation (4, 15-19). Urinary dilatation in pregnant women is explained by the effect of progesterone on the smooth muscle of the urinary system and the compression of the expanding uterus into the ureter (2, 4, 18, 20). Further observation of dilatations on the right side and twin pregnancies also supports this hypothesis (4). In addition, the crossing of the ureter by the ovarian vein at the pelvic brim on the right while running parallel on the left, dextrorotation of the uterus, and the relative protection of the left ureter provided by the sigmoid colon are also possible factors (2, 4, 18). As a matter of fact, maternal hydronephrosis usually improves spontaneously after delivery because the compression of the uterus is removed after birth (19, 20). And a few weeks after birth completely disappeared (15, 18, 20). The first-line imaging test to diagnose maternal hydronephrosis is ultrasonography (US) (21, 22).

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

Zeki Bayraktar, Ş. Tuğba Kahraman, E. Seçkin Alaç, I. Yengel, D. Sarıkaya Kalkan

Because US is a non-invasive and ionizing radiation-free imaging technique (21). In addition, maternal nephrosonography findings during pregnancy were quantitatively and qualitatively documented years ago (15, 16). Ultrasonographic evaluation has been the mainstay of obstetric imaging for many years (4). Maternal hydronephrosis can be detected with abdominal US from the beginning of the second trimester of pregnancy (23). US is excellent for the detection of hydronephrosis. However, there may be some problems in distinguishing between pregnancy-dependent physiological hydronephrosis and stone-dependent obstructive hydronephrosis. In fact, according to literature data, the success of conventional gray-scale US in detecting obstruction due to ureteral stones is 77-80%, as it cannot detect stones in the middle ureter usually (24). Magnetic resonance imaging (MRI) technique may be preferred in these patients (22). But the first step of the imaging method that should be preferred during pregnancy is US (21, 23). For detection of maternal renal dilatations, intrarenal calyceal dilatations or anteroposterior renal pelvis diameter (APD) are measured by US (4, 25, 26). The most common measurement for diagnosis and classification is APD. But it gives limited information in terms of prognostic. Because although APD is an objective, non-invasive and easily detectable measurement, it cannot show parenchymal changes and the true degree level of hydronephrosis (26). Treatment options for symptomatic maternal hydronephrosis are conservative treatment and surgery (1, 5). Conservative treatment includes close monitoring, analgesic, intravenous fluid and, if necessary, antibiotics. Surgical treatment includes double pigtail (JJ) ureteral stent insertion and percutaneous nephrostomy. And it is usually applied in severe flank pain that does not respond to medical treatment and in the presence of severe hydronephrosis (1, 5). However, it is not yet clear which treatment approach should be chosen for patients with symptomatic maternal hydronephrosis (1). Our aim in this study was to determine the proportion of maternal hydronephrosis and symptomatic cases requiring treatment in pregnant women without ureteral stones and the characteristics of these cases.

MATERIALS

AND METHODS

A prospective controlled study was designed. The study protocol was approved by the institutional ethics committee of the School of Medicine, Istanbul Medipol University, Turkey (15/02/2018-604.01.01-E.5443). Between February 2018 and April 2019, maternal renal ultrasonography was performed in all pregnant women followed up in the outpatient clinic of Gynecology and Obstetrics in our university(at least one ultrasonographic measurement in the first, second and third trimester and 2-3 months after birth). The presence and absence of hydronephrosis, if any, degree and side or it were noted. The maximum renal anteroposterior diameter of renal pelvis (APD) was measured in patients with hydronephrosis. Serum glucose, blood urea nitrogen (BUN), creatinine, white blood cell count (WBC), C-reac-

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

tive protein (CRP), urine analysis(presence of hematuria and leukocyturia) and urine culture-antibiogram were detected. Maternal age (year), gestational age (week), body mass index (BMI), number of pregnancies, number of fetuses, arterial blood pressure, amniotic fluid index (AFI), birth week, type of delivery, birth sex, baby weight (FBW) and 5. minutes Apgar score was recorded. Symptomatic patients were treated conservatively or surgically. Findings in both treatment groups were analyzed statistically. All ultrasonographic investigations and renal pelvis measurements were performed by radiologists and registered obstetricians who were trained in ultrasonograpy with experience ranging 7 to 25 years, using a LOGIC P6 PRO ultrasonography system with a 3.5 MHz broadband curvey array transducer (GE Healthcare, Gyeonggi, Korea). The visual analogue scale (VAS) was used to determine severity of the flank pain (0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; 0 and 10 points as no pain and maximum pain, respectively) (28). Hydronephrosis was classified according to a common grading system, and definitions followed the guidelines of the European Association of Urology (Grade 0, no renal pelvis dilation; Grade 1, mild renal pelvis dilation (anteroposterior diameter less than 10 mm) without dilation of the calyces nor parenchymal atrophy; Grade 2, moderate renal pelvis dilation (between 10 and 15 mm), including a few calyces; Grade 3, Renal pelvis dilation with all calyces uniformly dilated, normal renal parenchyma; Grade 4, as grade 3 but with thinning of the renal parenchyma, represents mild parenchymal loss; Grade 5, severe parenchymal loss (28). All hydronephrosis cases with flank pain (VAS > 2), fever and leukocyturia and/or leukocytosis were considered symptomatic. All symptomatic patients with hydronephrosis were referred to the Urology outpatient clinic and treated medically or surgically according to clinical and laboratory findings. First, position, analgesic and intravenous fluid treatment were applied in the medical treatment group. In patients with signs of infection such as fever, leukocytosis and elevation of CRP, Sefamezin was started if the antibiogram result was negative. If the antibiogram result was positive, antibiotic was determined according to antibiogram. The following cases were defined as the failure of medical treatment; 1) The infection findings do not improve within 48 hours despite antibiotic treatment, 2) Distortion of renal functions, 3) Increased flank pain, or no decrease in flank pain. The patients with at least one of these findings and all patients with hydronephrosis grade 3 were treated surgically by double-J ureteral stent insertion. For this, 6-8 Fr double-J ureteral stent (Boston Scientific, MA, USA) was inserted under local or general anesthesia with cystoscopic guidance to the side of hydronephrosis. In all cases, the hospitalization course and the complications of surgery were recorded. The stent was monitored ultrasound and it was removed one month after delivery. The data obtained were classified and analyzed statistically. Statistical analyses were performed using NCSS statistical software (Number Cruncher Statistical System,

Maternal hydronephrosis

N Age (years) Gestational age (weeks) Number of pregnancy Number of primipara women Number of multiple pregnancy Hydronephrosis side; Right Left Bilateral Trimester; 1 (< 14th weeks) 2 (14th-27 weeks) 3 (27th-41 weeks) Hydronephrosis; No (Grade 0) Hydronephrosis Grade 1 Grade 2 Grade 3 Treatment; Conservative Surgical Total

516 8

Mean ± SD % 27.7 ± 5.2 24.5 ± 8.5 1.7 ± 1.0 50.2% 0.7%

295 27 27

28.7% 2.6% 2.6%

108 489 429

10.5% 47.6% 41.8%

731 295 183 92 20 49 36 13 1.026

71.2% 28.7% 17.8% 8.9% 1.9% 4.7% 3.5% 1.2% 100%

Table 1. Patient characteristics of 1.026 pregnant women.

2007, Kaysville, Utah, USA). Descriptive statistics (mean ± SD and percentages) were used to present demographic information of the study participants. Discrete data are presented as numbers (N) and percentages (%). ANOVA test, t test and Chi square test were used for statistical analysis (when appropriate); P values less than 0.05 were considered statistically significant. This study was carried out with 1.026 pregnant women who met the inclusion criteria. Power calculation was performed. All proportional and parametric comparisons in subgroups are at least 95% power. Inclusion criteria Pregnant women followed in the obstetrics clinic. Exclusion criteria Renal tract calculi, structural renal parenchymal or collecting system anomalies (single kidney, horseshoe kidney, renal ectopia, duplicated collecting system, ectopic ureter, and extra renal pelvis), previous surgical intervention to the kidneys or ureters, and renal malignancy. Renal tract calculi was detected mainly by ultrasonography. However, MRI was performed in cases whose ureteral stones could not be completely excluded by ultrasonography, especially in middle ureteral stones.

RESULTS

A total of 1.026 pregnant women aged between 18 and 45 years (27.7 ± 5.2) were followed during the study period. The number of cases with

hydronephrosis was 295 (28.7%). The mean age of the patients with hydronephrosis was 27.1 ± 4.6 (18-43 years). Hydronephrosis was on the right side in 295 patients (28.7%) and on the left side in 27 patients (2.6%). The number of patients with bilateral hydronephrosis was 27 (2.6%). Of the 295 pregnant women with hydronephrosis, 246 (83.3%) were asymptomatic. Of the 49 patients (16.6%) with hydronephrosis, 36 (73.4%) were treated conservatively and 13 (26.5%) were treated surgically (Table 1). There was a positive correlation between hydronephrosis and gestational week (p < 0.001), VAS score (p < 0.001) and hematuria (p < 0.05). There was a negative correlation between hydronephrosis and maternal age (p < 0.05) and number of pregnancies (p < 0.001). There was no positive or negative correlation between maternal hydronephrosis and BMI, number of fetuses, glucose, BUN, creatinine, WBC, CRP, arterial blood pressure, leukocyturia, AFI, birth week, delivery type, FBW and Apgar score (p > 0.05) (Table 2). While leukocituria was positive in 28 of the symptomatic cases (57.1%), only 17 of these cases were culture posi-

Table 2. Patient characteristics and clinical data.

Age (years) BMI GA (weeks) GA at delivery Number of pregnancy Multiple pregnancy Glucose Serum BUN (mg/dl) Creatinine (mg/dl) WBC (x103 µl) CRP (mg/dl) Apgar score. 5-min FBW (kg) VAS score TA (mm/Hg); Systolic Diastolic Primipara Hematuria Leukocyturia AFI; Normal Polyhydramnios Oligohydramnios Trimester; 1 (< 14th weeks) 2 (14th-27 weeks) 3 (27th-41 weeks) Treatment; Conservative Surgical Participants Total

Grade 0 27.9 ± 5.3 26.7 ± 4.6 23.3 ± 8.6 38.7 ± 1.2 1.86 ± 1.1 5 (0.68%) 84.3 ± 12.6 9.2 ± 2.2 0.46 ± 0.13 9.2 ± 2.3 5.0 ± 2.3 9.7 ± 0.4 3.37 ± 0.4 0

Hydronephrosis N (%), Mean ± SD Grade 1 Grade 2 Grade 3 27.2 ± 4.5 26.6 ± 4.7 27.9 ± 5.2 27.1 ± 5.1 26.2 ± 3.3 31.9 ± 6.2 26.8 ± 6.8 28.7 ± 5.8 29.7 ± 6.9 38.8 ± 0.9 38.9 ± 0.8 39.2 ± 0.9 1.68 ± 1.0 1.43 ± 0.7 1.75 ± 0.8 1 (0.54%) 2 (2.1%) 0 (0%) 85.5 ± 12 82.8 ± 10.3 84.3 ± 11.2 10.3 ± 2.3 9.7 ± 2.7 10.4 ± 3.2 0.43 ± 0.2 0.38 ± 0.2 0.42 ± 0.3 9.5 ± 2.0 16.3 ± 9.3 17.4 ± 7.2 6.1 ± 2.6 7.4 ± 2.5 9.7 ± 2.9 9.7 ± 0.4 9.5 ± 0.6 9.9 ± 0.2 3.27 ± 0.3 3.30 ± 0.2 3.59 ± 0.4 3.3 ± 1.7 3.1 ± 1.9 6.2 ± 2.1

r = -0.070. p = 0.024 r = -0.021. p = 0.507 r = 0.233. p = 0.000 r = 0.091. p = 0.293 r = -0.128. p = 0.000 r = 0.016. p = 0.616 r = 0.068. p = 0.459 r = 0.170. p = 0.617 r = -0.102. p = 0.408 r = 0.165. p = 0.055 r = 0.297. p = 0.149 r = 0.095. p = 0.225 r = -0.028. p = 0.755 r = 0.382. p = 0.000

107.6 ± 12.4 65.2 ± 9.3 341 (46.6%) 23 (3.1%) 27 (3.7%)

107.9 ± 10.2 64.6 ± 8.2 104 (56.8%) 39 (21.3%) 48 (26.2%)

109.9 ± 12.7 66.6 ± 9.2 63 (68.4%) 44 (47.8%) 47 (51%)

107 ± 6.3 63 ± 8.5 11 (55%) 14 (70%) 13 (65%)

r = 0.018. p = 0.581 r = 0.007. p = 0.816 r = 0.016. p = 0.616 r = 0.244. p = 0.013 r = -0.068. p = 0.570

720 (98.4%) 12 (1.64%) 1 (0.13%)

176 (96.1%) 7 (3.8%) 0 (0%)

89 (96.7%) 2 (2.1%) 1 (1.1%)

19 (95%) 1 (5%) 0 (0%)

r = -0.32. p = 0.320

101 (13.8%) 356 (48.7%) 274 (37.4%) 0 (0%) 0 (0%) 0 (0%) 731 (71.2%) 731 (71.2%)

7 (3.8%) 83 (45.3%) 93 (50.8%) 11 (6.0%) 10 (5.4%) 1 (0.5%) 183 (62%)

0 (0%) 46 (50%) 46 (50%) 18 (19.5%) 16 (17.3%) 2 (2.1%) 92 (31.1%) 295 (28.7%)

0 (0%) 4 (20%) 16 (80%) 20 (%100) 10 (50%) 10 (50%) 20 (6.7%)

r = 0.213. p = 0.000

r = 0.133. p = 0.648

1.026 (100%)

GA, gestational age; BUN, blood urea nitrogen; WBC, White blood cells count; CRP, C- reactive protein; FBW, fetal body weight; VAS, visual analogue scala; TA, tension arterial, AFI, Amniotic fluid index; APD, anteroposterior diameter of renal pelvis.

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

Zeki Bayraktar, Ş. Tuğba Kahraman, E. Seçkin Alaç, I. Yengel, D. Sarıkaya Kalkan

Table 3. Patient characteristic and clinical data in treatment groups.

Age (years) Body mass index (BMI) Gestational age (weeks) Gestational age at delivery Cesarean section rate Fetal body weight (kg) Apgar score. 5-min Primipara Tension arterial (mm/Hg); Systolic Diastolic Visual analogue scala Serum blood urea nitrogen (mg/dl) Creatinine (mg/dl) White blood cells count (x103µl) C-reactive protein (mg/dl) Hospitalization (day) Culture positive rate Anteroposterior diameter of renal pelvis (mm); Right Left Amniotic fluid index (AFI); Normal Polyhydramnios Oligohydramnios Trimester; 1 (< 14th weeks) 2 (14th-27 weeks) 3 (27th-40 weeks)

Conservative (n = 36) 26.8 ± 4.4 29.7 ± 5.4 28.2 ± 6.6 38.7 ± 0.7 24 (66.6%) 3.36 ± 0.32 9.8 ± 0.2 25 (69.4%)

Surgical (n = 13) 28.9 ± 4.5 27 ± 4.2 30 ± 5.3 39.4 ± 0.9 8 (61.5%) 3.61 ± 0.37 9.9 ± 0.2 7 (53.8%)

P value p = 0.1492 p = 0.1099 p = 0.3813 p = 0.0063 p = 0.7432 p = 0.0310 p = 0.0923 p = 0.3163

106 ± 7 62 ± 8 3.1 ± 1.9 11.9 ± 3.3 0.71 ± 0.3 12.2 ± 3.3 11.7 ± 13 4.7 ± 2.6 13 (36.6%)

107 ± 6 66 ± 5 5.2 ± 1.9 12.4 ± 3.7 0.72 ± 0.3 13.5 ± 3.4 17.3 ± 15 4.1 ± 3.4 4 (30%)

p = 0.6496 p = 0.0993 p = 0.0013 p = 0.6522 p = 0.9184 p = 0.2331 p = 0.2074 p = 0.5149 p = 0.6718

15.7 ± 5.1 2.7 ± 1.9

27.9 ± 9.6 4.3 ± 3.7

p<0.0001 p = 0.0526

35 (97.2%) 1 (1.9%) 0

13 (100%) 0 (0%) 0

p = 0.5463 p = 0.6203

0 15 (41.6%) 21 (58.3%)

0 3 (23%) 10 (77%)

p = 0.2378 p = 0.2354

tive (34.6%). Sefamesin was used in 20 of these symptomatic cases, Nitrofurantoin in 5 and Ceftriaxon in 3 of these patients (according to antibiogram). No infection was observed without clinical response. There was no patient who developed sepsis or who did not respond clinically to these anitibiotic treatments. Almost all of the pregnant women with hydronephrosis were in the second and third trimester. In the third trimester, there were 155 (52.5%) hydronephrosis (grade 1; 93 (60%), grade 2; 46 (29.6%) grade 3; 16 (10.3%). In the second trimester, there was 133 (45%) hydronephrosis (grade 1; 83 (62%); grade 2; 46 (34.4%), grade 3; 4 (3%). The number of hydronephrosis in the first trimester was only 7 (2.3%), all of which were grade 1. Of the 49 patients treated due to hydronephrosis, 18 (36.7%) were in the second trimester and 31 (63.2%) were in the third trimester. The maximum APD on the right side of the patients in the surgical treatment group was significantly higher than the conservative group (27.9 ± 9.6 mm-15.7 ± 5.1 mm, p < 0.0001). Similarly, the VAS values were significantly higher in the surgical treatment group (5.2 ± 1.9-3.1 ± 1.9; p = 0.0013). FBW values were also higher in the surgical treatment group than the conservative treatment group (3.61 ± 0.37-3.36 ± 0.32; p = 0.031). There was no significant dif-

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

ference between the two treatment groups in terms of other parameters (Table 3). Double-J stent was easily inserted in all patients and successful responses were obtained in the surgical treatment group. Two of the patients in the surgical group (15.3%) complained of stent discomfort and flank pain. But no infection, stent migration, or fragmentation were observed. No invasive procedure such as percutaneous nephrostomy was required in any patient. The mean duration of stent insertion was 4.7 ± 1.2 months. Three months after delivery, no hydronephrosis was observed in any patient.

DISCUSSION

Our results in this study partially confirm the literature data. Some of our findings contradict the literature. In fact, while the rate of maternal hydronephrosis reported in the literature is up to 80-90% (1-4), the maternal hydronephrosis rate in our study is 28.7%. There may be two possible causes of this discrepancy. First, we used the common grading system for the detection and classification of hydronephrosis (28), not the maximal APD. However, most of the studies in the literature have used the maximal APD for hydronephrosis classification. However, although the APD value seems to be an objective measurement, it cannot show the true grade of hydronephrosis (26). The results also vary according to the criteria for hydronephrosis. As a matter of fact, maternal hydronephrosis rate was 21% according to a study in which APD value of 10 mm and above was accepted as hydronephrosis (29). The second, we have also accepted exclusion criteria for some diseases that may cause urinary obstruction such as renal tract calculi, structural renal parenchymal or collecting system anomalies (single kidney, horseshoe kidney, renal ectopia, duplicated collecting system, ectopic ureter, and extra renal pelvis), previous surgical intervention to the kidneys or ureters. This may have reduced our rates of hydronephrosis. Maternal hydronephrosis, which are considered physiologically normal, are mostly observed on the right side and usually develop after mid-gestation (4, 15-19). Our findings also confirm these data in the literature. However, while the rate of symptomatic maternal hydronephrosis reported in the literature is 0.2-3% (1, 2, 8-10), the rate of symptomatic hydronephrosis in our study is 4.7%. In other words, this ratio is relatively high compared to the literature average. However, the rate of semptomatic cases that need surgical treatment is 1.2%. This ratio coincides with the literature data. We observed a significant relationship between the degree of hydronephrosis and flank pain/VAS score. However, there are different data in the literature. For example, Farr et al. (27) evaluated that the association between maternal hydronephrosis and acute flank pain during pregnancy in a prospective pilot-study and reported that there is no clear association between the grade of maternal hydronephrosis and pain intensity, which complicates diagnostic assessment. In addition, Watson and Brost examined 81 pregnant

Maternal hydronephrosis

women and observed that there was no association between flank pain and hydronephrosis (29). Another finding that does not coincide with the literature data is the correlation between multiple pregnancies and hydronephrosis. According to the literature, more maternal hydronephrosis is observed in twin pregnancies (4). But we could not confirm this finding. Because the number of multiple pregnancies in our study was only 8 (0.7%) and it was not statistically sufficient to determine the positive correlation between maternal hydronephrosis and multiple pregnancies. Most of the pregnant women with maternal hydronephrosis in this study were asymptomatic (83.3%). In addition, a large proportion of symptomatic cases (73.4%) were treated conservatively. The number of cases requiring surgical treatment was only 1.2%. Our findings are consistent with the literature. Because the proportion of patients with symptomatic maternal hydronephrosis, which can be treated conservatively, is approximately 70-80%, some of which are reported as high as 96% (1, 2, 5). Symptomatic maternal hydronephrosis during pregnancy can be treated conservatively, especially in the presence of mild hydronephrosis. And also maternal-perinatal results are excellent. However, some cases may be resistant to conservative treatment. Surgical treatment should be considered for these cases, especially if severe hydronephrosis is present (1, 2, 5). Because symptomatic hydronephrosis may cause premature birth or maternal-fetal death when left untreated (13). Treatment method of symptomatic hydronephrosis in pregnancy is still unclear (1). According to the literature, approximately 70-80% of the pregnant women with symptomatic hydronephrosis can be treated with conservative approach. For the remaining 20-30%, additional treatments are required (1, 13). However, one of the high DJ stent insertion rate (72%) in the literature was published, and additionally, 4% of patients underwent percutaneous nephrostomy (1, 11). For this reason, the optimal treatment option in pregnant women with symptomatic hydronephrosis is unclear (1, 9). Fainaru et al. (2) reported that 73% of patients with maternal hydronephrosis had mild hydronephrosis and that they responded perfectly to conservative treatment in terms of maternal-perinatal outcomes, but that 7.1% of symptomatic patients with moderate or severe hydronephrosis did not respond to conservative treatment. Tsai et al. (5) reported 80% of patients with maternal hydronephrosis responding to conservative treatment during pregnancy and 0.27% of moderate to severe symptomatic maternal hydronephrosis. The response to conservative treatment reported in the literature is up to 96% (2, 5, 9). So, the authors reported that they obtained a lower rate of response to conservative treatment than the literature because they excluded patients with mild hydronephrosis from the study and included only patients with moderate to severe hydronephrosis (5). However, this rate reported by them is actually consistent with the literature. Because according to the literature, the rate of patients who respond to conservative treatment is about 70-80% (13). On the

other hand, there are studies reporting higher rates of surgical treatment. In fact, Ercil et al. (1) reported the treatment data of a total of 211 patients with symptomatic maternal hydronephrosis, of which 131 (62%) were conservatively treated and 80 (38%) were treated surgically. According to the authors, the high number of patients treated surgically (ie, double-J stent insertion) was related to the purpose of referring patients to the hospital. Because all patients were referred from another center and especially for surgical treatment. In addition to this, the presence of urinary tract infections is quite high due to our patient profile which is composed of patients with low socioeconomic level and poor hygienic conditions. In case a high level of antibiotic resistance due to unconscious antibiotic use is added, conservative approach was failed in these patients and surgical intervention was required (1). Double-J ureteral stent insertion is effective in the management of symptomatic hydronephrosis (5, 8, 19). Early or late complications of ureteral stents may occur if the stent is left for more than three months. However, the morbidity of pigtail stent insertion is minimal if the stent is left for less than three months (5). But some series reported the early and late complications of double pigtail ureteral stents. Early complications include patient discomfort, irritative bladder symptom, bacteriuria with or without urinary tract infection, urosepsis, hematuria, or flank pain, and later complications are upward or downward stent migration, calcification, and fragmentation (5, 12). As a matter of fact, in also this study, double-j stent were successfully inserted and removed in all patients in the surgical treatment group. There was no early or later serious complications in any patient. Only two patients (15.3%) complained of stent discomfort and flank pain. But no urosepsis, stent migration, calcification or fragmentation were observed. Another issue discussed for the treatment of maternal hydronephrosis is whether there are any parameters that can be used to determine the optimal treatment option. Ercil et al. (1) reported that CRP, WBC and VAS levels were higher in the surgical treatment group, which increased the likelihood of surgical treatment, thus high CRP and WBC levels seemed to be a predictor for surgical treatment. In our study, VAS scores was higher in the surgical treatment group. But we did not observe such a significant difference between the two groups in terms of CRP and WBC levels. There are also literature data supporting our findings. Generally, CRP levels are used to assess treatment response rather than predicting treatment in patients with symptomatic hydronephrosis (1, 5, 9). In a prospective randomized trial, Tsai et al. (5) also found no significant difference in WBC, BUN, creatinine levels between the conservative and surgical treatment groups. But, in Ercil et al’s study (1), no statistically significant difference was found by researchers between the treatment groups in terms of BUN and creatinine levels, whereas WBC level was found to be statistically higher for surgical treatment group than the conservative treatment group in both trimester. As the writers say, the main reasons of this difference may be the number of Archivio Italiano di Urologia e Andrologia 2021; 93, 1

Zeki Bayraktar, Ş. Tuğba Kahraman, E. Seçkin Alaç, I. Yengel, D. Sarıkaya Kalkan

patients or the fact that their study group is composed of more complicated patients, especially the higher number of patients with urinary infection (1). However, in pregnant women with flank or low back pain, the presence of obstruction due to urinary tract infection should also be considered, and if appropriate, these infections should be treated appropriately (1, 10-13, 27). Some limitations of this study should be taken into account. Although the number of pregnant women who were followed prospectively was adequate, the number of multiple pregnancies which could be correlated with maternal hydronephrosis was low. Because risk pregnancies including multiple pregnancies, are mostly followed in the central hospital of our university. However, the pregnant women who were followed in the central hospital of our university were not included in this study. Therefore, we could not determine the correlation between maternal hydronephrosis and multiple pregnancies. Hence, our cohort might not reflect an overall obstetric population in terms of the number of multiple pregnancies.

CONCLUSIONS

Most cases of maternal hydronephrosis in pregnant women without ureteral stones are asymptomatic. Also, a significant part of symptomatic cases can be treated conservatively. However, some of the cases require surgical treatment(double-J ureteral stent insertion). For this reason, maternal hydronephrosis cannot be described as a completely physiological phenomenon. In cases requiring surgical treatment, fetal body weight, visual analogue scale and anterior-posterior renal pelvis diameter were higher than asymptomatic cases.

REFERENCES 1. Ercil H, Arslan B, Ortoglu F, et al. Conservative/surgical treatment predictors of maternal hydronephrosis: results of a single-center retrospective non-randomized non-controlled observational study. Int Urol Nephrol. 2017; 49:1347. 2. Fainaru O, Amnog B, Gamzu R, et al. The management of symptomatic hydronephrosis in pregnancy. Br J Obstet Gynecol. 2002; 109:1385. 3. Goldfarb RA, Neerhurt GJ, Lederer E. Management of acute hydronephrosis of pregnancy by ureteral stenting: risk of stone formation. J Urol. 1989; 141:921. 4. Wadasinghe SU, Metcalf L, Metcalf P, Perry D. Maternal physiologic renal pelvis dilatation in pregnancy: sonographic reference data. J Ultrasound Med. Dec 2016; 35:2659. 5. Tsai YL, Seow KM, Yieh CH, et al. Comparative study of conservative and surgical management for symptomatic moderate and severe hydronephrosis in pregnancy: a prospective randomized study. Acta Obstet Gynecol Scand. 2007; 86:1047. 6. Docimo SG, Dewolf WC. High failure rate of indwelling ureteral stents in patients with extrinsic obstruction: experience at 2 institutions. J Urol. 1989; 142:277. 7. Jarrard DJ, Gerber GS, Lyon ES. Management of acute ureteral

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obstruction in pregnancy utilizing ultrasound-guided placement of ureteral stents. J Urol. 1993; 42:263. 8. Zwergel T, Lindenmeir T, Wullich B. Management of acute hydronephrosis in pregnancy by ureteral stenting. Eur Urol. 1996; 29:292. 9. Puskar D, Balagovic I, Filipovic A, et al. Symptomatic physiologic hydronephrosis in pregnancy: incidence, complications and treatment. Eur Urol. 2001; 39:260. 10. Jarrard DJ, Gerber GS, Lyon ES. Management of acute ureteral obstruction in pregnancy utilizing ultrasound-guided placement of ureteral stents. J Urol 1993; 42:263. 11. Hellawell GO, Cowan NC, Holt SJ, Mutch SJ. A radiation perspective for treating loin pain in pregnancy by doublepigtail stents. BJU Int. 2002; 90:801. 12. Ringel A, Richter S, Shalev M, Nissenkorn I. Late complications of ureteral stents. Eur Urol. 2000; 38:41. 13. Choi CI, Yu YD, Park DS. Ureteral stent insertion in the management of renal colic during pregnancy. Chonnam Med J. 2016; 52:123. 14. Wing DA, Fassett MJ, Getahun D. Acute pyelonephritis in pregnancy: an 18-year retrospective analysis. Am J Obstet Gynecol. 2014; 210:219e1. 15. Cietak KA, Newton JR. Serial qualitative maternal nephrosonography in pregnancy. Br J Radiol. 1985; 58:399. 16. Cietak KA, Newton JR. Serial quantitative maternal nephrosonography in pregnancy. Br J Radiol. 1985; 58:405. 17. Di Salvo DN. Sonographic imaging of maternal complications of pregnancy. J Ultrasound Med 2003; 22:69. 18. Rasmussen PE, Nielsen FR. Hydronephrosis during pregnancy: a literature survey. Eur J Obstet Gynecol Reprod Biol. 1988; 27:249. 19. Sadan O, Berar M, Sagiv R, et al. Ureteric stent in severe hydronephrosis of pregnancy. Eur J Obstet Gynecol Reprod Biol.1994; 56:79. 20. Clayton JD, Roberts JA. The effect of progesterone on ureteral physiology in a primate model. J Urol. 1972; 107:945. 21. Dell'Atti L. Our ultrasonographic experience in the management of symptomatic hydronephrosis during pregnancy. J Ultrasound. 2014; 21; 19:1. 22. Oto A, Ernst RD, Ghulmiyyah LM, et al. MR imaging in the triage of pregnant patients with acute abdominal and pelvic pain. Abdom Imaging. 2009; 34:243. 23. Di Salvo DN Sonographic imaging of maternal complications of pregnancy. J Ultrasound Med. 2003; 22:69. 24. Elgamasy A, Elsherif A. Use of Doppler ultrasonography and rigid ureteroscopy for managing symptomatic ureteric stones during pregnancy. BJU International. 2009; 106:262. 25. Faúndes A, Brícola-Filho M, Pinto e Silva JL. Dilatation of the urinary tract during pregnancy: proposal of a curve of maximal caliceal diameter by gestational age. Am J Obstet Gynecol. 1998; 178:1082. 26. Kajbafzadeh AM, Keihani S, Kameli SM, Hojjat A. Maternal Urinary Carbohydrate Antigen 19-9 as a Novel Biomarker for Evaluating FetalHydronephrosis: A Pilot Study. Urology. 2017; 101:90.

Maternal hydronephrosis

27. Farr A, Ott J, Kueronya V, et al. The association between maternal hydronephrosis and acute flank pain during pregnancy: a prospective pilot-study. J Matern Fetal Neonatal Med. 2017; 30:2417. 28. Naber KG, Bergman B, Bishop MC, et al. EAU guidelines for the management of urinary and male genital tract infections. Urinary

Tract Infection (UTI) Working Group of the Health Care Office (HCO) of the European Association of Urology (EAU). Eur Urol. 2001; 40:576. 29. Watson WJ, Brost BC. Maternal hydronephrosis in pregnancy: poor association with symptoms of flank pain. Am J Perinatol. 2006; 23:463.

Correspondence Zeki Bayraktar, MD (Corresponding Author) zbayraktar@medipol.edu.tr Department of Urology, School of Medicine, Istanbul Medipol University Çamlık Mah. Piri Reis Cad. Dilşad Sok. Papatya Sitesi No: 48, 34890-Pendik-Istanbul (Turkey) Şerife Tuğba Kahraman, MD stkahraman@medipol.edu.tr Elif Seçkin Alaç, MD esalac@medipol.edu.tr İ rem Yengel, MD

iyengel@medipol.edu.tr Deniz Sarıkaya Kalkan, MD dkalkan@medipol.edu.tr Department of Obstetrics and Gynecology, School of Medicine, Istanbul Medipol University, Istanbul (Turkey) Archivio Italiano di Urologia e Andrologia 2021; 93, 1

DOI: 10.4081/aiua.2021.1.42

ORIGINAL PAPER

Premature ejaculation patients and their partners: Arriving at a clinical profile for a real optimization of the treatment Paolo Verze 1, Roberto La Rocca 1, Lorenzo Spirito 1, Gianluigi Califano 1, Luca Venturino 1, Luigi Napolitano 1, Antonio Cardi 2, Davide Arcaniolo 3, Claudia Rosati 4, Alessandro Palmieri 1, Vincenzo Mirone 1 1 Department

of Neurosciences, Reproductive Sciences and Odontostomatology, Urology Section, University of Naples Federico II, Naples, Italy; of Urology, San Giovanni Hospital, Rome, Italy; 3 Department of Urology, Vanvitelli University, Naples, Italy; 4 Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy. 2 Department

Summary

The aim of the study is to extrapolate clinical features of Premature Ejaculation (PE) patients and female partners of men affected with PE, in order to get a profile that can be of assistance for physicians within the dynamics of a couple, one of which is a PE patient. An observational, non-interventional, cross-sectional epidemiological study entitled IPER (Italian Premature Ejaculation Research) was conducted and included two different cohorts of subjects that were randomly sampled from a patient dataset of selected General Practitioners: 1. IPER-M sub-cohort (1.104 subjects) was made of male subjects in which they were then distinguished patients with or without PE based on the score of the PEDT questionnaire; IPER-F sub-cohort (1.109 subjects) was made of female subjects from an independent sample of women (therefore not the partners of the IPER-M males) in which they then distinguished those partners of a male subject with PE or not. In addition to an identical general questionnaire to explore demographic aspects and habits, each subcohort was then evaluated using validated questionnaires. No differences were noted between PE+/PE- patients in terms of alcohol consumption, smoking habits, physical activity nor stress condition in everyday life, employment, socio-economic class and marital status. While the prevalence of PE proportionally increased with age, excluding the 50-59 and 70-80 years decades, in the IPER-M group an overall statistically significant difference for the mean age between the PE+ and PE- groups (p = 0.002) was detected, but without reaching any difference amongst the different age classes in the IPER-F group. The PE+ patients reported a significantly lower frequency rate of sexual intercourse, worse QoL (p = 0.006 and p < 0.0001, respectively), and increased anxiety status (p < 0.0001 for both subgroups). This study shows that, rather than talking with a patient affected by PE it would be advisable to introduce the concept of couple counseling with the person patient and his partner, because it is only through classification of both partners as one couple and a full understanding of their mutual sexual experience that PE treatment can be optimized and its results measured accurately.

KEY WORDS: Premature ejaculation; Partner; Profile; Clinical. Submitted 4 May 2020; Accepted 15 May 2020

INTRODUCTION

Premature Ejaculation (PE) is the most frequent male sexual disorder but, despite its high frequency, as a medical disorder it is poorly understood. Patients are often unwilling to discuss their symptoms and many physicians are not educated enough on effective treatments. As a result, patients may be misdiagnosed or mistreated (1). The ISSM Committee defines lifelong PE as an ejaculation that always or nearly always occurs prior to, or within about 1 minute of, vaginal penetration from the first sexual encounter, together with the inability to retard ejaculation during vaginal penetration which results in negative personal consequences such as distress, bother, frustration, and/or the avoidance of sexual intimacy (2). Based upon this definition, timing, a feeling of loss-ofcontrol and, couple distress are the main aspects to be taken into account when facing a patient with PE. In fact, PE has been associated with significant bother, interpersonal problems and dissatisfaction with sexual intercourse for both males and their partners (3-5). Therefore patient’s and their partner’s satisfaction play a crucial role in a PE diagnosis and physiopathology more than in other sexual dysfunction (6) and PE could even be categorized as a partner-oriented and indeed partnergenerated male sexual dysfunction, because the symptoms are strictly related to partner’s sexual physiology and to the female sexual response (7). Furthermore, data from previous studies show that all female sexual domains (including desire, arousal, lubrication, orgasm) become significantly impaired when partners of men affected with PE (8, 9). Despite some efforts to understand in detail the clinical characteristics of PE patients and their partners, to date it has proven difficult to provide a definitive clinical profile of a PE patient and the impact on their partner. The absence of this clinical information makes the profiling and management of the couple more complex. The primary objective of this study was to extrapolate the clinical features of PE patients and their partners in order to arrive at a profile that can be of assistance to physicians in treating couples, one of whom is an PE patient. No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

Clinical profile of PE patients

PATIENTS

AND METHODS

An observational, non-interventional, cross-sectional epidemiological study Italian Premature Ejaculation Research (IPER) was conducted on a cohort of adult males (IPER-M) and females (IPER-F) that were randomly sampled from a patient dataset of selected General Practitioners (GPs) throughout Italy, applying the same methodology for both cohorts. Main criteria for patient enrollment and study design have been previously described (10, 11). The inclusion criteria were adult men and women between the ages of 18 and 80, sexually active of any ethnicity, even if the subjects were predominantly Italian. Those who were unable to fill in questionnaires due to cognitive or linguistic problems or with a clear indication of no sexual activity at the time of questionnaire administration were excluded. All participants, after signing an informed consent form, received a series of questionnaires to be returned anonymously to their GPs in a sealed envelope that was then opened by an independent staff responsible for processing the data. A general questionnaire was administered for both IPERM and IPER-F cohorts. The IPER-M study population was asked to complete in the following validated selfadministered questionnaires: Premature Ejaculation Diagnostic Tool (PEDT), International Index of Erectile Function (IIEF-5), Sexual Quality of Life QuestionnaireMale) (SQoL-M), Self-rating Depression Scale (SDS) and Self-rating Anxiety Scale (SAS). The female patients from the IPER-F study cohort were asked to report on their partner’s ejaculation time (selfreported Intravaginal ejaculation latency time - IELT) and presence of sexual dysfunction (including no interest in sex, lack of or delayed orgasm, pain during ejaculation, anxiety and lubrication problems). Patients were also asked to complete the following validated questionnaires: adapted from Female Sexual Distress Scale (FSDS-R-PE), Sexual Quality of Life Questionnaire-Female (SQoL-F), SDS and SAS. The study did not involve any treatment or invasive diagnostic procedure. Per Italian law the survey was conducted in accordance with the Privacy Act and with the Declaration of Helsinki in all aspects which were applicable. Each subject was informed about the purpose of the investigation and was recruited after signing an informed consent form. Statistics A descriptive statistical analysis was applied to present results. When appropriate, intra-group comparisons were performed by 𝝌2 tests for categorical variables or by variance analysis (ANOVA) for continuous variables. Multiple logistic regression models were used to identify independent risk factors for PE. The statistical significance level (p) was 0.05 or less or all statistical tests. Data were normally distributed in line with an asymmetry and kurtosis analysis. Data were analyzed using SAS software, version 9.2 (SAS Institute Inc., Cary, NC, USA).

RESULTS

For the IPER-M sub-cohort a total of 2.571 male patients were sampled and 1.104 (43%) were recruited into the

study. For the IPER-F sub-cohort 3.104 female subjects were sampled and, of those, 1.109 were included in the study. Table 1 describes demographics and general characteristics of both IPER-M and IPER-F sample cohorts. The mean age of the IPER-M sample was 45.6 years ± 16.9, with 39.6% of the sample aged less than 45 years old. The mean age of the IPER-F cohort was 45.1 years ± 15.4 SD, with 44% of the sample aged less than 45 years old. No differences were noted between the PE+/PE- patients in both IPER-M and IPER-F sub-cohorts in terms of alcohol consumption?, smoking habits, physical activity or stress conditions in everyday life as well as employment status, socio-economic class and marital status. Instead a greater amount of PE+ patients with a lower Table 1. Demographics and general characteristics of the study population. A: Iper-M Sub-cohort PE+ Group (n = 119) PE- Group (n = 990) Age Median (SD) – 45.6 (± 16.9) Body Mass Index (kg/cm^2) Median (SD) Smoking habits (cig./day) Never (n. %) < 10 (n. %)) > 10 (n. %) ex smoker (n. %) Alcohol consumption Never (n. %) Occasional (n. %) Regular (n. %) Physical activity Never (n. %) Low (n. %) Moderate (n. %) Intense (n. %) Stress condition (everyday life) Never (n. %) Low (n. %) Moderate (n. %) Intense (n. %) Marital status Never married (n. %) Married (n. %) Divorced (n. %) Widower (n. %) Kind of cohabitation No stable partner (n. %) No cohabitation (n. %) stable cohabitation (n. %) Education No education (n. %) Primary (n. %) Secondary (n. %) High (n. %) Degree (n. %) Economic condition Insufficient (n. %) Quite insufficient (n. %) Sufficient (n. %) Good (n. %)

p < 0.6522 25.58 (3.72)

25.74 (4.81)

293 (41.50%) 108 (15.29%) 136 (19.26%) 169 (23.93%)

62 (38.50%) 20 (12.42%) 36 (22.36%) 43 (26.70%)

139 (19.85%) 437 (62.42%) 124 (17.71%)

22 (13.75%) 103 (64.37%) 35 (21.87%)

248 (35.42%) 152 (21.71%) 223 (31.85%) 77 (11.00%)

68 (43.03%) 30 (18.98%) 49 (31.01%) 11 (6.96%)

44 (6.24%) 279 (39.57%) 314 (44.53%) 68 (9.64%)

9 (5.59%) 52 (32.29%) 83 (51.55%) 17 (10.55%)

257 (36.35%) 398 (56.29%) 43 (6.08%) 9 (1.27%)

42 (26.25%) 102 (63.75%) 13 (8.12%) 3 (1.87%)

147 (21.64%) 145 (21.35%) 102 (65.80%)

33 (21.29%) 20 (12.90%) 102 (65.80%)

p = 0.5588

p = 0.1428

p = 0.2073

p = 0.3307

p = 0.0978

p = 0.0443

p = 0.5670 1 (0.14%) 43 (6.09%) 178 (25.21%) 367 (51.98%) 117 (16.57%)

12 (7.50%) 47 (29.37%) 72 (45.00%) 29 (18.12%)

64 (9.10%) 180 (25.60%) 432 (61.45%) 27 (3.84%)

11 (6.91%) 41 (25.78%) 96 (60.37%) 11 (6.91%)

p = 0.3177

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

P. Verze, R. La Rocca, L. Spirito, G. Califano, L.Venturino, L. Napolitano, A. Cardi, D. Arcaniolo, C. Rosati, A. Palmieri, V. Mirone

B: Iper-F Sub-cohort PE+ Group (n = 119) PE- Group (n = 990) Age Overall - 45.1 (± 15.4) Median (SD) Body Mass Index (kg/cm^2) Median (SD) Smoking habits (cig./day) Never (n. %) < 10 (n. %) > 1 (n. %) Ex smoker (n. %) Alcohol consumption Never (n. %) Occasional (n. %) Regular (n. %) Physical activity Never (n. %) Low (n. %) Moderate (n. %) Intense (n. %) Stress condition (everyday life) Never (n. %) Low (n. %) Moderate (n. %) Intense (n. %) Marital status never married (n. %) Married (n. %) Divorced (n. %) Widower (n. %) Kind of cohabitation no stable partner (n. %) no cohabitation (n. %) stable cohabitation (n. %) Education no education (n. %) Primary (n. %) Secondary (n. %) High (n. %) Degree (n. %) Economic condition Insufficient (n. %) quite insufficient (n. %) Sufficient (n. %) Good (n. %)

p = 0.002 48.6 (± 14.9)

45.1 (± 14.1) p < 0.0001

25.3 (± 4.17)

23.37 (± 3.99)

79 (66.66%) 15 (12.61%) 12 (9.90%) 13 (10.81%)

543 (54.86%) 136 (13.68%) 129 (13.00%) 182 (18.43%)

62 (52.29%) 46 (38.53%) 11 (9.17%)

460 (46.48%) 473 (47.73%) 57 (5.78%)

71 (60.00%) 17 (14.54%) 27 (21.81%) 4 (3.63%)

515 (51.99%) 151 (15.24%) 47 (4.89%) 277 (27.87%)

5 (4.50%) 37 (31.53%) 62 (51.35%) 15 (12.61%)

40 (4.07%) 312 (31.37%) 519 (52.54%) 119 (12.00%)

19 (16.51%) 92 (76.14%) 4 (3.66%) 4 (3.66%)

209 (21.10%) 671 (67.83%) 77 (7.78%) 33 (3.27%)

17 (14.28%) 19 (16.32%) 83 (69.38%)

76 (7.72%) 208 (20.98%) 706 (71.29%)

0 26 (21.81%) 27 (22.72%) 45 (38.18%) 21 (17.27%)

3 (0.33%) 55 (5.63%) 199 (19.95%) 526 (52.87%) 207 (21.19%)

10 (8.25%) 29 (24.77%) 77 (64.22%) 3 (2.75%)

73 (7.37%) 265 (26.78%) 619 (62.42%) 33 (3.40%)

p = 0.0881

p = 0.1185

N Mean age (SD) < 20 (%) 21-29 (%) 30-39 (%) 40-49 (%) 50-59 (%) > = 60 (%)

PE+ 139 47.9 (15.1) 1 (1%) 13 (9.5%) 17 (11.9%) 31 (22.4%) 32 (22.9%) 45 (32.4%)

PE641 43.2 (16.2) 9 (1.4%) 98 (15.3%%) 120 (18.7%) 126 (19.7%) 144 (22.4%) 144 (22.4%)

PE+ 90 48.6 (14.9) 0 5 (5.9%) 13 (14.8%) 22 (24.4%) 25 (28.1%) 24 (26.7%)

PE789 43.7 (14.1) 7 (0.8%) 91 (11.5%) 170 (21.6%) 210 (26.7%) 174 (22.1%) 137 (17.3%)

B: Iper-F Sub-cohort p = 0.4138

p = 0.9916

N Mean age (SD) < 20 (%) 21-29 (%) 30-39 (%) 40-49 (%) 50-59 (%) > = 60 (%)

p = 0.2348

p = 0.0651

p < 0.0001

p = 0.9355

BMI (22-25) (median 24.87) and PE- subjects with a higher BMI (26-30) (median 25.06) were included in the IPER-M, though without reaching a statistically significant difference. On the contrary, a higher BMI (PE+ 25.3 ± 4.17 vs PE- 23.37 ± 3.99; p < 0.0001) was recorded in the IPER-F PE+ sub-cohort. Furthermore, a general lower educational level (p < 0.0001) was reported in the PE + group of the IPER-F sub-cohort, while no differences were observed in this parameter in patients with or without PE in the IPER-M group. Table 2 reports the PE prevalence stratification data based on age class in the IPER-M and IPER-F subcohorts, according to the self-estimated IELT (< 1 minute). It is important to underline that within the IPER-M group, with the exception of 50-59 years and 70-80 years, the prevalence of PE proportionally

Table 2. PE Prevalence according to self-estimated IELT (< 1 minute) within IPER-M (A) and IPER-F (B) study populations. A: Iper-M Sub-cohort

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

increased with age. For each age class, the PEDT score and the self-estimated IELT by the patients showed a similar epidemiological trend increasing with age when the cut-off value for PE diagnosis was considered < 1 minute. It is worth highlighting that the same data is confirmed when women from the IPER-F sub-cohort reported the age of their PE partner. On the contrary, within the IPER-F group, an overall statistically significant difference for the mean age between the PE+ and Pe- groups (48.6 ± 14.9 yrs and 45.1 ± 14.1 yrs, respectively; p = 0.002) was detected, but without resulting in any differences amongst the different age classes. Table 3 reports data on sexual attitudes in both the IPERM and IPER-F sub-cohorts. It is interesting to note that PE+ patients from the IPER-M sub-cohort reported a significantly lower frequency rate of sexual intercourse than the PE- population and similar findings were also observed in the IPER-F group. Moreover, it was also revealed that PE+ categories in both IPER-M and IPER-F cohorts expressed a more frequent lack of sexual interest, lack of orgasm and pain during intercourse, based upon the questionnaire’s response of “Often” and “Always”, when compared with the PE- population. Table 4 reports data concerning overall quality of sexual life as evaluated by the SQoL questionnaire. The IPER-M sub-cohort showed a significantly worse QoL in PE+ subjects when compared to PE- patients (68.27 PE+ vs 89.90 PE-; p = 0.006, respectively). Similar findings were recorded for the PE+ category of IPER-F group (74.88 PE+ vs 86.13 PE-; p < 0.0001, respectively). Results reported in anxiety and depression scales in both sub-cohorts are presented in Table 5 Interestingly, within both the IPER-M and IPER-F cohorts, the PE+ categories presented a statistically significant higher score in the Z-SAS questionnaire with regards to anxiety status

Clinical profile of PE patients

Table 3. Sexual attitudes according to PE status. A: Iper-M Sub-cohort IPER-M Frequency of intercourse No sexual intercourse Less than once per month 2 to 3 times per month Once per week or more Pain during intercourse Never Sometimes Often Always Lack of orgasm Never Sometimes Often Always No interest for sex Never Sometimes Often Always

PE+ N (%) 64 (18.4%) 57 (16.4%) 111 (31.9%) 116 (33.3%) N (%) 205 (82.0%) 38(15.2%) 6 (2.4%) 1 (0.4%) N (%) 211 (81.5%) 27 (10.4%) 15 (5.8%) 6 (2.3%) N (%) 197 (62.7%) 78 (24.8%) 24 (7.6%) 15 (4.8%)

PEN (%) 102 (11.5%) 116 (13.1%) 256 (28.9%) 412 (46.5%) N (%) 660 (88.6%) 76 (10.2%) 9 (1.2%) 0 (0.0%) N (%) 631 (83.2%) 103 (13.6%) 16 (2.1%) 8 (1.1%) N (%) 592 (71.2%) 193 (23.2%) 27 (3.2%) 19 (2.3%)

PE+ N(%) 16 (15.5%) 14 (12.4%) 33 (34.9%) 31 (33.3%) N (%) 71 (79.6%) 17(17.8%) 6 (2.4%) 1 (0.0%) N (%) 75 (82.4%) 10 (11.6%) 3 (3.7%) 2 (2.3%) N (%) 52 (61.3%) 21 (24.3%) 8 (9.5%) 3 (3.9%)

PEN (%) 94 (13,2%) 101 (10,9%) 220 (25.9%) 372 (48 .5%) N (%) 659 (84.2%) 87 (11.2%) 26 (4.6%) 0 (0.0%) N (%) 660 (85.1%) 105 (12%) 15 (1.8%) 8 (1.1%) N (%) 618 (72.6%) 212 (25.4%) 12 (1.2%) 10 (0.8%)

Table 5. Anxiety and depression profile according to ZSAS and ZSDS questionnaires. A: Iper-M Sub-cohort P < 0.001

p = 0.021

p = 0.006

p = 0.001

Anxiety (Z-SAS questionnaire) Normal - Total score < 45 (n. %) Mild - Total score 45-59 (n. %) Moderate - Total score 60-74 (n. %) Depression (Z-SDS questionnaire) Normal - Total score < 45 (n. %) Mild - Total score 45-59 (n. %) Moderate - Total score 60-69 (n. %)

PE+ Group

PE- Group

123 (87.2%) 15 (10.6%) 3 (2.1%)

603 (95%) 31 (4.9%) 1 (0.2%)

131 (91.0%) 9 (6.3%) 4 (2.8%)

620 (95.5%) 28 (4.3%) 1 (0.2%)

p < 0.0001

p = 0.5237

B: Iper-F Sub-cohort Anxiety (Z-SAS questionnaire) Normal - Total score < 45 (n. %) Mild - Total score 45-59 (n. %) Moderate - Total score 60-74 (n. %) Depression (Z-SDS questionnaire) Normal - Total score < 45 (n. %) Mild - Total score 45-59 (n. %) Moderate - Total score 60-69 (n. %)

PE+ Group (n = 119)PE- Group (n = 990) p < 0.0001 82 (69.04%) 838 (84.65%) 32 (27.38%) 140 (14.15%) 5 (3.57%) 12 (1.19%) p = 0.4967 106 (88.75%) 896 (90.43%) 10 (8.75%) 84 (8.54%) 3 (2.50%) 10 (1.02%)

B: Iper-F Sub-cohort IPER-M Frequency of intercourse No sexual intercourse Less than once per month 2 to 3 times per month Once per week or more Pain during intercourse Never Sometimes Often Always Lack of orgasm Never Sometimes Often Always No interest for sex Never Sometimes Often Always

p < 0.001

p = 0.0247

p = 0.009

p = 0.001

Table 4. Mean Scores at SQoL Questionnaires A: Iper-M Sub-cohort IAll subjects n Mean St.Dev

950 85,32 20,09

PE+ subjects N 150 Mean 68,27 St.Dev 22,66

PE- subjects N 664 Mean 89,90 St.Dev 16,16

PE+ partner N Mean St.Dev Median

PE- partner N 897 Mean 86,13 St.Dev 15,73 Median 92,6

B: Iper-F Sub-cohort All subjects n Mean St.Dev Median

992 85,05 16,42 91,7

95 74,88 19,15 79,6

(Z-SAS score > 45) compared to the PE- group (IPER-M: 12.7 PE+ % vs 5,1 PE-, p < 0.0001; IPER-F: 30.95% vs 15.34%, respectively; p < 0.0001). On the contrary, with regards to depression status (Z-SDS score > 50), no statistically significant difference between the PE+ and PEgroups in both IPER-M and IPER-F sub-cohorts was revealed (p = 0.5237 IPER-M and p = 0.4967 IPER-F, respectively).

DISCUSSION

Data from this large observational, non-interventional, cross-sectional, epidemiological study help us to get clinical profiles of patients affected by PE and its impact on their partner, providing important details to treat the couple as a whole in an optimal way. As far as we know, this study has some peculiarities in the selection methodology of the samples that distinguish it from many previous publications. In particular, the sample extraction method guarantees an excellent representation of the real population of patients affected by this disorder. Secondly, the female sample of this study is not made up, as in previous publications, of the partners of the male patients analyzed, but rather by an independent sampling of women who reported having a partner with premature ejaculation. This distinction has allowed us to validate certain data (prevalence data, sexual attitudes, etc.) on two cohorts of totally independent subjects. Finally, the major strength of this study is that sexuality and neuro-psychic comorbidities have been evaluated by using validated questionnaires which provided a very precise general and sexual profile of the sample. Overall, what analysis of the data tells us is that in couples where one patient suffers from PE there is a significant problem of sexual dissatisfaction, which is accomArchivio Italiano di Urologia e Andrologia 2021; 93, 1

P. Verze, R. La Rocca, L. Spirito, G. Califano, L.Venturino, L. Napolitano, A. Cardi, D. Arcaniolo, C. Rosati, A. Palmieri, V. Mirone

panied by a progressive reduction in the frequency of sexual contact as well as the onset of a state of anxiety for both partners. From a general point of view, neither the patient nor the partners in the study present a personal profile or lifestyle that highlights risk factors which correlate with the presence of PE. Our study confirms data already reported in the literature, whereby PE is not affected by marital or income status (12). On the contrary, with regards to data concerning lifestyle, some of our data conflicts with previously published studies (13). In particular, in our series, obesity does not seem to characterize the PE patient, including, as well as, lack of physical activity, alcohol consumption and smoking status. Instead, a certain correlation with psychological factors such as emotional problems and stress is confirmed (14, 15). What is, instead, very important to highlight from an epidemiological point of view, is that our series reveal, contrary to conclusions in the literature, that there is a certain linear correlation between the prevalence of PE and age, which is confirmed by the two independent samples of the IPER-M and IPER-F sub-cohorts. We are aware of the novelty of this data, although it was already presented in a recent publication (10) of the PEPA survey, to date the most representative epidemiological study, which reported increased PE prevalence with age up to 45-50 years. However beyond this age range no further increase was reported and this result could be explained by the fact that the PEPA study had been conducted as an internet survey and perhaps 45-80 years old subjects were not fully representative of the general population (16). Data from previous studies show that both men with PE and their partners are more likely to report low satisfaction with their sexual relationship, low satisfaction with sexual intercourse, difficulty relaxing during intercourse, and less frequent intercourse (3, 17). This data is largely confirmed by our study in which first of all, there was a strong reduction in the interest in sexual activity in both the PE patients and partners, as demonstrated by the low weekly frequency of sexual relations. Once again the relevance of the data is strengthened by the fact that an identical trend comes from two subcohorts of completely independent subjects, who are not partners in a couple. As clearly demonstrated by the data concerning the sexual attitudes of study populations and by the results of the SQoL questionnaire, a couple in which there is a male subject affected by PE has a strongly altered sex life from a qualitative point of view in that there is a high risk of not achieving orgasm for both partners. This data, in our opinion, obviously closely correlates and explains the reduction in the frequency of sexual intercourse found in both sub-cohorts IPER-M and IPER-F in our study, since it is easy to imagine that a couple who does not have a satisfying sex life tends to reduce the frequency of intercourses. This finding contrasts with data from other Authors who showed that sex drive and overall interest in sex do not appear to be affected by PE (18). In our view, what remains extremely difficult to explain

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

is how it is possible that a couple that has a similar difficulty in a sexual relationship and above all a reduced quality of the same, tends not to seek help to solve the problem. In the Global Study of Sexual Attitudes and Behaviors survey, 78% of men who self-reported a sexual dysfunction sought no professional help or advice for their sexual problems, with men more likely to seek treatment for ED than for PE (19). Similarly, in the Premature Ejaculation Prevalence and Attitudes survey, only 9% of men with self-reported PE consulted a doctor (20). However, the negative impact of PE extends beyond sexual dysfunction with possible serious impact on the psychological profile of both patient and partner, and most importantly, detrimental consequences on the quality of life of the couple. Premature ejaculation can have a detrimental effect on self-confidence and the relationship with the partner, and may sometimes cause mental distress, anxiety, embarrassment and depression (3, 17). This data is amply confirmed by our study, which clearly shows that in a population of males affected by PE and of women partners of men affected by PE, there is a marked anxiety profile, with a significant percentage of subjects presenting a level of mild-to-moderate anxiety. On the contrary, compared to what was verified by other studies previously published, in our population of the IPER study there is no profile of a depressive state as demonstrated by the non-statistical significance of the differences in PE+ and PE- populations of both sub-cohorts. In our opinion, our data is reinforced by the use of a validated questionnaire such as the Z-SDS. Furthermore, our results showed a two-fold frequency of female sexual distress when the male partner is affected from PE. It has been widely accepted that PE represents a distressing condition, not only for men who suffer from the condition but also for their female partners and that it could lead to couple breakups and lower relationship satisfaction. In our mind, the most relevant data that emerges from this research is that, rather than talking about a male patient affected by PE it would be advisable to introduce the concept of the person affected by PE as part of a couple, because it is only through the classification of both partners and their sexual experience that the results of the treatment can be optimized. This is important, above all, in order to involve, once the diagnostic profiling phase is complete, involving both partners of the whole couple in the therapeutic process with the aim of optimizing the therapeutic outcome. Moreover, some preliminary studies have shown that a combination of dapoxetine and behavioral treatment was more effective than dapoxetine alone in patients with lifelong PE (21). There are some major limitations in the present study that must be acknowledged. Firstly, the design of the study (observational and cross-sectional) has allowed us to take a fixed picture of the condition of patients, without offering a dynamic assessment with control over time. Secondly, PE in men (IPER-M sample) has been defined without using the ISSM evidence-based definition but only based on the presence of IELT < 1 minute. Similarly, as regards to the female counterpart (IPER-F sample), the stratification data was based on a non-objective tool provided by the partner’s self-reported IELT.

Clinical profile of PE patients

CONCLUSIONS

Data from this large observational, non-interventional, cross-sectional, epidemiological study shows that in M-F couples involving a patient with PE there is a significant problem of sexual dissatisfaction for both partners, which is accompanied by a progressive reduction in the frequency of sexual contact as well as the onset of anxiety. Taking this into consideration, a full profile of the quality of a couple’s sex life is essential to optimize the results of the PE therapy of male partner.

REFERENCES

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ulation and depression: A PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore), 2016; 95:e4620. 16. Porst H, Montorsi F, Rosen RC, et al. The premature ejaculation prevalence and attitudes (PEPA) survey: prevalence, comorbidities, and professional help-seeking. Eur Urol. 2007; 51:816-23. 17. Rowland D, Perelman M, Althof S, et al. Self-reported premature ejaculation and aspects of sexual functioning and satisfaction. J Sex Med. 2004; 1:225. 18. Capece M, La Rocca R, Mirone V, et al. A systematic review on ischemic priapism and immediate implantation: do we need more data? Sexual Medicine Reviews. 2019; 7:530-534. 19. Laumann EO, Nicolosi A, Glasser DB, et al. Sexual problems among women and men aged 40-80 y: prevalence and correlates identified in the Global Study of Sexual Attitudes and Behaviors. Int J Impot Res. 2005; 17:39. 20. Porst H, Montorsi F, Rosen RC, et al. The Premature Ejaculation Prevalence and Attitudes (PEPA) survey: prevalence, comorbidities, and professional help-seeking. Eur Urol. 2007; 51:816. 21. Cormio L, Massenio P, La Rocca R, et al. The combination of dapoxetine and behavioral treatment provides better results than dapoxetine alone in the management of patients with lifelong premature ejaculation. J Sex Med. 2015; 12:1609.

5. Moore JT, Goldstein Y. Sexual problems among family medicine patients. J Fam Pract. 1980; 10:243-7. 6. Rowland DL, Cooper SE, Schneider M. Defining premature ejaculation for experimental and clinical investigations. Arch Sex Behav 2001; 30:235-253. 7. Limoncin E, Tomassetti M, Gravina GL, et al. Premature ejaculation results in female sexual distress: standardization and validation of a new diagnostic tool for sexual distress. J Urol. 2013; 189:1830-5. 8. Hartmann U, Schedlowski M, Kruger TH. Cognitive and partnerrelated factors in rapid ejaculation: Differences between dysfunctional and functional men. World J Urol. 2005; 23:93-101. 9. Abdo CH. The impact of ejaculatory dysfunction upon the sufferer and his partner. Transl Androl Urol. 2016; 5:460-9. 10. Verze P, Arcaniolo D, Palmieri A, et al. Premature ejaculation among Italian men: prevalence and clinical correlates from an observational, non-Interventional, cross-sectional, epidemiological study (IPER). Sex Med. 2018; 6:193-202. 11. Verze P, Arcaniolo D, Imbimbo C, et al. General and sex profile of women with partner affected by premature ejaculation: results of a large observational, non-interventional, cross-sectional, epidemiological study (IPER-F). Andrology. 2018; 6:714-719. 12. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA, 1999; 281:537. 13. Ventus D, Jern P. Lifestyle factors and premature ejaculation: are physical exercise, alcohol consumption, and body mass index associated with premature ejaculation and comorbid erectile problems? J Sex Med. 2016. 13:1482. 14. Dunn KM, Croft PR, Hackett GI. Association of sexual problems with social, psychological, and physical problems in men and women: a cross sectional population survey. J Epidemiol Community Health. 1999; 53:144. 15. Xia Y, Li J, Shan G, et al. Relationship between premature ejac-

Correspondence Paolo Verze, MD pverze@gmail.com Roberto La Rocca, MD (Corresponding Author) robertolarocca87@gmail.com Lorenzo Spirito, MD lorenzospirito@msn.com Gianluigi Califano, MD gianl.califano2@gmail.com Luca Venturino, MD luca.venturino86@gmail.com Luigi Napolitano, MD nluigi@libero.it Alessandro Palmieri, MD info@alessandropalmieri.it Vincenzo Mirone, MD mirone@unina.it Department of Neurosciences, Reproductive Sciences and Odontostomatology, Urology Section, University of Naples Federico II Via S. Pansini, 5 80131 Naples (Italy) Antonio Cardi, MD acardi@hsangiovanni.roma.it Department of Urology, San Giovanni Hospital, Rome (Italy) Davide Arcaniolo, MD davide.arcaniolo@gmail.com Department of Urology, Vanvitelli University, Naples (Italy) Claudia Rosati, MD claudia.rosati@unina.it Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples (Italy)

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

DOI: 10.4081/aiua.2021.1.48

ORIGINAL PAPER

Summary

Introduction: Severe Acute Respiratory Syndrome Coronavirus 2, (SARS-CoV-2) was first identified by the Chinese Centers for Disease Control and Prevention on January 8, 2020 and was declared as a global pandemic on March 11, 2020 by WHO. SARS-CoV-2 uses the Angiotensin-converting enzyme 2 (ACE2) receptor as an entry route, associated with the transmembrane serine protease protein (TMPRSS2), which makes the testis and particularly spermatogenesis potentially vulnerable, since this tissue has high expression of ACE2. Material and methods: We performed a systematic literature review by electronic bibliographic databases in Pubmed, Scopus and ScienceDirect up to August 2020 about the effect of SARS-CoV-2 on male sexual function and its transmission, to assess possible repercussions on sex organs and the existence of a sexual transmission path. Results: Although SARS-CoV-2 presence has not been found in testicle samples, it has been demonstrated that it causes histological changes compatible with orchitis, and sex hormone disturbances. TMPRSS2 is up-regulated in prostate cancer where it supports tumor progression, thus these patients may have a higher risk of SARS-CoV-2 infection. TMPRSS2 inhibitors may be useful for the treatment or prevention of COVID-19. No viral material has been found in blood or semen, however it has been proven to be present in stool and saliva. Conclusion: The male reproductive system would be highly vulnerable and susceptible to infection by SARS-CoV-2 given the expression of the ACE2 receptor in somatic and germ cells. The seminal fluid would remain free of viral presence in patients with COVID-19. Regardless, non-genital sex could be an important source of viral transmission. In assisted reproduction techniques all necessary tests must be carried out to ensure the donor is free of the virus at the time of collection and handling of the seminal sample.

KEY WORDS: COVID-19; Andrology; Fertility; Testis; Semen; Human. Submitted 22 August 2020; Accepted 5 October 2020

INTRODUCTION

On January 8, 2020, a new coronavirus was identified at the Chinese Centers for Disease Control and Prevention. It was named as Severe Acute Respiratory Syndrome Coronavirus 2, abbreviated as SARS-CoV-2. The disease that is caused by this virus was denominated Coronavirus Disease 2019 (COVID-19) and declared as notifiable by

WHO (1). Once COVID-19 is installed, its severity and prognosis depend on multiple factors, including sex (male), age (over 60 years), and the presence of pre-existing diseases (diabetes, hypertension, and cardiovascular diseases) (2). Coronaviruses (CoV) belong to the coronaviridae family and are characterized by being positive single-stranded RNA type, which encodes for topographically positioned proteins: spicules (S), envelope (E), membrane (M), and nucleocapsid (N). In pathogenicity, S proteins are essential to enter the host cell (3). The biology of the testicle represents an ideal model for the study and evaluation of pathologies, given that events of mitosis, meiosis, and cell differentiation occurring in it, in addition to its endocrine regulation. Also, the testicle is highly sensitive to variations in body homeostasis. Particularly in the case of SARS-CoV-2, which uses the Angiotensin-converting enzyme 2 (ACE2) receptor as an entry route, associated with the transmembrane serine protease protein (TMPRSS2), makes the testis and particularly spermatogenesis potentially vulnerable, since this tissue has high expression of ACE2 receptor (4, 5).

METHODS Review of studies and international experience A systematic review of the literature was performed using the electronic databases Pubmed, Scopus and Science Direct to assess the effect of SARS-CoV-2 on male sexual tract and function, and its possible sexual transmission. Multiple permutations of the following keywords were used: “COVID-19, SARS-CoV-2, transmission, testis, sperm, spermatogenesis, fertility cryopreservation, hormones, testosterone, sexual health”. The search was focused in original articles published between December 2019 and August 2020. There were also included papers that were found relevant to the research team in previous research. Editorials, correspondence, case reports were excluded. The experience in reproductive and testicular biology, spermatogenesis and seminal analysis of the work team was also considered in the making of this narrative review.

RESULTS

Across all databases a total of 371 articles were found. After reviewing the title and abstract of these, 46 papers No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

COVID-19 on male sexual organs

were preliminary selected. The selected papers were critically read, 20 were found to be the most relevant for the purpose of this review. ACE2 The ACE2 system plays an essential role in protecting cellular homeostasis against viral infection, specifically in COVID-19 infection and is widely distributed in the heart, kidney, lung, and testicles (4). ACE2 participates as an antagonist of the activation of the classic ReninAngiotensin System (RAS), protecting against cellular damage in hypertension, diabetes and some heart diseases. SARS-CoV-2 is characterized by occupying the ACE2 cell membrane receptor to enter the cell. In the lung, SARS-CoV-2 invades pneumocytes and macrophages using ACE2 receptors (4), although ACE2 normally has a protective effect against tissue damage. ACE2 is present in non-immune cells, eg, respiratory and digestive tract epithelia, endothelial cells, cells of the simple cubic epithelium of the proximal convoluted tubules of the kidney, and brain neurons, as well as in immune cells such as monocytes and macrophages (3). In other cell types the virus enters its host, but with lower affinity. The expression of ACE2 in adult human testis occurs predominantly in spermatogonial cells, Sertoli cells of the tubular compartment and Leydig cells in the interstitial compartment. These cells are also enriched with intercellular junctions (Leydig and Sertoli cells) and have low mitochondria concentration. The above described indicates that there are cells in the testicle that can potentially be targeted for infection with the SARS-CoV-2 virus. It has been described a high expression of ACE2 in different types of spermatogenesis cells, such as spermatogonia, early and late spermatocytes, round spermatids, and elongated spermatids (2, 4). It has also been described in somatic endothelial testis cells, Leydig cells, and monocytes, thus concluding that the human testis is a potential receptor for SARS-CoV-2 infection. Testicle In patients with the diagnosis of testicular cancer, or being treated for it, medical care should be taken as a

priority in-hospital care, although in general, they are at low risk for developing a severe COVID-19 infection (6). Although SARS-CoV-2 is the cause of multiple organic alterations, Wang et al. (1) states that the male reproductive system may not be immune to alterations. Dramatic changes in sex hormones are cited, suggesting a potential impairment of gonadal function (7). In parallel, it is mentioned that in the analysis of testicular biopsies (n = 6) of patients who died of SARS, several histopathological processes compatible with orchitis of variable intensity, such as apoptosis in the different types of spermatogenesis cells (cytos I and cytos II), absence or scarce sperm in the seminiferous tubules, a thickened peritubular compartment, and leukocyte infiltration, specifically citing the basal lamina (8). These findings should be compared with the normal testis morphology, as seen in Figure 1. Viral presence was not detected through in situ hybridization, but abundant IgG precipitates were detected (8). Finally, it is suggested that something similar could happen with COVID-19 (1). Yang et al. (9) analyzed testicular biopsies (n = 11) of patients who died from COVID-19. Morphological changes suggestive of damage to the seminiferous tubules were reported, such as Sertoli cell swelling, vacuolation, cytoplasmic rarefaction, and detachment from tubular basement. Interstitial changes consistent with viral orchitis were also described, with edema and mild lymphocytic inflammation, accompanied by a decrease in Leydig cell number. Although these findings would suggest SARSCoV-2 may be the causative agent of testicular tissue damage, the effect of hyperthermia, secondary infection, hypoxia, and steroidal therapy cannot be excluded. It is worth mentioning that no evidence of the presence of SARS-CoV-2 was found in the samples (9). COVID-19 effect on sex hormones Ma et al. (7) described that in SARS-CoV-2 infection dramatic changes are developed in sex hormones, Testosterone (T) and Luteinizing Hormone (LH), and in T/LH ratio. In this study, sex-related hormones were compared between reproductive-aged men with SARSCoV-2 infection and age-matched healthy men (7). It was found that COVID-19 patients had significantly

Figure 1. Testicular biopsies. Histology of the normal human testis (young and fertile adult male). Periodic acid-Schiff (PAS), hematoxylin (H), and Alcian Blue staining. A. The tubular compartment includes a simple columnar epithelium formed by Sertoli cells with a noticeable basal lamina of collagen IV, plus cytogenic epithelium forming spermatogenesis. Human spermatogenesis includes six cell stages, where 4 cycles complete a wave, including processes of mitosis (from dark spermatogonia to spermatocytes I), meiosis (with the most abundant pachytene stage) and cell differentiation (spermatocytes II, round and elongated spermatids). Therefore, there are few tubules in whose lumen sperm are found (< 10%). B. The peritubular compartment that limits the periphery of the seminiferous tubules is composed of 2-5 very thin layers of elongated cells arranged circularly. These cells have fibromuscular contractile characteristics. C. The interstitial compartment is the place where Leydig cells are located. Leydig cells are abundant and normally distributed in clumps. They have a rounded and central nucleus, and a strongly acidophilic cytoplasm. Additionally, c-kit cells, interstitial cells of Cajal and fibroblasts can be found in the interstitium. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

H. Rodriguez Bustos, G. Bravo Maturana, F. Cortés-Chau, J. Defaur Torres, F. Cortés-Pino, P. Aguirre, C. Arriaza Onel

higher serum LH and significantly decreased T/LH and FSH/LH ratio. No statistical difference in serum T, E2 or FSH was detected between both groups (7). Considering that T levels were similar between both groups, LH levels were dramatically increased in COVID-19 group, resulting in decrease in T/LH ratio. This could suggest that SARS-CoV-2 infection has an effect on the testes similar to what is seen in early stages of primary hypogonadism, in which T levels are maintained by the stimulated production of LH due to the impairment of negative feedback (7). The findings of similar FSH, E2 and T/E2 between both groups could be interpreted as unaltered suppression of FSH by inhibin B secreted by Sertoli cells, and conserved peripheral aromatization of androgens. This suggests that SARS-CoV-2 infection has an important effect on Leydig cell function, opposed to what appears to be an unscathed Sertoli cell function (7). Prostate According to the epidemiological information available on COVID-19, the disease is more prevalent in male patients, with a higher incidence compared to female patients. Even more in the elderly, where prostate cancer is prevalent (2). Montopoli et al. (10), described an action of SARS CoV-2 through the use of the ACE2 receptor and its interaction with the virus protein S by the transmembrane protein TMPRSS2. TMPRSS2 inhibition may work to block or decrease the severity of SARS-CoV-2 infections. Interestingly, TMPRSS2 is an androgen-regulated gene that is up-regulated in prostate cancer where it supports tumor progression and is involved in a frequent genetic translocation with the ERG gene. Thus, patients with prostate cancer have a higher risk of SARS-CoV-2 infections compared to patients without cancer. However, prostate cancer patients receiving androgen deprivation therapy appear to be partially protected from SARS-CoV-2 infections. Dana et al. (11) described that TMPRSS2 is the most common gene involved in primary prostate cancer, indicating that the administration of TMPRSS2 inhibitors, which are currently used for prostate cancer, may be useful for the treatment or prevention of COVID-19. Regulators of the expression of TMPRSS2 protein in the lung may overlap with the risk factors for prostate cancer with TMPRSS2-ERG-positive fusion. Explanation of sexspecific difference in the overall incidence of COVID-19 should consider possible differences in laboratory tests for SARS-CoV-2 and the presence and activity of TMPRSS2 - ERG associated with prostate cancer, as well as strong TMPRSS2 regulation. Androgen levels could suggest that TMPRSS2 could partially explain the male prevalence in the COVID-19 pandemic. When studying mRNA levels, the constitutive expression of TMPRSS2 in lung tissue does not appear to differ between men and women. It is tempting to speculate that androgen receptor inhibitory therapies could reduce COVID-19 susceptibility to lung symptoms and mortality (12). Gastrointestinal transmission Additionally, Zhang et al. (13) described that ACE2 is highly expressed in enterocytes, esophageal and colonic

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

epithelium, suggesting possible fecal-oral transmission of SARS-CoV-2. This hypothesis is sustained by the presence of genetic material of the virus in the faeces during respiratory disease and a few days after recovery (13). Detection of SARS-CoV-2 by saliva has become an alternative option for viral load sampling for diagnosis and follow-up in COVID-19 patients, providing a safer and easier alternative for medical personnel to obtain samples, in comparison to nasopharyngeal swabbing (14). Viral strains can be found in saliva up to 29 days after infection. Therefore COVID-19 can be transmitted by saliva directly or indirectly, even among patients without cough or other respiratory symptoms (14). Hence, since COVID-19 is present and detectable in saliva, this would indicate that it could potentially be transmitted through oral sex. Blood transmission Chang et al. (15), described that in SARS, in some patients, depending on the state of the evolution of the disease, it was possible to find the virus in blood plasma and lymphocytes, although in very low concentrations. Transmission of the disease through blood or plasma transfusion has not yet been described. Something very similar occurs in cases of MERS and COVID-19. Additionally, others describe that no cases have been reported yet and there is no information on the transmission of the virus through blood transfusion therapies. However, the absence of risk of blood transfusion or its therapeutic by-products cannot be guaranteed. It has been recommended and suggested the use of riboflavin and ultraviolet light, allowing to reduce the viral titers that could be present in whole blood to be used for transfusions. Blood products with pathogen reduction may be a safer option for critically ill patients with COVID-19, particularly those in high-risk categories (16, 17). Cryopreservation of spermatozoids In men who developed infections caused by viruses with viremic phases like Zika, Ebola and Mumps viruses, it is possible to find viral particles in semen for several months after their recovery (18). Therefore, when developing sperm cryopreservation processes, it is important to include laboratory protocols that allow ruling out any infection or presence of remains of viral particles. It is necessary to remember that the seminal fluid incorporates the functional and secretory results of several important organs, such as the prostate and seminal glands, and the testicular fluid. Yakass et al. (19) indicate that given the structure of the SARS-CoV-2 virus as enveloped RNA viruses, it could still be viable if it is cryopreserved and then heated to be transferred, even in cryopreservation in liquid nitrogen, similar to what is seen in Influenza virus infection. Therefore, the authors recommend always taking all necessary and sufficient safeguards. Although the presence of active viral particles of SARSCoV-2 has not yet been demonstrated in spermatogenesis or semen, there are warnings and procedures for sperm management obtained from donors for assisted fertilization procedures, suggesting a waiting require-

COVID-19 on male sexual organs

ment of at least 2 weeks if the donor has recovered from the disease and distancing if it comes from geographic areas with high risk of infection (20). Reproductive health in COVID-19 pandemic In a state of health emergency such as the COVID-19 pandemic, it is necessary to identify the biomedical contributions necessary to assist the population in their reproductive health care, considering both the population in confinement and the patients recovered from the disease. During strict confinement, behavioral adaptations occur inside the household that are generally associated with an overuse of digital technologies (telework and leisure). This implies a great overexposure to blue light (daylight and LED light from technological devices) that eventually and sooner rather than later leads to alteration in circadian rhythms, preventing the normal functioning of the pineal gland. This condition has been shown to alter the function of the ovary (21) and the testis (22), in addition to mental disorders. Since the pandemic was declared by the WHO, the most affected countries in Europe have been Italy and Spain. Currently, both countries have received the contributions of experts in reproductive health and their association with COVID-19. In Italy the Italian Association of Andrology (23) and in Spain the Association for the study of the Biology of Reproduction and the Spanish Association of Andrology, Sexual and Reproductive Medicine (24) were attentive to the recommendations of the WHO and new related scientific literature. The complexity of andrology research in pandemic times In South America, the pandemic has been causing health havoc similar to Europe, but with a lag of around 2 months. For example, in Chile strict quarantine confinement was decreed and implemented from the second week of March to date (August). With the foregoing, only activities classified as essential have been carried out, within which university teaching or research has not been included. Most medical services have been targeted or have been converted to COVID-19 response mode. Therefore, little to no scientific research has been possible to develop in this regard. Additionally, the management of the legal aspects regarding the handling of corpses and patient samples in pandemic states means that access to biological material is restricted.

CONCLUSIONS

The male reproductive system would be highly vulnerable and susceptible to infection by SARS-CoV-2 given the expression of the ACE2 receptor, both in somatic cells (Leydig, Peritubular, and Sertoli cells), as well as in almost all germ cells in their mitotic, meiotic, and differentiation stages. Added to this is the fact that the expression of TMPRSS2 is regulated by androgens. However, to date, no studies have been published that have found evidence of the virus in the testis, prostate tissue, or semen. Therefore, the seminal fluid would still remain free of viral presence in patients with COVID-19. Regardless, non-genital sex could be an important source

of viral transmission in asymptomatic and mild symptomatic patients. It is imperative to rule out that the sperm to be used in assisted reproduction techniques may come from donors who have suffered from COVID-19. All necessary tests must be carried out to ensure that the donor is free of the virus at the time of collection of the semen sample, during the procedures and handling of the samples. In case of prostate cancer with indication for radical prostatectomy, if the patient has reproductive intentions, the option of using sperm cryopreservation should be proposed, after studying the absence of active seminal SARS-CoV-2. Considering the difficulty to obtain tissue samples of COVID-19 deceased patients, due to the strict protocols and limitation put in order by governmental institutions, mostly all histological research has been done in testis, with almost no studies describing the effects of SARSCov-2 in prostate and seminal vesicles, leaving a huge gap in the body of evidence concerning this virus impact on the male reproductive tract.

REFERENCES

1. Wang S, Zhou X, Zhang T, Wang Z. The need for urogenital tract monitoring in COVID-19. Nat Rev Urol. 2020; 17:314-315. 2. Cheng H, Wang Y, Wang GQ. Organ-protective effect of angiotensin-converting enzyme 2 and its effect on the prognosis of COVID-19. J Med Virol. 2020; 92:726-730. 3. Magrone T, Magrone M, Jirillo E. Focus on receptors for Coronaviruses with special reference to angiotensin-converting enzyme 2 as a potential drug target - A perspective. Endocr Metab Immune Disord Drug Targets 2020; 20:807-811. 4. Li MY, Li L, Zhang Y, Wang XS. Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues. Infect Dis Poverty. 2020; 9:45. 5. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020; 181:271-280. 6. Secin FP. Priorities in testis cancer care during Covid-19 pandemic. Int Braz J Urol. 2020; 46:79-85. 7. Ma L, Xie W, Li D, et al. Effect of SARS-CoV-2 infection upon male gonadal function: A single center-based study. medRxiv. 2020. 8. Xu J, Qi L, Chi X, et al. Orchitis: A complication of severe acute respiratory syndrome (SARS). Biol Reprod. 2006; 74:410-416. 9. Yang M, Chen S, Huang B, et al. Pathological findings in the testes of COVID-19 patients: clinical implications. Eur Urol Focus. 2020; 6:1124-1129. 10. Montopoli M, Zumerle S, Vettor R, et al. Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (N = 4532). Ann Oncol. 2020; 31:10401045. 11. Maleki Dana P, Sadoughi F, Hallajzadeh J, et al. An insight into the sex differences in COVID-19 patients: what are the possible causes? Prehosp Disaster Med. 2020; 35:438-441. 12. Stopsack KH, Mucci LA, Antonarakis ES, et al. TMPRSS2 and COVID-19: Serendipity or opportunity for intervention? Cancer Discov. 2020; 10:779-782. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

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13. Zhang JC, Wang S Bin, Xue YD. Fecal specimen diagnosis 2019 novel coronavirus-infected pneumonia. J Med Virol. 2020; 92:680682. 14. Aponte Mendez M, Rivera Marval EK, Talebzade Toranji M, et al. Dental care for patients during the Covid-19 outbreak: a literature review. Int J Sci Res Dent Med Sci. 2020; 2:42-45. 15. Chang L, Yan Y, Wang L. Coronavirus Disease 2019: Coronaviruses and blood safety. Transfus Med Rev. 2020; 34:75-80. 16. Ragan I, Hartson L, Pidcoke H, et al. Pathogen reduction of SARS-CoV-2 virus in plasma and whole blood using riboflavin and UV light. PLoS One. 2020; 15:e0233947. 17. Keil SD, Ragan I, Yonemura S, et al. Inactivation of severe acute respiratory syndrome coronavirus 2 in plasma and platelet products using a riboflavin and ultraviolet light-based photochemical treatment. Vox Sang. 2020; 115:495-501. 18. Feldmann H. Virus in semen and the risk of sexual transmission. N Engl J Med. 2018; 378:1440-1441. 19. Yakass MB, Woodward B. COVID-19: should we continue to

Correspondence Héctor Rodriguez Bustos, MV, MSc, DBM, PhD (Corresponding Author) hector3@uchile.cl Gonzalo Bravo Maturana, MD gonzalo.bravo.m@ug.uchile.cl Felipe Cortés-Chau, MD felipe.cortes.c@ug.uchile.cl Joelle Defaur Torres, MD joelle.defaur@ug.uchile.cl Felipe Cortés-Pino, MD felipe.cortes.p@ug.uchile.cl Pablo Aguirre, MD pablo.aguirre@ug.uchile.cl Camilo Arriaza Onel, MD carriaza@med.uchile.cl Laboratorio de Morfología, ICBM, Facultad de Medicina. Universidad de Chile, Avda, Independencia 1027, Santiago (Chile)

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cryopreserve sperm during the pandemic? Reprod Biomed Online. 2020; 40:905. 20. Esteves SC, Lombardo F, Garrido N, et al. SARS-CoV-2 pandemic and repercussions for male infertility patients: A proposal for the individualized provision of andrological services. Andrology. 2021; 9:10-18. 21. Espino J, Macedo M, Lozano G, et al. Impact of melatonin supplementation in women with unexplained infertility undergoing fertility treatment. Antioxidants (Basel). 2019; 8:338. 22. Sun T-C, Li H-Y, Li X-Y, et al. Protective effects of melatonin on male fertility preservation and reproductive system. Cryobiology. 2020; 95:1-8. 23. Maretti C, Privitera S, Arcaniolo D, et al. COVID-19 pandemic and its implications on sexual life: Recommendations from the Italian Society of Andrology. Arch Ital Urol Androl. 2020; 92:73-77. 24. José FG, González JGÁ, Molina JMC, et al. Infección por SARSCoV-2: implicaciones para la salud sexual y reproductiva. Rev Int Androl. 2020; 18:117-23.

ORIGINAL PAPER

DOI: 10.4081/aiua.2021.1.53

The woman and the penile prosthetic implant. Primary or secondary role? Personal experiences on 355 implanted patients Diego Pozza 1, Alberto Berardi 2, Mariangela Pozza 1, Augusto Mosca 2, Carlotta Pozza 3 1 Studio

di Andrologia e di Chirurgia Andrologica, Rome, Italy; Urologia, S. Sebastiano Hospital, Frascati, Italy; 3 Department of FPM, Sapienza University, Rome, Italy. 2 U.O.

Summary

Objective: We evaluated the role of women (wife, partner, girlfriend, lover) in the decision and the results of Penile Prostheses Implants (PPI). Material and methods: In a group of 355 pts (21-82 years, average age 50.3 years) submitted to PPI since 2007, we recorded data concerning the relationships with their partner and their role in the surgical decision. We implanted 97 Semirigid (SPP), 136 Malleable (MPP) and 122 Inflatable (IPP) Prostheses. We collected data regarding some aspects of the sexual life of patients. We asked them if they were married, divorced or widowed; if they had a lover; if they go regularly to brothels; if they were satisfied of their actual couple’s life. After surgery we recorded data concerning their difficulties in utilizing the PPI and their level of satisfaction. Results: Most patients (93%) confirmed their satisfaction after PPI. Relational aspects: 44 out of 46 unmarried patients with difficult sexual intercourses managed to have regular sex and decided to marry after PPI, including 5 younger patients (2130 years old) who were not able to penetrate their girlfriends. In the group of married patients 5 pts were not able to penetrate their wives; after PPI they managed to have regular intercourses and pregnancies. Fifteen widowers and 22 divorced patients decided to have a PPI for possible sexual dating or stable relationships. Ninety-six out of 271 (28.2%) married patients declared a stable extramarital relationship that represented the main reason for having a PPI. Conclusions: In our opinion the simple act of penetrate and ejaculate in vagina, without considering the importance of personal, relational, emotional factors, often well linked to a specific woman, cannot be considered the ideal target of PPI.

KEY WORDS: Penile prosthesis; Penile prosthesis implant; Psychosexual factors; Couple. Submitted 22 September 2020; Accepted 22 November 2020

INTRODUCTION

Penile Prostheses Implants (PPI) have been considered as one of the ultimate treatments of Erectile Dysfunction (ED) since 1972 (1, 2). In most cases, evaluation of the patients to be submitted to PPI included various parameters such as age, race, metabolic and general diseases, hormonal conditions, cardiovascular diseases, tobacco smoking, alcohol, drugs. The role of women (wife, partner, girl-

friend, lover) is rarely evaluated while, in our opinion, the ongoing relationship with the woman is crucial when the male must make the decision to undergo surgery to solve his ED (3). In our experience, patients with ED try to find a solution (psychotherapy, drugs, hormones, 5PDEi, PGE1, urethral alprostadil, low intensity extracorporeal shockwave therapy, penile implants) not only to manage to have an erection but, mainly, if not exclusively, to have the opportunity to have sex with their partners. If a male does not have sexual intercourses for religious choices, personal principles, lack of interest, limits of freedom, geographical factors (deportations, emigration, work shifts) probably he is not particularly bothered by his ED. If the male feels the need to have an orgasm and ejaculation, he can obtain it with masturbation, possible even with a not fully erect penis. Many men over 50, of medium-high cultural level, with good profession, high work responsibilities, good income, one or more children, have no particular interest in having sex with their wives after 10-15 years of marriage (4-5) or even with a lover often because afraid of not being able to perform. Until 30-40 years ago, males could have regular sex only after marriage; in married couples usually the male took the initiative and the woman had little chance of refusing. Often, after giving birth to several children and as they became older, women might show a decline in sexual desire and, as menopause approached, the willingness to have sex might become less frequent and rewarding (6), due to the fatigue to take care of several children and the family and the lack of enough amusements and distractions. If a male complains ED and is less inclined to have sex, this doesn’t represent a problem for the wife and for the couple. A great number of patients, over 35 years of age, visiting our Center, states that they have sexual intercourses with their wives, generally, every 7-10 days; the frequency of sexual intercourses with the lovers is the same. For the couple, generally, the working time and the travel back home is tiring; they have to check if the children did their “job” and spend time with them; after dinner they watch TV or prepare for the next day and generally, they go to sleep after 11-12 p.m. and are very tired; they have to wake up early next morning. Generally, there isn’t enough time for sex. Things are different in the weekend or during holidays when the frequency of sexual intercourses

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

D. Pozza, A. Berardi, M. Pozza, A. Mosca, C. Pozza

increases significantly. Another factor influencing the frequency of marital intercourses, in the last 10-20 years, is represented by the sex-web with an increase of web-masturbation (7). Many men report web-masturbation several times a week. After masturbation, males have no feeling or strength to have a sexual intercourse with their wives. Today, most patients (> 40 years old) who visit our center for andrological problems generally refer sexual intercourses only in the weekend. The DE is no longer a drama, but something missing that becomes important only if a male begins an affair or wants children and would like to increase the frequency of sexual intercourses. Often only in these circumstances a male seeks an ultimate solution of his ED. For about 20 years we have been evaluating the relationships of our patients requiring a prosthetic solution for their ED. We started to consider the reactions of the partners; if they were informed of the surgical decision and if they supported or refused such a solution (8). In cases of married patients, we consider if they had extramarital relationships or if they buy prostitutes. In case of divorced or widowed patients, we investigated if the patients would prefer to remain alone in the future or if, instead, they would desire a new relationship both for domestic partnership and sexual activity.

MATERIALS

AND METHODS

Since 1984 more than 39.000 patients presented to our private Studio di Andrologia for erectile or ejaculatory dysfunctions (about 40%), infertility (40%) and/or urologic problems (15%) (9). After diagnosis, specific therapies have been suggested. For patients affected by ED (a group of 9.200 pts) after the visit and specific diagnostic examinations (metabolic analyses, hormonal evaluations, often Nocturnal Penile Tumescence test with Rigiscan, dynamic penile duplex sonography, magnetic resonance imaging, neurological and cardiological examinations), we prescribed the available therapeutic modalities (psychotherapy, drugs, vasodilators, venous surgery, 5PDEi, vasoactive injections, Medical Urethral System for Erection or MUSE, urethral alprostadil creams, Low Intensity Extracorporeal Shockwave Therapy or LIESWT). We suggested the penile prosthetic solution to 750 pts who didn’t report any satisfactory results. Out of them 577 accepted such option for treating their ED. In the first period (1984-2006) we recorded in our files only if the male was married or not. Since 2007 (i.e. for the last 355 pts) we are recording more complete information dividing the patients in 6 groups: 1. Single patients without no relationship and no sexual intercourses with women; 2. Single patients with the opportunity to have sexual intercourses; 3. Married patients with regular sexual activity; 4. Married patients with wives who avoided or refused sexual intercourses; 5. Married patients with sexual intercourses outside the marriage, with fixed relationships, lovers or prostitutes; 6. Divorced or widowed patients who would like to start stable relationships for the future.

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We did not use validated and dedicated questionnaires about QoL. The fact that medical visits had to be paid for limited the number of patients who mainly belonged to the middle or high class. Normally, we did not use to send patients to a psychologist before surgery. Patients were affected by various pathologies as venous or arterial and mixed vascular diseases; diabetes type 2; hypertension; Peyronie’s disease; prostate and pelvic surgery outcomes; psychological and relational problems. We implanted a wide variety of PPI [Semirigid, Silicone: 97 (SPP); Malleable: 136 (MPP); Inflatable: 122 (IPP)]. This was always justified by the search for low-cost PPI, because in Italy patients had to pay for the Clinic, Prosthesis and Surgeons. As a rule, we visited patients 710 days post-op and after about 1 and 12 months. A group of 36 pts did not comply to follow-up. Many patients continued to carry out periodic and regular checks for many years afterwards.

RESULTS

Results of PPI can be considered satisfying (1, 9) even if we recorded complications related to infections (14 pts, 3.9%) or malfunction of prosthetic cylinders and inflatable system (18 pts, 5.0%). In general, the patients who chose prosthetic surgery because they had ineffective sexual relationship, were able to have full sexual intercourses, although a share of them (15%) complained a shortening of the rod, a difficult penetration with semirigid and malleable prostheses (possible bending) and a significant loss of skin sensitivity. Unmarried Forty-four out of 46 unmarried patients with difficult sexual intercourses managed to have regular sex and decided to marry after PPI, including 5 younger patients (21-30 years old) who were not able to penetrate their girlfriends. Only two patients continued to avoid sexual relationships for performance anxiety or for the lack of a stable partner. Married All the married patients after PPI were able to have sexual intercourses, except three patients who reported a strong rejection by their wives who refused any kind of sexual intercourse. Five patients who were never able to have penetrative intercourses after marriage managed to have a full and satisfying sexual life after PPI. We did not test the index of appraisal of the women (10) after their husbands’ PPI (11). Extramarital relationships, divorced, widowed All pts who had a lover, referred good and improving sexual relationships. All divorced and widowed males who decided to have the PPI for a possible and new familial and sexual relationship referred to be fully satisfied of the PPI. Obviously in this group of patients we were not able to analyze the reactions of their partners. Psychological difficulties after IPP Many males, after PPI, were often blocked by the fear that a new partner might notice the presence of the cav-

Woman and penile prostheses

Table 1. Sexual activity and relationships of patients before surgery by age group. Patients Years < 21 21-30 31-40 41-50 51-60 61-70 71-80 81-90 Total

No. 6 30 44 75 98 64 33 5 355

GirlFriends Never had sex Sex difficulties 3 3 3 22 2 13 0 0 0 0 0 0 0 0 0 0 8 38

Marriage coexistence 0 5 28 69 92 54 22 1 271

Extramarital affairs 0 2 3 23 34 26 8 3 96

Table 2. Protheses implanted in 355 patients. Patients Years < 21 21-30 31-40 41-50 51-60 61-70 71-80 81-90 51.20 mean

Semirigid 6 18 16 17 20 14 5 1 97 total

Penile prostheses Malleable Inflatable 0 0 6 6 18 10 34 24 38 38 18 32 20 10 2 2 136 122

Total 6 30 44 75 96 64 35 5 355

ernous cylinders both semi-rigid and inflatable. In our experience, at least 5 patients with severe erectile dysfunction preventing sexual relationships, after the prosthetic implant admitted great difficulties in the first intercourses, because afraid of being discovered by their partner. Most of our patients with MPP implants referred a better acceptance by their partners, because the penetration was easy after usual foreplay without particulars manoeuvres. Patients with IPP could get better erection but they have to obtain it by inflating the IPP. A limited number of wives complained that the foreplay was compromised by these manoeuvres to have an artificial erection, thus changing the feeling about it. Three out of 110 partners of patients with IPP (2.7%) considered this a reason for rejecting sexual intercourses with their husbands (12 were lost at follow up). On the contrary, 220 out of 223 patients with SPP/MPP never referred that this was relevant (10 lost at follow up). In general, patients with partners who accepted or had been favourable to prosthetic surgery were able to use the prostheses earlier and with greater frequency of intercourses and satisfaction. This confirms the importance of the involvement and collaboration of the partner in the decision, preparation and post-op course of PPS (12). In our clinical experience, 15 patients already personally convinced and just included in the program for penile prostheses implantation gave up or had to give up surgery due to the firm opposition of their no longer young wives, who considered the decision of their partner not

Divorced

Widow

0 0 0 5 4 6 5 2 22

0 0 0 1 2 4 6 2 15

absolutely relevant to modify or improve their relationship, that they considered optimal even if with scarce or no sexual activity.

DISCUSSION

The PPI is an effective option to treat ED especially in patients where pharmacological solutions have not provided satisfactory results. Questionnaires, such as the Female Sexual Function Index (FSFI) (10, 13, 14), reporting the opinion of women on sexual function of their husbands or partners, are important to evaluate their sexual function and quality of life after PPI (15, 16). In the past, the Literature addressed women sexual satisfaction in a generic way when reporting the satisfaction shown by women in relation to the penile prostheses of their partners. Another problem begins to be observed in women with sexual dysfunction already existing before the resolution of the erectile dysfunction of their partners, who got used to the ED of their partners and after PPI begin to develop a high level of stress, as a result of the new requests and expectations made possible by the penile prosthetic implant (17). It has sometimes emerged that the wife, no longer young, begins to fear that the husband may be interested and involved in extramarital relationships, not possible as long as an ED was present. In those cases, it is important for the man to express his intention to integrate PPI into the sexual life of the couple. The man must make his wife understand, that the decision to have a PPI is aimed at restoring a correct sexuality in the couple. If this does not happen, it is probably too late to make that decision. The partner's decision should be understood and respected. Obviously, it is essential to evaluate the sexual life of a couple before the decision to have a PPI implanted, because a woman who has not been having sexual intercourses for a long time, due to her husband's ED, or had a decrease in desire, might not be cooperative and participate in her partner's decision. It is often the surgeon's clinical ability and sensibility to illustrate the positive effects of PPI in the couple's life. Until not long ago, the sexual life of menopausal women was culturally stigmatized. Today, with the advent of hormonal therapies and the challenging and often rewarding social role, this perception has changed, and active desire and sexual life are universally accepted even at this stage of life. PPI is often considered as an "inconvenient third" in the intimacy of the couple even if it makes significant changes in the sexual health of the couple itself. In the Literature, the importance of the women role in the treatment of patients is not taken into account. This can affect the overall vision about the surgery itself. In an Italian Survey (18) it was reported that about half of the sample (50.7% of men and 48.4% of women) was eager to choose (men) or to support (women) the choice of PPI in case of severe ED and the majority of both sexes (71.3% of males and 76.3% of females) did not oppose to the Archivio Italiano di Urologia e Andrologia 2021; 93, 1

D. Pozza, A. Berardi, M. Pozza, A. Mosca, C. Pozza

choice of PPI. Generally, the surgeon is not properly prepared, if not for personal factors and sensibility, to deal with the dynamics of the couple and, as a result, he/she often prefers not to involve the partner and to discuss all aspects only with the patient. Adjusting false expectations and addressing the patient's doubts and concerns implies a willingness to dialogue and the involvement of various specialists, which is almost never possible. It would be important, after surgery, to join in sexological counselling sessions to help the couple regain the intimacy they lost after the ED and to recover after PPI. The recent Clinical Recommendations of the European Society for Sexual Medicine points out that at present there are no standardized methods to determine the male and his partner expectations (19). Careful and scrupulous sexological counselling seems to be fundamental to prevent the negative aspects of PPI on the couple relationship. Even in these situations, the role of women is important in supporting the expectations of their partners and in driving the approach to consider having sex as a moment of intense couple relationship.

CONCLUSIONS

In most cases, people tend to consider the penile prosthesis as a significant change in the man’s or couple’s life. For this change to be actually positive, it should promote the reinstatement of the psychosexual well-being of the patient and the couple. The clinician should take into account the necessary integration between surgical therapy and psychosexual counselling in the path leading to penile prosthesis. PPI can in fact allow penetrative intercourses and reduce the patient's discomfort in his sexual life in general, but at the same time, due to the irreversibility of prosthetic choice, it could trigger personal and couple dynamics related to the loss of sexual freedom and spontaneity. It would therefore be appropriate to involve, after the patient's first visit, the current partner who could provide important elements in the diagnostic phase and, therefore, help to reinforce the choice of the best therapeutic solution. In the case of PPI in particular, the involvement of women, who can be informed about the technical aspects of PPI and actually support their partners, could reduce the possibility of postoperative psychosexual complications. In addition, an indepth knowledge of the couple and their sexuality could allow a better monitoring of the subsequent results. In such cases, it is important for the partner to express her concerns considering the possibility of integrating the prosthesis into the couple's sexual life. The man must be able to reassure his partner that the decision to undergo surgery is something aimed at recovering the couple sexuality. If that does not happen, maybe it's a little late to make such an important decision. This article aims at emphasizing how important it can be to consider the impact of such an important "surgical solution" as a PPI, not only as a simple procedure but also as a factor with psychosexual consequences on the life of the man but also on the one of his partners. Careful evaluation and psychosexual counselling are essential to prevent negative effects on the couple's life. In most cases the role of women is important, both to support the expectations of

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

their partners and to adapt to the feasibility for sexual intercourses when the sexual life as a couple is not particularly intense. Based on our over-35-year experience, we consider it important to be able to involve women from the very first steps, i.e. from the diagnosis and therapy phase of their partner's ED to the decision to undergo a PPI. Women can help their partners to take this delicate and complex surgical decision, in order to find a new functional reality of the couple and be able to share the benefits and possible difficulties related to PPS.

AKNOWLEDGEMENTS

We thank Dr Roberta Rossi, PhD, Istituto di Sessuologia Clinica of Rome for the invaluable advices and comments to the preparation of the article.

REFERENCES

1. Wilson SK, Delk JR. Historical advances in penile prostheses. Int J Imp Res. 2000; 12:101-7. 2. Chevallier D, Faix A, Bettocchi C, et al. Penile prosthesis in the treatment of erectile dysfunction: updates in 2020.Rev Med Suisse. 2020; 16:525-30. 3. Vakalopoulos I, Kampantais S, Ioannidis S, et al. High patient satisfaction after inflatable penile prostheses implantation correlates with female partner satisfaction. J Sex Med. 2013; 10:2774-81. 4. Carter A, Ford JV, Luetke M, et al. ”Fulfilling his needs, not mine”: reasons for not talking about painful sex and association with lack of pleasure in a national representative sample of women in the United States. J Sex Med. 2016; 16:1953-61. 5. Beutel ME, Burghardt J, Tibubos AN, et al. Declining sexual activity and desire in men-findings from representative German surveys 2005 and 2016. J Sex Med. 2018; 15:750-6. 6. Simonelli C, Eleuteri S, Petruccelli F, et al. Female sexual pain disorders: dyspareunia and vaginismus. Curr Opin Psychiatry. 2014; 27:406-12. 7. Duffy A, Dawson DL, Das Nair R. Pornography addiction in adults: a systematic review of definitions and reported impact. J Sex Med. 2016; 13:760-77. 8.Barton GJ, Carlos EC, Lentz AC. Sexual quality of life and satisfaction with penile prostheses. Sex Med Rev. 2019; 7:178-88. 9. Pozza D, Pozza M, Musy M, et al. 500 penile prostheses implanted by a surgeon in Italy in the last 30 years. Arch Ital Urol Andr. 2015; 87:216-23. 10. Rosen R, Brown C, Heiman J, et al. The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function. J Sex Marital Ther. 2000; 26:191-208. 11. Rosen RC , Riley A, Wagner G, et al. The International Index of Erectile Function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology. 1997; 49:822-30. 12. Özbay E, Aydın A, Salar Rm, et al. Sexual experiences between partners after penile prosthesis: Who is more satisfied? Andrologia. 2020; 52:13461-6. 13. Awwad AA, AboSeif AF, Fattag Farag MA, et al. Sexual functions of females married to males with semi-rigid penile Implants: a cross-sectional study. Urologia. 2019; 86:197-201.

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14. Isidori AM, Pozza C, Esposito K, et al. Development and validation of a 6-item version of the Female Sexual Function Index (FSFI) as a diagnostic tool for female sexual dysfunction. J Sex Med. 2010; 7:1139-46. 15. Gittens P, Moskovic JD, Desiderio Avila Jr, et al. Favorable female sexual function is associated with patient satisfaction after inflatable penile prosthesis Implantation. J Sex Med. 2011; 8:19962001. 16. Portman DJ, Gass MLS. Genitourinary syndrome of menopause: new terminology for vulvo vaginal atrophy from the international society for the study of women’s sexual Health and the North American Menopause Societ. J Sex Med. 2014; 11:2065-72. 17. Omonov D, Christopher AN, Blecher GA. et al. Clinical

Recommendations from the European Society for Sexual Medicine exploring partner expectations, satisfaction in male and phalloplasty cohorts, the impact of penile length, girth and implant type, reservoir placement, and the influence of comorbidities and social circumstances. J Sex Med. 2020; 17:210-37. 18. Pescatori ES, Baldini A, Parazzini F, et al. How much do people know about male sexual problems? A survey in a selected population sample. Arch Ital Urol Androl. 2019; 91:182-6. 19. Caraceni E, Utizi L. A questionnaire for the evaluation of quality of life after penile prosthesis implant: quality of life and sexuality with penile prosthesis (QoLSPP): to what extent does the implant affect the patient's life? J Sex Med. 2014; 11:1005-12.

Correspondence Diego Pozza, MD (Corresponding Author) diegpo@tin.it Mariangela Pozza, MD mariangela.pozza@gmail.com Carlotta Pozza, MD, PhD carlotta.pozza@gmail.com via B. Gozzoli, 82C, 00142 Rome (Italy) Alberto Berardi, MD alberto.berardi@alice.it Augusto Mosca, MD moscaugusto@gmail.com via Tuscolana, 2, 00044 Frascati-RM (Italy)

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

DOI: 10.4081/aiua.2021.1.58

ORIGINAL PAPER

Erectile dysfunction post radical cystectomy. The role of early rehabilitation with pharmacotherapy in nerve sparing and non-nerve sparing group: A randomized, clinical trial Mohamad Moussa 1, Athanasios G. Papatsoris 2, Mohamed Abou Chakra 3, Athanasios Dellis 4 1 Urology

Department, Zahraa Hospital, University Medical Center, Beirut, Lebanon; Department of Urology, School of Medicine, Sismanoglio Hospital, National and Kapodistrian University of Athens, Athens, Greece; 3 Faculty of Medical Sciences, Department of Urology, Lebanese University, Beirut, Lebanon; 4 Department of Urology/General Surgery, Areteion Hospital, Athens, Greece. 2 2nd

Summary

Objectives: No clinical studies testing erectile function (EF) post radical cystectomy (RC) were done. Our objective was to assess the effect of early pharmacologic therapy after RC using intracorporeal injection (ICI), phosphodiesterase inhibitor (PDE5i) and PDE5i+ICI. Materials and Methods: In our randomized, double-blinded study, we prospectively enrolled 160 potent male patients with invasive bladder cancer. Patients were operated by RC using the nerve-sparing (NS) or non-nerve sparing (NNS) technique. They were treated since 1 month postoperatively by different regimens (PDE5i vs. ICI vs. ICI+PDE5i). Patients were evaluated using the international index of erectile function questionnaire and were followed up regularly at 1, 3, 6, and 12 months using the same parameters. Results: One month after therapy, the mean of EF domain improved in both NS and NNS group. In the NNS group, in patients treated with ICI alone and ICI+PDE5i, the EF domain at 12 months moved to the moderate and to the mild category respectively. In patients treated by the NS approach, the mean value remained in the mild category with or without therapy. Conclusions: Early pharmacotherapy since one-month post RC using ICI and a combination of ICI+PDE5i can improve the erectile function of patients operated with a NNS approach.

KEY WORDS: Erectile dysfunction; Early rehabilitation; Radical cystectomy; Nerve-sparing; Non nerve-sparing. Submitted 21 September 2020; Accepted 27 October 2020

INTRODUCTION

Radical cystectomy (RC) remains the standard of therapy for high-grade invasive bladder cancer and some categories of superficial bladder cancer (1). Sexual dysfunction after RC may be related to multiple factors including surgical trauma to the neurovascular bundle, psychological stress, and type of urinary diversion. RC with urinary diversion significantly affects sexual functioning. The recovery percentage of the erectile function was 49% at 3 years and 79% at 5 years (2, 3). We performed a prospective study testing the erectile function of 160 potent males operated by RC with nerve-sparing and none-nerve sparing technique, dividing them into

groups that were treated early since 1 month after surgery by different drugs: intracorporeal injection (ICI), phosphodiesterase inhibitor (PDE5i) and a combination of both drugs. The objective of this study was to assess the erectile function (EF) in different subgroups of patients who were treated early postoperatively by comparing the preoperative ‘’international index of erectile function (IIEF) questionnaire’’ results with postoperative results to test the effect of early rehabilitation strategy on erectile dysfunction. There is no evidence in the current literature regarding sexual function recoverability after RC focusing and, in particular, early rehabilitation strategy of erectile function and its effect on other domains of male sexual function (orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction) in the nonnerve and nerve sparing group of patients by passing the early phase of recovery.

MATERIAL

AND

METHODS

Study design & participants This study was a randomized, double-blinded, clinical trial that evaluated the role of early pharmacologic therapy for the treatment of erectile dysfunction post RC. Between February 2014 and 2019, 160 potent male patients with non-metastatic invasive bladder cancer who were operated with radical cystectomy were included in the study. Patients were divided into 4 different groups: Group A including 40 patients who received no treatment. Group B including 40 patients who were treated by intracorporeal injection (ICI) of prostaglandin E1 (PGE1) at a dosage of 20 micrograms 2 times per week) after one month of surgery to 1 year. Group C including 40 patients who were treated by ICI+PDE5-i after one month of surgery to 1 year. Group D including 40 patients who were treated by PDE5i: Sildenafil, 50 mg after one month of surgery to 1 year. The patients were randomly allocated to each group based on the type of surgery performed. In each group, 20 patients were operated using the nerve sparing (NS) technique and 20 other patients operated using the nonNo conflict of interest declared.

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Erectile dysfunction post radical cystectomy

nerve sparing (NNS) technique. All patients included in the study fulfilled the following criteria: potent male, sexually active, tumors muscle invasive T3 or less (T2a, T2b, T1High grade), N0, M0, age 45-69, not receiving neoadjuvant chemotherapy. The patients and treating clinicians were blinded to the treatment allocation. Follow up visits were noted by another urologist within the same department. Sample size Based on previous studies, the difference in the mean change in the IIEF score between the two groups (NS and NNS) was 11.7. We conservatively set this value as 11. When a two-tailed test with a test power of 90% and a significance level of 5% was used, 80 patients are required in each group. For 4 treatment subgroups, the total sample size required for this study was estimated to be 160 patients. Study intervention The same urologist performed the RC+ Ileal conduit (90 patients) or neobladder (70 patients) with or without nerve sparing technique. RC was done with preservation of the neurovascular bundles as described by Walsh (5). Three groups of patients were treated since one month post operatively with PDE5i, ICI, PDE5i+ICI for a period of 1 year where they were followed. The study was performed at Zahraa Hospital, University Medical Center in Beirut which is an academic, tertiary care hospital with 300 beds. The Urology Department contains 22 beds; it is staffed by 8 urologists. The study was approved by our Institutional Review Board. Our study adheres to CONSORT guidelines. Descriptive tables of means and standard deviations were computed for different combinations. Outcome measurements Erectile function was assessed by IIEF- score before and after surgery at 1, 3, 6, 12 months postoperatively. Preoperative EF was tested using the IIEF questionnaire (4). The degree of the erection was categorized on the basis of the EF domain (six questions regarding EF) of IIEF questionnaire and classified as mild ED (score 1725), moderate ED (score 11-16), or severe dysfunction (score < 10); patients with score > 26 were considered as not having erectile dysfunction. Ethics statement The study was approved by our hospital IRB (approval No. 2014.12). Informed consent was confirmed by the IRB. Written informed consent was obtained from each participant. Statistical analysis Statistical analyses for estimated marginal means were performed using a mixed ANOVA with repeated measures. This test determines the interactions between dependent and independent variables. A mixed ANOVA with repeated measures was run on a sample of 160 patients to examine the effect of the treatment group of 4 levels (No therapy, PDE5-I, ICI, ICI+PDE5-I), the type of surgery of 2 levels (NS and

NNS) and the time points of assessment of 5 levels (preoperatively time, 1 month postoperatively, 3 months postoperatively, 6 months postoperatively, 12 months postoperatively) (3 independent variables) on the erectile function. The normal distribution and the homogeneity of variances assumptions for each combination of the groups were checked using respectively the Shapiro-wilk tests of normality and the Levene's Test of Equality of Error Variances. The data was processed using the Statistics software SPSS (Statistical Package for Social Sciences) Version 19.0. A p value of 0.05 was considered statistically significant.

RESULTS

Table1 summarizes the clinicopathologic characteristics of the patients from which reported data were obtained. Median patient age in the NS group was 62 vs. 61 in NNS group and both groups had the same comorbidities. Orthotopic neobladder was performed for 70 patients (45 patients in the NS group and 25 patients in the NNS group). Ileal conduit urinary diversion was performed in 90 patients (35 of them in the NS group and 55 others in the NNS group). The mean preoperative EF domain in NNS group was 20.7 wherein in NS group was 21.4. After 1 month it was 6 in NNS group wherein in NS group was 9.8 (severe erectile dysfunction). The mean values of EF domains differed in each subgroup of the 2 major groups (NS vs. NNS). After 1 month from surgery, NNS groups with no therapy, PDE5i, ICI and ICI+PDE5 I showed all the same value of 6. In NS groups with no therapy, PDE5i, ICI and ICI+PDE5 I subgroup mean value was 12.5, 10.5, 9 and 7.5 respectively. The mean value of EF domains in NNS group remained the same with no therapy and PDE5i at 3, 6, 12 months with a value of 6, whereas in the ICI subgroup it increased to 13.5 at 4 months remaining constant at 6 and 12 months and in the ICI+PDE5i association, it increased the mild range of 18 at 12 months. The mean of EF domains in NS group increased to become in all subgroups in the mild range. Those results are illustrated in details in Table 2. When assessing the difference of means between treatment subgroup, we found only a statistical significance (p < 0.05) when comparing the PDE5i subgroup with other treatment subgroups (ICI, ICI+PDE5i), where no statistical significance was found when comparing ICI Table 1. Clinicopathologic characteristics and comorbidities of the NS and NNS group. NS 25 21 19 15 20 13

pT 1 HG T2a T2b T3a Hypertension Diabetes

NNS 31 20 9 20 33 10

NS: nerve-sparing; NNS: non nerve sparing; HG: high grade.

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M. Moussa, A.G. Papatsoris, M. Abou Chakra, A. Dellis

Table 2. Mean of erectile function domains in the NS and NNS group divided into treatment subgroups.

EF_Preop 1 month postop 3 months postop 6 months postop 12 months postop

Type of surgery NNS 20.7 ± 2.9 NS 21.45 ± 2.8 NNS 6 ± 0 NS 9.8 ± 3.2 NNS 10.3 ± 1.4 NS 10.3 ± 3.3 NNS 10.7 ± 0.9 NS 19.1 ± 3.6 NNS 10.8 ± 1.1 NS 20.9 ± 2.9

None 22 ± 2.2 24 ± 1.4 6±0 12.5 ± 3.3 6±0 14.3 ± 2.2 6±0 17 ± 4.9 6±0 19.5 ± 3.1

Treatment subgroup PDE5-I ICI ICI+PDE5-I 19.5 ± 3 20.5 ± 2.9 21 ± 3.5 21.3 ± 3.2 21 ± 3.6 19.5 ± 3 6±0 6±0 6±0 10.5 ± 3.1 9 ± 3.5 7.5 ± 3 6±0 13.5 ± 3 15.8 ± 2.6 14.5 ± 5.7 18.8 ± 4.9 17.5 ± 0.6 6±0 13.5 ± 3 17.3 ± 0.9 18.3 ± 4.5 21.8 ± 2.6 19.3 ± 2.5 6±0 13.5 ± 3 18 ± 1.6 19.8 ± 2.9 22 ± 2.7 22.3 ± 2.9

PDE5-I: Phosphodiesterase inhibitor; ICI: Intracavernosal injection; EF: erectile function; NS: nerve–sparing; NNS: non nerve-sparing; post op: post operative period.

Table 4. Direct erectile function domain comparison between patient’s subgroups according to the type of surgery. Type of surgery NNS

Treatment subgroup 1 (G1) None

PDE5-I

ICI None

PDE5-I ICI

Treatment Mean Mean Mean subgroup 2 (G2) G1 G2 difference (G1-G2) PDE5-I 9.2 8.7 0.5 ICI 13.4 -4.2 ICI+PDE5-I 15.6 -6.4 ICI 8.7 13.4 -4.7 ICI+PDE5-I 15.6 -6.9 ICI+PDE5-I 13.4 15.6 -2.2 PDE5-I 17.45 16.85 0.6 ICI 18.5 -1.05 ICI+PDE5-I 17.2 0.25 ICI 16.85 18.5 -1.65 ICI+PDE5-I 17.2 -0.35 ICI+PDE5-I 18.5 17.2 1.3

P-value 1 0.039* 0.001* 0.016* < 0.0001* 0.8 1 1 1 1 1 1

NS: nerve-sparing; NNS: non nerve-sparing; PDE5-I: Phosphodiesterase inhibitor; ICI: Intracavernosal injection; none: patients not given any treatment.

Table 3. Mean of erectile function domains compared between treatment subgroups. Treatment subgroup 1 (G1) None

PDE5-I ICI

Treatment subgroup 2 (G2) PDE5-I ICI ICI+PDE5-I ICI ICI+PDE5-I ICI+PDE5-I

Mean G1 13.325

12.775 15.95

Mean G2 12.775 15.95 16.4 15.95 16.4 16.4

Mean difference (G1-G2) 0.55 -2.625 -3.075 -3.175 -3.625 -0.45

P-value 1 0.09 0.03* 0.02* 0.008* 1

PDE5-I: Phosphodiesterase inhibitor; ICI: Intracavernosal injection; None: patients not giving any treatment.

vs. ICI+PDE5i. Those results are illustrated in Table 3. Overall results demonstrated that means differ significantly according to the type of surgery, with 17.5 in NS to 1.72 in NNS group (p < 0.001) . Results of the treatment subgroups according to type of surgery are illustrated in Figure 1. We also assessed the differences of each treatment subgroup according to the type of surgery. We found statistical differences in the NNS group, when we compared no therapy with ICI or ICI+PDE5i whereas no difference was noted when comparing no therapy with PDE5i or comparing ICI with ICI+PDE5i. We didn’t find any statistical significance in the NS group when comparing all Figure 1. Two-way interactions for erectile function domain: Treatment subgroups × type of surgery.

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the subgroups between them; those results are illustrated in Table 4.

DISCUSSION

ED occurs frequently in patients operated by RC. Walsh et al. demonstrated that injury to the neurovascular bundles may contribute to impotence following radical prostatectomy (RP) (5). Based on those findings in 1984, Walsh used a surgical technique that preserves the branches of the pelvic plexus for the preservation of potency and this technique was called a nerve-sparing technique (6). Different sexual-preserving techniques have been described with a different effect on functional and oncological outcomes. The potency rates of capsule sparing cystectomy vs. nerve-sparing cystectomy were not significantly different (50% vs. 40%) as reported by Jacobs et al. (7). A study conducted by Colombo et al. evaluating 3 techniques of nerve sparing cystectomy showed a significant difference in sexual function preservation using the capsule sparing and seminal vesicle sparing vs. nerve sparing (91.6% vs. 84.25 vs 28.5%) but this study was limited due to a low number of patients operated (8). However, those techniques might be not oncologically safe with high metastasis rate (9). In addition, around half of the cystectomy specimens may contain urothelial carcinoma; cancer control may be compromised by leaving a part of the prostate in the capsule sparing technique (10). Therefore, both nerve-sparing cystectomy and prostate capsule sparing cystectomy appear to offer better urinary and sexual function in properly selected patients. More randomized clinical trials are necessary to use those techniques safely in bladder cancer era. Several studies reported that the recovery of erectile function after nerve-sparing radical cystoprostatectomy is around 30% to 80% of cases (2, 3, 11, 12).

Erectile dysfunction post radical cystectomy

There is a clear correlation between the age of the patient when operated and the erectile function recovery following nerve-sparing cystectomy as demonstrated by Schoenberg et al., who showed that the recovery rate of sexual function was the lowest in men 70-79 year old after 10 years of experience with nerve-sparing radical cystectomy (13). Younger age was associate with better sexual function after radical cystectomy then older patients (14-16). Impotence and lack of sexual desire were related to radical radiotherapy for bladder cancer with only 34% male patients sexually active after radiation therapy (17). The type of urinary diversion influence also the sexual activity after surgery where patients with ileal conduit diversion reported more erectile dysfunction (18, 19). Due to the lack of studies addressing the best treatment for erectile dysfunction post radical cystectomy, the response to oral therapy was extrapolated from series on post prostatectomy erectile dysfunction management, where sildenafil is considered an effective treatment after radical retropubic prostatectomy when both neurovascular bundles have been preserved with response rate after nerve-sparing approach reaching 80% (20, 21). Cavernous smooth muscle apoptosis is one mechanism of impotence as tested in multiple experimental studies. Apoptosis of smooth muscle in the rat penis was more significant after bilateral neurectomy vs. unilateral neurectomy (22, 23). Prostaglandin E1 and PDE5i, if given in the early postoperative period could improve erections by providing intracavernosal oxygenation and limiting fibrosis within the corpora cavernosa (24). PDE5i, if used as part of the early penile rehabilitation therapy after RP, could preserve intracorporeal smooth muscle content (25). Also, it had been shown that early use of PDE5i decreased the numbers of apoptotic cells and prevented apoptotic cell death in the penis following denervation (26). Zippe et al. demonstrated that sildenafil citrate cannot improve significantly erectile dysfunction after radical cystectomy: out of 22 patients taking sildenafil citrate post-surgery, only 2 (9%) responded positively (18). A study assessing the optimal time for intracavernous prostaglandin E1 administration after non-sparing RP found that early use of prostaglandin injection since 1 month postoperatively could promote the best response but increased the complication rate (27). Montorsi et al. conducted a study evaluating the early intracavernous injections of alprostadil after nerve-sparing RP. They reported that early injections after 6 months of follow up induced a significant improvement of the spontaneous erections where 67% of the group treated by early intracavernous aplrostadil injection recovered sufficient spontaneous erections for sexual intercourse (28). Padma-Nathan et al. demonstrated that early administration of sildenafil since one month after bilateral nervesparing RP may help in spontaneous erectile function recovery (29). Cavernous neurotomy may cause cavernous fibrosis and dysfunction by increasing expression of TGF-b1, and collagen I and III protein. This may explain why patients operated by nerve-sparing approach may respond partially to pharmacologic therapies for erectile dysfunction. Some new techniques using

intraoperative cavernous nerve stimulation may help in nerve preservation surgeries although those techniques need more investigations (30). There is widespread usage of Vacuum therapy (VT) as part of the penile rehabilitation after RP. The underlying hypothesis is that the artificial induction of erections shortly after surgery facilitates tissue oxygenation, reducing cavernosal fibrosis in the absence of nocturnal erections (31). Yuan et al. assessed the effects of VT on erectile dysfunction (ED) in a rat model of bilateral cavernous nerve crush (BCNC) demonstrating that EF was improved with VT. VT reduced hypoxia-inducible factor-1a (HIF1a) expression and apoptotic indices (AI) significantly compared with control. Animals exposed to VT had decreased transforming growth factor beta 1 (TGF-b1) expression, increased smooth muscle/collagen ratios (32). A web-based survey of members of the International Society for Sexual Medicine (ISSM) and its regional affiliates was performed to assess their practice pattern of post-RP pharmacological penile rehabilitation. As part of the primary rehabilitation strategy post RP, 30% of responders used vacuum device, 95% PDE5i and 75% used ICI (33). In a pilot study, it was demonstrated that initiating the use of a VT protocol at 1 month after RP improves early sexual function and helps to preserve penile length (34). Studies have shown that vacuum erectile device therapy improves erectile function in 8495% of patients and it is suggested that penile rehabilitation with VT should begin early after RP (35). The post-RP ED depends on several factors, including patient age, preoperative potency status (baseline EF) and comorbidities (36). Preoperative potency is of utmost importance, since patients who complain of some degree of ED or patients who already use PDE5-is prior to surgery are at higher risk of developing severe ED postoperatively, regardless of the surgical technique used (37). The main goals of prostate capsule sparing cystectomy are to improve erectile function. Eleven published series of prostate sparing cystectomy report 80% or greater rates of potency preservation, and 6 describe 90% or greater preservation (38). Jacobs et al. performed a singleinstitution trial of bladder cancer patients. No significant difference in functional results were found in men randomized to prostate capsule sparing or nerve-sparing cystectomy with neobladder creation. Mertens et al. reported a 20-year single-center experience of prostate sparing cystectomy for bladder cancer showing that erectile function was intact in 89.7% of patients (39). Back to our results, the mean of EF domain after 1 month of surgery was in the category of severe erectile dysfunction in both group NS and NNS, when the treatment was started after 1 month. The mean value improved in both groups to become at 12 months in the moderate and mild categories in patient treated with ICI and ICI+PDE5i in the NNS group. In other hands, in patients treated by the NS approach, the mean was in the mild category when they were treated by ICI or ICI+PDE5i or in the group not taking any drug. It is important to note that there was no difference between group not given any drug and PDE5i therapy alone in both groups (NS vs. NNS). It means that early therapy Archivio Italiano di Urologia e Andrologia 2021; 93, 1

M. Moussa, A.G. Papatsoris, M. Abou Chakra, A. Dellis

with PDE5i alone may be not effective in the early phase of erectile function recovery. It is also necessary to mention that in the NNS group the mean improve to mild category if ICI and PDE5i were associated together and used early post-surgery. It is critical to note the NS group results, showing that the mean of EF domain improved after 12 months to become in the same category in all subgroups, We cannot conclude if this improvement is due to early postoperative aid or related to neuropraxia phenomenon described previously. In the absence of studies assessing erectile dysfunction post cystectomy in both groups (NS vs. NNS), our results were discussed in front of those obtained in radical prostatectomies patients. The current study was limited by the methodology used to assess the erectile dysfunction. In fact, patients were evaluated using the international index of erectile function (IIEF) score only along a short period of follow up.

CONCLUSIONS

Erectile dysfunction is common after radical cystectomy surgery; it has a great impact on the quality of life of patients. Early rehabilitation plans using pharmacotherapy since one month after surgery with ICI and a combination of ICI+PDE5i can improve erectile function in patients operated with non-nerve sparing approach but not with nerve sparing approach. An early rehabilitative strategy with pharmacotherapy may be offered to patients undergoing a non nerve-sparing procedure in order to enhance the recovery of erectile function and improve all other domains. More studies addressing the early rehabilitative strategy of none nerve-sparing radical cystectomies are needed to confirm our findings.

REFERENCES

1. Stein JP, Skinner DG. Results with radical cystectomy for treating bladder cancer: a ‘reference standard’ for high-grade, invasive bladder cancer. BJU Int. 2003; 92:12-7. 2. Schlegel PN, Walsh PC. Neuroanatomical approach to radical cystoprostatectomy with preservation of sexual function. J Urol. 1987; 138:1402-6. 3. Miyao N, Adachi H, Sato Y, et al. Recovery of sexual function after nerve-sparing radical prostatectomy or cystectomy. Int J Urol.2001; 8:158-64. 4. Rosen RC, Riley A, Wagner G, et al. The International Index of Erectile Function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology. 1997; 49:822-830. 5. Walsh PC, Donker PJ. Impotence following radical prostatectomy: insight into etiology and prevention. J Urol 1982; 128:492-497. 6. Walsh PC, Mostwin JL. Radical prostatectomy and cystoprostatectomy with preservation of potency. Results using a new nerve-sparing technique. Br J Urol 1984; 56:694-697. 7. Jacobs BL, Daignault S, Lee CT, et al. Prostate capsule sparing versus nerve sparing radical cystectomy for bladder cancer: results of a randomized, controlled trial. J Urol. 2015; 193:64-70. 8. Colombo R, Pellucchi F, Moschini M, et al. Fifteen-year singlecentre experience with three different surgical procedures of nerve-

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sparing cystectomy in selected organconfined bladder cancer patients. World J Uro.l 2015; 33:1389-95. 9. Botto H, Sebe P, Molinie V, et al. Prostatic capsule- and seminalsparing cystectomy for bladder carcinoma: initial results for selected patients. BJU Int. 2004; 94:1021-5. 10. Revelo MP, Cookson MS, Chang SS, et al. Incidence and location of prostate and urothelial carcinoma in prostates from cystoprostatectomies: implications for possible apical sparing surgery. J Urol. 2004; 171:646. 11. Martis G, D'Elia G, Diana M, et al. Prostatic capsule- and nerve-sparing cystectomy in organ-confined bladder cancer: preliminary results. World J Surg. 2005; 29:1277-1281. 12. Horenblas S, Meinhardt W, Ijzerman W, Moonen LF. Sexuality preserving cystectomy and neobladder: initial results. J Urol. 2001; 166: 837-840. 13. Schoenberg MP, Walsh PC, Breazeale DR, et al. Local recurrence and survival following nerve sparing radical cystoprostatectomy for bladder cancer: 10-year followup. J Urol. 1996; 155:490-494. 14. Bjerre BD, Johansen C, Steven K. Sexological problems after cystectomy: bladder substitution compared with ileal conduit diversion. A questionnaire study of male patients. Scand J Urol Nephrol. 1998; 32:187-193. 15. Botto H, Sebe P, Molinie V, et al. Prostatic capsule- and seminal-sparing cystectomy for bladder carcinoma: initial results for selected patients. BJU Int. 2004; 94:1021-1025. 16. Kessler TM, Burkhard FC, Perimenis P, et al. Attempted nerve sparing surgery and age have a significant effect on urinary continence and erectile function after radical cystoprostatectomy and ileal orthotopic bladder substitution. J Urol. 2004; 172:1323-1327. 17. Fokdal L, Høyer M, Meldgaard P, von der Maase H. Long-term bladder, colorectal, and sexual functions after radical radiotherapy for urinary bladder cancer. Radiother Oncol. 2004; 72:139-145. 18. Zippe CD, Raina R, Massanyi EZ, et al. Sexual function after male radical cystectomy in a sexually active population. Urology. 2004; 64:682-685. 19. Hobisch A, Tosun K, Kinzl J, et al. Quality of life after cystectomy and orthotopic neobladder versus ileal conduit urinary diversion.World J Urol. 2000; 18:338-44. 20. Zagaja GP, Mhoon DA, Aikens JE, Brendler CB. Sildenafil in the treatment of erectile dysfunction after radical prostatectomy. Urology. 2000; 56: 631-634. 21. Zippe CD, Jhaveri FM, Klein EA, et al. Role of Viagra after radical prostatectomy. Urology. 2000; 55:241-245. 22. User HM, Hairston JH, Zelner D, et al. Penile weight and cell subtype specific changes in a postradical prostatectomy model of erectile dysfunction. J Urol. 2003; 169:1175-1179. 23. Klein LT, Miller MI, Buttyan R, et al. Apoptosis in the rat penis after penile denervation J Urol. 1997; 158:626-630. 24. R. Wang. Penile rehabilitation after radical prostatectomy: where do we stand and where are we going? J Sex Med. 2007; 4:1085-97. 25. Schwartz EJ, Wong P, Graydon RJ. Sildenafil preserves intracorporeal smooth muscle after radical retropubic prostatectomy. J Urol. 2004; 171:771-4. 26. La Vignera S, Condorelli R, D'Agata R, et al. Dysfunction of the endothelial-platelet pathway in patients with erectile dysfunction before and after daily treatment with tadalafil. Andrologia. 2012; 44:152-156.

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27. Gontero P, Fontana F, Bagnasacco A, et al. Is there an optimal timing for intracavernous PGE1 rehabilitation following nonnerve sparing radical prostatectomy Results from an hemodynamic perspective study J Urol. 2003; 169:2166-2169.

33. Teloken P, Mesquita G, Montorsi F, Mulhall J. Post-radical prostatectomy pharmacological penile rehabilitation: practice patterns among the international society for sexual medicine practitioners. J Sex Med. 2009; 6:2032-8.

28. Montorsi F, Guazzoni G, Strambi LF, et al. Recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil: results of a prospective, randomised trial. J Urol. 1997; 158:1408-1410.

34. Köhler TS, Pedro R, Hendlin K, et al. A pilot study on the early use of the vacuum erection device after radical retropubic prostatectomy. BJU Int. 2007; 100:858-62.

29. Padma-Nathan E, Mc Cullough, AR, Giuliano F. Postoperative nightly administration of sildenafil citrate significantly improves the return of normal spontaneous erectile function after bilateral nervesparing radical prostatectomy. J Urol. 2003; 4(Suppl):375. 30. Klotz L. Cavernosal nerve mapping: current data and applications. British Journal of Urology International. 2004; 93:9-13.

35. Lin H, Wang R. The science of vacuum erectile device in penile rehabilitation after radical prostatectomy. Transl Androl Urol. 2013; 2:61-66. 36. Saleh A, Abboudi H, Ghazal-Aswad M, et al. Management of erectile dysfunction post-radical prostatectomy. Res Rep Urol. 2015; 7:19-33. 37. Gallina A, Salonia A, Briganti A, et al. Prevention and management of postprostatectomy erectile dysfunction. Eur Urol Supplements. 2009; 8:80-7.

31. Yuan J, Hoang AN, Romero CA, et al. Vacuum therapy in erectile dysfunction--science and clinical evidence Int J Impot Res. 2010; 22:211-9.

38. Klotz L. Prostate capsule sparing radical cystectomy: oncologic safety and clinical outcome. Ther Adv Urol. 2009; 1:43-50.

32. Yuan J, Lin H, Li P, et al. Molecular mechanisms of vacuum therapy in penile rehabilitation: a novel animal study. Eur Urol. 2010; 58:773-80.

39. Mertens LS, Meijer RP, de Vries RR, et al. Prostate sparing cystectomy for bladder cancer: 20-year single center experience. J Urol. 2014; 191:1250-5.

Correspondence Mohamad Moussa, MD mohamadamoussa@hotmail.com Urology Department, Zahraa Hospital, University Medical Center, Beirut (Lebanon) Athanasios G. Papatsoris, MD agpapatsoris@yahoo.gr 2nd Department of Urology, School of Medicine, Sismanoglio Hospital, National and Kapodistrian University of Athens, Athens (Greece) Mohamed Abou Chakra, MD (Corresponding Author) mohamedabouchakra@hotmail.com Faculty of Medical Sciences, Department of Urology, Lebanese University, Beirut, (Lebanon), 1108 Athanasios Dellis, MD aedellis@gmail.com Department of Urology/General Surgery, Areteion Hospital, Athens (Greece)

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

DOI: 10.4081/aiua.2021.1.64

CASE REPORT

Retroperitoneal extension of massive ulcerated testicular seminoma through the inguinal canal: A case report Alessio Antonaci 1, Daniela Fasanella 1, Vikiela Galica 2, Nicola Tinari 3, Jamara Giampietro 4, Pietro Di Marino 4, Andrea Delli Pizzi 5, Raffaella Basilico 5, Luigi Schips 1, Michele Marchioni 1 1 Department

of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University of Chieti, Urology Unit, SS. Annunziata Hospital, Chieti, Italy; 2 Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila “San Salvatore” Hospital, L’Aquila, Italy; 3 Department of Medical, Oral and Biotechnological Sciences and Center for Advance Studies and Technology (CAST), G. D'Annunzio University of Chieti, Italy; 4 Clinical Oncology Unit, SS Annunziata Hospital, Chieti, Italy; 5 Department of Neuroscience, Imaging and Clinical Sciences, G. d'Annunzio University of Chieti, Chieti, Italy.

Summary

Introduction: Testicular cancers represent about 5% of all urological malignancies and 1-1.5% of all male neoplasms. Most of the testicular cancers are localized (68%) at diagnosis. Bulky masses in the scrotum are rare. We present a rare case of bulky testicular cancer with retroperitoneal spread through the inguinal canal. Case report: A 44-year-old man came to the emergency department referring weakness and the presence of a scrotal mass. At physical examination, a voluminous mass was found, with necrotic phenomena within the scrotum. Abdomen was tense and sore. Abdominal CT scan revealed a bulky testicular mass spreading to the retroperitoneal space through the inguinal canal with node enlargement. Patient underwent orchiectomy with excision of infiltrated scrotum skin. Histologic diagnosis confirmed a typical form seminoma. The patient was then treated with a cisplatin-based chemotherapy, with a partial response. The patient recently relapsed and he is being treated with a new line of chemotherapy and subsequent surgery with or without radiotherapy. Conclusions: We described a rare presentation of testicular cancer. This case highlights the importance of a multidisciplinary approach to rare testis tumour presentation and early diagnosis for testicular cancers.

KEY WORDS: Testicular cancer; Large seminoma; Retroperitoneal space; Inguinal lymph nodes. Submitted 2 June 2020; Accepted 6 July 2020

INTRODUCTION

Testicular tumours (TTs) represent about 5% of all urological malignancies and 1-1.5% of all male neoplasms (1). The incidence of testicular cancers is 3-6 new cases per 100.000 males in Western countries, with an increase observed in the past 30 years (2), probably as a consequence of pollution. These rare tumours are more frequent between 18 and 35 years and in Scandinavian countries (1, 3). Risk factors include the presence of a tumour in the contralateral testicle, Germ Cell Neoplasia in Situ (GCNIS), Klinefelter's syndrome, cryptorchidism or undescended testicle, family history of testicular cancer (2).

World Health Organization (WHO) classification distinguishes testicular neoplasms into germ cell-derived (95%) and non-germ cell neoplasms (2). The most frequent germ-cell tumours (GCTs) are seminoma (40-50% of cases). In about 80% of the cases, seminoma presents in a typical form (4). TTs are often localized (68%) and confined to the testis. Locally advanced tumours usually remain confined to the scrotum. Although rare, extension of the primary tumour to the inguinal canal can be observed, mostly among non-germ cell TTs (NGCTTs) (5). To the best of our knowledge, no previous case of large seminoma spreading in the retroperitoneum through inguinal canal has been described. In this study we report the first case of testicular cancer presenting as a voluminous ulcerated testicular mass.

CASE

REPORT

A 44-year-old man self-referred to the emergency room of our hospital because of a voluminous scrotal mass associated to abdominal and pelvic pain. The patient had no fever, poor nutritional conditions and pale skin. Clinical history included smoke and thyroid goitre. Physical examination showed a voluminous scrotal mass likely with colliquative necrotic phenomena and abdominal extension (Figure 1A). The abdomen was tense and slightly painful on deep palpation. Laboratory tests showed an anaemia with reduction in red blood cell (RBC) count (3.1 × 106 mm3; normal range 4.55.3 × 106 mm3), haemoglobin (Hgb) of 6.9 g/dl (normal range 13-16 g/dl), Hct of 24 % (normal value 37-49%). Tumour markers were elevated, in particular b-HGC was 4873 mIU/ml (normal range between 0-5 mUI/ml), a-fetoprotein was 33.4 ng/ml (normal values less than 6 ng/ml were evaluated) and LDH was 9047 U/L (normal range 313-618 U/L). Complete blood tests are shown in the Table 1. The patient underwent an abdominal CT scan, showing a voluminous scrotal sac (28 x 13 x 12 cm) with solid tissue sized 16 x 16 cm, occupying the scrotum with extension to the left inguinal canal and to the retroperiNo conflict of interest declared.

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Retroperitoneal seminoma

toneal space. Moreover, there was a pathological involvement of the left inguinal (11 x 7 cm) and iliac-obturator (10 x 6 cm) lymph nodes infiltrating the external iliac vein. In addition, pathologic retroperitoneal lymphatic tissue was documented along the abdominal aorta for a longitudinal extension of about 20 cm, resulting in compression of the inferior vena cava and infiltration of the external iliac vein, left renal vein and left ureter with signs of post-renal obstructive uropathy. No distant lesions to parenchymal organs were detected (Figure 1D-F). In the context of reduced Hgb, the patient underwent a transfusion and was hospitalized in the urology department. Unilateral orchiectomy with lymph node dissection was performed (Figure 1B). First, an inguinal incision was made and the enlarged nodes of left inguinal chain were identified. There was no clear distinction between metastatic lymph nodes and the testicular mass. After cautious isolation left inguinal nodes were dissected. Subsequently the inguinal portion of the tumour was also isolated and, after incision enlargement to the scrotum, was removed. Finally, scrotal portion of the mass was resected alongside with the surfacing necrotic skin (Figure 1C). The right testis and penile shaft were preserved (Figure 2). Histological examination showed a typical seminoma. The neoplasm infiltrated the skin up to ulcerating it and involved lymph nodes (pT4, pN3, pM1, S3). The presence of an intra-tumour phlogistic infiltrate was also revealed. Molecular morphology investigations with immunohistochemical characterization of the tumour showed positivity for Octamer-binding transcription factor (OCT) 3/4, Placental alkaline phosphatase (PLAP), b-HGC, CD117, Leukocyte common antigen (LCA, in the intra tumour inflammatory component) and CD30. Following surgery, the patient received four three-weekly cycles of standard BEP (Bleomycin 30 UI IV weekly on days 1.8 and 15; Etoposide 100 mg/m² IV on days 1-5; Cisplatin 20 mg/m² IV on days 1-5 (6). CT scan taken one month after the completion of chemotherapy showed a great deal of reduction in the retroperitoneal lymph node masses (6 x 4 cm current vs 17 x 12 cm prior). Serum level of tumour markers was also decreased (Table 2). Subsequently, the patient underwent CT-scan at 3-month intervals. Abdominal and chest imaging showed a stable disease (SD) according to the Response Evaluation Criteria in Solid Tumors (RECIST) (7) with no parenchymal metastases for one year and half. A progressive disease (PD) was documented after 18 months. CT-scan showed a new dimensional increase in the left periaortic lymph node tissue (55 x 35 mm current vs 50 x 25 mm prior), along the left external iliac chains (57 x 44 cm current vs 47 x 37 cm prior) and the appearance of infiltration of the left iliac and

Figure 1. (A) Voluminous and necrotic scrotum at the diagnosis. (B) Intra-operative photograph. (C) Post-operative photograph of resected scrotal mass. (D-F) Computed tomography shows extensive abdominal diffusion of tumour.

Table 1. Blood tests. Haemoglobin (g/dl) Red blood cells (mmc) Hematocrit (%) MCH (pg) MCHC (g/dl) White blood cells (u/L) Platelets (mmc) Fibrinogen (mg/dl) Glucose (mg/dl) Creatinine (mg/dl) Urea (mg/dl) Albumin (g/dl) Sodium (mmol/L) Potassium (mmol/L) Calcium (mmol/L) AST (U/L) ALT (U/L) Amylase (U/L) Lipase (U/L) CPK (U/L) Total Bilirubin (mg/dl) LDH (U/L) Beta-HCG (mUI/ml) Alpha-fetoprotein (ng/ml)

Result 6.9 3.1 24 21.8 28 8.97 479 542 117 0.90 20.0 2.6 138 5.40 2.3 35 21 73 157 21 0.60 9047 4873 33.4

Reference values 13.0-16.0 4.5-5.3 x 10˄6 37.0-49.0 25.0-35.0 32.0-36.0 4.00-10.0 x 10˄3 150-450 x 10˄ 189-400 74-106 0.66-1.25 9.0-20.0 2.5-5.2 136-146 3.50-5.10 2.1-2.55 15-46 11-66 30-110 313-618 55-170 0.20-1.30 313-618 0-5 <6

MCH: Mean Cell Hemoglobin, MCHC: Mean Cell Hemoglobin Concentration, AST: Aspartate aminotransferase, ALT: Alanine aminotransferase, CPK: Creatin phosphokinase, LDH: Lactate Dehydrogenase, HCG: Human Chorionic Gonadotropin.

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A. Antonaci, D. Fasanella, V. Galica, et al.

Figure 2. (A) Post-operative photograph. An inguinal and scrotal incision was made and the voluminous necrotic scrotal mass was removed. (B) Photograph of inguino-scrotal region on follow-up at 12 months.

Table 2. Tumour markers in the eighteen months following chemotherapy. Alpha-fetoprotein (ng/ml) Beta-HCG (mUI/ml) LDH (U/L)

November 2018 9 <1 422

March 2019 3.20 <1 179

June 2019 1.60 <1 216

April 2020 60.79 <1 2580

psoas muscles by the pathological lymph node tissue (7). Moreover, the patient underwent a PET-CT scan that showed an intense metabolic activity corresponding to a voluminous lymph node masses (10 x 13 cm) in the left iliac region, infiltrating the left ileo-psoas muscle. After considering the disease progression, we had a multi-disciplinary meeting. As salvage chemotherapy the patient is being treated with four three-weekly cycles of standard TIP (Paclitaxel 175 mg/m² IV on day 1; Cisplatin 20 mg/m² IV on days 1-5; Ifosfamide 1000 mg/m² IV on days 1-5). In case of mass reduction, a combined surgical retroperitoneal lymph node dissection (RPLND) and radiotherapeutic approach will be evaluated.

DISCUSSION

In this report, we described a rare case of large seminoma extending to the inguinal canal with diffuse retroperitoneal spreading and skin ulceration. Presentation at advanced stage or even metastatic at diagnosis is more common for NGCTTs (5). Our case is paradigmatic for several reasons. First of all, the age of diagnosis. Our patient presented a primary testicular cancer in the absence of risk factors and at an age older than usual. This highlights the importance of genital examination at every age, even when the probability of a testicular tumour is low. Moreover, our patient had a very unusual presentation. Indeed, while most of testis cancers are diagnosed as localized tumours of few centimeters in diameter, in our case the patient turned to physicians only when symptomatic. When investigating the reasons why the patient delayed the primary intervention, a complex mix of personal, familiar and social causes emerged. Several studies have shown a detrimental effect of low socio-economic and familiar status on

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cancer awareness and intervention timing (8, 9). In a recent analysis Macload et al. showed that socio-economic status was associated with poorer oncological outcomes and a more difficult access to primary treatment in patients with testicular cancer (10). Our case corroborates these evidences and suggests the importance of a social tissue that could led to prompt access to primary care and early diagnosis. It is of note that the Italian one is a single payer healthcare system. In consequence, cure costs are not one of the major barriers to early diagnosis and treatment. However, even in this context weaker social strata still exist. Within this strata population could be more susceptible to experiment worse oncological outcomes. In fact, even after a wide surgical excision and associated chemotherapy, as recommended by international guidelines (11), we obtained only a partial response with a subsequent relapse of the disease. Furthermore, in our case is evident how, even if cisplatin-based regimen is effective on testis cancer, a multidisciplinary approach should be warranted. Early diagnosis, a multidisciplinary approach and a close follow-up remain mandatory to improve prognosis of testicular cancer (12, 13). After relapse, our patient will undergo four cycles of TIP (14). Surgery and radiotherapy should be considered in the case of mass reduction and resectable masses with small residual tumour (15). Moreover, a close follow-up of all psychological aspects was planned in consideration of the high psychological burden of testis cancer.

CONCLUSIONS

In conclusion, we reported an extremely rare presentation of locally advanced testis cancer, resulting from the combination of cancer and patient related conditions. Early diagnosis is fundamental to guarantee a good oncological prognosis for testis cancer. Moreover, a multidisciplinary approach is important to guarantee a good oncological outcome.

REFERENCES

1. Chia VM, Quraishi SM, Devesa SS, et al. International trends in the incidence of testicular cancer, 1973-2002. Cancer Epidemiol Biomark Prev. 2010; 19:1151-9. 2. Huyghe E, Matsuda T, Thonneau P. Increasing incidence of testicular cancer worldwide: a review. J Urol. 2003; 170:5-11. 3. Shanmugalingam T, Soultati A, Chowdhury S, et al. Global incidence and outcome of testicular cancer. Clin Epidemiol. 2013; 5:417-27. 4. Moch H, Cubilla AL, Humphrey PA, et al. The 2016 WHO classification of tumours of the urinary system and male genital organsPart A: Renal, penile, and testicular tumours. Eur Urol. 2016; 70:93-105. 5. Palumbo C, Mistretta FA, Mazzone E, et al. Contemporary incidence and mortality rates in patients with testicular germ cell tumors. Clin Genitourin Cancer. 2019; 17:e1026-35. 6. Saxman SB, Finch D, Gonin R, Einhorn LH. Long-term follow-up of a phase III study of three versus four cycles of bleomycin, etoposide, and cisplatin in favorable-prognosis germ-cell tumors: the Indian University experience. J Clin Oncol. 1998; 16:702-6.

Retroperitoneal seminoma

7. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 1990. 2009; 45:228-47. 8. Mihor A, Tomsic S, Zagar T, et al. Socioeconomic Inequalities in Cancer Incidence in Europe: A Comprehensive Review of Populationbased Epidemiological Studies. Radiol Oncol. 2020; 54:1-13. 9. Marchioni M, Martel T, Bandini M, et al. Marital status and gender affect stage, tumor grade, treatment type and cancer specific mortality in T1-2 N0 M0 renal cell carcinoma. World J Urol. 2017; 35:1899-905. 10. Macleod LC, Cannon SS, Ko O, Schade GR, et al. Disparities in Access and Regionalization of Care in Testicular Cancer. Clin Genitourin Cancer. 2018; 16:e785-93. 11. Honecker F, Aparicio J, Berney D, et al. ESMO Consensus

Conference on testicular germ cell cancer: diagnosis, treatment and follow-up. Ann Oncol. 2018; 29:1658-86. 12. Warde P, Specht L, Horwich A, et al. Prognostic factors for relapse in stage I seminoma managed by surveillance: a pooled analysis. J Clin Oncol 2002;20:4448-52. 13. Aparicio J, Germà JR, García del Muro X, et al. Risk-adapted management for patients with clinical stage I seminoma: the Second Spanish Germ Cell Cancer Cooperative Group study. J Clin Oncol. 2005; 23:8717-23. 14. Park S, Lee S, Lee J, et al. Salvage chemotherapy with paclitaxel, ifosfamide, and cisplatin (TIP) in relapsed or cisplatin-refractory germ cell tumors. Onkologie. 2011; 34:416-20. 15. Oldenburg J, Fosså SD, Nuver J, et al. Testicular seminoma and non-seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol Off J Eur Soc Med Oncol. 2013; 24 Suppl 6:vi125-132.

Correspondence Alessio Antonaci, MD Luigi Schips, MD Michele Marchioni, MD Daniela Fasanella, MD (Corresponding Author) danielafasanella@libero.it Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University of Chieti, Urology Unit, SS Annunziata Hospital Via dei Vestini, 66100, Chieti (Italy) Vikiela Galica, MD Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila “San Salvatore” Hospital, L’Aquila (Italy) Nicola Tinari, MD Department of Medical, Oral and Biotechnological Sciences and Center for Advance Studies and Technology (CAST), G. D'Annunzio University of Chieti, Chieti (Italy) Jamara Giampietro, MD Pietro Di Marino, MD Clinical Oncology Unit, SS Annunziata Hospital, Chieti (Italy) Andrea Delli Pizzi, MD Raffaella Basilico, MD Department of Neuroscience, Imaging and Clinical Sciences, G. D'Annunzio University of Chieti, Chieti (Italy) Archivio Italiano di Urologia e Andrologia 2021; 93, 1

CASE REPORT

DOI: 10.4081/aiua.2021.1.68

Clear-cell renal cell carcinoma single thyroid metastasis: A single-center retrospective analysis and review of the literature Isabella Ricci 1, Francesco Barillaro 2, Enrico Conti 2, Donatella Intersimone 3, Paolo Dessanti 3, Carlo Aschele 1 1 Department

of Oncology, Ospedale S. Andrea, La Spezia, Italy; of Urology, Ospedale S. Bartolomeo, Sarzana, Italy; 3 Department of Pathology, Ospedale S. Andrea, La Spezia, Italy. 2 Department

Summary

Renal cell carcinoma (RCC) is known to cause metastasis to unusual sites, which can be both synchronous or metachronous. Thyroid gland is a rare site for metastasis. However, RCC is the most common primary neoplasm to metastasize to the Thyroid gland. Report of three cases and review of the literature.

KEY WORDS: Renal cell carcinoma; Thyroid; Metastasis. Submitted 26 June 2020; Accepted 20 August 2020

INTRODUCTION

Kidney cancer accounts for 5% and 3% of all adult malignancies in men and women, respectively, representing the 7th most common cancer in men and the 10th most common cancer in women. Renal cell carcinoma (RCC) accounts for 80% of all kidney cancers. Common metastatic sites of RCC are lung, lymph nodes, bone and liver. RCC is responsible of unusual metastatic sites, although it is the most common primary neoplasm that metastasizes to thyroid gland (1). The incidence of thyroid metastasis has been reported to be higher on autopsy studies (2) and ranges from 0.5% to 24% in high stage malignancies. Metastasis can occur many years after initial diagnosis, but are extremely rare in clinical practice. A thyroid nodule in a patient with a history of RCC should be considered potentially metastatic. We retrospectively reviewed our database searching patients who developed recurrence of RCC with thyroid metastases. The total number of RCC patients observed from 2004 to 2019 in our institution was of about 208 cases. Out of these, only three cases developed recurrence of RCC with thyroid metastases many years after nephrectomy in a 15 year follow-up range (3).

CASE

REPORT/CASE PRESENTATION

Case 1 A 61-year-old female admitted to our hospital in April 2004, presented with left flank pain and history of weight loss. An MRI was performed showing an exophytic, hypervascular, solid mass, measuring 7 x 8 cm. The MRI findings were in keeping with a malignant renal tumor.

Two weeks later, the patient underwent left radical nephrectomy. The histopathological examination reported clear-cell renal cell carcinoma. TNM staging was T3a with G3 Fuhrman grade. She was followed up by the oncologist for 10 years without evidence of recurrence. After ten years, a PET/CT was performed demonstrating a metabolically active area in the thyroid right lobe. Ultrasound imaging confirmed the presence of a solid hypoechoic, well-demarcated nodule of 2.2 cm. Decision was made to perform a radical thyroidectomy in November 2014. The histopathological examination showed metastatic RCC of clear cell type (Figure 1A). Three year after thyroidectomy, in a further follow-up, two pulmonary nodules were detected and consequently the patient underwent thoracotomy for atypical double resection of the upper lobe and left pulmonary lingula. TNM staging was T1a and histology showed lung lipid adenocarcinoma (Figure 1E, F) while the other nodule instead was comparable with metastasis from RCC (Figure 1G, H). The subsequent follow-up was negative. The average latency time before the detection of thyroid metastases was 10 years (4). Case 2 A76-year-old male underwent a right radical nephrectomy for a solid mass clear cell renal carcinoma in March 2016. TNM staging was T3aN0M0. In April 2018 he underwent laparoscopy and subsequently to lower pole resection of the left kidney. The histopathological examination reported papillary carcinoma. TNM staging T1b G2. One year after surgery, a solid nodule in the right lobe of the thyroid gland (4.5 x 3 x 3.5 cm) was detected. The patient presented a painful mass associated with cough and dysphagia. Size of metastases was significantly higher in this patient compared to those with painless mass. Ultrasound imaging followed by computed tomography (CT) showed a well-defined hypodense nodule in the right lobe of the thyroid gland. Our 79-year-old patient underwent thyroidectomy, after FNA cytology, in 2019. The histopathological examination reported metastatic RCC of clear cell type which developed in his third follow-up year. The subsequent follow-up was negative. The average latency time before the detection of thyroid metastases was 3 years. No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

Unusual presentation of single thyroid metastasis

Figure 1. A: Thyroid (bottom left) with metastasis of adult renal cell carcinoma clear cell (conventional) (top right). Hematoxylin Eosin 40x. B: Thyroid (upper half) with nodular hyperplasia and with metastasis of adult renal cell carcinoma (lower half). Hematoxylin Eosin 20x. C-D: Renal cell metastasis showed immunoreactivity for RCC/Renal cell carcinoma marker (c) and negativity for thyroglobulin (d), which was positive in the thyroid parenchyma. E-F: Lung metastasis (lingular lobe left lung) of renal cell carcinoma. Hematoxylin Eosin 20x (e). Lung metastasis (lingular lobe left lung) of renal cell carcinoma. Hematoxylin Eosin 20x (f). G-H: Lung adenocarcinoma (lower lobe left lung) with predominantly lepidic type growth. Napsin A 40x (g). The neoplastic cells show intense nuclear immunoreactivity for Pax 8 confirming their renal origin. Pax 8, 20x (h).

roid lobe. On positron emission tomography/computed tomography there was a metabolically active area in the thyroid right lobe. Ultrasound imaging confirmed a solide hypoechoic nodule. The patient subsequently underwent fine needle aspiration cytology which showed borderline neoplastic cells, although it poses the diagnostic doubt. A thyroidectomy was therefore carried out. The istopathological examination showed metastatic RCC of clear cell type (Figure 1B). Mean latency time before the detection of thyroid metastases was 10 years. The subsequent follow-up was negative.

DISCUSSION

RCC accounts for approximately 3-4% of all adult malignancies. It is more common in males and occurs predominantly in the 6th to 8th decade of life. Major histopathological subtypes include clear cell carcinoma, papillary carcinoma, chromophobe carcinoma, medullary carcinoma. The metastasis may be detected at the time of diagnosis (synchronous) or may be found years after the diagnosis and treatment (metachronous) (5-11). It has been estimated that 20-30% of patients including those who have undergone nephrectomy with curative intent will develop recurrence and out of these 50% will relapse distantly (6). Moreover, solitary metastasis from RCC occurs with an incidence rate of about 1-4% of which about 1% occur in the thyroid gland. Most of the recurrences appears within 3 years from surgery, but delayed recurrences even after decades have been reported (7). Characteristics of patients described in literature are reported in Table 1 (11). RCC metastasis to thyroid generally are symptomatic or painless mass but can be also completely asymptomatic and discovered incidentally during follow-up. Size of metastases was higher in symptomatic patients compared to those with painless mass and asymptomatic ones. Rarely may present dysphagia, dysphonia or dyspnea. Moreover, there was a weak correlation between lag time and size of metastases. Table 1. Characteristics of patients described in literature.

Case 3 A 78 year-old female presented with a history of a lump on the neck for the last 3 months in May 2014. The past medical history encompassed RCC on the right side around 10 years before. At that time she has been treated surgically undergoing left radical nephrectomy and left adrenalectomy for a large renal mass measuring 11 x 7 x 7 cm. The histology showed clear cell RCC G2 sec Fuhrman. Tumor was not infiltrating through the capsule. Surgical margins were free of tumor and TNM staging T2bN0M0. She was followed-up by the oncologist for almost 10 years and no evidence of recurrence was noted. The examination of the neck revealed evidence of a 3 cm nodule in the right thy-

Characteristics of patients Age (yr) mean ± SD Male Female Sex percentage (number of patients) Male Female Initial CCRCC stage Stage I CCRCC Stage II CCRCC Stage III CCRCC Stage IV CCRCC Lag time (years) from initial diagnosis of CCRCC 8.7 ± 6.5 mean ± SD Symptoms Asymptomatic Symptomatic or painless mass Surgery Total thyroidectomy Subtotal thyroidectomy

64 ± 10 64 ± 11 47% (69) 53% (77) 32% (21) 29% (19) 31% (20) 8% (5)

30% (33) 70% (76) 62% (75) 38% (46)

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

I. Ricci, F. Barillaro, E. Conti, D. Intersimone, P. Dessanti, C. Aschele

Regarding the tests performed for the diagnosis of RCC metastases to the thyroid gland, ultrasound of the neck was the most frequently used imaging tecnique followed by computed tomography (CT scan) and positron emission tomography (PET scan). Usually metastatic thyroid lesions appear as solid hypoechoic, well-demarcated nodules with irregular vascularity on ultrasound imaging and cold nodules on radioisotope uptake studies. These radiological features are not specific and it is not possible to distinguish between primary and secondary thyroid neoplasms on imaging. Only a case demonstrated incidental thyroid abnormalities on positron emission tomography/computed tomography and ultrasound later confirmed as a metastases of renal cell carcinoma. Fine needle aspiration (FNA) cytology is necessary to establish preoperative diagnosis. A challenge it is sometimes distinguishing metastasis from tumors of thyroid, because can have clear cell component on FNA cytology alone. In these cases, immunohistochemistry is helpful and aids in differential diagnosis. In our cases cytocheratin, vimentin and CD 10, traditional immunohistochemical markers for renal cell carcinoma, were positive; thyroglobulin, thyroid transcription factor-1 (TTF-1), and calcitonin, markers used for identifying primary thyroid malignancies, were negative (Figure 1C, D). Definitive diagnosis of metastatic RCC is usually made by histopathological examination after thyroidectomy (8). Surgical resection with either partial or radical thyroidectomy should be performed if thyroid gland is the only site for metastasis. Prognosis is good in this group (9, 10). Thyroid metastasis from RCC has a better survival rate according to the Literature. Patients with disseminated disease have poor prognosis and should undergo thyroidectomy only for palliation for compressive symptoms. Treatment choice in metastatic renal cell carcinoma depends on different factors including the extent of the disease and prognostic risk factors such as Karnofsky performance status, diagnosis timeline and laboratory findings. Direct treatments to the thyroid metastasis result in prolonged survival especially in solitary thyroid gland metastasis where surgical treatment is recommended. It is demonstrated a favorable prognosis in patients treated with radical surgery (average 5-year survival rate 30-60%). Clinically it has been observed that the overall survival rate in patients undergoing thyroidectomy for metastases of RCC is more affected by general health status rather than by tumor-related factors. Sunitinib could be effective for the treatment of these metastases. His mechanism of action is based on causing reduction in thyroid volume. Negative adverse reaction of this drug can results in a various grade of thyroid dysfunction from hypothyroidism to thyroid atrophy, in particular in patients who receive the drug over a long period of time, and that could result in irreversible hypothyroidism. This is thought to be a result of a possible sunitinib-induced thyrotoxicosis along with a direct effect of the drug which could cause degeneration of thyroid follicular cells. To understand the possible effectiveness of Sunitinib on thyroid further investigations are needed.

CONCLUSIONS

A thyroid nodule in a patient with a history of RCC should be considered as potentially metastatic. It’s chal-

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

lenging to distinguish between primary and secondary thyroid neoplasms on imaging, and clinical manifestation and radiographic findings are non-specific. FNA cytology and immunohistochemistry are helpful in establishing diagnosis and should be obtained in suspected cases. The average latency time before the detection of thyroid metastases was variable. However, a lifelong follow-up is recommended. Our cases demonstrate the importance of considering RCC metastases to the thyroid even years after nephrectomy to avoid potential delays in diagnosis (11).

REFERENCES

1. Chen H, Nicol TL, Udelsman R. Clinically significant, isolated metastatic disease to the thyroid gland. World J Surg. 1999; 23:177-80. 2. Willis RA. Metastatic tumours in the thyroid gland. Am J Pathol. 1931; 7:187-208.3. 3. Bayrakter Z, Albayrak S. Metastasis of renal cell carcinoma to the thyroid gland 9 years after nephrectomy: a case report and literature review. Arch Ital Urol Androl. 2017; 89:151-153. 4. Cilengir AH, Kalayci TO, Duygulu G, et al. Metastasis of renal clear cell carcinoma to thyroid gland mimicking adenomatous goiter. Pol J Radiol. 2016, 81:618-621. 5. Motzer RJ, Bander NH, Nanus DM. Renal cell carcinoma. NEJM. 1996. 335:865-875. 6. Flanigan RC, Campbell SC, Clark JI, et al. Metastatic renal cell carcinoma Curr Treat Options Oncol. 2003; 4:385-390. 7. Eggener SE, Yossepowitch O, Pettus JA, et al. Renal cell carcinoma recurrence after nephrectomy for localized disease: predicting survival from time of recurrence, JCO. 2006; 24:3101-3106. 8. Aljiabri KS, Bokhari SA, Fadag RB, et al. Thyroid metastasis from renal cell carcinoma, Archives of endocrinology and diabetes care. 2018; 1:65-70. 9. Chung AY, Tran TB, Brumund KT, et al. Metastases to the tyroid: a review of the literature from the last decade, Thyroid. 2012; 22:258-68. 10. De Stefano R, Carluccio R, Zanni E, et al, Management of thyroid nodules as secondary involvement of renal cell carcinoma case report and literature review, Anticancer research. 2009; 29:473-6. 11. Khaddour K, Marernych N, Ward WL, et al. Characteristics of clear cell renal cell carcinoma metastases to the thyroid gland: a systematic review, World J Clin Cases. 2019; 7:3474-3485. Correspondence Isabella Ricci, MD (Corresponding Author) isabella.ricci@asl5.liguria.it Carlo Aschele, MD carlo.aschele@asl5.liguria.it Department of Oncology, Ospedale S. Andrea, La Spezia (Italy) Francesco Barillaro, MD francesco.barillaro@asl5.liguria.it Enrico Conti, MD enrico.conti@asl5.liguria.it Department of Urology, Ospedale S. Bartolomeo, Sarzana (Italy) Donatella Intersimone, MD donatella.intersimone@asl5.liguria.it Paolo Dessanti, MD paolo.dessanti@asl5.liguria.it Department of Pathology, Ospedale S. Andrea, La Spezia (Italy)

DOI: 10.4081/aiua.2021.1.71

CASE COLLECTION

Oncology and complications Giuseppe Giordano 1, Evangelia Kyriazi 2, Charalampos Mavridis 3, Francesco Persico 4, 5, Charalampos Fragkoulis 6, Piergiorgio Gatto 7, George Georgiadis 3, Irene Giagourta 2, Ioannis Glykas 6, Rodolfo Hurle 4, Massimo Lazzeri 4, Giovanni Lughezzani 4, 8, Vincenzo Magnano San Lio 1, Charalampos Mamoulakis 3, Diego Meo 1, Helen A. Papadaki 9, George Piaditis 2, Charalampos Pontikoglou 9, Georgios Stathouros 6 1 Unit

of Diagnostic and Interventional Radiology, ARNAS “Garibaldi-Nesima”, Catania, Italy; Department, General Hospital of Athens “G. Gennimatas”, Athens, Italy; 3 Department of Urology, University General Hospital of Heraklion, University of Crete, Medical School, Heraklion, Crete, Greece; 4 Humanitas Clinical and Research Center - IRCCS, Department of Urology, Rozzano, Milan, Italy; 5 University of Naples Federico II, Department of Neurosciences, Sciences of Reproduction, and Odontostomatology, Naples, Italy; 6 Urology Department, General Hospital of Athens “G. Gennimatas”, Athens, Greece; 7 Ospedale di Sestri Levante - ASL 4 Liguria, Dipartimento Medico ad Elevata Integrazione Territoriale, Sestri Levante, Italy; 8 Humanitas University, Department of Biomedical Sciences, Rozzano, Milan, Italy; 9 Department of Hematology, University General Hospital of Heraklion, University of Crete, Medical School, Heraklion, Crete, Greece. 2 Endocrinology

Summary

This collection of cases describes some unusual urological tumors and complications related to urological tumors and their treatment. Case 1: A case of uretero-arterial fistula in a patient with long-term ureteral stenting for ureteral oncological stricture and a second case associated to retroperitoneal fibrosis were described. Abdominal CT, pyelography, cystoscopy were useful to show the origin of the bleeding. Angiography is useful for confirming the diagnosis and for subsequent positioning of an endovascular prosthesis which represents a safe approach with reduced post-procedural complications. Case 2: A case of patient who suffered from interstitial pneumonitis during a cycle of intravesical BCG instillations for urothelial cancer. The patient was hospitalized for more than two weeks in a COVID ward for a suspected of COVID-19 pneumonia, but he did not show any evidence of SARS-CoV-2 infection during his hospital stay. Case 3: A case of a young man with a functional urinary bladder paraganglioma who was successfully managed with complete removal of the tumor, leaving the urinary bladder intact. Case 4: A case of a 61 year old male suffering from muscle invasive bladder cancer who was admitted for a radical cystectomy and on the eighth postoperative day developed microangiopathic hemolytic anemia and thrombocytopenia, which clinically defines thrombotic microangiopathy.

KEY WORDS: Ureter-arterial fistula; BCG; Pneumonitis; Bladder tumors; Cystectomy; Paraganglioma; Thrombotic thrombocytopenic purpura. Submitted 26 July 2020; Accepted 21 August 2020

CASE 1 ROLE OF

INTERVENTIONAL RADIOLOGY IN THE TREATMENT OF URETERO-ARTERIAL FISTULAS: TWO-CASES OF ENDOVASCULAR TREATMENT

(Giuseppe Giordano, Diego Meo, Vincenzo Magnano San Lio )

INTRODUCTION

Uretero-arterial fistulas (FUA) are defined as a pathological connection between the ureter and the iliac artery (1, 2). The known risk factors for this pathology are pelvic or genitourinary surgery, pelvic radiotherapy treatments, vascular pathologies such as iliac aneurysms and being chronic carriers of ureteral stents (3). It represents a rare occurrence that is found today more frequently in relation to the increase in life expectancy of patients with pelvic neoplasms (4). It is difficult to diagnose and it is associated with high rates of morbidity and mortality. Different therapeutic approaches are possible, in particular interventional radiology techniques, ranging from the use of balloon catheters to intra-arterial embolization and placement of covered stents, have proven to be a less invasive and faster option, offering excellent results in terms of resolution of the pathology. In this report we describe, in addition to the role of interventional radiology in the treatment of this pathology, two cases successfully treated at our center with an endovascular approach.

CASE

REPORT

A patient (male, 61 years old) was subjected to left hemicolectomy for neoplasia in 2017 and subsequently to pelvic exenteratio with uretero-cutaneous-ileostomy according to Bricker for loco-regional relapse. In January

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

G. Giordano, E. Kyriazi, C. Mavridis, et al.

2018 in the presence of bilateral hydroureteronephrosis, due to tightened stenosis at the level of the ileal ureteral anastomosis caused by the appearance of pathological tissue attributable to recurrent disease, nephrostomies were placed with subsequent stenting of the ureters with a 8 Fr pig tail stent. One year later (January 2019) repeated episodes of intermittent hematuria occurred. In the same month, during a routine control for replacement of urinary stents, performed in the angiography room, a copious bleeding from the right mono J ureteral catheter was appreciated. Pyelography was then performed from the ureteral stent. Increasing pressure in the ureter, opacification of the common ipsilateral iliac artery was observed through reflux (Figure 1). In the same session, therefore, through right transCase 1 - Figure 1. Pyelography at high pressure showing opacification of the common iliac artery.

Case 1 - FIgure 2. Pyelography at high pressure showing opacification of the common iliac artery.

Case 1 - FIgure 3. CT scan showing clots in the right ureter.

Case 1 FIgure 4. Placement of uncoated balloon expandable stent 8 mm diameter 60 mm long in the external iliac artery.

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

femoral approach with a 9 Fr introducer, it was positioned at the level of the left common iliac artery, on a 0.035 guide, a metal coated stent 9 mm diameter 60 mm long that was subsequently dilated with a 8 mm diameter 4 cm long balloon catheter (Figure 2). At the end of the procedure, complete stop of bleeding was observed, which no longer occurred until to the patient's death after about 6 months due to progression of the neoplastic pathology. A patient (male 63 years old) affected by retroperitoneal fibrosis determining bilateral hydroureteronephrosis was subjected to bilateral ureteral stenting with cystoscopic approach; after repeated episodes of hematuria and severe anemization with need for blood transfusions in May 2019, he performed a CT scan in June 2019 that did not show any signs of active bleeding but showed the presence of clots in the right ureter (Figure 3). In relation to the finding, confirmed by a cystoscopic evaluation with direct visualization of clots in the bladder coming from the right ureter, the patient was taken to the angiographic room and, after recovering the bladder end of the right urinary stent with a goose neck catheter, an introducer 7 Fr 35 cm long was advanced on a metallic guide via transurethral access to the right ureteral meatus to perform a pyelography which however does not show a fistulous route to the iliac artery. However, due to the numerous episodes of hematuria, the clots inside the right ureter, the absence of other bleeding foci and the contiguity of the right ureter with the right common iliac artery at the passage in the external iliac, it was decided to position a 10 mm diameter 59 mm long modular stent via a right transfemoral approach using an 8 Fr introducer and to dilate it in its proximal portion in the common iliac with a 12 mm diameter 40 mm long balloon catheter. The procedure was completed by placing an additional uncoated balloon expandable stent 8 mm diameter 60 mm long in the external iliac artery in the presence of a iatrogenic focal dissection (Figure 4). The patient, currently was undergoing follow-up and no longer presented hematuria with resolution of anemia.

CONCLUSIONS

Despite the paucity of the literature data, due also to the rarity of this pathology, the interventional radiology techniques, compared to surgery, should be considered as first choice, especially in urgency, for treatment of uretero-arterial fistula; in particular the positioning of covered stents at the level of the artery in correspondence with the fistula has proved to be a fast, safe and effective system in resolving the hemorrhagic situation and increasing the survival of these patients. Thanks also to technological upgrade of modular coated stents, today it is possible to treat fistulous lesions by more precisely calibrating the dimensions of the prosthesis even in vascular districts with different diameters, obtaining a greater hold of the stent with the vessel walls.

REFERENCES

1. Moschowitz A. Simultaneous ligation of both external iliac arteries for secondary hemorrhage following bilateral ureterolithotomy. Ann Surg. 1908; 48:872-5.

Oncology and complications

2. Van den Bergh RC, Moll FL, de Vries JP, et al. Arterioureteral fistulas: unusual suspects systematic review of 139 cases. Urology. 2009; 74:251-5. 3. Krambeck AE, DiMarco DS, Gettman MT, et al. Ureteroiliac artery fistula: diagnosis and treatment algorithm. Urology. 2005; 66:990-4. 4. Fox JA, Krambeck A, McPhail EF, et al. Ureteroarterial fistula treatment with open surgery versus endovascular management: long-term outcomes. J Urol. 2011; 185:945-50.

CASE 2 THE EFFECT

OF BACILLUS CALMETTE-GUÉRIN (BCG) INSTILLATIONS ON THE IMMUNE SYSTEM: A CASE REPORT OF HYPERSENSITIVITY PNEUMONITIS DURING THE COVID-19 PANDEMIC

(Francesco Persico, Massimo Lazzeri, Giovanni Lughezzani, Piergiorgio Gatto, Rodolfo Hurle)

INTRODUCTION

BCG is a live attenuated vaccine derived from Mycobacterium bovis that was developed against tuberculosis at the beginning of the 20th century at the Institut Pasteur in Paris (1). Since then, it has been the most used vaccine in the world, with around 130 million children vaccinated every year. Moreover, BCG intravesical instillation is a widely used treatment for high-risk non-muscle invasive Bladder Cancer (NMIBC) (2). Although the exact mechanism of BCG on tumor prevention is still unclear, a local immune response is presumed. The BCG-induced activation of the immune system involves CD4(+) and CD8(+) lymphocytes, natural killer cells, macrophages, granulocytes, and dendritic cells. Bladder cancer cells are killed through cell-mediated cytotoxicity, by the secretion of soluble factors such as TRAIL (tumour necrosis factor-related apoptosis-inducing ligand), and, to a certain extent, by the direct action of BCG (3). Recent studies has also suggested that the trained immunity induced by BCG vaccination is protective against multiple infections (1). In this case report, we presented a peculiar case of a male patient with a medical history of recent BCG instillations for NMIBC who suffered from interstitial pneumonitis and did not contract SARS-CoV-2 infection despite his prolonged hospitalization in a COVID ward.

CASE

REPORT

A 63-year-old man was admitted to the ER for the suspect of a SARS-CoV-2 induced interstitial pneumonia during BCG treatment for high-grade NIMBC. He did not have a personal history of direct exposure to individuals with SARS-CoV-2 infection. The patient’s past medical history included a diagnosis of high-grade NMIBC in 2012 followed by a BCG induction cycle (one instillation weekly for 6 weeks) and maintenance (one instillation for 3 weeks on months 3, 6, 12, 18, 24) [SWOG protocol] in 2012-2013. During follow-up, in July 2017, he underwent a diagnostic ureteroscopy for suspicion of upper tract urothelial neoplasm based on positive urinary cytology and a suspicious computed tomography (CT). Biopsies histological examination revealed a carcinoma in situ (CIS) of

left ureter. Consequently, the patient underwent an open left nephroureterectomy for CIS of the left ureter in September 2017. After surgery, he resumed BCG instillations and underwent 3 bladder mappings resulted negative for urothelial cancer. During the treatment, the patient developed severe irritative symptoms, suggestive for BCG-induced chemical cystitis, that were treated first conservatively with hyaluronic acid instillations in April 2019. In January 2020, after a negative cystoscopy with suspicious cytology, he underwent right flexible ureterorenoscopy with mapping of renal pelvis (negative for urothelial cancer) and selective urinary cytology of right upper urinary tract (suspicious for malignancy). During the procedure, the surgeon placed a JJ ureteral stent 6 French x 28 Centimeters to perform upper urinary tract instillations. The patient subsequently received intravesical Bacillus Calmette-Guerin (BCG) instillation at weekly intervals. Four doses were administered without relevant problems. After the fourth BCG instillation on 13th of March, the patient developed influenza-like symptoms; fever, anorexia, night sweats, shivering, cough, and chest distress persisted for about three weeks, with the body temperature reaching a maximum of 38.1°C. On March 27st, the ureteral stent was removed for a suspicion of an urinary infection and the patient started an empirical antibiotic therapy with ciprofloxacin and trimetoprim-sulfametoxazole as prescribed by his general practicioner. On March 31st, he came to the emergency department of the Hospital of Sestri Levante for a respiratory distress and a physical examination highlighted fine inspiratory crackles in both lungs. Upon admission, the patient‘s body temperature was 38.3°C. Haemogasanalysis showed oxygen pressure (PO2) and Carbon Dioxide pressure (PCO2) of 43 mmHg and 30 mmHg on room air, respectively, with pH of 7.5. The blood exams showed leukocytosis (16760 cells/mm3) with increased levels of C-reactive protein (6 mg/dL) D-Dimer, transaminases, LDH and creatinine (1.54 mg/dL). Chest radiography highlighted widespread accentuation of the bronchovascular texture. Therefore, he was admitted to a COVID ward with the suspicion for COVID-19 pneumonia. According to institutional protocols, he began a therapy with clarithromycin, ceftriaxone, hydroxychloroquine, enoxaparin and oxygen therapy. The patient performed on the 1st and on the 11th of April two SARS-CoV-2 oropharyngeal swabs that resulted negative. Serology for SARS-CoV-2 was negative as well. Blood culture and urine culture performed on the April 1st were both negative. On April 8th, a chest CT was performed revealing a bilateral subpleural patchy ground-glass appearance associated to the presence of small centrilobular nodules (Figure 1). On April 10th, the patient underwent bronchoscopy with Broncho-Alveolar Lavage (BAL) that resulted negative for BCG and SARS-CoV-2. The clinical status improved gradually with normalization of PCR, DDimer, transaminases, LDH and creatinine. Oxygen therapy was suspended on April 13th and the patient was discharged on April 15th with diagnosis of hypersensitivity pneumonitis BCG-induced. Medical therapy consisted of omeprazole, enoxaparin, levofloxacin and prednisone for one month. On June 22th the patient underwent uriArchivio Italiano di Urologia e Andrologia 2021; 93, 1

G. Giordano, E. Kyriazi, C. Mavridis, et al.

Case 2 - FIgure 1. Chest imaging of the patient. The computed tomography scans taken on the 8th of April 2020 showed multiple patchy ground-glass opacities in bilateral subpleural areas with small nodular formations with centerlobulary localization. The image is published under agreement of the patient.

In the current case-report, we present a young man with a functional urinary bladder paraganglioma who was successfully managed with complete removal of the tumor, leaving the urinary bladder intact.

CASE

nary cytology and transurethral cystoscopy that were both negative. He did not report significative respiratory symptoms and abnormal findings on chest CT disappeared.

CONCLUSIONS

This case report emphasizes the importance of understanding the real effect of BCG on immune system. Further researches are needed to understand the possible protective role of immunotherapy with BCG in presence of COVID-19 infection.

REFERENCES

1. Arts RJW, et al. BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell Host Microbe. 2018; 23:89100.e5. 2. Malmstrom PU, et al. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for nonmuscleinvasive bladder cancer. Eur Urol. 2009; 56:247. 3. Redelman-Sidi G, Glickman MS, Bochner BH. The mechanism of action of BCG therapy for bladder cancer-a current perspective. Nat Rev Urol. 2014; 11:153-162.

CASE 3 PARAGANGLIOMA OF THE URINARY BLADDER. A CASE REPORT AND REVIEW OF THE LITERATURE

(Evangelia Kyriazi, Charalampos Fragkoulis, Irene Giagourta, Ioannis Glykas, Georgios Stathouros, George Piaditis) Tumors arising from the chromaffin cells, derived from the embryonic neural crest, usually originate from the adrenal medulla, are designated as pheochromocytomas. Paragangliomas (PGLs) are such tumors occurring in extra-adrenal locations and represent 10% of all pheochromocytomas (1). PLGs are either functional or non-functional depending in the secretion of catecholamines (2). Urinary bladder PLGs are rare as they represent 6% of all PLGs with most common locations the dome or the trigone. PLGs located in other sites of the genitourinary system are less common as bladder is the primary site of such tumors (80%) followed by the urethra (12.7%), pelvis (4.9%) and ureter (3.2%) (3, 4).

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

REPORT

A 38-year-old man experiencing palpitation, headache, diaphoresis, and abdominal painafter micturition was referred to the endocrinology Department for evaluation and further investigation. When further enquired, he described an 8 year history of the aforementioned symptoms, accompanied by characteristic facial pallor and high blood pressure ranging from 170/95 mmHg to 190/110 mmHg. Apart from the moment of episodes coincided with urination, the patient’s blood pressure was marginally elevated. His physical examination and medical history were otherwise unremarkable. The clinical suspicion of a PHEO/PGL was confirmed by a 24h urine collection demonstrating elevated levels of urine metanephrine 3257 (100-800 μg/24h) and normetanephrine 3177 (88-44 μg/24h). Subsequently, a CT scanning of the abdomen documented the presence of a multi-lobular, homogenously contrast-enhanced mass (5.5 cm x 3.5 cm) arising from the right posterior wall of the urinary bladder. A CT scanning of his neck and thorax was performed but did not reveal any additional pathological findings. Patient was referred to the Urology Department to surgically remove the mass. Preoperative preparation included the administration of phenoxybenzamine (a-adrenergic blocking agent) and fluids (NaCl 0.9%) in order to restore arterial blood pressure and intravascular volume and avoid intra-operative hypertensive crisis and postresection hypotension. A sub-umbilical midline incision was performed, bladder was mobilized, right ureter was recognized, and the mass was resected from the bladder wall detrusor muscle. The resection was successfully performed without opening the bladder. A single extraperitoneal drain was placed which was removed on the third postoperative day. Blood loss during surgery was minimal (< 100 ml). No complications were recorded postoperatively. Patient remained normotensive and was subsequently discharged without receiving any antihypertensive treatment. Pathology report confirmed the presence of a PGL embedded in smooth muscle fibers of the urinary bladder detrusor muscle. Macroscopically, the tumor was a solid, ovular, brown in color mass (4.5 x 3.5 x 3 cm) which was partially encapsulated. Microscopically, the neoplasm had developed among smooth muscle cells, was of moderate to high cellularity and had grown in a typical “zellbalen” pattern. The cells had abundant, amphophilic cytoplasm with moderate to high nuclear pleomorphism. Focally located giant multinucleated cells were also observed. Mitoses were scarce (0-1/10 High Power Fields). Neither necrosis nor vascular invasion was observed. The tumor cells were positive for CgA, SYP, NSE, focally positive for S-100 and p53 (12%) and negative for CKAE1/AE3, p63, Her2-neu.

Oncology and complications

The proliferation index Ki67 (MIB-1) was estimated > 3% (focally up to 8%). Follow-up protocol included a 24h urine collection for metanephrines 3 months after surgery which was normal and a post-operative MRI of the abdomen which revealed no pathological findings. Our patient had neither clinical features implying a syndrome related to PGL nor a positive family history. Nevertheless, taking into consideration his young age and the histopathologically proven presence of PGL, we proceeded to his genetic testing to exclude a germline mutation. No disease-associated sequence changes were identified in SDHB, SDHC, SDHD, SDHA and SDHAF2 genes.

CONCLUSIONS

Paraganglioma of the urinary bladder is a rare tumor which, when secretory, has a typical presentation usually related to micturition. In our case, owing to the tumor’s favorable location, the patient was managed with complete resection of his mass leaving the bladder mucosa intact and without the need of partial cystectomy. Our case is an exception to the rule, given that urinary bladder PGLs management usually entails more invasive and extensive procedures. Genetic testing should always be considered, because it provides with invaluable information which may modify our patients’ surveillance and improve their prognosis. Finally, it is worth underscoring that patients with PGLs should receive life-long follow-up because of the peculiar biological behavior and the malignant potential of their disease.

REFERENCES

1. Leestma JE, Price EB Jr. Paraganglioma of the urinary bladder. Cancer. 1971; 28:1063-73. 2. Al-Zahrani AA. Recurrent urinary bladder paraganglioma. Adv Urol. 2010; 2010:912125. 3. Peng C, Bu S, Xiong S, et al. Non-functioning paraganglioma occurring in the urinary bladder: A case report and review of the literature. Oncol Lett. 2015; 10: 321-324. 4. Lenders JW, Duh QY, Eisenhofer G, et al. Endocrine Society. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014; 99:1915-42.

CASE 4 THROMBOTIC

THROMBOCYTOPENIC PURPURA AS A COMPLICATION AFTER RADICAL CYSTECTOMY

(Charalampos Mavridis, George Georgiadis, Charalampos Pontikoglou, Helen A. Papadaki, Charalampos Mamoulakis)

INTRODUCTION

Thrombotic Thrombocytopenic Purpura (TTP) is a rare entity associated with Microangiopathic Hemolytic Anemia (MAHA) and thrombocytopenia (1). Acute kidney injury, fever, and neurological symptoms may also be present. TTP is fatal if left untreated. Triggering factors usually remain unknown but major surgery-induced stress may result in TTP (1). The aim of the present report is to highlight the importance of close follow-up during the postoperative period following major surgery

and to underline the importance of immediate PEX treatment. To the best of our knowledge, this is the first TTP case reported after radical cystectomy.

CASE

REPORT

A 61 year old male with multiple high grade/in situ transitional cell bladder tumor and squamous cell bladder cancer and with a past medical history significant for hypertension and diabetes mellitus was admitted for elective radical cystectomy. Abdominal/thorax computed tomography (CT) scans and bone scintigraphy showed no metastases and the preoperative laboratory work-up was insignificant as well. The perioperative course was uneventful; two units of red blood cells (RBC) were intraoperatively transfused. On the 6th post-operative day (PD), there was an increase in serum LDH level and a decrease in PLT count. PLT count decrease was initially attributed to the low-molecular-weight heparin administration (heparin-induced thrombocytopenia), which was then replaced by fondaparinux. On the 8th PD he developed uncontrolled hyperglycemia, confusion, headache and blurred vision. Arterial blood gas levels were normal and brain, abdomen-pelvis CT scans showed no abnormalities. Laboratory tests revealed an acute HT and PLT count decrease, negative direct Coombs test, normal prothrombin/activated partial thromboplastin time, normal fibrinogen level, normal troponin level and mildly elevated ddimers. Peripheral blood smear revealed five schistocytes per high power field, thereby defining microangiopathic anemia. The combination of microangiopathic anemiathrombocytopenia suggested thrombotic microangiopathy (TMA). A second sample sent for analysis within hours showed further HT and PLT count deterioration, acute increase in LDH and acute kidney injury (Table 1). In view of these findings and taking into consideration Case 4 - Table 1. Laboratory results and PEX procedures. Crea Tbil (mg/dl) (mg/dl) Dos PD1 PD2 PD3 PD4 PD5 PD6 PD7 PD8 PD9 (1st PEX) PD10 (2nd PEX) PD11 (3rd PEX) PD12 (4th PEX) PD13 (5th PEX) PD14 (6th PEX) PD15 PD16 PD33

1.04 1.07 1.12 1.19 0.9 1.08 1.06 1.11 1.47 1.55 1.39 1.35 1.27 1.25 1.22 1.09 1.09 1.02

1.01 2.6 2.3 1.29 0.9 1.4 1.9 1.8 2.8 3.6 4.4 3.2 1.85 1.35 1.35 0.9 0.8 0.5

WBC PLT Ht count count (%) (103/μl) (109/L) 11.7 242 36 12.7 251 35.1 14.5 271 35.2 11.6 333 33 14.2 277 34.1 16.9 228 34.6 15 110 33.6 14 35 30.6 20 8 21 27.1 19 17.2 22.9 41 23.8 32.5 59 26 36.1 88 27 34 84 28.9 14.5 140 30 23 170 30.1 15.1 204 30.4 10.9 290 33.2

LDH Schistocytes (IU/L) (per HPF) 360 390 410 382 390 380 525 705 1024 1246 1705 707 622 540 440 300 175 221

n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. 5 3 2 n.a. 1 1 n.a. n.a. 0 n.a.

Crea, serum creatinine; Dos: day of surgery; HPF: high power field; Ht: hematocrit; LDH: lactate dehydrogenase; PD: post-operative day; PEX: plasma exchange therapy: PLT: platelet; Tbil: total bilirubin; WBC: white blood cell.

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G. Giordano, E. Kyriazi, C. Mavridis, et al.

the neurological symptoms of the patient the presumptive diagnosis of TTP was made and immediate treatment was initiated: prednisolone (25 mg t.i.d.) intravenously plus transfusion of two RBC units and nine units of fresh frozen plasma as a temporary measure since PEX therapy, the mainstay treatment of TTP (2), is not readily available in our hospital. The next day (9th PD), PEX therapy was initiated. The patient eventually improved and was discharged on the 33st PD in good condition. Later the diagnosis was made by adamts13 activity test.

CONCLUSIONS

Major surgery in a patient with coexisting chronic and severe disorders may trigger TTP due to release of unknown factors that can cause disruption of homeostatic blood mechanisms, thus it is deemed crucial to closely follow-up these patients even beyond the 7th PD. TTP should be considered in the differential diagnosis of MHA and thrombo-

cytopenia, associated with renal impairment and neurological manifesta-tions that occurs during the postoperative period, in the absence of another clinically apparent etiology. Since TTP is fatal if left untreated, physicians must be aware of this rare postoperative complication and immediate PEX therapy should be initiated.

ACKNOWLEDGEMENTS

The authors would like to thank the Special Research Account of the University of Crete for supporting the publication of this study (ELKE No 3550).

REFERENCES

1. Eskazan AE, Buyuktas D, Soysal T. Postoperative thrombotic thrombocytopenic purpura. Surg Today. 2015; 45:8-16. 2. Scully M, Goodship T. How I treat thrombotic thrombocytopenic purpura and atypical haemolytic uraemic syndrome. Br J Haematol. 2014; 164:759-66.

Correspondence Giuseppe Giordano, MD g.giorda@gmail.com Diego Meo, MD (Corresponding Author) diegomeo@hotmail.it Vincenzo Magnano San Lio, MD v.magnano@alice.it Unit of Diagnostic and Interventional Radiology ARNAS “Garibaldi-Nesima” Via Palermo 636, 95122 Catania (Italy) Francesco Persico, MD (Corresponding Author) francesco.persico90@gmail.com Massimo Lazzeri, MD lazzeri.maximus@gmail.com Giovanni Lughezzani, MD g.lughezzani@gmail.com Piergiorgio Gatto, MD piergiorgio.gatto@asl4.liguria.it Rodolfo Hurle, MD rodolfo.hurle@humanitas.it Humanitas Clinical and Research Center - IRCCS - Via Manzoni 56, 20089 Rozzano (MI) (Italy) Evangelia Kyriazi, MD kyrevan@windowslive.com Charalampos Fragkoulis, MD harisfrag@yahoo.gr Irene Giagourta, MD irene_giag@yahoo.com Ioannis Glykas, MD (Corresponding Author) giannis.glykas@gmail.com Georgios Stathouros, MD gstathouros@yahoo.gr George Piaditis, MD edk-pgna@otenet.gr General Hospital of Athens G. Gennimatas, Athens (Greece) Charalampos Mavridis, MD ch.mavridis@uoc.gr George Georgiadis, MD geokosgeo@yahoo.gr Charalampos Pontikoglou, MD xpontik@uoc.gr Helen A. Papadaki, MD e.papadaki@uoc.gr Charalampos Mamoulakis, MD (Corresponding Author) mamoulak@uoc.gr University General Hospital of Heraklion, University of Crete, Medical School, Heraklion, Crete (Greece)

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

DOI: 10.4081/aiua.2021.1.77

CASE COLLECTION

Oncological cases and complications in Urology Massimiliano Bernabei 1, Antonia Di Domenico 2, Gil Falcao 3, Charalampos Fragkoulis 4, Andrea Benelli 2, Martina Beverini 2, Luís Campos Pinheiro 3, Cabrita Carneiro 3, Nicolò Fabbri 5, Ioannis Glykas 4, Salvatore Greco 6, Carlo Introini 2, Konstantinos Ntoumas 4, Georgios Papadopoulos 4, Mariangela Rutigliani 7, Panagiotis Stamatakos 4, João Vasco Barreira 8 1 Department

of Urology, Azienda USL di Ferrara, Lagosanto, Italy; Department, E.O. Galliera, Genoa, Italy; 3 Urologist, Lisbon, Portugal; 4 Urology Department, General Hospital of Athens “G. Gennimatas”, Athens, Greece; 5 Unit of General Surgery, Azienda Unità Sanitaria Locale di Ferrara, Lagosanto, Italy; 6 Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy; 7 Pathology Unit, E.O. Galliera, Genoa, Italy; 8 Medical Oncologist, Lisbon, Portugal. 2 Urology

Summary

This collection of cases describes some unusual urological tumors and complications related to urological tumors and their treatment. Case 1: A case of left hydronephrosis referred four years after a right radical mastectomy for lobular breast carcinoma was described. Computed tomography scan revealed a left hydronephrosis with dilated ureter up to the proximal third. An exploratory laparoscopy was performed and the definitive histopathology examination showed a recurrence of the carcinoma with a right tubal metastasis and peritoneal carcinosis. Case 2: A rare case of an extensive penile squamous cell carcinoma in a young man. The patient was treated with radical surgery and modified inguinal lymphadenectomy. No recurrence was noticed so far. Case 3: A rare case of left sided Inferior Vena Cava (IVC) in a patient diagnosed with renal cell cancer who underwent open left partial nephrectomy. Case 4: A case of urethrorrhagia, caused by a recent trauma from an urinary catheter placed in a patient submitted to gastric resection due to a neoplastic pathology. Urethrorrhagia only temporarily responded to conservative treatment and ultimately resolved by coagulation with an endoscopic approach.

KEY WORDS: Penile cancer; HPV; Rare tumors; Urethrorrhagia; Endoscopy; Coagulation. Submitted 26 July 2020; Accepted 28 September 2020

CASE 1 HYDRONEPHROSIS

AS UNUSUAL PRESENTATION OF METASTATIC LOBULAR BREAST CANCER

(Di Domenico Antonia, Benelli Andrea, Beverini Martina, Rutigliani Mariangela, Introini Carlo)

INTRODUCTION

Breast cancer is currently the most common malignancy in women, with an observed incidence rate of 127.5 cases per 100.000 women per year according to the Surveillance, Epidemiology and End Results (SEER) pro-

gram. Invasive lobular carcinoma (ILC) accounts for 14% of all breast cancers; however due to the large incidence ILC affects a large number of women. Metastatic spread is the single most significant predictor of poor survival. Patients with distant metastases have a five-year survival rate of 27% (2008-2014). Typical breast cancer metastatization sites are bones, liver, lungs and brain, but many other localizations have been described in literature, including gynecological organs and peritoneum. Fallopian tube metastasis from non-gynecological malignancies are rarely described in literature especially from breast cancer (1). The aim of this report is to describe our experience regarding an unusual case of breast cancer metastasis in a middle age woman focusing on the diagnosis process and clinical management.

CASE

REPORT

A 61-year-old woman with a history of lobular breast cancer presented incidental finding of left hydronephrosis at a CT scan of the chest during oncological follow-up. This patient was treated 4 years before with right radical mastectomy and subsequent adjuvant ormonotherapy and radiotherapy. In her history there was a subtotal hysterectomy with finding of uterine carcinoma in situ. The subsequent CT scan of the abdomen showed a bilateral hydroureteronephrosis with an unclear thickening of the distal ureteral wall. A thin circumferential thickening of the rectum was also described. Due to these findings a diagnostic ureteroscopy and a colonscopy were perfomed; a biopsy of the suspicious tissue was performed and in both cases the pathology results were negative. A repeat CT scan of the abdomen after 2 months revealed circumferential thickening of the rectum and the last ileal loop, bilateral hydronephrosis, thickening of wide ligaments with inhomogeneity of the annexial region bilaterally. A large peritoneal “sausage”- shaped mass was described. The patient underwent a PET-CT showing a increased uptake of the intestine areas but turned out to be negative in the pelvis. On physical examination the patient was found to have a palpable mass in the right upper quadrant

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

M, Bernabei, A, Di Domenico, G. Falcao, et al.

Case 1 - Figure 1. A) Metastatic lobular carcinoma of breast growing beneath tubal epithelium. (Hematoxylin-eosin staining magnification 20x). B) Immunohistochemical Estrogen slide showing diffuse and intense positive of the majority of tumor cells (Estrogen, magnification 20x). C) Metastatic lobular carcinoma: immunostaining with GATA 3 shows a characteristic canalicular pattern (GATA3, magnification 20x). D) The Ki-67 proliferation index is 20% (KI-67 Mib1, magnification 20x).

cinoma is not the most common histological subtype of breast carcinoma, but it is the most frequent related to gastrointestinal, gynecological and peritoneal metastases. In a series of 100 cases, Rabban et al. found that the two main primary tumors metastasizing to the fallopian tube were colon (35%) and the breast (15%) (3). Carcinomatosis can occur in 2.6% of cases. The literature rarely mention peritoneal metastasis from breast cancer, and peritoneal recurrences are described after a variable time interval between 5 and 10 years from the diagnosis of primary breast cancer. This late onset might not always be related to a late metastasis development rather than to a late metastasis detection, which results very difficult in the absence of any specific symptom. Moreover, modern imaging techniques resulted scarcely accurate in peritoneal carcinomatosis diagnosis (2). To our knowledge, this is the first reported case of tubal metastasis and peritoneal carcinomatosis from a lobular breast cancer diagnosed by an incidental finding of hydronephrosis. This case emphasizes the role of the fallopian tubes as a potential conduit between the gynecological tract and the peritoneal cavity.

REFERENCES

1. Bigorie V, Morice P, Duvillard P, et al. Ovarian metastases from breast cancer: report of 29 cases. Cancer. 2010; 116:799-804.

of the abdomen. An exploratory laparoscopy was than performed with evidence of intense pelvic tissue thickening, in particular a mass was evidenced in right pelvis that as first hypothesis was compatible with hydrosalpinx. Peritoneal and cecal nodules were biopsied. Macroscopic examination of the resected specimen showed fallopian tube congestion with lumen in part ectasic in part reduced and thickened and edematous wall. Microscopic section showed small and relatively uniform tumor cells growing in single line and solid. The mitotic index was 3 mitoses/10 high power fields (HPF). By immunohistochemistry, the tumor cells were positive for cytokeratin 7 (clone SP52, prediluited, Ventana), GATA 3 (clone L50-823, prediluited, Cell Marque), Estrogen (clone SP1, prediluited, Ventana), Progesterone (clone 1E2, prediluited, Ventana). They were negative for HER 2 (clone 4B5, 1/100, Ventana), E-cadherin (EP700Y, prediluited, Cell Marque) cytokeratin 20 (clone SP33 prediluited, Ventana). Ki-67 (clone 30-9, prediluited, Ventana) immunostaining showed nuclear labeling in 20% of the cells. We diagnosed metastases of invasive lobular breast cancer to the fallopian tube (Figure 1). Actually the patient is alive and undergoing chemotherapy with partial radiologic regression of the peritoneal mass. She still needs bilateral double J ureteral stents in order to protect the renal function during chemotherapy.

CONCLUSIONS

Breast cancer is the most common site-specific cancer in women and is the leading cause of death from cancer for patients aged 20-59 years. The interval between diagnosis of primary and metastatic disease is described in literature between 5 and 20 years; in our case the presentation was after 4 years from the primary treatment (2). Metastatic patterns of breast carcinoma have been studied, suggesting two important factors impacting the site of tumor spread: the estrogen receptor (ER) status and the pathology of cancer (ductal versus lobular). Lobular car-

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

2. Winston CB, Hadar O, Teitcher JB, et al. Metastatic lobular carcinoma of the breast: patterns of spread in the chest, abdomen, and pelvis on CT. AJR Am J Roentgenol. 2000; 175:795-800. 3. Rabban JT, Vohra P, Zaloudek CJ. Nongynecologic metastases to fallopian tube mucosa: a potential mimic of tubal high-grade serous carcinoma and benign tubal mucinous metaplasia or nonmucinous hyperplasia. Am J Surg Pathol. 2015; 39:35-51.

CASE 2 SQUAMOUS

CELL CARCINOMA OF THE PENIS

(Gil Falcão, Cabrita Carneiro, Luís Campos Pinheiro, João Vasco Barreira)

INTRODUCTION

Penile cancer is uncommon. The incidence of penile cancer increases with age with a peak in the sixth decade, but it does occur in younger men. About one third of cases are attributed to HPV-related carcinogenesis. Squamous cell carcinoma accounts for over 95% of penile malignancies. Early inguinal lymphadenectomy in clinically node-negative patients is superior for longterm patient survival compared to later lymphadenectomy with regional nodal recurrence. Patient education is an essential part of follow-up. In patients with long-term survival after penile cancer treatment, sexual dysfunction, voiding problems and cosmetic penile appearance may adversely affect the patient’s quality of life (QoL). Since penile cancer is rare, patients should be referred to a center with experience and expertise in local treatment, pathological diagnosis, chemotherapy and psychological support for penile cancer patients.

CASE

REPORT

The authors present a clinical case of a man in the fifth decade of life with no comorbidities. The presenting fea-

Oncology and complications

Case 2 - Figure 1. A-B: At clinical examination complete dissociation of foreskin with exposure of corpora cavernosa, lesion of bulky dimension about 5-10 cm, no palpable inguinal lymph nodes, purulent exudate. A.

of malignant tumors. It also embodies a rare clinical observation, which justifies reporting this case with the purpose to highlight the importance of a multidisciplinary team in the management of cancer patients (1).

REFERENCES

1. Joura E, Jenkins D, Guimera N. Vulvar, penile, and scrotal human papillomavirus and non–human papillomavirus cancer pathways, In D. Jenkins, F. Xavier Bosch (Eds) Human Papillomavirus providing and using a viral cause for cancer, Academic Press 2020, pages 219-230.

ture was a 4-years onset history of a penile lesion. At the clinical examination we highlight complete dissociation of foreskin with exposure of corpora cavernosa, lesion of bulky dimension about 5-10 cm, no palpable inguinal lymph nodes, purulent exudate (Figure 1). The histopathological findings of a biopsy of the lesion were compatible with a squamous cell carcinoma (SCC) with overexpression of p16. Staging was performed with thoraco-abdominal-pelvic computed tomography (CT) which revealed a voluminous penile mass, centered on the dorsum of the penis, involving cavernous bodies, spongy body and urethra; the mass contacted the scrotum, with no evident cleavage plan and with no distant sign of disease. At the multidisciplinary evaluation, the patient was proposed for surgical approach. The histopathological report of the radical penectomy with modified radical lymphadenectomy revealed a squamous cell carcinoma pT3G2N0, R0.

DISCUSSION

In industrialized countries, penile cancer is uncommon. The incidence of penile cancer increases with age with a peak in the sixth decade, but it does occur in younger men. About one third of cases are attributed to HPVrelated carcinogenesis. A significantly better five-year disease-specific survival has been reported for HPV-related compared with HPV-negative cases. Squamous cell carcinoma accounts for over 95% of penile malignancies. It is not known how often SCC is preceded by premalignant lesions. Early inguinal lymphadenectomy in clinically node-negative patients is superior for long-term patient survival compared to late lymphadenectomy for regional nodal recurrence. Local recurrence is easily detected by physical examination, by the patient himself or his physician. Patient education is an essential part of follow-up. In patients with long-term survival after penile cancer treatment, sexual dysfunction, voiding problems and cosmetic penile appearance may adversely affect the patient’s quality of life (QoL). However, there is very few data on sexual function and QoL after treatment for penile cancer. Since penile cancer is rare, patients should be referred to a center with experience and expertise in local treatment, pathological diagnosis, chemotherapy and psychological support for penile cancer patients. This case is a reminder of how the perception of individual skin findings can lead to the diagnosis

CASE 3 LEFT SIDED

INFERIOR VENA CAVA IN A PATIENT DIAGNOSED WITH RENAL CELL CARCINOMA

(Charalampos Fragkoulis, Ioannis Glykas, Panagiotis Stamatakos, Georgios Papadopoulos, Konstantinos Ntoumas)

INTRODUCTION

Inferior vena cava (IVC) is a large retroperitoneal vein responsible for the deoxygenated blood transportation from the lower extremities and the abdomen through diaphragm to the right atrium. Anatomically is formed by the confluence of the right and left iliac veins at the level of L5 vertebrae. After its formation it lies along the right anterolateral aspect of the vertebral column and passes through the central tendon of the diaphragm around the T8 vertebral level (1). Many anatomic anomalies of the IVC are described. Most clinically significant are left sided IVC, double IVC, intrahepatic IVC agenesis and total absence of infrarenal IVC (2). Left sided IVC has a suspected prevalence up to 0.5% and it is caused by the regression of the right supracardinal vein and the persistence of the left supracardinal vein (3). Injuries of the IVC may occur during operations of the right kidney. Although major vascular injuries involving IVC during laparoscopic or open partial nephrectomy are rare, it is of outmost importance to recognize major anatomic landmarks and to identify anatomic anomalies prior to surgery in order to be able to face any intraoperative complication (4). Therefore, recognizing left sided inferior vena cava variation before surgery through the imaging techniques is very important for the surgeon’s preparation of possible vascular damage.

CASE

REPORT

We present a case of a 75-year-old male who was referred to our department due to a 5 cm left renal tumor located in the lower pole. In the CT performed we recognized IVC located in the left of the midline as well as total aplasia of superior vena cava (Figure 1). Vein drainage above the diaphragm was performed through the vein system of azygos and hemiazygos veins. Left renal vein was drained straight to the IVC but as IVC was located to the left side, it did not pass in front of the aorta as usual (Figure 2). A successful open partial nephrectomy was performed by a retroperitoneal approach. The patient was informed in detail by the treating physician for inclusion in the case presentation and signed an informed consent prior to participation. In the form the Archivio Italiano di Urologia e Andrologia 2021; 93, 1

M, Bernabei, A, Di Domenico, G. Falcao, et al.

Case 3 - Figure 1. CT showing IVC located in the left of the midline as well as total aplasia of superior vena cava.

Case 3 - Figure 2. Left renal vein draining straight to the IVC but as IVC was located to the left side not passing in front of the aorta as usual.

patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published.

CONCLUSIONS

Left sided inferior vena cava is an exceedingly rare entity. Recognizing this rare anatomic variation before surgery through the imaging techniques is very important for the surgeon’s preparation of possible intraoperative complications.

REFERENCES

1. Petik B. Inferior vena cava anomalies and variations: imaging and rare clinical findings. Insights Imaging. 2015; 6:631-9. 2. Kaufman JA, Waltman AC, Rivitz SM, Geller SC. Anatomical observations on the renal veins and inferior vena cava at magnetic resonance angiography. Cardiovasc Intervent Radiol. 1995; 18:153-157. 3. Giordano JM, Trout HH. Anomalies of the inferior vena cava. J Vasc Surg. 1986; 3:924-8. 4. McAllister M, Bhayani SB, Ong A, et al. Vena caval transection during retroperitoneoscopic nephrectomy: report of the complication and review of the literature. J Urol. 2004; 172:183-185.

CASE 4 ENDOSCOPIC TREATMENT OF RECURRENT URETHRORRHAGIA

(Massimiliano Bernabei, Nicolò Fabbri, Salvatore Greco) Lesions of the urethra due to urethral catheterization or dislocation of the catheter itself are well known and may sometimes occur with urethrorrhagia and subsequent anemia. The causes may be found in "false paths", stenosis, urethro-penile fistulas, or more rarely, pseudoaneurysms of the bulbar arteries of the penis. The goldstandard treatment consists of percutaneous angioembolization (1, 2). We introduce a case of urethrorrhagia,

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

caused by a recent trauma from the urinary catheter, only temporarily responding to conservative treatment and ultimately resolved by the endoscopic approach.

CASE

REPORT

A 72-year-old man was admitted to the General Surgery Unit of our hospital in Lagosanto (Ferrara) for gastric resection due to a neoplastic pathology. Before undergoing surgery, he first underwent a cycle of neoadjuvant chemotherapy. In his clinical history, he reported colic diverticulosis, hemorrhoidal syndrome, bilateral inguinal hernioplasty, and mild thrombocytopenia of unknown origin. In the pre-operative period, the patient had reported pollakiuria and dysuria, without requiring urological or medical examinations. The postoperative observation period was complicated with an accidental self-removal of the urinary catheter, accurately positioned before surgery, with a consequent nocturnal episode of urethrorrhagia. The patient did not need the repositioning of the catheter because of spontaneous urination and was discharged after ten days since the operation, with a regular postoperative course and with the urological indication to take tamsulosin 0.4 mg/day combined with dutasteride 0.5 mg/day at home. Two days after being discharged, the patient underwent another episode of urethrorrhagia at home, which resolved spontaneously. After three more days (on the 15th postoperative day), the patient presented again to emergency ward for recurrent urethrorrhagia, but this third episode was more persistent and severe. Blood exams documented anemization (hemoglobin levels ranging from 9.4 to 8 g/dL in the few hours of stay at the emergency room). It was positioned "per uretram" a latex catheter (20 Ch diameter) and tranexamic acid was administered both locally and orally. Due to only partial resolution of the bleeding, it was admitted to our Urology department. During the hospital stay, the treatment consisted of compression of both penile shaft and perineum with local application of ice; he also needed to be transfused with two units of concentrated red blood cells. After rapid resolution of the urethrorrhagia, a modest urethral bleeding persisted and, in the hypothesis of a lesion of the distal urethra, peri-catheter endo-urethral injection of etilefrine was administered, resulting in an apparent and rapid regression of bleeding. However, urethrorrhagia presented again two days later, contextually with the evacuation of some clots from the bladder catheter and suprapubic pain symptoms. We, therefore, decided to consider the patient eligible for urgent operative urethro-cystoscopy, to carry out a bladder washing, waiting for angiography and, if necessary, percutaneous angioembolization. Because of the unavailability of these procedures in our hospital, it was planned to refer the patient to our reference hub hospital in Cona (Ferrara). The introduction of the cystoscope (Olympus) allowed us to highlight a hyperemic urethral area of about 1 cm, located immediately before the membranous tract of urethra at 7 o’clock position, without evidence of active bleeding. Retrograde endoscopy ruled out further lesions, allowing, once in the bladder, to find and contextually evacuate several intraluminal clots. During the

Oncology and complications

Case 4 - Figure 1. A) Urethroscopy with visualization of the right ventral bulbar urethral lesion, just before the membranous tract. B) Monopolar coagulation of the margins of the urethral lesion C) Completion of coagulation D) Final result.

first option. In the postoperative period, careful monitoring of the urine color, as well as of the patient’s hemodynamic and hematochemical parameters, to exclude any occult bleeding, could be sufficient to avoid further radiological-guided procedures that are not free from possible complications, even functional, as impotence.

REFERENCES

1. Radhakrishnan S, Marsh R, Sheikh N, et al. Urethral catheter induced pseudoaneurysm of the bulbar artery. Int J Urol. 2005; 12:922-4. 2. Bettez M, Aubé M, Sherbiny ME, et al. A bulbar artery pseudoaneurysm following traumatic urethral catheterization. Can Urol Assoc J. 2017; 11:E47-E49. 3. Campos SJ, Besser PN, Aguirre AP, et al. Urethrorrhagia secondary to traumatic penile pseudoaneurysm. Urol Case Rep. 2016; 7:10-13. 4. Schober JP, Iqbal S, Marcantonio A, MacLachlan L. Endoscopic management of a trauma-induced urethral pseudoaneurysm. J Endourol Case Rep. 2019; 5:96. Correspondence

execution of the final antegrade urethroscopy, monopolar diathermocoagulation (DTC) was performed on part of the margin of the a forementioned urethral lesion (Figure 1). After removing the instrument, a two-way “Tiemann” catheter (20 Ch) was then placed. The latter was removed on the third postoperative day, with discharge at home the next day after satisfactory spontaneous normochromic urination. After a further three months of observation, the patient resulted to have no more episodes of urethrorrhagia or abdominal pain symptoms, and the urinary dynamics always remained regular.

CONCLUSIONS

Urethral lesions are well known and frequent in urology, although they result in urethrorrhagia only on rare occasions (3). In cases where this event occurs, conservative treatment (i.e. transurethral catheterization associated with perineal compression) allows resolution in most cases. If this approach is not effective, the more usual alternative is radio-guided angioembolization. Unfortunately, this procedure may not be readily available in all hospital centers, as it happened for our hospital. To date, only a few reports of endoscopic treatment, as alternative to angioembolization, have been reported in the literature.What we suggest, in the case that radiologicalinterventional treatment (angiography and percutaneous embolization) is not immediately available, is the endoscopic approach. This procedure should aim to endoluminal compression (4), but also to coagulation of any possible active bleeding. Furthermore, in case of significant bleeding, as happened in our case, simple bladder washing may be not effective due to the formation of blood clots that need to be removed with an endoscopic procedure. The "gold standard" treatment should be cystoscopy followed by angiography with embolization; unfortunately, the lack of interventional radiology in our hospital led us to choose an endoscopic attempt to stop bleeding as the

Antonia Di Domenico, MD antonia.didomenico@galliera.it Andrea Benelli, MD (Corresponding Author) andrebenne@gmail.com - andrebene85@hotmail.com Martina Beverini, MD martina.beverini@live.it Mariangela Rutigliani, MD mariangela.rutigliani@galliera.it Carlo Introini, MD carlo.introini@galliera.it E.O Galliera, Genoa (Italy) Gil Falcão, MD (Corresponding Author) gilfalcao145@gmail.com Cabrita Carneiro, MD jpcabritacarneiro@gmail.com Luís Campos Pinheiro, MD luiscampospinheiro@gmail.com João Vasco Barreira, MD joaovascobarreira@gmail.com Lisbon, Portugal Charalampos Fragkoulis, MD harisfrag@yahoo.gr Ioannis Glykas, MD (Corresponding Author) giannis.glykas@gmail.com Panagiotis Stamatakos, MD pvstamatakos@gmail.com Georgios Papadopoulos, MD gipapadopoulos@yahoo.gr Konstantinos Ntoumas, MD ntoumask@yahoo.com Urology Department, General Hospital of Athens “G. Gennimatas”, Athens (Greece) Massimiliano Bernabei, MD m.bernabei@ausl.fe.it Nicolò Fabbri, MD (Corresponding Author) n.fabbri@ausl.fe.it Salvatore Greco, MD salvatore.greco@unife.it Azienda USL di Ferrara, via Valle Oppio, 2, Lagosanto, Italy University of Ferrara, Ferrara, Italy Archivio Italiano di Urologia e Andrologia 2021; 93, 1

LETTER TO EDITOR

DOI: 10.4081/aiua.2021.1.82

Movember in a pandemic - it matters, more than ever Submitted 4 November 2020; Accepted 1 December 2021

Dear Editor, in recent years there has been an increase in the number of new cases of cancer. This increase, in part, is closely related to the increase in average life expectancy, as well as more accurate diagnostic techniques and well-defined screening programs. Nowadays, the world faces a new challenge, a pandemic, an outbreak of a new beta-coronavirus. WHO has declared the new coronavirus disease (COVID-19), caused by SARS-CoV-2, an international public health emergency. Given the unprecedented situation of the pandemic, those programs may begin to slow down. Movember is the leading charity changing the face of men´s health on a global scale, focusing on mental health and suicide prevention, prostate cancer and testicular cancer. Commenced in 2003 with the dual aims of raising funds and awareness of prostate cancer and mental health, incorporating testicular cancer and physical inactivity in recent years, the term was created from the combination of “Mo” – Australian slang for mustache – and November. The strength of the Movember campaign is in its fundraising capacities. To date, has raised millions and funded over thousands programmes worldwide. The campaign makes outstanding use of social media with accounts on Facebook, Twitter and Instagram, but most of their marketing focus on encouraging men to grow facial hair. With a trademark combination of humor, companionship, and competitive nature they managed to do the seemingly impossible: turn huge numbers of men into energetic fundraisers, much as women do for breast cancer. Movember in a pandemic - does it matters? Coronavirus disease 2019 (COVID-19) is caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and first emerged in December 2019 in Wuhan, Hubei province, China. Since then, the virus has rapidly spread to many countries with a daily increase in the number of confirmed cases and infection-related deaths. COVID-19 morbidity and mortality has been associated with factors such as age and comorbidities. Infection in frail patients assumes a worse prognosis, resulting more often in hospitalization, admission to intensive care units with a consequent need for invasive mechanical ventilation. Among these, cancer patients represent a large subgroup with a high risk of developing infection associated with coronavirus and, consequently, serious complications. The challenges caused by the COVID-19 pandemic required an enormous effort to adapt and reorganize medical services. The consequent internal restructuring to respond to the new demands determined by COVID-19 had to be done simultaneously taking care of people and working as a team, focusing on identifying the most appropriate solutions at all times for the different contexts of the dynamics. The question of how to organize the screening programs during the COVID-19 pandemic is crucial It is indisputable to join efforts to fight the SARS-CoV-2 pandemic, but let us not agree that the virus contaminates our national health system. The Emergency Committee of the World Health Organization (WHO) anticipated that the COVID-19 pandemic will last a long time and, therefore, it is necessary to continue efforts to contain it worldwide. The challenges are immense, but there are lives beyond COVID-19 that need to be taken on account. By this we mean that the pandemic caused by COVID-19 has not made the illnesses of these potential patients disappear, who continue to need our attention and care. If, on the one hand, it is more than clear that we should be aware that with the current pandemic situation it is impossible to maintain all normal activity and simultaneously treat COVID-19 patients; on the other hand, we cannot ignore the remaining problems in our health system in addition to this virus.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

Movember in a pandemic - it matters, more than ever

"The pandemic is a health crisis that occurs once in a century and its effects will be felt in the decades to come," said WHO Director-General Tedros Adhanom Ghebreyesus. These effects are valid for both Covid and non-Covid patients. So, the answer to whether the Movember movement makes sense in times as troubled as those we currently live in, our answer is a categorical yes.

REFERENCES

1. Movember Foundation (US). Mo History. < https://us.movember.com > 2. Ambrosini F, Di Stasio A, Mantica G, et al. COVID-19 pandemic and uro-oncology follow-up: A "virtual" multidisciplinary team strategy and patients' satisfaction assessment. Arch Ital Urol Androl. 2020; 92. doi: 10.4081/aiua.2020.2.78. PMID: 32597103.

João Vasco Barreira 1, Gil Falcão 2, Mariana Amaral 3, Pedro Barreira 3 1 Medical

Oncologist, Lisbon, Portugal; 2 Urologist, Lisbon, Portugal; 3 Family Doctor, Lisbon, Portugal.

All the Authors contributed equally to the paper.

Correspondence João Vasco Barreira (Corresponding Author) joaovascobarreira@gmail.com Medical Oncologist, Lisbon, Portugal Gil Falcão Urologist, Lisbon, Portugal Mariana Amaral Pedro Barreira Family Doctor, Lisbon, Portugal

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

LETTER TO EDITOR

DOI: 10.4081/aiua.2021.1.84

Clinical impact of combined PTEN and ERG rearrangements in localized prostate cancer Submitted 30 December 2020; Accepted 7 January 2021

To the Editor, Prostate cancer (PCa) is nowadays the second most common malignancy diagnosed among men and is responsible for one of the leading causes of cancer mortality. Clinically localized disease may present with a wide variety of clinical behavior including tumors of low clinical significance as well as highly aggressive ones. Among patients treated with either radical prostatectomy or radiotherapy there is a risk of biochemical failure (BF). As a result, it is of outmost interest to develop new markers predicting the risk of BF development. Several genes and molecular pathways are implicated in the disease development and progression including phosphatase and tensin homolog gene (PTEN) and ETS Related Gene (ERG). PTEN is a tumor suppressor gene located in chromosome 10q23.3. It encodes the PTEN protein, a dual lipid phosphatase enzyme, which acts as a negative regulator of the PI3K-Akt survival pathway. PTEN protein dephosphorylates PIP3 converting it back to PIP2. As a result, the phosphorylation of Akt mediated by PIP2 conversion to PIP3 is inhibited and a G1 cell cycle arrest is induced. In addition, PTEN may promote oncogenesis in a PIP3 independent mechanism involving MAPK pathway crosstalk with PTEN pathway, cell migration, cell adhesion, tumor angiogenesis and DNA repair and tumor invasion. ERG is an oncogene member of the ETS family located in chromosome 21q22.2. The connection between the ERG protein and prostate cancer is well documented. ERG protein is mostly involved in this process as a fusion protein with transmembrane protease serine 2 (TMPRSS2), a protein encoded by TMPRSS2 gene, located in chromosome 21q22.3 (1). Although PTEN loss and ERG rearrangement are the most common genomic aberrations in prostate cancer, the relationship between them and how they interfere with cancer recurrence and progression is still unclear. Recently, a systematic review and metanalysis was published by Liu et al regarding the impact of PTEN loss and ERG rearrangement on recurrence after treatment with radical prostatectomy or brachytherapy. A total of 6744 patients from 17 papers were included in the metanalysis and primary endpoints assessed were biochemical recurrence free (BRF) survival and recurrence free survival (RFS). A subgroup analysis was performed according to the degree of PTEN deletion, ERG rearrangement and Gleason score. In terms of results, prostate cancer with PTEN deletion faced a higher risk for recurrence. BRF and RFS were lower in a statistically significant way in both groups with heterozygous or homozygous PTEN loss. The effect was more profound in the homozygous deletion. On the other hand, no correlation was documented regarding the association of ERG rearrangement, regardless of PTEN deletion or not, and the risk for recurrence after radical prostatectomy or brachytherapy. Nevertheless, Gleason score was proved to be a significant factor predicting recurrence (2). In terms of clinical impact in decision making, there are several clinical trials investigating the use of drugs targeting PTEN and ERG pathways. MAPK inhibitors are under investigation as there is a correlation between PTEN molecular pathway and MAPK signaling. PI3K inhibitor LY294002 and pan-AKT inhibitor AZD5363 deliver promising results in terms of slowing prostate cancer growth. In addition, multikinase inhibitors such as sorafenib, buparlisib and regorafenib also interfere with PI3K/AKT/mTOR pathway and present as possible treatment options. Moreover, cIAP-1 antagonist AT-IAP can sensitize PTEN deficient tumors to radiotherapy in vitro. Moreover, a recent phase II clinical trial of everolimus, an mTOR inhibitor, plus bicalutamide for castration-resistant prostate cancer presented valuable results with 75% of the patients treated with everolimus plus bicalutamide having a decrease in PSA of greater than or equal to 50% (1). The prognostic value of PTEN loss and ERG rearrangement was also evaluated by Bismar et al. in a study including 463 patients where the PTEN and ERG status was correlated with clinical and pathological features such as Gleason score, patients’ outcomes, and possible androgen deprivation therapy. ERG expression and PTEN loss was documented in

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

PTEN and ERG in prostate cancer

28.2% and 38% of patients, respectively. It was quite interesting that among PTEN negative tumors, 21.8% presented as ERG positive. In cases where PTEN was intact patients presented with better cancer specific survival. On the other hand, patients with decreased PTEN intensity without ERG positivity showed the worst clinical outcome compared to those with no PTEN loss and no ERG expression, where they had best clinical outcome. Patients with ERG expression with or without PTEN loss showed intermediate risk in relation to lethal disease (3). The correlation between PTEN and ERG protein expression and prostate cancer is a field of investigation where many mechanisms and pathways are still being discovered in ongoing trials. There is a need of results from new, large clinical trials in order to establish the clinical utility of both PTEN and ERG status in the management of PCa patients.

REFERENCES

1. Ullman D, Dorn D, Rais-Bahrami S, Gordetsky J. Clinical Utility and Biologic Implications of Phosphatase and Tensin Homolog (PTEN) and ETS-related Gene (ERG) in Prostate Cancer. Urology. 2018; 113:59-70. 2. Liu R, Zhou J, Xia S, Li T. The impact of PTEN deletion and ERG rearrangement on recurrence after treatment for prostate cancer: a systematic review and meta-analysis. Clin Transl Oncol. 2020; 22:694-702. 3. Bismar TA, Hegazy S, Feng Z, et al. Clinical utility of assessing PTEN and ERG protein expression in prostate cancer patients: a proposed method for risk stratification. J Cancer Res Clin Oncol. 2018; 144:2117-2125.

Charalampos Fragkoulis ¹, Ioannis Glykas ¹, Athanasios Dellis 2, Konstantinos Ntoumas ¹, Athanasios Papatsoris 3 1 Urology

Department, General Hospital of Athens “G. Gennimatas”, Athens, Greece. Department of Urology, School of Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece. 3 2nd Department of Urology, School of Medicine, Sismanoglio Hospital, National and Kapodistrian University of Athens, Athens, Greece. 2 1st

Correspondence Charalampos Fragkoulis, MD harisfrag@yahoo.gr Ioannis Glykas, MD Konstantinos Ntoumas, MD Urology Department, General Hospital of Athens “G. Gennimatas”, Athens (Greece) Athanasios Dellis, MD 1st Department of Urology, School of Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens (Greece) Athanasios Papatsoris, MD 2nd Department of Urology, School of Medicine, Sismanoglio Hospital, National and Kapodistrian University of Athens, Athens (Greece)

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

LETTER TO EDITOR

DOI: 10.4081/aiua.2021.1.86

Red man syndrome caused by intracavernous irrigation with vancomycin at the time of placing penile implants Submitted 8 December 2020; Accepted 20 December 2020

To the Editor, Erectile dysfunction is a condition that affects more than half of men between 40 and 70 years of age. Penile prosthesis (PP) implant is recognized, at present, as the most effective option to obtain an artificial erection satisfactory for sexual intercourse in those patients in which the pharmacological approach is contraindicated or ineffective (1). Postoperative infection is the most feared complication of genitourinary prosthetic surgery. The literature contains several interventions that have been shown to reduce the rate of PP infection. One of the intraoperative approaches is to use an antiseptic washout solution containing vancomycin and gentamycin (2). We report a case of a 65-year-old male patient who developed red man syndrome (RMS) soon after the initiation of intracavernous irrigation of vancomycin during the implantation of a PP. The case was successfully managed with diphenhydramine. RMS is an idiopathic pseudo-allergic drug reaction that may develop after the administration of vancomycin. It is frequently observed with the infusion of vancomycin. The patient shows signs and symptoms of an allergic reaction, but without any classic allergy immunologic mechanism (3). Discontinuation of the vancomycin infusion and administration of diphenhydramine can abort most of the reactions. Slow intravenous administration of vancomycin should minimize the risk of infusion-related adverse effects (4). A 65-year-old male with poorly controlled diabetes mellitus type 2 presented for inflatable PP insertion. He has no known food or drug allergies. On pre-procedure assessment, his blood pressure was 110/80 mmHg, heart rate 72 beats per minute, respiratory rate 13 per minute, and temperature 37.1C°. In the supine position, prepping and draping in the usual sterile manner done. Under spinal anesthesia, a penoscrotal incision was made. The dartos fascia is now exposed and incised. Skin hooks are placed. The tunica albuginea of both corporas is exposed and the urethral catheter is palpated in the midline. A stab wound is made with a scalpel into each corpora and, using Metzenbaum scissors, a 3-cm vertical corporotomy is performed between two 2-0 stay sutures. Corporal dilatation is performed. Vigorous intracavernous washout was done using an antimicrobial solution (500 mg vancomycin and 80 mg gentamicin sulfate diluted in a 1 liter of normal saline solution). After 5 minutes, erythema developed along the patient’s right forearm. At the same time, the patient developed redness of his right neck and itching of his scalp, mainly on his left side. Adequate oxygenation by a face mask was initiated. Vital signs were stable. This was identified as RMS secondary to vancomycin. The adverse reaction was resolved after the discontinuation of intracavernous irrigation with vancomycin and administration of diphenhydramine. The planned procedure was completed. This report of RMS after intracavernous irrigation with vancomycin is believed the first in the literature. The patient’s symptoms disappeared within one hour after the medication was discontinued. This case demonstrates the need to closely monitor for side effects of intracavernous irrigation with vancomycin and to carefully consider this approach.

REFERENCES

1. Bettocchi C, Palumbo F, Spilotros M, et al. Penile prostheses. Ther Adv Urol. 2010; 2:35-40. 2. Swanton AR, Munarriz RM, Gross MS. Updates in penile prosthesis infections. Asian J Androl. 2020; 22:28-33.

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

Red man syndrome caused by intracavernous irrigation with vancomycin at the time of placing penile implants

3. Arroyo-Mercado F, Khudyakov A, Chawla GS, et al. Red man syndrome with oral vancomycin: a case report. Am J Med Case Rep. 2019; 7:16-17. 4. Sivagnanam S, Deleu D. Red man syndrome. Crit Care. 2003; 7:119-20.

Mohamad Moussa 1, Mohamad Abou Chakra 2, Athanasios Papatsoris 3, Athanasios Dellis 4, Yasmine Moussa 5 1 Urology

Department, Zahraa Hospital, University Medical Center, Lebanese University, Beirut, Lebanon; 2 Faculty of Medicine, Department of Urology, Lebanese University, Beirut, Lebanon 3 2nd Department of Urology, School of Medicine, Sismanoglio Hospital, National and Kapodistrian University of Athens, Athens, Greece; 4 Department of Urology/General Surgery, Areteion Hospital, Athens, Greece; 5 Clinic of Dermatology, Dr. Brinkmann, Schult & Samimi-Fard, Gladbeck, Germany.

Correspondence Mohamad Moussa, MD mohamadamoussa@hotmail.com Head of Urology Department, Zahraa Hospital, University Medical Center, Lebanese University, Beirut, Lebanon Mohamad Abou Chakra, MD (Corresponding Author) mohamedabouchakra@hotmail.com Faculty of Medicine, Department of Urology, Lebanese University, Beirut, Lebanon, 1108 Athanasios Papatsoris, MD agpapatsoris@yahoo.gr 2nd Department of Urology, School of Medicine, Sismanoglio Hospital, National and Kapodistrian University of Athens, Athens, Greece. Athanasios Dellis, MD aedellis@gmail.com Department of Urology/General Surgery, Areteion Hospital, Athens, Greece Yasmine Moussa, MD moussa.yasmin@yahoo.com Clinic of Dermatology, Dr. Brinkmann, Schult & Samimi-Fard Barbarastraße 15, 45964 Gladbeck, Germany

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

PRESENTED

AT THE

SIEUN CONGRESS ANCONA 30 NOVEMBER - 1 DECEMBER 2020 DOI: 10.4081/aiua.2021.1.88

ORIGINAL PAPER

MRI/US fusion prostate biopsy in men on active surveillance: Our experience Vito Lacetera 1, Angelo Antezza 2, Alessio Papaveri 2, Emanuele Cappa 1, Bernardino Cervelli 1, Giuliana Gabrielloni 1, Michele Montesi 1, Roberto Morcellini 1, Gianni Parri 1, Emilio Recanatini 1, Valerio Beatrici 1 1 Azienda

Ospedaliera Ospedali Riuniti Marche Nord, Division of Urology, Pesaro, Italy; Politecnica delle Marche-Azienda Ospedaliera Ospedali Riuniti Torrette di Ancona, Italy;

2 Università

Summary

Aim: The upgrading or staging in men with prostate cancer (PCA) undergoing active surveillance (AS), defined as Gleason score (GS) ≥ 3+4 or more than 2 area with cancer, was investigated in our experience using the software-based fusion biopsy (FB) Methods: We selected from our database, composed of 620 biopsies, only men on AS according to criteria of John Hopkins Protocol (T1c, < 3 positive cores, GS = 3+3 = 6). Monitoring consisted of PSA measurement every 3 months, a clinical examination every 6 months, confirmatory FB within 6 months and then annual FB in all men. The suspicious MRI lesions were scored according to the Prostate Imaging Reporting and Data System (PI-RADS) classification version 2. FB were performed with a transrectal elastic free-hand fusion platform. The overall and clinically significant cancer detection rate was reported. Secondary, the diagnostic role of systematic biopsies was evaluated. Results: We selected 56 patients on AS with mean age 67.4 years, mean PSA 6.7 ng/ml and at least one follow-up MRI-US fusion biopsy (10 had 2 or 3 follow-up biopsies). Lesions detected by MRI were: PIRADS-2 in 5, PIRADS-3 in 28, PIRADS-4 in 18 pts and PIRADS-5 in 5 patients. In each MRI lesion, FB with 2.1 ± 1.1 cores were taken with a mean total cores of 13 ± 2.4 including the systematic cores. The overall cancer detection rate was 71% (40/56): 62% (25/40) in target core and 28% (15/40) in systematic core. The overall significant cancer detection rate was 46% (26/56): 69% (18/26) in target vs 31% (8/26) in random cores. Conclusions: The incidence of clinical significant cancer was 46% in men starting active surveillance, but it was more than doubled using MRI/US Target Biopsy 69% (18/26) rather than random cores (31%, 8/26). However, 1/3 of disease upgrades would have been missed if only the targeted biopsies were performed. Based on our experience, MRI/US fusion target biopsy must be associated to systematic biopsies to improve detection of significant cancer, reducing the risks of misclassification.

KEY WORDS: Fusion Biopsy; MRI-US guided Fusion Biopsy; Prostate Cancer; Active Surveillance. Submitted 14 January 2021; Accepted 27 January 2021

INTRODUCTION

Active surveillance (AS) is currently the most rapidly growing management strategy for men with low risk prostate

cancer (PCA). Aim of AS is to defer or avoid treatments preventing the side effects after active treatments (urinary incontinence and erectile dysfunction) (1). Biopsy criteria for AS vary from one protocol to another: in the original AS was offered only for men with small Gleason score (GS) 3+3 = 6 PCA according to Epstein criteria of indolent PCA (2-3), but now in few programs the criteria include men with more extensive GS 3+3 = 6 lesions and even some with GS 3+4 (5). Upgrading beyond the low-risk cancer found initially has been reported in 35-45% during the first year of follow-up using systematic biopsies (SB) (6, 7). Early disease upgrading likely indicates that the initial biopsy findings were inaccurate therefore a more accurate characterization of prostate pathologic findings from the beginning of AS (and during follow-up) would be desirable. Magnetic resonance imaging and MRI-US fusion biopsy (FB) has been shown to help characterizing pathologic findings more accurately than SB, leading to improved detection of significant PCA. Use of this new biopsy method has not yet fully evaluated among men undergoing active surveillance (7-9). We present our experience using MRI-US FB in men undergoing AS of PCA.

MATERIALS

AND METHODS

This retrospective single center study included 620 consecutive patients who underwent FB between May 2016 and January 2019. We selected from our database only patients on AS. All patients had at least one suspicious lesion at mpMRI, that were performed in different centers as it often happens in community setting without a central review. The suspicious lesions were scored according to the PI-RADS classification v.2. FB were performed with Koelis™ system (Koelis, Meylan, France), using Koelis Trinity™ platform.Koelis™ system creates a precise and highly detailed 3D map of the prostate integrating 3D ultrasound, elastic fusion and Organ-Based Tracking®. All the biopsies considered in the study were performed with a transrectal approach, as reported in our initial experienceby 3 experienced urologists dedicated to FB (10). Biopsy were performed and specimens collected according to Italian guidelines (11). PCA was considered clinically significant in case of findings of No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

MRI/US fusion prostate biopsy

Figure 1. Fusion + systematic biopsy in a patient on Active Surveillance: 3 targets on a PIRADS 3 lesion in TZa right middle gland and 13 random cores avoiding the previous tracks (blue cores). Results: 2 positive cores GS 3+3 = 6 on target lesion, AS was continued.

Figure 2. Anterior-posterior view shows the target core inside the anterior TZ PIRADS 3 lesion at MRI.

Figure 3. Confirmatory biopsy in a 54 yo patient on AS: Fusion biopsy (6 target and 6 sistematyc cores) was PCA positive in 3/6 cores (GS 4+3 = 7). Patient undergone to RARP (Final pathology confirmed a GS = 4+3 = 7 pT2R0N0).

pts; PIRADS 5 = 5 pts. 46 pts had only 1 confirmatory FB, 7 pts had 2 follow-up FB, 3 pts had 3 follow-up FB. Mean cores from each MRI target lesion were 2.1 ± 1.1; mean total cores were 13 ± 2.4. Overall PCA detection rate was 71% (40/56); overall significant PCA (Gleason Score > = 3+4) detection rate was = 46% (26/56); PCA in target core = 62% (25/40); PCA in random core = 28% (15/40); significant PCA in target cores = 69% (18/26); significant PCA in systematic core = 31% (8/26) (as summarized in Table 2). Table 1. Characteristics of the patients.

Gleason score > 6, or more than 2 cores of Gleason score 6 (or more than 1 core outside the target) as suggested by criteria of many AS protocols. The overall and clinically significantcancer detection rate (oCDR, cs CDR) of Koelis™ system was obtained. Secondary the diagnostic role of additional SB was evaluated (Figures 1-3).

RESULTS

We selected from our database 56/620 patients on AS with at least 1 follow-up FB. The characteristics of the 56 patients (summarized in Table 1) were: mean age 67.4 years (CI ± 8.8); mean PSA 6.7 ng/ml ± 3.1; mean prostate volume 49.2 ± 21 ml. Lesions detected by MRI: PIRADS 2 = 5 pts; PIRADS 3 = 28 pts; PIRADS 4 = 18

Number of patients Age (years), mean (CI) PSA (ng/ml), mean (CI) Prostate volume (ml), mean (CI) PIRADS of targets (maximum score in case of multiple targets) PIRADS 2 PIRADS 3 PIRADS 4 PIRADS 5 Mean target cores Mean total cores

56 67.4 ± 8.8 6.7 ± 3.1 49.2 ± 21 5 28 18 5 2.1 ± 1.1 13 ± 2.4

Table 2. Results. Characteristic Overall PCA detection rate Significant PCA detection rate PCA detected in target cores PCA in detected in systematic cores Significant PCA detected in target cores Significant PCA detected in systematic cores

Number 71% (40/56) 46% (26/56) 62% (25/40) 28% (15/40) 69% (18/26) 31% (8/26)

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

V. Lacetera, A. Antezza, A. Papaveri, et al.

DISCUSSION

Among the devices used for FB, Koelis™ is supported by severalrobust evidences (12-14), showing a CDR ranging from 48% to 80%. We compared our results with Nassiri et al. (15), who analyzed 259 men (196 with GS 3+3 and 63 with GS 3+4) who were diagnosed by MRI/US FB (period 20092015) and who underwent subsequent FB for as long as 4 years of AS: 63% of men with GS 3+4 were upgraded by the third surveillance year, compared with 18.0% of men with initial GS 3+3 (p < 0.01). Moreover, 97% of all upgrades (32/33) occurred within an MRI-visible or a tracked site of tumor, rather than a previously-negative systematic site. Jayadevan et al. (17) analyzed men with a new diagnosis of Gleason grade Group (GG) 1 PCA (period 2009-2017). The initial diagnostic biopsy was performed by various methods in community settings and within one year from diagnosis, all the men underwent confirmatory FB. Confirmatory biopsy and all follow-up biopsies were performed using a MRI-guided biopsy system. The end point was a finding of at least GG3 disease during follow-up, which then excluded those patients from active surveillance. Of 332 patients in the total cohort of AS, 114 had normal findings on confirmatory biopsy, 175 had GG1 disease, and 43 had GG2 disease. There were 39 patients (11.7%) with upgrading to at least GG3 during the study period with 43% of upgraded cases detected only by target biopsies (TB) and 46% d only by SB. Thus, if only one biopsy method was implemented, at least 43% of disease upgrades would have been missed. Similar findings were seen in Improvement in the Detection of Aggressive Prostate Cancer by Targeted Biopsies Using Multiparametric MRI Findings (MRI-FIRST) and the Prospective Assessment of Image Registration in the Diagnosis of Prostate Cancer (PAIREDCAP) trials (17, 18). An analysis of patients undergoing AS by Frye et al. (19) at the National Cancer Institute also found that the combination of SB and TB should be used during AS followup, given that only 30% of pathologic disease upgrades were identified by SB alone. The efficacy of the combination of both biopsy techniques has been recently confirmed a by Klots et al. (20) and Ma et al. (21). In order to reduce side effects of systematic biopsy, several non-invasive strategies has been proposed (22). The PSA-density, as supported by Roscigno et al. (23), was used with a cut-off ≥ 0.20 ng/mL to improve the predictive accuracy of mpMRI results for reclassification of patients in AS, whereas a PSAD value < 0.10 ng/mL identifies a lower risk of harboring clinically significant cancer. Nowadays, the combination of target and SB represents the standard for patients on AS; our study strengthens this recommendation, showing that additional random cores improved the overall CDR of 28% and clinically significant CDR of 31%.

CONCLUSIONS

FB represents a useful tool to address many of the limitations of contemporary systematic biopsy. According to most recent evidences and our experience, we believe

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

that MRI/US fusion biopsy improve overall cancer detection rate, clinical significant cancer detection rate and risk stratification among men on active surveillance. Our data suggest that confirmatory and follow-up fusion biopsies with MRI guidance when associated to SB provide a more accurate risk assessmentin order to reduce the oncological risks of AS.

REFERENCES

1. Cooperberg MR. Active surveillance for low-risk prostate cancer - an evolving international standard of care. JAMA Oncol. 2017; 3:1398-1399. 2. Gasparrini S, Cimadamore A, Mazzucchelli R, et al. Pathology and molecular updates in tumors of the prostate: towards a personalized approach. Expert Rev Mol Diagn. 2017; 17:781-789. 3. Montironi R, Santoni M, Mazzucchelli R, et al. Prostate cancer: from Gleason scoring to prognostic grade grouping. Expert Rev Anticancer Ther. 2016; 16:433-40. 4. Mazzucchelli R, Galosi AB, Lopez-Beltran A, et al. Pathological issues in biopsy specimens of men with prostate cancer eligible for active surveillance. Arch Ital Urol Androl. 2014; 30;86:314-8. 5. Klotz L. Active surveillance for prostate cancer: overview and update. Curr Treat Options Oncol. 2013; 14:97-108. 6. Dinh KT, Mahal BA, Ziehr DR et al. Incidence and predictors of upgrading and upstaging among 10,000 contemporary patients with low risk prostate cancer. J Urol. 2015; 194:343-349. 7. Barrett T, Haider MA. The. emerging role of MRI in prostate cancer active surveillance and ongoing challenges. AJR Am J Roentgenol. 2017; 208:131-139. 8. Elkhoury FF, Simopoulos DN, Marks LS. Targeted prostate biopsy in the era of active surveillance. Urology. 2018; 112:12-19. 9. Kasivisvanathan V, Rannikko AS, Borghi M, et al. PRECISION Study Group Collaborators. MRI-targeted or standard biopsy for prostate-cancer diagnosis. N Engl J Med. 2018; 378:1767-1777. 10. Lacetera V, Cervelli B, Cicetti A, et al. MRI/US fusion prostate biopsy: our initial experience. Arch Ital Urol Androl. 2016; 88:296-299. 11. Fandella A, Scattoni V, Galosi A, et al. Italian Prostate Biopsies Group: 2016 Updated Guidelines Insights. Anticancer Res. 2017; 37:413-424. 12. Baco E, Rud E, Eri LM, et al. A randomized controlled trial to assess and compare the outcomes of two-core prostate biopsy guided by fused magnetic resonance and transrectal ultrasound images and traditional 12-core systematic biopsy. Eur Urol. 2016; 69:149-156. 13. Ukimura O, Gross ME, de Castro Abreu AL, et al. A novel technique using three-dimensionally documented biopsy mapping allows precise re-visiting of prostate cancer foci with serial surveillance of cell cycle progression gene panel. Prostate. 2015; 75:863-71. 14. Mozer P, Rouprêt M, Le Cossec C, et al. First round of targeted biopsies using magnetic resonance imaging/ultrasonography fusion compared with conventional transrectal ultrasonography-guided biopsies for the diagnosis of localised prostate cancer. BJU Int. 2015; 115:50-7. 15. Nassiri N, Margolis DJ, Natarajan S, et al. Targeted biopsy to detect Gleason score upgrading during active surveillance for men with low versus intermediate risk prostate cancer. J Urol. 2017; 197:632-639. 16. Jayadevan, et al. Magnetic resonance imaging–guided confirma-

MRI/US fusion prostate biopsy

tory biopsy for initiating active surveillance of prostate cancer JAMA Netw Open. 2019; 2:e1911019. 17. Rouvière O, Puech P, Renard-Penna R, et al. MRIFIRST Investigators. Use of prostate systematic and targeted biopsy on the basis of multiparametric MRI in biopsy-naive patients (MRIFIRST): a prospective, multicentre, paired diagnostic study. Lancet Oncol. 2019; 20:100-109. 18. Elkhoury FF, Felker ER, Kwan L, et al. Comparison of targeted vs systematic prostate biopsy in men who are biopsy naive: the Prospective Assessment of Image Registration in the Diagnosis of Prostate Cancer (PAIREDCAP) study JAMA Surg. 2019; 154:811-818. 19. Frye TP, et al. Magnetic resonance imaging-transrectal ultrasound guided fusion biopsy to detect progression in patients with existing lesions on active surveillance for low and intermediate risk prostate cancer. J Urol. 2017; 197:640-646.

20. Klotz L, Loblaw A, Sugar L, et al. Active Surveillance Magnetic Resonance Imaging Study (ASIST): results of a randomized multicenter prospective trial. Eur Urol. 2019; 75:300-309. 21. Ma TM, Tosoian JJ, et al. The role of multiparametric magnetic resonance imaging/ultrasound fusion biopsy in active surveillance. Eur Urol. 2017; 71:174-180. 22. Cimadore A, Scarpelli M, Raspolini MR, et al. Prostate cancer pathology: What has changed in the last 5 years. Urologia 2020; 87:3-10. 23. Roscigno M, Stabile A, Lughezzani G, et al The use of multiparametric magnetic resonance imaging for follow-up of patients included in active surveillance protocol. Can PSA density discriminate patients at different risk of reclassification? Clin Genitourin Cancer. 2020; 18:e698-e704.

Correspondence Vito Lacetera, MD (Corresponding Author) vlacetera@gmail.com Emanuele Cappa, MD cappa.emanuele@gmail.com Bernardino Cervelli, MD Bernardo.Cervelli@ospedalimarchenord.it Giuliana Gabrielloni, MD Giuliana.Gabrielloni@ospedalimarchenord.it Michele Montesi, MD Michele.Montesi@ospedalimarchenord.it Roberto Morcellini, MD Roberto.Morcellini@ospedalimarchenord.it Gianni Parri, MD Gianni.Parri@ospedalimarchenord.it Emilio Recanatini, MD Emilio.Recanatini@ospedalimarchenord.it Valerio Beatrici, MD Valerio.Beatrici@ospedalimarchenord.it Urologist, Azienda Ospedaliera Ospedali Riuniti Marche Nord, Pesaro, Division of Urology A.O. Ospedali Riuniti Marche Nord, Piazzale Cinelli 4, 61121 Pesaro (Italy) Angelo Antezza, MD angelo.antezza@yahoo.it Alessio Papaveri, MD alessio.papaveri1@gmail.com Resident in Urology, Università Politecnica delle Marche-Azienda Ospedaliera Ospedali Riuniti Torrette di Ancona (Italy)

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

PRESENTED

AT THE

SIEUN CONGRESS ANCONA 30 NOVEMBER - 1 DECEMBER 2020 DOI: 10.4081/aiua.2021.1.92

REVIEW

Detection limits of significant prostate cancer using multiparametric MR and digital rectal examination in men with low serum PSA: Up-date of the Italian Society of Integrated Diagnostic in Urology Andrea B. Galosi 1, Erika Palagonia 1, Simone Scarcella 1, Alessia Cimadamore 2, Vito Lacetera 3, Rocco F. Delle Fave 1, Angelo Antezza 1, Lucio Dell’Atti 1 1 Division

of Urology, School of Medicine, Università Politecnica delle Marche, Ancona, Italy; of Pathology, School of Medicine, Università Politecnica delle Marche, Ancona, Italy; 3 Division of Urology, Azienda Ospedaliera Marche Nord, Pesaro, Italy. 2 Division

Summary

Reasons why significant prostate cancer is still missed in early stage were investigated at the 22nd National SIEUN (Italian Society of integrated diagnostic in Urology, Andrology, Nephrology) congress took place from 30th November to 1st December 2020, in virtual modality. Even if multiparametric magnetic resonance (MR) has been introduced in the clinical practice several, limitations are emerging in patient with regular digital rectal examination (DRE) and serum prostate specific antigen (PSA) levels approaching the normal limits. The present paper summarizes highlights observed in those cases where significant prostate cancer may be missed by PSA or imaging and DRE. The issue of multidisciplinary interest had been subdivided and deepened under four main topics: biochemical, clinical, pathological and radiological point of view with a focus on PI-RADS 3 lesions.

KEY WORDS: Prostate cancer; Prostate needle biopsy; Radical prostatectomy; Diagnosis; Magnetic Resonance Imaging. Submitted 9 January 2021; Accepted 21 January 2021

INTRODUCTION

The present paper summarizes highlights in the field of prostate cancer (PCa) focusing on significant types that do not rise serum PSA, those that are undetected by imaging or those that are unpalpable. This issue rises several implications such as development of early PCa and limitations in cancer detection using updated technologies (1, 2). The knowledge is useful for patient and physician information before any further invasive diagnostic procedure such as biopsy or before any therapy of concurrent benign prostatic hyperplasie (BPH) (3). The believes of most men is that every cancer is detected if we use magnetic resonance given that prostatic specific antigen (PSA) and digital rectal examination (DRE) may miss sometimes early cancer, therefore prostate mpMR (magnetic resonance) imaging is extremely required even if is not clinically indicated. As examples of this we refer to two clinical scenarios commonly observed in clinical practice: the first, is T1b PCa detected after BPH surgery in patients with in-range PSA and normal DRE, the second, the inci-

dence of those significant PCa undetected in screening trials that are even now responsible of specific mortality and are called “escapes cancers”. The occurrence of one of the above scenarios is overwhelming for the patients and unpredicted for the physician. Then we addressed limitations and reasons to understand why early significant cancer may be still missed nowadays. These issues of multidisciplinary interest had been subdivided and deepened under four main arguments: the radiological point of view, biochemical and clinical point of view, pathological point of view and focus on PI-RADS 3 lesions: transition zone (TZ) vs peripheral zone (PZ). Biochemical and clinical point of view Evaluate the presence of PCa in case of men with low PSA level is a new challenge to reduce the mortality due to PCa and increase the detection in case of disease risk. The National comprehensive cancer network (NCCN) (version 2020.1) described the low level of PSA as the presence of a serum PSA < 3 ng/ml according to Beckman standard, which cut-off is 4.0 ng/ml. This value translated to WHO is 3.0 ng/ml. Over time the international guidelines changed dramatically based on results of milestone studies by Thompson et al. (4). They presented a clinical trial in which 9459 men were analysed for a PCa Prevention Trial (PCPT): 2950 men presented a PSA level < 4.0 ng/ml and negative DRE. All the population received biopsy at the end study per protocol. The prevalence of PCa was 15.2% in the group with low PSA level and the incidence of csPCa is summarized in Table 1. That means that there is a csPCa also in patients with low PSA level. To limit the number of patients to undergo prostate biopsy other clinical evaluations need to be considered: DRE, imaging, prostate volume, age and genetic risk. Advantage must be balanced to probability of prostate biopsy complications (5). Digital rectal examination and PSA The decision to do a prostate biopsy can change after the DRE. Based on this fact, Halpern et al. analysed the DRE of 35,350 men and stratified the results by PSA level and No conflict of interest declared.

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

Significant prostate cancer with low PSA

Table 1. Correlation of PSA level, prostate cancer (PCa) and high grade PCa (Gleason score ≥ 7) (from Thompson et al. 2004). PSA level ng/ml

3.1-4 2.1-3.0 1.1-2.0 0.6-1.0 < 0.5

Men with PCa (n = 449)

26.9% 23.9% 17.0% 10.1%

6.6%

Men with high grade PCa (Gleason Score ≥ 7) (n = 67)

25%

12.5%

19.1% 11.8%

10%

DRE positivity (6). Overall, the incidence of clinically significant PCa was higher in men with suspicious DRE independently of the PSA level. Furthermore, the results highlight that in patients with PSA level between 3-4.9 ng/ml the positivity of DRE increased the risk of clinically significant PCa from 9.2% to 15.7%; in patients with a level between 2-2.9 from 3.5% to 6.5%; between 1-1.9 ng/ml from 1.2% to 2.3% and in patients with a PSA < 1 ng/ml from 0.2% to 0.7%. Positive DRE is correlated with cancer even at low level of PSA. Age and PSA Another important aspect is the age of this men and how the time could influence the probability of develop PCa. In particular, a study analysed the probability of men to develop a PCa after 25 years from the first assessment (7). In the range from 37 to 42 years of age with a low PSA level the risk to have a PCa metastasis after 25 years increased with concentrations in the highest 10th of PSA (≥ 1.3 ng/ml) and the highest quarter of PSA (≥ 0.9 ng/ml). In the range of 45 to 49 years of age the risk to develop cancer metastasis or to die for PCa increased in patients with a PSA level in the highest decile (≥ 1.6 ng/ml) and the highest quarter of PSA ≥ 1.1 ng/ml. PSA velocity Lifelong PSA trend can help for rigorous follow-up of young men. This evaluation is called PSA Velocity (PSAV) and calculates how quickly PSA rises over time. The increase in PSA is greater in patients who have a higher risk of developing a lethal PCa (8). There is a cut-off level of 0.35 ng/ml per year of PSAV which could individualize patients with the risk of death from PCa. Men having a PSAV above 0.35 5 to10 years before the diagnosis of the tumor, had a relative risk of PCa death of 10.7 compared to men with a lower PSAV. These results were confirmed extending the retrospective analysis to 15 years, with a relative risk of 4.7. Moreover, Vickers et al. assessed that only 8% of men with a PSA < 2.5 ng/ml and negative DRE had a PSAV over 0.35 ng/ml/year and that in this population the risk to develop a PCa was 18% while in a population with a lower PSAV the risk was 14% (9). However, the risk of csPCa is not high in both the two groups. These considerations can help us to better evaluate and follow certain young patients with normal PSA and negative DRE. PSA density and mpMR PSA Densisty (PSAD) is obtained dividing serum total PSA value by prostate volume calculated by imaging (transrectal ultrasound or mpMR) (10). Since 1990, the PSAD enhanced the specificity of cancer detection in men with a normal DRE and an intermediate PSA level (11). Recently,

several studies demonstrated that the combination of PSAD and mpMRI findings allows the better risk stratification in a cohort of biopsy-naive and previously negative biopsy patients. Pagniez et al. increased the negative predictive value of mpMRI from 84.4% to 90.4% by using the PSAD with a cut off of 0.15 ng/ml/cc (12). Even in cancer active surveillance an emerging body of evidence is growing. Roscigno et al. evaluated the role of PSAD in identifying patients presenting a different risk of reclassification at confirmatory or follow-up biopsy: higher PSAD was associated with higher risk of reclassification for all PI-RADS lesions (13). PSAD was an independent predictor of reclassification using 0.20 as cut-off. Furthermore, Bhat et al. showed that none of the patients in active surveillance presented a risk of disease reclassification in case of PI-RADS scores of 1 to 3 and PSAD 0.15 ng/mL/cc as upper limit (14). PSAD might spare some men from the morbidity associated with a prostate biopsy and diagnosis of low-grade prostate cancer, therefore should be included in the flow-chart of prostate cancer diagnosis. Low or normal PSA and mpMR The negative predictive value (NPV) of mpMR is variable: in literature there are many studies that report a NPV more than 80% and others that set this value around 60% (15). The main variable to set NPV is the type of population taken into account for the analysis. If we considered a population with a low risk of PCa the NVP is 50%, this means that a negative mpMRI in a patient halves the risk of PCa, but a very high residual risk remains. On the other hand, in a population with a high risk of PCa, the mpMRI can even reach a NPV of 88%. The patient's baseline risk must be valuated and there are calculators used to determine the patient's risk (by example, Prostate Cancer Risk Calculators) (16). Long-term NPV has been addressed in a recent study: 84% of patients with negative mpMR were free of cancer even after 4 years of follow-up, whereas 16% developed PCa although only 4% developed a csPCa (17). Characterization of the familiar history and genetic There are men with low PSA level, negative mpMRI and unpalpable disease with PCa (18). These men have usually familiar history of PCa and undergo premature serial PSA exams, clinic visits, and rectal examination. The genetic tests are suggested in men with one brother or father or two or more male relatives with one of the following: diagnosed with PCa at age less than 60 years (recommended), any of whom died of PCa (recommended), any of whom had metastatic PCa (recommend) (19). Genetic testing should be considered in men with family history of 2 or more cancers in hereditary breast and ovarian cancer, or Lynch syndrome in any relatives on the same of the family (especially if diagnosed at age < 50 years) (20). The BRCA2 mutation leads to a three times greater risk of death (21). There are many other important aspects of genetics that have been identified over the years by numerous studies. First, carriers of BRCA1 and mostly BRCA2 mutations are at high risk of developing PCa. Germline mutations in the BRCA genes, mainly in BRCA2, also have implications in the prognosis and management of the disease, with mediArchivio Italiano di Urologia e Andrologia 2021; 93, 1

A.B. Galosi, E. Palagonia, S. Scarcella, A. Cimadamore, V. Lacetera, R.F. Delle Fave, A. Antezza, L. Dell’Atti

an cause-specific survival (CSS) for carriers of 2.1 years compared with 12.4 years for non-carriers (22). Secondly, Lynch syndrome is a type of inherited cancer syndrome associated with germline mutations mainly in the MSH2 and MSH6 genes; affected individuals are at an increased risk for colorectal cancer but also for other associated tumors including utero and ovary, stomach and small bowel, pancreas, ureter or renal pelvis, biliary tract, brain and prostate. The risk of developing PCa in this patients is twofold higher than general population (23). Criteria of hereditary PCa from John Hopkins University (JHU) included at least 3 first-line relatives with PCa or cases of PCa in three generations, as well as 2 relatives with PCa < 56 years of age (24). Approximately 8% of young PCa patients have hereditary PCa. The recommendation of the National Comprehensive Cancer Network (NCCN) is to use Next Generation Sequencing to sequence the multigene panel, which includes at least BRCA1, BRCA2, ATM, BRIP1, CHEK2, NBN, HOXB13, MLH1, MSH2, MSH6 and PMS2 (25). Men with age between 45-75 years with PSA < 1 ng/mL, DRE normal or PSA 1-3 ng/ml and DRE normal are often underestimated, this led to correctly frame the patient who needs annual checks for PCa early detection. However, a personalised risk-adapter strategy for early detection PCa could be associated with an important risk reduction of over-diagnosis and over-biopsy (26, 27). Pathological point of view: Definition of csPCa Although Epstein criteria have a suboptimal accuracy for predicting significant PCa, the pathological concept of significant prostate cancer is a lesion with volume of > 0.2 ml, a Gleason Grade ≥ 7 or extraprostatic extension (28), The index lesion is defined as the larger and/or containing high grade tumor (pattern 4 or 5) (29). These values were defined assessing 185 patients who underwent radical prostatectomy with a median of five years follow-up in which Epstein et al. demonstrated that none of the patients with palpable tumors clinical T2 with a volume < 0.2 cc had extra-prostatic extension (EPE) or biochemical recurrence (BCR) (30). However, there was a high incidence of multifocal PCa and consequently summing the volumes of many small prostate tumors would result in a total volume higher than 0.2 ml, although actually there is no evidence that these smaller multifocal tumors impact on the prognosis of the index tumor (31). In the era of cognitive guided fusion biopsies, in the last years several studies showed that imaging driven biopsy help to target the cancer properly increasing the grading assessment through biopsy (32, 33). PCa is considered a paradigm of morphologic heterogeneity and the role of the pathologist and of biopsy technique assumes great importance for the choice of treatment and appropriate follow-up (26). Grade Group 1 (Gleason score 3+3 = 6), pathologically composed of individual discrete wellformed separated glands, is very homogeneous with an excellent prognosis (34, 35). In a population of 20845 men with clinically localized PCa treated by radical prostatectomy in four different American Hospitals, Epstein et al. did not observe distant metastasis or cancer-specific mortality in a subgroup of more than 6000 men with organ-confined and negative

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

margins with pure Gleason score 6 disease; the risk of progression in this group is approaching 0% (36). Despite these results, we must consider that not all tumors that “look good” from a clinical point of view (PSA < 3 ng/ml, negative DRE, negative transrectal ultrasound, PI-RADS 3 at mpMR) are also good from the histological and molecular point of view. Kamoun et al. subdivided prostate tumors in three different genetical signatures profiled on DNA methylation, SNP arrays and mRNA arrays. Molecular subtype “S2” tumors, which mainly included ISUP group 1 and 2, present with TMPRSS2-ERG fusions with constancy in other molecular subgroups and were also characterized by an almost total absence of mutations in PTEN, in the phosphoinositol kinase pathway and in p53. However a little percentage of ISUP 3 and 4 tumors was represented also in this class (37). Cribriform histology and intraductal carcinoma While pure Gleason score 6 prostate cancers have an excellent outcome in terms of progression, absence of distant metastasis and disease-free survival, areas of cribriform pattern 4 histology, intraductal carcinoma and PCa with reactive stroma are characterized by aggressive genetic alterations and worse oncological outcomes. Presence of pattern 4 with cribriform histology must be reported because its presence and its quantitative representation (in terms of percentage) aggravate prognosis (38). Cribriform can be confused by an inexperienced pathologist with other histotypes like glomeruloid glands, fused glands and poorly formed glands. Hollemans et al. distinguished cribriform type into two groups: small cribriform (< 12 lumina) and large cribriform (> 12 lumina): patients with large invasive cribriform growth belong to a more aggressive subgroup with an increased risk for biochemical recurrence and metastasis (39). Intraductal carcinoma (IDC-P) is pathologically recognized by its cribriform or solid growth pattern distending preexistent acini and prostatic ducts with preservation of basal cells; in most cases IDC-P is closed associated to presence of high grade PCa and high volume cancers (40). Percentage of grade 4, grade 4 cribriform pattern and the presence of intraductal carcinoma at biopsy have an important impact on the prognosis. The presence of intraductal growth or invasive cribriform cancer at biopsy outperforms percentage Grade 4 in predicting outcome of Gleason score 3+4 = 7 PCa: in 370 men with GS 3+4 = 7 prostatic cancer was demonstrated that invasive cribriform and/or intraductal carcinoma are independent parameters for BCR after radical prostatectomy, while percentage of Gleason group 4 is not. The majority of IDC-P derived from adjacent highgrade invasive carcinoma via retrograde spreading of cancer cells along benign ducts and acini; a small group of IDC-P may represent the transformation of precancerous intraductal proliferation induced by various oncogenic alterations (41). The prevalence of IDC-P increased significantly from 2.1% in low-risk patient up to 56.0% in metastatic or recurrent PCa patients (42). Interestingly, in patients treated with androgen deprivation therapy (ADT) or chemotherapy, IDC-P was reported in 60% of PCa indicating that IDC-P may correlate with the development of castration-resistant prostate cancer.

Significant prostate cancer with low PSA

PCa with reactive stroma Another important overview is focused on PCa with reactive stroma (also called stromogenic PCa), that is, by definition, composed by at least 50% reactive stroma (stroma/epithelium ratio ≥ 1). The prototypic “stromogenic” carcinoma is of the classic acinar subtype, with well-formed glands surrounded by an evident amount of stroma. This pathological feature is correlated with a worse prognosis; in samples with high reactive stroma, metabolites and genes linked to immune functions and extracellular matrix remodeling are significantly upregulated (43). PSA - Negative prostatic tumors PSA has been used as serum marker for PCa screening in the male population, but its specificity is low due to its production by normal epithelial tissue. PSA antibody is currently used in immunohistochemistry to determine whether tumor masses of unknown origin can be assigned to a prostate cancer. However, some prostatic tumors do not express PSA in immunohistochemistry and do not determine increases in PSA levels in the blood (34). In poorly differentiated tumors or metastatic foci, PSA expression might be decreased or even lost. PCa with neuroendocrine differentiation often lost PSA expression (44). More specific markers such as PSMA and NKX3.1 are now available to overcome the limited sensitivity of PSA (Figure 1) (45). Moreover, other tumor types, although rare, such as prostatic stromal and smooth muscle tumors, both benign and malignant, solitary fibrous, neural, germ cell, hematopoietic and melanocytic tumors, can form a palpable mass in the prostate, without giving an increase of the serum PSA (46). PSA screening alone is not sufficient to exclude a prostatic tumor; a physical inspection with digital rectal examination is highly recommended and should not be replaced by a PSA screening alone. Figure 1. Hematoxylin & Eosin-stained section of a prostate cancer bone metastasis (A) with a focal expression of PSA (B) and a diffuse and strong expression of PSMA (C) and NKX 3.1 (D).

The role of mpMR According to the most recent update of the European Urology Association Guidelines, the introduction of mpMR in the diagnostic pathway in all patients with PSA elevation leads to significant improvement of clinically significant PCa detection (2). The lesion detected by imaging is then targeted by biopsies under the guide of MRI/ultrasound fusion technology. This increases the detection of csPCa, lowering the detection of insignificant disease. Also “biopsy naïve” patients have a benefit with a MR evaluation. However, it is of outmost importance that a negative MR does not exclude the possibility of significant PCa. Moreover, deciding whether or not is safe to avoid a biopsy in a naïve patient with negative imaging should also rely on PSAD, digital rectal evaluations, nomograms, new biomarkers and family history (10). The PROMIS study showed that the use of mpMRI reduces of a 5% the detection rate of indolent cancers lowering the need of biopsy in 27% of patients (47). Moreover, the application of mpMR/TRUS fusion biopsy technology increased of a 18% the rate of diagnosis of csPCa compared to the traditional systematic biopsy. The need of systematic biopsy is underlined by several studies that reported a significant percentage (5% up to 16%) of csPCa missed by MR-guided biopsy. Results found by Rouvière et al. highlighted the role of systematic biopsy to detect csPCa in men with abnormal PSA and negative imaging/DRE (48). They stated that the mpMR in biopsy naïve patients can improve csPCa detection rate using target biopsy plus concurrent systematic biopsy. Any differences in detection rate of high grade cancers (ISUP grade ≥ 2) was observed between targeted and systematic biopsies, but they found a significant improvement (plus 5% up to 7%) using the combination of both techniques (48). Are we ready to avoid biopsy in negative mpMR? Yes, since the benefit is reduced in both detection of indolent disease and number of men undergoing biopsy. However, from 5% to 20% of csPCa have negative mpMR imaging (49). This rate of undetected csPCa should guide the clinician to the best tailored strategy for the single patient balancing monitoring versus early biopsy approach in terms of morbidity of biopsy and delayed cancer diagnosis. In patients with PSA below the limit and normal DRE, the mpMR is not indicated and not supported by Guidelines (2). Therefore, based on available knowledge, the use of mpMR as a screening tool in patients with normal PSA and negative DRE must be discouraged. The negative predictive value (NPV) of mpMR changes significatively in relation to the risk of PCa in a population, where the incidence of cancer is low (normal PSA) the diagnostic performance dropped significatively to 50%, while in high risk is up 88%. To improve the NPV of mpMR in men with normal PSA, other factors such as genetic, PSAD or PSAV should be evaluated to select those men with higher risk to have cancer (50). A recent and very interesting study estimated the risk to detect cancer over the time after a negative mpMR at baseline (17). After 4 years of follow-up, they found 84% of patients remained free of cancer and overall 16% Archivio Italiano di Urologia e Andrologia 2021; 93, 1

A.B. Galosi, E. Palagonia, S. Scarcella, A. Cimadamore, V. Lacetera, R.F. Delle Fave, A. Antezza, L. Dell’Atti

developed PCa but only 4% csPCa. Although of its several limitations (e.g. control group, highly selected cases in referral centre), this study shows that a negative mpMR predict a lower risk over the time to develop csPCa: 4% (1 man every 20) compared to 8% of calculated risk for a man to be diagnosed with clinically significant PCa throughout his lifetime. Limits of mpMR Despite the wide acknowledged improvements cited in the previous paragraph and being advocate as the reference standard for prostate radiological imaging, mpMR is not exempt from drawbacks. According to Quon et al., mpMR missed up to 20% of csPCa lesions or underestimated its size (51). After a second-look of MR imaging, 58% of the missed lesions were not confirmed as benign findings. In fact, this technique needs further implementations to reduce inter-observer variability and to reduce false negative rates. The radiologist's experience is shown to be a key factor in imaging interpreting and PCa recognition. A recent study analysed the different reports of 9 radiologists on the same mpMRI by comparing their experience (52). Among PI-RADS 2 results, the possibility of finding clinically significant PCa in the biopsy ranged from 15 to 35%. The detection of any type of PCa in PI-RADS 2 ranged from 15 to 75%. In 2018 Johnson et al. analysed the mpMRI performed on 588 patients before radical prostatectomy, using a 3 Tesla MRI in a single institution with expert radiologists (48). Overall, the mpMRI detected 541 out of 1213 pathologic lesions, which represent a sensitivity of 45%, a positive predictive value of 81% and a false positive rate of 19%. Therefore larger (> 0.5 ml), high grade and solitary tumors were more likely to be detected. Comparing mpMR and surgical specimens, 90% of the non-csPCa were missed, but also the 40% of Gleason Score 3+4, the 26% of Gleason Score 4+3 and the 22% of Gleason Score ≥ 8. In a recently published review, Chatterjee et al. found that the inter-observer variability and lack of standardisation in reporting radiological findings are the most important interpretative drawbacks (53). They described a variety of interpretative and technical pitfalls that influenced negatively mpMR performances: 1) different anatomic features can simulate PCa such as the anterior fibromuscular stroma, the periprostatic venous plexus and the pseudocapsule of the Transitional Zone (TZ); 2) others histologic benign conditions such as inflammation and prostatitis, could mimic PCa; 3) postbiopsy haemorrhage, prostatic calcifications associated with benign prostatic hyperplasia nodules in the transitional zone; 4) technical artifacts or image distortion due to endorectal coil placements and motion artefacts. The low-intensity T2 signal and the heterogeneity of enhancement patterns in the peripheral zone are reported to reduce the diagnostic yield of mpMR (53). Improvements of MR imaging: PI-RADS 2.1 The first version of the Prostate Imaging Reporting and Data System (PI-RADS v1) released in 2012 by the European Society of Urogenital Radiology and then updated to Version 2.0 in 2015 has been considered and

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

adopted as the reference standard tool to report and early detect PCa. The most reported limit of this scoring system is the inter-reader concordance ratio (moderate), which limits the diagnostic performance of this system. Moreover, despite technological improvements, the study of the transition zone remains challenging if compared to the peripheral zone due to the presence of benign hyperplasia as a mimic of PCa (2). In 2019 the PI-RAD system was updated to version 2.1 with leading changes regarding the transition zone mpMRI conundrum (54). The most important ones are: 1) the definition of atypical nodules in the TZ and the downgrading to category score 1 of the completely encapsulated nodules (encapsulated or homogeneous circumscribed defined as PI-RADS 2 in the previous category system); 2) the characterisation of these nodules trough diffusion weighted imaging (DWI) features to improve detection and localization of PI-RADS 3 areas. Focus on PI-RADS 3 lesions in the TZ vs PZ MRI lesions PI-RADS 3 are termed as “equivocal” for the presence of clinically csPCa. PI-RADS 3 represents a “grey zone” that needs to be further investigated to solve the issue of biopsy or not biopsy. They could be malignant lesions but mostly they are benign lesions or nonsignificative cancer (55). The PI-RADS version 2 uses a 5-point scale based on the likelihood (probability) that a combination of mpMR findings on T2-weighted imaging (T2W), diffusion-weighted imaging (DWI), and dynamic contrast enhancement (DCE) correlates with the presence of a clinically significant cancer depending on cancer volume (> 0.5 ml), location and background tissue within the prostate gland. The Peripheral Zone (PZ) of the prostate has a high risk of develop prostate cancer compared to the Transizion Zone (TZ). Therefore, doubtful MR imaging (defined as PIRADS 3) has different diagnostic value taken into account prostatic anatomical zones. This is supported by Yang et al. who analyzed cancer detection rate in 683 patients with PI-RADS 3 lesions of the PZ and TZ (56). They reported 37% cancer detection and 18.7% of csPCa in the PZ, while in the TZ the overall cancer detection was 16.4% and the rate of csPCa was 6.0%. Furthermore, using a PSAD greater than 0.15 and age greater than 68 years, they calculated that 24% of biopsy could be omitted by losing only one csPCa, with a sensitivity of 80% and a negative predictive value of 92.3%. They conclude that significant cancer is uncommon in TZ and the active surveillance is the optimal choice, especially among patients without risk factors such as those with low PSAD. Many studies report that mpMR is very reliable as a negative predictive value, but it depends on prevalence of disease in the population studied and the a priori risk of developing disease. Since, PI-RADS 3 does not identify the same risk of cancer in different prostate zones, the predictive value of PI-RADS 3 should be considered as low in the TZ respect to PZ. However, the estimating of the predictive value of PIRADS 3 lesions has methodological bias because it do not represent the primary endpoint of published studies,

Significant prostate cancer with low PSA

Figure 2. as Maggi et al. very recently underlined after an extensive review (57). In 28 studies with Clinical pathway in biopsy naïve patient with PI-RADS 3 lesions. 10.176 patients (56.5% with PCa and 40.0% with csPCa), 1,759 men with targeted biopsies on PI-RADS 3 lesions were retrieved: the overall rate of csPCa detection was 36% and 18.5%. The combination technique (targeted and systematic biopsy) has the better detection rate of 37% versus the 24% of exclusive targeted biopsy. There is no significantly relevant difference between version 1 and version 2 of PI-RADS in the detection of prostate cancer (57). However, they did not differentiate the cancer detection comparing prostatic zones. Byun et al. evaluated the PI-RADS v2.1 diagnostic performances and inter-reader agreement on the PCa detection in the TZ comparing results with the previous version (58). Their results demonstrated that the last version has both higher sensitivity and specificity for the overall detection of PCa for category higher than 3 lesions, independently of against saving biopsies (side effects) and overdiagnosing the prostatic zone. Furthermore, they reported a reducof insignificant PCa on an individual basis. tion of proportion of category 3 lesions, while the detecVan Der Sar et al. investigated retrospectively outcomes tion rates of csPCa at this cut-off value significantly such as window of curability and complication and costs increased accordingly with the inter-reader agreement. of clinical surveillance compared to immediate biopsy Same findings were confirmed by Wang et al. that also (63). All outcomes were not influenced by both stratesuggested that PI-RADS version 2.1 improves the overall gies as well as the risk profile of the cancers appeared detection rates of PCa, specifically in the TZ zone, comsimilar. pared to v2.0 (54). The large part of patients preferred clinical surveillance Recently, several studies evaluated the role of PSAD as (57%) compared to immediate biopsy (43%). Frye et al. predictive variable to predict csPCa in PI-RADS 3 monitoring PI-RADS 3 lesions in active surveillance lesions: a cut-off 0.15 ng/ml/cc was the most significant reported a rate of progression of 20% precisely on the positive predictive value for detect csPCa. Hansen and area of the target lesion PI-RADS 3 compared to 29% of Ullrich et al. confirm that the choice to execute biopsies overall progression (64). in the group of PI-RADS 3 with PSAD > 0.15 ng/ml/cc Therefore, we can assume that defer the biopsy in PIpermit to avoid 53.4% of biopsies in this population of RADS 3 lesion in the TZ can be a safe strategy, as we sugpatients (59, 60). Also Venderink et al. calculated that gested in a flow-chart summarized in the Figures 2, 3. 42% patients with PI-RADS 3 lesions and PSAD less than 0.15 could avoid biopsy with the loss of only 6% of cs PCa (95% Figure 3. C.I. 2-15) (61). Lowering the cut-off to Clinical pathway in biopsy negative patient with PI-RADS. 0.12 they spared 26% of avoidable biopsies without losing any csPCa (61). Schoots et al. reviewed the probability of csPCa in PI-RADS 3 lesions observed in biopsy naïve, previous negative biopsy, and active surveillance patients: they retrieved 21%, 16% and 17% of csPCa, respectively (62). They focused on size of the lesion: PI-RADS 3 lesions in both peripheral zone (PZ) and transition zone (TZ) greater than 10 mm should be re-classified as PI-RADS 4 according to their results. Other than diameter, the decision to proceed with the biopsy must include clinical elements such as PSAD, PSAV and previous biopsies. The risk of missing csPCa must be discussed with the patients and balanced Archivio Italiano di Urologia e Andrologia 2021; 93, 1

A.B. Galosi, E. Palagonia, S. Scarcella, A. Cimadamore, V. Lacetera, R.F. Delle Fave, A. Antezza, L. Dell’Atti

In conclusion the management PI-RADS 3 lesion should be based on shared decision to immediate biopsy or follow-up considering the following points: 1) estimation of prostate cancer risk based on nomograms and risk calculators, 2) use carefully mpMR in patients with low risk of csPCa and normal PSA, 3) MR should be done in quality checked centers (controlled incidence of PI-RADS 3 lesions and correlation between radiological and pathological finding), 3) lower urinary tract symptoms 4) use of PSAD, anatomical zone (TZ vs PZ), and family history. All those factors should be taken into account and patient should be involved in the final decision to perform a fusion prostate biopsy.

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63. van der Sar ECA, Kasivisvanathan V, Brizmohun M, Freeman A, Punwani S, Hamoudi R, et al. Management of radiologically

Correspondence Andrea B. Galosi, MD (Corresponding Author) a.b.galosi@univpm.it Department of Clinical Sciences, Politecnica delle Marche University Via Conca 71, 60126 Ancona, Italy Erika Palagonia, MD erika.palagonia@gmail.com Simone Scarcella, MD simoscarc@gmail.com Rocco F. Delle Fave, MD checcoboss90@gmail.com Angelo Antezza, MD angelo.antezza@yahoo.it Lucio Dell’Atti, MD dellatti@hotmail.com Division of Urology, School of Medicine, Università Politecnica delle Marche, Ancona (Italy) Alessia Cimadamore, MD a.cimadamore@staff.univpm.it Division of Pathology, School of Medicine, Università Politecnica delle Marche, Ancona (Italy) Vito Lacetera, MD vito.lacetera@gmail.com Division of Urology, Azienda Ospedaliera Marche Nord, Pesaro (Italy)

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Archivio Italiano di Urologia e Andrologia 2021; 93, 1

PRESENTED

AT THE

SIEUN CONGRESS ANCONA 30 NOVEMBER - 1 DECEMBER 2020 DOI: 10.4081/aiua.2021.1.101

ORIGINAL PAPER

Robot-assisted segmental ureterectomy with psoas hitch ureteral reimplantation: Oncological, functional and perioperative outcomes of case series of a single centre Erika Palagonia 1, 2, 3, Simone Scarcella 1, Lucio Dell’Atti 1, Giulio Milanese 1, Peter Schatteman 2, 3, Frederiek D’Hondt 2, 3, Geert De Naeyer 2, 3, Andrea Galosi 1, Alexandre Mottrie 2, 3 1 Division

of Urology, United Hospital of Ancona, School of Medicine Marche Polytechnic University, Ancona, Marche, Italy; Academy, Melle, Belgium; 3 Department of Urology, Onze Lieve Vrouw Hospital, Moorselbaan 164, 9300, Aalst, Belgium. 2 ORSI

Summary

Introduction: According to the Urology guidelines, in selected cases of distal upper tract urothelial carcinoma (UTUC) segmental ureterectomy (SU) can be offered. There is no consensus in the surgical technique of preference. Robot-assisted SU could be an option to overcome all the limitations of open and laparoscopic techniques. We describe our first experience of robot assisted SU with psoas hitch ureteral reimplantation (RAPHUR). Materials and methods: 11 patients underwent RAPHUR for distal UTUC between 2013 and 2017 in a single centre. Pre-, intra-, and postoperative outcomes were assessed. Conventional imaging was performed after 1, 3, 6 months and 1 year from surgery as follow up protocol. We retrospectively evaluated the technical feasibility, oncological and functional outcomes. Results: Median age was 71 years (57-91). The median length of the ureteral defect was 23 mm (10-40). Median preoperative creatinine level was 1.22 mg/dl (0.7-1.85) and median eGFR was 57.5 ml/min/1.73m2 (31-80). Five (45.5%) patients were symptomatic and 7 (63.6%) had hydronephrosis. Median operative time was 185 min (120-240), with a median blood loss of 100 ml (50-300). No case required conversion to open surgery. Overall, only 1 (9%) patient developed Clavien Dindo ≥ 3 postoperative complications. Average hospital stay was 7 (2-9) days. Mean postoperative creatinine was 1.05 mg/dl (0.8-1.85) and mean postoperative eGFR was 72 (36-83). During a median follow up time of 25.5 months (12-53), 4 (36.4%) patients experienced recurrence of urothelial cancer at conventional imaging follow up and 2 (18.2%) died due to its progression. Conclusions: In our initial experience RAPHUR can be proposed to selected cases of distal ureteral carcinoma with optimal perioperative and functional outcomes. However, cancer control may be undermined compared to nephroureterectomy. Thus, further prospective studies are needed to confirm our findings.

KEY WORDS: Robotics; Segmental ureterectomy; Ureter; Urothelial carcinoma; Psoas hitch reimplantation. Submitted 9 January 2021; Accepted 21 January 2021

INTRODUCTION

Open radical nephroureterectomy represents the treatment option for the management of distal upper tract urothelial carcinoma (UTUC) (1, 2). However, segmental

ureterectomy (SU) with ureteral reimplantation could be an option in selected cases with low grade distal ureteral tumour or impaired renal function and high grade distal UTUC (2-4). In these cases, the ureteral reimplantation became challenging due to the reduction of length of the ureter necessary for oncological radicality. The advent of robotic surgery with its 3-D magnified view, 7 degree of freedom and steadiness of instruments and camera, allowed to overcome the limitations of the conventional laparoscopic and open approaches for the reconstruction. Thank to this more complex robotic tension-free ureteral reimplantation procedures have been described, such as Psoas Hitch (PH) techniques (5). The feasibility and safety surgical profile of the robotassisted SU with ureteral reimplantation was reported by several authors (6-12). However, some of these studies focused on surgical technique and functional outcomes concentrating patients with heterogeneous aetiology and short follow up. While other studies focused on oncologic outcomes with no consistent on surgical technique considered. Under this light, we aim to assess intra-, peri-, postoperative and oncological outcomes of a single centre series of patients with distal UTUC, exclusively treated with RAPHUR tension-free reimplantation, with a minimum follow-up of one year. The safety of the procedure was evaluated in agreement with the standardized methodology to report complications proposed by European Association of Urology (EAU) guidelines (13).

MATERIALS

AND METHODS

Study population We retrospectively analyzed 11 patients with distal UTUC treated with RAPHUR between October 2013 and 2017. All patients presented non-metastatic disease. All surgeries were performed by two surgeons with extensive experience in robotic surgery. The study protocol was approved by the institutions’ medical ethics committees and all patients provided informed consent. Surgical techniques of Robot-assisted segmental ureterectomy with Psoas Hitch ureteral reimplantation The ureter is identified at the bifurcation of the common

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

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E. Palagonia, S. Scarcella, L. Dell’Atti, G. Milanese, P. Schatteman, F. D’Hondt, G. De Naeyer, A. Galosi, A. Mottrie

iliac artery and cautiously mobilized caudally until the identification of the disease segment. After mobilization of the bladder, the segment of the ureter involved by cancer is clipped before its dissection in order to avoid tumor seeding, then the disease segment is dissected and sent for frozen section. A formal bladder cuff is excised for oncological radicality and a regional lymph nodes dissection is also performed. The ureter is spatulated anteriorly for 2 cm. To perform a PH, a 2-0 non-absorbable suture is used to fix the external part of the ipsilateral dome of the bladder to the psoas muscle and its tendon. This allows to perform a tension-free reimplantation and to provide a strong and durable fixation with a low risk of genito-femoral nerve and iliac vessel injury (14). A longitudinal incision of 3-4 cm is made at the level of the bladder dome along the anterolateral surface. The ureter is spatulated and inserted inside a sub-mucosal tunnel developed at the cranial part of the bladder. Then a mucosa to mucosa anastomosis is performed using 4-0 Monocryl suture in a running way. A double J stent is placed in a retrograde fashion using a guide wire. Thereafter, the bladder is closed with 30 cm 2-0 V-lock suture in double layer. Variable definition and follow-up Preoperative variables consisted of age at surgery, gender, comorbid conditions (Charlson comorbidity index) (15), previous abdominal surgery, preoperative haematuria, preoperative hydronephrosis at computer tomography (CT) scan, side of the disease, length of the ureteral disease at preoperative CT scan, preoperative symptoms, preoperative serum creatinine and estimated glomerular filtration rate (eGFR). Follow-up consisted of control visit at 1, 6 months and then annually with consecutive serum creatinine, eGFR analysis and clinical evaluation of symptoms. Conventional imaging such as abdominal CT scan, abdominal ultrasound and cystoscopy were performed to exclude cancer recurrence after 1 month, 3, 6 months and yearly or in case of lower urinary tract symptoms and haematuria after surgery. Study outcomes and statistical analysis Intraoperative outcomes (operative time, blood loss, intraoperative complications) were assessed and reported according to Satava classification, perioperative outcomes (length of stay, urinary catheter and stent removal) were also assessed (16). Intermediate-term postoperative functional outcomes (postoperative serum creatinine and eGFR), hydronephrosis at conventional imaging and presence of symptoms were also evaluated. Postoperative complications were collected according to Clavien-Dindo (CD) classification system, moreover the quality criteria of accuracy recommended by the EAU guidelines on reporting and grading of complications were fulfilled (Supplementary Table 1) (13). 90-day readmission rate was also evaluated. Pathological reports were assessed. Cancer recurrence and mortality was assessed. Medians and ranges, as well as frequencies and proportions were reported for continuous or categorical variables, respectively. For all statistical analyses, SPS software environment for statistical computing was used.

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Table 1. Baseline characteristics. Variables Age (yr), median (range) Gender, n (%) • Male • Female Charlson comorbidity index, n (%) 0 1 ≥2 Abdomen previous surgery, n (%) Aetiology, n (%) • Low-stage urothelial tumour • High-stage urothelial tumour Side, n (%) • Left • Right Length disease (mm), median (range) Preoperative hydronephrosis at CT scan, n (%) Preoperative haematuria, n (%) Pre-operative symptoms, n (%) • Yes • No

Overall (n = 11) 71 (57-91) 9 (81.8) 2 (18.2) 2 (18.2) 3 (27.3) 6 (54.5) 9 (81.8) 6 (54.5) 5 (45.5) 8 (72.7) 3 (27.3) 23 (10-40) 7 (63.6) 4 (36.4) 5 (45.5) 6 (54.5)

Table 2. Intraoperative and perioperative outcomes. Post-operative outcomes. Intra and perioperative outcomes Variables Operating time (min), median (range) Blood loss (ml), median (range) Intra- operative complications, n (%) Length of stay (days), median (range) Catheter removal (days), median (range) Stent removal (days), median (range) Post-operative outcomes Variables 90-day postoperative complications Clavien ≥ II, n (%) Post-operative Creatinine (mg/dL), median (range) Post-operative eGFR (mL/min/1.73 m2), median (range) Post-operative hydronephrosis, n (%) Readmission, n (%)

Overall (n = 11) 185 (120-240) 100 (50-300) 0 7 (2-9) 10 (2-20) 21 (15-44) Overall (n = 11) 2 (18.2) 1.05 (0.8-1.85) 72 (36-83) 1 (9) 1 (9)

Table 3. Summary of 90 day postoperative complications. Overall complications (n = 4) 36.4% Category Type of complication Clavien Dindo I Prolonged catheterization due to leakage at cystography (n = 3, 27.3%) Transitory sensory loss of the leg (femoral or saphenous nerve damage) Clavien Dindo III IIIa: Lymphocele* treated with percutaneous drainage (n = 1, 9%)

N 1 2 1**

*Lymphocele was defined as any clearly definable fluid collection and was considered clinically significant when requiring treatment. Ultrasound examination was used to detect lymphoceles. ** Patient readmitted.

RESULTS

All the descriptive characteristics of the study population are recorded in Table 1. Median follow-up was 25.5 months (12-53). Nine (81.8%) patients were male and 2

Robot-assisted ureterectomy with ureteral reimplantation

(18.2%) female. Disease side was right in 3 (27.3%) patients and left in 8 (72.2%). Median age was 71 years (57-91). The median length of the ureteral defect was 22.6 mm (10-40 mm). Median pre-operative creatinine level was 1.2 mg/dl (0.72-1.50) and median estimated glomerular filtration rate (eGFR) was 58,00 ml/min/1.73m2 (3180). 5 (45.5%) patients were symptomatic, 4 (36.4%) presented macrohematuria and 3 (27.3%) had ipsilateral flank pain. 7 (63.3%) had preoperative hydronephrosis at abdomen CT scan. Median operative time was 185 min (120-240), with a median blood loss of 100 ml (50-300) (Table 2). All surgeries were completed without conversion to open technique. No intraoperative complications were recorded. Overall, 1 (9%) of the patients developed a postoperative complication classified with Clavien Dindo ≥ 3, the patient developed a lymphocele after few weeks from surgery and he was readmitted to the hospital to insert a percutaneous drainage through radiological intervention (Table 3). Median hospital stay was 7 (2-9) days. The VAS score was optimal (0) at discharge moment. Bladder catheter was removed after cystogram and with a median of 10 (2-20) days while the double J ureteral stent was Table 4. Pathological report and oncologic outcomes. Pathological report pTa n (%) pT1 n (%) pT2 n (%) pT3 n (%) N0 n (%) N1 n (%) N2 n (%) Positive surgical margins Oncologic outcomes Cancer recurrence n (%) Adjuvant chemotherapy n (%) Trans-urethral resection n (%) Mortality n (%)

G1 G2 G2 G3 G3 G3

3 (27.3) 1 (9) 2 (18.2) 2 (18.2) 1 (9) 2 (18.2) 10 (89) 0 1 (9) 0 4 (36.4) 3 (27.3) 3 (27.3) 2 (18.2)

removed after a median of 21 (15-44) days. Median postoperative creatinine was 1.05 mg/dl (0.8-1.85) and median postoperative eGFR was 72 ml/min/1.73m2 (36-83). Pathological stage was pTa in 4 (36,4%) cases, pT1 in 4 (36.4%) cases, pT2 in 1 (9%) case and pT3 in 2 (18.2%) cases (Table 4). Only 1 (9%) patient had positive lymph nodes after surgery (pT2 N2). No positive surgical margins were found. During a median follow up time of 25.5 (12-53) months, 4 (36.4%) patients experienced recurrence of urothelial cancer at conventional imaging or cystoscopy. Three (27.3%) of these cases experienced intravesical cancer recurrence, and the patients underwent trans-urethral resection. Adjuvant chemotherapy was performed on 3 (27.3%) patients. Two (18.2%) patients died due to its progression; 1 (9%) patient died due to cardiological problems after 1 year from surgery.

DISCUSSION

The International Associations of Urology identified open radical nephroureterectomy as the gold standard treatment for UTUC (1). However, evidences showed how the management of UTUC should be individualized to tumor’s risk and patient’s characteristics. In this scenario the kidney sparing surgery could be an option in selected cases with low grade distal ureteral tumor or impaired renal function and high grade distal UTUC, thus SU gives the similar oncological outcomes with the advantage of renal function preservation (2-4). In these cases, the ureteral reimplantation became challenging due to the reduction of length of the ureter necessary for oncological radicality. With the advent of robotic surgery, and the advantages it brings, its use for UTUC management is increasingly widespread worldwide. Our first experience of distal UTUC treated with robot assisted SU and subsequent psoas hitch ureteral reimplantation provides new data confirming the feasibility and safety profile of this procedure in selected cases. Furthermore we fulfilled the 14-item standardized reporting tool for postoperative complications as supported by EAU guidelines (13). Unlike the study of Campi et al. on robotic SU and robotic nephroureterectomy our study standardized the surgical

Supplementary Table 1. Postoperative complications: quality criteria for accurate and comprehensive reporting of surgical outcome. Criteria 1. Define the method of accruing data* 2. Define who collected the data 3. Indicate the duration of follow-up* 4. Include outpatient information* 5. Include mortality data and causes of death* 6. Include definitions of complications* 7. Define procedure-specific complications* 8. Report intraoperative and postoperative complications separately 9. Use a severity grading system for postoperative complications* 10. Postoperative complications should be presented in a table either by grade or by complication type 11. Include risk factors* 12. Include readmissions and causes 13. Include reoperations, types and causes 14. Include the percentage of patients lost to follow-up

Retrospective data collection based on chart review and patient interview Data were collected by dedicated data manager 90 d Outpatient information were collected Mortality and cause of death were collected Complications were defined as any deviation from the ideal postoperative course Procedure-specific complications were defined and collected Intraoperative and postoperative complications were reported separately The Clavien-Dindo system was used Postoperative complications were presented in a table by complication type The Charlson Comorbidity-index was prospectively collected for all patients. Data on readmissions were collected Data on reoperation, types and causes were collected 0 patients were lost to 90d follow up

*Outcomes in common with the Martin Criteria.

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RAPHUR, RABFUR, Single ureteral end-to-end centre anastomosis, 3 surgeons Lich Gregoir, ureteroneocystostomy

RAUR, RAPHUR, Multicentre (2) endo-to end anastomosis, (nephroureterectomies and nephroureterectomies)

RAUR, RAPHUR, RABFUR

Musch et al 2013

Hemal et al. 2010

Schimpf et al. 2009

Single centre

44: 18 (distal) 12 (proximal) 10 (ablative) 4 (miscellaneous)

20 (robotic): 6 (RAPHUR) 85 (laparoscopic) 25 (open)

35 RAPHUR

Ureteroneocystostomy, Single RAPHUR, RABFUR centre 5 surgeons

centre

6: 1 (RAPHUR)

4: 2 (RAPHUR)

6 (robotic)

Not reported

reported

Not

Not reported

Median: 236 (219-305) of 20 robotic

(184–254) of 10 pts

Median: 224

Mean: 268.5 (188–400)

Not reported

Mean and median: 189 (145-240) overall

Mean: 190 (160-240) of 5 pts

overall

Mean 1.6

Mean: 1.8 (1-2)

Mean: 81 (25-300) overall

Mean: 100 of 5 pts

Mean: 2.4 Median 2 (1-5) overall

Mean 3,5 of 5 pts

Median: 7.5 (5-35) overall

Median: 100 Median: 2 (63-200) (2-4) of of 20 robotic 20 robotic

50 (25-100) overall

Median:

Mean: 72.5 (< 30–150)

25% of 4 pts Median: 250 Not (153-320) reported Median: 320 (218-320) lymphadenectomy)

Not reported

10 pts

40% of

16.7

Not reported

28-56

reported

Not

7 to 10

Not reported

Median: 12 42 days (1-53 range) overall

Mean: 10 of 5 pts

Median: 11 Not reported overall

Range (7-10)

Not reported

Median: 4 Median: 38 Median: 8 of 20 robotic (29-45) of 20 (8-10) of robotic 20 robotic

overall

Median: 6

Mean: 33 (28–39)

Not reported

27 overall

4.5 overall

75 overall, 100 of 4 pts

Not reported

Not reported Not reported (9,5% of major complications)

3.6 overall

16.6

60, overall

Not reported

Δ Creatinine median: 0

Not reported

0 (radionuclide scintigraphy)

Not reported

(hydronephrosis)

3 pts

Not reported

ΔeGFR: -1

Not reported

Postoperative functional outcomes (mean serum creatinine and eGFR)

Single

Elsamra et al. 2014

Study

55 (robotic):

Procedure

RABFUR, end-to end anastomosis, Ureterolysis, Ureterolithotomy

Centre (n)

RAUR, RAPHUR,

Overall number of patients (n)

Fifer

Number of patients treated for distal UTUC

et al. 2014

Length of the stricture mm (median or mean) Not reported

Hydronephrosis and/or ureteral stenosis at postoperative imaging

4: 3B (RAPHUR)

TCC Recurrence rate (%)

6 (robotic)

Operative time (min)

Ureteroneocystostomy, Single RAPHUR, centre Ureteroureterostomy

Blood loss (ml)

McClain et al. 2012

LOS (days) Median: 4 (3–7) Median: 21 Not reported (14–38)

Follow up (months)

Median: 180 (100–210)

Stent time (days)

46,7% of 15 Median: 140 pts 26,7% (110–220) intravescical 20% ipsilateral ureter

Catheter removal (days)

17 (10–46)

Post-operative complications rate (%)

RNU, RAPHUR, Multicentre (3), 81 (robotic): 10: Ureteroneocystostomy 8 surgeons 15 (ureterectomy) 4 (RAPHUR) 66 (nephroureterectomy)

Post-operative symptoms evaluated with VAS score

Campi et al. 2019

E. Palagonia, S. Scarcella, L. Dell’Atti, G. Milanese, P. Schatteman, F. D’Hondt, G. De Naeyer, A. Galosi, A. Mottrie

Table 5. Series on distal ureteral robotic reimplantation for UTUC.

Robot-assisted ureterectomy with ureteral reimplantation

procedure of ureteral reimplantation after SU (9). Indeed, they presented 15 patients who underwent robot-assisted SU, out of them 5 patients were treated with primary ureteroureterostomy, 4 with ureteroneocystostomy, 4 with psoas hitch ureteroneocystostomy and 2 were tumor of the pelvis treated with robotic pyeloplasty (9). This factor generalizes the feasibility and safety results of the surgical technique but confirms that SU can be a valid option in terms of oncological outcomes. Previously McClain collected a series of robotic SU with long follow up, demonstrating the efficacious and durable management of robotic surgery on distal UTUC, but they reported only 6 patients treated with different procedures (10). A direct comparison with other available robotic series on distal ureteral reimplantation is difficult because these studies are clustering outcomes for different ureteral reimplantation techniques and patients with different etiological disease, considering also other pathologies besides urothelial carcinoma (Table 5) (6-8). Furthermore, there is a lack of data in terms of postoperative evaluation (i.e.: symptoms evaluation, functional outcomes, radiologic imaging follow-up, oncological outcomes) which does not allow an adequate analysis of use of robotic platform in case of ureteral cancer. Our study, with a minimum of one year follow-up and complete postoperative data, aims to validate the use of SU exclusively with RAPHUR techniques for distal UTUC, supporting its feasibility, safety and reproducibility. Our results were reported below. First of all, we reported good operative and perioperative outcomes: the median OT, blood loss and LOS were 185 min (range: 120-240 min), 100 ml (range: 50-300 ml) and 7 days (range: 2-9) respectively; median catheter and DJ stent removal were respectively 10 (range: 2-20 days) and 21 days (range: 15-44 days). These findings cannot fairly be compared with other available robotic series given the heterogeneity of the ureteral reimplantation techniques included and the clustering of the outcomes reported (Table 5). Second, we fulfilled the standardized methodology recommended by EAU guidelines on grading and reporting postoperative complications (13) (Supplementary Table 1). This confirms high reliability of data report on postoperative complications. The overall rate of complications was 36.4%. Of these, only one complication requiring additional percutaneous intervention (CD IIIa) for lymphocele drainage. The safety profile of RAPHUR techniques is also supported by the absence of intraoperative complication. All postoperative outcomes (i.e. symptoms, functional outcomes and oncological outcomes) were assessed. Renal function improved with a D = 0.2 in median serum creatinine and with median eGFR becoming 72 ml/min/1.73 m2 (range: 36-83) from 58. The VAS score at discharge and last follow-up were acceptable. All these findings strongly confirm that the robotic approach for distal UTUC is feasible and offers an excellent alternative to open surgery in terms of functional and oncologic outcomes with the benefits of minimally invasive surgery. To the best of our knowledge, our study represents the largest series available so far (considering the rarity of the condition) from a single robotic high-volume centre of robot-assisted ureteral reimplantation for distal UTUC exclusively treated with RAPHUR (Table 5). Despite these results, our study has several limitations.

The retrospective nature of the current analysis and the small sample size, considering the rarity of the condition and the exclusivity of the treatment, are the main limitations. Furthermore, there is a lack of a control group treated with open or laparoscopic approach for direct comparison on surgical terms, or a control group of nephroureterectomy for comparison on oncological outcomes. However, it must be considered that the main goal of the current study was to report these refined robotic surgical techniques for distal UTUC with psoas hitch ureteral reimplantation.

CONCLUSIONS

In our experience RAPHUR can be proposed to selected cases of distal ureteral carcinoma of low-grade disease or in patients with impaired renal function and high-grade disease with optimal perioperative, functional and oncologic outcomes. However, cancer control may be undermined compared to nephroureterectomy. Thus, further prospective studies are needed to confirm our findings.

ACKNOWLEDGEMENTS

Thank to Professor Alexandre Mottrie, the ERUS Educational Working Group and the YAU working group on robot-assisted surgery.

REFERENCES

1. Margulis V, Shariat SF, Matin SF, et al. Outcomes of radical nephroureterectomy: A series from the upper tract urothelial carcinoma collaboration. Cancer. 2009; 115:1224-33. 2. Mazzucchelli R, Scarpelli M, Galosi AB, et al. Pathology of upper tract urothelial carcinoma with emphasis on staging. Vol. 27, International Journal of Immunopathology and Pharmacology. England. 2014; p. 509-16. 3. Colin P, Ouzzane A, Pignot G, et al. Comparison of oncological outcomes after segmental ureterectomy or radical nephroureterectomy in urothelial carcinomas of the upper urinary tract: Results from a large French multicentre study. BJU Int. 2012; 110:1134-41. 4. Jeldres C, Lughezzani G, Sun M, et al. Segmental ureterectomy can safely be performed in patients with transitional cell carcinoma of the ureter. J Urol. 2010 Apr; 183:1324-9. 5. Uberoi J, Harnisch B, Sethi AS, et al. Robot-assisted laparoscopic distal ureterectomy and ureteral reimplantation with psoas hitch. J Endourol. 2007; 21:368-72. 6. Hemal AK, Nayyar R, Gupta NP, Dorairajan LN. Experience with robot assisted laparoscopic surgery for upper and lower benign and malignant ureteral pathologies. Urology. 2010; 76:1387-93. 7. Fifer GL, Raynor MC, Selph P, et al. Robotic ureteral reconstruction distal to the ureteropelvic junction: a large single institution clinical series with short-term follow up. J Endourol. 2014; 28:1424-8. 8. Elsamra SE, Theckumparampil N, Garden B, et al. for Benign and Malignant Ureteral Lesions: A Comparison of Over 100 Minimally Invasive Cases. 2014; 28:1455-9. 9. Campi R, Cotte J, Sessa F, et al. Robotic radical nephroureterectomy and segmental ureterectomy for upper tract urothelial carcinoma: a multi-institutional experience. World J Urol. 2019; 37:2303-11. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

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10. McClain PD, Mufarrij PW, Hemal AK. Robot-assisted reconstructive surgery for ureteral malignancy: Analysis of efficacy and oncologic outcomes. J Endourol. 2012; 26:1614-7. 11. Schimpf MO, Wagner JR. Robot-assisted laparoscopic distal ureteral surgery. JSLS J Soc Laparoendosc Surg. 2009; 13:44-9. 12. Musch M, Hohenhorst L, Pailliart A, et al. Robot-assisted reconstructive surgery of the distal ureter: single institution experience in 16 patients. 2013; 773-83. 13. Mitropoulos D, Artibani W, Graefen M, Remzi M. EAU

Correspondence Erika Palagonia, MD - erika.palagonia@gmail.com Simone Scarcella, MD - simoscarc@gmail.com Lucio Dell’Atti, MD - dellatti@hotmail.com Giulio Milanese, MD - g.milano972@gmail.com Andrea Galosi, MD - galosiab@yahoo.it Division of Urology, United Hospital of Ancona, School of Medicine Marche Polytechnic University Via Conca 71, 60126 Ancona (Italy) Peter Schatteman, MD - peter.schatteman@olvz-aalst.be Frederiek D’Hondt, MD - frederiek.dhondt@olvz-aalst.be Geert De Naeyer, MD - geert.De.Naeyer@olvz-aalst.be Alexandre Mottrie, MD - alexandre.mottrie@olvz-aalst.be Department of Urology, Onze Lieve Vrouw Hospital Moorselbaan 164, 9300 Aalst (Belgium)

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Guidelines on Reporting and Grading of Complications after Urologic Surgical Procedures. 2016. 14. Maldonado PA, Slocum PD, Chin K, Corton MM. Anatomic relationships of psoas muscle: clinical applications to psoas hitch ureteral reimplantation. Am J Obstet Gynecol. 2014; 211:563.e1-6. 15. Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol. 1994; 47:1245-51. 16. Satava RM. Identification and reduction of surgical error using simulation. Minim Invasive Ther Allied Technol. 2005; 14:257-61.

PRESENTED

AT THE

SIEUN CONGRESS ANCONA 30 NOVEMBER - 1 DECEMBER 2020 DOI: 10.4081/aiua.2021.1.107

ORIGINAL PAPER

Buccal mucosa graft in surgical management of Peyronie’s disease: Ultrasound features and clinical outcomes Andrea Fabiani 1, Fabrizio Fioretti 1, Maria Pia Pavia 2, Luca Lepri 1, Emanuele Principi 1, Lucilla Servi 1 1 Urology

Unit, Surgical Department, ASUR Marche Area Vasta 3, Macerata, Italy; Division of Urology, Marche Polythecnic University, Ancona, Italy.

2 Resident,

Summary

Introduction: Plaque incision and grafting represent the best surgical approach to the Peyronie’s Disease (PD). The grafting procedures must be restricted to patients with normal preoperative status, excessive curvature and/or deformities. However, the ideal graft has not been identified yet. Buccal mucosa grafts (BMG) provided excellent short-term results, ensuring the fast return of spontaneous erections and preventing shrinkage, which is the main cause of graft failure. Another fearsome surgical complication is de novo erectile dysfunction (ED). We report our results with BMG focusing on the analysis of ultrasonographic and clinical data demonstrating buccal mucosa as determinant factor that allow to avoid complications. Materials and methods: From 2013 to 2019 we performed at our Urology Unit 27 corporoplasties with BMG to correct complex penile curvature due to PD. Clinical, post-surgical and ultrasound follow up data were evaluated. All patients were no responders to medical treatment or previous surgical procedures. The evaluation period was 72 months. Data regarding pre-operative work-up, including IIEF (IIEF-5) questionnaire administration, detailed clinical history and penile dynamic ultrasound (PGE1-induced erection) were collected. The time of spontaneous erection resumption was recorded for each patient. To improve blood supply to the graft, a low-dose PDE5-i was prescribed for all patients for a period of two months, starting immediately after discharge. Check-ups were scheduled every 3 months, starting from 1 month after surgery. In each visit, patients underwent a penile ultrasound evaluation of graft features. After 6 and 12 months, all patients underwent a penile dynamic ultrasound for Erection Hardness Score determination, then standard ultrasound and clinical evaluation yearly. Our analyses were focused on BMG as a major determinant of the surgical success. Results: Mean age of 27 patients was 57 years (42-71) with a maximum follow up time of 72 months and minimum of 3. Site of penile curvature was dorsal in 18 (67%) patients, ventral in 2 (7%), complex in 7 (26%). The degree of the curvature was < 60° in 11 (41%) patients, > 60° in 16 (59%). Straightening of penis was reached in 100% of cases. Penile shortening resulted in 7.4% (2/27). De novo ED appeared in 2/27 cases with a post-operative rate of PDE5i users increasing from 12 to 14 patients (45% vs 52%). Ultrasound aspects of BMG, recorded at every follow up visit, results in a hypoechoic plaque with an iperechoic rim that become isoechoic over the time in all cases. No case of scars or seroma was registered. Small intra-graft cystic lesions were highlighted in 3 cases (11%). Conclusions: BMG may represent a good choice in grafts pro-

cedures for PD surgical management. The functional results obtained by BMG procedures were related to the good anatomical characteristics of the patch and were highlighted in our series by use of penile ultrasound, during the follow up period.

KEY WORDS: Peyronie’s disease; Buccal mucosa; Ultrasound; Graft; Erectile dysfunction. Submitted 13 January 2021; Accepted 27 January 2021

INTRODUCTION

Peyronie’s disease (PD) is a benign condition causing penile deformities, shortening, loss of penile flexibility and sexual dysfunctions (1). The diagnoses are increasing in number, even in the younger population, because of the increased knowledge about the topic (2). Surgical treatment remains the gold standard and it includes penis plication, grafting, and placement of inflatable prosthesis with the aim to restore coital functions (3). Buccal mucosa grafts (BMG) provided excellent shortterm results, suggested by the early recovery of spontaneous erections and the prevention of late shrinkage, which is the main cause of graft failure. It also seems to be safe and reproducible, thus representing a valuable treatment option for PD. Clinical series are limited yet but functional and cosmetics results are very promising (4). We analyzed our surgical results with the BMG technique applied to 27 patients focusing on the ultrasonographic follow-up and clinical data.

METHODS

From our surgical data base, we evaluated 27 consecutive cases treated with a plaque incision and BMG to correct the secondary penile curvature due to PD. Clinical, postsurgical and ultrasound follow up data were evaluated. All patients were no responders to medical treatment or previous surgical procedures. The evaluation period was 72 months. Data regarding pre-operative work-up, including IIEF (IIEF-5) questionnaire administration, detailed clinical history and penile dynamic ultrasound (PGE1-induced erection) features were collected (5, 6). The surgical procedures were done previous penile degloving and using a relaxing incision (double Y or H shaped) at the point of maximum curvature on the penis. The albuginea defects were covered using BMG grafting

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

107

A. Fabiani, F. Fioretti, M.P. Pavia, L. Lepri, E. Principi, L. Servi

technique (7, 8). The buccal mucosa grafts were harvested as described by Eppley et al. (9). After “defatting”, BMG was apposite to cover the albuginea defect with the submucosa surface in contact with the cavernous tissue in order to obtain a quick blood supply and sutured with a 3/0 adsorbable running sutures (MaxonTM) in each side (Figure 1). Artificial erection was repeated to evaluate the curvature and deformity correction, defining the need of complementary tunica albuginea plications (10). Buck’s fascia was accurately closed with interrupted adsorbable suture, especially in correspondence with the patch site to avoid patch enlargement. In cases of ventral curvatures, urethra was fixed to corpora cavernosa with a tension-free stitches. A small drainage was placed between the Buck’s fascia and the dartos. Circumcisional incision was closed and dressed. Patients were discharged at third post-operative day after catheter, drainage and dressing removal. The time of spontaneous erection resumption was recorded for each patient. To improve blood supply to the graft, a lowdose PDE-5 inhibitor (PDE-5i) was prescribed for all patients for a period of two months, starting immediately after discharge. Check-ups were scheduled every 3 months, starting from 1 month after surgery. In each visit, they underwent a penile ultrasound evaluation of graft feaTable 1. Salient pre-operative clinical data. Number of patients Age (years) Penile curvature degree pre-op Duration of PD (months) IIEF score pre -operative Curvature side PDE5i use pre-op Diabetes mellitus Previous PD surgery Previous radical prostatectomy Dupuytren disease associated Psoriasis Preputial Lichen Sclerosus Cardiovascular disease

27 (100%) 57 (42-71) 61.9°(45-90) 16.5 (6-48) 22.5 (18-24) Dorsal 18 (67%) Ventral 2 (7%) Complex 7 (26%) 12 (45%) 4 (14.8%) 1 (3.8%) 4 (14.8%) 1 (3.7%) 1 (3.7%) 2 (7.4%) 2 (7.4%)

Table 2. Results and complications. RESULTS Mean follow up time (months) Time of spontaneous erections resumption (days) IIEF score post operative at last follow up PDE5i post operative use Functional penile straightening Penile shortening COMPLICATIONS Hemorrage at the donor site Penile shaft hematoma Glandular erection pain Preputial edema Skin necrosis Cystic intra-graft lesions Penile abscess Recurvatum relapse De novo erectile dysfunction

108

(range; %) 28.3 (3-72) 3.2 (1-7) 23.1 (15-24) 14 (52%) 27 (100%) 2 (7.4%) 1 (4.7%) 1 (4.7%) 1 (3.7%) 4 (14.8%) 1 (3.7%) 3 (11%) 1 (3.7%) 0 (0%) 2 (7.4%)

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

Figure 1. Surgical steps for BMG procedures in a case of ventral curvature. A. Buccal mucosa graft harvesting; B. Idraulic erection after penile degloving; C. Urethral isolation; D. Marked transversal incision (double Y) on the plaque; E. Buccal mucosa grafting; F. Final result.

tures. After 6 and 12 months, all patients underwent a penile dynamic ultrasound for Erection Hardness Score determination, then standard ultrasound and clinical evaluation yearly. All consecutive cases who underwent BMG in a 72-month period of time were analyzed. We studied the ultrasonographic appearance of the BMG at 1, 3, 6 and 12 months after surgery and yearly cosmetics and functional outcomes.

RESULTS

We performed 27 procedures in men with mean penile curvature of degree 61.9° (range 45°-90°), mean age 57 years (42-71) and after mean follow-up of 28.3 months (min 3 max 72). The degree of the curvature was < 60° in 11 (41%) patients, > 60° in 16 (59%). Site of penile curvature (degree 61.9° in mean; range 45°-90°), was dorsal in 18 (67%) patients, ventral in 2 (7%), complex in 7 (26%). Pre-operative data and results are summarized in Tables 1, 2. The patient medical history was characterized from different comorbidities recognized as erectile dysfunction (ED) risk factors. Diabetes mellitus was reported in 4 (14.8%) patients; cardiovascular disease in 2 (7.4%), previous radical prostatectomy in 4 (14.8%), preputial lichen sclerosis in 2 (7.4%) and psoriasis in 1. One patient had a failed plication procedure. Pre-operative use of PDE-5i was referred by 12 patients (45%). Pre-operative IIEF score was 22.5 in mean (11-24). After a follow up period of 28.3 months (3-72), we reported a functional straightening of penis reached in 100% of cases. Penile shortening resulted in 7.4% (2/27). All patients had complete spontaneous erections in a period of 1 to 7 days after surgery, however paraphimosis occurred in three cases (14.2%), requiring surgical revision, and one patient (4.7%) develop skin preputial necrosis managed by topical therapy. Post-operative mean IIEF score, at the last follow up was 23.1 (1524). De novo ED appeared in 2/27 cases. Post-operative amount of PDE5i users increasing from 12 to 14 patients (45% vs 52%). Ultrasound was applied at each follow-up visit. Ultrasound features during follow up are showed in

Buccal mucosa and Peyronie’s disease

Figure 2. A. Ultrasound patch (white arrow) appearance 3 months after surgery.

B. Ultrasound patch (green arrow) appearance after surgery (6 months).

Figure 2a, b and Figure 3. In all cases, post-operative images consisted in a hypoechoic plaque with hyperechoic rim, observed in the graft area during the first month after surgery. Progressively, we described the ultrasound disappearance of graft, which has become isoechoic respect the tunica albuginea and not distinguishable from albuginea rim. No case of scars or seroma was registered. Small intragraft cystic lesions highlighted in 3 cases (11%).

DISCUSSION

Severe PD (> 60°) is still treated by surgical approach that leads an efficient solution in a relatively short time (11). In spite of this, results are not devoid of complications, the most serious is the development of de-novo ED, which seems to be caused by complete surgical excision of the plaque (12). Nowadays, plaque incision surgery with grafting is the preferred therapeutic approach (3, 8). In 2005, buccal mucosa was introduced as free autograft in the surgical treatment of PD (13) and then, during the Figure 3. Complete patch disappearance in ultrasound evaluation (star; 6 years after surgery).

Figure 4. Small intra-patch cystic lesion.

years, evaluated in several others series (14-19). Promising results were reported by Shioshvili et al. (13) who observed the complete straightening of penis in 92.3% of 26 patients treated with a residual curvature (< 10°) in 7.7%. The shortening of penis was observed in four patients (15.4%) and in two patients (7.7%) a partial reduction of erectile function. They concluded that buccal mucosa showed high properties of adaptation and revascularization, good anatomical and functional clinical results, demonstrating a stable elasticity without late shrinkage. Similarly, Liu et al. (14) showed that buccal mucosa remained stable with good elasticity over time. They performed replacing the plaque by free autograft of buccal mucosa on 24 patients and obtained satisfactory results: complete penile straightening was achieved in 21/24, slight residual curvature (< 15 degrees) noted in 3 (12.5%), a little shortening of the penis (< 1 cm) in 2 (8.3%). As advancement in term of prevention of de novo ED, Cormio and co-workers (15) introduced important technical modifications consisting in the plaque incision instead of excision. BMG was performed similar than others series. In 15 consecutive surgical procedures they reported a 100% of penile straightening, no curvature recurrence and any de novo ED. These results were confirmed by Zucchi et al. (16) in 32 patients treated with plaque incision and BMG between 2006 and 2013: in 28 cases, they reported one curvature relapse after 1 year (3.5%) and an immediate significant improvement of IIEF scores in half of cases, although after 2 years the trend was in reduction. They concluded that corporoplasty with buccal mucosa represent a good treatment choice for most forms of PD. The complete penis straightening was achieved in 73% of 33 patients by Gvasalia et al. (17), however a residual curvature (< 20°) was observed in 27% and de novo ED in 18%, commonly in elderly patients, but with a good response to PDE-5i. Molina-Escudero et al. (18) reported the short-term results (penile length, angle of curvature and erectile function) of 10 patients treated through corporoplasty with oral mucosa graft. The straightening of penis was reached in 100% with a shortening rate of 80% and 10 % of de novo ED. In our previous experience with 17 cases (19), we reported favorable results. In this series, that take account of 10 more patients passing from 17 to 27 cases, we have similar results with a longer follow-up. All the procedures were performed as the main indication the failure or inability to sexual intercourse and psychological impairment due to the penile curvature. Patients are variably aging, with a medical general history characterized from different comorbidities as, in example, diabetes mellitus, cardiovascular disease, previous pelvic surgical procedure for prostate cancer (Table 1). One patient underwent a previous failed plication procedure. Pre-operative use of PDE5 inhibitors was referred by 12 patients (45%). Recognized that several patients had more risk factors of post-operative ED (baseline sexual function, age, graft size or position) (12), the probability of de novo ED should be higher, than that observed. We obtained a very good functional results with 7.4% of de novo ED and a post-operative increase of PDE5i users to 52% from 45%. In literature the rate of de novo ED ranges between 0% to 18%. These results may be explained by the nature of buccal mucosa that is a living Archivio Italiano di Urologia e Andrologia 2021; 93, 1

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tissue with an elevated binding capacity and revascularization which is immediately supplied with blood from the cavernous tissue. In this way, buccal mucosa tends to heal rapidly, immediately integrating with the surrounding albuginea tissue. This translates into a more rapid resumption of spontaneous erections (mean of 3,26 days in our experience) and sexual activity and into a reduced risk of curvature relapse (20). Penile ultrasound validated these results showing the process of mucosal patch integration with tunica albuginea. Ultrasound has been showed to be a method of choice because his cost effectiveness, repeatability and low invasiveness, if compared to others methods (ie. Magnetic Resonance) (21). US is mainly used in diagnosis and staging of PD. There are only few reports regarding the ultrasound usefulness in the follow up after treatment. In relapses or in dilations patch evaluation, ultrasound is still decisive (22). In our series, US showed that BMG appears initially as hypoechoic plaques with hyperechoic rim (Figure 2a, b) and then evolved in isoechoic over the time. After six years from surgical procedure, we reported a complete disappearance of the patch aspect, confounded with the albuginea (Figure 3). No cases of scars, and consequently, of curvature relapse, or seroma were registered. Small intra-graft cystic lesions highlighted in 3 cases (11%) (Figure 4). Any patch bulging has been reported yet.The perfect seal of BMG and the accurate closure of Buck’s fascia are important key-factors to obtain a successful result. The biologic characteristics of buccal mucosa reduced the risk of curvature relapse as demonstrated by the high rate of penile straightening reported in 100% in our series while is 87.5-100% in literature. Patch ultrasound evaluation confirm these aspects and it is needed in the surgical management of PD.

CONCLUSIONS

The functional results obtained by BMG procedures in PD surgical treatment were related to the great anatomical characteristics of the patch and highlighted in our series by use of penile ultrasound during the follow up period. Ultrasound features confirmed the characteristics of buccal mucosa as perfect seal in the tunica albuginea defect, created after fibrotic plaque incision, allowing to reduce the risk of de novo ED.

REFERENCES

1. Hatzimouratidis K, et al. EAU Giudelines on Erectile dysfunction, Premature Ejaculation, Penile curvature and Priapism. 2018. 2. Paulis G., Cavallini G., Barletta D. et al. Clinical and epidemiological characteristics of young patients with Peyronie’s disease: a retrospective study. Res Rep Urol. 2015; 7:107-111. 3. Hatzimouratidis K, Hatzichristou DG. Plaque incision and grafting represents the best surgical approach to Peyronie’s Disease patient: Con. Current Sexual Health Reports. 2006; 3:56-60. 4. Garcia Gomez B, Ralph D, Levine L, et al. Grafts for Peyronie’s disease: a comprehensive review. Andrology. 2017; 6:117-126. 5. Martino P, Galosi AB, Bitelli M, et al. Practical recommendations for performing ultrasound scanning in the urological and andrological fields.Arch Ital Urol Androl. 2014; 86:56-78. 6. Dell'Atti L, Galosi AB. Ultrasound findings of ruptured Peyronie's

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plaque: Case report and review of the literature. Arch Ital Urol Androl. 2017; 89:85-86. 7. Dell'Atti L, Polito M, Galosi AB. Is Degloving the Best Method to Approach the Penile Corporoplasty With Yachia's Technique? Urology. 2019; 126:204-208. 8. Brant WO, Bella AJ, Garcia MM, et al. Correction of Peyronie’s disease: plaque incision and grafting. BJU Int. 2006; 97:1353-60. 9. Eppley BL, Keating M, Rink R. A buccal mucosal harvesting technique for urethral reconstruction. J Urol. 1997; 157:1268. 10. Dell'Atti L, Scarcella S, Tallè M, et al. Simultaneous curvature correction at the time of the penile fracture repair: surgical and functional outcomes. Res Rep Urol. 2019; 11:105-110. 11. Mulhall J, Anderson M, Parker M. A surgical algorithm for men with combined Peyronie's disease and erectile dysfunction: functional and satisfaction outcomes. J Sex Med. 2005; 2:132-138. 12. Flores S, Choi JM, Alex B, et al. Erectile dysfunction after plaque incision and grafting: short term incidence and predictors. J Sex Med. 2011; 8:2031-37 13. Shioshvili TJ, Kakonashivili AP. The surgical treatment of Peyronie’s disease: replacement of plaque by free autograft of buccal mucosa. Eur Urol. 2005; 48:129-35 14. Liu B, Zhu XW, Zhong DC, et al. Replacement of plaque by buccal mucosa in the treatment of Peyronie’s disease: a report of 27 cases Zhonghua Nan Ke Xue. 2009; 15:45-7. 15. Cormio L, Zucchi A, Lorusso F, et al. Surgical treatment of Peyronie’s disease by plaque incision and grafting with buccal mucosa. Eur Urol 2009; 55:1469-1475. 16. Zucchi A, Silvani M, Pastore AL, et al.Corporoplasty using buccal mucosa graft in Peyronie disease: is it a first choice? Urology. 2015; 85:679-83. 17. Gvasalia B, Kochetov A, Abramov R, et al. Buccal mucosa in the surgical treatment of Peyronie's disease. J Sex Med. 2014; 11(Suppl 1):33. 18. Molina Escudero R, Alvarez-Ardura M, Redon-Galvez L, et al. Cavernoplastia con injerto de mucosa oral para el tratamiento quirurgico de la enfermedad de La peyronie. Actas Urologicas Espanolas. 2016; 40:328-332. 19. Fabiani A, Servi L, Fioretti F, et al. Buccal mucosa is a promising graft in Peyronie’s disease surgery. Our experience and a brief literature review on autologous grafting materials. Arch Ital Urol Androl. 2016; 88:115-121. 20. Costantini E, Zucchi A. Reconstructive surgery in Peyronie’s disease: What’s new? World J Clin Urol. 2015; 4:1-4. 21. Dell'Atti S, Manno S, Scarcella, et al. Analysis of penile ultrasound in Peyronie Disease: Variability and interpretation of sonographic patterns.European Urology Supplements. 2018; 17:e2751. 22. Rolle L, Tamagnone A, Bollito E, et al. Could plaque excision surgery with sis graft induce a new fibrotic reaction in la Peyronie’s disease patient? Arch Ital Urol Androl. 2007; 79:167-169. Correspondence Andrea Fabiani, MD (Corresponding Author) andreadoc1@libero.it Fabrizio Fioretti, MD - fa.fioretti@libero.it Lepri Luca, MD - luca.lepri@sanita.marche.it Emanuele Principi, MD - emanuele.principi@sanita.marche.it Lucilla Servi, MD - lucilla.servi@sanita.marche.it Urology Unit, Surgical Dpt, ASUR Marche Area Vasta 3, Macerata (Italy) Maria Pia Pavia, MD - mariapia.pavia@gmail.com Resident, Division of Urology, Marche Polythecnic University, Ancona (Italy)

PRESENTED

AT THE

SIEUN CONGRESS ANCONA 30 NOVEMBER - 1 DECEMBER 2020

ORIGINAL PAPER

DOI: 10.4081/aiua.2021.1.111

Italian experiences in the management of andrological patients at the time of Coronavirus pandemic Carlo Maretti 1, Andrea Fabiani 2, Fulvio Colombo 3, Alessandro Franceschelli 3, Giorgio Gentile 3, Franco Palmisano 3, Valerio Vagnoni 3, Luigi Quaresima 4, Massimo Polito 5 1 Department

of Andrology, CIRM Medical Center, Piacenza, Italy; of Urology, Surgical Department, Macerata Hospital, Area Vasta 3, ASUR Marche, Macerata, Italy; 3 Andrology Unit, University Hospital S.Orsola-Malpighi, Bologna, Italy; 4 Urology Division at the Civitanova Marche Hospital, Civitanova Marche, Italy; 5 Department of Clinical and Specialist Sciences, Division of Urology, Polytechnic University of the Marche Region Medical School, Ancona, Italy. 2 Unit

Summary

The SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) was first reported in December 2019, then its rapid spread around the world caused a global pandemic in March 2020 recording a high death rate. The epicenter of the victims moved from Asia to Europe and then to the United States. In this Pandemic, the different governance mechanisms adopted by local health regional authorities made the difference in terms of contagiousness and mortality together with a community strong solidarity. This document analyzes the andrological urgencies management in public hospitals and in private practice observed in Italy and in particular in two of the most affected Italian Regions: Emilia-Romagna and Marche.

KEY WORDS: SARS-CoV-2; Pandemic; Andrology; Public hospitals; Private practice. Submitted 9 January 2021; Accepted 21 January 2021

INTRODUCTION

The International Committee on Taxonomy of Viruses (ICTV), responsible for defining the official classification of viruses and the taxonomy of the Coronaviridae family, has officially classified under the name SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) the virus provisionally called by the World Health Organization (WHO) 2019-nCoV and responsible for COVID-19 cases ("CO" stands for corona, "VI" for virus, "D" for disease and "19" indicates the year in which it occurred) (1-3). SARS-CoV-2 was identified for the first time in Wuhan, in the province of Hubei in China. Italy was the first country outside of China involved by pandemic. The Italian Council of Ministers declared the state of emergency from 31.01.2020. The Italian Prime Minister extended some restrictive measures concerning gatherings and movements throughout the national territory with effect from 10th March. This logic of restrictions was above all to reduce the contagiousness (R0) of COVID-19. The WHO declared the world pandemic on 11 March 2020 (4). WHO had warned each country of the risk of the "tsunami" of information, in particular fake news would have led to panic situations (supermarket raids, unnecessary visits to hospital emergency rooms, uncontrolled depar-

tures to other places, riots in prisons, etc.). At the declaration of a pandemic, the WHO added the risk of an “Infodemia”, that is the dissemination of a considerable amount of information, coming from different and often unverifiable sources. Providing the correct information would be an important issue to help and reduce contagiousness and so mortality. SARS-CoV-2 has widely spread in less than three months because of a globally interconnected world. SARS-Cov-2 appears to spare children while older population with concomitant morbidity are severely affected, in particular males (5, 6). The symptomatic picture includes various symptoms according to the evolution of the disease. The symptoms most commonly observed in patients before hospitalization may be fever, chills, dry cough, dyspnea, asthenia, myalgias and/or arthralgias, while nausea and vomit, nasal congestion, hemoptysis, diarrhea, conjunctival congestion are less common (7). This symptomatology can be complicated starting from the third/fourth week, often in a dramatically increasing manner such as to require hospitalization. In severe cases, pneumonia, acute respiratory distress syndrome, sepsis and septic shock, endothelial dysfunction with thromboembolism can occur till to the patient’s death (8). It is important to remember that the patient with SARSCoV-2 can also be asymptomatic or pauci-symptomatic, thus contributing to the spread of the virus in the community (9). In humans, the transmission pathways of the COVID-19 virus are mainly direct, that is, through the respiratory tract with the inhalation of respiratory droplets that are generated when an infected person speaks, coughs or sneezes. Viral transmission can also be indirect, i.e. mediated by inanimate vectors (soil, personal effects, paper sheets, money, plastic or metal surfaces, etc.) and in any case it will depend on the viral load present on that surface. Relatively to the potential COVID-19 sexual transmission, there are no definitive data. The impact on male fertility and the potential of the spermatozoa to serve as vectors for the sexual transmission of this disease are not clear yet, although some biological characteristics of spermatozoa must leave researchers open to these possi-

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

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bilities (10, 11). This document analyzes the various experiences of Italian uro-andrologists in their hospital wards as well as in andrological private urgencies in EmiliaRomagna and Marche, in this lockdown period.

EXPERIENCES IN ANDROLOGY MANAGEMENT IN ITALIAN CENTERS DURING COVID-19 PANDEMIC Department of Andrology, CIRM Medical Center, Piacenza From 30.01.2020 when the Italian Council of Ministers declared a state of health emergency, it was decided to study in details the dynamics transmission of COVID-19 infection, trying to make a critical review of the scientific literature data in order to better manage a possible state of emergency. The perception of an individual threat, is the fear that triggers some physiological reaction of anxiety, which can also generate sexual troubles (erectile dysfunction, for example). Working in the private sector of andrology, it was tried to protect patients and personnel adopting several precautions to limit the contagion (disposable surgical masks, shoe covers, gloves, aprons, headgears and visors). Only urgent visits were scheduled and telematic advice was produced in required cases. On the first days of lockdown there was not any request for andrological visit and the ones previously booked were cancelled by the patients themselves. After about ten days, people with a probable erectile dysfunction of stressogenic nature, began to call for telematic suggestions. It was clear that confinement, the loss of the usual routine, and the reduction of social relationships had increased the sense of insecurity and anguish (12, 13). During the same period most of the urgent visits to males were related to infections (testicular, prostatic, urethral, glans or preputial), probably related to an increased frequency of sexual acts during the lockdown period. The patients were received individually, equipped with disposable PPE (Personal Protective Equipment, the Italian DPI ) waiting alone for their turn. No visits for couple infertility were performed, according to the indication claimed by National Health Authorities regarding the need to stop the search for children. Uro-Andrologic Unit, Policlinico di S.Orsola, Bologna From March 10, due to the measures introduced to limit the spread of the COVID-19, our academic hospital established urgent measures to reduce outpatient procedures, use of operating theatres and non-urgent clinical activity. Initially, the Uro-Andrologic Department has been turned into medical department due to need for the management and treatment of patients with SARS-CoV2; then, Urological procedures were referred to another Centre with limited number of beds, reduction of operating theatres (from four to one per day) and priority for malignancy and obstructive uropathy conditions while andrological activities has been dramatically cancelled except for one case of three-components penile prosthesis reservoir removal for confirmed local infection. To date, no malignancies or other urgent andrological procedures were scheduled during the restriction. In this scenario, the staff of Urology and Andrology Department

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has been used to enhance assistance in the medical departments in order to support the activity of Internists. Outpatient activities were limited to urgent consultations while patients with non-urgent (whenever possible consulted by telephone) have been postponed, pending provisions relating to the end of the lockdown. The psychological impact of the COVID-19 outbreak among the whole and specifically andrological patients is still unknown. As expected, our web and Facebook pages counted an increase in visualization as well as an increasing in requests regarding access to outpatient consultation. Interestingly, most of the patients reported conditions related to psychological burden such as penile enlargement and erectile dysfunction surgery. Department of Surgery, Section of Urology, Macerata Hospital In this public community hospital in the Marche Region, the shift from patient centered medicine to a community centered approach was immediate. The cancellation of the scheduled operating sessions was the consequence of the need to make surgical decision no longer based on individual patients’ needs but on the availability of beds in intensive and sub-intensive care for the management of patients suffering from SARS-CoV-2, mainly from neighboring areas of the northern part of the Region. The immediate cancellation meant the suspension of the surgical treatment of the non-oncological pathologies. In this situation, the andrological surgery, in its vast part, has suffered a drastic stop. Circumcisions, Peyronie’s disease or congenital recurvatum surgeries, varicocele and infertility surgeries, surgical treatment of erectile dysfunction have been cancelled. Urology Division in Macerata Hospital has a 10-bed ward and, normally, 6 full time urologists and 1 resident of the Marche Polytechnic University: before Covid pandemic about 1000 surgical procedures and 4500 visits per year were performed. Our attitude was prompted to define our surgical and outpatient activities by following the provisions elaborated by the reference scientific societies (13-16). However, the feeling was to be neglected by the medical direction regarding priorities in the planning of procedures. It was difficult to obtain anesthesiologist assistance in non- oncological urological procedures (for example: ureteral stenting). The feeling was that it was forbidden to have pathology other than SARS-CoV-2. Urology Division was managed as a mixed ward hosting non-COVID and COVID patients who did not require intensive care support. One Urologist per week was commanded to participate at medical activities, alone or alongside with Internal Medicine colleagues. Consequently, from the beginning of the lockdown, the andrological activity was reduced to the management of several cases with complications such as phimosis whose surgery had been postponed, one spermatic cord torsion (Figure 1), two testicular neoplasms, metastatic priapism (two cases), one penile cancer (Figure 2) and three cases of Mondor’s disease (Figure 3). Requests for advice in relation to non-acute testicular pain, even by telephone, were increased. There have been no cases of penile trauma which had been unusually more frequent in the 6 months preceding the pandemic.

Andrological patients at the time of COVID-19

Figure 1. Spermatic cord torsion. Pre- (left) and post (right)-derotation testicle aspect.

Figure 2. Penile cancer localized in the inner part of the foreskin (A, B). In C and D were reported the dorsal (C) and ventral (D) post surgical aspects after sleeve circumcision (squamocellular carcinoma with sarcomatoid aspect, HPV induced, pT1Nx). Figure 3. Mondor disease. Clinical aspect (left) in a circumcised penis. Ultrasound features (right) with thrombus (white star) occluding the dorsal superficial vein lumen.

U.O.S. Urologic Surgery, Azienda Ospedali Riuniti, Ancona The Marche Region was the 5th Italian Region in terms of numbers of patients, hospitalized and deaths. The Ospedali Riuniti in Ancona, which play the role of Regional Referral Centre (Hub), immediately gave its orders to convert surgical beds, thus limiting all the other surgical activity, in order to grant, for resuscitation purposes, and therefore to provide physician availability for emergency and non-intensive medical unit for Covid. Eight Unit dedicated to Covid were established in a few weeks. The elective Andrological activity was interrupted. The urological ward was reduced to 15 of 22 beds and a waiting room (2 beds) was dedicated to patients admitted from emergency waiting the result of Covid-test analysis. Surgery was planned only for emergency/urgency, symptomatic tumors, kidney failure, infection, diseases with ongoing complications and traumatic events. Urological and Andrological outpatient activity, diagnostic ultrasound and cystoscopy, and endovesical chemo or BCG were temporary closed. To date, the lockdown throughout the country has greatly reduced the incidence of traumatic events related to road traffic and work activities. In the first 50 days we had to intervene on two traumas of the genital tract that happened due to working activities. We listed criteria to plan andrological surgery in agreement with our experience, the Covid Task Force Unit in our hospital and published

Guidelines on urological surgery (17-21). The andrological surgical activity included two orchiectomies for testicular cancer, one penile amputation with inguinal and ipsilateral pelvic lymph node dissection for penile cancer (Figure 4) and one surgery for severe gangrenous necrotizing fasciitis of the genitals in a 58-year male with diabetes, HIV and drugs addiction. This case resolved after 75 days (Figure 5). The overall surgical activity was reduced by 47% with 262 procedures from March 1st to May 30th 2020 compared to 492 during the same time period in 2019. However the Urology resident training was guaranteed all the time also supported by web lessons (22). Urology Division at the Civitanova Marche Hospital As soon as the pandemic from Coronavirus emerged, the community Hospital in Civitanova Marche was been converted into a Covid-Hospital, as well as most of the staff who were employed in it. All departments were progressively occupied by symptomatic COVID-19 positive patients, diverting patients affected by other pathologies to other hospitals (Macerata, Ancona) and suspending the outpatient and surgical activity. From March 24, 2020, urologists started to work as an internist-type ward in shifts of medium-low care intensity, with a shift of 8 Figure 4. Simultaneous right inguinal and pelvic lymph node dissection through modified inguinal incision (Surgical Andrology Unit, Ospedali Riuniti, Ancona).

Figure 5. Genitalia gangrene management (Surgical Andology Unit, Ospedali Riuniti, Ancona).

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hours a day. During their shifts, urologists were also called to perform urological consultations for positive Covid-19 patients hospitalized in the various wards of the hospital; during this activity in the hospital, there was no request for some andrological advice. In addition to the hospital activity, private Andrologist activity was continued by activating an online consultancy function with video consultations: this activity has proven to be safe, effective and pleasing to the patients who have used it. During this activity, five requests for advice for erectile deficit mainly of recent onset were received. The cause of these deficits is often psychogenic, probably linked to the state of prostration, inhibition related to social distancing and quarantine. Therefore, it is important not to increase the patient's concern or treat him as an organic erectile deficit, but to deepen the diagnosis if it persists even after the lockdown phase.

CONCLUSIONS

Males and andrology community are still paying the price of a delay in the management of the pandemic, fueled by first conflicting messages and fake news. The key-role of andrologists in Italy was to offer themselves to support COVID patients and support andrological patients seeking help by web, phone and email. Andrological surgery is still restricted in most hospitals and, especially in public setting, nevertheless how and when re-schedule suppressed operations is missing yet. The lack of epidemiological data on andrological pathologies in the lockdown period stimulated us to expose our experiences which, in addition to an interruption of the specialist activity in hospital structures, highlighted above all the andrological pathologies that had been managed in a private setting.

REFERENCES

1. Lefkowitz EJ, Dempsey DM, Hendrickson RC, et al. Virus taxonomy: the database of the International Committee on Taxonomy of Viruses (ICTV). Nucleic Acids Res. 2018; 46:D708-D717. 2. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol. 2020; 5:536-544. 3. Song Z, Xu Y, Bao L, et al. From SARS to MERS, thrusting coronaviruses into the spotlight. Viruses. 2019; 11:59. 4. Decrete of the president of the council of ministers, Italy, 8 March 2020. OJ No. 59 of 8-3-2020 5. Wölfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with COVID2019. Nature. 2020; 581:465469. 6. Hui DSC, Zumla A. Severe acute respiratory syndrome: historical, epidemiologic, and clinical features. Infect Dis Clin North Am. 2019; 33:869-889. 7. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395:497-506. 8. Jin Y, Yang H, Ji W, et al. Virology, epidemiology, pathogenesis, and control of COVID-19. Viruses. 2020; 12:372. 9. Borges do Nascimento IJ, Cacic N, Abdulazeem HM, et al. Novel

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coronavirus infection (COVID-19) in humans: a scoping review and meta-analysis. J Clin Med. 2020; 9:941. 10. Aitken RJ. COVID-19 and human spermatozoa-Potential risks for infertility and sexual transmission? Andrology. 2020 Jul 10:10.1111/andr.12859. 11. Maretti C, Privitera S, Arcaniolo D, et al. COVID-19 pandemic and its implications on sexual life: Recommendations from the Italian Society of Andrology. Arch Ital Urol Androl. 2020; 92:73-77. 12. Brooks SK, Webster RK, Smith, LE, et al. The psychological impact of quarantine and how to reduce it: rapid review of the evidence. Lancet. 2020; 395:912. 13. Leonardi R, Bellinzoni P, Broglia L, et al. Hospital care in Departments defined as COVID-free: A proposal for a safe hospitalization protecting healthcare professionals and patients not affected by COVID-19. Arch Ital Urol Androl. 2020 Apr 24; 92:67-72. 14. Simonato A, Giannarini G, Abrate A, et al. Pathways for Urology patients during the Covid19 pandemic. Minerva Urol Nefrol. 2020; 72:376-383. 15. Ficarra V, Novara G, Abrate A, et al. Urology practice during COVID-19 pandemic. Minerva Urol Nefrol. 2020; 72:369-375. 16. Stensland KD, Morgan TM, Moinzadeh A, et al. Considerations in the triage of urologic surgeries during the COVID-19 pandemic. Eur Urol. 2020; 77:663-666. 17. Martino P, Galosi AB, Bitelli M, et al. Imaging Working GroupSocieta Italiana Urologia (SIU); Società Italiana Ecografia Urologica Andrologica Nefrologica (SIEUN). Practical recommendations for performing ultrasound scanning in the urological and andrological fields. Arch Ital Urol Androl. 2014; 86:56-78. 18. Maselli G, Cordari M, Catanzariti F, et al. Penile Gangrene by Calciphylaxis: An Unusual Clinical Presentation in a Patient with Diabetic Nephropathy on Hemodialysis. J Emerg Med 2017; 52:e255e256. 19. Galosi AB, Capretti C, Leone L, et al. Pseudoaneurysm with arteriovenous fistula of the prostate after pelvic trauma: Ultrasound imaging. Arch Ital Urol Androl. 2016; 88:317-319. 20. Dell'Atti L, Cantoro D, Maselli G, Galosi AB. Distant subcutaneous spreading of Fournier's gangrene: An unusual clinical identification by preoperative ultrasound study. Arch Ital Urol Androl. 2017; 89:238-239. 21. Dell'Atti L, Scarcella S, Tallè M, et al. Simultaneous curvature correction at the time of the penile fracture repair: surgical and functional outcomes. Res Rep Urol. 2019; 11:105-110. 22. Busetto GM, Del Giudice F, Mari A, et al. How Can the COVID19 Pandemic Lead to Positive Changes in Urology Residency? Front Surg. 2020; 7:563006. Correspondence Carlo Maretti, MD - carlomaretti@tin.it Department of Andrology, CIRM Medical Center, Piacenza, Italy Andrea Fabiani, MD - andreadoc1@libero.it Unit of Urology, Surgical Department, Macerata Hospital, Area Vasta 3, ASUR Marche, Macerata, Italy Fulvio Colombo, MD - fulvio.colombo@aosp.bo.it Alessandro Franceschelli, MD - alessandrofranceschelli@yahoo.it Giorgio Gentile, MD - dr.giorgio.gentile@gmail.com Franco Palmisano, MD - franco.palmisano@hotmail.it Valerio Vagnoni, MD - vagnoni.dr@gmail.com Andrology Unit, University Hospital S.Orsola-Malpighi, Bologna, Italy Luigi Quaresima, MD - luigiquaresima@yahoo.it Urology Division at the Civitanova Marche Hospital, Civitanova Marche, Italy Massimo Polito, MD - max_polito@virgilio.it Department of Clinical and Specialist Sciences, Division of Urology, Polytechnic University of the Marche Region Medical School, Ancona, Italy

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SIEUN CONGRESS ANCONA 30 NOVEMBER - 1 DECEMBER 2020 DOI: 10.4081/aiua.2021.1.115

REVIEW

COVID-19 and male fertility: Taking stock of one year after the outbreak began Rocco Francesco Delle Fave, Giordano Polisini, Gianluca Giglioni, Arnaldo Parlavecchio, Lucio Dell’Atti, Andrea Benedetto Galosi Division of Urology, University Hospital “Ospedali Riuniti”, School of Medicine, Department of Clinical, Special and Dental Sciences, Marche Polytechnic University, Ancona, Italy.

Summary

Objectives: The aim of this review is to summarize, following a timeline, the current knowledge regarding the effects of the Sars-cov2 virus on male fertility, researching the pathological and clinical results of the studies published in the last year. Methods: A systematic research was performed on the major international online databases; Thirty-five articles were selected. Results: A statistically significant reduction in testosterone levels and sperm quality in subjects with COVID-19 has been highlighted in several papers; however, in many cases the tests have been conducted in patients with active disease and long-term consequences are still not known. Some studies have confirmed the presence of the virus in the testis in a low percentage of patients; viral presence in sperm has only been found in one study. Testicular discomfort, which could indicate viral orchitis, was highlighted in several works, with an incidence of up to 19% percent of patients. The presence of inflammatory lymphocytic infiltrates, IgG and inflammatory cytokines have been documented in several works; pathological signs of inflammation were found in 60.9% of testicular biopsies performed in one study. The entry of the virus into the testis cells, both stromal and seminal cells appeared to be Angiotensin Converting Enzyme-2 (ACE2) mediated, as it also occurs in other tissues. DNA fragmentation, reactive oxygen species (ROS) formation, autoantibody production and ACE2 mediated effect have all been hypothesized as cause of cellular damage. Conclusions: The results on effects of COVID-19 infection on the male reproductive system are currently insufficient as they are based on a small number of patients and therefore are often contradictory.Certain mechanisms of testicular damage are still to be assessed, as any risk categories like age, ethnicity, or others. As for the transmission of the virus through sperm, there is insufficient evidence to ensure that this cannot happen.

KEY WORDS: COVID-19; SARS-CoV-2; Male fertility; Infertility; Sperm. Submitted 11 January 2021; Accepted 21 January 2021

INTRODUCTION

Coronaviridae are single-chain RNA viruses, with an envelope covered with spikes that give the viruses the typical "crown" appearance. There are four subtypes (alpha, beta, gamma and delta) and among these differ-

ent species are responsible for zoonoses, infecting mammals such as bats, cats, dogs, various rodents (1), and eventually passing to humans. Seven types of coronaviruses have been identified that have caused infections in humans so far; humanity has already challenged epidemics caused by these viruses, last of which were severe acute respiratory syndrome (SARS) in 2003 and Middle East respiratory syndrome (MERS) in 2012 (2). In December 2019 in the Chinese town of Wuhan several cases of acute respiratory syndrome were reported; etiological agent was found to be Severe acute respiratory syndrome coronavirus 2 (SARS-COV2); infectious cases spread rapidly through continents. Transmission occurs most frequently through droplets and contact but the virus has also been identified in saliva, faeces and urine (3, 4). Lu et al. (5) first described the mechanism of infection: the virus binds to the angiotensin 2 converting enzyme (ACE2) through glycoproteins membrane S; the S1 domain deals with the binding with the host cell while the S2 domain is responsible for the fusion of the membranes undergoing a proteolytic priming by the transmembrane serine protease TMPRSS2(6) (Figure 1). The ACE2 enzyme is strongly expressed in lung, kidney, cardiac, gastrointestinal, bladder and testicular cells (7). In the testis it is found in both in the cells of the seminiferous ducts, in particular spermatogonia, and in the cells of Leydig and Sertoli (8). Hence the hypothesis that the testicle may be a reservoir of the disease. The aim of this study focuses on the search for results regarding the parameters of male fertility, the pathological aspects of the testicle and the presence of the virus in the seminal fluid.

MATERIALS

AND METHODS

A systematic search of the peer reviewed literature was conducted on PubMed, Google scholar and Medline databases until 30 December 2020. A combination of Medical Subject Headings (MeSH) terms was used. The keywords were: “Covid” ,“male fertility”, “infertility” “sperm”, “testosterone” and “quality”. All titles and abstracts published in English were evaluated. All studies were considered, with the exception of those performed on animals, comments, letters, editorials and case reports. The initial search yielded a total of 47 articles. The articles deemed

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

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Figure 1. COVID-19 virus replication cycle.

valid were selected discarding the duplicates and then the off topic articles; A total of 35 articles strictly related to our issue were finally evaluated and reviewed by the authors.

RESULTS

Table 1. Findings about fertility parameters Authors Ma et al. (9)

N° of Testosterone LH FSH Semen patients levels quality 81 =/↓ ↑ -

Rastrelli et al. (10)

↓

Schroeder et al. (11)

↓

Holtmann et al. (12)

↓

Xu et al. (13)

Other findings ↓T/LH, ↓T/FSH, associazione fra alti livelli di PCR e basso T/LH Lower baseline levels of T nd cfT (free-testosterone) levels predict poor prognosis and mortality High estradiol level in both male e female sars-cov2 patients ↓ Sperm concentration, n° of sperm per ejaculate, motility Negative correlation between high estradiol levels and disease duration

Table 2. Findings about pathologic aspects of the testis in COVID-19 patients. Authors Song et al. (14) Shen et al. (15) Yang et al. (16)

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N° of Covid in testis patients biopsy 13 no 3 12 1

Li et al. (17)

Achua et al. (18)

Lynphocytic Cytokines Other findings infiltration Ace2 levels are greather at 30 y CD3+, CD8+ Variable tubular damage (> 50%) CD3+, CD8+ IL-6, TNF (60.9%) + (in 14.2%) Spikes at electronic microscope in 1 case; high Ace2 levels in patients with impaired spermatogenesis

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COVID-19 and fertility parameters A study published in March 2020 (9) performed on 81 patients with active disease hospitalized for moderate and severe symptoms showed that serum luteinizing hormone (LH) was significantly increased compared to a control group of 100 patients without symptoms and negative nasopharyngeal swab; furthermore, testosterone (T) to LH ratio and follicle stimulating hormone (FSH) to LH ratio were significantly decreased. There also was a strong association in multivariate regression analysis between high levels of c reactive protein (RCP) and low T/LH ratio; although there may be other factors involved, such as stress and the use of corticosteroids that may have altered the hypothalamus-pituitary-gonadal axis, the risk of hypogonadism in Covid patients was highlighted for the first time. This was followed by other works that demonstrated the condition of hypotestosteronemia in sick and recently recovered patients (10, 11). In August, a cohort study by Holtmann et al. (12) was published. Sperm samples were analyzed from 18 patients one month after recovery from Covid and 14 control cases. In patients who had Covid with mild symptoms that did not require hospitalization, there was no impact on sperm quality in the short one-month follow-up; patients who had moderate symptoms had worse sperm quality (sperm concentration, total number of sperm per ejaculate, total number of progressive motility, total number of complete motility). One among these patients also had testicular symptoms (discomfort). Xu H et al. (13) published in Andrology a study on 39 patients with COVID-19. The authors studied after recovery and compared to 22 controls subject. They found neither significant changes in blood testosterone, FSH and LH levels, nor associations between disease duration or severity and testosterone levels. There was a statistically significant negative association (p < 0.001) between blood estradiol levels and disease duration, as it was lower in patients who had had long illness, i.e. greater than 50 days, compared to the subgroup with normal-term disease. Three possible explanations for

COVID-19 and male fertility

Table 3. Findings about sperm presence of the virus. Authors Song et al. (14) Paoli et al. (19) Ning et al. (20) Li et al. (17) Pan et al. (22) Holtman et al. (12)

N° of patients 13 1 17 38 34 18

Presence of the virus and details no no no Yes, 6 patients, four with active disease no no

this difference have been hypothesized, identifying the possible cause in the variation in estradiol levels in the direct cellular damage from the virus, in the massive inflammatory response of the organism or in the use of some drugs, such as corticosteroids (Table 1). COVID-19 and testis pathological aspects In April 2020 a study by the Nanjing Medical University showed that testicular biopsy was performed on a patient who died of COVID-19, looking for viral RNA; also, sperm samples of 13 patients were analyzed. Viral RNA was not found in any of the samples (14). In August 2020 Shen Q et al. (15) observed that the expression of ACE2 in the testis is related to age, has a peak around 30 years and very low from 60 years onwards. Young men might therefore be more at risk for reproductive disorders than older men and very young children. In European Urology Focus, Yang et al. (16) analyzed the testicles of 12 patients who died from Covid with an average age of 65 and found tissue damage in more than half of them (cellular damage and necrosis in both germinal and Sertoli cells, tubules, edema and mild inflammation of the interstitium with T lymphocytes). Damage to the seminal tubules was classified into three groups: absent, mild (< 10%. 2 cases), moderate (10-50%. 5 cases) and severe (> 50%. 4 cases). These findings were compared with 5 control subjects who died for causes other than Covid. In 2 cases no tubular damage and in 3 cases mild tubular damage was found. The virus was found in the lungs of 10 out of 12 patients, but only in 1 patient was it found in the testis. Li H et al. (17) performed histopathological examinations on testicular and epididymal specimens, and also performed TUNEL assay and immunohistochemistry on 6 patients who died of Covid and 23 who recovered from Covid, identifying the presence of interstitial edema, congestion, red blood cells exudate in the testis and epididymis, thinned seminiferous tubules with high apoptosis rate, interstitial T lymphocytes infiltrate interstitial, IgG in the seminiferous ducts and increase of IL-6 and TNF; finally they showed oligozoospermia in 39.1% of the subjects and in 60.9% of cases a leukocyte infiltrate. Subsequently, other authors analyzed the results of 6 autopsies of casualties from COVID-19 infection and 3 control cases with negative swab who had died from other causes; results were published in the World Journal of Man's Health. Also, a testicular biopsy from living with active disease was analyzed. The samples were studied by histo-morphological examination and

electron microscope. Three of the six positives had abnormal spermatogenesis. One of the six patients had a testicular lymphocyte and macrophage infiltrate as from inflammation. The testicular cells of four Covid patients were examined with electron microscopy and of these 1 had visible spike particles, the same in which inflammatory infiltrate was present; spikes were also found in the testicular biopsy sample from the living patient. Using immune-fluorescence they quantitatively assessed the presence of the ACE2 receptor and showed a correlation between low expression of the ACE2 receptor in patients with normal spermatogenesis and high expression in patients with impaired spermatogenesis, i.e. pathological Sertoli cells, hypospermia, early maturation arrest, sclerosis of the seminiferous ducts (18) (Table 2). COVID-19 findings in semen As already mentioned, in the study by Song et al. (14) the virus was not found in the semen of 13 infected patients; twelve patients were recovering, one of them was in the acute phase of the disease. Also, an Italian group in Rome searched for the viral RNA in the sperm and urine of a volunteer patient eight days after the virus diagnosis using PCR without findings (19); the same result has been obtained by Ning et al. (20) who searched for the nucleocapsid (N) and Orf1 genes with the PCR method in 17 sperm samples, 9 of which from patients with active disease and 8 from cured patients. A cohort study from Beijing detected the virus in the seminal fluid of 6 out of 38 patients analyzed; two thirds of these six patients were in the acute phase of the disease while one third of them were recovering (21). In June 2020 Pan et al. (22) searched with the PCR technique the viral genome of the virus in 34 patients, most of them about one month after diagnosis (range from 8 to 75 days). Also in this case, the N genes of the nucleocapsid and the ORF1ab gene were searched in particular. The virus was not detected in any of them. Six patients (19%) complained of testicular discomfort suggesting viral orchitis. In the aforementioned Holtmann study (12) the viral RNA presence was investigated in sperm with the PCR technique, dividing patients into three groups: patients with moderate symptoms (only 4 patients), convalescents (14 patients) and control group (other 14 subjects). In none of these specimens the virus was found (Table 3).

DISCUSSION

Viruses so far known to cause orchitis include hepatitis B and C viruses, human papilloma virus, flu virus, herpes simplex virus, Epstein-Barr virus, Coxsackie virus, HIV, Zika virus, Ebola virus, Arbovirus, Marburgvirus and the SARS-Cov virus (23). There are various hypotheses on the mechanism of testicular inflammation. SARS-COV2 could, through various pathogenic pathways, increase oxidative stress, increase DNA methylation and fragmentation and decrease male fertility. Also direct cellular damage is possible through the ace enzyme on Leidig cells and spermatocytes (24, 25). The blood-testis barrier (BTB) is responsible for protecting Archivio Italiano di Urologia e Andrologia 2021; 93, 1

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seminal cells from the immunity system, especially T lymphocytes. During active viraemia, persistent high temperature from fever can tamper with the blood-testis barrier and cause the passage of viruses. This is demonstrated by the fact that normally only a few CD3 and CD8 lymphocytes are found in the interstitium in the testes. In patients with SARS, there is an increase in T lymphocytes and macrophages of 4.5% and 11.7% respectively (26) and in IgG immunoreaction. This indicates that the barrier is compromised in these patients. DNA damage is the result of apoptosis and excessive production of ROS and inflammation and can lead to an increase in the DNA fragmentation index (DFI) with consequent infertility. Since DFI is useful for assessing changes in fertility, it could be introduced as an additional method of diagnosing infertility in COVID patients (27-28). Very interesting data comes from genetic studies; Wang et al. (29) showed that spermatogonia with an ACE2 + expression similar to lung AT2 cells are only 1.28% of all spermatogonia, while in the study by Pan et al. (22) only 4 on 6490 testicular cells studied contained both the ACE2 gene and TMPRR2; these data could indicate that in most cases the virus does not directly affect the testicle. Inflammatory cytokines, such as Il-6, may also play a role in the inflammatory response; it has been shown that its concentration is high in patients with Covid (30). Even the hypothesis of production of anti-sperm antibodies (ASA) following damage to the blood-testicular barrier may be valid (31, 32). In patients with SARS-cov2, the use of inhibitors of the renin angiotensin system unfortunately does not confer protective effects on the testis in terms of cell mortality, probably not even with regard to spermatozoa (33). The studies analyzed, although of high quality, have some limitations. First of all, the number of patients studied is limited; furthermore, the follow-up is so short that the possible future implications and the impact that SARS-COV-2 infection can have on long-term male fertility are not known. However, it may be important to perform a Covid screening during fertility treatment, for which there are already guidelines for conduct for fertility care, identified and summarized in the study of Papathanasiou (34) from 4 publications by the European Society of Human Reproduction and Embryology (ESHRE), American Society for Reproductive Medicine (ASRM), British Fertility Society/Association of Reproductive and Clinical Scientists (BFS/ARCS) and Canadian Fertility and Andrology Society (CFAS). For patients who are interested in sperm cryopreservation, some rules should be followed. Adiga SK (35) illustrated that the measures aimed at minimizing the risk of viral contamination in sperm cryopreservation are: blood tests before starting treatment, fully follow the correct protocols of cryopreservation and proper washing of gametes and embryos during preservation with sterile LN2. Although in some studies the virus has been identified in the testes and there is significant evidence of hypogonadism and hypotestosteronemia, further data is needed to better understand the effects of this virus on reproductive organs, to identify how the virus eventually affects fertility parameters and to ensure that the testis is not a virus reservoir (36).

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To date, no cases of virus transmission from sperm have been recorded. However active patients and patients recovered from COVID-19 are advised against donating sperm and performing assisted fertilization (37).

REFERENCES

1. Su S, Wong G, Shi W, et al. Epidemiology, genetic recombination, and pathogenesis of coronaviruses. Trends in Microbiology 2016; 24:490-502 2. Ferran Garcìa J, Alvarez Gonzales JG, Corral Molina JM. Infección por SARS-CoV-2: implicaciones para la salud Sexual y reproductiva. Una declaraciòn de la posición de la Asociación Espanola de Andrología, Medicina Sexual y reproductora (ASESA). Rev Int Androl. 2020; 18:117-123. 3. John Hopkins University of Medicine, Coronavirus resource center, http://coronavirus.jhu.edu/map.html 4. Peng L, Liu J, Xu W, et al. 2019 Novel Coronavirus can be detected in urine, blood, anal swabs and oropharyngeal swabs samples. J Med Virol. 2020; 92:1676-1680. 5. Lu R, Zhao X., Li J, et. al. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus Origins and Receptor binding. Lancet 2020; 395:565-574. 6. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181:271-80.e8. 7. Zou X, Chen K, Zou J, et al. Single-cell RNAseq Data analysis on the receptor ACE2 Expression reveals the potential risk of different human organs vulnerable to 2019nCoV infection. Front Med. 2020; 14:185-92. 8. Reis AB, Araújo FC, Pereira VM. Angiotensin (1-7) and its receptor Mas are expressed in the human testis: implications for male infertility. J Mol Histol. 2010; 41:75-80. 9. Ma L, Xie W, Li D, et al. Effect of SARS-CoV-2 infection upon male gonadal function: A single centerbased study. Medxriv March 2020, doi.org/10.1101/2020.03.21.20037267. 10. Rastrelli G, Di Stasi V, Inglese F, et al. Low testosterone levels predict clinical ad¬verse outcomes in SARS-CoV-2 pneumonia patients. Androl¬ogy 2020; 00:1-11, doi.org/10.1111/andr.12821. 11. Schroeder M, Tuku B, Jarczak D, et al. The majority of male patients with COVID-19 pres¬ent low testosterone levels on admission to intensive care in Hamburg, Germany: a retrospective cohort study. medRxiv May 2020, doi.org/10.1101/2020.05.07.20073817. 12. Holtmann N, Edimiris P, Andree M, et al. Assessment of SARSCoV-2 in human semen—a cohort study. Fertil Steril. 2020; 114:233-238. 13. Xu H, Wang Z, Feng C, et al. Effects of SARS-CoV-2 infection on male sex-related hormones in recovering patients. Andrology. 2020 Nov 5. doi: 10.1111/andr.12942. 14. Song C, Wang Y, Li W, et al. Absence of 2019 novel coronavirus in semen and testes of COVID-19 patients. Biol Reprod. 2020; 103:4-6. 15. Shen Q, Xiao X, Aierken A, et al. The ACE2 expression in Sertoli cells and germ cells may cause male reproductive disorder after SARS-CoV-2 infection. J Cell Mol Med. 2020; 24:9472-9477. 16. Yang M, Chen S, Huang B, et al. Pathological findings in the testes of COVID-19 patients: clinical implications. Eur Urol Focus. 2020; 6:1124-1129.

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17. Li H, Xiao X, Zhang J, et al. Impaired spermatogenesis in COVID-19 patients, EClinicalMedicine. 2020; 28:100604.

of SARS-CoV-2 action on male gonadal function and fertility: Current status and future prospects. Andrologia. 2020; e13883.

18. Achua JK, Chu KY, Ibrahim E, et al. Histopathology and ultrastructural findings of fatal COVID-19 infections on testis. World J Mens Health 2021; 39:65-74.

29. Wang Z, Xu X. scRNA-seq Profiling of Human Testes Reveals the Presence of the ACE2 Receptor, A Target for SARS-CoV-2 Infection in Spermatogonia, Leydig and Sertoli Cells. Cells. 2020; 9:920.

19. Paoli D, Pallotti F, Colangelo S, et al. Study of SARS-CoV-2 in semen and urine samples of a volunteer with positive naso-pharyngeal swab. J Endocrinol Invest. 2020; 43:1819-1822.

30. Mahmudpour M, Roozbeh J, Keshavarz M, et al. COVID-19 cytokine storm: The anger of inflammation. Cytokine, 2020; 133:155151.

20. Ning J, Li W, Ruan Y, et al. Effects of 2019 novel coronavirus on male reproductive system: a retrospec¬tive study. Preprints 2020, 2020040280, doi: 10.20944/preprints202004.0280.v1

31. Fan C, Li K, Ding Y, et al. ACE2 expression in kidney and testis may cause kidney and testis damage after 2019- nCoV infection. Preprint from medRxiv. Febr 2020 22418, doi.org/10.1101/2020. 02.12.20022418

21. Li D, Jin M, Bao P, et al. Clinical characteristics and results of semen tests among men with coronavirus disease 2019. JAMA Netw Open. 2020; 3:e208292. 22. Pan F, Xiao X, Jingtao G, et al. No evidence of severe acute respiratory syndrome-coronavirus 2 in semen of males recovering from coronavirus disease 2019. Fertil Steril. 2020; 113:1135-1139. 23. Khalili MA, Leisegang K, Majzoub A, et al. Male Fertility and the COVID-19 Pandemic: Systematic Review of the Literature. World J Mens Health. 2020; 38: 506-520 24. Anifandis G, Messini CI, Daponte A, et al. COVID-19 and fertility: a virtual reality. Reprod Biomed Online. 2020; 41:157-159. 25. Barbagallo F, Calogero A, Cannarella R, et al. The testis in patients with COVID-19: virus reservoir or immunization resource? Transl Androl Urol. 2020; 9:1897-1900. 26. Xu J, Lihua Q, Chi X, et al. Orchitis: A5. complication of severe acute respiratory syndrome (SARS). Biol Reprod. 2006; 74:410-416. 27. Santi D, Spaggiari G, Simoni M. Sperm DNA fragmentation index as a promising predictive tool for male infertility diagnosis and treatment management - Meta-analyses. Reprod Biomed Online. 2018; 37:315-326 28. Haghpanah A, Masjedi F, Alborzi S, et al. Potential mechanisms

32. Li R, Yin T, Fang F, et al. Potential risks of SARS-CoV-2 infection on reproductive health. Reprod Biomed Online. 2020; 41:89-95. 33. Yokoyama Y, Aikawa T, Takagi H, et al. Association Of reninangiotensin-aldosterone system inhibitors with mortality and testing positive of COVID-19: Meta-analysis. J Med Virol 2020 Oct 10; 10.1002/jmv.26588. 34. Papathanasiou A. COVID-19 screening during fertility treatment: how do guidelines compare against each other? J Assist Reprod Genet 2020; 37:1831-1835. 35. Adiga SK, Tholeti P, Uppangala S, et al. Fertility preservation during the COVID-19 pandemic: mitigating the viral contamination risk to reproductive cells in cryostorage, Reprod Biomed Online 2020; 41:991-997. 36. Dell’Atti L, Galosi AB. The role of the serum testosterone levels as a predictor of prostate cancer in patients with atypical small acinar proliferation at the first prostate biopsy. Asian J Androl. 2018; 20:15-18. 37. Maretti C, Privitera S, Arcaniolo D, et al. COVID-19 pandemic and its implications on sexual life: Recommendations from the Italian Society of Andrology. Arch Ital Urol Androl. 2020 Jun 23; 92:73-77.

Correspondence Rocco Francesco delle Fave, MD dellefavefrancesco@alice.it Giordano Polisini, MD gio.pol.93@gmail.com Gianluca Giglioni, MD piallu88@gmail.com Arnaldo Parlavecchio, MD aldoparl90@gmail.com Lucio Dell’Atti, MD, PhD (Corresponding Author) dellatti@hotmail.com Andrea Benedetto Galosi, MD a.b.galosi@univpm.it Division of Urology, University Hospital “Ospedali Riuniti”, Marche Polytechnic University Via Conca 71, 60126 Ancona (Italy)

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CASE COLLECTION

Unusual clinical scenarios in Urology and Andrology Lucio Dell’Atti 1, Andrea Fabiani 2, Erika Palagonia 1, Agostini Edoardo 1, Maria Pia Pavia 2, Simone Scarcella 1, Valentina Maurelli 2, Emanuele Principi 2, Marco Tiroli 1, Giulio Milanese 1, Lucilla Servi 2, Andrea Benedetto Galosi 1 1 Division

of Urology, University Hospital “Ospedali Riuniti”, School of Medicine, Department of Clinical, Special and Dental Sciences, Marche Polytechnic University, Ancona, Italy; 2 Urology Unit, Surgery Department, Macerata Civic Hospital, Area Vasta 3 Asur Marche, Italy.

Summary

This collection includes some unusual cases and how they were diagnosed and treated.

Case 1: A case of a patient with primary hyperthyroidism presenting with a submucosal ureteral stone after endoscopic lithotripsy was described. After multiple endoscopic treatment, the stone was successfully removed by open ureterolithotomy recovering ureteral patency and normal renal function. Case 2: A case of burned-out testicular cancer with atypical lymphatic spread (stage II A) was presented. After right orchiectomy and complete remission of tumor markers, due to atypical metastases location and uncertain histology, the patient was treated with systemic therapy based on bleomycin, etoposide and cisplatin (PEB). At re-staging after chemotherapy computed tomography showed reduction of all node metastases and an observation protocol was proposed. Case 3: A patient was readmitted to hospital after 12 days from an uneventful Robot-Assisted Radical Prostatectomy (RARP) for prostate cancer due to lower abdominal pain plus abdominal distension, nausea and constipation not responsive to medical therapy. Computed Tomography showed colon and small bowel dilatation without any evidence of anatomical or mechanical obstruction. Laparoscopic abdominal exploration confirmed bowel distension without evidence of obstructing lesions. Ogilvie’s Syndrome or acute colonic pseudo-obstruction (ACPO) was diagnosed. The patient fully recovered and was discharged six days after the procedure. Case 4: A case of recurrent Acute Idiopathic Scrotal Edema (AISE) was diagnosed on clinical signs together with the decisive help of pathognomonic ultrasound findings as the “fountain sign”. Case 5: Small bilateral testicular nodules were diagnosed in a 30-years old patient undergoing scrotal ultrasound in follow up of acute lymphoblastic leukemia. Ultrasound guided testis sparing surgery was performed demonstrating Leydig cell tumors.

KEY WORDS: Submucosal ureteral stone; Burened-out testicular cancer; Ogilvie’s Syndrome; Acute Colonic Pseudo-Obstruction (ACPO); Acute Idiopathic Scrotal Edema (AISE); Ultrasound guided testis sparing surgery. Submitted 9 January 2021; Accepted 21 January 2021

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CASE 1. COMPLICATION

MANAGEMENT OF ATYPICAL SUBMUCOSAL URETERAL STONE LOCALIZATION AFTER MULTIPLE ENDOSCOPIC TREATMENTS IN A PATIENT WITH ELEVATED PARATHYROID HORMONE LEVELS

(Erika Palagonia, Marco Tiroli, Lucio Dell’Atti, Andrea Benedetto Galosi)

INTRODUCTION

Submucosal ureteral stone is a very atypical location and rare condition that can occur after multiple endoscopic procedures. In the literature, there is a complete lack of evidence in the management of this condition. The European Association of Urology guidelines describe an overall complication rate after retrograde ureterorenoscopy (URS) ranging between 9% and 25% (1). The most frequent complications reported in the literature are: fever and sepsis, steinstrasse and ureteral lesions (2).

CASE

REPORT

A 24-years-old man was referred to our urology department due to recurrent right flank pain, not amenable with medical therapy, within two weeks from endoscopic lithotripsy with rigid URS for ureteral stone. Blood test analysis showed a serum creatinine level of 1.28 mg/dl with an estimated glomerular filtration rate (eGFR) of 73 ml/min/1.73m2, white cells count of 13.39 x103/mmc, and remaining indexes within the range of normality. A non-contrast enhanced Computed Tomography scan of the abdomen described a grade IV hydroureteronephrosis due to a 1.9 cm lumbar ureteral stone with concomitant inflammation and edema of perirenal tissues. A subsequent Renal Scintigraphy with Technetium (99mTC) dimercaptosuccinic acid was performed defining a residual function of 31.6% for the right renal unit. A right URS was attempted without success due to edema and extensive phlogistic reaction of ureteral orifice and a 26 cm 6 Ch double J ureteral stent (DJS) was placed to drain the renal unit. The patient was discharged the next day and scheduled for a second URS treatment. Within 3 months the patient was readmitted due to abdominal right flank pain non-responsive to medical treatment despite the presence of DJS. Fluoroscopy and retrograde pyelography showed both a proximal calcification of the right DJS and the ureteral No conflict of interest declared.

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stone located at lumbar level. In the light of the impossibility of an endoscopic removal of the JJ stent, the patient was submitted to an extracorporeal shock wave lithotripsy (ESWL) session to fragment the calcified proximal part of the DJS with 1600 shocks at maximum power. The DJS was then removed and a subsequent URS was performed to complete endoscopically the lithotripsy of residual calcified fragments and to treat the ureteral stone. Under direct endoscopic view of the ureter no intraluminal stone was evidenced. However, the radiogram of the abdomen evidenced the presence of a ureteral stone located at the level of the right lumbar ureter. A multidisciplinary meeting was held with nephrologist to decide the appropriate treatment and due to the worsening of renal function and overall clinical conditions an open laparotomy surgery was scheduled. Intraoperatively an uretero-lithotomy was necessary to expose the submucosal ureteral stone. A longitudinal incision of the ureter allowed the extraction of the stone and a replacement of the 26 cm X 6 Ch DJS. The chemical and physical analysis of the stone showed a medium hard stone composed of calcium oxalate and calcium magnesium phosphate. General condition of the patient rapidly improved with both resolution of symptoms and improvement of blood test analysis: serum creatinine level of 1 mg/dl and eGFR of 98 ml/min/1,73m2. Further laboratory investigations showed a serum calcium level of 11.2 mg/dl and a parathyroid hormone (PTH) level of 196 pg/ml (14-85 pg/ml). Due to the elevated levels of the PTH level an endocrinologist evaluation was requested. The right DJS was removed within 20 days from the procedure. Retrograde pyelography did not show ureteral strictures or ureteral stone recurrences and absence of hydronephrosis. After 1 year of follow up abdomen ultrasound showed absence of hydronephrosis and the presence of a small 5 mm stone in the lower pole of the right kidney. Endocrinological investigation demonstrated a primary hyperparathyroidism; the parathyroid scintigraphy with Technetium (99mTC) sestamibi and 99mTC pertechnetate showed a hyper-capturing area in the lower lobe of the right portion of the thyroid lodge, suggestive of a hyperfunctioning parathyroid gland. The patient was scheduled for surgical treatment.

CONCLUSIONS

Systematic review of literature on this argument showed limited evidence. Major complications following endoscopic surgery are potentially numerous and extremely varied, but submucosal ureteral stone localization was not found in any of the studies considered. In our case we believed that the atypical localization of the stone is related to the specific clinical condition of the patient. A condition of primary hyperparathyroidism can lead to an increased risk of calcification in the kidney and ureter, especially in case of concomitant other factors such as infections, changes in urinary pH and the presence of proteins and electrolytes (3). Identifying patients at risk of complications after endoscopic treatments is essential to reduce the need of re-intervention. A widely accepted protocol including management of rare complications could represent a topic of great interest for the urological community to guide the best practice.

REFERENCES

1. Türk C, Petrík A, Sarica K, Seitz C, et al. EAU Guidelines on Interventional Treatment for Urolithiasis. Eur Urol. 2016; 69:475482. 2. Cindolo L, Castellan P, Primiceri G, et al. Life-Threatening complications after ureteroscopy for urinary stones: Survey and systematic literature review. Minerva Urol Nefrol. 2017; 69:421-431. 3. Dell'Atti L, Papa S. Ten-year experience in the management of distal ureteral stones greater than 10 mm in size. G Chir. 2016; 37:27-30.

CASE 2. CLINICAL

STAGE IIA BURNED-OUT TESTICULAR CANCER WITH ATYPICAL LYMPHATIC SPREAD: A THREATENING CLINICAL SCENARIO

(Edoardo Agostini, Giulio Milanese, Lucio Dell’Atti, Andrea Benedetto Galosi)

INTRODUCTION

Burned out testicular neoplasm is a rare form of cancer accounting 5% of all germ cell tumors (GCT). GCT clinical stage (CS) IIA is defined as any T stage with lymph node metastases less than 2 cm (cN1), with or without stage I tumor markers. Depending on main histology and markers level, international guidelines suggest different treatments, ranging from radiotherapy to chemotherapy and retroperitoneal lymph-node dissection (RPLND). Optimal management in these patients is still a matter of debate. Furthermore, a critical feature in treatment choice is the metastatic pattern to the retroperitoneum lymph-nodes. We report the threatening case of a CS IIA burned out right testicular cancer with negativized markers and atypical metastatic spread.

CASE

REPORT

We report the case of a 44 years-old man referred at our institution for a localized right scrotal pain. Ultrasound using a 10MHz linear probe was performed and revealed a 3 cm well-defined highly echogenic lesion with calcified areas in the right testis. Preoperative tumor markers were slightly raised: AFP 17 ng/mL, HCG 52 mlU/mL, LDH 165. The patient underwent right orchiectomy, and histological specimens revealed regressed GCT. Chest and abdomen computed tomography (CT) scan performed after surgery showed retroperitoneal pathologically enlarged lymph nodes on the left side of aorta, a little cranially to common iliac arteries origin. The patient repeated tumor markers 10, 15 and 25 days after surgery, showing complete remission since the first analysis. Due to atypical metastases location and uncertain histology, we advised for treating patient with systemic therapy based on bleomycin, etoposide and cisplatin (PEB). Three months after systemic therapy, we re-staged the patient with contrast enhanced chest-abdomen CT scan, showing reduction of all node metastases, now measuring less than 1 cm each. As the largest part of small residual masses after systemic therapy usually contain fibronecrotic tissue, we proposed the patient for observation protocol. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

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DISCUSSION

Burned out tumor, also named regressed tumor, is a germ cell tumor that has completely or partially regressed, leaving a scar in the testicular parenchyma with vestiges of GCT. It accounts 5% of all GCT. Pure seminoma is considered the main histology presenting with regressed aspect. The mechanism behind tumor regression is mainly attributed to immunological response by cytotoxic T lymphocytes or ischemic injury. Diagnosis is often incidental (ultrasound) or secondary to symptoms of metastatic spread. About primary tumor, a general disorganization of the sound pattern of parenchyma and focal/diffuse hypoechoic lesions are common features, with or without calcifications (1). In 2017 was described a new pattern consisting of welldefined highly echogenic lesion with calcified areas resembling a pearl-oyster (2). In our report, staging by imaging revealed a clinical stage IIA with negative markers and with exclusively contralateral metastatic pattern. Past elegant studies about retroperitoneum lymphatic supply, showed that right testis drains primarily to the interaortocaval nodes with some drainage to the right paracaval nodes. Only in some studies a small but appreciable amount of lymphatic drainage from the right testis was found draining to left para-aortic region. About treatment, clinical stage IIA, particularly marker-negative non-seminoma, is actually one of main concern in testicular cancer management. However, National Comprehensive Cancer Network (NCCN), American Urological Association (AUA) and European Association of Urology (EAU) guidelines agree in recommending chemotherapy as possible firstline treatment for patients with marker-negative clinical stage IIA non seminoma germ cell tumor (NSGCT) of the testicle (3). Criteria as larger or multiple lymph nodes or metastatic lesions outside the primary landing zone (as in our patient) can be useful in treatment choice.

CONCLUSIONS

Treatment of CS IIA GCT with negative markers represents a recurrent impasse for the clinician, with different possible first line effective treatments, depending on primary histopathology and markers. In our case we present this intricate situation, complicated by atypical lymphatic spread and rare histologic specimen (with typical ultrasound pattern). In this threatening setting, we could establish the effectiveness of chemotherapy in this scenario and the usefulness of criteria as metastatic spread pattern for the choice of treatment.

REFERENCES

1. Angulo JC, González J, Rodríguez N, et al. Clinicopathological study of regressed testicular tumors (apparent extragonadal germ cell neoplasms). J Urol. 2009; 182:2303-2310. 2. Dell'Atti L, Galosi AB. "Pearl oyster": a new ultrasonographic sign of the regressed testicular tumor. J BUON. 2017; 22:1610-1611 3. Honecker F, Aparicio J, Berney D, et al. ESMO Consensus Conference on testicular germ cell cancer: diagnosis, treatment and follow-up. Ann Oncol. 2018; 29:1658-1686.

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CASE 3. OGILVIE’S

SYNDROME IN POST ROBOT-ASSISTED RADICAL PROSTATECTOMY: THE IMPORTANCE OF DIFFERENTIAL DIAGNOSIS AND SURGICAL TREATMENT

(Simone Scarcella, Lucio Dell’Atti, Giulio Milanese, Andrea Benedetto Galosi)

INTRODUCTION

Ogilvie’s Syndrome or acute colonic pseudo-obstruction (ACPO) is characterized by massive non-toxic acute intestinal distension in the absence of clear anatomical or mechanical obstructions. It was first described by Sir William Ogilvie in 1948 (1). Throughout academic literature, numerous articles regarding ACPO have been published describing this rare occurrence after general abdominal surgery, spinal surgery and multiple trauma surgeries in patients with an average onset age of 64-74 years (2). However, reviewing all published articles, only few cases have been reported after genitourinary surgeries (3). Certain risk factors have widely been accepted such as a recent major surgery, even in the absence of abdominal involvement, pregnancy, pre-existing medical comorbidities and coexistence of multiple precipitating conditions (systemic illnesses, infections, diabetes or cardiovascular diseases) (4, 5). Despite this recognition, there is a substantial lack of a specific etiology and this phenomenon is classified as a disorder of the intestinal motility due to dysfunction of the interstitial cells of the enteric nervous system and concurrent autonomic imbalance. Bowel injuries rarely occur in robot-assisted radical prostatectomy during intestinal manipulation or instruments introduction. Ogilvie’s Syndrome is a sporadic, under-reported diagnosis of exclusion. It can mimic symptoms of intestinal ischemia or perforation but the appropriate treatments of these conditions are different. In this setting, an accurate differential diagnosis is mandatory and atypical cases of colonic obstruction should always raise suspicion. We encountered a case of a patient who developed Ogilvie’s Syndrome after an uneventful robot-assisted radical prostatectomy (RARP), requiring laparoscopic abdominal explorative surgery.

CASE

REPORT

A 65 years-old patient with no previous medical history was scheduled at our urological unit for Robot-Assisted Radical Prostatectomy (RARP) to treat an organ confined 3+4 = 7 Gleason Score (Grade Group 2) prostate cancer. PSA was 12 ng/ml and further radiological evaluation through abdominal computed tomography and bones scintigraphy resulted negative for both lymphatic spread and bone metastasis. Briganti’s nomogram score for suspected lymphatic invasion resulted 3.5% with no indication to perform lymphadenectomy. A six-port approach with open Hasson optical trocar placement was used with instruments insertion completed under direct vision to avoid bowel injuries, as routinely performed by our team during robot assisted and pure laparoscopic surgeries. No intestinal lesion was suspected during the surgery and the procedure was completed uneventfully, with bilateral nerve sparing technique and no lymphadenectomy, by a senior urologist with over twenty years’ experience. Within three days the patient was dis-

Unusual clinical scenarios in Urology and Andrology

charged with regular intestinal canalization and blood test panel in normal range. After 12 days from RARP he was re-admitted to our institution for lower abdominal pain plus abdominal distension, nausea and constipation not responsive to medical therapy. A full blood test panel showed leukocytosis and elevated acute phase reactants with normal renal function, urea and electrolytes ruling out an electrolyte imbalance and the possibility of a chemical ileus as potential cause for the clinical findings. A consultation of a general surgeon was requested and prompt conservative management was started. Presuming a bowel sub-obstruction, the attending general surgeon prescribed bowel rest, nasogastric and rectal drainage associated with the infusion of metoclopramide to treat nausea and for its prokinetic intestinal effect. Intravenous empiric antibiotic therapy with co-amoxiclavulanate and metronidazole was started to prevent potential intra-abdominal sepsis. After an initial improvement of symptoms both blood test analysis and clinical condition of the patient worsen and an abdominal Computed Tomography scan (CT) was planned. It showed a dilated caecum with collapsing descending colon and rectum without any evidence of anatomical or mechanical obstruction. Despite the presence of linear pneumatosis within the ascending colon to the hepatic flexure, raising suspect of intestinal ischemia and perforation, no clear evidence of obstructive occlusion was observed (Figure 1). The patient clinically deteriorated and accordingly with the radiological findings of suspected visceral rupture and clinical symptoms of peritonitis an emergency laparoscopic explorative abdominal surgery was performed. It confirmed small bowel and colonic distension with a small amount of free fluid in the pelvis, but all intestinal structures resulted viable without evidence of obstructing lesions. Only minor adherences were detected and incised within the small Figure 1 - Case 3. CT of the abdomen showing colonic and small bowel dilatation.

bowel. Both stool cultures for infective colitis and additional virology blood screening resulted negative. Within three days the abdominal drain was removed and the patient was discharged six days from the procedure, after complete recovery. From the combination of radiological, microbiological and clinical data an APCO diagnosis was determined, having excluded other causes of both functional and mechanical bowel obstruction (Table 1).

CONCLUSIONS

With this case report we aim to raise awareness of Ogilvie’s Syndrome. It remains a sporadic and underreported occurrence of intestinal motility impairment with no defined causes within the urological community. It mimics obstructive symptoms without any definable mechanical obstruction, leading to massive colonic and small bowel intestinal distension. Supportive medical management aims to prevent progression to peritonitis and intestinal perforation. In patients failing to respond to conservative approaches urgent surgical intervention is mandatory, to minimize morbidity and mortality.

REFERENCES

1. Ogilvie H. Large-intestine colic due to sympathetic deprivation; a new clinical syndrome. Br Med J. 1948; 2:671-673. 2. Wegener M, Borsh G. Acute colonic pseudo-obstruction (Ogilvie’s Syndrome). Presentation of 14 of our own cases and analysis of 1027 cases reported in the literature. Surg Endosc. 1987; 1:169-174. 3. Kevin T.McVary, Daniel P. Dalton and Michael D.Blum. Acute Intestinal Pseudo-Obstruction (Ogilvie’s Syndrome) complicating Radical Retropubic Prostatectomy. J Urol. 1989; 141:1210-1212. 4. Vanek VW, Al-Salti M. Acute pseudo-obstruction of the colon (Ogilvie’s Syndrome). An analysis of 400 cases. Dis Colon Rectum. 1986; 29:203-210. 5. Galosi AB, Dell'Atti L, Bertaccini A, et al. Clinical evaluation of the iXip index to reduce prostate re-biopsies. Cancer Treat Res Commun. 2018; 16:59-63.

CASE 4. SONOGRAPHIC

FINDING OF “FOUNTAIN SIGN” IN ERYTHEMATOUS SCROTUM: A CASE OF RECURRENT ACUTE IDIOPATHIC SCROTAL EDEMA

(Maria Pia Pavia, Andrea Fabiani, Emanuele Principi, Lucilla Servi)

INTRODUCTION

Table 1 - Case 3. Summary of differential diagnosis between acute colonic pseudo-obstruction (ACPO) and bowel obstruction. Mechanical - dynamic - Mural (malignant/inflammatory stricture) - Extramural (congenital bands/adhesions, volvulus) - Intraluminal (colorectal carcinoma) - Infective colitides - Inflammatory bowel disease

Functional - adynamic - Ileus - Acute mesenteric arterial occlusion - Mesenteric vein thrombosis

Acute Idiopathic Scrotal Edema (AISE) is a self-limiting cause of acute scrotum that mainly affects child population. We present a case of recurrent AISE, which diagnosis was made based on clinical signs together with the decisive help of pathognomonic ultrasound findings as the “fountain sign”.

CASE

REPORT

A nine-year-old patient presented to the Emergency Department with a 6-hour hystory of bilateral scrotal dyscomfort, swelling and redness. Blood test and urinalysis were normal. He was referred to our Urology Unit. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

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The patient was afebrile and asymptomatic. Previous medical history was unremarkable. On clinical examination, the scrotum was enlarged but painless and the skin was red and tender at palpation (Figure 1). The child underwent scrotal ultrasound (US) scan demonstrating the absence of hydrocele and showing an hyperemic thickened scrotal wall around the testicles in trasverse scan (Figure 2). Color Doppler US showed normal appearance of both testis and epydydimis. Diagnosis of AISE was made. The patient was discharged with anti-inflammatory therapy improving in a few days. One month later, he returned to the Emergency Department presenting the same symptoms. Clinical and ultrasonographic findings were stackable. The mother reported that he woked up on morning with swollen lips. Diagnosis of AISE was confirmed. The patient was referred to pediatrics for internal evaluation work-up. AISE is defined as a self-limiting condition that mainly affects children between ages 5 to 11 and accounts for > 10% of cases of acute scrotum in childhood. Diagnosis of AISE made in the original reports was reviewed by Santi et al. according to the following criteria: acute onset of redness and swelling of the scrotal sac produced by subcutanous edema, associated with normal testes, after exclusion of further possible cause of acute scrotum (1). The etiology is still unknown and recurrences are reported in approximately 10% of cases. It has been suggested that AISE is common among patients with atopic diathesis and it could represent a hypersensitivity reaction related to a angioneurotic edema’s variant. In our case, Figure 1 - Case 4. First (left) and recurrent (right) presentation of AISE: Erythema and redness on the anterior surface of the scrotum.

Figure 2 - Case 4. The patognomonic “fountain sign”: Hypervascularity of the interscrotal septum was configured as an increased Color Doppler Signal resembling a fountatin at the transverse scan.

the patient experienced swelling of the lips which could confirm the correlation with this disease. However, laboratory tests were normal at all. Diagnosis is defined as clinically based, but as in our case it may be very difficult to make a certain diagnosis based on clinical findings. Reaching an accurate and timely diagnosis is paramount, as it allows to exclude testicular malignancies or diseases requiring urgent care. Ultrasonography is the first-line imaging modality to evaluate the acute scrotum. Combined with anamnesis and clinical examination, sonographic results become even more helpful when testicular torsion is highly suspected (2). To date, very few papers underlined the role of ultrasonography in the management of the disease. Lee et al. stressed the importance of ultrasonography in managing this disorder, describing characteristic US and Doppler imaging findings that may help to avoid unnecessary surgical indication (3, 4). The homogeneous thickening and edema of the scrotal wall together with hyperemia of the scrotum were described in previous studies as specific sonographic findings for AISE. The “fountain sign” was first described by Geiger et al. (5). Similarly, in our case we noticed a marked thickening of the scrotal skin characterized by an inhomogeneous US echostructure and an increase in the vascular texture to the Color Doppler Scan (CDS); at the transverse CDS, the intense blood supply to the interscrotal septum was configured as an increased Color Doppler signal that resembles a fountain. Sonographic finding of “fountain sign” was the only one that allowed us to make a certain diagnosis of AISE. In their report, Patoulias et al. also highlighted the role of US in the AISE diagnosis, stigmatizing the ongoing uncertainty of the diagnosis of exclusion and stressing the need to diagnose the disease based on pathognomic ultrasound signs.

CONCLUSIONS

AISE is not such a rare condition; the fast and self-limiting resolution underestimates its incidence and limits clarity about its possible etiology. For this reason, the constant use of ultrasonography allows a more rapid and certain clinical diagnosis. However, it has to be proven if the systematic search for the pathognomonic sign can help to define the real spread of the condition and ensure more information about its etiology. It is no longer relevant to define AISE as a diagnosis of exclusion. Diagnosis can be certainly made through the sonographic finding of “fountain sign”, which is the diagnostic key of the disease.

REFERENCES

1. Santi M, Lava SAG, Simonetti GD, et al. Acute Idiopathic Scrotal Edema: Systematic Literature Review. Eur J Pediatr Surg. 2018; 28:222-226. 2. Martino P, Galosi AB, Bitelli M, et al. Imaging Working GroupSocieta Italiana Urologia (SIU); Società Italiana Ecografia Urologica Andrologica Nefrologica (SIEUN). Practical recommendations for performing ultrasound scanning in the urological and andrological fields. Arch Ital Urol Androl. 2014; 86:56-78. 3. Lee A, Park SJ, Lee HK, et al. Acute idiopathic scrotal edema: ultrasonographic findings at an emergency unit. Eur Radiol. 2009; 19:2075-2080.

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4. Dell’Atti L. Successful management of an asymptomatic bilateral synchronous testicular carcinoid tumor with a testicular-sparing surgery. Asian J Androl. 2017; 19:507-508.

Figure 2 - Case 5. Surgical procedure.

5. Patoulias D, Rafailidis V, Feidantsis T, et al. Fountain's sign as a diagnostic key in acute idiopathic scrotal edema: case report and review of the literature. Acta Medica (Hradec Kralove). 2018; 61:37-39.

CASE 5. ULTRASOUND OF BILATERAL

INTRAOPERATIVE MANAGEMENT CELL TUMOR IN A YOUNG PATIENT

LEYDIG

(Andrea Fabiani, Maria Pia Pavia, Valentina Maurelli)

INTRODUCTION

Testis ultrasound increased detection of small and not palpable testicular lesions. In small nodular lesions, ultrasound guided excision is mandatory. We report a case of a 30-years old patient undergoing an ultrasound guided testis sparing surgery for a small bilateral testicular lesion.

hematoma. Histopathologic exam diagnosed a Leydig cell tumor with surgical margins free from disease.

CASE

CONCLUSIONS

REPORT

In April 2015, a young patient underwent a scrotal ultrasound evaluation in follow up of acute lymphoblastic leukemia treated by bone marrow transplantation in 2004. Two hypo-echoic small testicular nodules sized 5 mm and 3 mm were diagnosed in left testis mediastinum. In October 2015, at our Urologic Department, also a diagnosis of a right 5 mm nodular testicular lesion was made. Half yearly ultrasound follow up was performed until the evidence of progressive growth of one left nodules (diameter of 1.17 cm from 5 mm) in 2020. Male fertility diagnostic work up revealed a non-obstructive azoospermia. The oncologic markers were negative. We decided to perform a bilateral ultrasound guided excisional nodular testicular biopsy (UGENT) with an inguinal approach. After scrotum incision, ultrasound was used to identify the lesions. The nodules were marked with a 23-gauge needle (Figure 1). After incision of tunica albuginea, the testicular nodule was bluntly dissected and the surgical specimen was sent to frozen section examination. Diagnosis of Leydig cell tumor for each of three nodules was made. The tunica albuginea was closed. After tunica vaginalis eversion, both testes were replaced in the scrotum (Figure 2). Testis ultrasound evaluation was performed immediately after nodules excision. Ultrasound study of the testis, performed at post-operative day 1, showed the complete disappearance of the lesions without evidence of intra-testicular Figure 1 - Case 5. Nodules were marked with a 23-gauge needle (white arrow).

The detection of small and not palpable testicular lesions is increased due to the widespread use of scrotal ultrasound (1). Small testicular masses are often benign and do not always require radical orchidectomy. Preoperative ultrasound can assess lesion size and the smaller the nodule, the less likely that it is malignant (2). In fact, in selected patients, active ultrasound surveillance may obviate the need for surgical resection. Sub centimetric testicular lesions are more likely to be impalpable and are therefore usually detected incidentally on scrotal ultrasound performed for various kind of indications. For hypo-echoic lesions, as in our case, the size is an independent risk factor for malignancy and the risk of the malignancy increase with the lesion size (cut off value: 5 mm) (2). However, nodular size is not always associated with the benign feature. As presented in our previous experience, in a series of 8 small testicular nodules (< 1 cm), we found 37.5% of malignant tumors (4 mm, 6 mm, 8 mm) (3). Ultrasound surveillance permits monitoring of lesion size, which may allow more accurate risk stratification. There is no consensus on the appropriate ultrasound surveillance protocol to follow up the small testicular lesions. Germ cell tumor doubling time has been reported to be 10 to 30 days based on which some authors recommend a surveillance interval of 3 months, but others applied a 6-month follow up strategy (2). It is also mandatory to underline the importance of intra-operative ultrasound in localization of the lesion, in order to permit the frozen section examination (FSE) of the complete excided entire nodule (3). Technical aspects of UGENT have been extensively illustrated in scientific literature with or without microsurgical approach, independently from use of advanced ultrasound techniques (2). As demonstrated in this case, the simple and low cost needle use (23 Gauge) allowed to locate the small nodular lesion and permitted the complete removal. The UGENT may be very difficult in case of very small nodules, especially in cases of lesions < 5 mm (3), posing problems both in terms of sending a sufArchivio Italiano di Urologia e Andrologia 2021; 93, 1

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ficient tissue amount to the FSE and for the absence of a sure resection margin. In all cases, also the close collaboration with the pathologist is very useful in reducing diagnostic and therapeutic errors (3). Testicular sparing surgery is mandatory in case of benign lesions and also in monorchid. This case highlights the importance of ultrasound testis follow up of small nodules, especially in young patient with infertility risk factors and, mostly, the role of intraoperative ultrasound in testicular sparing approach for small testicular lesions.

REFERENCES

1. Galosi AB, Fulvi P, Fabiani A, et al. Testicular sparing surgery in small testis masses: a multinstitutional experience. Arch Ital Urol Androl 2016; 4:320-324. 2. Dell’Atti L. Efficacy of ultrasound-guided testicle-sparing surgery for small testicular masses. J Ultrasound. 2015; 19:29-33. 3. Dell'Atti L, Fulvi P, Galosi AB. Are ultrasonographic measurements a reliable parameter to choose non-palpable testicular masses amenable to treatment with sparing surgery? J BUON. 2018; 23:439-443.

Correspondence Lucio Dell’Atti, MD, PhD (Corresponding Author) dellatti@hotmail.com Erika Palagonia Marco Tiroli Andrea Benedetto Galosi Division of Urology, University Hospital “Ospedali Riuniti”, Marche Polytechnic University, Via Conca 71, 60126 Ancona (Italy) Lucio Dell’Atti, MD, PhD (Corresponding Author) dellatti@hotmail.com Agostini Edoardo Giulio Milanese Andrea Benedetto Galosi Division of Urology, University Hospital “Ospedali Riuniti”, Marche Polytechnic University, Via Conca 71, 60126 Ancona (Italy) Lucio Dell’Atti, MD, PhD (Corresponding Author) dellatti@hotmail.com Simone Scarcella Giulio Milanese Andrea Benedetto Galosi Division of Urology, University Hospital “Ospedali Riuniti”, Marche Polytechnic University, Via Conca 71, 60126 Ancona (Italy) Maria Pia Pavia Andrea Fabiani andreadoc1@libero.it Emanuele Principi Lucilla Servi Urology Unit, Surgery Department, Macerata Civic Hospital, Area Vasta 3 Asur Marche (Italy) Andrea Fabiani andreadoc1@libero.it Maria Pia Pavia Valentina Maurelli Urology Unit, Surgery Department, Macerata Civic Hospital, Area Vasta 3 Asur Marche (Italy)

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ORIGINAL PAPER - SUPPLEMENTARY MATERIALS

Ontario School of Medicine, Thunder Bay, ON, Canada; of Economics, Lakehead University, Thunder Bay, ON, Canada.

2 Department

REGRESSION ANALYSIS - LINEAR MODELS (CRUDE AND AGE STANDARDIZED BC INCIDENCE

RATES)

SET I

No conflict of interest declared. Archivio Italiano di Urologia e Andrologia 2021; 93, 1

S. Trigo, K. Gonzalez, L. Di Matteo, A. Ismail, H. Elmansy, W. Shahrour, O. Prowse, A. Kotb

SET II

SET III

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

Bacillus Calmette-Guerin vaccine and bladder cancer incidence

REGRESSION ANALYSIS - LOG-LINEAR MODELS (AGE STANDARDIZED BC INCIDENCE RATES)

Archivio Italiano di Urologia e Andrologia 2021; 93, 1

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DRUGS, DIET SUPPLEMENTS, NUTRACEUTICALS, MEDICAL DEVICES

Authors of papers that contain references to registered drugs, diet supplements, nutraceuticals and medical devices are requested to buy a minimum amount of 100 reprints at a cost of € 1.500 (1 to 4 pages) or € 2.000 (5 to 8 pages). Prices for the purchase of number of reprints greater than 100 can be negotiated with Edizioni Scripta Manent. At present, Edizioni Scripta Manent let everyone to read, print and download papers from website, but retains copyright for republishing and distribution rights for commercial purpose.

UROLOGIA

ANDROLOGIA

in Italian language can be published after translation (expenses will be charged to the Authors). Manuscripts should be typed double spaced with wide margins. They must be subdivided into the following sections:

ORIGINAL TITLE

PAPERS

REVIWS

It must contain: a) title; b) a short (no more than 40 characters) running head title; c) first, middle and last name of each Author without abbreviations; d) University or Hospital, and Department of each Author; e) last name, address and e-mail of all the Authors; f) corresponding Author; g) acknowledgement of conflict of interest and financial support. PAGE

SUMMARY - Authors must submit a summary (300 words, 2000 characters) divided

by subheadings as follows: Objective(s), Material and method(s), Result(s), Conclusion(s). After the summary, three to ten key words must appear, taken from the standard Index Medicus terminology.

TEXT - For original articles concerning experimental or clinical studies, the following

stan¬dard scheme must be followed: Summary - Key Words - Introduction - Material and Methods - Results - Discussion - Conclusions - References - Tables - Legends Figures. Supplementary Materials can be added for online publication.

SIZE OF MANUSCRIPTS - Literature reviews and Original articles should not exceed 3500 words with 3-5 figures or tables, and no more than 30 references.

CASE

REPORTS

Case reports are not accepted as free-standing papers. However, they can be embedded in special articles published once in a year containing up to 5 case reports on similar topics. For this purpose, a shortened not structured version not exceeding 500 words with only one table or figure and no more than three references should be enclosed to the full-length Case report including Title page, Introduction (optional), Case report(s), Discussion, Conclusions, References, Tables and Figures. The short version will be embedded in the cumulative paper, while the full-length text will be published as Supplementary Material. No more than four Authors are permitted.

LETTERS

TO THE EDITORS

REFERENCES - References must be sorted in order of quotation and numbered with arabic digits between parentheses. Only the references quoted in the text can be listed. Unpublished studies cannot be quoted, however articles “in press” can be listed with the proper indication of the journal title, year and possibly volume. References must be listed as follows. JOURNAL ARTICLES - All Authors if there are six or fewer, otherwise the first three, followed by “et al.”. Complete names for Work Groups or Committees. Complete title in the original language. Title of the journal following Index Medicus rules. Year of publication; Volume number: First page. Example: Starzl T, Iwatsuki S, Shaw BW, et al. Left hepatic trisegmentectomy Surg Gynecol Obstet. 1982; 155:21. BOOKS -

Authors - Complete title in the original language. Edition number (if later than the first). City of publication: Publisher, Year of publication. Example: Bergel DIA. Cardiovascular dynamics. 2nd ed. London: Aca de mic Press Inc., 1974.

BOOK CHAPTERS - Authors of the chapters - Complete chapter title. In: Book Editor, complete Book Title, Edition number. City of publication: Publisher, Publication year: first page of chapter in the book. Example: Sagawa K. The use of central theory and system analysis. In: Bergel DH (Ed), Cardiovascular dynamics. 2nd ed. London: Aca demic Press Inc., 1964; 115. TABLES -

Tables must be numbered in Arabic digits and referred to in the text by progressive numbers. Every table must be accompanied by a brief title. The meaning of any abbreviations must be explained at the bottom of the table itself.

FIGURES -

TRANSLATION

Translation of manuscripts in Italian language is offered on payment. Translation and reprints can be requested to Edizioni Scripta Manent by e-mail to info@edizioniscriptamanent.eu

AUTHORS’

RESPONSIBILITIES

Manuscripts are accepted with the understanding that they have not been published or submitted for publication in any other journal. Authors must submit the results of clinical and experimental studies conducted according to the Helsinki Declaration on clinical research and to the Ethical Code on animal research set forth by WHO (WHO Chronicle 1985; 39:51). The Authors must obtain permission to reproduce figures, tables and text from previously published material. Written permission must be obtained from the original copyright holder (generally the Publisher).

MANUSCRIPT

PRESENTATION

Authors must submit their manuscripts (MAC and WINDOWS Microsoft Word are accepted) after registration and login to the link: http://www.aiua.it. Surface or e-mail submission are not accepted. Manuscripts must be written in English language in accordance with the “Uniform Requirements for Manuscripts submitted to biomedical journals” defined by The International Committee of Medical Journal Editors (http://www.ICMJE.org). Manuscripts

(Graphics, algorithms, photographs, drawings). Figures must be numbered and quoted in the text by number. The meaning of symbols or abbreviations must be indicated. Histology photograph legends must include the enlargement ratio and the staining method. Legends must be collected in one or more separate pages. • Do not include any illustrations as part of your text file. • Do not prepare any figures in Word as they are not workable. • Line illustrations must be submitted at 600 DPI. • Halftones and color photos should be submitted at a minimum of 300 DPI. • Power Point files cannot be uploaded. • If possible please avoid transmitting electronic files in JPEG format or save the JPEG at the highest quality available • PDF files may be uploaded.

MANUSCRIPT

REVIEW

Manuscripts are evaluated by the Editorial Board and/or by two referees designated by the Editors. The Authors are informed in a time as short as possible on whether the paper has been accepted, rejected or if a revision is deemed necessary. The Editors reserve the right to make editorial and literary corrections with the goal of making the article clearer or more concise, without altering its contents. Submission of a manuscript implies acceptation of all above rules.

PROOFS

Authors are responsible for ensuring that all manuscripts are accurately typed before final submission. Galley proofs will be sent to the first Author. Proofs should be returned within seven days from receipt.